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WO2011113175A1 - Dérivés de promédicament de cytarabine et utilisation associée dans la résistance contre le cancer ou une tumeur - Google Patents

Dérivés de promédicament de cytarabine et utilisation associée dans la résistance contre le cancer ou une tumeur Download PDF

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WO2011113175A1
WO2011113175A1 PCT/CN2010/000321 CN2010000321W WO2011113175A1 WO 2011113175 A1 WO2011113175 A1 WO 2011113175A1 CN 2010000321 W CN2010000321 W CN 2010000321W WO 2011113175 A1 WO2011113175 A1 WO 2011113175A1
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cytarabine
group
prodrug derivative
cytarabine prodrug
mmol
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Chinese (zh)
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高峰
徐峻
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical

Definitions

  • the invention relates to the technical field of medicine, in particular to a novel cytarabine prodrug derivative and a synthetic route thereof, and the invention also relates to a cytarabine prodrug derivative preparation, a preparation method thereof and a cytarabine The use of drug derivatives and their preparations in anti-cancer and anti-tumor.
  • Cancer is currently the most important disease that threatens human health.
  • the existing methods of treating cancer include: surgical resection, radiotherapy, chemotherapy or the combination of these methods.
  • Chemotherapy has gained widespread use and has been used in the treatment of many different types of cancer.
  • most of the anticancer drugs used in chemotherapy are limited to delaying the deterioration of cancer and prolonging the life of the patient.
  • the pathogenesis of various types of cancer varies, they are actually a large group of syndromes with common characteristics.
  • the physiological difference from normal cells is not large. This is a huge challenge for developing drugs that selectively clear cancer cells without killing normal cells.
  • Another major challenge in the development of anticancer drugs is cancer cell resistance, which is the drug resistance caused by a period of chemotherapy.
  • Cytarabine is an analog of cytidine nucleoside, an inhibitor of DNA polymerase. It can block DNA synthesis, can also be incorporated into DNA, interfere with DNA replication, and can also block the reduction of cytosine nucleotides into Deoxycytosine (Sylvester, RK, Fisher, AJ, and Lobell, ⁇ , Drug Intelligence & Clinical Pharmacy: Vol. 21, No. 2, pp. 177-180 (1987); Boyer et al., Novel Cytarabine Monophospate Prodrugs, United States Patent Application Publication, Pub. No. : US 2007/0037774 A 1, (Feb.
  • cytarabine is mainly used for the treatment of acute leukemia. It is the best for acute myeloid leukemia. It is also effective for acute monocytic leukemia and acute lymphoblastic leukemia. It has certain curative effect on malignant lymphoma, lung cancer, digestive tract cancer, head and neck cancer. It has viral keratitis and epidemic. Conjunctivitis and the like also have a certain effect, however, it is ineffective for most solid tumors. The activity of cytarabine is not very high.
  • cytarabine is generally associated with other drugs, such as: methoxy daunorubicin, all-trans retinoic acid combined with arsenic trioxide, pirarubicin, topotecan - Etoposide-cyclophosphamide, fludarabine, etc. are used in combination.
  • Cytarabine has side effects such as myelosuppression and digestive tract reaction.
  • a few patients may have side effects such as abnormal liver function, fever, and rash (Bolwell, BJ, Cassileth, PA, Gale, RP Leukemia. 2(5): 253-60 ( 1988); Kimby, E., Nygren, P., Glimelius, B. Acta Oncol.
  • Cytarabine is an antimetabolite, which is phosphorylated by deoxycytidine in cells, converted to active cytarabine, and further converted to the corresponding diphosphate and cytarabine. effect. Cytarabine inhibits DNA polymerase by interfering with the deoxycytidine triphosphate required for DNA synthesis, interfering with nucleotide incorporation into DNA, and inhibiting nucleotide reductase, preventing nucleotides from being converted into Deoxynucleotide, but has no significant effect on the synthesis of RNA and protein.
  • miftine and adefovir have been approved as anti-viral therapeutics for hepatitis B (Starrett, et al., "Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9 - [2 - (pho sphonomethoxy)ethy 1] adenine (PMEA)," J Med Chem., 37(12): 1857-64 (1994); Shaw, et al”"Pharmacokinextics and Metabolism of Selected Prodrugs of PMEA in Rats," Drug Metabolism Dis., 25(3): 362-366 (1997); Wacher, VJ, et al., Advanced Drug Delivery Reviews 46:89-102 (2001); Wacher, et al., "Active Secretion And Enterocytic Drug Metabolism Barriers to Drug Absorption," Adv.
