CN101440096A - 1-(3',4',5'- trisubstituted phenyl)- tetrahydroisoquinoline compound and its use - Google Patents
1-(3',4',5'- trisubstituted phenyl)- tetrahydroisoquinoline compound and its use Download PDFInfo
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Abstract
The invention relates to a 1-(3', 4', 5'-trisubstituted phenyl)-isoquinolin compound with tumor cytotoxicity shown in a formula (1) and intermediate compounds thereof or pharmaceutical salts or solvates thereof, The invention also relates to a method for preparing the compounds in the formula (1), pharmaceutical compositions and medicinal application thereof. The compounds have certain activity of inhibiting growth of tumor cells, and can be expected to be used as anti-tumor drugs. A structural formula (1) of the invention is shown in a figure.
Description
The application is to be on July 11st, 2005 applying date, and application number is dividing an application of 200510082721.2 Chinese patent application.
Technical field
The invention belongs to pharmaceutical chemistry and pharmacology technical field.Particularly, the present invention relates to the isoquinoline compound of four series and its preparation method and at these series compounds to six kinds of tumor cell lines such as Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the growth of tumour cell that human cervical carcinoma cell (Hela) is carried out suppresses screening active ingredients.This compounds is found has certain inhibition tumor cell growth activity, can expect as the antitumor drug purposes.
Background technology
At present, because the problems of bringing in the industrial development such as environmental pollution, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the specifics of treatment tumor disease can not be satisfactory, and at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, limited the general applicability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to the research of antitumor drug.
Isoquinoline compound is the class natural product that nature extensively exists, and pharmacological research shows that they have many-sided biological activity, comprises antibioticly, and analgesia is regulated immunologic function, anti-platelet aggregation, anti-heart disorder, step-down etc.In recent years, people find that also isoquinoline compound has anti-tumor activity, and it can suppress cell proliferation and conversion, and it may play a role as topoisomerase enzyme inhibitor.
And separate from natural phant that the aryl-tetralin lignans compounds podophyllotoxin obtain also has antimitotic and to the destruction of cancer cells.Its two derivative Etoposide (VP-16) and teniposide (VM-26) all have the intensive anti-tumor activity, have become a kind of important antitumor drug of present clinical use.Shown in their structure is descended suc as formula (A):
Wherein, when R is a hydrogen atom, R
1During for methyl, be expressed as podophyllotoxin; Work as R
1Be hydrogen atom, R is β-D-ethylidene glucopyranoside base or is expressed as Etoposide and teniposide during for β-methene pyrrole glucoside group respectively.
The inventor superposes according to the constructional feature of above-mentioned two compounds, and in 1 introducing 3,4 of isoquinoline 99.9 parent nucleus, the 5-trisubstd phenyl obtains a series of compounds with novel structure thereby synthesize.According to the whole world especially susceptibility of often swell the knurl spectrum of disease and the tumour cell of China, we have selected Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the index that human cervical carcinoma cell (Hela) six strain tumour cells are estimated as cell in vitro cytotoxic activity pharmacology has been carried out the cytotoxicity screening to all compounds and the intermediate that synthesizes.
Summary of the invention
The object of the present invention is to provide a kind of have the 1-that suppresses tumor cell growth activity (3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound.Particularly, the invention provides a kind of isoquinoline compound shown in the formula (1) that has:
Wherein:
Can be carbon nitrogen singly-bound or two key between 1,2, can be carbon-carbon single bond or two key between 3,4;
R
1, R
2, R
3Can be identical or different, can be selected from hydrogen respectively, contain the alkoxyl group of 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R
1And R
2Also can be connected to form together with dimethoxy or together with diethoxy;
R
4, R
5, R
6Can be identical or different, can be selected from the alkoxyl group that contains 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R respectively
4, R
5And R
5, R
6Between can also form together with dimethoxy or together with diethoxy.
R
4, R
5, R
6Can not be for containing the alkoxyl group that contains 1-2 carbon of same structure; Between 1 and 2, when being singly-bound simultaneously between 3 and 4, R
2, R
4, R
6Can not be hydrogen simultaneously; Work as R
1, R
2When being all methoxyl group, R
3, R
4, R
6Can not be hydrogen simultaneously; R
4, R
5, R
6Be all methoxyl group and R
3During for hydrogen, R
1, R
2Can not be for together with dimethoxy or together with diethoxy.
When being carbon-to-nitrogen double bon between 1,2, R
7Do not exist;
When between 1,2 during carbon nitrogen singly-bound, R
7Can be selected from hydrogen atom, replace or unsubstituting phenenyl formyl radical or cyclopropane carbonyl; Can be selected from halogen as the substituting group that replaces, amino, nitro, sulfydryl contains the alkyl of 1-8 carbon, the alkoxyl group of 1-8 carbon, the acyl group of 1-8 carbon, phenyl, or aryl.
Another object of the present invention has provided the preparation method of formula (1) compound;
Another object of the present invention has provided intermediate formula (IV) compound:
Another object of the present invention has provided formula (1) and formula (IV) compound is used to prepare the purposes of preventing and treating the tumor disease medicine.
The invention provides the 1-shown in a kind of formula (1) (3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound:
Wherein:
Can be the two keys of carbon nitrogen singly-bound between 1,2, can be carbon-carbon single bond or two key between 3,4;
R
1, R
2, R
3Can be identical or different, can be selected from hydrogen respectively, contain the alkoxyl group of 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R
1And R
2Also can be connected to form together with dimethoxy or together with diethoxy;
R
4, R
5, R
6Can be identical or different, can be selected from the alkoxyl group that contains 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R respectively
4, R
5And R
5, R
6Between can also form together with dimethoxy or together with diethoxy.
R
4, R
5, R
6Can not be for containing the alkoxyl group that contains 1-2 carbon of same structure; Between 1 and 2, when being singly-bound simultaneously between 3 and 4, R
2, R
4, R
6Can not be hydrogen simultaneously; Work as R
1, R
2When being all methoxyl group, R
3, R
4, R
6Can not be hydrogen simultaneously; R
4, R
5, R
6Be all methoxyl group and R
3During for hydrogen, R
1, R
2Can not be for together with dimethoxy or together with diethoxy.
When being carbon-to-nitrogen double bon between 1,2, R
7Do not exist;
When between 1,2 being carbon nitrogen singly-bound, R
7Can be selected from hydrogen atom, replace or unsubstituting phenenyl formyl radical or cyclopropane carbonyl; Can be selected from halogen as the substituting group that replaces, amino, nitro, sulfydryl contains the alkyl of 1-8 carbon, the alkoxyl group of 1-8 carbon, the acyl group of 1-8 carbon, phenyl, or aryl.
In formula of the present invention (1) compound, be carbon-carbon single bond between 1,2 and between 3,4 wherein, R
7Be selected from hydrogen atom, replace or when unsubstituting phenenyl formyl radical or cyclopropane carbonyl, for following formula (I-A) and (I-B) compound: 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-1,2,3, the 4-tetrahydro isoquinoline compound:
Formula (I-A) formula (I-B)
R wherein
1, R
2, R
3, R
4, R
5, R
6Definition and formula (1) identical.
The preferred formula of the present invention (I-A) and (I-B) compound comprise:
Compound I-A1:N-benzoyl-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A2:N-(4 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A3:N-(4 " chlorobenzene formacyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A4:N-(3 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ' 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A5:N-(3 " methyl benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A6:N-(4 " anisoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A7:N-(3 " the itrile group benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A8:N-(4 " nitro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A9:N-(2 ", 6 " difluoro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A10:N-benzoyl-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A11:N-(4 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A12:N-(3 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A13:N-(2 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A14:N-benzoyl-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A15:N-benzoyl-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-isopentene oxygen base phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A16:N-cyclopropane carbonyl-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A17:N-(3 " chlorobenzene formacyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A18:N-(2 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A19:N-(2 " chlorobenzene formacyl)-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A20:N-benzoyl-6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A21:N-(4 " fluoro benzoyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A22:N-(4 " the chlorobenzene formacyl base)-6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A23:N-(3 " fluoro benzoyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-A24:N-(3 " chlorobenzene formacyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' ' benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-B1:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline,
Compound I-B2:6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline.
In the formula of the present invention (1), wherein between 1,2 and 3,4 when all being carbon-carbon double bond, R
7Do not exist, for following formula (II) compound: 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound:
Formula (II)
Wherein:
Can be carbon nitrogen singly-bound or two key between 1,2, can be carbon-carbon single bond or two key between 3,4;
R
1, R
2, R
3Can be identical or different, can be selected from hydrogen respectively, contain the alkoxyl group of 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R
1And R
2Also can be connected to form together with dimethoxy or together with diethoxy;
R
4, R
5, R
6Can be identical or different, can be selected from the alkoxyl group that contains 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R respectively
4, R
5And R
5, R
6Between can also form together with dimethoxy or together with diethoxy.
When 1 and 2,3 and 4 when being two key simultaneously, R
1, R
2, R
3, R
4Can not be hydrogen simultaneously; Work as R
1, R
2For together with dimethoxy or dimethoxy the time, R
4, R
6During for hydrogen, R
5Can not be hydroxyl or benzyloxy; R
1, R
2, R
4, R
6When being methoxyl group, R
5Can not be hydrogen; R
1Be methoxyl group, R
2Be benzyloxy or hydroxyl, R
4, R
6During for hydrogen, R
5Can not be hydroxyl, benzyloxy or methoxyl group.
