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WO2015110040A1 - Dérivé de chlorambucil, procédé de préparation et utilisation - Google Patents

Dérivé de chlorambucil, procédé de préparation et utilisation Download PDF

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WO2015110040A1
WO2015110040A1 PCT/CN2015/071322 CN2015071322W WO2015110040A1 WO 2015110040 A1 WO2015110040 A1 WO 2015110040A1 CN 2015071322 W CN2015071322 W CN 2015071322W WO 2015110040 A1 WO2015110040 A1 WO 2015110040A1
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cancer
hydroxycamptothecin
chloroethyl
amino
bis
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Chinese (zh)
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张跃华
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    • 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
    • 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

Definitions

  • the present invention relates to a benzoic acid nitrogen mustard derivative, a pharmaceutically acceptable salt thereof, a preparation method, a preparation, and use as an antitumor drug.
  • targeted therapy has become an important direction for cancer treatment, using a single drug-targeted treatment mode, such as irinotecan (CPT-11) for the treatment of advanced colorectal cancer acting on DNA topoisomerase I.
  • paclitaxel (Taxol) or the like for treating ovarian cancer and breast cancer acting on intracellular microtubules.
  • tumors are different from general diseases. Its growth and survival depend not only on the conduction of a receptor or a signaling pathway, but the strategy of acting on a single target does not completely kill tumor cells and is easy to produce. Drug resistance. Therefore, the combination of multiple drugs has become the main means of clinical treatment of cancer.
  • Camptothecin (20(s)-camptothecin, formula 1-1) and its derivatives have excellent antitumor activity and are an important class of DNA topoisomerase I (Top I) inhibitors.
  • the I-DNA cleavable complex binds to form a CPT-Top I-DNA ternary complex, thereby stabilizing the cleavable complex, resulting in cell death.
  • camptothecin derivatives have been synthesized in order to increase the water solubility of the drug and preserve the anti-tumor properties of the parent compound.
  • Topotecan (formula 1-4) and irinotecan (Irinotrcan, formula 1-5) have been approved by the US Food and Drug Administration (FDA) for clinical use, respectively, for the treatment of ovarian cancer. , lung cancer and rectal cancer.
  • FDA US Food and Drug Administration
  • topotecan and irinotecan have obvious shortcomings, including short half-life in the body, large side effects and limited therapeutic effects.
  • camptothecin derivatives are in clinical research.
  • Nitrogen mustard compounds are anticancer drugs for clinical use and achieving outstanding therapeutic effects. It is a highly active compound which is a dichloroethylamine alkylating agent. After entering the body, nitrogen mustard compounds form a highly active ethyleneimine ion by intramolecular ring formation, and rapidly react with nucleophilic groups of various organic substances under neutral or weak base conditions (such as carboxyl and amino groups of proteins). The alkyl group is bonded to the thiol group, the amino group of the nucleic acid, and the hydroxyl group and the phosphate group. The most important reaction of nitrogen mustard compounds is to covalently bind to the 7th nitrogen of guanine, resulting in cross-linking within the double strand of DNA or cross-linking of different bases within the same strand of DNA.
  • the object of the present invention is to provide a chlorambucil derivative having the chemical structure of formulas I, II and III, which is 4-[bis(2-chloroethyl)amino]phenylbutyric acid with camptothecin or hi
  • R is H or a C1-C6 linear or branched saturated or unsaturated hydrocarbon group, preferably H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 or CH(CH 3 ) 2 , more preferably H or CH 2 CH 3 .
  • Another object of the present invention is to provide a method for synthesizing the chlorambucil derivative compounds I, II and III.
  • the above compound I, II or III can be produced by esterification of 4-[bis(2-chloroethyl)amino]phenylbutyric acid with camptothecin or camptothecin derivatives. Two preparation methods are preferred,
  • DMAP 4-dimethylaminopyridine
  • CMPI 2-chloro-1-methylpyridinium iodide
  • DCC N,N'-dicyclohexylcarbodiimide
  • DMAP dimethyl methacrylate
  • esterification reagents are coupling agents, 4-[bis(2-chloroethyl)amino]phenylbutyric acid directly with 7-R-10-hydroxycamptothecin or 10-hydroxycamptothecin or hi
  • the base is reacted to form a compound having the structure of the formula I or II or III, wherein R of the 7-R-10-hydroxycamptothecin is a C1-C6 linear or branched saturated or unsaturated hydrocarbon group, preferably R is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 or CH(CH 3 ) 2 .
