WO2012174699A1 - Série d'analogues d'ectéinascidines ayant un effet anticancéreux - Google Patents

Série d'analogues d'ectéinascidines ayant un effet anticancéreux Download PDF

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WO2012174699A1
WO2012174699A1 PCT/CN2011/075920 CN2011075920W WO2012174699A1 WO 2012174699 A1 WO2012174699 A1 WO 2012174699A1 CN 2011075920 W CN2011075920 W CN 2011075920W WO 2012174699 A1 WO2012174699 A1 WO 2012174699A1
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group
alkoxy
compound
substituents
pharmaceutically acceptable
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PCT/CN2011/075920
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English (en)
Chinese (zh)
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刘站柱
陈晓光
董文芳
刘伟
廖祥伟
王晔
贯宝和
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中国医学科学院药物研究所
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Publication of WO2012174699A1 publication Critical patent/WO2012174699A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to the field of medical technology, and relates to a structural analog of a class of antitumor marine natural product ecteinascidin and a pharmaceutically acceptable salt thereof, and an antitumor preparation containing the above compound and a pharmaceutically acceptable salt thereof.
  • Cancer is one of the malignant diseases that seriously endanger human health.
  • the number of cancer deaths in the world is more than 5 million per year. In recent years, the incidence of cancer has increased year by year, and the mortality rate ranks first among various diseases. .
  • Chemotherapy is a commonly used and effective cancer treatment method in clinical practice. However, due to the multidrug resistance of cancer cells and the serious side effects of existing anticancer drugs, there is an urgent need for new anticancer effects with good side effects and light side effects. drug.
  • Bistetrahydroisoquinoline alkaloids are a large class of natural products with strong anti-tumor activity, including ecteinascidins renieramycins saframycins, among which ecteinascidins is a type of tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinata. The most potent antitumor activity of this type of alkaloid.
  • US Pat. No. 5,256,663 describes a preparation for the medicinal ingredient of the ecteinascidins mixture isolated from the squirt Ecteinascidia turbinata, and the medicinal preparation of the preparation for antibacterial, antiviral and antitumor effects; US Pat. No. 5,089,273 Several tetrahydroisoquinoline compounds, namely ecteinascidins 729, 743, 745, 759A, 759B and 770, have been isolated from the squirt Ecteinascidia turbinata, and these compounds have antibacterial and/or antitumor activity; US Pat. No.
  • 5,478,932 describes The ecteinascidins were isolated from the Caribbean sea squirt Ecteinascidia turbinata. These compounds showed in vivo activity in P388 lymphoma, B16 melanoma, M5076 ovarian cancer, Lewis lung cancer, LX-1 human lung cancer, and MX-1 human breast cancer; US Pat. No. 5,654,426 describes ecteinascidins isolated from the Caribbean sea squirt Ecteinascidia turbinata, which exhibit in vivo activity against P388 lymphoma, B16 melanoma, M5076 ovarian cancer, Lewis lung cancer, LX-1 human lung cancer, and MX-1 human breast cancer.
  • ecteinascidin 743 (Et-743, trade name trabectedin, Yondelis) is the most active one, and its anti-tumor activity in vitro is higher than that of Taxol and Cam tothecin Adriamycin currently used clinically.
  • Mitomycin C Cisplatin Bleomycin and Etopside are 1-3 orders of magnitude higher. It was marketed in Germany in 2007 for the treatment of soft tissue tumors and was subsequently approved within the European Community. It was marketed in Korea in 2008 for the treatment of advanced soft tissue tumors.
  • the common structural features of bis-tetrahydroisoquinoline natural products such as Ecteinascidins saframycins and renieramycins have the following five-and-loop rigid structure; A and E rings are either benzene or oxime structures; B and D rings are two Hexahydropiperidine ring; the C ring is a piperazine ring; the substitution patterns on the two aromatic rings are also common, that is, the 6 and 16 positions are all methyl substituted; 7, 8 and 17, 18 are attached to the oxygen atom at four positions; The 5 and 15 positions are either attached to an oxygen atom or have no substituents.