The preferred formula of the present invention (II) compound comprises:
Compound I I-A1:6-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-isoquinoline 99.9,
Compound I I-A2:6-hydroxyl-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-isoquinoline 99.9,
Compound I I-A3:6-allyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-isoquinoline 99.9,
Compound I I-A4:6-isopentene Oxy-1-(3 ', 5 '-dimethoxy-4 ' '-isopentene oxygen base phenyl)-isoquinoline 99.9,
Compound I I-B1:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-isoquinoline 99.9,
Compound I I-B2:6,7-methylene-dioxy-1-(3 ', 4 ', 5 '-three benzyloxy phenyl)-isoquinoline 99.9,
Compound I I-B3:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-isoquinoline 99.9,
Compound I I-B4:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-isoquinoline 99.9,
Compound I I-B5:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-isopentene oxygen base phenyl)-isoquinoline 99.9,
Compound I I-C1:6,8-dimethoxy-7-benzyloxy-1-(3 ' 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-isoquinoline 99.9,
Compound I I-C2:6,8-dimethoxy-7-benzyloxy-1-(3 ', 4 ', 5 '-three benzyloxy phenyl)-isoquinoline 99.9,
Compound I I-C3:6,8-dimethoxy-7-hydroxyl-1-((3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-isoquinoline 99.9,
Compound I I-C4:6,8-dimethoxy-7-allyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-isoquinoline 99.9.
In the formula of the present invention (1), be carbon-carbon double bond between 1,2 wherein, when being carbon-carbon single bond between 3,4, R
7Do not exist, for following formula (III) compound: 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-3, the 4-dihydro-isoquinoline compound:
Wherein:
Can be carbon nitrogen singly-bound or two key between 1,2, can be carbon-carbon single bond or two key between 3,4;
R
1, R
2, R
3Can be identical or different, can be selected from hydrogen respectively, contain the alkoxyl group of 1-8 carbon, benzyloxy, hydroxyl, halogen, amido, R
1And R
2Also can be connected to form together with dimethoxy or together with diethoxy;
R
4, R
5, R
6Can be identical or different, can be selected from respectively and contain 1---the alkoxyl group of 8 carbon, benzyloxy, hydroxyl, halogen, amido, R
4, R
5And R
5, R
6Between can also form together with dimethoxy or together with diethoxy.
Between 1 and 2 two keys, when being singly-bound between 3 and 4, R
1, R
2, R
3, R
4Have more than three and can not be hydrogen simultaneously; Work as R
4, R
6Be all methoxyl group, R
1, R
2Be all methoxy or ethoxy mutually or be respectively hydroxyl and during methoxyl group, R
5Can not be hydrogen; R
4, R
5, R
6When being all methoxyl group, R
1, R
2Can not be simultaneously together with dimethoxy or together with diethoxy; Work as R
1, R
2For hydroxyl inequality, methoxyl group or benzyloxy replace R
3, R
4, R
6When being all hydrogen, R
5Can not be hydrogen or methoxyl group or benzyloxy.
The preferred formula of the present invention (III) compound comprises:
Compound III-A1:6-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-A2:6-hydroxyl-1-(3 ' 5 '-dimethoxy-4 ' '-hydroxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-B1:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-B2:6,7-methylene-dioxy-1-(3 ' 4 ', 5 '-three benzyloxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-B3:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-B4:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-B5:6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-isopentene oxygen base phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-C1:6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-3, the 4-dihydro-isoquinoline,
Compound III-C1:6,8-dimethoxy-7-benzyloxy-1-(3 ', 4 ', 5 '-three benzyloxy phenyl)-3, the 4-dihydro-isoquinoline.
Another object of the present invention provided 1-in the formula (1) (3 ', 4 ', 5 '-tri-substituted phenyl)-preparation method of isoquinoline compound, the feature of this synthetic route is: with substituted benzoic acid and substituted phenyl ethylamine is that raw material makes intermediate N (substituted benzene ethyl)-benzamide (IV), compound (IV) dehydration closed-loop under the Phosphorus Oxychloride existence condition make 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-3,4-dihydro-isoquinoline compound (III), compound (III) can be a catalyzer with palladium carbon, and perhydronaphthalene is a solvent, under 200 ℃ the high-temperature catalytic condition dehydrogenation make 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound (II); On the other hand, in the presence of sodium borohydride, compound (III) also can be reduced make compound 1-(3 '; 4 ', 5 '-tri-substituted phenyl)-1,2; 3; 4-tetrahydro isoquinoline compound (I-B), compound (I-B) can make with the reaction of various Benzoyl chlorides or cyclopropyl formyl chloride again corresponding N-acyl group-1-(3 ', 4 '; 5 '-tri-substituted phenyl)-1; 2,3,4-tetrahydro isoquinoline compound (I-A).
Concrete preparation process is as follows:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7Definition identical with the definition of formula (1) compound.
Need to prove radicals R in above-claimed cpd
1, R
2, R
3, R
4, R
5, R
6, R
7Containing the compound that hydroxyl replaces and all obtained by corresponding benzyloxy substitution compound catalytic hydrogenation deprotection, is by the protection of III-A1 debenzylation and obtain as III-A2; And radicals R
1, R
2, R
3, R
4, R
5, R
6, R
7In contain allyloxy, the compound that isopentene group oxygen base replaces all is to be obtained with allyl bromide 98 or isopentene group bromine reaction under the salt of wormwood condition by corresponding oxy-compound, is to be made by II-C3 as II-C4.
In the reaction process, the N-shown in the intermediate formula (IV) (substituted benzene ethyl)-benzamide compounds also has weak biological activity:
The preferred formula of the present invention (IV) compound comprises:
Compound IV-1:N-(3-benzyloxy) styroyl-(3 ', 5 '-dimethoxy-4 ' '-benzyloxy) benzamide,
Compound IV-2:N-(3-hydroxyl) styroyl-(3 ', 5 '-dimethoxy-4 ' '-hydroxyl) benzamide,
Compound IV-3:N-(4-benzyloxy) styroyl-(3 ', 5 '-dimethoxy-4 ' '-benzyloxy) benzamide,
Compound IV-4:N-(4-hydroxyl) styroyl-(3 ', 5 '-dimethoxy-4 ' '-hydroxyl) benzamide,
Compound IV-5:N-(4-methoxyl group) styroyl-(3 ', 5 '-dimethoxy-4 ' '-benzyloxy) benzamide,
Compound IV-6:N-(4-methoxyl group) styroyl-(3 ' 5 '-dimethoxy-4 ' '-hydroxyl) benzamide,
Compound IV-7:N-(3, the 4-methylene-dioxy) styroyl-(3 ' 5 '-dimethoxy-4 ' '-benzyloxy) benzamide,
Compound IV-8:N-(3, the 4-methylene-dioxy) styroyl-(3 ', 5 '-dimethoxy-4 ' '-hydroxyl) benzamide,
Compound IV-9:N-(3, the 4-methylene-dioxy) styroyl-(3 ', 4 ', 5 '-three benzyloxies) benzamide,
Compound IV-10:N-(3, the 4-methylene-dioxy) styroyl-(3 ', 4 ', 5 '-trihydroxy-) benzamide,
Compound IV-11:N-(3,5-dimethoxy-4 '-benzyloxy) styroyl-(3 ', 5 '-dimethoxy-4 ' '-benzyloxy) benzamide,
Compound IV-12:N-(3,5-dimethoxy-4 '-hydroxyl) styroyl-(3 ', 5 '-dimethoxy-4 ' '-hydroxyl) benzamide,
Compound IV-13:N-(3,5-dimethoxy-4 '-benzyloxy) styroyl-(3 ', 4 ', 5 '-three benzyloxies) benzamide.
Embodiment
Further specify the present invention below by preparation example and embodiment.Preparation example and embodiment have provided synthetic and the dependency structure appraising datum and the part activity data of representative new compound.Mandatory declaration, following preparation example and embodiment are used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Preparation example 1:Compound IV-1[N-(3-benzyloxy) styroyl-(3 ', 5 '-dimethoxy-4 ' '-benzyloxy) benzamide] preparation:
With 3,5-methoxyl group-4-benzyloxy-phenylformic acid 4.4g (16.0mmol) is dissolved in the 200ml exsiccant methylene dichloride, drips oxalyl chloride 20ml (230mmol) under the condition of ice bath, finishes room temperature reaction 2 hours, removes excessive oxalyl chloride under reduced pressure.Resistates is dissolved in the 50ml exsiccant methylene dichloride again, under the condition of ice bath, be added drop-wise in the 200ml dichloromethane solution that is dissolved with 3-benzyloxy phenylethylamine 4.5g (19.8mmol) and 0.5ml triethylamine, after the stirred overnight at room temperature, add 10% sodium hydroxide solution 50ml, stirred 30 minutes, tell organic phase, use saturated sodium carbonate (50ml * 2) respectively, water (50ml * 2) and saturated aqueous common salt (50ml * 2) washing.Through anhydrous magnesium sulfate drying, after the solvent evaporated, be that eluent separates with silica gel column chromatography with ethyl acetate/petroleum ether (1:5), get white solid 2.62g, productive rate is 33.0%.
The IV-1 compound:
Rf (ethyl acetate/petroleum ether: 1/1): 0.63;
1H NMR (400MHz, CDCl
3): δ 2.90 (t, 2H, J=6.7,6.9Hz, CH
2-Ar), 3.68 (q, 2H, J=6.9,6.7,6.0Hz, CH
2-NH), 3.80 (s, 6H, OCH
3* 2), 5.02 (s, 4H, OCH
2Ph * 2) 6.04 (brs, 1H, NH), 6.84-6.88 (m, 3H, H-2, H-4, H-6), 6.87 (s, 2H, H-2, H-6), 7.24 (dd, 1H, J=15.4,0.3Hz, H-5), 7.24-7.46 (m, 10H, OCH
2Ph-H * 2);
MS (EI) m/e (relative abundance): 497 (M)
+(3), 287 (1), 210 (2), 181 (8), 91 (100).