  • Cytarabine is generally not used to treat liver cancer because its N4 amino group (see Figure 1) is metabolically deactivated and causes toxicity when its nucleoside skeleton structure enters the liver; on the other hand, its glycocalyx structure
  • the O5 hydroxyl group (see Figure 1) must be activated by phosphorylation, and this activation process is too slow in the liver. Summary of the invention
  • the present invention aims to overcome the deficiencies of the above prior art and provide an efficient, low toxicity, non-resistance, a cytarabine prodrug derivative capable of being rapidly activated, and a synthetic route of a cytarabine prodrug derivative and a preparation method of a cytarabine prodrug derivative preparation, and the present invention also provides an arsenic cell Experimental data on the use of glycoside prodrug derivatives and their formulations in anticancer and antitumor applications.
  • the cytarabine prodrug derivative of the present invention characterized in that the cytarabine prodrug derivative has any one of the following general formulae (I), (II) and (III) compound of:
  • X represents any one of OH, O-P OXOR ⁇ and phosphorus Stt
  • the monument Stt is any one of a monophosphoric acid group, a diphosphate group and a triphosphate group
  • R 2 is a C 1S saturated or unsaturated aliphatic group containing one or more unsaturated groups, the unsaturated group comprising a cis or trans isomer;
  • A represents O or S or CH 2 or no group;
  • R 3 is an amino group, an alkyl-substituted amino group, an aryl-substituted amino group, a heterocyclic-substituted amino group, NHOH, NHOR 4 and any of the following groups:
  • R 4 is a halogen atom, an amino group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a carboxyl group, a hydroxyl group, a cyano group, a trifluoromethyl group, a benzyl group, a phenyl group, an aromatic group, Any one of an acyl group, a carbonyl group, a substituted amino group, a yellow acid group, an amide group, a yellow amide group, an amino acid, a carbocyclic group and a heterocyclic group.
  • R 1 may be any one of H, Cw 8 alkyl, C 18 cycloalkyl, benzyl, phenyl and aromatic ring;
  • R 2 AH dC 18 alkyl, C 3-18 cycloalkyl Any one of C 2-18 alkenyl, C 2-18 alkynyl, cycloalkenyl, benzyl, phenyl, aryl, cyclic amino, carbocyclyl, heterocyclyl, anilino and substituted anilino .
  • Each of these groups may be further substituted, and may contain a hetero atom therein.
  • the cytarabine prodrug derivative of the formula (I) of the present invention includes a representative formula having the following structural formula
  • the cytarabine prodrug derivative of the formula (III) of the present invention includes a representative compound having the following structural formula:
  • alkyl means various saturated straight-chain, side-chain or cyclic hydrocarbon groups, particularly including small alkyl groups containing ten or ten carbons or less.
  • alkyl means various saturated straight-chain, side-chain or cyclic hydrocarbon groups, particularly including small alkyl groups containing ten or ten carbons or less.
  • a linear, branched or cyclic hydrocarbon group having at least one carbon-carbon double bond such as a vinyl group, a propenyl group, a butenyl group, a pentenyl group, and the like.
  • the "block group" used in the present invention is the above alkyl group or a sulfhydryl group and contains at least one carbon-carbon triple bond. Therefore, the alkynyl group includes a linear chain having two to ten carbon atoms and containing at least one carbon-carbon triple bond. A branched or cyclic hydrocarbon or alkynyl group such as ethynyl, propynyl, butynyl and pentynyl.
  • “Saturated” in the present invention means that the group does not contain an unsaturated bond, such as a carbon-carbon double bond or a carbon-carbon triple bond; and “unsaturated” means that the group contains one or more carbon-carbon doubles. Key or carbon-carbon triple bond.
  • the "cycloalkyl group” used in the present invention is a cyclic hydrocarbon group and preferably a cycloalkyl group having three to eight carbons.
  • cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane are all under this definition typical example.
  • a cycloalkyl group contains one or two carbon-carbon double bonds to form a "cycloalkenyl group".
  • the cycloalkyl group may also carry an alkyl group, an alkenyl group, an alkynyl group, and other groups.