  • the technical problem to be solved by the present invention is to provide a class of ecteinascidin structural analogs of the general formula (I) and pharmaceutically acceptable salts thereof;
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising the compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • a further technical problem to be solved by the present invention is to provide a compound of the formula (I) and a pharmaceutically acceptable salt thereof for use in the preparation of an antitumor drug;
  • the compound of the present invention having the formula (I) and a pharmaceutically acceptable salt thereof are structurally characterized in that the ear-regeneration pattern of the ring A of the ring A and the ecteinascidins, renieramycins and saframycins of the ring A are different. Both of the 6 and 16 positions are bonded to an oxygen atom, and the 5, 8, 15 and 18 positions are free of any substituents, and the 7 and 17 positions are bonded to an oxygen atom; another structural feature of the compound of the present invention is The carboxylic acid at position 23 is a type of ct, ⁇ -unsaturated, and the double bond between the 25 and 26 carbon atoms is in the E-configuration.
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of: H, a linear or branched alkyl group of dC 18 , a C 2 -C 18 alkenyl group, a C 2 -C 18 block group, An aryl group, an aryl group-substituted alkyl group; and, R 3 and R 4 may be bonded to form a ring;
  • X is selected from 0, NH, S, CH 2 ;
  • R 5 is selected from an aryl group or a heteroaryl group: these aryl or heteroaryl groups may have one or more substituents selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde groups, Carbamoyl, halogen, N0 2 , CN, 18 straight or branched alkyl, ⁇ 18 alkoxy, C r C 18 alkylamino, C r C 18 alkoxy CrC 18 alkyl, aryl substituted 18 alkoxy, C 2- C18 alkenyl, C 2 -C 18 block, aryl, heterocyclic aryl.
  • substituents selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde groups, Carbamoyl, halogen, N0 2 , CN, 18 straight or branched alkyl, ⁇ 18 alkoxy, C r C 18 alkylamino
  • Preferred aryl or heteroaryl groups are selected from the group consisting of phenyl, pyridyl, naphthyl, quinolyl, indolyl, benzothiazolyl, benzofuranyl.
  • R 2 , R 3 and R 4 are independently selected from the group consisting of: H, dC 6 linear or branched alkyl, C 2 -C 6 alkenyl, C 2 -C 6 block, benzene a substituted alkyl group; and, R 3 and may be bonded to form a ring;
  • X is selected from the group consisting of 0, NH, S.
  • R 5 is selected from an aryl or heteroaryl group: the aryl group is selected from the group consisting of phenyl and naphthyl; the heteroaryl group is selected from pyridyl, quinolyl, decyl, benzothiazolyl, benzo Further, the aryl or heteroaryl group may have one or more substituents selected from the group consisting of H, 0H, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, halogen, N0 2 , CN, 12 linear or branched alkyl, dC 12 alkoxy, Ci-Ci23 ⁇ 43 ⁇ 43 ⁇ 4 3 ⁇ 4 Ci-Ci2 3 ⁇ 43 ⁇ 43 ⁇ 4, Ci-Ci2 3 ⁇ 43 ⁇ 43 ⁇ 4 fang and 3 ⁇ 4 Ci-Cu C2-C12 alkenyl, C 2 -C 12 Base, aryl, heterocyclic aryl.
  • R 2 , R 3 are independently selected from the group consisting of: -CH 3 , -C 2 H 5 , -CH 2 Ph;
  • R 2 , R 3 and R 4 are linked to each other, and R r R 2 , R 3 - R 4 are independently selected from -CH 2 -,
  • X is selected from 0, NH.
