CN104672136A - 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof - Google Patents

1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof Download PDF

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CN104672136A
CN104672136A CN201310705739.8A CN201310705739A CN104672136A CN 104672136 A CN104672136 A CN 104672136A CN 201310705739 A CN201310705739 A CN 201310705739A CN 104672136 A CN104672136 A CN 104672136A
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dimethoxy
phenanthryl
tetrahydroisoquinoline
trimethoxy
alkyl
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CN104672136B (en
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赵冬梅
宋帅
程卯生
王永瑞
张祯
郝晨洲
高禄华
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms

Abstract

The invention belongs to the field of medicine synthesis, relates to a 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as a preparation method and a purpose thereof and in particular relates to a 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative with substituted phenanthrene ring on 1 position and alkyl or acyl substituted on nitrogen atoms as well as a preparation method and a medical application of the 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative. The 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative is shown as a general formula (I); shown by an antitumor effect in vitro experiment, a compound shows good activity and physiological activity, is high in study value in the aspects of inhibiting tumor cell migration and invasion and can be further developed into a novel antitumor drug.

Description

1-replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative and its production and use
Technical field
The invention belongs to pharmaceutical synthesis field, relate to 1-and replace phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative and its production and use.Be specifically related to a kind of have at 1 replace 6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivatives of phenanthryl, and preparation method thereof and application medically.
Background technology
Tumour is ripe or at developing normal cell in body, under the effect of related factors, presents hyperplasia or abnormal differentiation and the true tumor that formed, usually forms lump, therefore named tumour.Tumour is divided into optimum and pernicious two classes, and malignant tumour is often called cancer, is a kind of common disease, frequently-occurring disease of serious threat human health.Now, cancer has become the deputy lethal cause of disease in the whole world, 2007, and nearly 7,600,000 people die from cancer, accounts for global dead patient's 13%.Up-to-date report " the cancer report of the 2008 worlds " display that international cancer research institution (IARC) issues, by 2010, cancer will surmount cardiovascular and cerebrovascular diseases, become mankind's number one killer; To the year two thousand thirty, global cancer patients will reach 7,500 ten thousand, and death toll will reach 1,700 ten thousand.Become the primary lethal cause of disease in China's cancer, the cancer mortality of Jin20Nian Lai China rises 29%.Therefore, the method finding the treatment tumour of high-efficiency low-toxicity is the major issue that Medical and pharmacy researcher should urgently solve.
Antitubulin is the important antitumor drug of a class, and the antitumor drug acting on tubulin of clinical application is mainly derived from natural phant, as taxanes and vinca, but these toxicity of compound are large, bioavailability is low, expensive.
Noscapine (noscapine) is the alkaloid in opium with tetrahydroisoquinoline structure, clinical in antibechic, and without analgesia, the characteristics such as calmness and respiration inhibition, do not make people produce floaty euphoria or dependency yet.In recent years, be that the tetrahydroisoquinoline natural product of representative and derivative thereof have also attracted gazing at of people at the potential application foreground of anti-tumor aspect with Noscapine.To in the random antitumor action screening process of colchicine analog structure compound, Joshi research group has found the anti-tumor activity of Noscapine.Noscapine and derivative Noscapine thereof and derivative thereof can act on microtubule, suppress its dynamic instability, thus the mitotic division of interference tumour cell, play antitumor action.They have the features such as anti-tumor activity effect is obvious, toxic side effect is little, wide spectrum, mechanism of action unique, oral absorption is good, convenient, safety, derivative are many, have development space widely.Therefore Noscapine and derivative thereof are expected to be developed to new class antitumor drug.
Natural product Combretastatin family is the antineoplastic compound that a class has bright prospects, and wherein because it has efficient anti-tumor activity, particularly overriding resistance tumor promotion, highly selective, hypotoxicity become study hotspot to Compound C ombretastatinA-4 (CA-4).CA-4 and colchicine structural similitude, playing active function much smaller than during its MTD, can compete binding site on tubulin with colchicine.A series of structure activity study shows, this product belongs to colchicine sample microtubules inhibitor, but not vinca.
Along with the continuous increase of global tumour patient, develop new there is higher pharmacologically active, the antitumor drug of determined curative effect will be an inexorable trend of medicament research and development to adapt to clinical needs.
Summary of the invention:
Adopt active fragments principle of hybridization; the isobenzofuranone fragment of Noscapine is replaced with the structure fragment of cis-stilbene by us; then toluylene fragment is carried out intramolecular coupling; namely obtain 1-and replace phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2; 3; 4-tetrahydro isoquinoline derivative, investigates tetrahydroisoquinoline 1 bit substituent to the impact of its anti-tumor activity, studies mechanism of action and the structure activity relationship of this compounds.Lead to method according to the synthesis of tetrahydroisoquinoliderivs derivs, we have designed and synthesized 20 and have had luxuriant and rich with fragrance cyclosubstituted tetrahydroisoquinoliderivs derivs, and carry out deep research to its antitumor propagation and migration invasion and attack activity.
The object of this invention is to provide the novel tetrahydro isoquinoline compound with good antitumor propagation and migration invasion and attack activity, be specifically related to a kind of 1 and there are 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolicompounds compounds and the analogues thereof replacing phenanthryl.
Another object of the present invention is to provide above-mentioned 1 and has replacement 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolicompounds compounds of phenanthryl and the preparation method of derivative thereof.
Novel 1-of the present invention replaces the structure that phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative has following general formula (I):
Wherein
R=C 1-C 10alkyl, C 1-C 10alkyl acyl, C 6-C 12aryl-acyl, amino acid, amino acid salts, C 1-C 10alkyl or C 6-C 12aryl replaces amine formyl;
R 1=H, C 1-C 10alkyl, C 1-C 10alkoxyl group; It replaces number is 1,2 or 3;
R 2=H, OH, C 1-C 10alkyl, C 1-C 10alkoxyl group, it replaces number is 1,2 or 3.
Wherein preferred: R=C 1-C 4alkyl, C 1-C 4alkyl acyl, C 6-C 12aryl-acyl, amino acid, amino acid salts, C 1-C 4alkyl or C 6-C 12aryl replaces amine formyl.