  • aromatic group used in the present invention is a cyclic conjugated aromatic system and may contain one or more non-carbon atoms (other than carbon other nitrogen such as nitrogen) such as phenyl, naphthyl and pyridine in the ring. Base.
  • heterocyclic group which is also commonly used in the present invention means a cyclic group and a compound in which any plurality of atoms are constituted by a covalent bond, and which contains at least one non-carbon atom.
  • a heterocyclic group includes a five- and six-membered ring system containing a nitrogen, sulfur or oxygen non-carbon atom such as pyrazole, pyrrole, pyridine or pyrimidine.
  • alkoxy group in the present invention means an alkyloxy group formed by linking an oxygen atom to a linear or branched alkyl group.
  • alkoxy groups include a decyloxy group, an ethoxy group, a propoxy group or an isopropoxy group and the like.
  • alkylthio refers to an alkylthio group formed by linking a sulfur atom to a straight or branched alkyl group.
  • alkylthio group examples include a methylthio group, an ethylthio group, a propylthio group or an isopropylthio group.
  • halogen atom group in the present invention is fluorine, chlorine, bromine or iodine.
  • amino acid in the present invention means a substituted natural and non-natural amino acid, a pure L- or D-configuration or a racemic mixture, and a group derived from an amino group.
  • substituents defined above also include groups which are further substituted, wherein these new substituents may also contain other groups.
  • a ruthenium atom on an alkyl or aromatic group is substituted by an amino group, a halogen or other group to become a new group belonging to each of the above definitions.
  • the "prodrug” in the present invention means a compound which cleaves or increases the biological action formed by a certain structural unit in the body after the cytarabine prodrug derivative of the present invention is used in the body.
  • the organic solvents mentioned in the present invention include: benzotriazole hexafluorophosphate-1 benzyl-oxytripyrrole Phosphorus (PyBOP), 4-dimethylaminopyridine (DMAP), hydrazine, hydrazine-dimercaptocarboxamide (DMF), dimethyl sulfoxide (DMSO), polyethylene glycol (PEG) and tetrahydrofuran (THF) ).
  • Another technical problem solved by the present invention is to provide a simple and effective synthetic route for a plurality of cytarabine prodrug derivatives of the formula (I), (II) or (III), the technical disclosures of which are as follows :
  • a synthetic route for cytarabine prodrug derivatives characterized by:
  • the acid anhydride compound is any one of succinic anhydride, glutaric anhydride, adipic anhydride, and diglycolic anhydride;
  • the fatty alcohol is methanol, ethanol, n-octanol, lauryl alcohol, n-nonanol, and tetradecyl Any of alcohol, n-hexadecanol and stearyl alcohol. (Refer to synthetic route 1 ⁇ 5, 8, 9, 11, 12, 16-23)
  • the acid anhydride compound is any one of succinic anhydride, glutaric anhydride, adipic anhydride, and diglycolic anhydride. (Refer to synthetic route 14, 15)
  • the acid anhydride compound is any one of succinic anhydride, glutaric acid, adipic anhydride, and diethylene glycol;
  • the fatty alcohol is decyl alcohol, ethanol, n-octanol, n-nonanol, lauryl alcohol, Any one of tetradecanol, n-hexadecanol and stearyl alcohol. (Refer to synthetic route 6, 7, 10, 13)
  • a method for preparing a cytarabine prodrug derivative preparation characterized in that:
  • the preparation solution is further diluted with physiological saline or glucose injection to prepare a cytarabine prodrug derivative preparation.
  • the organic solvent is any one of ethanol, propylene glycol, glycerin, glyceride, polyethylene glycol (PEG), hydrazine, fluorenyl-dimercapto amide (DMF) and dimercapto sulfoxide (DMSO) or A variety of combinations of solvents.
  • the cytarabine prodrug derivative preparation of the present invention is characterized in that it is a product prepared by the above-described preparation method of the cytarabine prodrug derivative.
  • Such cancers include, but are not limited to, leukemia, solid tumors, lung cancer, colon cancer, liver cancer, central nervous system tumors, ovarian cancer, and kidney cancer.
  • the cancer includes, but is not limited to, cancer including leukemia, solid tumor, lung cancer, colon cancer, liver cancer, central nervous system tumor, Ovarian cancer and kidney cancer.
