WO2015090216A1 - 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative and manufacturing method thereof, pharmaceutical composition comprised thereof, and application thereof - Google Patents

6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative and manufacturing method thereof, pharmaceutical composition comprised thereof, and application thereof Download PDF

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Publication number
WO2015090216A1
WO2015090216A1 PCT/CN2014/094210 CN2014094210W WO2015090216A1 WO 2015090216 A1 WO2015090216 A1 WO 2015090216A1 CN 2014094210 W CN2014094210 W CN 2014094210W WO 2015090216 A1 WO2015090216 A1 WO 2015090216A1
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Prior art keywords
dimethoxy
tetrahydroisoquinoline
phenanthryl
compound
trimethoxy
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PCT/CN2014/094210
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French (fr)
Chinese (zh)
Inventor
赵冬梅
程卯生
宋帅
郝晨洲
冯岩
张祯
高禄华
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沈阳药科大学
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Publication of WO2015090216A1 publication Critical patent/WO2015090216A1/en

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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

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and relates to 1-substituted phenanthrenyl-N-alkyl(acyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and preparation method thereof , pharmaceutical compositions comprising the same, and uses thereof. Specifically, it relates to a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative having a substituted phenanthryl group at the 1-position, a preparation method thereof, a pharmaceutical composition comprising the same, and In medical applications.
  • a tumor is a mature or developing normal cell in the body. Under the influence of relevant factors, a new organism formed by excessive proliferation or abnormal differentiation usually forms a mass, hence the name tumor.
  • Tumors are divided into benign and malignant types. Malignant tumors, often called cancer, are common and frequently-occurring diseases that seriously threaten human health.
  • IARC International Agency for Research on Cancer
  • the 2008 World Cancer Report shows that by 2010, cancer will surpass cardiovascular and cerebrovascular diseases and become the number one killer of human beings; by 2030, the number of cancer patients worldwide will reach 75 million, the number of deaths It will reach 17 million.
  • cancer has become the leading cause of death.
  • the cancer death rate in China has increased by 29%. Therefore, the search for high-efficiency and low-toxic treatment of tumors is an important issue that medical and pharmaceutical researchers should urgently solve.
  • Tubulin inhibitors are an important class of anti-tumor drugs.
  • the anti-tumor drugs for clinical application of tubulin are mainly derived from natural plants such as paclitaxel and vinblastine, but these compounds are highly toxic and have low bioavailability. ,expensive.
  • Noscapine is an alkaloid with tetrahydroisoquinoline structure in opioids. It is clinically used for antitussive, no analgesic, sedative and respiratory depression, and does not cause euphoria or dependence.
  • the potential application prospects of tetrahydroisoquinoline natural products and derivatives thereof represented by narcotine in anti-tumor have also attracted attention.
  • the Joshi team discovered the anti-tumor activity of narcotine. Narcidine and its derivatives can act on microtubules, inhibiting their dynamic instability, thereby interfering with swelling The mitosis of tumor cells plays an anti-tumor effect.
  • narcotine and its derivatives are expected to be developed as a new class of anti-tumor drugs.
  • Combretastatin family is a promising anti-tumor compound, in which the compound Combretastatin A-4 (CA-4) has high antitumor activity, especially anti-drug resistance, high selectivity and low toxicity.
  • CA-4 is similar in structure to colchicine and can exert its activity when it is much smaller than its MTD (maximum tolerated dose), and can compete with colchicine for binding sites on tubulin.
  • MTD maximum tolerated dose
  • the object of the present invention is to provide a novel tetrahydroisoquinoline compound having good anti-tumor proliferation and migration invasive activity, in particular to a 6,7-dimethoxy-1,2 having a substituted phenanthryl group. 3,4-tetrahydroisoquinoline compounds and analogs thereof.
  • Another object of the present invention is to provide a process for producing the above-mentioned 1,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline compound having a substituted phenanthrenyl group and a derivative thereof.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier.
  • the invention provides a compound of formula (I),
  • R C 1 -C 10 alkyl, C 1 -C 10 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 10 alkyl or C 6 -C 12 aryl Substituted carbamoyl;
  • R 1 H, C 1 -C 10 alkyl or C 1 -C 10 alkoxy; the number of substitutions is 1, 2 or 3;
  • R 2 H,OH, C 1 -C 10 alkyl or C 1 -C 10 alkoxy, the number of substitutions being 1, 2 or 3, and in the presence of 2 or 3 R 2
  • Each R 2 may be the same or different from each other.
  • R C 1 -C 4 alkyl, C 1 -C 4 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 4 alkyl or C 6 -C 12 aryl substituted carbamoyl.
  • R 1 H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, preferably: methoxy or ethoxy.
  • R 2 H, OH, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, preferably: OH, OCH 3, OC 2 H 5 or OCH (CH 3) 2.
  • R CH 3, C 2 H 5, COCH 3, COPh, amino acid, amino acid salt, a formyl group or phenethylamine.
  • R 1 , R 2 H, CH 3 , OH, OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
  • the compound is selected from the group consisting of
  • the present invention provides a process for the preparation of a compound of the above formula (I), the process comprising:
  • R, R 1 and R 2 are as defined above.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above compound or pharmaceutical composition for the preparation of a medicament for antitumor.
  • the compound of the invention shows good activity in the anti-tumor experiment in vitro, has good physiological activity, has high research value in inhibiting tumor cell migration and invasion, and can be further developed into a novel anti-tumor. drug.
  • novel 1-substituted phenanthryl-N-alkyl(acyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative of the present invention has the following general formula (I) Structure:
  • R C 1 -C 10 alkyl, C 1 -C 10 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 10 alkyl or C 6 -C 12 aryl (The C 6 -C 12 aryl group herein encompasses a C 6 -C 12 aralkyl group such as benzyl) substituted carbamoyl;
  • R 1 H, C 1 -C 10 alkyl, or C 1 -C 10 alkoxy; the number of substitutions (ie, the number of R 1 ) is 1, 2 or 3;
  • R 2 H,OH, C 1 -C 10 alkyl, or C 1 -C 10 alkoxy, the number of substitutions (ie, the number of R 2 ) is 1, 2 or 3, and in the presence of 2 In the case of 3 or 3 R 2 , each R 2 may be the same or different from each other.
  • R C 1 -C 4 alkyl, C 1 -C 4 alkyl acyl, C 1 -C 4 aryl acyl, amino acid, amino acid salt, or C 1 -C 4 alkyl or C 6 -C 12 aryl Substituted carbamoyl group.
  • R 1 H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, more preferably: methoxy or ethoxy.
  • R 2 H, OH, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, more preferably from: OH, OCH 3, OC 2 H 5 or OCH (CH 3) 2.
  • R CH 3 , C 2 H 5 , COCH 3 , COCh, amino acid, amino acid salt, or phenethyl formyl group.
  • R 1 H, CH 3 , OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
  • R 2 H, CH 3 , OH, OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
  • Preferred compounds 1-20 of the invention have the following structure:
  • the compound of the formula (I) of the present invention is produced by the following method:
  • R, R 1 and R 2 are as defined above.
  • the preparation process of the compound 1 of the present invention is as follows:
  • the preparation process includes:
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde i.e., p-methoxybenzaldehyde
  • anisaldehyde i.e., p-methoxybenzaldehyde
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenylethylamine are acylated, cyclized, reduced, methylated to give 1-(3,6,7-trimethoxy) N--9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 1).
  • 3,4-Dimethoxyphenylacetic acid and 3,4-dimethoxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,4,6,7-tetramethoxy-9-phenanthronic acid.
  • 3,4,6,7-tetramethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(2,3,6 ,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 2), specific to each step
  • the reaction conditions are the same as or similar to those of the above compound 1.
  • 3,4-Dimethoxyphenylacetic acid and 4-isopropoxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed.
  • 3-isopropoxy-6,7-dimethoxy-9-phenanthic acid 3-(isopropoxy-6,7-dimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(3- Isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 7)
  • the specific reaction conditions of each step are the same as or similar to those of the above compound 1.
  • the preparation process of the compound 8 of the present invention is as follows:
  • the 3,5,5-trimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,5,6,7-trimethoxy-9-phenanthronic acid.
  • 3,5,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(3,5,6, 7-Tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 9), specific reaction of each step
  • the conditions are the same as or similar to those of the above compound 1.
  • the preparation process of the compound 10 of the present invention is as follows:
  • 3,4-Dimethoxyphenylacetic acid and 3-methoxy-4-methylbenzaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 2,6,7-trimethoxy-3-methyl-9 - phenamic acid.
  • 2,6,7-trimethoxy-3-methyl-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(2,6 ,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 10),
  • the specific reaction conditions of each step are the same as or similar to those of the above compound 1.
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and ethylated to give 1-(3,6,7-trimethoxy) Benzyl-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 11), specific reaction conditions of each step and the above compound 1 The same or similar, wherein the ethylation reaction process is as follows:
  • the preparation process of the compound 12 of the present invention is as follows:
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and finally 1-(3,6 , 7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and tert-butoxycarbonyl protected S-phenylalanine Acylation and deprotection to give 1-(3,6,7-trimethoxy-9-phenanthryl)-N
  • the preparation process of the compound 14 of the present invention is as follows:
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and finally 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and protecting group protected S-tyrosine The acid is acylated and deprotected to give 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)
  • the preparation process of the compound 15 of the present invention is as follows:
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and the final reaction is 1-(3) ,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and tert-butoxycarbonyl protected S-lysine The acylation and deprotection reactions take place to obtain 1-(3,6,7-trimethoxy-9-phenanth
  • the preparation process of the compound 16 of the present invention is as follows:
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
  • the specific reaction conditions of each step are the same or similar to those of the above compound 1, and the final reaction is 1-(3) ,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and tert-butoxycarbonyl protected S-lysine Acylation, deprotection, and salt formation occur to give 1-((R)-3,6,7- Trimeth
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and the final reaction is 1-(3) , 6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is acylated with protecting group-protected S-glutamic acid , deprotection, salt formation, to give 1-((R)-3,6,7-trimethoxy-9
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and finally acetylated to give 1-(3,6,7-trimethoxy) -9-phenanthryl)-N-acetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 18), specific reaction conditions of each step and the above compound 1 The same or similar, the final reaction process is:
  • the preparation process of the compound 20 of the present invention is as follows:
  • 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid.
  • 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and finally acylated and substituted to obtain 1-(3,6, 7-Trimethoxy-9-phenanthryl)-N-benzylaminoformyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 20), each step
  • the specific reaction conditions are the same as or similar to those of the above compound 1, and the final reaction process is:
  • the 1-substituted phenanthryl-N-alkyl(acyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative of the present invention has an in vitro antitumor experiment,
  • the compound of the invention shows good activity and has good physiological activity; and has high research value in inhibiting migration and invasion of tumor cells, and can be further developed into a novel anti-tumor drug.
  • N-(3,4-dimethoxyphenethyl)-3,6,7-trimethoxy 9-phenanthamide (11.5 g, 24 mmol) was dispersed in 120 mL of ethylene glycol under argon atmosphere.
  • ether DME
  • POCl 3 the disposable added phosphorus oxychloride
  • the reaction was heated at reflux for 3.5h, TCL reaction was complete.
  • Most of the solvent was distilled off, 30 mL of toluene was added, and the solvent was evaporated in vacuo. The above operation was repeated three times to obtain a brown oil which was directly subjected to the next reaction without purification.
  • the preparation process of the compound 2 is the same as the preparation method of the compound 1, in which 3,4-dimethoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid are used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl- 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 2), total yield 17.2%.
  • the preparation process of compound 3 is similar to the preparation method of compound 2, in which 3-hydroxy-4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid are used as starting materials, and condensation, esterification and coupling are carried out. , hydrolysis, acylation, cyclization, reduction, alkylation, deprotection to give 1-(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7- Dimethoxy-1,2,3,4-tetrahydroisoquinoline.
  • the preparation process of Compound 4 is similar to the preparation method of Compound 3. Using 4-hydroxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, deprotection are obtained. -(3-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 4), the yield was 14.2%.
  • the preparation process of Compound 5 is similar to the preparation method of Compound 3. Using 3-hydroxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, deprotection are obtained. -(2-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 5), the yield was 13.1%.
  • the preparation process of Compound 6 is similar to the preparation method of Compound 3. Using 3-methoxy-4-hydroxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation Deprotection group gives 1-(3-hydroxy-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4- Tetrahydroisoquinoline (Compound 6), yield 11.8%.