  • R 5 is selected from an aryl or heteroaryl group: the aryl group is selected from the group consisting of phenyl and naphthyl; the heteroaryl group is selected from pyridyl, quinolyl, decyl, benzothiazolyl, benzo Further, the aryl or heteroaryl group may have one or more substituents selected from the group consisting of H, 0H, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, halogen, N0 2 , CN, C r C 6 linear or branched alkyl, C r C 6 alkoxy, Ci-C 6 Ci-C 6 Ci-C 6 aromatic and 3 ⁇ 4 Ci-C 6 C 2 -C 6 ; J# ,
  • Ri R 2
  • Ri ⁇ BR 2 , R 3 and B are interconnected, and Ri - R 2 , R 3 - are independently selected from -CH 2 -,
  • X is selected from 0, NH;
  • R 5 is selected from aryl or heteroaryl: the substituents on these aryl or heteroaryl are independently selected from: H, 0H, SH, NH 2 , COOH, CF3, aldehyde, carbamoyl, halogen, N0 2 , CN, 1 8 linear or branched alkyl, 18 alkoxy, dC 18 alkylamino, dC 18 alkoxy C r C 18 alkyl, aryl substituted 18 alkoxy, C 2 -C 18 alkenyl, C 2 -C 18 block, aryl, heterocyclic aryl; substituents on these aryl or heteroaryl are preferably selected from: H, 0H, SH, NH 2 , COOH, CF3, aldehyde Base, carbamoyl, halogen, N0 2 , CN, dC 6 straight or branched alkyl, dC 6
  • the substituents on these aryl or heteroaryl groups are most preferably selected from the group consisting of: H, 0H, SH, NH 2 , COOH, CF3, aldehyde groups, carbamo
  • R 5 can be taken from the following groups:
  • the substituent on the phenyl-: benzene ring may be one or more; for example, the benzene ring may be mono-substituted or di- and tri-substituted; the substitution position on the mono-substituted benzene ring is 2- or 4-position; The positions of the substituents on the disubstituted benzene ring are 2, 4- and 3, 4-; the substitution positions of the trisubstituted benzene ring are 2, 3, 4- or 3, 4, 5-position; these substituents are independent, Selected from the following substituents:
  • the substituent on the 2-pyridine ring may be one or more; for example, the pyridine ring may be mono- or di-substituted; the position of the substituent on the mono-substituted pyridine ring is 4- and 6-position The position of the substituent on the disubstituted pyridine ring is 3, 5-, 3, 4-, 3, 6-position, and these substituents are each independently selected from the following substituents:
  • the substituent on the 4-pyridine ring may be one or more; for example, the pyridine ring may be mono- or di-substituted; the position of the substituent on the mono-substituted pyridine ring is 2- and 3-position The position of the substituent on the disubstituted pyridine ring is 2, 3-, 3, 5-, 2, 6-position, and these substituents are each independently selected from the following substituents:
  • the substituent on the 3-pyridine ring may be one or more; for example, the pyridine ring may be mono- or di-substituted; the position of the substituent on the mono-substituted pyridine ring is 2-, 4-, 5 - and 6-position; the positions of the substituents on the disubstituted pyridine ring are 4, 6-, 5, 6-position, and these substituents are each independently selected from the following substituents:
  • (X-naphthyl) (The substituent on the X-naphthyl ring may be one or more; for example, the mono substituent is on the 4-, 5-, or 8-position of the naphthalene ring; the di-substituent is on the naphthalene ring 4, 5-, 4, 8- or 5, 8-position, these substituents are each independently selected from the following substituents:
  • the substituent on the ⁇ -naphthyl ring may be one or more; for example, the mono substituent is on the 1-, 4-, 5-, or 8-position of the naphthalene ring; the disubstituted group is a naphthalene ring. 1, 4-, 4, 5-, 4, 8- or 5, 8-position, these substituents are each independently selected from the following substituents:
  • aryl group replaces the cc 6 alkoxy group, the c 2 -c 6 alkenyl group, and the c 2 -c 6 block group.