  • the cytarabine prodrug derivative preparation may also be used in combination with other chemotherapeutic drugs in anti-cancer and anti-tumor, the other chemotherapeutic drugs including alkylating agents, plant alkaloids, antibacterial anti-tumor amides, platinum Drugs, anti-metabolites and other known anti-cancer drugs.
  • at least one of the representative cytarabine prodrug derivatives having the above-listed enumeration is employed.
  • the pharmaceutical preparation is prepared by using the cytarabine prodrug derivative of the present invention as a component, and can be administered orally or parenterally.
  • the parenteral administration referred to herein means subcutaneous, intravascular, intraarterial, ⁇ ! Within a few flesh, in the atria, in the synovium, intrathoracic injection or drip.
  • the present invention contemplates the design of cytarabine prodrugs using new design techniques.
  • Cytarabine (see Figure 1) cannot be used to treat liver cancer.
  • its nucleoside skeleton structure enters the liver, its N4 amino group is metabolically deactivated and causes toxicity.
  • its glycoside structure The O5 hydroxyl group on it must be activated by phosphorylation, and this activation process is too slow in the liver.
  • the cytarabine prodrug derivative of the present invention is designed by chemically modifying the position of N4, 05 to design a novel prodrug derivative, thereby avoiding metabolic failure of N4 amino group and causing toxicity; It is easily activated by phosphorylation.
  • the main beneficial effects are: increased bioavailability, reduced multi-drug resistance (multi-targeted design techniques), increased solubility, and increased ester solubility.
  • the invention provides a synthetic route of a cytarabine prodrug derivative, a cytarabine prodrug derivative preparation and a preparation method thereof, and proves the cytarabine prodrug derivative of the present invention through a large amount of experimental data. Use in anti-cancer and anti-tumor.
  • Figure 1 is a schematic diagram showing the structure of cytarabine and the position of modification of N4, 05.
  • Fig. 2 is a view showing the structure of a representative cytarabine prodrug derivative of the formula -I of the present invention.
  • Fig. 3 is a view showing the structure of a representative cytarabine prodrug derivative of the formula -II of the present invention.
  • Fig. 4 is a view showing the structure of a representative cytarabine prodrug derivative of the formula -III of the present invention.
  • Fig. 5 is a graph showing the drug concentration-inhibition rate of the cytosine prodrug derivative of the present invention inhibiting the BEL-7402 liver cancer cell line. detailed description
  • cytarabine prodrug derivative 8 (Scheme 8): cytarabine (1 g, 4.1 mmol), first intermediate ⁇ 8 (0.81 g, 5.0 mmol) PyBOP ( 2.35 g, 4.5 mmol) and DMAP (0.055 g, 0.41 mmol) dissolved in DMF (10 ml).
  • cytarabine prodrug derivative 10 (Scheme 10): cytarabine hydrochloride (1.4 g, 5 mmol) and third intermediate D10 (1.92 g, 6.0 mmol) are dissolved in DMF (12 ml) Stir at room temperature for 2 days. DMF was distilled off. The oil was stirred and solidified with 25 ml of acetic acid for three times. The obtained semisolid crude product was neutralized with 10 ml of a 1 mol/L aqueous solution of NaHC0 3 .
  • Second intermediate C15 (Scheme 15): cycloalkylbenzimidazole (0.53 g, 2.1 mmol), succinic anhydride (0.25 g, 2.5 ml) and DMAP (0.2 g, 1.6 mmol) in Route 15 above. ) Dissolved in tetrahydrofuran (20 ml) at a controlled temperature of 35. C, reaction for 3 hours. After pouring into water, a solid was precipitated, and the second intermediate C15 of the obtained solid was filtered and used directly to the next reaction without further purification.
  • the cytarabine prodrug derivatives encompassed by the present invention have a function of inhibiting tumor cell proliferation and an antitumor effect.
  • Tumor cell cancers include, but are not limited to, blood cancer, intestinal cancer, skin cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, gastric cancer, uterine cancer, brain tumor, pigmentoma, prostate cancer, and the like. Synthetic drug tumor cytotoxicity
  • HL-60 cell line suspension growth, using RPMI 1640 containing 10% fetal bovine serum (Hyclone)
  • the cell culture medium was cultured, and the initial cell concentration was maintained at about 3*10 5 /ml, and passaged 1:3 once every three days. Passage (5* 10 5 /ml) one day before the experiment, the cell concentration during the experiment is between 7.5 ⁇ 10*10 5 /ml.