  • Example 7 1-(3-Isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4- Preparation of tetrahydroisoquinoline (compound 7)
  • the preparation process of Compound 7 is similar to the preparation method of Compound 1.
  • 4-hydroxybenzaldehyde (2.68 g, 22 mmol), isopropanol (2.52 mL, 33 mmol) and triphenylphosphine (PPh 3 ) (8.65 g, 33 mmol) were dissolved in 130 mL of tetrahydrofuran (THF) and the reaction was cooled to At 0 ° C, diethyl azodicarboxylate (DIAD) (6.6 mL, 33 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. %.
  • DIAD diethyl azodicarboxylate
  • Example 8 1-(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetra Preparation of hydrogen isoquinoline (compound 8)
  • the preparation process of Compound 8 is similar to the preparation method of Compound 3. Using 4-hydroxybenzaldehyde and 3,4,5-trimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation and deprotection are obtained. 1-(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 8), yield 12.5%.
  • the preparation process of Compound 9 is similar to the preparation method of Compound 1. Using 4-methoxybenzaldehyde and 3,4,5-trimethoxyphenylacetic acid as starting materials, after condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, 1- (3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 9 ), the yield was 14.9%.
  • Example 10 1-(3-Methyl-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Preparation of isoquinoline (compound 10)
  • the preparation process of Compound 10 is similar to the preparation method of Compound 1. Using 3,4-dimethoxyphenylacetic acid and 3-methoxy-4-methylbenzaldehyde as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, methylation To give 1-(2,6,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Isoquinoline (Compound 10).
  • the preparation process of Compound 11 is similar to the preparation method of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinoline.
  • the preparation process of Compound 12 is similar to the preparation method of Compound 1. 4-methoxybenzaldehyde and 4-methoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation to give 1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7- Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 12), total yield 16.4%.
  • the preparation process of Compound 13 is similar to the preparation method of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinoline.
  • N-Boc-protected phenylalanine (0.26 g, 1.00 mmol) was dissolved in 15 mL of dry dichloromethane, EDCI (0.29 g, 1.5 mmol), HOBt (0.2 g, 1.5 mmol) .
  • EDCI EDCI
  • HOBt 0.2 g, 1.5 mmol
  • 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.46 g, 1.00) under ice bath Methyl acetate (0.34 mL, 2 mmol) was reacted at room temperature for 1.5 h. Allow to stand and dispense. The organic layer was washed once with saturated aqueous sodium The desiccant was filtered off, the solvent was evaporated under reduced pressure and purified by column chromatography.
  • Example 14 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxyphenyl)-propanoyl)-6 Of 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 14)
  • the preparation process of Compound 14 is similar to the preparation of Compound 13.
  • 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials.
  • the preparation process of Compound 15 is similar to the preparation method of Compound 13.
  • 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials.
  • the preparation process of Compound 16 is similar to the preparation of Compound 13.
  • 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials.
  • the preparation process of Compound 16 is similar to the preparation of Compound 13.
  • 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials.
  • the preparation process of Compound 18 is similar to the synthesis of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinoline.
  • Compound 19 was similar to the synthesis of Compound 18. Using 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, after condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction, 1-(3,6, 7-Trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, which is acylated with benzoyl chloride to give 1-(3,6 ,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 19), total yield 18.8 %.
  • the preparation process of Compound 20 is similar to the synthesis of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction of 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline.
  • Example 21 In vitro anti-tumor cell activity test
  • human cervical cancer cell Hela and human breast cancer cell MCF-7 were provided by the research group of Professor Chihiro Ikeda of Shenyang Pharmaceutical University.
  • the above ten tumor cells were inoculated into RPMI 1640 medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, and the culture flask was placed in a 37 ° C, 5% CO 2 saturated humidity incubator. Every 1-2 days Change the culture solution once. When the cells were grown to cover most of the surface of the bottom wall of the bottle, the adherent cells were digested with 0.25% trypsin and passaged.
  • thiazole blue (MTT) colorimetric assay on the growth of adherent tumor cells: logarithmic growth phase cells cultured in 96-well culture plates, 100 ⁇ l per well (approximately 3000 tumor cells), placed at 37 ° C, 5% Culture in a CO2 incubator.
  • the drug-administered group was added with different concentrations of the compound 1-20 of the present invention, and each cell was set in four dose groups (100 ⁇ mol/L, 10 ⁇ mol/L, 1 ⁇ mol/L, 0.1 ⁇ mol/L), and each group was set at least. Three parallel holes.
  • the control group was added with an equal volume of solvent in the administration group, and cultured at 37 ° C in a 5% CO 2 incubator.
  • the inhibition rate of the drug on the cells was calculated by the following formula, and the inhibition rate of each concentration was calculated according to the calculation, and the Logit method was used.
  • the half-inhibitory concentration (IC 50 ) was calculated, and the test was repeated 3 times, and the average was taken as the final result.
  • the regression equation was calculated by the logarithm of the concentration of the compound and the inhibition rate. The calculations showed that all the compounds had antitumor activity, and the activity of the compound 14 was the best.

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Abstract

Disclosed in the present invention is a formula (I) compound and manufacturing method thereof, pharmaceutical composition comprised thereof, and application thereof, wherein R, R1 and R2 are as defined herein. The compound set forth in the present invention shows good activity in in-vitro anti-tumour tests, and has good physiological activity.

Description

6，7-二甲氧基-1，2，3，4-四氢异喹啉衍生物及其制备方法、包含其的药物组合物及它们的用途6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative, preparation method thereof, pharmaceutical composition containing the same, and use thereof 技术领域Technical field
本发明属于药物合成领域，涉及1-取代菲基-N-烷基(酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉衍生物及其制备方法、包含其的药物组合物及它们的用途。具体涉及一种在1位具有取代菲基的6，7-二甲氧基-1，2，3，4-四氢异喹啉衍生物，及其制备方法、包含其的药物组合物及它们在医学上的应用。The invention belongs to the field of pharmaceutical synthesis, and relates to 1-substituted phenanthrenyl-N-alkyl(acyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and preparation method thereof , pharmaceutical compositions comprising the same, and uses thereof. Specifically, it relates to a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative having a substituted phenanthryl group at the 1-position, a preparation method thereof, a pharmaceutical composition comprising the same, and In medical applications.
背景技术Background technique
肿瘤是机体中成熟的或在发展中的正常细胞，在有关因素的作用下，呈现过度增生或异常分化而形成的新生物，通常形成肿块，故名肿瘤。肿瘤分为良性和恶性两类，恶性肿瘤常称为癌症，是一种严重威胁人类健康的常见病、多发病。现今，癌症已成为全世界第二位的致死病因，2007年，大约有760万人死于癌症，占全球死亡病人的13％。国际癌症研究机构(IARC)发布的最新报告《2008世界癌症报告》显示，到2010年，癌症将超越心脑血管疾病，成为人类头号杀手；到2030年，全球癌症患者将达7500万，死亡人数将达1700万。在我国，癌症已成为第一位的致死病因，近20年来我国的癌症死亡率上升了29％。因此，寻找高效低毒的***的方法是当前医学及药学科研工作者应迫切解决的重要问题。A tumor is a mature or developing normal cell in the body. Under the influence of relevant factors, a new organism formed by excessive proliferation or abnormal differentiation usually forms a mass, hence the name tumor. Tumors are divided into benign and malignant types. Malignant tumors, often called cancer, are common and frequently-occurring diseases that seriously threaten human health. Today, cancer has become the second leading cause of death in the world. In 2007, approximately 7.6 million people died of cancer, accounting for 13% of the world's dead. According to the latest report released by the International Agency for Research on Cancer (IARC), the 2008 World Cancer Report shows that by 2010, cancer will surpass cardiovascular and cerebrovascular diseases and become the number one killer of human beings; by 2030, the number of cancer patients worldwide will reach 75 million, the number of deaths It will reach 17 million. In China, cancer has become the leading cause of death. In the past 20 years, the cancer death rate in China has increased by 29%. Therefore, the search for high-efficiency and low-toxic treatment of tumors is an important issue that medical and pharmaceutical researchers should urgently solve.
微管蛋白抑制剂是一类重要的抗肿瘤药物，临床应用的作用于微管蛋白的抗肿瘤药物主要来源于天然植物，如紫杉醇类和长春碱类，但这些化合物毒性大、生物利用度低、价格昂贵。Tubulin inhibitors are an important class of anti-tumor drugs. The anti-tumor drugs for clinical application of tubulin are mainly derived from natural plants such as paclitaxel and vinblastine, but these compounds are highly toxic and have low bioavailability. ,expensive.
那可丁(noscapine)是阿片中具有四氢异喹啉结构的生物碱，临床用于镇咳，无镇痛、镇静和呼吸抑制等特性，也不使人产生欣快感或依赖性。近年来，以那可丁为代表的四氢异喹啉天然产物及其衍生物在抗肿瘤方面的潜在应用前景也吸引了人们的注目。在对秋水仙碱相似结构化合物的随机抗肿瘤作用筛选过程中，Joshi研究小组发现了那可丁的抗肿瘤活性。那可丁及其衍生物可作用于微管，抑制其动态不稳定性，从而干扰肿 瘤细胞的有丝***，起到抗肿瘤作用。它们具有抗肿瘤活性作用明显、毒副作用小、广谱、作用机制独特、口服吸收好、方便、安全、衍生物多等特点，具有广泛的开发空间。因此那可丁及其衍生物有望被开发为新一类抗肿瘤药物。Noscapine is an alkaloid with tetrahydroisoquinoline structure in opioids. It is clinically used for antitussive, no analgesic, sedative and respiratory depression, and does not cause euphoria or dependence. In recent years, the potential application prospects of tetrahydroisoquinoline natural products and derivatives thereof represented by narcotine in anti-tumor have also attracted attention. In the screening of random anti-tumor effects of similar structural compounds of colchicine, the Joshi team discovered the anti-tumor activity of narcotine. Narcidine and its derivatives can act on microtubules, inhibiting their dynamic instability, thereby interfering with swelling The mitosis of tumor cells plays an anti-tumor effect. They have obvious anti-tumor activity, small toxic and side effects, broad spectrum, unique mechanism of action, good oral absorption, convenience, safety, and many derivatives. They have extensive development space. Therefore, narcotine and its derivatives are expected to be developed as a new class of anti-tumor drugs.
天然产物Combretastatin家族是一类具有广阔前景的抗肿瘤化合物，其中化合物Combretastatin A-4(CA-4)因其具有高效的抗肿瘤活性，特别是抗耐药肿瘤活性、高选择性、低毒性而成为研究热点。CA-4与秋水仙碱结构相似，能在远小于其MTD(最大耐受剂量)时即可发挥活性作用，可与秋水仙碱竞争微管蛋白上的结合位点。一系列的构效关系研究表明，该产品属于秋水仙碱样微管组装抑制剂，而非长春碱类。The natural product Combretastatin family is a promising anti-tumor compound, in which the compound Combretastatin A-4 (CA-4) has high antitumor activity, especially anti-drug resistance, high selectivity and low toxicity. Become a research hotspot. CA-4 is similar in structure to colchicine and can exert its activity when it is much smaller than its MTD (maximum tolerated dose), and can compete with colchicine for binding sites on tubulin. A series of studies on structure-activity relationships have shown that this product belongs to colchicine-like microtubule assembly inhibitors, rather than vinblastine.
随着全球肿瘤患者的不断增加，开发新的具有较高的药理活性、疗效确切的抗肿瘤药物以适应临床的需要将是药物研发的一个必然趋势。With the increasing number of cancer patients worldwide, it is an inevitable trend to develop new anti-tumor drugs with high pharmacological activity and curative effect to meet clinical needs.
发明内容Summary of the invention
本发明的目的是提供具有良好的抗肿瘤增殖及迁移侵袭活性的新型四氢异喹啉类化合物，具体涉及一种1位具有取代菲基的6，7-二甲氧基-1，2，3，4-四氢异喹啉类化合物及其类似物。The object of the present invention is to provide a novel tetrahydroisoquinoline compound having good anti-tumor proliferation and migration invasive activity, in particular to a 6,7-dimethoxy-1,2 having a substituted phenanthryl group. 3,4-tetrahydroisoquinoline compounds and analogs thereof.
本发明的另一目的是提供上述1位具有取代菲基的6，7-二甲氧基-1，2，3，4-四氢异喹啉类化合物及其衍生物的制备方法。Another object of the present invention is to provide a process for producing the above-mentioned 1,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline compound having a substituted phenanthrenyl group and a derivative thereof.