  • the substituent on the 4-quinoline ring may be one or more; for example, a single substituent is on the 2-, 5-, 6-, 7- or 8-position of the quinoline ring;
  • the base is 5, 6-, 5, 7-, 5, 8- or 6, 7-position on the quinoline ring, and these substituents are each independently selected from the following substituents:
  • the substituent on the 3-quinoline ring may be one or more; for example, a mono substituent is at the 2-, 4-, 5-, 6-, 7- or 8-position of the quinoline ring;
  • the disubstituted group is 5, 6-, 5, 7-, 5, 8- or 6, 7-position on the quinoline ring, and these substituents are each independently selected from the following substituents:
  • the substituent on the 3-anthracene ring may be one or more; for example, a monosubstituent is at the 2-, 4-, 5-, 6- or 7-position of the indole ring;
  • the 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7- or 6, 7-position on the anthracene ring, these substituents are each independently selected from the following substituents:
  • the substituent on the 2-anthracene ring may be one or more; for example, a single substituent is at the 3-, 4-, 5-, 6- or 7-position of the indole ring;
  • the 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7- or 6, 7-position on the anthracene ring, these substituents are each independently selected from the following substituents:
  • Preferred compounds of formula I include, but are not limited to, the compounds shown by IA
  • the ⁇ is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolyl, Representing one or more substituents, these substituents may be bonded to W at any suitable position, and these substituents are independently selected from the group consisting of H, OH, SH, NH 2 , COOH, aldehyde group, carbamoyl group, halogen, N0. 2 , CN, Ci-C 6 linear or branched alkyl, Ci-C 6 alkoxy, Ci-C 6 alkylamino, dC 6 alkoxy CC 6 alkyl, aryl substituted dC 6 alkoxy Base, C 2 -C 6 alkenyl, C 2 -C 6 block.
  • Preferred compounds of formula IA include, but are not limited to, the compounds shown by IA1
  • ⁇ 1 is selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, F, Cl, Br, I, N0 2 , CN, C1-C4 linear or branched alkyl group, Ci -C 4 alkoxy, Ci-C 4 alkylamino, Ci-C 4 alkoxy dC 4 alkyl, aryl substituted dC 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 block .
  • Preferred compounds of formula IA include, but are not limited to, the compounds shown by IA2
  • Preferred compounds of formula IA include, but are not limited to, the compounds shown by IA3
  • Preferred compounds of formula IA include, but are not limited to, the compounds shown by IA4
  • H selected from H, OH, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, F, Cl, Br, I, N0 2 , CN, C1-C4 linear or branched alkyl group, Ci -C 4 alkoxy, Ci-C 4 alkylamino, Ci-C 4 alkoxy dC 4 alkyl, aryl substituted dC 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 block .
  • Rv represents one or more substituents, and these substituents may be bonded to any suitable position, and these substituents are independently selected from the group consisting of g H, OH, SH, NH 2 , COOH, aldehyde group, carbamoyl group, halogen,
  • Ci-C 6 linear or branched alkyl Ci-C 6 alkoxy, Ci-C 6 alkylamino, dC 6 alkoxy CC 6 alkyl, aryl substituted dC 6 alkane Oxyl, C 2 -C 6 alkenyl, C 2 -C 6 block.
  • Preferred compounds of formula IB include, but are not limited to, the compounds shown in IB1
  • IB1 R 7 i is selected from H, OH, SH, NH 2 , COOH, CF3, aldehyde, carbamoyl, F, Cl, Br, I, N0 2 , CN, C1-C4 linear or branched alkyl , Ci-C 4 alkoxy, Ci-C 4 alkylamino, Ci-C 4 alkoxy dC 4 alkyl, aryl substituted dC 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 Block base.
  • Preferred compounds of formula IB include, but are not limited to, the compounds shown in IB4
  • R 74 is selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, F, Cl, Br, I, N0 2 , CN, C1-C4 linear or branched alkyl group, Ci-C 4 alkoxy, Ci-C 4 alkylamino, Ci-C 4 alkoxy dC 4 alkyl, aryl substituted dC 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 block base.
  • Preferred compounds of formula IB include, but are not limited to, the compounds shown in IB5.
  • R 75 is selected from a linear or branched alkyl group selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde, carbamoyl, F, Cl, Br, I, N0 2 , CN, CC 4 , CC 4 alkoxy, CC 4 alkylamino, dC 4 courtyard oxygen dC 4 courtyard, aryl aryl Ci-C 4 alkoxy, C 2 -C 4 ; J# base, C 2 -C 4 alkyne base.
  • R 8 represents one or more substituents, and these substituents may be bonded to any suitable position, and these substituents are independently selected from the group consisting of g H, OH, SH, NH 2 , COOH, aldehyde group, carbamoyl group, halogen,
  • Preferred compounds represented by the formula IC include, but are not limited to, the compounds shown by IC1.