  • the cancer includes, but is not limited to, a cancer of the blood system, such as leukemia, lymphoma, myeloma; 2 non-blood cancer, such as solid tumor cancer (such as breast cancer, ovarian cancer, pancreatic cancer, colon cancer, rectal cancer, non-small Cell lung cancer, bladder cancer, stomach cancer, liver cancer, etc.), sarcoma, skin cancer and glioma.
  • a cancer of the blood system such as leukemia, lymphoma, myeloma
  • 2 non-blood cancer such as solid tumor cancer (such as breast cancer, ovarian cancer, pancreatic cancer, colon cancer, rectal cancer, non-small Cell lung cancer, bladder cancer, stomach cancer, liver cancer, etc.), sarcoma, skin cancer and glioma.
  • the medicament comprises a therapeutically effective amount of a compound of formula I or II or III and a pharmaceutically acceptable pharmaceutical carrier. It may be an injection, an oral preparation or an external preparation. Preferred are emulsions, microemulsions, micelles, liposomes, tablets or capsules, and ointments.
  • Camptothecin and its derivatives have excellent antitumor activity and are an important class of DNA topoisomerase I (Top I) inhibitors, which can bind to Top I-DNA cleavable complexes to form CPT-Top. I-DNA ternary complexes, thereby stabilizing the cleavable complex, leading to cancer cell death.
  • Top I DNA topoisomerase I
  • 4-[Bis(2-chloroethyl)amino]phenylbutyric acid is a nitrogen mustard derivative which is a dichloroethylamine alkylating agent which is compatible with the 7th nitrogen of guanine of DNA.
  • chlorambucil is a nitrogen mustard derivative which is a dichloroethylamine alkylating agent which is compatible with the 7th nitrogen of guanine of DNA.
  • the combination of valences results in cross-linking within the double strand or cross-linking of different bases within the same strand, causing cancer cells to die. Similar to cyclophosphamide, it has inhibitory effects on various tumors and is clinically used for chronic lymphocyte white Blood diseases, lymphosarcoma, He Jinjie's disease, ovarian cancer, breast cancer, villus epithelioma, multiple myeloma, etc.
  • the molecules of the compounds I, II and III of the present invention simultaneously contain a dichloroethylamine alkylation group which can cross-link DNA bases and a camptothecin structure which inhibits DNA topoisomerase I (Top I), an expected molecule
  • the drug itself or its metabolites are produced in two types of cells for use in cancer cells, thereby producing a synergistic effect of inhibiting and killing cancer cells to improve efficacy and reduce toxic side effects.
  • the invention further relates to formulations of the novel chlorambucil derivatives, including emulsion or microemulsions, micelles, liposomes, tablets, capsules and ointments.
  • the emulsion comprises the chlorambucil derivative of the invention, one or more surfactants, an oil phase (lipophilic medium) and an aqueous phase.
  • the emulsion can be of the oil-in-water or water-in-oil type.
  • the micelle comprises the chlorambucil derivative of the present invention, a co-solvent and one or more surfactants and an aqueous phase.
  • Liposomal agents include the chlorambucil derivatives of the present invention, phospholipids (most notably lecithin, phosphatidylcholine), cholesterol and aqueous phases.
  • Tablets include the chlorambucil derivatives and adjuvants of the present invention.
  • Capsules include the chlorambucil derivatives and adjuvants of the present invention.
  • the ointment formulation includes the chlorambucil derivative and matrix of the present invention.
  • the technical solution adopted is an emulsion or microemulsion of the chlorambucil derivative of the present invention, and the composition thereof comprises:
  • Oil phase including:
  • a benzoic acid mustard derivative micelle of the present invention the composition of which comprises:
  • a phenylbutyrate mustard derivative liposome preparation of the present invention the composition of which comprises:
  • a tablet of the chlorambucil derivative of the present invention the composition of which comprises:
  • excipients include: 1 diluents, such as starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline cellulose (MCC), inorganic calcium salts, such as calcium sulfate.