本发明的另一目的是提供包含上述化合物和药用载体的药物组合物。Another object of the present invention is to provide a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier.
在一方面，本发明提供通式(I)的化合物，In one aspect, the invention provides a compound of formula (I),
Figure PCTCN2014094210-appb-000001
Figure PCTCN2014094210-appb-000001
R＝C1-C10烷基，C1-C10烷基酰基，C6-C12芳基酰基，氨基酸，氨基酸盐，或者被C1-C10烷基或C6-C12芳基取代的胺甲酰基；R=C 1 -C 10 alkyl, C 1 -C 10 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 10 alkyl or C 6 -C 12 aryl Substituted carbamoyl;
R1＝H，C1-C10烷基或C1-C10烷氧基；其取代个数为1个、2个或3个； R 1 =H, C 1 -C 10 alkyl or C 1 -C 10 alkoxy; the number of substitutions is 1, 2 or 3;
R2＝H，OH，C1-C10烷基或C1-C10烷氧基，其取代个数为1个、2个或3个，并且在存在2个或3个R2的情况下，各个R2可以彼此相同或不同。R 2 =H,OH, C 1 -C 10 alkyl or C 1 -C 10 alkoxy, the number of substitutions being 1, 2 or 3, and in the presence of 2 or 3 R 2 Each R 2 may be the same or different from each other.
在一个优选实施方案中，R＝C1-C4烷基，C1-C4烷基酰基，C6-C12芳基酰基，氨基酸，氨基酸盐，或者被C1-C4烷基或C6-C12芳基取代的胺甲酰基。In a preferred embodiment, R = C 1 -C 4 alkyl, C 1 -C 4 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 4 alkyl or C 6 -C 12 aryl substituted carbamoyl.
在一个优选实施方案中，R1＝H，C1-C4烷基或C1-C4烷氧基，优选：甲氧基或乙氧基。In a preferred embodiment, R 1 =H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, preferably: methoxy or ethoxy.
在一个优选实施方案中，R2＝H，OH，C1-C4烷基或C1-C4烷氧基，优选：OH、OCH3，OC2H5或OCH(CH3)2。In a preferred embodiment, R 2 = H, OH, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, preferably: OH, OCH 3, OC 2 H 5 or OCH (CH 3) 2.
在一个优选实施方案中，R＝CH3，C2H5，COCH3，COPh，氨基酸，氨基酸盐，或苯乙胺甲酰基。In a preferred embodiment, R = CH 3, C 2 H 5, COCH 3, COPh, amino acid, amino acid salt, a formyl group or phenethylamine.
在一个优选实施方案中，R1、R2＝H，CH3，OH，OCH3，OC2H5或OCH(CH3)2。In a preferred embodiment, R 1 , R 2 = H, CH 3 , OH, OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
在一个优选实施方案中，所述化合物选自：In a preferred embodiment, the compound is selected from the group consisting of
1-(3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(2，3，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(2-羟基-3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ;
1-(3-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(2-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(3-羟基-2，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-hydroxy-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ;
1-(3-异丙氧基-6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-Isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Porphyrin
1-(3-羟基-5，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉； 1-(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ;
1-(3，5，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(2，6，7-三甲氧基-3-甲基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2,6,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Porphyrin
1-(3，6，7-三甲氧基-9-菲基)-N-乙基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(3，6-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-苯丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-phenylpropionyl)-6,7-dimethoxy-1,2,3, 4-tetrahydroisoquinoline;
1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-3-(4-羟基苯基)-丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxyphenyl)-propionyl)-6,7-dimethyl Oxy-1,2,3,4-tetrahydroisoquinoline;
1-(3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-hexanoyl)-6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline;
1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基盐酸盐-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diaminohydrochloride-hexanoyl)-6,7-dimethyl Oxy-1,2,3,4-tetrahydroisoquinoline;
1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-4-羧酸钠盐-丁酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl)-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline;
1-(3，6，7-三甲氧基-9-菲基)-N-乙酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-acetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(3，6，7-三甲氧基-9-菲基)-N-苯甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；或1-(3,6,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
1-(3，6，7-三甲氧基-9-菲基)-N-苯乙胺基甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉。1-(3,6,7-trimethoxy-9-phenanthryl)-N-phenylethylaminoformyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline .
在另一方面，本发明提供一种上述通式(I)的化合物的制备方法，所述方法包括：In another aspect, the present invention provides a process for the preparation of a compound of the above formula (I), the process comprising:
(a)以下式的取代苯乙酸与下式的取代苯甲醛为起始原料，经缩合、酯化、偶联、水解得到取代的菲甲酸；然后该取代的菲甲酸与3，4二甲氧基苯乙胺经酰化、环合、还原得到下式的四氢异喹啉衍生物；最后使该四氢异喹啉衍生物经由烷基化和/或酰化以及任选的脱保护或成盐反应使该四氢异喹啉化合物的N原子上连接R基团从而得到所述式(I)的化合物； (a) a substituted phenylacetic acid of the following formula and a substituted benzaldehyde of the following formula as a starting material, which are subjected to condensation, esterification, coupling, hydrolysis to obtain a substituted phenanthrenecarboxylic acid; then the substituted phenanthrenecarboxylic acid and 3,4 dimethoxy Acylation, cyclization, reduction of phenylethylamine to give a tetrahydroisoquinoline derivative of the formula; finally, the tetrahydroisoquinoline derivative is subjected to alkylation and/or acylation and optionally deprotection or a salt-forming reaction to attach an R group to the N atom of the tetrahydroisoquinoline compound to obtain the compound of the formula (I);
Figure PCTCN2014094210-appb-000002
Figure PCTCN2014094210-appb-000002
(b)直接以上述步骤(a)中的四氢异喹啉衍生物作为原料，经由烷基化和/或酰化以及任选的脱保护或成盐反应使该四氢异喹啉衍生物的N原子上连接R基团，从而得到所述式(I)的化合物，(b) directly using the tetrahydroisoquinoline derivative in the above step (a) as a raw material, and subjecting the tetrahydroisoquinoline derivative via alkylation and/or acylation and optionally deprotection or salt formation reaction The R group is attached to the N atom to obtain the compound of the formula (I),
其中R、R1和R2如上所定义。Wherein R, R 1 and R 2 are as defined above.
在另一方面，本发明提供一种药物组合物，其包含上述化合物和药用载体。In another aspect, the invention provides a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier.
在另一方面，本发明提供上述化合物或药物组合物在制备用于抗肿瘤的药物中的应用。In another aspect, the present invention provides the use of the above compound or pharmaceutical composition for the preparation of a medicament for antitumor.
本发明所述的化合物在体外抗肿瘤实验中显示了良好的活性，具有较好的生理活性；在抑制肿瘤细胞迁移、侵袭方面，具有较高的研究价值，可进一步研制开发为新型的抗肿瘤药物。The compound of the invention shows good activity in the anti-tumor experiment in vitro, has good physiological activity, has high research value in inhibiting tumor cell migration and invasion, and can be further developed into a novel anti-tumor. drug.
具体实施方式detailed description
本发明的新型1-取代菲基-N-烷基(酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉衍生物具有下述通式(I)的结构： The novel 1-substituted phenanthryl-N-alkyl(acyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative of the present invention has the following general formula (I) Structure:
Figure PCTCN2014094210-appb-000003
Figure PCTCN2014094210-appb-000003
其中among them
R＝C1-C10烷基，C1-C10烷基酰基，C6-C12芳基酰基，氨基酸，氨基酸盐，或者被C1-C10烷基或C6-C12芳基(本文中的C6-C12芳基涵盖C6-C12芳烷基如苄基)取代的胺甲酰基；R=C 1 -C 10 alkyl, C 1 -C 10 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 10 alkyl or C 6 -C 12 aryl (The C 6 -C 12 aryl group herein encompasses a C 6 -C 12 aralkyl group such as benzyl) substituted carbamoyl;
R1＝H，C1-C10烷基，或C1-C10烷氧基；其取代个数(即R1的数量)为1个、2个或3个；R 1 =H, C 1 -C 10 alkyl, or C 1 -C 10 alkoxy; the number of substitutions (ie, the number of R 1 ) is 1, 2 or 3;
R2＝H，OH，C1-C10烷基，或C1-C10烷氧基，其取代个数(即R2的数量)为1个、2个或3个，并且在存在2个或3个R2的情况下，各个R2可以彼此相同或不同。R 2 =H,OH, C 1 -C 10 alkyl, or C 1 -C 10 alkoxy, the number of substitutions (ie, the number of R 2 ) is 1, 2 or 3, and in the presence of 2 In the case of 3 or 3 R 2 , each R 2 may be the same or different from each other.
其中优选：Among them:
R＝C1-C4烷基，C1-C4烷基酰基，C1-C4芳基酰基，氨基酸，氨基酸盐，或者被C1-C4烷基或C6-C12芳基取代的胺甲酰基。R=C 1 -C 4 alkyl, C 1 -C 4 alkyl acyl, C 1 -C 4 aryl acyl, amino acid, amino acid salt, or C 1 -C 4 alkyl or C 6 -C 12 aryl Substituted carbamoyl group.
R1＝H，C1-C4烷基或C1-C4烷氧基，更优选：甲氧基或乙氧基。R 1 =H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, more preferably: methoxy or ethoxy.
R2＝H，OH，C1-C4烷基或C1-C4烷氧基，更优选：OH、OCH3，OC2H5或OCH(CH3)2。 R 2 = H, OH, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, more preferably from: OH, OCH 3, OC 2 H 5 or OCH (CH 3) 2.
更优选：More preferably:
R＝CH3，C2H5，COCH3，COPh，氨基酸，氨基酸盐，或苯乙胺甲酰基。R = CH 3 , C 2 H 5 , COCH 3 , COCh, amino acid, amino acid salt, or phenethyl formyl group.
R1＝H，CH3，OCH3，OC2H5或OCH(CH3)2。R 1 =H, CH 3 , OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
R2＝H，CH3，OH，OCH3，OC2H5或OCH(CH3)2。 R 2 = H, CH 3 , OH, OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
本发明优选的化合物1-20具有以下的结构：Preferred compounds 1-20 of the invention have the following structure:
Figure PCTCN2014094210-appb-000004
Figure PCTCN2014094210-appb-000004
Figure PCTCN2014094210-appb-000005
Figure PCTCN2014094210-appb-000005
本发明的通式(I)的化合物通过下述方法制备：The compound of the formula (I) of the present invention is produced by the following method:
(a)以下式的取代苯乙酸与下式的取代苯甲醛为起始原料，经缩合、酯化、偶联、水解得到取代的菲甲酸；然后该取代的菲甲酸与3，4二甲氧基苯乙胺经酰化、环合、还原得到下式的四氢异喹啉衍生物；最后使该四氢异喹啉衍生物经由烷基化和/或酰化以及任选的脱保护或成盐反应使该四氢异喹啉化合物的N原子上连接R基团从而得到所述式(I)的化合物； (a) a substituted phenylacetic acid of the following formula and a substituted benzaldehyde of the following formula as a starting material, which are subjected to condensation, esterification, coupling, hydrolysis to obtain a substituted phenanthrenecarboxylic acid; then the substituted phenanthrenecarboxylic acid and 3,4 dimethoxy Acylation, cyclization, reduction of phenylethylamine to give a tetrahydroisoquinoline derivative of the formula; finally, the tetrahydroisoquinoline derivative is subjected to alkylation and/or acylation and optionally deprotection or a salt-forming reaction to attach an R group to the N atom of the tetrahydroisoquinoline compound to obtain the compound of the formula (I);
Figure PCTCN2014094210-appb-000006
Figure PCTCN2014094210-appb-000006
(b)直接以上述步骤(a)中的四氢异喹啉衍生物作为原料，经由烷基化和/或酰化以及任选的脱保护或成盐反应使该四氢异喹啉衍生物的N原子上连接R基团，从而得到所述式(I)的化合物，(b) directly using the tetrahydroisoquinoline derivative in the above step (a) as a raw material, and subjecting the tetrahydroisoquinoline derivative via alkylation and/or acylation and optionally deprotection or salt formation reaction The R group is attached to the N atom to obtain the compound of the formula (I),
其中R、R1和R2如上所定义。Wherein R, R 1 and R 2 are as defined above.
例如，本发明化合物1的制备过程如下：For example, the preparation process of the compound 1 of the present invention is as follows:
Figure PCTCN2014094210-appb-000007
Figure PCTCN2014094210-appb-000007
具体地，制备工艺包括：Specifically, the preparation process includes:
3，4-二甲氧基苯乙酸和茴香醛(即对甲氧基苯甲醛)经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化得到1-(3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物1)。3,4-Dimethoxyphenylacetic acid and anisaldehyde (i.e., p-methoxybenzaldehyde) are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthronic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenylethylamine are acylated, cyclized, reduced, methylated to give 1-(3,6,7-trimethoxy) N--9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 1).