  • R 81 is selected from a linear or branched alkyl group selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde, carbamoyl, F, Cl, Br, I, N0 2 , CN, dC 4 , dC 4 alkoxy, dC 4 alkylamino, Ci-C43 ⁇ 43 ⁇ 4 ⁇ 4, Ci-C 4 3 ⁇ 43 ⁇ 43 aryl aryl, Ci-C t ⁇ oxy, C 2 -C 4 ; J; Hickey, C 2 -C 4 blocks.
  • Preferred compounds represented by the formula IC include, but are not limited to, the compounds shown by IC3
  • R 83 is selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, F, Cl, Br, I, N0 2 , CN, dC 4 linear or branched alkyl group, dC 4 alkoxy, dC 4 alkylamino, dC 4 Alkoxy dc 4 alkyl, aryl substituted dC 4 alkoxy, c 2 -c 4 alkenyl, c 2 -c 4 block.
  • R 9 represents one or more substituents, and these substituents may be bonded to any suitable position, and these substituents are independently selected from the group consisting of g H, OH, SH, NH 2 , COOH, aldehyde group, carbamoyl group, halogen,
  • Ci-C 6 linear or branched alkyl Ci-C 6 alkoxy, Ci-C 6 alkylamino, dC 6 alkoxy CC 6 alkyl, aryl substituted dC 6 alkane Oxyl, C 2 -C 6 alkenyl, C 2 -C 6 block.
  • Preferred compounds represented by formula ID include, but are not limited to, the compounds shown by ID1.
  • ID1 R91 is selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, F, Cl, Br, I, N0 2 , CN, dC 4 linear or branched alkyl group, dC 4 Alkoxy, dC 4 alkylamino, dC 4 alkoxy dC 4 alkyl, aryl substituted dC 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 block.
  • Preferred compounds represented by formula ID include, but are not limited to, the compounds shown by ID4.
  • R94 is selected from the group consisting of H, OH, SH, NH 2 , COOH, CF3, aldehyde, carbamoyl, F, Cl, Br, I, N0 2 , CN, dC 4 linear or branched alkyl, dC 4 Alkoxy, dC 4 alkylamino, dC 4 alkoxy dC 4 alkyl, aryl substituted dC 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 block.
  • Rio represents one or more substituents which may be bonded to any suitable position, and these substituents are independently selected from the group consisting of g H, OH, SH, NH 2 , COOH, aldehyde group, carbamoyl group, halogen,
  • Preferred compounds of formula IE include, but are not limited to, the compounds shown in IE1
  • Rioi is selected from H, OH, SH, NH 2 , COOH, CF3, aldehyde, carbamoyl, F, Cl, Br, I, N0 2 , CN, dC 4 linear or branched alkyl, dC 4 Alkoxy, dC 4 alkylamino, Ci-C4 3 ⁇ 43 ⁇ 4 ⁇ 4, Ci-C 4 3 ⁇ 43 ⁇ 43 aryl aryl, Ci-C t ⁇ oxy, C 2 -C 4 ; J; Hickey, C 2 -C 4 base.
  • Preferred compounds of formula I include, but are not limited to, the compounds shown by IF
  • the W is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolyl, fluorenyl;
  • Rii denotes one or more substituents which may be bonded to any of the appropriate positions, such as H, OH, SH, NH 2 , COOH, aldehyde, carbamoyl, halogen,
  • Ci-C 6 linear or branched alkyl Ci-C 6 alkoxy, Ci-C 6 alkylamino, dC 6 alkoxy CC 6 alkyl, aryl substituted dC 6 alkane Oxyl, C 2 -C 6 alkenyl, C 2 -C 6 block.
  • Preferred compounds of formula IF include, but are not limited to, the compounds shown by IF1
  • Riii is selected from the group consisting of H, OH, SH, NH 2 , COOH, CF 3 , aldehyde group, carbamoyl group, F, Cl, Br, I, N0 2 , CN, dC 4 linear or branched alkyl group, dC 4 Alkoxy, dC 4 alkylamino, Ci-C4 3 ⁇ 43 ⁇ 4 ⁇ 4, Ci-C 4 3 ⁇ 43 ⁇ 43 aryl aryl, Ci-C t ⁇ oxy, C 2 -C 4 ; J; Hickey, C 2 -C 4 base.