R 1=H, C 1-C 4alkyl or C 1-C 4alkoxyl group, preferably: methoxyl group, oxyethyl group.
R 2=H, OH, C 1-C 4alkyl or C 1-C 4alkoxyl group, preferably: OH, OCH 3, OC 2h 5or OCH (CH 3) 2.
More preferably:
R=CH 3, C 2h 5, COCH 3, COPh, amino acid, amino acid salts, phenylethylamine formyl radical.
R 1, R 2=H, CH 3, OH, OCH 3, OC 2h 5or OCH (CH 3) 2.
The preferred compound of the present invention has the structure of following compound 1-20:
Novel 1-of the present invention replaces phenanthryl-N-alkyl (acyl group)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinolicompounds compounds and derivative thereof are prepared by following method: the toluylic acid adopting phenyl aldehyde and the replacement replaced, substituting group as claimed in claim.Basic be master with alkoxyl group is starting raw material, through condensation, esterification, coupling, hydrolysis, obtains the phenanthrenecarboxylic acid of replacement; The phenanthrenecarboxylic acid and 3 replaced, 4 dimethoxy-phenylethylamines obtain corresponding compound 1-20 through acidylate, cyclization, reduction, nitrogen atom (acylations).
The preparation process of the compounds of this invention 1 is as follows:
The preparation technology of described compound 1 comprises:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylating obtains 1-(3; 6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 1).
The preparation process of the compounds of this invention 2 is as follows:
3,4-dimethoxyphenylacetic acid and Veratraldehyde obtain 3,4,6,7-tetramethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,4,6,7-tetramethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylating obtains 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 2).
The preparation process of the compounds of this invention 3 is as follows:
3,4-dimethoxyphenylacetic acid and 3-benzyloxy 4-methoxybenzaldehyde obtain 2-benzyloxy-3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.2-benzyloxy-3; 6; 7-trimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylate, deprotection obtains 1-(2-hydroxyl-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 3).
The preparation process of the compounds of this invention 4 is as follows:
3,4-dimethoxyphenylacetic acid and 4-benzoxybenzaldehyde obtain 3-benzyloxy-6,7-dimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3-benzyloxy-6; 7-dimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylate, deprotection obtains 1-(3-hydroxyl-6; 7-dimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 4).
The preparation process of the compounds of this invention 5 is as follows:
3,4-dimethoxyphenylacetic acid and 3-benzoxybenzaldehyde obtain 2-benzyloxy-6,7-dimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.2-benzyloxy-6; 7-dimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylate, deprotection obtains 1-(2-hydroxyl-6; 7-dimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 5).
The preparation process of the compounds of this invention 6 is as follows:
3,4-dimethoxyphenylacetic acid and 3-methoxyl group-4-benzoxybenzaldehyde obtain 3-benzyloxy-2,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3-benzyloxy-2; 6; 7-trimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylate, deprotection obtains 1-(3-hydroxyl-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 6).
The preparation process of the compounds of this invention 7 is as follows:
3,4-dimethoxyphenylacetic acid and 4-isopropoxide benzaldehyde obtain 3-isopropoxy-6,7-dimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3-isopropoxy-6; 7-dimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylate, deprotection obtains 1-(3-isopropoxy-6; 7-trimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 7).
The preparation process of the compounds of this invention 8 is as follows:
3,4,5-trimethoxy phenyl acetic acid and 4-benzoxybenzaldehyde obtain 3-benzyloxy-5,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3-benzyloxy-5; 6; 7-trimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylate, deprotection obtains 1-(3-hydroxyl-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 8).
The preparation process of the compounds of this invention 9 is as follows:
3,4,5-trimethoxy phenyl acetic acid and aubepine obtain 3,5,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,5,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylating obtains 1-(3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 9).
The preparation process of the compounds of this invention 10 is as follows:
3,4-dimethoxyphenylacetic acid and 3-methoxyl group-4-tolyl aldehyde obtain 2,6,7-trimethoxy-3-methyl-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.2; 6; 7-trimethoxy-3-methyl-9-phenanthrenecarboxylic acid and 6; 7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylating obtains 1-(2,6,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 10).
The preparation process of the compounds of this invention 11 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylating obtains 1-(3; 6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 11).
The preparation process of the compounds of this invention 12 is as follows:
4-methoxyphenylacetic acid and aubepine obtain 3,6-dimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6-dimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine through acidylate, cyclization, reduce, methylating obtains 1-(3; 6-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2; 3,4-tetrahydroisoquinoline (compound 12).
The preparation process of the compounds of this invention 13 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline through acidylate, cyclization, reduction.
1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; S-phenylalanine generation acidylate, deprotection reaction that 4-tetrahydroisoquinoline and tert-butoxycarbonyl are protected; obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-hydrocinnamoyl)-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 13).
The preparation process of the compounds of this invention 14 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline through acidylate, cyclization, reduction.1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; S-tyrosine generation acidylate, deprotection reaction that 4-tetrahydroisoquinoline and protecting group are protected; obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxy phenyl)-propionyl)-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 14).
The preparation process of the compounds of this invention 15 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline through acidylate, cyclization, reduction.1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; S-Methionin generation acidylate, deprotection reaction that 4-tetrahydroisoquinoline and tert-butoxycarbonyl are protected, obtain 1-(3,6; 7-trimethoxy-9-phenanthryl)-N-((2S)-2; 6-diamino-caproyl)-6,7-dimethoxys-1,2; 3,4-tetrahydroisoquinoline (compound 15).
The preparation process of the compounds of this invention 16 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline through acidylate, cyclization, reduction.1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline and tert-butoxycarbonyl protect S-Methionin generation acidylate, deprotection, salt-forming reaction, obtain 1-((R)-3,6; 7-trimethoxy-9-phenanthryl)-N-((2S)-2; 6-diamino hydrochloride-caproyl)-6,7-dimethoxys-1,2; 3,4-tetrahydroisoquinoline (compound 16).
The preparation process of the compounds of this invention 17 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline through acidylate, cyclization, reduction.1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline and protecting group protect S-L-glutamic acid generation acidylate, deprotection, salt-forming reaction; obtain 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl radicals)-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 17).