本发明化合物2的制备过程如下：The preparation process of the compound 2 of the present invention is as follows:
Figure PCTCN2014094210-appb-000008
Figure PCTCN2014094210-appb-000008
(本文中的8个步骤即为缩合、酯化、偶联、水解以及酰化、环合、还原、甲基化反应)(The eight steps in this article are condensation, esterification, coupling, hydrolysis, and acylation, cyclization, reduction, methylation)
3，4-二甲氧基苯乙酸和3，4-二甲氧基苯甲醛经缩合、酯化、偶联、水解得到3，4，6，7-四甲氧基-9-菲甲酸。3，4，6，7-四甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化得到1-(2，3，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物2)，各步的具体反应条件与上述化合物1的相同或类似。3,4-Dimethoxyphenylacetic acid and 3,4-dimethoxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,4,6,7-tetramethoxy-9-phenanthronic acid. 3,4,6,7-tetramethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(2,3,6 ,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 2), specific to each step The reaction conditions are the same as or similar to those of the above compound 1.
本发明化合物3的制备过程如下：The preparation process of the compound 3 of the present invention is as follows:
3，4-二甲氧基苯乙酸和3-苄氧基4-甲氧基苯甲醛经缩合、酯化、偶联、水解得到2-苄氧基-3，6，7-三甲氧基-9-菲甲酸。2-苄氧基-3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化，最后脱保护得到1-(2-羟基-3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物3)，各步的具体反应条件与上述化合物1的相同或类似，该脱保护的反应过程为如下： 3,4-Dimethoxyphenylacetic acid and 3-benzyloxy 4-methoxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed to give 2-benzyloxy-3,6,7-trimethoxy- 9-phenanthrenecarboxylic acid. 2-Benzyloxy-3,6,7-trimethoxy-9-phenanthic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated, and finally deprotected to obtain 1 -(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( Compound 3), the specific reaction conditions of each step are the same as or similar to the above compound 1, and the deprotection reaction process is as follows:
Figure PCTCN2014094210-appb-000009
Figure PCTCN2014094210-appb-000009
本发明化合物4的制备过程如下：The preparation process of the compound 4 of the present invention is as follows:
3，4-二甲氧基苯乙酸和4-苄氧基苯甲醛经缩合、酯化、偶联、水解得到3-苄氧基-6，7-二甲氧基-9-菲甲酸。3-苄氧基-6，7-二甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化，最后脱保护得到1-(3-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物4)，各步的具体反应条件与上述化合物1的相同或类似，该脱保护的反应过程为如下：The 3,4-dimethoxyphenylacetic acid and 4-benzyloxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3-benzyloxy-6,7-dimethoxy-9-phenanthic acid. 3-Benzyloxy-6,7-dimethoxy-9-phenanthic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated, and finally deprotected to obtain 1- (3-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 4 The specific reaction conditions of each step are the same as or similar to those of the above compound 1, and the deprotection reaction process is as follows:
Figure PCTCN2014094210-appb-000010
Figure PCTCN2014094210-appb-000010
本发明化合物5的制备过程如下：The preparation process of the compound 5 of the present invention is as follows:
3，4-二甲氧基苯乙酸和3-苄氧基苯甲醛经缩合、酯化、偶联、水解得到2-苄氧基-6，7-二甲氧基-9-菲甲酸。2-苄氧基-6，7-二甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化，最后脱保护得到1-(2-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物5)，各步的具体反应条件与上述化合物1的相同或类似，该脱保护的反应过程为如下： The 3,4-dimethoxyphenylacetic acid and 3-benzyloxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed to give 2-benzyloxy-6,7-dimethoxy-9-phenanthic acid. 2-Benzyloxy-6,7-dimethoxy-9-phenanthic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated, and finally deprotected to obtain 1- (2-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 5 The specific reaction conditions of each step are the same as or similar to those of the above compound 1, and the deprotection reaction process is as follows:
Figure PCTCN2014094210-appb-000011
Figure PCTCN2014094210-appb-000011
本发明化合物6的制备过程如下：The preparation process of the compound 6 of the present invention is as follows:
3，4-二甲氧基苯乙酸和3-甲氧基-4-苄氧基苯甲醛经缩合、酯化、偶联、水解得到3-苄氧基-2，6，7-三甲氧基-9-菲甲酸。3-苄氧基-2，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化、脱保护得到1-(3-羟基-2，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物6)，各步的具体反应条件与上述化合物1的相同或类似，该脱保护的反应过程为如下：Condensation, esterification, coupling and hydrolysis of 3,4-dimethoxyphenylacetic acid and 3-methoxy-4-benzyloxybenzaldehyde to give 3-benzyloxy-2,6,7-trimethoxy -9-phenanthrenecarboxylic acid. 3-Benzyloxy-2,6,7-trimethoxy-9-phenanthic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated, deprotected to give 1- (3-hydroxy-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound) 6), the specific reaction conditions of each step are the same as or similar to the above compound 1, and the deprotection reaction process is as follows:
Figure PCTCN2014094210-appb-000012
Figure PCTCN2014094210-appb-000012
本发明化合物7的制备过程如下：The preparation process of the compound 7 of the present invention is as follows:
Figure PCTCN2014094210-appb-000013
Figure PCTCN2014094210-appb-000013
3，4-二甲氧基苯乙酸和4-异丙氧基苯甲醛经缩合、酯化、偶联、水解得 到3-异丙氧基-6，7-二甲氧基-9-菲甲酸。3-异丙氧基-6，7-二甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化得到1-(3-异丙氧基-6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物7)，各步的具体反应条件与上述化合物1的相同或类似。3,4-Dimethoxyphenylacetic acid and 4-isopropoxybenzaldehyde are condensed, esterified, coupled, and hydrolyzed. To 3-isopropoxy-6,7-dimethoxy-9-phenanthic acid. 3-(isopropoxy-6,7-dimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(3- Isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 7) The specific reaction conditions of each step are the same as or similar to those of the above compound 1.
本发明化合物8的制备过程如下：The preparation process of the compound 8 of the present invention is as follows:
3，4，5-三甲氧基苯乙酸和4-苄氧基苯甲醛经缩合、酯化、偶联、水解得到3-苄氧基-5，6，7-三甲氧基-9-菲甲酸。3-苄氧基-5，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化，最后脱保护得到1-(3-羟基-5，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物8)，各步的具体反应条件与上述化合物1的相同或类似，该脱保护的反应过程为如下：Condensation, esterification, coupling and hydrolysis of 3,4,5-trimethoxyphenylacetic acid and 4-benzyloxybenzaldehyde to give 3-benzyloxy-5,6,7-trimethoxy-9-phenanthic acid . 3-Benzyloxy-5,6,7-trimethoxy-9-phenanthic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated, and finally deprotected to obtain 1 -(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( Compound 8), the specific reaction conditions of each step are the same as or similar to the above compound 1, and the deprotection reaction process is as follows:
Figure PCTCN2014094210-appb-000014
Figure PCTCN2014094210-appb-000014
本发明化合物9的制备过程如下：The preparation process of the compound 9 of the present invention is as follows:
Figure PCTCN2014094210-appb-000015
Figure PCTCN2014094210-appb-000015
3，4，5-三甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，5，6，7-三甲氧基-9-菲甲酸。3，5，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化得到1-(3，5，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物9)，各步的具体反应条件与上述化合物1的相同或类似。 The 3,5,5-trimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,5,6,7-trimethoxy-9-phenanthronic acid. 3,5,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(3,5,6, 7-Tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 9), specific reaction of each step The conditions are the same as or similar to those of the above compound 1.
本发明化合物10的制备过程如下：The preparation process of the compound 10 of the present invention is as follows:
Figure PCTCN2014094210-appb-000016
Figure PCTCN2014094210-appb-000016
3，4-二甲氧基苯乙酸和3-甲氧基-4-甲基苯甲醛经缩合、酯化、偶联、水解得到2，6，7-三甲氧基-3-甲基-9-菲甲酸。2，6，7-三甲氧基-3-甲基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化得到1-(2，6，7-三甲氧基-3-甲基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物10)，各步的具体反应条件与上述化合物1的相同或类似。3,4-Dimethoxyphenylacetic acid and 3-methoxy-4-methylbenzaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 2,6,7-trimethoxy-3-methyl-9 - phenamic acid. 2,6,7-trimethoxy-3-methyl-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(2,6 ,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 10), The specific reaction conditions of each step are the same as or similar to those of the above compound 1.
本发明化合物11的制备过程如下：The preparation process of the compound 11 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、乙基化得到1-(3，6，7-三甲氧基-9-菲基)-N-乙基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物11)，各步的具体反应条件与上述化合物1的相同或类似，其中乙基化的反应过程为如下：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and ethylated to give 1-(3,6,7-trimethoxy) Benzyl-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 11), specific reaction conditions of each step and the above compound 1 The same or similar, wherein the ethylation reaction process is as follows:
Figure PCTCN2014094210-appb-000017
Figure PCTCN2014094210-appb-000017
本发明化合物12的制备过程如下： The preparation process of the compound 12 of the present invention is as follows:
Figure PCTCN2014094210-appb-000018
Figure PCTCN2014094210-appb-000018
4-甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6-二甲氧基-9-菲甲酸。3，6-二甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、甲基化得到1-(3，6-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物12)，各步的具体反应条件与上述化合物1的相同或类似。4-methoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6-dimethoxy-9-phenanthrenecarboxylic acid. 3,6-Dimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, methylated to give 1-(3,6-dimethoxy- 9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 12), the specific reaction conditions of each step are the same as those of the above compound 1 Or similar.
