WO2015090216A1 - Dérivé de 6, 7-dimethoxy-1, 2, 3, 4-tétrahydroisoquinoline et son procédé de production, sa composition pharmaceutique et son application - Google Patents

Dérivé de 6, 7-dimethoxy-1, 2, 3, 4-tétrahydroisoquinoline et son procédé de production, sa composition pharmaceutique et son application Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
dimethoxy
tetrahydroisoquinoline
phenanthryl
compound
trimethoxy
Prior art date
Application number
PCT/CN2014/094210
Other languages
English (en)
Chinese (zh)
Inventor
赵冬梅
程卯生
宋帅
郝晨洲
冯岩
张祯
高禄华
Original Assignee
沈阳药科大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 沈阳药科大学 filed Critical 沈阳药科大学
Publication of WO2015090216A1 publication Critical patent/WO2015090216A1/fr

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule (I) et son procédé de production, la composition pharmaceutique le contenant et son application. Dans la formule, R, R1 et R2 sont tels que définis dans la spécification. Le composé de l'invention présente une bonne activité in-vitro dans des tests anti-tumoraux et une bonne activité physiologique.
PCT/CN2014/094210 2013-12-19 2014-12-18 Dérivé de 6, 7-dimethoxy-1, 2, 3, 4-tétrahydroisoquinoline et son procédé de production, sa composition pharmaceutique et son application WO2015090216A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310705739.8 2013-12-19
CN201310705739.8A CN104672136B (zh) 2013-11-30 2013-12-19 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和用途

Publications (1)

Publication Number Publication Date
WO2015090216A1 true WO2015090216A1 (fr) 2015-06-25

Family

ID=53404984

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/094210 WO2015090216A1 (fr) 2013-12-19 2014-12-18 Dérivé de 6, 7-dimethoxy-1, 2, 3, 4-tétrahydroisoquinoline et son procédé de production, sa composition pharmaceutique et son application

Country Status (2)

Country Link
CN (1) CN104672136B (fr)
WO (1) WO2015090216A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112876474A (zh) * 2021-01-18 2021-06-01 林剑雄 二甲氧基四氢异喹啉取代嘌呤类衍生物及其制备方法和在抗肿瘤药物中的应用
CN113816903B (zh) * 2021-09-22 2023-11-14 蚌埠医学院 一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1896065A (zh) * 2005-07-11 2007-01-17 浙江大学 1－(3′,4′,5′－三取代苯基)－异喹啉类化合物及其制备方法和用途
CN1922147A (zh) * 2004-03-12 2007-02-28 阿纳里特康股份有限公司 作为类胰岛素生长因子第1类受体抑制剂的新颖杂环化合物
CN101258130A (zh) * 2005-09-09 2008-09-03 阿纳里特康股份有限公司 作为胰岛素样生长因子-1受体抑制剂的异喹啉
CN101282935A (zh) * 2005-09-09 2008-10-08 阿纳里特康股份有限公司 作为胰岛素样生长因子-1受体抑制剂的异喹啉衍生物
CN101735229A (zh) * 2009-12-24 2010-06-16 沈阳药科大学 四氢异喹啉类化合物及其制备方法和用途
CN102060764A (zh) * 2010-12-24 2011-05-18 中国药科大学 四氢异喹啉衍生物、其制备方法及用途
CN102060765A (zh) * 2010-12-24 2011-05-18 中国药科大学 四氢异喹啉衍生物、其制备方法及用途
WO2012095836A1 (fr) * 2011-01-14 2012-07-19 University College Dublin - National University Of Ireland, Dublin Composé anti-angiogénique

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1922147A (zh) * 2004-03-12 2007-02-28 阿纳里特康股份有限公司 作为类胰岛素生长因子第1类受体抑制剂的新颖杂环化合物
CN1896065A (zh) * 2005-07-11 2007-01-17 浙江大学 1－(3′,4′,5′－三取代苯基)－异喹啉类化合物及其制备方法和用途
CN101258130A (zh) * 2005-09-09 2008-09-03 阿纳里特康股份有限公司 作为胰岛素样生长因子-1受体抑制剂的异喹啉
CN101282935A (zh) * 2005-09-09 2008-10-08 阿纳里特康股份有限公司 作为胰岛素样生长因子-1受体抑制剂的异喹啉衍生物
CN101735229A (zh) * 2009-12-24 2010-06-16 沈阳药科大学 四氢异喹啉类化合物及其制备方法和用途
CN102060764A (zh) * 2010-12-24 2011-05-18 中国药科大学 四氢异喹啉衍生物、其制备方法及用途
CN102060765A (zh) * 2010-12-24 2011-05-18 中国药科大学 四氢异喹啉衍生物、其制备方法及用途
WO2012095836A1 (fr) * 2011-01-14 2012-07-19 University College Dublin - National University Of Ireland, Dublin Composé anti-angiogénique

Also Published As

Publication number Publication date
CN104672136B (zh) 2017-01-25
CN104672136A (zh) 2015-06-03

Similar Documents

Publication Publication Date Title
JP6437060B2 (ja) 縮合環類似体の抗線維症剤
CN107162928B (zh) 抗纤维化剂的卤代类似物
KR101391746B1 (ko) 인다논 유도체, 이의 약학적으로 허용되는 염 또는 이의 광학 이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 바이러스성 질환의 예방 또는 치료용 약학적 조성물
CN102887904B (zh) 2,3-二氧乙基-5-甲基-8,9-二甲氧基苯并菲啶衍生物及其制备方法和应用
JP7123417B2 (ja) 抗不安重水素化合物及びその医薬的用途
JP6298768B2 (ja) ７−置換ハンファンギチンｂ誘導体、その調製方法及び使用
KR101124350B1 (ko) 항암 활성을 갖는 페난트렌 락탐 유도체, 이의 제조방법 및이를 포함하는 약학 조성물
CN111303121A (zh) 含喹喔啉酮的4-苯氧基吡啶类化合物及其应用
US5162335A (en) Di- and tetrahydroisoquinoline derivatives
CN101735229A (zh) 四氢异喹啉类化合物及其制备方法和用途
WO2015090216A1 (fr) Dérivé de 6, 7-dimethoxy-1, 2, 3, 4-tétrahydroisoquinoline et son procédé de production, sa composition pharmaceutique et son application
CN103347859A (zh) 芳基及杂芳基喹啉衍生物之合成及抗癌活性
CN110240539B (zh) 一种氟取代二苯乙烷类化合物及制备方法和应用
Wu et al. First total synthesis of (−)-and (+)-6-O-desmethylantofine
CN115368306B (zh) 含四氢异喹啉类结构的hdac抑制剂、组合物及其用途
CN107573336B (zh) 苯并杂环-甲酰胺-吡啶酮衍生物及其制备方法和用途
Sweeney et al. The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes
US8552028B2 (en) 8-phenylisoquinolines and pharmaceutical composition used in treatment for sepsis
CN112390781B (zh) 二芳基取代的1,1-乙烯类化合物、制备方法及用途
JP2015512404A (ja) シュワインフルチン類似体
CN113620931A (zh) 一种雄激素受体抑制剂及其用途
CN108586426B (zh) 一种烷氧基联苯/查尔酮杂合类化合物、其制备方法及医药用途
CN110526854A (zh) 一种ɑ,β-不饱和酮衍生物、制备方法及作为药物的用途
CN112500308A (zh) 金色酰胺醇酯及其氟化衍生物及制备方法和应用
Deepthi et al. Synthesis of some modified aurones as antileukemic and antibacterial agents

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14871074

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14871074

Country of ref document: EP

Kind code of ref document: A1