Preparation example 2-13:Prepare preparation example 2-13 compound shown in the following table one according to method with above preparation example 1:
Table one
What list below is the physicochemical data of each compound in the table one:
IV-2: jelly, Rf (ethyl acetate/petroleum ether 2:1): 0.12;
1H NMR (400Mz, CD
3OD): δ 2.82 (t, 2H, J=7.7,7.0Hz, CH
2-Ar), 3.55 (t, 2H, J=7.3,7.4Hz, CH
2-NH), 3.87 (s, 6H, OCH
3* 2), 6.62-6.72 (m, 3H, H-2, H-6), 7.08 (d, 1H, J=7.7Hz, H-5), 7.12 (s, 2H, H-2 ', H-6 ').
IV-3: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.73;
1H NMR (400MHz, CDCl
3): δ 2.89 (t, 2H, J=6.9,6.5Hz, CH
2-Ar), 3.66 (q, 2H, J=6.4,6.9,6.2Hz, CH
2-NH), 3.82 (s, 6H, OCH
3* 2), 5.04 (s, 2H, OCH
2Ph), 5.05 (s, 2H, OCH
2Ph), 6.20 (brs, 1H, NH), 6.89 (s, 2H, H-2 ', H-6 '), 6.94 (dd, 2H, J=6.5,2.0Hz, H-3, H-5), 7.17 (dd, 2H, J=6.6,2.0Hz, H-3, H-5), 7.27-7.47 (m, 10H, OCH
2Ph-H * 2).
IV-4: jelly, Rf (ethyl acetate/petroleum ether 2:1): 0.34;
1H NMR (400MHz, CD
3OD) δ 2.81 (t, 2H, J=7.7,7.3Hz, CH
2-Ar), 3.52 (t, 2H, J=7.7,7.3Hz, CH
2-NH), 3.87 (s, 6H, OCH
3* 2), 6.71 (dd, 2H, J=6.4,1.8Hz, H-3, H-5), 7.07 (d, 2H, J=8.4Hz, H-2, H-6), 7.11 (s, 2H, H-2 ', H-6 ').
IV-5: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.52;
1H NMR (400MHz, CDCl
3) δ 2.87 (t, 2H, J=6.9Hz, CH
2-Ar), 3.66 (q, 2H, J=5.8,5.6,5.7Hz, CH
2-NH), 3.79 (s, 3H, OCH
3), 3.83 (s, 6H, OCH
3* 2), 5.04 (s, 2H, OCH
2Ph), 6.05 (brs, 1H, NH), 6.88 (s, 2H, H-2 ', H-6 '), 6.87 (d, 2H, J=8.8Hz, H-3, H-5), 7.16 (d, 2H, J=8.5HZ, H-2, H-6), 7.29-7.47 (m, 5H, OCH
2Ph-H).
IV-6: jelly, Rf (ethyl acetate/petroleum ether 2:1): 0.60;
1H NMR (400MHz, CD
3OD) δ 2.84 (t, 2H, J=7.7,7.0Hz, CH
2-Ar), 3.53 (t, 2H, J=7.3Hz, CH
2-NH), 3.75 (s, 3H, OCH
3), 3.87 (s, 6H, OCH
3* 2), 6.85 (dd, 2H, J=6.6,2.2Hz, H-3, H-5), 7.11 (s, 2H, H-2 ', H-6 '), 7.16 (dd, 2H, J=8.4,1.8Hz, H-2, H-6).
IV-7: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.55;
1H NMR (400MHz, CDCl
3) δ 2.84 (t, 2H, J=6.9Hz, CH
2-Ar), 3.63 (q, 2H, J=6.7,6.2,6.7Hz, CH
2-NH), 3.83 (s, 6H, OCH
3* 2), 5.04 (s, 2H, OCH
2Ph), 5.93 (s, 2H, OCH
2O), 6.12 (brs, 1H, NH), 6.68 (dd, 1H, J=7.8,1.6Hz, H-6), 6.73 (d, 1H, J=1.6Hz, H-2), 6.76 (d, 1H, J=7.8Hz, H-5), 6.90 (s, 2H, H-2 ', H-6 '), 7.29-7.47 (m, 5H, OCH
2Ph-H).
IV-8: jelly, Rf (ethyl acetate/petroleum ether 1:1): 0.25;
1H NMR (400MHz, DMSO-d6) δ 2.74 (t, 2H, J=7.4,7.2Hz, CH
2-Ar), 3.41 (q, 2H, J=6.3,6.0,7.2Hz, CH
2-NH), 3.79 (s, 6H, OCH
3* 2), 5.96 (s, 2H, OCH
2O), 6.69 (d, 1H, J=8.0Hz, H-6), 6.82 (s, 1H, H-2), 6.83 (d, 1H, J=7.4Hz, H-5), 7.14 (s, 2H, H-2 ', H-6 ').
IV-9: white solid, Rf (ethyl acetate/oily ether 1:1): 0.65;
1H NMR (400MHz, CDCl
3) δ 2.82 (t, 2H, J=6.9,6.7Hz, CH
2-Ar), 3.62 (q, 2H, J=6.5,6.3,6.6Hz, CH
2-NH), 5.08 (s, 2H, OCH
2Ph), 5.10 (s, 2H, OCH
2Ph), 5.92 (s, 2H, OCH
2O), 5.99 (t, 1H, J=5.2,5.9Hz, NH), 6.66 (dd, 1H, J=7.8,1.0Hz, H-6), 6.75 (t, 2H, J=7.8,8.8Hz, H-2, H-5), 6.99 (s, 2H, H-2 ', H-6 '), 7.23-7.42 (m, 15H, OCH
2Ph-H * 3).
IV-10: jelly, Rf (ethyl acetate/petroleum ether 1:1): 0.7;
1H NMR (400MHz, CD
3OD) δ 2.78 (t, 2H, J=7.7,7.3Hz, CH
2-Ar), 3.47 (q, 2H, J=7.3,1.1,6.6Hz, CH
2-NH), 5.88 (s, 2H, OCH
2O), 6.68 (dd, 1H, J=8.0,1.5Hz, H-6), 6.72 (s, 1H, H-2), 6.74 (t, 1H, J=5.5,1.5Hz, H-5), 6.80 (s, 2H, H-2 ', H-6 ').
IV-11: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.60;
1H NMR (400MHz, CDCl
3) δ 2.88 (t, 2H, J=7.0Hz, CH
2-Ar) 3.69 (q, 2H, J=6.4,6.6,6.8Hz, CH
2-NH), 3.78 (s, 6H, OCH
3* 2), 3.83 (s, 6H, OCH
3* 2), 4.98 (s, 2H, OCH
2Ph), 5.05 (s, 2H, OCH
2Ph), 6.08 (brs, 1H, NH), 6.44 (s, 2H, H-2, H-6), 6.89 (s, 2H, H-2 ', H-6 '), 7.27-7.50 (m, 10H, OCH
2Ph-H * 2).
IV-12: jelly, Rf (ethyl acetate/petroleum ether 1:3): 0.45;
1H NMR (400MHz, CD
3OD) δ 2.86 (t, 2H, J=9.2Hz, CH
2-Ar), 3.66 (q, 2H, J=8.8Hz, CH
2-NH), 3.84 (s, 6H, OCH
3* 2), 3.89 (s, 6H, OCH
3* 2), 5.44 (brs, 1H, OH), 5.81 (brs, 1H, OH), 6.08 (brs, 1H, NH), 6.45 (s, 2H, H-2, H-6), 6.94 (s, 2H, H-2 ', H-6 ').
IV-13: white solid, Rf (ethyl acetate/petroleum ether 1:2): 0.42;
1H NMR (400Mz, CDCl
3) δ 2.84 (t, 2H, J=6.8,7.0Hz, CH
2-Ar), 3.64 (q, 2H, J=6.4HZ, CH
2-NH), 3.76 (s, 6H, OCH
3* 2), 4.96 (s, 2H, OCH
2Ph), 5.07 (s, 2H, OCH
2PH), 6.06 (brs, 1H, NH), 6.41 (s, 2H, H-2, H-6), 6.98 (s, 2H, H-2 ', H-6 '), 7.23-7.46 (m, 20H, OCH
2Ph-H * 4).
Preparation example 14:Compound III-A1[6-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-3, the 4-dihydro-isoquinoline] preparation:
Compound (IV-1) (seeing preparation example 1) 638mg (1.28mmol) is suspended in the 50ml toluene, adds Phosphorus Oxychloride 0.25ml (2.6mmol), refluxed 4 hours, be chilled to room temperature, pressure reducing and steaming toluene is dissolved in resistates in the 30ml ethyl acetate, and the ice bath cooling is transferred PH to 8-9 with strong aqua down, divide water-yielding stratum, with ethyl acetate extraction (10ml * 2), merge organic phase, water (10ml * 2) successively, saturated aqueous common salt (10ml * 2) washing, anhydrous sodium sulfate drying.Filter, crude product uses column chromatography purifying (eluent is ethyl acetate/petroleum ether 1:2) and gets the 370mg solid after concentrating, and productive rate is 60.3%.