The preparation process of the compounds of this invention 18 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6,7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3 through acidylate, cyclization, reduction, acetylize; 6,7-trimethoxy-9-phenanthryl)-N-ethanoyl-6,7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 18).
The preparation process of the compounds of this invention 19 is as follows:
4-methoxyphenylacetic acid and aubepine obtain 3,6-dimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3,6-dimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine obtain 1-(3 through acidylate, cyclization, reduction, acidylate; 6,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 19).
The preparation process of the compounds of this invention 20 is as follows:
3,4-dimethoxyphenylacetic acid and aubepine obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid through condensation, esterification, coupling, hydrolysis.3; 6; 7-trimethoxy-9-phenanthrenecarboxylic acid and 6,7-dimethoxy-phenylethylamine, through acidylate, cyclization, reduction, acidylate, replacement, obtain 1-(3; 6; 7-trimethoxy-9-phenanthryl)-N-phenylethylamine base formyl radical-6,7-dimethoxy-1,2; 3,4-tetrahydroisoquinoline (compound 20).
1-involved in the present invention replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative, and anticancer experiment in vitro shows, compound of the present invention shows good activity, has good physiologically active; In inhibition tumor cell migration, invasion and attack, there is higher researching value, can develop further as novel antitumor drug.
Embodiment:
The preparation of embodiment one: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 1)
1) preparation of (E)-2-(3,4-Dimethoxyphenyl)-3-(4-p-methoxy-phenyl) hexenoic acid
By 3; 4-dimethoxyphenylacetic acid (19.6g; 0.1mol), aubepine (16.3g, 0.12mol) acetic anhydride (38mL) and triethylamine (19mL) join in 100mL eggplant-shape bottle, reflux 9h under argon shield.Stopped reaction, by the 150mL10% aqueous sodium hydroxide solution of reaction solution impouring heat, reflux 0.5h, is cooled to room temperature.Solution, with extracted with diethyl ether (3 × 100mL), discards organic layer, adds concentrated hydrochloric acid solution and adjusts pH=3, separate out a large amount of khaki color solid, stir 0.5h, suction filtration, filtration cakes torrefaction under water layer ice bath.Obtain khaki color look solid 16.62g, yield 53.3%.
2) preparation of (E)-2-(3,4-Dimethoxyphenyl)-3-(4-p-methoxy-phenyl) hexenoic acid methyl esters
(E)-2-(3,4-Dimethoxyphenyl)-3-(4-p-methoxy-phenyl) hexenoic acid (16.62g, 0.053mol) is dissolved in 200mL anhydrous methanol, adds the 1mL vitriol oil, reflux 20h under argon shield.Stopped reaction, solution is cooled to room temperature, separates out Light yellow crystals.Suction filtration, filter cake anhydrous methanol washs, dry, obtains light yellow solid 12.9g, yield 74.3%.
3) preparation of 3,6,7-trimethoxy 9-phenanthrenecarboxylic acid methyl esters
By (E)-2-(3; 4-Dimethoxyphenyl)-3-(4-p-methoxy-phenyl) hexenoic acid methyl esters (12.9g; 39mmol) be dissolved in the methylene dichloride that 130mL heavily steams under argon shield; trifluoro vanadyl (6.5g is slowly added under cryosel bath condition; trifluoro vanadyl (is dissolved in the mixed solution heavily steaming methylene dichloride and ethyl acetate (70mL+70mL) by solution 52mmol); argon shield); 1.5h finish; insulated and stirred reaction 0.5h, TLC detection reaction completes.By in reaction solution impouring trash ice, room temperature stirs 0.5h.Dichloromethane extraction (3 × 50mL), merges organic phase, and saturated aqueous common salt (3 × 50mL) washs, and anhydrous sodium sulfate drying spends the night, filtering siccative, and filtrate concentrates to obtain crude product.Column chromatography purification, obtains ivory buff product 10.4g, yield 80.04%.
4) preparation of 3,6,7-trimethoxy 9-phenanthrenecarboxylic acids
By 3,6,7-trimethoxy 9-phenanthrenecarboxylic acid methyl esters (10.4g, 33mmol) be dissolved in methyl alcohol (10mL) with the mixed solvent of water (100mL), add sodium hydroxide (10g, 0.25mol), reflux 4h, TLC detect, and reaction completes.Under ice bath, concentrated hydrochloric acid solution adjusts pH=3, separates out a large amount of white solid, suction filtration, and filter cake is washed, dry.Obtain white solid 9.8g, yield 95.3%.
5) preparation of the luxuriant and rich with fragrance methane amide of N-(3,4-Dimethoxyphenethyl)-3,6,7-trimethoxy 9-
By 3,6,7-trimethoxy 9-phenanthrenecarboxylic acid (9.8g, 31.4mmol) be dissolved in the dichloromethane solution of 200mL drying, 1-hydroxy benzo triazole (HOBt) (6.37g, 47.2mmol) is added, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (9.02g under condition of ice bath, 47.2mmol), room temperature reaction 3.5h.Add diisopropylethylamine (DIEA) (8.1g, 62.8mmol), 3,4-dimethoxy-phenylethylamine (5.68g, 31.4mmol), room temperature reaction 1h, TLC detect, and reaction completes.Add 20mL water, cancellation is reacted.Extraction, water washing organic layer (2 × 20mL), 2N salt acid elution (2 × 20mL), saturated sodium bicarbonate washing (2 × 20mL), saturated common salt water washing (3 × 50mL), anhydrous sodium sulfate drying.Filtering siccative, filtrate concentrates to obtain crude product.Column chromatography purification, obtains white solid 11.5g, yield 77.3%.
6) preparation of 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-3,4-dihydro-isoquinolines
Under argon shield condition; by N-(3; 4-Dimethoxyphenethyl)-3; the luxuriant and rich with fragrance methane amide (11.5g, 24mmol) of 6,7-trimethoxy 9-is scattered in 120mL glycol dimethyl ether; disposablely add phosphorus oxychloride (22.1mL; 0.24mmol), heating reflux reaction 3.5h, TCL detection reaction completes.Steam except most of solvent, add toluene 30mL, azeotropic steams and desolventizes, and repeats above operation three times, obtains brown oil, without the need to purifying, directly carries out next step reaction.