  • Preferred compounds of formula I include, but are not limited to, the compounds shown by IG
  • Rl2 represents one or more substituents which may be bonded to the phenyl group at any suitable position, and these substituents are independently selected from the group consisting of g H, OH, SH, NH 2 , COOH, aldehyde group, carbamoyl group, halogen. , N0 2 , CN, Ci-C 6 linear or branched alkyl, Ci-C 6 alkoxy, Ci-C 6 alkylamino, dC 6 alkoxy CC 6 alkyl, aryl substituted dC 6 Alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 block.
  • the 26 carbon atom may be bonded to R 5 at any suitable position of the aryl or heteroaryl group.
  • C r C 18 straight or branched alkyl groups of the present invention are dC 12 straight or branched alkyl groups.
  • Preferred among the dC 12 linear or branched alkyl groups of the present invention are dC 6 linear or branched alkyl groups.
  • Preferred among the dC 6 linear or branched alkyl groups of the present invention are CC 4 straight or branched alkyl groups.
  • C 2 -C 18 alkenyl groups of the present invention are C 2 -C 12 alkenyl groups.
  • Preferred among the C 2 -C 12 alkenyl groups of the present invention are C 2 -C 6 alkenyl groups.
  • Preferred among the C 2 -C # groups of the present invention are C 2 -C 4 alkenyl groups.
  • Preferred among the c 2 -c 18 blocks of the present invention are c 2 -c 12 blocks.
  • Preferred among the c 2 -c 12 blocks of the present invention are C 2 -C 6 blocks.
  • the present invention ⁇ - ⁇ block group is preferably C 2 -C 4 block basis.
  • Preferred dc 6 straight or branched alkyl groups are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, isopentyl.
  • the 4 straight or branched alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl.
  • Preferred aryl groups are selected from the group consisting of phenyl and naphthyl.
  • Preferred heteroaryl groups are selected from the group consisting of pyridyl, quinolyl, decyl, benzothiazolyl, benzofuranyl.
  • the halogen is selected from the group consisting of F, Cl, Br, and I.
  • the pharmaceutically acceptable salt of the above preferred compound with an acid also forms part of the present invention, and the basic nitrogen atom in the molecule of the compound of the present invention may form a salt with an acid, as long as it is capable of forming a salt with a base, and is pharmaceutically Acceptable acids are acceptable, and there are no particular restrictions thereto.
  • Examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid; and organic acids such as oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid
  • organic acids such as oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the N-methylated product 6 is obtained by reacting the compound R with a substituent R, R 2 , R 3 and F as the case of the above formula (I) with formaldehyde-formic acid at 70 ° C;
  • the product of Reaction 7 can also form a salt of formula (I) with the organic or inorganic acids listed above.
  • the definitions of R1, R2, R3, R4 and R5 are the same as described above.
  • a further aspect of the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyelid, lung. And the respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w, w/o and double emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops Agent, nasal drops, lotion and expectorant, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • the diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the humectant may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch pulp, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin pulp, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrant can be dry starch, microcrystalline cellulose, low-
  • Tablets may also be further formulated into coated tablets such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidant varieties used to prepare the tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizer or cosolvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose, or the like may be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
  • the compounds of the present invention can be used in combination with other anticancer drugs for the treatment of tumors, which are also part of the present invention.
  • anticancer drugs include: taxol, paclitaxel, taxotere, docetaxel, vincristine, vinblastine, 5-fluorouracil, cytarabine, gemcitabine, Pentostatin, methotrexane, cyclophosphamide, ifosphamide, adriamycin, doxorubicin, pharmorubicin, epirubicin, etoposide, tamoxifen, flutamide, leuprorelin, goserelin, cyorotrone, octreotide, herceptin, cis-platin, carboplatin, oxaplatin, dexamethasone, etc.
  • the compounds of the present invention may also be used in combination with compounds belonging to the following classes of antitumor drugs, including: paclitaxel, ghost white toxins, vinblastine, nitrogen mustards, anthraquinones. , estrogens, antiestrogens, androgens, antiandrogens, antibody derivatives, platinum, matrix protease inhibitors, and the like.