The III-A1 compound:
Rf (ethyl acetate/petroleum ether 1:3) 0.18;
1H NMR (400MHz, CDCl
3) δ 2.82 (t, 2H, J=7.4,6.9Hz, CH
2-4), 3.84 (t, 2H, J=7.0,7.1Hz, CH
2-3), 3.83 (s, 6H, OCH
3* 2), 5.07 (s, 2H, OCH
2Ph), 5.14 (s, 2H, OCH
2Ph), 6.84 (s, 2H, H-2 ', H-6 '), 6.91-6.86 (m, 2H, H-5, H-7), 7.52-7.30 (m, 11H, OCH
2Ph-H * 2, H-8);
MS (EI) m/e (relative abundance) 479 (M)
+(6), 480 (M+1)
+(2), 478 (M-1)
+(2), 388 (12), 297 (8), 279 (6), 91 (100).
Preparation example 15:Compound III-A2[6-hydroxyl-1-(3,5-dimethoxy-4 '-hydroxyl) phenyl-3,4-dihydro-isoquinoline] preparation:
Compound (III-A1) (seeing preparation example 14) 127mg (0.265mmol) is dissolved in the 15ml methyl alcohol, add 10% palladium carbon 30mg, normal temperature and pressure catalysis hydrogenation 3 hours, filtering palladium carbon, the reddish-brown oily liquids of filtrate steaming removal solvent, get the 70mg red oil with purification by silica gel column chromatography (eluent is chloroform/methanol 50:1), productive rate is 88.6%.
III-A2 compound: Rf (chloroform/methanol 50:1) 0.20;
1H NMR (400MHz, CD
3OD) δ 2.92 (t, 2H, J=7.5,6.6Hz, CH
2-4), 3.71 (t, 2H, J=6.6,7.8Hz, CH
2-3), 3.83 (s, 6H, OCH
3* 2), 6.54 (m, 2H, H-5, H-7), 6.87 (s, 2H, H-2 ', H-6 '), 7.29 (dd, 1H, J=9.0,1.2Hz, H-8);
MS (EI) m/e (relative abundance) 299 (M)
+(100), 300 (M+1)
+(15), 298 (M-1)
+(84), 282 (62), 268 (50), 253 (35), 146 (38).
Preparation example 16-20:Prepare preparation example 16-20 compound shown in the following table one according to method with above preparation example 14-15:
Table two
What list below is the physicochemical data of each compound in the table two:
III-B1: yellow solid, Rf (ethyl acetate/petroleum ether 1:1): 0.25;
1H NMR (400MHz, CDCl
3) δ 2.71 (t, 2H, J=7.4,7.2Hz, CH
2-4), 3.84 (t, 2H, J=7.0,7.3Hz, CH
2-3), 3.83 (s, 6H, OCH
3* 2), 5.06 (s, 2H, OCH
2Ph), 5.99 (s, 2H, OCH
2O), 6.76 (s, 1H, H-5), 6.78 (s, 2H, H-2 ', H-6 '), 6.79 (s, 1H, H-8), 7.29-7.51 (m, 5H, OCH
2Ph-H).
III-B2:: yellow solid, Rf (ethyl acetate/petroleum ether 1:1): 0.35;
1H NMR (400Mz, CDCl
3) δ 2.71 (t, 2H, J=7.4,7.2Hz, CH
2-4), 3.77 (t, 2H, J=8.2,6.5Hz, CH
2-3), 5.10 (s, 2H, OCH
2Ph), 5.12 (s, 4H, OCH
2Ph), 5.99 (s, 2H, OCH
2O), 6.70 (s, 1H, H-5), 6.75 (s, 1H, H-8), 6.92 (s, 2H, H-2 '., H-6 '), 7.25-7.44 (m, 15H, OCH
2Ph-H * 3).
III-B3: red solid, Rf (chloroform/methanol 50:1): 0.30;
1H NMR (400MHz, CDCl
3) δ 2.77 (t, 2H, J=7.4,7.2Hz, CH
2-4), 3.80 (t, 2H, J=8.2,6.5Hz, CH
2-3), 3.92 (s, 6H, OCH
3* 2), 6.02 (s, 2H, OCH
2O), 6.79 (s, 1H, H-5), 6.87 (s, 1H, H-8), 6.92 (s, 2H, H-2 '., H-6 ').
III-C1: yellow solid, Rf (ethyl acetate/petroleum ether 3:1): 0.35;
1H NMR (400MHz, CDCl
3) δ 2.71 (t, 2H, J=8.8,9.6Hz, CH
2-4), 3.73 (t, 2H, J=8.8,9.6Hz, CH
2-3), 3.38 (s, 3H, OCH
3-8), 3.82 (s, 6H, OCH
3* 2), 3.92 (s, 3H, OCH
3-6), 4.92 (s, 2H, OCH
2Ph), 5.05 (s, 2H, OCH
2Ph), 6.62 (s, 1H, H-5), 6.73 (s, 2H, H-2 '., H-6 '), 7.26-7.50 (m, 10H, OCH
2Ph-H * 2).
III-C2: yellow solid, Rf (ethyl acetate/petroleum ether 1:1): 0.15;
1H NMR (400Mz, CDCl
3) δ 2.69 (t, 2H, J=6.8,7.0Hz, CH
2-4), 3.72 (t, 2H, J=6.6,7.2Hz, CH
2-3), 3.29 (s, 3H, OCH
3-8), 3.91 (s, 3H, OCH
3-6), 5.08 (s, 2H, OCH
2Ph), 5.10 (s, 6H, OCH
2Ph * 2), 6.61 (s, 1H, H-5), 6.85 (s, 2H, H-2 '., H-6 '), 7.23-7.45 (m, 20H, OCH
2Ph-H * 4).
Preparation example 21:Compound III-B4[6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-3, the 4-dihydro-isoquinoline] preparation
Compound (III-B3) (seeing preparation example 18) 275mg (0.84mmol) is dissolved in the 20ml acetone, add Anhydrous potassium carbonate 138mg (1mmol), stir adding allyl bromide 98 0.2ml (2.3mmol) down, reflux is cooled to room temperature to reacting completely, remove solvent under reduced pressure, resistates is dissolved in the 30ml water,, merges extracted organic phase with anhydrous diethyl ether extraction (10ml * 3), use 10% sodium hydroxide (10ml * 2) successively, water (10ml * 2) and saturated aqueous common salt (10ml * 2) washing.Behind the anhydrous magnesium sulfate drying, crude product gets the 86mg product with purification by silica gel column chromatography (eluent is ethyl acetate/petroleum ether 1:3), and productive rate is 27.9%.
The III-B4 compound:
Rf (ethyl acetate/petroleum ether 1:1): 0.20;
1H NMR (400MHz, CDCl
3) δ 2.70 (t, 2H, J=7.6,7.1Hz, CH
2-4), 3.75 (t, 2H, J=8.3,6.6Hz, CH
2-3), 3.85 (s, 6H, OCH
3* 2), 4.55 (d, 2H, J=6.4Hz, OCH
2CH), 5.18 (d, 1H, J=10.3Hz, trans-CH=CH
2), 5.30 (dd, 1H, J=17.1,1.2Hz, cis-CH=CH
2), 5.98 (s, 2H, OCH
2O), 6.11 (m, 1H, OCH
2CH=CH
2), 6.75 (s, 1H, H-5), 6.78 (s, 2H, H-2 '., H-6 '), 6.80 (s, 1H, H-8);
MS (EI) m/e (relative abundance) 367 (M)
+(35), 326 (100), 311 (6), 296 (40), 149 (28).
Preparation example 22:Compound III-B5[6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-isopentene oxygen base phenyl)-3, the 4-dihydro-isoquinoline] preparation:
According to the method identical with preparation example 21, substitute allyl bromide 98 with the isopentene group bromine, obtain the faint yellow compound of formula IV-B5, productive rate is 34.0%.
The III-B5 compound:
Rf (ethyl acetate/petroleum ether 1:1): 0.30;
1H NMR (400MHz, CDCl
3) δ 1.65 (s, 3H, CH
3), 1.71 (s, 3H, CH
3), 2.75 (t, 2H, J=7.6,7.1Hz, CH
2-4), 3.80 (t, 2H, J=7.1,7.4Hz, CH
2-3), 3.86 (s, 6H, OCH
3* 2), 4.55 (d, 2H, J=7.1Hz, OCH
2CH), 5.57 (t, 1H, J=7.3,7.1Hz, OCH
2CH=C (CH
3)
2), 6.00 (s, 2H, OCH
2O), 6.77 (s, 1H, H-5), 6.80 (s, 2H, H-2 '., H-6 '), 6.83 (s, 1H, H-8); MS (EI) m/e (relative abundance) 327 (M-CH
2CHC (CH
3)
2))
+(6), 296 (2), 149 (100).
Preparation example 23:Compound I I-A1[6-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-isoquinoline 99.9] preparation:
Compound (III-A1) (seeing preparation example 14) 2.5g (5.25mmol) is dissolved in the 60ml perhydronaphthalene, add 10% palladium carbon 300mg, 200 ℃ of reactions 12 hours, be cooled to room temperature then, filtering palladium carbon, remove solvent under reduced pressure, resistates is got the 842mg product with column chromatography purification (eluent is ethyl acetate/petroleum ether 1:2), productive rate is 33.5%.
The II-A1 compound:
Rf (ethyl acetate/petroleum ether 1:1): 0.50;
1H NMR (400MHz, CDCl
3) δ 3.87 (s, 6H, OCH
3* 2), 5.10 (s, 2H, OCH
2Ph), 5.14 (s, 2H, OCH
2Ph), 6.89 (s, 2H, H-2 '., H-6 '), 7.22-7.55 (m, 13H, OCH
2Ph-H * 2, H-4, H-5, H-7), 8.07 (d, 1H, J=9.34Hz, H-8), 8.51 (d, 1H, J=5.8Hz, H-3);
MS (EI) m/e (relative abundance) 477 (M)
+(9), 386 (25), 295 (3), 91 (100).