本发明化合物13的制备过程如下：The preparation process of the compound 13 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，各步的具体反应条件与上述化合物1的相同或类似，最后为1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉与叔丁氧基羰基保护的S-苯丙氨酸发生酰化、脱保护反应，得到1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-苯丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物13)，其反应过程为如下：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and finally 1-(3,6 , 7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and tert-butoxycarbonyl protected S-phenylalanine Acylation and deprotection to give 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-phenylpropionyl)-6,7-dimethoxy Base-1,2,3,4-tetrahydroisoquinoline (Compound 13), the reaction process is as follows:
Figure PCTCN2014094210-appb-000019
Figure PCTCN2014094210-appb-000019
本发明化合物14的制备过程如下：The preparation process of the compound 14 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，各步的具体反应条件与上述化合物1的相同或类似，最后为 1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉与保护基保护的S-酪氨酸发生酰化、脱保护反应，得到1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-3-(4-羟基苯基)-丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物14)，其反应过程为如下：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and finally 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and protecting group protected S-tyrosine The acid is acylated and deprotected to give 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxyphenyl)- Propionyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 14), the reaction process is as follows:
Figure PCTCN2014094210-appb-000020
Figure PCTCN2014094210-appb-000020
本发明化合物15的制备过程如下：The preparation process of the compound 15 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，各步的具体反应条件与上述化合物1的相同或类似，最后的反应为1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉与叔丁氧基羰基保护的S-赖氨酸发生酰化、脱保护反应，得到1-(3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物15)，其反应过程为如下：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and the final reaction is 1-(3) ,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and tert-butoxycarbonyl protected S-lysine The acylation and deprotection reactions take place to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-hexanoyl)-6,7- Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 15), the reaction process is as follows:
Figure PCTCN2014094210-appb-000021
Figure PCTCN2014094210-appb-000021
本发明化合物16的制备过程如下：The preparation process of the compound 16 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，各步的具体反应条件与上述化合物1的相同或类似，最后的反应为1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉与叔丁氧基羰基保护的S-赖氨酸发生酰化、脱保护、成盐反应，得到1-((R)-3，6，7- 三甲氧基-9-菲基)-N-((2S)-2，6-二氨基盐酸盐-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物16)，其反应过程为如下：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and the final reaction is 1-(3) ,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and tert-butoxycarbonyl protected S-lysine Acylation, deprotection, and salt formation occur to give 1-((R)-3,6,7- Trimethoxy-9-phenanthryl)-N-((2S)-2,6-diaminohydrochloride-hexanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro Isoquinoline (Compound 16), the reaction process is as follows:
Figure PCTCN2014094210-appb-000022
Figure PCTCN2014094210-appb-000022
本发明化合物17的制备过程如下：The preparation process of the compound 17 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，各步的具体反应条件与上述化合物1的相同或类似，最后的反应为1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉与保护基保护的S-谷氨酸发生酰化、脱保护、成盐反应，得到1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-4-羧酸钠盐-丁酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物17)，其反应过程为如下：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized and reduced to give 1-(3,6,7-trimethoxy-9- Phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the specific reaction conditions of each step are the same or similar to those of the above compound 1, and the final reaction is 1-(3) , 6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is acylated with protecting group-protected S-glutamic acid , deprotection, salt formation, to give 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl)- 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 17), the reaction process is as follows:
Figure PCTCN2014094210-appb-000023
Figure PCTCN2014094210-appb-000023
本发明化合物18的制备过程如下：The preparation process of the compound 18 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原、最后乙酰化得到1-(3，6，7-三甲氧基-9-菲基)-N-乙酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物18)，各步的具体反应条件与上述化合物1的相同或类似，最后的反应过程为： 3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and finally acetylated to give 1-(3,6,7-trimethoxy) -9-phenanthryl)-N-acetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 18), specific reaction conditions of each step and the above compound 1 The same or similar, the final reaction process is:
Figure PCTCN2014094210-appb-000024
Figure PCTCN2014094210-appb-000024
本发明化合物19的制备过程如下：The preparation process of the compound 19 of the present invention is as follows:
4-甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6-二甲氧基-9-菲甲酸。3，6-二甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原，最后酰化得到1-(3，6，7-三甲氧基-9-菲基)-N-苯甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物19)，各步的具体反应条件与上述化合物1的相同或类似，最后的反应过程为：4-methoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6-dimethoxy-9-phenanthrenecarboxylic acid. 3,6-Dimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and finally acylated to give 1-(3,6,7-trimethoxy) -9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 19), specific reaction conditions of each step and the above compound 1 The same or similar, the final reaction process is:
Figure PCTCN2014094210-appb-000025
Figure PCTCN2014094210-appb-000025
本发明化合物20的制备过程如下：The preparation process of the compound 20 of the present invention is as follows:
3，4-二甲氧基苯乙酸和茴香醛经缩合、酯化、偶联、水解得到3，6，7-三甲氧基-9-菲甲酸。3，6，7-三甲氧基-9-菲甲酸与6，7-二甲氧基苯乙胺经酰化、环合、还原，最后进行酰化、取代，得到1-(3，6，7-三甲氧基-9-菲基)-N-苯甲胺基甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物20)，各步的具体反应条件与上述化合物1的相同或类似，最后的反应过程为：3,4-Dimethoxyphenylacetic acid and anisaldehyde are condensed, esterified, coupled, and hydrolyzed to obtain 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid. 3,6,7-trimethoxy-9-phenanthroic acid and 6,7-dimethoxyphenethylamine are acylated, cyclized, reduced, and finally acylated and substituted to obtain 1-(3,6, 7-Trimethoxy-9-phenanthryl)-N-benzylaminoformyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 20), each step The specific reaction conditions are the same as or similar to those of the above compound 1, and the final reaction process is:
Figure PCTCN2014094210-appb-000026
Figure PCTCN2014094210-appb-000026
本发明所涉及的1-取代菲基-N-烷基(酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉衍生物，体外抗肿瘤实验表明，本发明所述的化合物显示了良好的活性，具有较好的生理活性；在抑制肿瘤细胞迁移、侵袭方面，具有较高的研究价值，可进一步研制开发为新型的抗肿瘤药物。 The 1-substituted phenanthryl-N-alkyl(acyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative of the present invention has an in vitro antitumor experiment, The compound of the invention shows good activity and has good physiological activity; and has high research value in inhibiting migration and invasion of tumor cells, and can be further developed into a novel anti-tumor drug.
具体实施方式detailed description
实施例一：1-(3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物1)的制备Example 1: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Preparation of (Compound 1)
1)(E)-2-(3，4-二甲氧基苯基)-3-(4-甲氧基苯基)乙烯酸的制备(缩合)1) Preparation (condensation) of (E)-2-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)ethene acid
将3，4-二甲氧基苯乙酸(19.6g，0.1mol)、对甲氧基苯甲醛(16.3g，0.12mol)、醋酸酐(Ac2O)(38mL)和三乙胺(TEA)(19mL)加入到100mL茄形瓶(北京欣维尔公司)中，在氩气保护下加热回流9h。停止反应，将反应液倾入热的150mL 10％氢氧化钠水溶液，加热回流0.5h，降温至室温。溶液用***萃取(3×100mL)，弃去有机层，水层在冰浴下加浓盐酸溶液调pH＝3，析出大量土黄色固体，搅拌0.5h，抽滤，滤饼干燥。得土黄色色固体16.62g，收率53.3％。3,4-Dimethoxyphenylacetic acid (19.6 g, 0.1 mol), p-methoxybenzaldehyde (16.3 g, 0.12 mol), acetic anhydride (Ac 2 O) (38 mL) and triethylamine (TEA) (19 mL) was added to a 100 mL eggplant-shaped bottle (Beijing Xinwei Company), and heated under reflux for 9 hours under argon gas protection. The reaction was stopped, and the reaction solution was poured into a hot 150 mL of 10% aqueous sodium hydroxide solution, heated to reflux for 0.5 h, and then cooled to room temperature. The solution was extracted with diethyl ether (3×100 mL), and the organic layer was discarded. The aqueous layer was then concentrated with hydrochloric acid to adjust to pH=3, and a large amount of solid solids was precipitated, stirred for 0.5 h, filtered, and dried. The obtained yellowish solid was 16.62 g, yield 53.3%.
2)(E)-2-(3，4-二甲氧基苯基)-3-(4-甲氧基苯基)乙烯酸甲酯的制备(酯化)2) Preparation of (E)-methyl 2-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)ethene (esterification)
将(E)-2-(3，4-二甲氧基苯基)-3-(4-甲氧基苯基)乙烯酸(16.62g，0.053mol)溶于200mL无水甲醇中，加入1mL浓硫酸，氩气保护下加热回流20h。停止反应，溶液冷却至室温，析出浅黄色结晶。抽滤，滤饼用无水甲醇洗涤，干燥，得浅黄色固体12.9g，收率74.3％。(E)-2-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)ethene (16.62 g, 0.053 mol) was dissolved in 200 mL of anhydrous methanol and 1 mL was added Concentrated sulfuric acid, heated under reflux for argon for 20 h. The reaction was stopped and the solution was cooled to room temperature to precipitate a pale yellow crystal. After suction filtration, the cake was washed with anhydrous methanol and dried to give a pale yellow solid (12.9 g).
3)3，6，7-三甲氧基9-菲甲酸甲酯的制备(偶联)3) Preparation of 3,6,7-trimethoxy 9-phenanthroic acid methyl ester (coupling)
将(E)-2-(3，4-二甲氧基苯基)-3-(4-甲氧基苯基)乙烯酸甲酯(12.9g，39mmol)在氩气保护下溶解于130mL重蒸的二氯甲烷(DCM)中，在冰盐浴条件下缓慢加入三氟氧钒(VOF3)(6.5g，52mmol)的溶液(将三氟氧钒溶解在重蒸二氯甲烷和乙酸乙酯(EA)(70mL+70mL)的混合液中，同时加入三氟乙酸(TFA)(2mL)、三氟乙酸酐(TFAA)(0.2mL)，氩气保护)，1.5h加毕，保温搅拌反应0.5h，薄层色谱法(TLC)检测反应完成。将反应液倾入碎冰中，室温搅0.5h。二氯甲烷萃取(3×50mL)，合并有机相，饱和食盐水(3×50mL)洗涤，无水硫酸钠干燥过夜，滤除干燥剂，滤液浓缩得粗品。柱层析纯化，得浅黄白色产品10.4g，收率80.04％。Methyl (E)-2-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)ethene (12.9 g, 39 mmol) was dissolved in 130 mL weight under argon In distilled dichloromethane (DCM), slowly add a solution of vanadium trifluoride (VOF 3 ) (6.5 g, 52 mmol) in an ice salt bath (dissolve vanadium trifluorooxide in re-distilled dichloromethane and acetic acid Add a mixture of ester (EA) (70mL + 70mL), add trifluoroacetic acid (TFA) (2mL), trifluoroacetic anhydride (TFAA) (0.2mL), argon gas protection), add 1.5h, heat and stir The reaction was completed for 0.5 h and the reaction was completed by thin layer chromatography (TLC). The reaction solution was poured into crushed ice and stirred at room temperature for 0.5 h. The organic layer was combined and washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate and filtered and evaporated. Purification by column chromatography gave a pale yellow-white product (10.4 g, yield: 80.04%).
4)3，6，7-三甲氧基9-菲甲酸的制备(水解) 4) Preparation of 3,6,7-trimethoxy 9-phenanthroic acid (hydrolysis)
将3，6，7-三甲氧基9-菲甲酸甲酯(10.4g，33mmol)溶于甲醇(10mL)与水(100mL)的混合溶剂中，加入氢氧化钠(10g，0.25mol)，加热回流4h，TLC检测，反应完成。冰浴下，浓盐酸溶液调pH＝3，析出大量白色固体，抽滤，滤饼水洗，干燥。得白色固体9.8g，收率95.3％。3,6,7-trimethoxy 9-phenanthroic acid methyl ester (10.4 g, 33 mmol) was dissolved in a mixed solvent of methanol (10 mL) and water (100 mL), and sodium hydroxide (10 g, 0.25 mol) was added and heated. After refluxing for 4 h, TLC was detected and the reaction was completed. Under ice bath, the concentrated hydrochloric acid solution was adjusted to pH=3, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water and dried. A white solid of 9.8 g was obtained in a yield of 95.3%.
5)N-(3，4-二甲氧基苯乙基)-3，6，7-三甲氧基9-菲甲酰胺的制备(酰化)5) Preparation of N-(3,4-dimethoxyphenethyl)-3,6,7-trimethoxy 9-phenanthroamide (acylation)
将3，6，7-三甲氧基9-菲甲酸(9.8g，31.4mmol)溶于200mL干燥的二氯甲烷溶液中，冰浴条件下加入1-羟基苯并三氮唑(HOBt)(6.37g，47.2mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(9.02g，47.2mmol)，室温反应3.5h。加入二异丙基乙胺(DIEA)(8.1g，62.8mmol)
Figure PCTCN2014094210-appb-000027
，4-二甲氧基苯乙胺(5.68g，31.4mmol)，室温反应1h，TLC检测，反应完成。加入20mL水，淬灭反应。萃取，水洗涤有机层(2×20mL)，2N盐酸洗涤(2×20mL)，饱和碳酸氢钠洗涤(2×20mL)，饱和食盐水洗涤(3×50mL)，无水硫酸钠干燥。滤除干燥剂，滤液浓缩得粗品。柱层析纯化，得白色固体11.5g，收率77.3％。3,6,7-trimethoxy 9-phenanthic acid (9.8 g, 31.4 mmol) was dissolved in 200 mL of dry dichloromethane and added 1-hydroxybenzotriazole (HOBt) (6.37) under ice bath. g, 47.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (9.02 g, 47.2 mmol). Add diisopropylethylamine (DIEA) (8.1 g, 62.8 mmol)
Figure PCTCN2014094210-appb-000027
4-Dimethoxyphenethylamine (5.68 g, 31.4 mmol), reacted at room temperature for 1 h, detected by TLC, and the reaction was completed. The reaction was quenched by the addition of 20 mL of water. The organic layer was washed with water (2×20 mL), brine (2×20 mL), EtOAc (EtOAc) The desiccant was filtered off and the filtrate was concentrated to give a crude material. Purification by column chromatography gave 11.5 g of white solid.
6)1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-3，4-二氢异喹啉的制备(环合)6) Preparation of 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-3,4-dihydroisoquinoline (cyclohexane)
氩气保护条件下，将N-(3，4-二甲氧基苯乙基)-3，6，7-三甲氧基9-菲甲酰胺(11.5g，24mmol)分散于120mL乙二醇二甲醚(DME)中，一次性加入三氯氧磷(POCl3)(22.1mL，0.24mmol)，加热回流反应3.5h，TCL检测反应完成。蒸除大部分溶剂，加入甲苯30mL，共沸蒸除溶剂，重复以上操作三次，得棕色油状物，无需纯化，直接进行下一步反应。N-(3,4-dimethoxyphenethyl)-3,6,7-trimethoxy 9-phenanthamide (11.5 g, 24 mmol) was dispersed in 120 mL of ethylene glycol under argon atmosphere. ether (DME), the disposable added phosphorus oxychloride (POCl 3) (22.1mL, 0.24mmol ), the reaction was heated at reflux for 3.5h, TCL reaction was complete. Most of the solvent was distilled off, 30 mL of toluene was added, and the solvent was evaporated in vacuo. The above operation was repeated three times to obtain a brown oil which was directly subjected to the next reaction without purification.