  • antitumor drugs including: paclitaxel, ghost white toxins, vinblastine, nitrogen mustards, anthraquinones. , estrogens, antiestrogens, androgens, antiandrogens, antibody derivatives, platinum, matrix protease inhibitors, and the like.
  • the compounds of the present invention may also be used in combination with compounds belonging to the following classes of antitumor drugs, which also form part of the present invention, including: tubulin modulators, antimetabolites, alkylating drugs, DNA Targeted antitumor drugs, topoisomerase-targeted drugs, hormones and hormone agonists or antagonists, drugs targeting cancer cell signaling, gene therapy or anti-righteous therapy Therapeutic drugs, antibody therapeutic drugs, marine-derived active compounds, hormone analogs, anti-inflammatory drugs or antiemetic drugs.
  • antitumor drugs which also form part of the present invention, including: tubulin modulators, antimetabolites, alkylating drugs, DNA Targeted antitumor drugs, topoisomerase-targeted drugs, hormones and hormone agonists or antagonists, drugs targeting cancer cell signaling, gene therapy or anti-righteous therapy
  • Therapeutic drugs antibody therapeutic drugs, marine-derived active compounds, hormone analogs, anti-inflammatory drugs or antiemetic drugs.
  • the compound of the present invention can be used alone or as a pharmaceutically active ingredient for the treatment of leukemia, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, Patients with colon cancer and other diseases.
  • composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably
  • the above dosages can be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation. detailed description:
  • the precursor alcohol C is prepared by a multi-step reaction via the carboxylic acid intermediate A and the tetrahydroisoquinoline intermediate B.
  • the preparation method is as follows:
  • L-DOPA a (Boc) 2 0, Et 3 N, DMF; b: Me 2 S0 4 , K 2 C0 3 , CH3COCH3, reflux; c: lN KOH/CH3OH Synthesis of intermediate 1: with electromagnetic stirring To a 100 ml round bottom flask of a condenser, 6.0 g of L-dopa (0.030 mol), 7.8 g (Boc) 2 0 (0.036 mol), 4.8 ml of triethylamine and 200 ml of DMF were added, and the mixture was heated to 60 ° C for 2 hours. , TLC showed complete reaction.
  • the organic liquid was washed with a small amount of water and brine, and dried over anhydrous sodium sulfate. After concentration, a solid was obtained, which was purified by column chromatography to give a solid.
  • the preparation method of the compound 2 is the same as the compound 1, melting point: 101.5-103.0 °C
  • the preparation method of the compound 4 is the same as the compound 1, melting point: 132.5-134.0 °C
  • the preparation method of the compound 5 is the same as the compound 1, melting point: 142.0-143.5 °C
  • the preparation method of the compound 7 is the same as the compound 1, melting point: 117.2-119.5 °C
  • the preparation method of the compound 8 is the same as the compound 1, melting point: 130.2-133.0 °.
  • the preparation method of the compound 9 is the same as the compound 1, melting point: 123.5-125.0 °C
  • the preparation method of the compound 10 is the same as the compound 1, melting point: 140.5-142.5 °C
  • the preparation method of the compound 11 is the same as the compound 1, melting point: 151.0-153.5 °C
  • the preparation method of the compound 12 is the same as the compound 1, melting point: 136.7-138.5 °C
  • the preparation method of the compound 13 is the same as the compound 1, melting point: 152.0-153.5 °C
  • the preparation method of the compound 15 is the same as the compound 1, melting point: 130.1-131.5 °.
  • the preparation method of the compound 16 is the same as the compound 1, melting point: 126.5-128 C
  • the preparation method of the compound 17 is the same as the compound 1, melting point: 124.6-125 C
  • the preparation method of the compound 18 is the same as the compound 1, melting point: 137.8-138.9 °C
  • the preparation method of the compound 19 is the same as the compound 1, melting point: 132.3-133.5 °C
  • intermediate 6a 15.0 g of intermediate 5, 22.4 g of anhydrous potassium carbonate, 430 ml of acetone, 16.3 g of diiodomethane were sequentially added to a 1000 ml eggplant-shaped flask, and refluxed for 10 hours, and the excess potassium carbonate was filtered off, and the solvent was evaporated. Ethyl acetate was dissolved, and the mixture was washed with EtOAc EtOAc EtOAc.