Preparation example 24:Compound I I-A2[6-hydroxyl-1-(3 ', 5 '-dimethoxy-4 ' '-hydroxy phenyl)-isoquinoline 99.9] preparation:
According to the method identical with preparation example 15, be that raw material makes formula II-A2 compound (productive rate 92.5%) with II-A1, wherein raw material II-A1 is made by preparation example 23.
The II-A2 compound:
Rf (ethyl acetate/petroleum ether 2:1): 0.30;
1HNMR (400MHz, CDCl
3): δ 3.77 (s, 6H, OCH
3* 2), 6.83 (s, 2H, H-2 ', H-6 '), 7.12 (m, 2H, H-5, H-7), 7.50 (d, 1H, J=5.7Hz, H-4), 7.98 (t, 1H, J=9.2,0.7Hz, H-8), 8.30 (d, 1H, J=5.7Hz, H-3);
MS (EI) m/e (relative abundance) 297 (M)
+(100), 298 (M+1)
+(22), 296 (M-1)
+(65), 282 (26), 266 (25).
Preparation example 25:Compound I I-A3[6-allyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the allyloxy phenyl)-isoquinoline 99.9] preparation:
According to the method identical with preparation example 21, be that raw material makes formula II-A3 compound (productive rate 35.3%) with II-A2, wherein raw material II-A2 is made by preparation example 24.
The II-A3 compound:
Rf (ethyl acetate/petroleum ether 2:1): 0.80;
1H NMR (400MHz, DMSO-d6) δ 3.80 (s, 6H, OCH
3* 2), 4.49 (dt, 2H, J=5.9,1.5Hz, OCH
2CH=CH
2), 4.74 (dt, 2H, J=5.1,1.5Hz, OCH
2CH=CH
2), 5.17 (dq, 1H, J=10.5,1.5,1.8,1.1Hz, trans-CH=CH
2-4 '), 5.30 (dq, 1H, J=10.3,1.5,1.8,1.1Hz, trans-CH=CH
2-6), 5.34 (dq, 1H, J=16.3,1.5,1.8Hz, cis-CH=CH
2-4 '), 5.46 (dq, 1H, J=17.2,1.5,1.8Hz, cis-CH=CH
2-6), 6.01-6.09 (M, 2H, OCH
2CH=CH2 *
2), 6.88 (s, 2H, H-2 ', H-6 '), 7.28 (dd, 1H, J=.2,2.6Hz, H-7), 7.42 (d, 1H, J=2.6Hz, H-5), 7.69 (d, 1H, J=5.5Hz, H-4), 8.01 (d, 1H, J=9.5Hz, H-8), 8.44 (s, 1H, J=5.5Hz, H-3);
MS (EI) m/e (relative abundance) 377 (M)
+(100), 337 (24), 336 (100), 295 (8).
Preparation example 26:Compound I I-A4[6-isopentene Oxy-1-(3 ', 5 '-dimethoxy-4 ' '-isopentene oxygen base phenyl)-isoquinoline 99.9] preparation:
According to the method identical with preparation example 22, be that raw material makes formula II-A4 compound (productive rate 22.0%) with II-A2, wherein raw material II-A2 is made by preparation example 24.
The II-A4 compound:
Rf (ethyl acetate/petroleum ether 1:1): 0.45;
1H NMR (400MHz, DMSO-d6) δ 1.72 (s, 1H, CH
3), 1.77 (s, 1H, CH
3), 1.80 (s, 1H, CH
3), 1.83 (s, 1H, CH
3), 3.89 (s, 6H, OCH
3* 2), 4.58 (d, 2H, J=7.1Hz, OCH
2CH-4 '), 4.68 (d, 2H, J=6.9Hz, OCH
2CH-6), 5.56 (t, 1H, J=1.4,1.4Hz, OCH
2CH=C-4 '), 5.62 (t, 1H, J=1.5,1.5Hz, OCH
2CH=C-6), 6.88 (s, 2H, H-2 ', H-6 '), 7.15 (d, 1H, J=2.5Hz, H-5), 7.20 (dd, 1H, J=9.3,2.5Hz, H-7), 7.55 (d, 1H, J=5.5Hz, H-4), 8.06 (d, 1H, J=9.2Hz, H-8), 8.50 (d, 1H, J=5.8Hz, H-3);
MS (EI) m/e (relative abundance) 433 (M)
+(2), 365 (82), 297 (100), 282 (32), 251 (23).
Preparation example 27-35:Prepare preparation example 27-35 compound shown in the following table three according to method with above preparation example 23-26:
Table three
What list below is the physicochemical data of each compound in the table three:
II-B1: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.45;
1H NMR (400MHz, CDCl
3) δ 3.92 (s, 6H, OCH
3* 2), 5.11 (s, 2H, OCH
2Ph), 6.21 (s, 2H, OCH
2O), 6.97 (s, 2H, H-2 ', H-6 '), 7.31-7.54 (m, 7H, OCH
2Ph-H, H-5, H-8), 7.72 (d, 1H, J=6.2Hz, H-4), 8.49 (d, 1H, J=6.2Hz, H-3).
II-B2: white solid, Rf (ethyl acetate/petroleum ether 1:2): 0.65;
1H NMR (400MHz, CDCl
3) δ 5.15 (s, 2H, OCH
2Ph-4 '), 5.18 (s, 4H, OCH
2Ph * 2), 6.12 (s, 2H, OCH
2O), 6.97 (s, 2H, H-2 ', H-6 '), 7.14 (s, 1H, H-5), 7.24 (s, 1H, H-8), 7.27-7.48 (m, 15H, OCH
2Ph-H * 3), 7.52 (d, 1H, J=5.4Hz, H-4), 8.45 (d, 1H, J=5.8Hz, H-3).
II-B3: faint yellow solid, Rf (ethyl acetate/petroleum ether 1:1): 0.15;
1H NMR (400MHz, CDCl
3) δ 3.93 (s, 6H, OCH
3* 2), 6.09 (s, 2H, OCH
2O), 6.88 (s, 2H, H-2 ', H-6 '), 7.14 (s, 1H, H-5), 7.40 (s, 1H, H-8), 7.48 (d, 1H, J=5.5Hz, H-4), 8.43 (d, 1H, J=5.7Hz, H-3).
II-B4: faint yellow solid, Rf (ethyl acetate/petroleum ether 1:1): 0.40;
1H NMR (400MHz, CDCl
3) δ 3.89 (s, 6H, OCH
3* 2), 4.60 (dt, 2H, J=6.05,1.1,1.4Hz, OCH
2CH), 5.22 (dq, 1H, J=10.5,1.1,0.8,0.8Hz, trans-CH=CH
2), 5.35 (dq, 1H, J=18.7,1.7,1.4,1.4Hz, cis-CH=CH
2), 6.10 (s, 2H, OCH
2O), 6.15 (m, 1H, OCH
2CH), 6.85 (s, 2H, H-2 ', H-6 '), 7.15 (s, 1H, H-5), 7.40 (s, 1H, H-8), 7.51 (d, 1H, J=5.8Hz, H-4), 8.44 (d, 1H, J=5.8Hz, H-3).
II-B5: faint yellow solid, Rf (ethyl acetate/petroleum ether 1:1): 0.60;
1H NMR (400MHz, CDCl
3) δ 1.72 (s, 3H, CH
3), 1.773H, CH
3), 3.89 (s, 6H, OCH
3* 2), 4.58 (d, 2H, J=10.1Hz, OCH
2CH), 5.62 (t, 1H, J=1.37Hz, OCH
2CH), 6.10 (s, 2H, OCH
2O), 6.84 (s, 2H, H-2 ', H-6 '), 7.14 (s, 1H, H-5), 7.40 (s, 1H, H-8), 7.51 (d, 1H, J=5.8Hz, H-4), 8.44 (d, 1H, J=5.8Hz, H-3).
II-C1: white solid, Rf (ethyl acetate/petroleum ether 1:2): 0.55;
1H NMR (400MHz, CDCl
3) δ 3.25 (s, 3H, OCH
3-8), 3.84 (s, 6H, OCH
3-3 ', OCH
3-5 '), 4.01 (s, 3H, OCH
3-6), 5.06 (s, 2H, OCH
2Ph), 5.09 (s, 2H, OCH
2Ph), 6.70 (s, 2H, H-2 ', H-6 '), 6.96 (s, 1H, H-5), 7.28-7.56 (m, 10H, CH
2Ph-H * 2), 7.50 (d, 1H, J=5.6Hz, H-4), 8.44 (d, 1H, J=5.6Hz, H-3).
II-C2: white solid, Rf (ethyl acetate/petroleum ether 2:3): 0.40;
1H NMR (400MHz, CDCl
3) δ 3.17 (s, 3H, OCH
3-8), 4.05 (s, 3H, OCH
3-6), 5.05 (s, 2H, OCH
2Ph-7), 5.17 (s, 6H, OCH
2Ph * 3), 6.92 (s, 2H, H-2 ', H-6 '), 7.07 (s, 1H, H-5), 7.22-7.52 (m, 20H, CH
2Ph-H * 4), 7.80 (d, 1H, J=5.6Hz, H-4), 8.67 (d, 1H, J=5.6Hz, H-3).
II-C3: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.15;
1H NMR (400MHz, DMSO-d6) δ 3.14 (s, 3H, OCH
3-8), 3.74 (s, 6H, OCH
3-3 ', OCH
3-5 '), 3.96 (s, 3H, OCH
3-6), 6.68 (s, 2H, H-2 ', H-6 '), 7.23 (s, 1H, H-5), 7.58 (d, 1H, J=5.5Hz, H-4), 8.25 (d, 1H, J=5.5Hz, H-3).