7)1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉的制备(还原)7) Preparation of 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (reduction)
将新鲜制得的1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-3，4-二氢异喹啉溶于120mL无水甲醇中，反应体系降温至-5℃，将硼氢化钠(NaBH4)(7.3g，0.19mol)缓慢的分批加入反应体系中，约1h加完。保温反应0.5h，室温反应12h，析出大量白色固体，抽滤，滤饼以无水甲醇洗涤，干燥。得白色固体8.6g，收率74.9％。 The freshly prepared 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-3,4-dihydroisoquinoline was dissolved in 120 mL of anhydrous methanol. The reaction system was cooled to -5 ° C, sodium borohydride (NaBH 4 ) (7.3 g, 0.19 mol) was slowly added portionwise to the reaction system, and the addition was completed in about 1 h. The reaction was kept for 0.5 h, and reacted at room temperature for 12 h. A large amount of white solid was precipitated and filtered, and the filter cake was washed with anhydrous methanol and dried. A white solid 8.6 g was obtained in a yield of 74.9%.
8)1-(3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉的制备(甲基化)8) Preparation of 1-(3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (methylation)
将上述步骤7制备的化合物(8.6g，18.8mmol)溶于100mL丙酮中，室温条件下，加入碘甲烷(MeI)(1.17mL，18.8mmol)和无水碳酸钾(3.1g，22.6mmol)，室温反应4h，TLC检测反应完成。加入1.2mL二乙胺，室温搅拌1h，滤除不溶物，蒸除溶剂。柱层析纯化，得目标产物，白色固体8.09g，收率90.8％。1H-NMR(300MHz，CDCl3，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，J1＝9.7，J2＝2.2)，7.48(s，1H)，7.62-7.64(d，1H，J2＝2.2)，8.30-8.33(d，1H，J＝9.7)，9.13(s，1H)；ESI-MS：m/z 474.1[M+H]+。The compound prepared in the above step 7 (8.6 g, 18.8 mmol) was dissolved in 100 mL of acetone, and then, at room temperature, iodomethane (MeI) (1.17 mL, 18.8 mmol) and anhydrous potassium carbonate (3.1 g, 22.6 mmol) were added. The reaction was carried out for 4 h at room temperature, and the reaction was completed by TLC. 1.2 mL of diethylamine was added, and the mixture was stirred at room temperature for 1 hour, and the insoluble material was filtered off, and the solvent was evaporated. Purification by column chromatography gave the title compound (yield: 8. 1 H-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/z 474.1 [M+H] + .
实施例二：1-(2，3，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物2)的制备Example 2: 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Preparation of isoquinoline (Compound 2)
化合物2的制备过程同化合物1的制备方法，其中采用3，4-二甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料。经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化得到1-(2，3，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物2)，总收率17.2％。1H-NMR(300MHz，CDCl3，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 process of the compound 2 is the same as the preparation method of the compound 1, in which 3,4-dimethoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid are used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, 1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl- 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 2), total yield 17.2%. 1 H-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/z 504.2 [M+H] + .
实施例三：1-(2-羟基-3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物3)的制备Example 3: 1-(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetra Preparation of hydrogen isoquinoline (compound 3)
化合物3的制备过程与化合物2的制备方法相似，其中采用3-羟基-4-甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化、脱保护得到1-(2-羟基-3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉。 The preparation process of compound 3 is similar to the preparation method of compound 2, in which 3-hydroxy-4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid are used as starting materials, and condensation, esterification and coupling are carried out. , hydrolysis, acylation, cyclization, reduction, alkylation, deprotection to give 1-(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7- Dimethoxy-1,2,3,4-tetrahydroisoquinoline.
1-(2-羟基-3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(0.25g，0.46mmol)溶于100mL无水甲醇中，加入30mg10％的无水Pd/C，1，4环己二烯(作为供氢体)(0.26mL，2.75mmol)，25℃超声反应1.5小时，滤除Pd/C，蒸除滤液，柱层析纯化得目标产物，总收率12.5％。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/z 490.3[M+H]+。1-(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.25 g, 0.46 mmol) dissolved in 100 mL of anhydrous methanol, 30 mg of 10% anhydrous Pd/C, 1,4 cyclohexadiene (as hydrogen donor) (0.26 mL, 2.75 mmol), ultrasonic reaction at 25 ° C After 1.5 hours, Pd/C was filtered off, the filtrate was evaporated, and purified by column chromatography to give the desired product. 1 H-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/z 490.3 [M+H] + .
实施例四：1-(3-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物4)的制备Example 4: 1-(3-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Preparation of isoquinoline (compound 4)
化合物4的制备过程与化合物3的制备方法相似。采用4-羟基苯甲醛及3，4-二甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化、脱保护基得到1-(3-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物4)，收率14.2％。1H-NMR(300MHz，CDCl3，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，J1＝9.7，J2＝2.2)，7.48(s，1H)，7.62-7.64(d，1H，J2＝2.2)，7.82(s，1H)，8.30-8.33(d，1H，J＝9.7)，9.13(s，1H)；ESI-MS：m/z 459.9[M+H]+。The preparation process of Compound 4 is similar to the preparation method of Compound 3. Using 4-hydroxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, deprotection are obtained. -(3-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 4), the yield was 14.2%. 1 H-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/z 459.9 [M+H] + .
实施例五：1-(2-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物5)的制备Example 5: 1-(2-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Preparation of isoquinoline (compound 5)
化合物5的制备过程与化合物3的制备方法相似。采用3-羟基苯甲醛及3，4-二甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化、脱保护基得到1-(2-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物5)，收率13.1％。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)，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/z 460.4[M+H]+。The preparation process of Compound 5 is similar to the preparation method of Compound 3. Using 3-hydroxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, deprotection are obtained. -(2-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 5), the yield was 13.1%. 1 H-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/z 460.4 [M+H] + .
实施例六：1-(3-羟基-2，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物6)的制备Example 6: 1-(3-hydroxy-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetra Preparation of hydrogen isoquinoline (compound 6)
化合物6的制备过程与化合物3的制备方法相似。采用3-甲氧基-4-羟基苯甲醛及3，4-二甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化、脱保护基得到1-(3-羟基-2，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物6)，收率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/z 490.3[M+H]+。The preparation process of Compound 6 is similar to the preparation method of Compound 3. Using 3-methoxy-4-hydroxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation Deprotection group gives 1-(3-hydroxy-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4- Tetrahydroisoquinoline (Compound 6), yield 11.8%. 1 H-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 / z 490.3 [m + H] +.
实施例七：1-(3-异丙氧基-6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物7)的制备Example 7: 1-(3-Isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4- Preparation of tetrahydroisoquinoline (compound 7)
化合物7的制备过程与化合物1的制备方法相似。将4-羟基苯甲醛(2.68g，22mmol)、异丙醇(2.52mL，33mmol)及三苯基磷(PPh3)(8.65g，33mmol)溶于130mL四氢呋喃(THF)中，反应液冷至0℃，滴加偶氮二羧酸二乙酯(DIAD)(6.6mL，33mL)，室温搅拌2h，减压蒸除溶剂，残余物经硅胶柱色谱分离得黄色油状物2.69g，收率78.5％。以制得的4-异丙氧基苯甲醛、3，4-二甲氧基苯乙酸为原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化得到1-(3-异丙氧基-6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物7)。总收率：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，J1＝9.7，J2＝2.2)，7.48(s，1H)，7.62-7.64(d，1H，J2＝2.2)，8.30-8.33(d，1H，J＝9.7)，9.13(s，1H)；ESI-MS：m/z 502.0[M+H]+。 The preparation process of Compound 7 is similar to the preparation method of Compound 1. 4-hydroxybenzaldehyde (2.68 g, 22 mmol), isopropanol (2.52 mL, 33 mmol) and triphenylphosphine (PPh 3 ) (8.65 g, 33 mmol) were dissolved in 130 mL of tetrahydrofuran (THF) and the reaction was cooled to At 0 ° C, diethyl azodicarboxylate (DIAD) (6.6 mL, 33 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. %. Using the obtained 4-isopropoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as raw materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation are obtained. -(3-isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 7). Total yield: 13.2%. 1 H-NMR (300MHz, CDCl 3 , 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/z 502.0 [M+H] + .
实施例八：1-(3-羟基-5，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物8)的制备Example 8: 1-(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetra Preparation of hydrogen isoquinoline (compound 8)
化合物8的制备过程与化合物3的制备方法相似。采用4-羟基苯甲醛及3，4，5-三甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化、脱保护基得到1-(3-羟基-5，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物8)，收率12.5％。1H-NMR(300MHz，CDCl3，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/z 489.9[M+H]+。The preparation process of Compound 8 is similar to the preparation method of Compound 3. Using 4-hydroxybenzaldehyde and 3,4,5-trimethoxyphenylacetic acid as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation and deprotection are obtained. 1-(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 8), yield 12.5%. 1 H-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, 1 H); ESI-MS: m/z 489.9 [M+H] + .
实施例九：1-(3，5，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物9)的制备Example 9: 1-(3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Preparation of isoquinoline (compound 9)
化合物9的制备过程与化合物1的制备方法相似。采用4-甲氧基苯甲醛及3，4，5-三甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化得到1-(3，5，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物9)，收率14.9％。1H-NMR(300MHz，CDCl3，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/z 504.4[M+H]+。The preparation process of Compound 9 is similar to the preparation method of Compound 1. Using 4-methoxybenzaldehyde and 3,4,5-trimethoxyphenylacetic acid as starting materials, after condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation, 1- (3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 9 ), the yield was 14.9%. 1 H-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/z 504.4 [M+H] + .
实施例十：1-(3-甲基-6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物10)的制备Example 10: 1-(3-Methyl-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Preparation of isoquinoline (compound 10)
化合物10的制备过程与化合物1的制备方法相似。采用3，4-二甲氧基苯乙酸和3-甲氧基-4-甲基苯甲醛为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原、甲基化得到1-(2，6，7-三甲氧基-3-甲基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物10)。1H-NMR(300MHz， CDCl3，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/z 458.1[M+H]+。The preparation process of Compound 10 is similar to the preparation method of Compound 1. Using 3,4-dimethoxyphenylacetic acid and 3-methoxy-4-methylbenzaldehyde as starting materials, condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, methylation To give 1-(2,6,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro Isoquinoline (Compound 10). 1 H-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/z 458.1 [M+H] + .
实施例十一：1-(3，6，7-三甲氧基-9-菲基)-N-乙基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物11)的制备Example 11: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquine Preparation of porphyrin (Compound 11)
化合物11的制备过程同化合物1的制备方法类似。采用4-甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料。经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉。The preparation process of Compound 11 is similar to the preparation method of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinoline.
将1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(0.22g，4.7mmol)溶于30mL丙酮(Acetone)中，室温条件下，加入碘乙烷(C2H5I)(0.29mL，4.7mmol)，无水碳酸钾(0.78g，5.7mmol)，室温反应4h，TLC检测反应完成。加入0.3mL二乙胺，室温搅拌1h，滤除不溶物，蒸除溶剂。柱层析纯化，得1-(3，6，7-三甲氧基-9-菲基)-N-乙基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物11)，总收率16.8％。1H-NMR(300MHz，CDCl3，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，J1＝9.7，J2＝2.2)，7.48(s，1H)，7.62-7.64(d，1H，J2＝2.2)，8.30-8.33(d，1H，J＝9.7)，9.13(s，1H)；ESI-MS：m/z 488.6[M+H]+。Dissolve 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.22 g, 4.7 mmol) In 30 mL of acetone (Acetone), ethyl iodide (C 2 H 5 I) (0.29 mL, 4.7 mmol), anhydrous potassium carbonate (0.78 g, 5.7 mmol) was added at room temperature for 4 h at room temperature. carry out. 0.3 mL of diethylamine was added, and the mixture was stirred at room temperature for 1 hour, and the insoluble material was filtered off, and the solvent was evaporated. Purification by column chromatography to give 1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso Quinoline (Compound 11), total yield 16.8%. 1 H-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/z 488.6 [M+H] + .