  • the precursor alcohol C-l is prepared in the same manner as the precursor alcohol C except that the tetrahydroisoquinoline precursor B-1 is substituted for B:
  • the preparation method of the compound 20 is the same as the compound 1, melting point: 124.0-125.5 °.
  • the preparation method of the compound 21 is the same as the compound 1, melting point: 139.2-141.0 °C
  • the preparation method of the compound 22 is the same as the compound 1, melting point: 147.0-148.5 °C
  • the precursor alcohol C-2 is prepared in the same manner as the precursor alcohol C, except that the carboxylic acid intermediate A-1 is used instead of A:
  • CDCI3 6.69 (s, 1H, Ar-H), 6.62 (s, 1H, Ar-H), 6.58 (s, 1H, Ar-H), 6.52 (s, lH, Ar-H) :
  • the preparation method of the compound 24 is the same as the compound 1, melting point: 140.0-141.5 °C
  • the preparation method of the compound 25 is the same as the compound 1, melting point: 136.0-137.5 °C
  • the preparation method of the compound 27 is the same as the compound 1, melting point: 132.0-133.5 °C
  • step b the diiodomethane interstitial A-2 is replaced by 1,2-dibromoethane:
  • the preparation method is the same as that of tetrahydroisoquinoline intermediate B, and is replaced by 1,2-dibromoethane in step d.
  • the preparation method of the compound 28 is the same as the compound 1 , melting point: 151.0-153.2 ° C
  • the preparation method of the compound 29 is the same as the compound 1 , melting point: 141.0-142.5 °C
  • the preparation method is the same as the tetrahydroisoquinoline intermediate oxime, and in the step d, diethyl sulphate is used instead of dimethyl sulfate to obtain the intermediate B-3:
  • the preparation method of the compound 30 is the same as the compound 1, melting point: 118.0-120.0 °C
  • Human solid tumor cell lines were selected: colon cancer cell line (HCT-8), liver cancer cell line (Bel-7402), ovarian cancer cell line CA2780), lung cancer cell line (A549) and gastric cancer cell line (BGC-823), RPMI1640 medium containing 10% serum, cells cultured at 37 ° C, 5% CO 2 , were digested with 0.25% trypsin, and counted in a 96-well plate at a certain ratio (37 ° C, 5% C0 2 ) Culture for 24h.
  • the samples were all dissolved in DMSO and diluted to 10 min serum RPMI 1640 medium to a working night concentration, and added to a 96-well plate at a final concentration of 100, 10, 1 ⁇ M.
  • the drug was in contact with the cells for 72 h.
  • Force B MTT (0.05%) was incubated at 37 ° C, 5% CO 2 for 4 h, and DMSO was added.
  • BIO The RAD450 microplate reader detects the optical density at two wavelengths of 570-655 nm and calculates its IC 5 . value.

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Abstract

La présente invention concerne des composés de formule (I), leurs sels pharmaceutiquement acceptables, des procédés de préparation et des compositions pharmaceutiques comprenant ceux-ci. Les composés de formule (I) et leurs sels pharmaceutiquement acceptables en tant qu'agents anticancéreux peuvent être utilisés pour traiter des cancers ou des tumeurs.
PCT/CN2011/075920 2011-06-20 2011-06-20 Série d'analogues d'ectéinascidines ayant un effet anticancéreux WO2012174699A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102190658A (zh) * 2010-03-15 2011-09-21 中国医学科学院药物研究所 一类抗肿瘤海洋天然产物ecteinascidins的结构类似物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102190658A (zh) * 2010-03-15 2011-09-21 中国医学科学院药物研究所 一类抗肿瘤海洋天然产物ecteinascidins的结构类似物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHAN-ZHU LIU ET AL.: "Synthesis and antitumor activity of simplified ecteinascidin-saframycin analogs.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 5, 2006, pages 1282 - 1285 *

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