II-C4: white solid, Rf (ethyl acetate/petroleum ether 1:1): 0.35;
1H NMR (400MHz, CDCl
3) δ 3.39 (s, 3H, OCH
3-8), 3.83 (s, 6H, OCH
3-3 ', OCH
3-5 '), 3.99 (s, 3H, OCH
3-6), 4.55 (dt, 2H, J=6.1,1.1,1.4Hz, OCH
2CH), 4.57 (dt, 2H, J=6.5,1.1,1.4Hz, OCH
2CH), 5.17 (dq, 1H, J=4.8,0.8,0.4,0.8Hz, trans-CH=CH
2-7), 5.20 (dq, 1H, J=4.0,0.8,0.41.5Hz, trans-CH=CH
2-4 '), 5.30 (dq, 1H, J=6.2,1.5Hz, cis-CH=CH
2-7), 5.34 (dq, 1H, J=6.2,1.5Hz, cis-CH=CH
2-4 '), 6.02-6.18 (m, 2H, OCH
2CH * 2), 6.68 (s, 2H, H-2 ', H-6 '), 6.95 (s, 1H, H-5), 7.48 (d, 1H, J=5.6Hz, H-4), 8.41 (d, 1H, J=5.6Hz, H-3).
Preparation example 36:Compound I-B1[6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline] preparation:
Compound (III-B1) (seeing preparation example 16) 2.1g (5mmol) is dissolved in the 100ml methyl alcohol, add diethylamine 0.2ml, under ice bath cooling, added the 1g sodium borohydride in about 30 minutes then in batches, room temperature reaction is 3 hours then, steaming desolventizes, resistates is dissolved in the mixed solution of 150ml ethyl acetate/water (1/1), tell organic phase, water merges organic phase, water with ethyl acetate extraction 3 times (25ml * 3), the saturated common salt water washing, anhydrous magnesium sulfate drying, filtering and concentrating get product 1.6g, productive rate 76.3%.
The I-B1 compound:
Rf (ethyl acetate/petroleum ether/diethylamine 10:10:0.1): 0.25;
1H NMR (400MHz, CDCl
3) δ 2.75 (m, 1H, H-4), 3.03 (m, 2H, H-3, H-4), 3.23 (m, 1H, H-3), 3.79 (s, 6H, OCH
3* 2), 4.98 (s, 1H, H-1), 5.00 (s, 2H, OCH
2Ph), 5.89 (dd, 2H, J=8.2,1.4Hz, OCH
2O), 6.24 (s, 1H, H-5), 6.52 (s, 2H, H-2 ', H-6 '), 6.60 (s, 1H, H-8), 7.50-7.28 (m, 5H, OCH
2Ph-H);
MS (EI) m/e (relative abundance) 419 (M)
+(60), 328 (100), 296 (22), 176 (36), 91 (16).
Preparation example 37:Compound I-B2[6,8-dimethoxy-7-benzyloxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline] preparation:
According to the method identical, be that raw material makes formula I-B2 compound (productive rate 52.3%, wherein raw material II I-C1 is made by preparation example 20 with III-C1 with preparation example 36.
The I-B2 compound:
Rf (ethyl acetate/petroleum ether/diethylamine 10:10:0.1): 0.25;
1H NMR (400MHz, CDCl
3) δ 2.81 (m, 1H, H-4), 2.91 (m, 1H, H-4), 2.96 (m, 1H, H-3), 3.08 (m, 1H, H-3), 3.28 (s, 3H, OCH
3-8), 3.73 (s, 6H, OCH
3-3 ', OCH
3-5 '), 3.85 (s, 3H, OCH
3-6), 4.93 (q, 2H, J=10.8,6.0,10.8Hz, OCH
2Ph-7), 5.01 (s, 2H, OCH
2Ph-4 '), 5.30 (s, 1H, H-1), 6.40 (s, 2H, H-2 ', H-6 '), 6.48 (s, 1H, H-5), 6.60 (s, 1H, H-8), 7.22-7.46 (m, 10H, OCH
2Ph-H * 2);
MS (EI) m/e (spending abundance mutually) 541 (M)
+(33), 450 (100), 359 (10), 298 (50), 91 (40).
Preparation example 38:Compound I-A1[N-benzoyl-6,7-methylene-dioxy-1-(3 ', 5 '-dimethoxy-4 ' '-the benzyloxy phenyl)-1,2,3, the 4-tetrahydroisoquinoline] preparation:
Compound I-B1 (seeing preparation example 36) 200mg (0.48mmol) is dissolved in the 40ml methylene dichloride, add 3 DMF, under ice bath, drip Benzoyl chloride 0.06ml (0.51mmol) then, finishing room temperature reaction spends the night, add 10% sodium hydroxide solution 5ml then, stirred 30 minutes, tell organic phase, use saturated sodium carbonate (10ml * 2) respectively, water (10ml * 2) and saturated aqueous common salt (10ml * 2) washing.Through anhydrous magnesium sulfate drying, after the solvent evaporated, be that eluent separates with silica gel column chromatography with ethyl acetate/petroleum ether (1:5), get white solid 165mg, productive rate is 65.7%.
The I-A1 compound:
Rf (ethyl acetate/petroleum ether 1:2): 0.50;
1H NMR (400MHz, CDCl
3) δ 2.62 (M, 1H, H-4), 2.90 (m, 1H, H-4), 3.29 (m, 1H, H-3), 3.62 (m, 1H, H-3), 3.75 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.90 (dd, 2H, J=13.4,1.2Hz, OCH
2O), 6.13 (s, 1H, H-1), 6.57 (s, 2H, H-2 ', H-6 '), 6.64 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.27-7.61 (m, 10H, OCH
2Ph-H, Ar are " H);
MS (ESI) m/e (spending abundance mutually) 524 (M+1)
+(100).
Preparation example 39-61:According to the method for above preparation example 38, and the method for preparation example 24-26 prepares preparation example 39-61 compound shown in the following table four:
Table four
What list below is the physicochemical data of each compound in the table four:
I-A2: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.50;
1H NMR (400MHz, CDCl
3) δ 2.66 (m, 1H, H-4), 2.92 (m, 1H, H-4), 3.33 (m, 1H, H-3), 3.61 (m, 1H, H-3), 3.74 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.96 (d, 2H, J=12.8Hz, OCH
2O), 6.13 (s, 1H, H-1), 6.55 (s, 2H, H-2 ', H-6 '), 6.65 (s, 1H, H-5), 6.87 (s, 1H, H-8), 7.10 (t, 2H, J=8.6,8.6Hz, H-3 ", H-5 "), 7.28-7.40 (m, 5H, OCH
2Ph-H), 7.49 (t, 2H, J=10.7,7.2Hz, H-2 ", H-6 ").
I-A3: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.55;
1H NMR (400MHz, CDCl
3) δ 2.58 (m, 1H, H-4), 2.79 (m, 1H, H-4), 3.12 (m, 1H, H-3), 3.49 (m, 1H, H-3), 3.65 (s, 6H, OCH
3* 2), 4.89 (s, 2H, OCH
2Ph), 5.85 (dd, 2H, J=12.8,1.2Hz, OCH
2O), 6.02 (s, 1H, H-1), 6.45 (s, 2H, H-2 ', H-6 '), 6.58 (s, 1H, H-5), 6.76 (s, 1H, H-8), 7.17-7.40 (m, 9H, OCH
2Ph-H, Ar " H).
I-A4: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.55;
1H NMR (400MHz, CDCl
3) δ 2.63 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.32 (m, 1H, H-3), 3.56 (m, 1H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.96 (dd, 2H, J=13.8,1.0Hz, OCH
2O), 6.11 (s, 1H, H-1), 6.55 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.83 (s, 1H, H-8), 7.06 (m, 2H, H-4 ", H-5 "), 7.12 (d, 2H, J=7.7Hz, H-2 "), 7.26-7.50 (m, 6H, OCH
2Ph-H, H-6 ").
I-A5: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.60;
1H NMR (400MHz, CDCl
3) δ 2.38 (s, 3H, CH
3), 2.62 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.30 (m, 1H, H-3), 3.71 (m, 1H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=13.0,1.2Hz, OCH
2O), 6.16 (s, 1H, H-1), 6.58 (s, 2H, H-2, H-6 '), 6.62 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.14-7.23 (m, 3H, H-2 ", H-4 ", H-5 "), 7.27-7.40 (m, 6H, OCH
2Ph-H, H-6 ").
I-A6: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.30;
1H NMR (400MHz, CDCl
3) δ 2.62 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.30 (m, 1H, H-3), 3.74 (m, 7H, OCH
3-3 ', OCH
3-5 ', H-3), 3.84 (s, 3H, OCH
3-4 "), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=13.8,1.4Hz, OCH
2O), 6.16 (brs, 1H, H-1), 6.58 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.88 (s, 1H, H-8), 6.91 (dt, 2H, J=8.9,2.8,2.2Hz, H-3 ", H-5 "), 7.27-7.50 (m, 7H, OCH
2Ph-H, H-2 " and H-6 ").
I-A7: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.55;
1H NMR (400MHz, CDCl
3) δ 2.70 (M, 1H, H-4), 2.90 (m, 1H, H-4), 3.38-3.58 (m, 2H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (d, 2H, J=7.7Hz, OCH
2O), 6.10 (s, 1H, H-1), 6.58 (s, 2H, H-2, H-6 ') 6.62 (s, 1H, H-5), 6.85 (s, 1H, H-8), 7.27-7.50 (m, 5H, OCH
2Ph-H), 7.55 (t, 1H, J=7.7Hz, H-5 "), 7.62 (dd, 1H, J=8.0,0.8Hz, H-4 "), 7.69 (d, 1H, J=0.6Hz, H-2 "), 7.72 (dd, 1H, J=8.2,0.6Hz, H-6 ").