7) preparation of 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
By fresh obtained 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-3,4-dihydro-isoquinoline is dissolved in 120mL anhydrous methanol, and reaction system is cooled to-5 DEG C, by sodium borohydride (7.3g, 0.19mol) add in reaction system slowly, about 1h adds in batches.Insulation reaction 0.5h, room temperature reaction 12h, separate out a large amount of white solid, suction filtration, filter cake washs with anhydrous methanol, dry.Obtain white solid 8.6g, yield 74.9%.
8) preparation of 1-(3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
Compound 7 (8.6g, 18.8mmol) is dissolved in 100mL acetone, under room temperature condition, add methyl iodide (1.17mL, 18.8mmol), Anhydrous potassium carbonate (3.1g, 22.6mmol), room temperature reaction 4h, TLC detection reaction completes.Add 1.2mL diethylamine, stirring at room temperature 1h, filtering insolubles, steaming desolventizes.Column chromatography purification, obtains target product, white solid 8.09g, yield 90.8%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.34(s，3H)，2.63-2.84(m，2H)，3.20-3.34(m，2H)，3.96(s，3H)，4.02(s，3H)，4.04(s，3H)，4.05(s，3H)，4.08(s，3H)，4.59(s，1H)，6.15(s，1H)，6.63(s，1H)，6.92-7.03(dd，1H，J 1=9.7，J 2=2.2)，7.48(s，1H)，7.62-7.64(d，1H，J 2=2.2)，8.30-8.33(d，1H，J=9.7)，9.13(s，1H)；ESI-MS：m/z474.1[M+H] +。
The preparation of embodiment two: 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 2)
The preparation process of compound 2 is with the preparation method of compound 1.Veratraldehyde and 3,4-dimethoxyphenylacetic acid is adopted to be starting raw material.1-(2,3,6 is obtained through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation; 7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2; 3,4-tetrahydroisoquinoline (compound 2), total recovery 17.2%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.25(s，3H)，2.70(s，1H)，2.85-2.88(d，1H)，3.25-3.26(d，1H)，3.40(s，3H)，3.50(s，1H)，3.87(s，3H)，3.95(s，3H)，4.05(s，3H)，4.07(s，3H)，4.08(s，3H)，4.59(s，1H)，6.15(s，1H)，6.63(s，1H)，6.92(s，1H)，7.48(s，1H)，7.63(s，1H)，8.31(s，1H)，9.01(s，1H)；ESI-MS：m/z504.2[M+H] +。
The preparation of embodiment three: 1-(2-hydroxyl-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 3)
The preparation process of compound 3 is similar to the preparation method of compound 2.Adopt 3-hydroxyl-4-methoxybenzaldehyde and 3; 4-dimethoxyphenylacetic acid is starting raw material; 1-(2-hydroxyl-3 is obtained through alkylation, condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation; 6; 7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2; 3,4-tetrahydroisoquinoline.
1-(2-hydroxyl-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.25g, 0.46mmol) is dissolved in 100mL anhydrous methanol, adds the anhydrous Pd/C of 30mg10%, Isosorbide-5-Nitrae cyclohexadiene (0.26mL, 2.75mmol), 25 DEG C of ultrasonic reactions 1.5 hours, filtering Pd/C, steams except filtrate, column chromatography purification obtains target product, total recovery 12.5%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.35(s，3H)，2.62-2.63(t，1H)，2.85-2.88(d，1H)，3.25-3.26(d，1H)，3.50(s，1H)，3.93(s，3H)，3.98(s，3H)，4.02(s，3H)，4.07(s，3H)，4.08(s，3H)，4.63(s，1H)，6.22(s，1H)，6.59(s，1H)，6.88(s，1H)，7.48(s，1H)，7.61(s，1H)，7.82(s，1H)，8.31(s，1H)，9.01(s，1H)；ESI-MS：m/z490.3[M+H] +。
The preparation of embodiment four: 1-(3-hydroxyl-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 4)
The preparation process of compound 4 is similar to the preparation method of compound 3.Adopt 4-hydroxy benzaldehyde and 3; 4-dimethoxyphenylacetic acid is starting raw material; 1-(3-hydroxyl-6 is obtained through alkylation, condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation, Deprotection; 7-dimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline (compound 4), yield 14.2%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.34(s，3H)，2.63-2.84(m，2H)，3.20-3.34(m，2H)，3.96(s，3H)，4.02(s，3H)，4.05(s，3H)，4.08(s，3H)，4.59(s，1H)，6.15(s，1H)，6.63(s，1H)，6.92-7.03(dd，1H，J 1=9.7，J 2=2.2)，7.48(s，1H)，7.62-7.64(d，1H，J 2=2.2)，7.82(s，1H)，8.30-8.33(d，1H，J=9.7)，9.13(s，1H)；ESI-MS：m/z459.9[M+H] +。
The preparation of embodiment five: 1-(2-hydroxyl-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 5)
The preparation process of compound 5 is similar to the preparation method of compound 3.Adopt 3-hydroxy benzaldehyde and 3; 4-dimethoxyphenylacetic acid is starting raw material; 1-(2-hydroxyl-6 is obtained through alkylation, condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation, Deprotection; 7-dimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline (compound 5), yield 13.1%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.35(s，3H)，2.62-2.63(t，1H)，2.85-2.88(d，1H)，3.25-3.26(d，1H)，3.50(s，1H)，3.93(s，3H)，4.02(s，3H)，4.07(s，3H)，4.08(s，3H)，4.63(s，1H)，6.22(s，1H)，6.59(s，1H)，6.72(s，1H)，7.03(s，1H)，7.48(s，1H)，7.55(s，1H)，7.58(s，1H)，8.01(s，1H)，8.87(s，1H)；ESI-MS：m/z460.4[M+H] +。
The preparation of embodiment six: 1-(3-hydroxyl-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 6)
The preparation process of compound 6 is similar to the preparation method of compound 3.Adopt Vanillin and 3; 4-dimethoxyphenylacetic acid is starting raw material; 1-(3-hydroxyl-2 is obtained through alkylation, condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation, Deprotection; 6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1; 2; 3,4-tetrahydroisoquinoline (compound 6), yield 11.8%. 1H-NMR(300MHz，CDCl3，ppm)δ：2.35(s，3H)，2.62-2.63(t，1H)，2.85-2.88(d，1H)，3.25-3.26(d，1H)，3.50(s，1H)，3.93(s，3H)，3.98(s，3H)，4.02(s，3H)，4.07(s，3H)，4.08(s，3H)，4.63(s，1H)，6.22(s，1H)，6.59(s，1H)，6.88(s，1H)，7.48(s，1H)，7.61(s，1H)，7.82(s，1H)，8.31(s，1H)，9.01(s，1H)；ESI-MS：m/z490.3[M+H] +。
The preparation of embodiment seven: 1-(3-isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 7)