  • the BEL-7402 cell line and the HT-29 cell line were adherently grown and cultured in D-MEM cell culture medium of 10% fetal bovine serum (Hyclone).
  • the initial cell concentration of the conventional culture was about 3*10 5 /ml, 2 ⁇ 3 days 1: 3 pass once. On the day before the experiment, 1: 2 passage, the cell concentration during the experiment was between 5 ⁇ 10*10 5 /ml.
  • Cell seeding The cells were cultured 24 hours after passage and grew well. The cells were routinely harvested, and the cell concentration was adjusted to 2 x 10 5 /ml (adherent cells) ⁇ 3 x 10 5 /ml (suspended cells) with fresh medium. The adherent cells were inoculated at 100 ⁇ /well, cultured in a 37 ° C, 5% CO 2 incubator for 24 h, and the old culture solution was discarded, and fresh culture medium was added at 95 ⁇ M/well. Suspension cells were inoculated directly to 95 ⁇ /well.
  • Drug treatment There are 6 concentration gradients for each drug, 3 duplicate wells for each concentration, and 5 duplicate wells for the drug blank control group. Ara-C control was performed simultaneously for each test. The concentrations of HT-29 and BEL-7402 cells were 5, 2.5, 1.25, 0.625, 0.3125, 0.16 mM, 5 ⁇ l per well, and the final concentrations were 0.25, 0.125, 0.0625, 0.03125, 0.016, 0.008 mM, respectively.
  • the group was added with 5 ⁇ of normal saline; the concentration of HL-60 cells added to the drug was 5 ⁇ l (T 3 , 2.5xl0- 3, 1.25xl0- 3, 0.625xl0- 3 , 0.3125x10- 3, 0.16x10- 3 mM, corresponding to a final concentration followed 2.5 ⁇ 10 -4, 1.25 ⁇ 10 -4, 6 ⁇ 25 ⁇ 10 -5, 3 ⁇ 125 ⁇ 10 -5 , 1 ⁇ 6 ⁇ 10 -5 , 8xlO" 6 mM, 5 ⁇ saline was added to the control group.
  • Figure 5 is a graph showing the drug concentration-inhibition rate of cytosine prodrug derivative inhibiting BEL-7402 liver cancer cell line, wherein JF001, JF017, JF019, JF020 and JF033 are respectively according to the above synthetic routes 1, 17, 19, The cytarabine derivative obtained by synthesizing 20 and 33.
  • Table 1-2 lists representative cytarabine prodrug derivatives that inhibit the biological activity of different tumor cells.
  • JF004, JF006, JF007, JF009, JF010, JF013, JF014 and JF021 are cytarabine derivatives synthesized according to the above synthetic routes 4, 6, 7, 9, 10, 13, 14 and 21, respectively.

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Abstract

La présente invention concerne des dérivés de promédicament de cytarabine de formules générales (I), (II) et (III), leurs voies de synthèse, leurs préparations et leurs procédés de préparation, ainsi que leur utilisation dans la résistance contre le cancer ou une tumeur. Les dérivés sont préparés par modification chimique aux positions N4, O5 de la cytarabine, ce qui permet d'éviter la perte d'efficacité et l'induction de la toxicité provoquée par le métabolisme du groupe N4-amino, et ce qui facilite la phosphorylation et l'activation du groupe O5-hydroxy. Les dérivés permettent d'accroître la biodisponibilité, la solubilité et la liposolubilité, et de réduire la résistance pléïotrope.
PCT/CN2010/000321 2010-03-15 2010-03-15 Dérivés de promédicament de cytarabine et utilisation associée dans la résistance contre le cancer ou une tumeur Ceased WO2011113175A1 (fr)

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CN102351691A (zh) * 2011-09-26 2012-02-15 江苏同禾药业有限公司 一种己二酸单乙酯的合成方法
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CN102351691A (zh) * 2011-09-26 2012-02-15 江苏同禾药业有限公司 一种己二酸单乙酯的合成方法
WO2015044365A1 (fr) * 2013-09-27 2015-04-02 Astex Therapeutics Limited Dérivés de dinucléosides sous forme de promédicaments à base de gemcitabine et de cytarabine

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