I-A8: yellow solid, Rf (ethyl acetate/petroleum ether 1:2): 0.45;
1H NMR (400MHz, CDCl
3) δ 2.68 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.42 (m, 1H, H-3), 3.70 (m, 1H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=12.9,0.9Hz, OCH
2O), 6.10 (brs, 1H, H-1), 6.58 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.88 (s, 1H, H-8), 7.27-7.50 (m, 5H, OCH
2Ph-H), 7.56 (dd, 2H, J=7.8,1.7Hz, H-2 ", H-6 "), 8.28 (dt, 2H, J=8.7,1.9,1.8Hz, H-3 ", H-5 ").
I-A9: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.65;
1H NMR (400MHz, CDCl
3) δ 2.60-2.78 (m, 1H, H-4), 2.88-3.07 (m, 1H, H-4), 3.21-3.46 (m, 2H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=14.5,1.2Hz, OCH
2O), 6.20 (s, 1H, H-1), 6.52 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.66 (s, 1H, H-8), 6.90-7.02 (m, 2H, H-3 ", H-6 "), 7.27-7.40 (m, 5H, OCH
2Ph-H), 7.48 (dd, 2H, J=10.2,3.2Hz, H-4 ").
I-A10: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.15;
1H NMR (400MHz, CDCl
3) δ 2.62 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.30 (m, 1H, H-3), 3.62 (m, 1H, H-3), 3.80 (s, 6H, OCH
3* 2), 5.55 (s, 1H, OH), 5.90 (dd, 2H, J=14.0,1.2Hz, OCH
2O), 6.15 (brs, 1H, H-1), 6.58 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.35-7.40 (m, 5H, Ar " H).
I-A11: no coloring agent, Rf (ethyl acetate/petroleum ether 2:3): 0.20;
1H NMR (400MHz, CDCl
3) δ 2.63 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.36 (m, 1H, H-3), 3.61 (m, 1H, H-3), 3.80 (s, 6H, OCH
3* 2), 5.52 (s, 1H, OH), 5.90 (d, 2H, J=13.8Hz, OCH
2O), 6.15 (brs, 1H, H-1), 6.56 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.85 (s, 1H, H-8), 7.10 (t, 2H, J=8.6,8.4Hz, H-3 ", H-5 "), 7.40 (t, 2H, J=10.7,7.2Hz, H-2 ", H-6 ").
I-A12: no coloring agent, Rf (ethyl acetate/petroleum ether 1:1): 0.30;
1H NMR (400MHz, CDCl
3) δ 2.63 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.32 (m, 1H, H-3), 3.58 (m, 1H, H-3), 3.80 (s, 6H, OCH
3* 2), 5.55 (s, 1H, OH), 5.95 (dd, 2H, J=13.5,1.2Hz, OCH
2O), 6.15 (brs, 1H, H-1), 6.59 (s, 2H, H-2 ', H-6 ') 6.62 (s, 1H, H-5), 6.83 (s, 1H, H-8), 7.08 (m, H, H-4 ", H-5 "), 7.14 (d, 2H, J=7.6Hz, H-2 "), 7.40 (dd, 1H, J=7.8,13.3Hz, H-6 ").
I-A13: no coloring agent, Rf (ethyl acetate/petroleum ether 1:1): 0.30;
1H NMR (400MHz, CDCl
3) δ 2.58-2.79 (m, 2H, H-4), 3.30-3.51 (m, 2H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.55 (s, 1H, OH), 5.95 (d, 2H, J=15.9Hz, OCH
2O), 6.18 (brs, 1H, H-1), 6.58 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.10 (t, 1H, J=9.2,8.8Hz, H-3 "); 7.20 (t, 2H, J=7.3,7.6Hz, H-6 "), 7.34-7.42 (m, 2H, H-4 ", H-5 ").
I-A14: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.45;
1H NMR (400MHz, CDCl
3) δ 2.62 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.32 (m, 1H, H-3), 3.62 (m, 1H, H-3), 3.78 (s, 6H, OCH
3* 2), 4.52 (d, 2H, J=8.7Hz, OCH
2CH), 5.18 (d, 1H, J=10.6Hz, trans-CHCH
2), 5.34 (dd, 1H, J=15.8,8.8Hz, cis-CHCH
2), 5.98 (dd, 2H, J=13.4,0.9Hz, OCH
2O), 6.10 (m, 2H, H-1, OCH
2CH), 6.58 (s, 2H, H-2 ' H-6 '), 6.62 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.33-7.50 (m, 5H, Ar " H).
I-A15: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.35;
1H NMR (400MHz, CDCl
3) δ 1.66 (s, 3H, CH
3), 1.74 (s, 3H, CH
3) 2.62 (m, 1H, H-4), 2.90 (m, 1H, H-4), 3.35 (m, 1H, H-3), 3.62 (m, 1H, H-3), 3.78 (s, 6H, OCH
3* 2), 4.46 (d, 2H, J=6.8Hz, OCH
2CH), 5.58 (t, 1H, 7.7,7.3Hz, OCH
2CH), 5.98 (dd, 2H, J=13.2,1.2Hz, OCH
2O), 6.16 (brs, 1H, H-1), 6.58 (s, 2H, H-2 ' H-6 '), 6.62 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.34-7.46 (s, 5H, Ar " H).
I-A16: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.45;
1H NMR (400MHz, CDCl
3) δ 0.84 (m, 4H, H-2 ", H-3 "), 1.26 (m, 1H, H-1 "), and 2.64-3.00 (m, 2H, H-4), 3.20-3.55 (m, 2H, H-3), 3.72 (s, 6H, OCH
3* 2), 5.96 (d, 2H, J=17.2Hz, OCH
2O), 6.20 (s, 1H, H-1), 6.44 (s, 2H, H-2 ', H-6 '), 6.57 (s, 1H, H-5), 6.75 (s, 1H, H-8), 7.27-7.50 (m, 5H, OCH
2Ph-H).
I-A17: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.40;
1H NMR (400MHz, CDCl
3) δ 2.65 (m, 1H, H-4), 2.92 (m, 1H, H-4), 3.37 (m, 1H, H-3), 3.59 (m, 1H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=13.2,1.2Hz, OCH
2O), 6.12 (s, 1H, H-1), 6.55 (s, 2H, H-2 ', H-6 '), 6.64 (s, 1H, H-5), 6.85 (s, 1H, H-8), 7.23-7.49 (m, 9H, OCH
2Ph-H, Ar " H).
I-A18: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.30;
1H NMR (400MHz, CDCl
3) δ 2.58-2.79 (m, 2H, H-4), 3.30-3.51 (m, 2H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=16.5,1.4Hz, OCH
2O), 6.18 (brs, 1H, H-1), 6.55 (s, 2H, H-2 ' H-6 '), 6.63 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.10 (t, 1H, J=9.2,8.8Hz, H-3 "), 7.20 (t, 2H, J=7.3,7.6Hz, H-6 "), 7.26-7.51 (m, 7H, OCH
2Ph-H, H-4 ", H-5 ").
I-A19: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.45;
1H NMR (400MHz, CDCl
3) δ 2.58-2.82 (m, 2H, H-4), 3.22-3.42 (m, 2H, H-3), 3.78 (s, 6H, OCH
3* 2), 5.00 (s, 2H, OCH
2Ph), 5.98 (dd, 2H, J=12.0,0.8Hz, OCH
2O), 6.10 (s, 1H, H-1), 6.57 (s, 2H, H-2 ', H-6 '), 6.62 (s, 1H, H-5), 6.92 (s, 1H, H-8), 7.29-7.50 (m, 9H, OCH
2Ph-H, Ar " H).
I-A20: no coloring agent, Rf (ethyl acetate/petroleum ether 1:4): 0.10;
1H NMR (400MHz, CDCl
3) δ 2.64-3.60 (m, 4H, H-3, H-4), 3.46 (s, 3H, OCH
3-8), 3.69 (s, 6H, OCH
3* 2), 3.86 (s, 3H, OCH
3-6), 4.98 (q, 2H, J=11.0,9.5,10.8Hz, OCH
2Ph-7), 5.05 (s, 2H, OCH
2Ph-4 '), 6.18 (s, 1H, H-1), 6.55 (s, 2H, H-2 ', H-6 '), 7.11 (s, 1H, H-5), 7.23-7.49 (m, 15H, OCH
2Ph-H * 2, Ar " H).
I-A21: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.50;
1H NMR (400MHz, CDCl
3) δ 2.64-2.96 (m, 2H, H-4), 3.02-3.8 (m, 2H, H-3), 3.46 (s, 3H, OCH
3-8), 3.69 (s, 6H, OCH
3* 2), 3.86 (s, 3H, OCH
3-6), 4.97 (q, 2H, J=10.9,9.7,9.1Hz, OCH
2Ph-7), 5.03 (s, 2H, OCH
2Ph-4 '), 6.13 (s, 1H, H-1), 6.54 (s, 2H, H-2 ', H-6 '), 7.10 (t, 3H, J=6.6,6.8Hz, H-3 ", H-5 ", H-5), 7.22-7.43 (m, 12H, OCH
2Ph-H * 2, H-2 ", H-6 ").
I-A22: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.45;
1H NMR (400MHa.CDCl
3) δ 2.62-3.05 (m, 2H, H-4), 3.22-3.60 (m, 2H, H-3), 3.46 (s, 3H, OCH
3-8), 3.69 (s, 6H, OCH
3* 2), 3.86 (s, 3H, OCH
3-6), 4.97 (m, 2H, OCH
2Ph-7), 5.02 (s, 2H, OCH
2Ph-4 '), 6.12 (s, 1H, H-1), 6.54 (s, 2H, H-2 ', H-6 '), 7.08 (s, 1H, H-5), 7.21-7.49 (m, 14H, OCH
2Ph-H * 2, Ar " H).