  • 1 diluents such as starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline cellulose (MCC), inorganic calcium salts, such as calcium sulfate.
  • Adhesives such as distilled water, ethanol, starch slurry, sodium carboxymethyl cellulose sodium (CMC-Na), hydroxypropyl cellulose ( Hydroxypropylcellulose, HPC), methylcellulose and ethylcellulose (Methylcellulose, MC; Ethylcellulose, EC), Hydroxypropylmethylcellulose (HPMC), other binders (5% to 20% gelatin solution, 50% to 70% sucrose solution, 3% to 5% aqueous solution of polyvinylpyrrolidone (PVP) or alcohol solution); 3 Disintegrants such as dry starch, sodium carboxymethyl starch (Carboxymethyl) Starch sodium, CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross-linked polyvinyl pyrrolidone (also known as cross-linked PVP), cross-linked carboxymethyl cellulose Sodium (Croscarmellose sodium CCN
  • Tablets can be prepared by wet granulation tableting, dry granulation tableting and direct compression.
  • a capsule of the chlorambucil derivative of the present invention comprises a hard capsule and a soft capsule. Its ingredients include:
  • Common excipients for hard capsules include, but are not limited to: 1 diluent: used to improve the physical properties of the contents and increase the volume, often with a certain compressibility. Commonly used diluents are mannitol, microcrystalline cellulose, lactose, pregelatinized starch 1500, corn starch and the like. 2 Lubricant: To prevent adhesion of powder to metal materials. Commonly used are magnesium stearate, glyceryl monostearate, stearic acid, talc, and the like. 3 Glidant: Improve the fluidity of the contents. Commonly used are micro-silica gel and talcum powder. 4 disintegrant: to ensure the disintegration of the contents.
  • crosslinked cellulose corn starch, crospovidone, pregelatinized starch 1500, glycyl starch sodium, alginic acid and the like.
  • 5 Wetting agent increase the wettability of the drug and the dissolution medium to ensure the efficacy of the preparation.
  • Tween 80 sodium lauryl sulfate and the like.
  • Excipients in the soft capsule contents include, but are not limited to, oily dispersion or PEG dispersion, and the contents may be solutions, suspensions, emulsions, semi-solids, and the like.
  • Oily dispersion (lipophilic) content excipients include: 1 oily carrier: soybean oil, Castor oil, medium chain fatty acid, etc.; 2 semi-solids for viscosity adjustment include hydrogenated castor oil, beeswax, etc.; 3 surfactants such as phospholipids can improve the suspension stability of the suspension. Other stabilizers such as antioxidant BHT and the like may also be added.
  • the PEG-dispersed (hydrophilic) content excipients are typically PEG 400 and 600, and the semi-solid can be used with both low molecular weight PEG 200, 300 and polymeric PEG 4000-10000.
  • the hard capsule shell is similar to the soft capsule shell. It mainly contains gelatin, gum arabic, water, plasticizer (such as glycerin, and can also be added with proper amount of propylene glycol and polyethylene glycol 200. Mannitol or sorbitol can replace glycerin as plastic for plasticizing. Agents, preservatives (such as potassium sorbate, paraben, etc.), sunscreens and pigments, etc., wherein water acts as a solvent.
  • a paste of the chlorambucil derivative of the present invention the composition of which comprises:
  • Commonly used substrates include: hydrocarbons (such as petrolatum, paraffin wax, liquid paraffin, silicone), lipids (such as lanolin, beeswax and cetyl, dimethicone), oils and fats (such as animal and plant higher fatty acid glycerides) Its mixture).
  • hydrocarbons such as petrolatum, paraffin wax, liquid paraffin, silicone
  • lipids such as lanolin, beeswax and cetyl, dimethicone
  • oils and fats such as animal and plant higher fatty acid glycerides
  • the chlorambucil derivatives of the present invention are soluble in a lipophilic medium.
  • the lipophilic medium (or carrier) can be any one of a biocompatible lipophilic medium, and representative biocompatible lipophilic media include:
  • Fats and oils that can be used as lipophilic media including fatty acids and esters of different chain lengths, which are mostly linear, but may also be branched, such as capric acid, caprylic acid, caproic acid, lauric acid, nutmeg, hard Fatty acid, oleic acid, linoleic acid, and other saturated or unsaturated fatty acids and esters.