实施例十二：1-(3，6-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物12)的制备Example 12: 1-(3,6-Dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Preparation of (Compound 12)
化合物12的制备过程同化合物1的制备方法类似。采用4-甲氧基苯甲醛及4-甲氧基苯乙酸为起始原料。经过缩合、酯化、偶联、水解、酰化、环合、还原、烷基化得到1-(3，6-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物12)，总收率16.4％。1H-NMR(300MHz，CDCl3， 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，J1＝8.7，J2＝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 process of Compound 12 is similar to the preparation method of Compound 1. 4-methoxybenzaldehyde and 4-methoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction, alkylation to give 1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7- Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 12), total yield 16.4%. 1 H-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/z 444.1 [M + H] + .
实施例十三：1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-苯丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物13)的制备Example 13: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-((2R)-2-amino-phenylpropionyl)-6,7-dimethoxy-1 Of 2,3,4-tetrahydroisoquinoline (Compound 13)
化合物13的制备过程同化合物1的制备方法类似。采用4-甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料。经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉。The preparation process of Compound 13 is similar to the preparation method of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinoline.
将N-Boc保护的苯丙氨酸(0.26g，1.00mmol)溶于15mL干燥的二氯甲烷中，加入EDCI(0.29g，1.5mmol)，HOBt(0.2g，1.5mmol)，室温反应3.5h。冰浴下加入1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(0.46g，1.00mmol)，DIEA(0.34mL，2mmol)，室温反应1.5h，加入3mL水淬灭反应。静置，分液。有机层饱和碳酸氢钠洗涤一次，饱和食盐水洗涤三次，无水硫酸镁干燥。滤除干燥剂，减压蒸除溶剂，柱层析纯化。N-Boc-protected phenylalanine (0.26 g, 1.00 mmol) was dissolved in 15 mL of dry dichloromethane, EDCI (0.29 g, 1.5 mmol), HOBt (0.2 g, 1.5 mmol) . Add 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.46 g, 1.00) under ice bath Methyl acetate (0.34 mL, 2 mmol) was reacted at room temperature for 1.5 h. Allow to stand and dispense. The organic layer was washed once with saturated aqueous sodium The desiccant was filtered off, the solvent was evaporated under reduced pressure and purified by column chromatography.
所得产物溶于15mL二氯甲烷中，加入0.2mL三氟乙酸(CF3COOH)，室温反应1h。减压蒸除溶剂。产物柱层析纯化，得1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-苯丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物13)。总收率：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，J1＝12.4，J2＝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)，6.13(s，1H)，6.61(s，1H)，7.20-7.23(dd，1H，J1＝8.7，J2＝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/z 607.4[M+H]+。The obtained product was dissolved in 15 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid (CF 3 COOH) was added and allowed to react at room temperature for 1 h. The solvent was distilled off under reduced pressure. The product was purified by column chromatography to give 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-phenylpropanoyl)-6,7-dimethoxy. -1,2,3,4-tetrahydroisoquinoline (compound 13). Total yield: 10.5%. 1 H-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, 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/z 607.4 [M+H] + .
实施例十四：1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-3-(4-羟基苯基)-丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物14)的制备 Example 14: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxyphenyl)-propanoyl)-6 Of 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 14)
化合物14的制备过程同化合物13的制备方法类似。以3，4-二甲氧基苯乙酸和对甲氧基苯甲醛为原料经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，其与O-叔丁基-N-Boc-酪氨酸经酰化、脱保护得到1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-3-(4-羟基苯基)-丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物14)。总收率：8.8％。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，J1＝12.4，J2＝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，J1＝8.7，J2＝2.4)，7.58-7.63(m，3H)，8.46(s，1H)；ESI-MS：m/z 623.3[M+H]+。The preparation process of Compound 14 is similar to the preparation of Compound 13. 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials. -9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, which is acylated with O-tert-butyl-N-Boc-tyrosine, Deprotection gives 1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxyphenyl)-propanoyl)-6,7 -Dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 14). Total yield: 8.8%. 1 H-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, 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), 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/z 623.3 [M+H] + .
实施例十五：1-(3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物15)的制备Example 15: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-hexanoyl)-6,7-dimethoxy Preparation of -1,2,3,4-tetrahydroisoquinoline (Compound 15)
化合物15的制备过程同化合物13的制备方法类似。以3，4-二甲氧基苯乙酸和对甲氧基苯甲醛为原料经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，其与N-双-Boc-赖氨酸经酰化、脱保护得1-(3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物15)。总收率：11.2％。1H-NMR(300MHz，CDCl3，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，J1＝2.1，J2＝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/z 588.1[M+H]+。The preparation process of Compound 15 is similar to the preparation method of Compound 13. 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials. -9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, which is acylated and deprotected with N-bis-Boc-lysine. -(3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-hexanoyl)-6,7-dimethoxy-1,2,3 , 4-tetrahydroisoquinoline (Compound 15). Total yield: 11.2%. 1 H-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/z 588.1 [M+H] + .
实施例十六：1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基盐酸盐-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物16)的制备 Example 16: 1-((R)-3,6,7-Trimethoxy-9-phenanthryl)-N-((2S)-2,6-diaminohydrochloride-hexanoyl)-6 , Preparation of 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 16)
化合物16的制备过程同化合物13的制备方法类似。以3，4-二甲氧基苯乙酸和对甲氧基苯甲醛为原料经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，其与N-双-Boc-赖氨酸经酰化、脱保护后，滴加饱和盐酸乙酸乙酯溶液直至固体不再析出，室温搅拌1h，抽滤即得到1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基盐酸盐-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物16)。总收率：5.3％。1H-NMR(300MHz，CDCl3，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，J1＝2.1，J2＝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/z 588.1[M+H]+，610.1[M+Na]+，1197.1[2M+Na]+。The preparation process of Compound 16 is similar to the preparation of Compound 13. 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials. ,yl-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, after acylation and deprotection with N-bis-Boc-lysine, The saturated ethyl acetate solution was added dropwise until the solid was no longer precipitated, stirred at room temperature for 1 h, and filtered to give 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N- (2S -2,6-Diaminohydrochloride-hexanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 16). Total yield: 5.3%. 1 H-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/z 588.1 [M+H] + , 610.1 [M+Na] + , 1197.1 [2M+Na] + .
实施例十七：1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-4-羧酸钠盐-丁酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物17)的制备Example 17: 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl)-6,7- Preparation of dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 17)
化合物16的制备过程同化合物13的制备方法类似。以3，4-二甲氧基苯乙酸和对甲氧基苯甲醛为原料经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，其与N-Boc-(O-Bzl)-谷氨酸经酰化、脱保护后，用2M氢氧化钠乙醇溶液成盐得1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-4-羧酸钠盐-丁酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物17)。总收率：7.4％。1H-NMR(300MHz，CDCl3，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，J1＝2.1，J2＝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/z 589.5[M+H]+，611.5[M+Na]+。 The preparation process of Compound 16 is similar to the preparation of Compound 13. 1-(3,6,7-trimethoxy) is obtained by condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction with 3,4-dimethoxyphenylacetic acid and p-methoxybenzaldehyde as raw materials. -9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, which is acylated with N-Boc-(O-Bzl)-glutamic acid, After deprotection, it is salted with 2M sodium hydroxide in ethanol to give 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylate sodium salt. -butyryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 17). Total yield: 7.4%. 1 H-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 / z 589.5 [M + H] +, 611.5 [M + Na] +.
实施例十八：1-(3，6，7-三甲氧基-9-菲基)-N-乙酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物18)的制备Example 18: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-acetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquine Preparation of porphyrin (compound 18)
化合物18的制备过程同化合物1的合成方法类似。采用4-甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料。经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉。The preparation process of Compound 18 is similar to the synthesis of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction to obtain 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinoline.
将1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(0.46g，1mmol)溶于15mL丙酮中，加入无水碳酸钾(0.17g，1.2mmol)、乙酰氯(0.08g，1mmol)，室温反应1.5h，滤除不溶物，减压浓缩滤液，所得固体柱层析纯化，得到1-(2，3，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物18)，总收率19.3％。1H-NMR(300MHz，CDCl3，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，J1＝9.4，J2＝2.3)，7.48(s，1H)，7.54(s，1H)，7.62-7.63(d，1H，J2＝2.3)，7.79-7.80(d，1H，J2＝2.3)，8.33(s，1H)；ESI-MS：m/z 502.2[M+H]+。Dissolving 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.46 g, 1 mmol) Anhydrous potassium carbonate (0.17 g, 1.2 mmol) and acetyl chloride (0.08 g, 1 mmol) were added to 15 mL of acetone, and the mixture was reacted at room temperature for 1.5 h, and the insoluble material was filtered out, and the filtrate was concentrated under reduced pressure. -(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (compound 18), the total yield was 19.3%. 1 H-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/z 502.2 [M+H] + .
实施例十九：1-(3，6，7-三甲氧基-9-菲基)-N-苯甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物19)的制备Example 19: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso Preparation of quinoline (compound 19)
化合物19的制备过程同化合物18的合成方法类似。采用4-甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料，经过缩合、酯化、偶联、水解、酰化、环合、还原得到1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉，其与苯甲酰氯发生酰基化得到1-(3，6，7-三甲氧基-9-菲基)-N-苯甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物19)，总收率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，J1＝9.7，J2＝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，J2＝2.2)，8.33(s，1H)；ESI-MS：m/z 564.2[M+H]+。 The preparation of Compound 19 was similar to the synthesis of Compound 18. Using 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid as starting materials, after condensation, esterification, coupling, hydrolysis, acylation, cyclization and reduction, 1-(3,6, 7-Trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, which is acylated with benzoyl chloride to give 1-(3,6 ,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Compound 19), total yield 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/z 564.2 [M+H] + .
实施例二十：1-(3，6，7-三甲氧基-9-菲基)-N-苯乙胺基甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(化合物20)的制备Example 20: 1-(3,6,7-Trimethoxy-9-phenanthryl)-N-phenylethylaminoformyl-6,7-dimethoxy-1,2,3,4- Preparation of tetrahydroisoquinoline (compound 20)
化合物20的制备过程同化合物1的合成方法类似。采用4-甲氧基苯甲醛及3，4-二甲氧基苯乙酸为起始原料。经过缩合、酯化、偶联、水解、酰化、环合、还原1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉。The preparation process of Compound 20 is similar to the synthesis of Compound 1. 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid were used as starting materials. After condensation, esterification, coupling, hydrolysis, acylation, cyclization, reduction of 1-(3,6,7-trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline.
将1-(3，6，7-三甲氧基-9-菲基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉(0.46g，1mmol)、吡啶(Py)(0.21mL，2.5mmol)溶于10mL二氯甲烷中，冰浴下，滴加氯甲酸苯酯(PhOCOCl)(0.17mL，1.3mmol)的二氯甲烷溶液10mL，滴毕继续保持0℃反应3小时，停止反应，将反应液转移至分液漏斗中，加50mL二氯甲烷稀释，有机层水洗三次，5％盐酸洗一次，饱和NaHCO3洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩，得到黄色固体，硅胶柱层析纯化，得1-(3，6，7-三甲氧基-9-菲基)-N-苯氧甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉0.36g，收率75.2％。1-(3,6,7-Trimethoxy-9-phenanthryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.46 g, 1 mmol), pyridine (Py) (0.21 mL, 2.5 mmol) was dissolved in 10 mL of dichloromethane, and 10 mL of chloro chloroformate (PhOCOCl) (0.17 mL, 1.3 mmol) in dichloromethane was added dropwise. ℃ reaction for 3 hours, the reaction was stopped, the reaction solution was transferred to a separatory funnel, diluted with 50mL of methylene chloride, the organic layer was washed three times with water, a 5% hydrochloric acid, washed once with saturated NaHCO 3, once with saturated brine, dried over anhydrous sulfate Sodium is dry. Concentration to give a yellow solid, which was purified by silica gel column chromatography toiel 2,3,4-tetrahydroisoquinoline 0.36 g, yield 75.2%.
将1-(3，6，7-三甲氧基-9-菲基)-N-苯氧甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉(0.36g，0.75mmol)、苄胺(78mg，0.75mmol)溶于5mL N，N-二甲基甲酰胺(DMF)，室温反应5小时，停止反应，将反应液倾入冰水，析出灰白色固体，抽滤，滤饼水洗，干燥，粗品乙醇重结晶得白色固体0.21g，总收率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/z 593.3[M+H]+。1-(3,6,7-Trimethoxy-9-phenanthryl)-N-phenoxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( 0.36g, 0.75mmol), benzylamine (78mg, 0.75mmol) was dissolved in 5mL N,N-dimethylformamide (DMF), reacted at room temperature for 5 hours, the reaction was stopped, and the reaction solution was poured into ice water to precipitate an off-white solid. After suction filtration, the filter cake was washed with water, dried, and recrystallized from crude ethanol to give a white solid (0.21 g). 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/z 593.3 [M+H] + .