The preparation process of compound 7 is similar to the preparation method of compound 3.By 4-hydroxy benzaldehyde (2.68g, 22mmol), Virahol (2.52mL, 33mmol) and triphenyl phosphorus (8.65g, 33mmol) be dissolved in 130mL tetrahydrofuran (THF), reaction solution is chilled to 0 DEG C, drip DIAD (6.6mL, 33mL), stirring at room temperature 2h, removes solvent under reduced pressure, residue by silicagel column chromatographic separation obtains yellow oil 2.69g, yield 78.5%.With obtained 4-isopropoxide benzaldehyde, 3; 4-dimethoxyphenylacetic acid is raw material; 1-(3-isopropoxy-6 is obtained through alkylation, condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation; 7-trimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 7).Total recovery: 13.2%. 1H-NMR(300MHz，CDCl3，ppm)δ：1.02(s，6H)，2.34(s，3H)，2.63-2.84(m，2H)，3.20-3.34(m，2H)，3.96(s，3H)，4.02(s，3H)，4.04(s，1H)，4.05(s，3H)，4.08(s，3H)，4.59(s，1H)，6.15(s，1H)，6.63(s，1H)，6.92-7.03(dd，1H，J 1=9.7，J 2=2.2)，7.48(s，1H)，7.62-7.64(d，1H，J 2=2.2)，8.30-8.33(d，1H，J=9.7)，9.13(s，1H)；ESI-MS：m/z502.0[M+H] +。
The preparation of embodiment eight: 1-(3-hydroxyl-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 8)
The preparation process of compound 8 is similar to the preparation method of compound 3.Adopt 4-hydroxy benzaldehyde and 3; 4; 5-trimethoxy phenyl acetic acid is starting raw material, obtains 1-(3-hydroxyl-5,6 through alkylation, condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation, Deprotection; 7-trimethoxy-9-phenanthryl)-N-methyl-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline (compound 8), yield 12.5%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.55(s，3H)，2.71-2.84(m，2H)，2.97-2.99(m，1H)，3.12-3.16(m，1H)，3.91(s，3H)，3.94(s，3H)，3.99(s，3H)，4.03(s，1H)，4.05(s，3H)，4.08(s，3H)，5.39(s，1H)，6.15(s，1H)，6.57(s，1H)，6.89(s，1H)，6.98(s，1H)，7.48(s，1H)，7.55(s，1H)，7.75(s，1H)，8.43(s，1H)，9.16(s，1H)；ESI-MS：m/z489.9[M+H] +。
The preparation of embodiment nine: 1-(3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 9)
The preparation process of compound 9 is similar to the preparation method of compound 1.Adopt 4-methoxybenzaldehyde and 3; 4,5-trimethoxy phenyl acetic acid is starting raw material, obtains 1-(3 through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation; 5; 6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1; 2; 3,4-tetrahydroisoquinoline (compound 9), yield 14.9%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.57(s，3H)，2.72-2.84(m，2H)，2.97-3.00(m，1H)，3.13-3.17(m，1H)，3.78(s，3H)，3.92(s，3H)，3.95(s，3H)，3.99(s，3H)，4.02(s，1H)，4.04(s，3H)，4.06(s，3H)，5.33(s，1H)，6.25(s，1H)，6.61(s，1H)，6.89(s，1H)，6.98(s，1H)，7.52(s，1H)，7.79(s，1H)，8.63(s，1H)，9.04(s，1H)；ESI-MS：m/z504.4[M+H] +。
The preparation of embodiment ten: 1-(3-methyl-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 10)
1H-NMR(300MHz，CDCl 3，ppm)δ：2.57(s，3H)，2.72-2.84(m，2H)，2.97-3.00(m，1H)，3.13-3.17(m，1H)，3.78(s，3H)，3.92(s，3H)，3.95(s，3H)，3.99(s，3H)，4.02(s，1H)，4.04(s，3H)，4.06(s，3H)，5.33(s，1H)，6.25(s，1H)，6.61(s，1H)，6.89(s，1H)，6.98(s，1H)，7.52(s，1H)，7.79(s，1H)，8.63(s，1H)，9.04(s，1H)；ESI-MS：m/z458.1[M+H] +。
The preparation of embodiment 11: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 11)
The preparation process of compound 11 is with the preparation method of compound 1.4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid is adopted to be starting raw material.Through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduce, obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
By 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.22g, 4.7mmol) is dissolved in 30mL acetone, under room temperature condition, add methyl iodide (0.29mL, 4.7mmol), Anhydrous potassium carbonate (0.78g, 5.7mmol), room temperature reaction 4h, TLC detection reaction completes.Add 0.3mL diethylamine, stirring at room temperature 1h, filtering insolubles, steaming desolventizes.Column chromatography purification, obtains 1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 11), total recovery 16.8%. 1H-NMR(300MHz，CDCl 3，ppm)δ：1.02(t，3H)，2.23(t，2H)，2.63-2.84(m，2H)，3.20-3.34(m，2H)，3.96(s，3H)，4.02(s，3H)，4.04(s，3H)，4.05(s，3H)，4.08(s，3H)，4.59(s，1H)，6.15(s，1H)，6.63(s，1H)，6.92-7.03(dd，1H，J 1=9.7，J 2=2.2)，7.48(s，1H)，7.62-7.64(d，1H，J 2=2.2)，8.30-8.33(d，1H，J=9.7)，9.13(s，1H)；ESI-MS：m/z488.6[M+H] +。
The preparation of embodiment 12: 1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 12)
The preparation process of compound 12 is with the preparation method of compound 1.4-methoxybenzaldehyde and 4-methoxyphenylacetic acid is adopted to be starting raw material.1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1 is obtained through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, alkylation; 2; 3,4-tetrahydroisoquinoline (compound 12), total recovery 16.4%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.25(s，3H)，2.62-2.70(m，1H)，2.80-2.85(d，1H)，3.19-3.24(m，2H)，4.03(s，3H)，4.06(s，3H)，4.52(s，1H)，6.15(s，1H)，6.62(s，1H)，7.20-7.23(dd，1H，J 1=8.7，J 2=2.4)，7.48(d，1H，J=9.1)，7.59-7.60(d，1H，J=2.4)，7.79-7.82(d，1H，J=8.7)，7.85-7.86(s，3H)；ESI-MS：m/z444.1[M+H] +。
The preparation of embodiment 13: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-hydrocinnamoyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 13)
The preparation process of compound 13 is with the preparation method of compound 1.4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid is adopted to be starting raw material.Through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduce, obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
The phenylalanine (0.26g, 1.00mmol) that N-Boc protects is dissolved in the methylene dichloride of 15mL drying, adds EDCI (0.29g, 1.5mmol), HOBt (0.2g, 1.5mmol), room temperature reaction 3.5h.1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxys-1 are added under ice bath, 2,3,4-tetrahydroisoquinoline (0.46g, 1.00mmol), DIEA (0.34mL, 2mmol), room temperature reaction 1.5h, add 3mL shrend and to go out reaction.Leave standstill, separatory.Organic layer saturated sodium bicarbonate washs once, saturated common salt water washing three times, anhydrous magnesium sulfate drying.Filtering siccative, removes solvent under reduced pressure, column chromatography purification.