I-A23: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.45;
1H NMR (400MHz, CDCl
3) δ 2.63-3.06 (m, 2H, H-4), 3.22-3.63 (m, 2H, H-3), 3.45 (s, 3H, OCH
3-8), 3.68 (s, 6H, OCH
3* 2), 3.86 (s, 3H, OCH
3-6), 4.97 (m, 2H, OCH
2Ph-7), 5.03 (s, 2H, OCH
2Ph-4 '), 6.12 (s, 1H, H-1), 6.51 (s, 2H, H-2 ', H-6 '), 7.07 (s, 1H, H-5), 7.09-7.18 (m, 3H, H-2 ", H-4 ", H-5 "), 7.23-7.49 (m, 11H, OCH
2Ph-H * 2, H " 6).
I-A24: no coloring agent, Rf (ethyl acetate/petroleum ether 1:2): 0.40;
1H NMR (400MHz, CDCl
3) δ 2.64-3.11 (m, 2H, H-4), 3.20-3.60 (m, 2H, H-3), 3.45 (s, 3H, OCH
3-8), 3.70 (s, 6H, OCH
3* 2), 3.88 (s, 3H, OCH
3-6), 4.98 (s, 2H, OCH
2Ph-7), 5.02 (s, 2H, OCH
2Ph-4 '), 6.11 (s, 1H, H-1), 6.55 (s, 2H, H-2 ', H-6 '), 7.08 (s, 1H, H-5), 7.22-7.50 (m, 14H, OCH
2Ph-H * 2, Ar " H).
Formula (1) compound has important biological, external six strain tumour cells are comprised Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), (oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the test of the cytotoxic activity of human cervical carcinoma cell (Hela) show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound (specifically seeing embodiment) thereof are inhibited to growth of tumour cell, might develop into new control tumour medicine.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can combine with spoke material or carrier pharmaceutically commonly used, have the active pharmaceutical composition that can be used for anti-curing oncoma of growth of tumour cell inhibition thereby prepare.Above-mentioned all kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can with antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active cytotoxicity composition, can be used for treating tumor disease.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
In order to understand essence of the present invention better, respectively with the inhibiting The pharmacological results of compound, its new purposes in pharmacy field is described below to six kinds of tumor cell line growths.Embodiment has provided the part activity data of representative compounds.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Pharmacology embodiment 1:Compound IV a is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, and the dimethyl sulfoxide solution of the compound VI a that will newly join joins in each hole with concentration gradient respectively, makes that the compound ultimate density is respectively 100 μ g/mL in the hole, 33.3 μ g/mL, 11.1 μ g/mL and 3.7 μ g/mL.After 72 hours, the phosphate buffered saline buffer that adds 10 μ L MIT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Wherein compound IV a is to KB cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of compound IV a
50For: 32 * 10
-5M
Experiment conclusion: the KB cell is test compounds to the Cytotoxic effective tool of tumour cell and comments index.This experiment show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound thereof, the KB cell is had stronger cytotoxicity, might develop into new medicine with antitumor action.
According to the method for embodiment 1, we have tested the pharmacologically active of prepared compound to the KB cell, and concrete data see Table five.
Table five
| The compound code name | VIIc | IVb |
| IC 50 | 1.7×10 -6M | 9.6×10 -5M |
Pharmacology embodiment 2:Compound Vf is to the cytotoxic activity of PC-3 cell
PC-3 (prostate cancer) cell F-12 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound Vf
50For: 7.6 * 10
-6M
Experiment conclusion: this experiment show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound thereof have stronger cytotoxicity to the PC-3 cell, might develop into the new medicine with antitumor action.
According to the method for embodiment 2, we have tested the pharmacologically active of prepared compound to the PC-3 cell, and concrete data see Table six:
Table six
| The compound code name | IVb | IVa |
| IC 50 | 9.74×10 -5M | 6.28×10 -6M |
Pharmacology embodiment 3:Compound IV a is to the cytotoxic activity of CNE cell
CNE (nasopharyngeal carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.With every hole 5 * 10
3The concentration of cell joins in 96 orifice plates, contains 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound IV a
50For: 1.99 * 10
-5M
Experiment conclusion: this experiment show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound thereof have stronger cytotoxicity to the CNE cell, might develop into the new medicine with antitumor action.
According to the method for embodiment 3, we have tested the pharmacologically active of prepared compound to the CNE cell, and concrete data see Table seven.
Table seven
| The compound code name | IVb | VIIIf |
| IC 50 | 9.8×10 -6M | 2.7×10 -6M |
Pharmacology embodiment 4:Compound I k is to the cytotoxic activity of A549 cell
A549 (people's lung cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of Compound I k
50For: 3.1 * 10
-6M
Experiment conclusion: this experiment show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound thereof have stronger cytotoxicity to the A549 cell, might develop into the new medicine with antitumor action.
According to the method for embodiment 4, we have tested the pharmacologically active of prepared compound to the A549 cell, and concrete data are example (seeing Table eight) with several embodiment.
Table eight
| The compound code name | IVa | Ic |
| IC 50 | 6.4×10 -5M | 3.7×10 -5M |
Pharmacology embodiment 5::Compound IV a is to the cytotoxic activity of BEL-7404 cell
BEL-7404 (people's liver cancer) cell contains 10% foetal calf serum, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound IV a
50For: 3.7 * 10
-5M
Experiment conclusion: this experiment show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound thereof have stronger cytotoxicity to the BEL-7404 cell, might develop into the new medicine with antitumor action.
According to the method for embodiment 5, we have tested the pharmacologically active of prepared compound to the BEL-7404 cell, and concrete data see Table nine.
Table nine
| The compound code name | VIIc | VIIIb |
| IC 50 | 3.6×10 -5M | 2.4×10 -5M |
Pharmacology embodiment 6:Compound IV f is to the cytotoxic activity of Hela cell
Hela (human cervical carcinoma) cell contains 10% foetal calf serum, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 1.
The IC of compound Vf
50For: 1.7 * 10
-5M
Experiment conclusion: this experiment show this type of 1-(3 ', 4 ', 5 '-tri-substituted phenyl)-isoquinoline compound and intermediate series compound thereof have stronger cytotoxicity to the Hela cell, might develop into the new medicine with antitumor action.
According to the method for embodiment 6, we have tested the pharmacologically active of prepared compound to the Hela cell, and concrete data see Table ten.
Table ten
| The compound code name | IVb | IVd |
| IC 50 | 1.8×10 -5M | 2.5×10 -5M |
Claims (4)
1. a 1-(3 ＇, 4 ＇, 5 ＇-tri-substituted phenyl)-tetrahydro isoquinoline compound and pharmaceutically useful salt thereof has structure shown in the formula (I-A):
Formula (I-A);
It is characterized in that: formula (I-A) compound is to be selected from down array structure:
N-benzoyl-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " chlorobenzene formacyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " methyl benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " anisoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " the itrile group benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " nitro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(2 ", 6 " difluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-benzoyl-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-hydroxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-hydroxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-hydroxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(2 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-hydroxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-benzoyl-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-allyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-benzoyl-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-isopentene oxygen base phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-cyclopropane carbonyl-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " chlorobenzene formacyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(2 " fluoro benzoyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(2 " chlorobenzene formacyl)-6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-benzoyl-6,8-dimethoxy-7-benzyloxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " fluoro benzoyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(4 " chlorobenzene formacyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " fluoro benzoyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
N-(3 " chlorobenzene formacyl)-6,8-dimethoxy-7-benzyloxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
6,7-methylene-dioxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline;
6,8-dimethoxy-7-benzyloxy-1-(3 ＇, 5 ＇-dimethoxy-4 ' ＇-benzyloxy phenyl)-1,2,3,4-tetrahydroisoquinoline.
2. the application in preparation control tumor disease medicine of compound according to claim 1 and pharmaceutically useful salt thereof.
3. the application in preparation control tumor disease medicine of compound according to claim 1 and pharmaceutically useful salt thereof is characterized in that: what contain the treatment significant quantity in the described medicine is the mixture of described compound and its pharmacologically acceptable salt as activeconstituents.
4. according to claim 2 or 3 described application, it is characterized in that: described medicine becomes pharmaceutical composition by the mixture of described compound and pharmaceutically useful salt or above-mentioned substance with preparation allowable pharmaceutical excipients or preparing carriers.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030756A (en) * | 2010-12-03 | 2011-04-27 | 沈阳药科大学 | 6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline derivative and preparation method and application thereof |
| CN104245674A (en) * | 2012-04-17 | 2014-12-24 | 霍夫曼-拉罗奇有限公司 | New phenyl-tetrahydroisoquinoline derivatives |
-
2005
- 2005-07-11 CN CNA2008101890467A patent/CN101440096A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030756A (en) * | 2010-12-03 | 2011-04-27 | 沈阳药科大学 | 6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline derivative and preparation method and application thereof |
| CN102030756B (en) * | 2010-12-03 | 2014-05-21 | 沈阳药科大学 | 6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline derivative and preparation method and application thereof |
| CN104245674A (en) * | 2012-04-17 | 2014-12-24 | 霍夫曼-拉罗奇有限公司 | New phenyl-tetrahydroisoquinoline derivatives |
| CN104245674B (en) * | 2012-04-17 | 2017-07-11 | 霍夫曼-拉罗奇有限公司 | Phenyl tetrahydro isoquinoline derivative |
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