实施例二十一：体外抗肿瘤细胞活性测试Example 21: In vitro anti-tumor cell activity test
所用实验材料与试剂：人***细胞Hela和人乳腺癌细胞MCF-7等十种细胞株由沈阳药科大学池岛乔教授课题组提供。上述十种肿瘤细胞分别接种于含10％胎牛血清，100U/mL青霉素，100μg/mL链霉素的RPMI 1640培养基中，将培养瓶置于37℃，5％CO2饱和湿度培养箱培养，每1-2天 换培养液一次。当细胞生长到足以覆盖瓶底壁的大部分表面时，贴壁细胞用0.25％胰蛋白酶消化，传代。The experimental materials and reagents used: human cervical cancer cell Hela and human breast cancer cell MCF-7 were provided by the research group of Professor Chihiro Ikeda of Shenyang Pharmaceutical University. The above ten tumor cells were inoculated into RPMI 1640 medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin, and the culture flask was placed in a 37 ° C, 5% CO 2 saturated humidity incubator. Every 1-2 days Change the culture solution once. When the cells were grown to cover most of the surface of the bottom wall of the bottle, the adherent cells were digested with 0.25% trypsin and passaged.
噻唑蓝(MTT)比色法检测对贴壁肿瘤细胞生长的影响：对数生长期细胞培养于96孔培养板内，每孔100μl(大约含3000个肿瘤细胞)，置于37℃，5％CO2温箱中培养。次日，给药组分别加入含有不同浓度的本发明化合物1-20，每种细胞设4个剂量组(100μmol/L、10μmol/L、1μmol/L、0.1μmol/L)，每组至少设三个平行孔。对照组加入与给药组等体积的溶剂，置于37℃，5％CO2温箱中培养。48小时后弃培养液，每孔加50μl 1mg/mL MTT溶液(培养基配制)。37℃孵育4小时，弃上清，每孔加入DMSO 150μl溶解甲簪颗粒(培养过程中产生，其作为细胞生长抑制的主要测试指标衡量化合物的活性)，轻度振荡溶解。用酶标仪在波长490nm条件下测定光密度值(OD)，以溶剂对照处理的细胞为对照组，用下面公式计算药物对细胞的抑制率，根据计算得到各浓度的抑制率，通过Logit方法计算得到半数抑制浓度(IC50)，重复测试3次，取平均值为最终结果。The effect of thiazole blue (MTT) colorimetric assay on the growth of adherent tumor cells: logarithmic growth phase cells cultured in 96-well culture plates, 100 μl per well (approximately 3000 tumor cells), placed at 37 ° C, 5% Culture in a CO2 incubator. On the next day, the drug-administered group was added with different concentrations of the compound 1-20 of the present invention, and each cell was set in four dose groups (100 μmol/L, 10 μmol/L, 1 μmol/L, 0.1 μmol/L), and each group was set at least. Three parallel holes. The control group was added with an equal volume of solvent in the administration group, and cultured at 37 ° C in a 5% CO 2 incubator. After 48 hours, the culture solution was discarded, and 50 μl of a 1 mg/mL MTT solution (culture medium) was added to each well. After incubating at 37 ° C for 4 hours, the supernatant was discarded, and 150 μl of dissolved formazan particles (produced during the culture, which is a measure of the activity of the compound as a main measure of cell growth inhibition) was added to each well, and the mixture was gently shaken and dissolved. The optical density value (OD) was measured by a microplate reader at a wavelength of 490 nm, and the cells treated with the solvent control were used as a control group. The inhibition rate of the drug on the cells was calculated by the following formula, and the inhibition rate of each concentration was calculated according to the calculation, and the Logit method was used. The half-inhibitory concentration (IC 50 ) was calculated, and the test was repeated 3 times, and the average was taken as the final result.
并以化合物浓度的对数和抑制率作回归方程，计算，表明所有化合物都有抗肿瘤活性，其中化合物14的活性最佳。 The regression equation was calculated by the logarithm of the concentration of the compound and the inhibition rate. The calculations showed that all the compounds had antitumor activity, and the activity of the compound 14 was the best.
化合物对体外肿瘤细胞生长的抑制作用Inhibition of compound growth on tumor cells in vitro
Figure PCTCN2014094210-appb-000028
Figure PCTCN2014094210-appb-000028

Claims (10)

  1. 通式(I)的化合物，a compound of the formula (I),
    Figure PCTCN2014094210-appb-100001
    Figure PCTCN2014094210-appb-100001
    R＝C1-C10烷基，C1-C10烷基酰基，C6-C12芳基酰基，氨基酸，氨基酸盐，或者被C1-C10烷基或C6-C12芳基取代的胺甲酰基；R=C 1 -C 10 alkyl, C 1 -C 10 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 10 alkyl or C 6 -C 12 aryl Substituted carbamoyl;
    R1＝H，C1-C10烷基或C1-C10烷氧基；其取代个数为1个、2个或3个；R 1 =H, C 1 -C 10 alkyl or C 1 -C 10 alkoxy; the number of substitutions is 1, 2 or 3;
    R2＝H，OH，C1-C10烷基或C1-C10烷氧基，其取代个数为1个、2个或3个，并且在存在2个或3个R2的情况下，各个R2彼此相同或不同。R 2 =H,OH, C 1 -C 10 alkyl or C 1 -C 10 alkoxy, the number of substitutions being 1, 2 or 3, and in the presence of 2 or 3 R 2 Next, each R 2 is the same or different from each other.
  2. 权利要求1所述的化合物，其中：The compound of claim 1 wherein:
    R＝C1-C4烷基，C1-C4烷基酰基，C6-C12芳基酰基，氨基酸，氨基酸盐，或者被C1-C4烷基或C6-C12芳基取代的胺甲酰基。R=C 1 -C 4 alkyl, C 1 -C 4 alkyl acyl, C 6 -C 12 aryl acyl, amino acid, amino acid salt, or C 1 -C 4 alkyl or C 6 -C 12 aryl Substituted carbamoyl group.
  3. 权利要求1或2所述的化合物，其中：The compound of claim 1 or 2, wherein:
    R1＝H，C1-C4烷基或C1-C4烷氧基，优选：甲氧基或乙氧基。R 1 =H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, preferably: methoxy or ethoxy.
  4. 权利要求1或2或3所述的化合物，其中：The compound of claim 1 or 2 or 3 wherein:
    R2＝H，OH，C1-C4烷基或C1-C4烷氧基，优选：OH、OCH3，OC2H5或OCH(CH3)2。R 2 = H, OH, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, preferably: OH, OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
  5. 权利要求1-4中任一项所述的化合物，其中：The compound of any one of claims 1 to 4, wherein:
    R＝CH3，C2H5，COCH3，COPh，氨基酸，氨基酸盐或苯乙胺甲酰基。R = CH 3 , C 2 H 5 , COCH 3 , COCh, amino acid, amino acid salt or phenethyl formyl group.
  6. 权利要求1-5中任一项所述的化合物，其中：The compound of any one of claims 1 to 5, wherein:
    R1、R2＝H，CH3，OH，OCH3，OC2H5或OCH(CH3)2。R 1 , R 2 =H, CH 3 , OH, OCH 3 , OC 2 H 5 or OCH(CH 3 ) 2 .
  7. 权利要求1-6中任一项所述的化合物，其选自：A compound according to any one of claims 1 to 6 which is selected from the group consisting of:
    1-(3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉； 1-(3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(2，3，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2,3,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(2-羟基-3，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2-hydroxy-3,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ;
    1-(3-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(2-羟基-6，7-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2-hydroxy-6,7-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(3-羟基-2，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-hydroxy-2,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ;
    1-(3-异丙氧基-6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-Isopropoxy-6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Porphyrin
    1-(3-羟基-5，6，7-三甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3-hydroxy-5,6,7-trimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ;
    1-(3，5，6，7-四甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,5,6,7-tetramethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(2，6，7-三甲氧基-3-甲基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(2,6,7-trimethoxy-3-methyl-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Porphyrin
    1-(3，6，7-三甲氧基-9-菲基)-N-乙基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(3，6-二甲氧基-9-菲基)-N-甲基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6-dimethoxy-9-phenanthryl)-N-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-苯丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-phenylpropionyl)-6,7-dimethoxy-1,2,3, 4-tetrahydroisoquinoline;
    1-(3，6，7-三甲氧基-9-菲基)-N-((2R)-2-氨基-3-(4-羟基苯基)-丙酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2R)-2-amino-3-(4-hydroxyphenyl)-propionyl)-6,7-dimethyl Oxy-1,2,3,4-tetrahydroisoquinoline;
    1-(3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diamino-hexanoyl)-6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline;
    1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-2，6-二氨基盐酸盐-己酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-2,6-diaminohydrochloride-hexanoyl)-6,7-dimethyl Oxy-1,2,3,4-tetrahydroisoquinoline;
    1-((R)-3，6，7-三甲氧基-9-菲基)-N-((2S)-4-羧酸钠盐-丁酰基)-6，7-二甲氧基-1，2，3，4-四氢异喹啉； 1-((R)-3,6,7-trimethoxy-9-phenanthryl)-N-((2S)-4-carboxylic acid sodium salt-butyryl)-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline;
    1-(3，6，7-三甲氧基-9-菲基)-N-乙酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；1-(3,6,7-trimethoxy-9-phenanthryl)-N-acetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(3，6，7-三甲氧基-9-菲基)-N-苯甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉；或1-(3,6,7-trimethoxy-9-phenanthryl)-N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
    1-(3，6，7-三甲氧基-9-菲基)-N-苯乙胺基甲酰基-6，7-二甲氧基-1，2，3，4-四氢异喹啉。1-(3,6,7-trimethoxy-9-phenanthryl)-N-phenylethylaminoformyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline .
  8. 一种制备权利要求1的通式(I)的化合物的方法，所述方法包括：A method of preparing a compound of formula (I) according to claim 1, the method comprising:
    (a)以下式的取代苯乙酸与下式的取代苯甲醛为起始原料，经缩合、酯化、偶联、水解得到取代的菲甲酸；然后该取代的菲甲酸与3，4二甲氧基苯乙胺经酰化、环合、还原得到下式的四氢异喹啉衍生物；最后使该四氢异喹啉衍生物经由烷基化和/或酰化以及任选的脱保护或成盐反应使该四氢异喹啉化合物的N原子上连接R基团从而得到所述通式(I)的化合物；(a) a substituted phenylacetic acid of the following formula and a substituted benzaldehyde of the following formula as a starting material, which are subjected to condensation, esterification, coupling, hydrolysis to obtain a substituted phenanthrenecarboxylic acid; then the substituted phenanthrenecarboxylic acid and 3,4 dimethoxy Acylation, cyclization, reduction of phenylethylamine to give a tetrahydroisoquinoline derivative of the formula; finally, the tetrahydroisoquinoline derivative is subjected to alkylation and/or acylation and optionally deprotection or a salt-forming reaction to attach an R group to the N atom of the tetrahydroisoquinoline compound to obtain the compound of the formula (I);
    Figure PCTCN2014094210-appb-100002
    Figure PCTCN2014094210-appb-100002
    或or
    (b)直接以上述步骤(a)中的四氢异喹啉衍生物作为原料，经由烷基化和/或酰化以及任选的脱保护或成盐反应使该四氢异喹啉衍生物的N原子上连接R基团，从而得到所述通式(I)的化合物，(b) directly using the tetrahydroisoquinoline derivative in the above step (a) as a raw material, and subjecting the tetrahydroisoquinoline derivative via alkylation and/or acylation and optionally deprotection or salt formation reaction The R group is attached to the N atom to obtain the compound of the formula (I),
    其中R、R1和R2如权利要求1所定义。Wherein R, R 1 and R 2 are as defined in claim 1.
  9. 一种药物组合物，包含权利要求1-7中任一项所述的化合物和药用载体。A pharmaceutical composition comprising the compound of any one of claims 1-7 and a pharmaceutically acceptable carrier.
  10. 权利要求1-7中任一项所述的化合物或权利要求9所述的药物组合物在制备用于抗肿瘤的药物中的应用。 Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 9 for the preparation of a medicament for antitumor.
PCT/CN2014/094210 2013-12-19 2014-12-18 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative and manufacturing method thereof, pharmaceutical composition comprised thereof, and application thereof WO2015090216A1 (en)

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