Products therefrom is dissolved in 15mL methylene dichloride, adds 0.2mL trifluoroacetic acid, room temperature reaction 1h.Artificial tooth steams and desolventizes.Product column chromatography purification, obtains 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-hydrocinnamoyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 13).Total recovery: 10.5%. 1H-NMR(300MHz，CDCl3，ppm)δ：2.24(s，3H)，2.60-2.69(m，1H)，2.79-2.84(d，1H)，3.14-3.16(dd，1H，J 1=12.4，J 2=6.6)，3.17-3.23(m，2H)，3.19-3.21(dd，1H，J=12.4，J 2=6.6)，3.72(s，3H)，3.95-3.96(d，1H，J=6.6)，4.03(s，3H)，4.06(s，3H)，4.53(s，1H)，5.11(s，2H)，6.13(s，1H)，6.61(s，1H)，7.20-7.23(dd，1H，J 1=8.7，J 2=2.4)，7.26-7.45(m，3H)，7.53-7.59(m，3H)，7.61-7.82(m，3H)，7.93(s，1H)；ESI-MS：m/z607.4[M+H] +。
Embodiment 14: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxy phenyl)-propionyl)-6; 7-dimethoxy-1; the preparation of 2,3,4-tetrahydroisoquinoline (compound 14)
The preparation process of compound 14 is with the preparation method of compound 13.With the O-tertiary butyl-N-Boc-tyrosine, 1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline is starting raw material;-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxy phenyl)-propionyl)-6 is obtained through acidylate, deprotection; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 14).Total recovery: 8.8%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.24(s，3H)，2.60-2.69(m，1H)，2.79-2.84(d，1H)，3.14-3.16(dd，1H，J 1=12.4，J 2=6.6)，3.17-3.23(m，2H)，3.19-3.21(dd，1H，J=12.4，J2=6.6)，3.72(s，3H)，3.95-3.96(d，1H，J=6.6)，4.03(s，3H)，4.06(s，3H)，4.53(s，1H)，5.11(s，2H)，5.38(s，1H)，6.13(s，1H)，6.61(s，1H)，6.73-6.79(d，2H，J=9.7)，7.12-7.18(d，2H，J=9.7)，7.20-7.23(dd，1H，J 1=8.7，J 2=2.4)，7.58-7.63(m，3H)，8.46(s，1H)；ESI-MS：m/z623.3[M+H] +。
The preparation of embodiment 15: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-caproyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 15)
The preparation process of compound 15 is with the preparation method of compound 13.With N-two-Boc-Methionin, 1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline is starting raw material, obtains 1-(3,6 through acidylate, deprotection; 7-trimethoxy-9-phenanthryl)-N-((2S)-2; 6-diamino-caproyl)-6,7-dimethoxys-1,2; 3,4-tetrahydroisoquinoline (compound 15).Total recovery: 11.2%. 1H-NMR(300MHz，CDCl 3，ppm)δ：1.16(s，2H)，1.26-1.33(m，2H)，1.47-1.52(m，1H)，1.59-1.66(m，1H)，2.39-2.42(m，2H)，2.77-2.81(d，1H)，3.03-3.14(m，1H)，3.23-3.27(m，1H)，3.75-3.80(m，1H)，3.96(s，3H)，4.04(s，3H)，4.39(s，1H)，5.36(s，2H)，5.98-6.03(d，2H，J=15.0)，6.73(s，H)，6.90(s，2H)，7.20-7.23(dd，1H，J 1=2.1，J 2=8.7)，7.29(s，H)，7.33-7.35(d，1H，J=10.1)，7.38-7.43(t，2H)，7.54-7.56(d，2H，J=8.9)，7.65-7.68(d，1H，J=11.9)，7.70(s，4H)，8.08(s，1H)，8.15-8.16(d，1H，J=2.0)。ESI-MS：m/z588.1[M+H] +。
Embodiment 16: 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2; 6-diamino hydrochloride-caproyl)-6,7-dimethoxys-1,2; the preparation of 3,4-tetrahydroisoquinoline (compound 16)
The preparation process of compound 16 is with the preparation method of compound 13.With N-two-Boc-Methionin, 1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline is starting raw material, obtains 1-((R)-3,6 through acidylate, deprotection, salify; 7-trimethoxy-9-phenanthryl)-N-((2S)-2; 6-diamino hydrochloride-caproyl)-6,7-dimethoxys-1,2; 3,4-tetrahydroisoquinoline (compound 16).Total recovery: 5.3%. 1H-NMR(300MHz，CDCl 3，ppm)δ：1.16(s，2H)，1.26-1.33(m，2H)，1.47-1.52(m，1H)，1.59-1.66(m，1H)，2.39-2.42(m，2H)，2.77-2.81(d，1H)，3.03-3.14(m，1H)，3.23-3.27(m，1H)，3.75-3.80(m，1H)，3.96(s，3H)，4.04(s，3H)，4.39(s，1H)，5.36(s，2H)，5.98-6.03(d，2H，J=15.0)，6.73(s，H)，6.90(s，2H)，7.20-7.23(dd，1H，J 1=2.1，J 2=8.7)，7.29(s，H)，7.33-7.35(d，1H，J=10.1)，7.38-7.43(t，2H)，7.54-7.56(d，2H，J=8.9)，7.65-7.68(d，1H，J=11.9)，7.89(s，4H)，8.08(s，1H)，8.15-8.16(d，1H，J=2.0)，8.36(s，2H)。ESI-MS：m/z588.1[M+H] +，610.1[M+Na] +，1197.1[2M+Na] +。
Embodiment 17: 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl radicals)-6; 7-dimethoxy-1; the preparation of 2,3,4-tetrahydroisoquinoline (compound 17)
The preparation process of compound 16 is with the preparation method of compound 13.With N-Boc-(O-Bzl)-L-glutamic acid, 1-(3,6,7-trimethoxy-9-phenanthryl)-6; 7-dimethoxy-1,2,3; 4-tetrahydroisoquinoline is starting raw material; 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl radicals)-6 is obtained through acidylate, deprotection, salify; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (compound 17).Total recovery: 7.4%. 1H-NMR(300MHz，CDCl 3，ppm)δ：1.16(s，2H)，1.38-1.42(m，1H)，1.59-1.66(m，1H)，2.39-2.42(m，2H)，2.77-2.81(d，1H)，3.03-3.14(m，1H)，3.23-3.27(m，1H)，3.75-3.80(m，1H)，3.96(s，3H)，4.04(s，3H)，4.39(s，1H)，5.36(s，2H)，5.98-6.03(d，2H，J=15.0)，6.73(s，H)，6.90(s，2H)，7.20-7.23(dd，1H，J 1=2.1，J 2=8.7)，7.29(s，H)，7.33-7.35(d，1H，J=10.1)，7.38-7.43(t，2H)，7.54-7.56(d，2H，J=8.9)，7.65-7.68(d，1H，J=11.9)，7.70(s，4H)，8.08(s，1H)，8.15-8.16(d，1H，J=2.0)。ESI-MS：m/z589.5[M+H] +，611.5[M+Na] +。
The preparation of embodiment 18: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethanoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 18)
The preparation process of compound 18 is with the synthetic method of compound 1.4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid is adopted to be starting raw material.Through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
By 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.46g, 1mmol) is dissolved in 15mL acetone, adds Anhydrous potassium carbonate (0.17g, 1.2mmol), Acetyl Chloride 98Min. (0.08g, 1mmol), room temperature reaction 1.5h, filtering insolubles, concentrating under reduced pressure filtrate, gained solid column chromatography purification, obtains 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 18), total recovery 19.3%. 1H-NMR(300MHz，CDCl 3，ppm)δ：2.32(s，3H)，2.66-2.69(m，1H)，2.72-2.74(d，1H，J=7.4)，3.23-3.27(m，2H)，3.86(s，3H)，3.97(s，3H)，4.04(s，3H)，4.06(s，3H)，4.11(s，3H)，4.65(s，1H)，6.17(s，1H)，6.65(s，1H)，6.89-7.02(dd，1H，J 1=9.4，J 2=2.3)，7.48(s，1H)，7.54(s，1H)，7.62-7.63(d，1H，J 2=2.3)，7.79-7.80(d，1H，J 2=2.3)，8.33(s，1H)；ESI-MS：m/z502.2[M+H] +。
The preparation of embodiment 19: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 19)
The preparation process of compound 19 is with the synthetic method of compound 18.Adopt 4-methoxybenzaldehyde and 3; 4-dimethoxyphenylacetic acid is starting raw material; 1-(3 is obtained through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction, acylations; 6,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1; 2; 3,4-tetrahydroisoquinoline (compound 19), total recovery 18.8%.δ：2.65-2.68(m，1H)，2.82-2.85(d，1H，J=10.9)，3.24-3.35(m，2H)，3.75(s，3H)，4.03(s，3H)，4.04(s，3H)，4.06(s，3H)，4.08(s，3H)，4.53(s，1H)，6.15(s，1H)，6.62(s，1H)，6.92-7.03(dd，1H，J 1=9.7，J 2=2.2)，7.30-7.36(m，2H)，7.39-7.44(m，3H)，7.48(s，1H)，7.54(s，1H)，7.62-7.63(d，1H，J 2=2.2)，8.33(s，1H)；ESI-MS：m/z564.2[M+H] +。
The preparation of embodiment 20: 1-(3,6,7-trimethoxy-9-phenanthryl)-N-phenylethylamine base formyl radical-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 20)
The preparation process of compound 20 is with the synthetic method of compound 1.4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid is adopted to be starting raw material.Through condensation, esterification, coupling, hydrolysis, acidylate, cyclization, reduction 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
By 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxys-1,2,3,4-tetrahydroisoquinoline (0.46g, 1mmol), pyridine (0.21mL, 2.5mmol) are dissolved in 10mL methylene dichloride, under ice bath, drip the dichloromethane solution 10mL of phenyl chloroformate (0.17mL, 1.3mmol), drip Bi Jixu and keep 0 DEG C to react 3 hours, stopped reaction, be transferred to by reaction solution in separating funnel, add 50mL dchloromethane, organic layer washes three times, 5% salt pickling once, saturated NaHCO 3wash once, saturated common salt is washed once, anhydrous sodium sulfate drying.Concentrated, obtain yellow solid, purification by silica gel column chromatography, obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-N-benzene oxygen formyl radical-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 0.36g, yield 75.2%.
By 1-(3,6,7-trimethoxy-9-phenanthryl)-N-benzene oxygen formyl radical-6,7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline (0.36g; 0.75mmol), benzylamine (78mg, 0.75mmol) is dissolved in 5mL DMF; room temperature reaction 5 hours, stopped reaction, by reaction solution impouring frozen water; separate out pale solid, suction filtration, filter cake is washed; drying, crude product ethyl alcohol recrystallization obtains white solid 0.21g, total recovery 6.5%.δ：2.54-2.59(m，1H)，2.76-2.82(d，1H)，3.16-3.19(m，2H)，3.92(s，3H)，3.99(s，3H)，4.03(s，3H)，4.05(s，3H)，4.06(s，3H)，4.25(s，2H)，4.55(s，1H)，6.19(s，1H)，6.75(s，1H)，6.96-6.99(d，1H，J=8.4)，7.36-7.44(m，3H)，7.46(s，1H)，7.52-7.55(d，1H，J=7.3)，7.61(s，1H)，8.00(s，1H)，8.24-8.27(d，1H，J=8.8)，8.31(s，1H)，10.48(s，1H)；ESI-MS：m/z593.3[M+H] +。
Embodiment 21: extracorporeal anti-tumor cytoactive is tested
Experiment material used and reagent: human cervical carcinoma cell Hela, Proliferation of Human Ovarian Cell SKOV3 are provided by institute of Materia Medica,Chinese Academy of Medical Sciences pharmacological room old twilight teach problem group.People source tumor cell inoculation is in containing 10% foetal calf serum, and 100U/mL penicillin, in the RPMI1640 substratum of 100 μ g/mL Streptomycin sulphates, is placed in 37 DEG C by culturing bottle, and 5%CO2 saturated humidity incubator is cultivated, and every 1-2 days changes nutrient solution once.When Growth of Cells is to when being enough to the most surfaces covering bottle diapire, attached cell 0.25% tryptic digestion, goes down to posterity.
Mtt assay detects the impact on attached tumor cells growth: logarithmic phase cell cultures is in 96 well culture plates, and every hole 100 μ l (approximately containing 3000 tumour cells), puts 37 DEG C, cultivate in 5%CO2 incubator.Next day, administration group adds the compound containing different concns, and often kind of cell establishes 4 dosage groups (100 μm of ol/L, 10 μm of ol/L, 1 μm of ol/L, 0.1 μm of ol/L), often organizes and at least establishes three parallel holes.Control group adds solvent isopyknic with administration group, puts 37 DEG C, cultivates in 5%CO2 incubator.Abandon nutrient solution after 48 hours, every hole adds 50 μ l1mg/mL MTT solution (substratum preparation).Hatch 4 hours, abandon supernatant for 37 DEG C, every hole adds DMSO150 μ l and dissolves first hairpin particle, and gentle agitation dissolves.Under wavelength 490nm condition, optical density value (OD) is measured by microplate reader, with the cell of solvent control process for control group, with formulae discovery medicine the following to the inhibiting rate of cell, according to the inhibiting rate calculating each concentration, half-inhibition concentration (IC50) is calculated by Logit method, repeated test 3 times, averages as net result.
Inhibiting rate=(1-administration group mean OD value/control group mean OD value) × 100%
And make regression equation with the logarithm of compound concentration and inhibiting rate, calculate, show that most compounds has anti-tumor activity.
Inhibition Effects of Compoundson the Growth of Tumor Cells In Vitro

Claims (10)

1. the 1-of logical formula I replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative,
R=C 1-C 10alkyl, C 1-C 10alkyl acyl, C 6-C 12aryl-acyl, amino acid, amino acid salts, C 1-C 10alkyl or C 6-C 12aryl replaces amine formyl
R 1=H, C 1-C 10alkyl, C 1-C 10alkoxyl group; It replaces number is 1,2 or 3;
R 2=H, OH, C 1-C 10alkyl, C 1-C 10alkoxyl group, it replaces number is 1,2 or 3.
2. derivative according to claim 1, wherein
R=C 1-C 4alkyl, C 1-C 4alkyl acyl, C 6-C 12aryl-acyl, amino acid, amino acid salts, C 1-C 4alkyl or C 6-C 12aryl replaces amine formyl.
3. the derivative described in claim 1 or 2, wherein
R 1=H, C 1-C 4alkyl or C 1-C 4alkoxyl group, preferably: methoxyl group, oxyethyl group.
4. claim 1 or the derivative described in 2 or 3, wherein:
R 2=H, OH, C 1-C 4alkyl or C 1-C 4alkoxyl group, preferably: OH, OCH 3, OC 2h 5or OCH (CH 3) 2.
5. the derivative of claim 1-4 described in any one, wherein:
R=CH 3, C 2h 5, COCH 3, COPh, amino acid, amino acid salts, phenylethylamine formyl radical.
6. the derivative of claim 1-5 described in any one, wherein:
R 1, R 2=H, CH 3, OH, OCH 3, OC 2h 5or OCH (CH 3) 2.
7.1-replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative, is selected from:
1) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
2) 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
3) 1-(2-hydroxyl-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
4) 1-(3-hydroxyl-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
5) 1-(2-hydroxyl-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
6) 1-(3-hydroxyl-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
7) 1-(3-isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
8) 1-(3-hydroxyl-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
9) 1-(3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
10) 1-(2,6,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
11) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
12) 1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
13) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-hydrocinnamoyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
14) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxy phenyl)-propionyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines
15) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-caproyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
16) 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino hydrochloride-caproyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines
17) 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl radicals)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
18) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethanoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
19) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
20) 1-(3,6,7-trimethoxy-9-phenanthryl)-N-phenylethylamine base formyl radical-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
。
8. a 1-as claimed in claim 1 replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3, the preparation method of 4-tetrahydro isoquinoline derivative, it is characterized in that the toluylic acid adopting phenyl aldehyde and the replacement replaced is starting raw material, through condensation, esterification, coupling, hydrolysis, obtain the phenanthrenecarboxylic acid replaced; The phenanthrenecarboxylic acid and 3 replaced, 4 dimethoxy-phenylethylamines obtain corresponding compound through acidylate, cyclization, reduction, nitrogen atom (acylations).
9. a pharmaceutical composition, comprises the 1-of claim 1-7 described in any one and replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative.
10. the 1-of claim 1-8 described in any one replaces phenanthryl-N-alkyl (acyl group)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline derivative or composition according to claim 9 is preparing the application in antitumor drug.
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