  • Vitamin E refers to the natural or synthetic vitamin E series, commonly referred to as tocopherols and tocotriols (tocopherols and tocotrienols), tocopherols including alpha-tocopherol (D, DL, L), beta - Tocopherol (D type, DL type, L type), ⁇ -tocopherol (D type, DL type, L type) and ⁇ -tocopherol (D type, DL type, L type).
  • Tocotrienol is structurally similar to tocopherol, but tocotrienol has three double bonds on the side chain phytyl of carbon-2.
  • Tocotrienols include ⁇ -tocotrienol (D type, DL type, L type), ⁇ -tocotrienol (D type, DL type, L type), ⁇ -tocotrienol (D type, DL) Type, L type) and ⁇ -tocotrienol (D type, DL type, L type).
  • Vitamin E derivatives include all tocopherol and tocotrienol derivatives such as vitamin E succinate, vitamin E acetate and the like.
  • Monoglycerides, diglycerides or triglycerides formed by esterification of fatty acids with glycerol, whether they are synthetic or natural, can be used as lipophilic media, for example, glycerides such as soybean oil, cottonseed oil, Rapeseed oil, fish oil, acetylated monoglyceride, glycerol monooleate, triacetin, and diacetyl tartaric acid ester, monoglyceride, castor oil and the like.
  • glycerides such as soybean oil, cottonseed oil, Rapeseed oil, fish oil, acetylated monoglyceride, glycerol monooleate, triacetin, and diacetyl tartaric acid ester, monoglyceride, castor oil and the like.
  • Fatty alcohols such as benzyl alcohol, stearyl alcohol, lauryl alcohol, etc., or their esters or ethers, such as benzyl benzoate.
  • Representative surfactants include:
  • Polyethylene glycol surfactants such as polyoxyethylene castor oil EL (Cremophor EL), Tween series surfactants, and the like.
  • Phospholipids such as lecithin and pegylated phospholipids.
  • vitamin E derivatives such as vitamin E succinate polyethylene glycol (d- ⁇ -tocopherol polyethylene glycol 1000succinate, TPGS).
  • Polyoxyethylene polyoxypropylene block copolymer block copolymer of POLOXAMERS or PLURONICS (H(OCH2CH2)a(OCH2CH2CH2)b(OCH2CH2)aOH).
  • organic co-solvents include:
  • Ethanol polyethylene glycol, propylene glycol, glycerin, N-methylpyrrolidone, and the like.
  • Polyethylene glycol (PEG) is hydrophilic, and the chemical structure of the repeating unit is -CH 2 CH 2 O-, the formula is H-(CH 2 CH 2 ) n -OH, and the molecular weight range is generally from 200 to 10,000. .
  • PEG polyethylene glycol
  • PEG-300 polyethylene glycol 400, and the like.
  • the chlorambucil derivatives of the present invention are included in the formulation.
  • emulsion refers to a droplet formed by a heterogeneous liquid dispersion system, such as oil and water, formed by the dispersion of one phase liquid in a droplet state in another phase liquid under the action of a surfactant. Its diameter is generally from 0.1 to 3.0 microns.
  • the emulsion can form a stable microemulsion.
  • microemulsion means that two immiscible liquids form a thermodynamically stable isotropic, transparent or translucent dispersion.
  • a microemulsion dispersion of oil and water is an interface formed by surfactant molecules.
  • the membrane is stable.
  • the microemulsion has an average droplet diameter of less than 200 nm, typically 10 to 50 nm.
  • the oil phase and the water phase are included in the emulsion or microemulsion.
  • the emulsion or microemulsion may be an oil-in-water emulsified or water-in-oil type.
  • a homogeneous, transparent drug-containing solution formed by the mixing of an oil phase, a nonionic surfactant, and a co-emulsifier is called a self-emulsifying drug delivery system (SEDDS).
  • the phenylbutyric acid mustard derivative of the present invention accounts for 0.005% to 5.0% by weight of the formulation; preferably, the weight percentage in the formulation is 0.01% to 2.5%; in a more preferred embodiment, the chlorambucil derivative of the present invention accounts for 0.1% to 1.5% by weight of the formulation.
  • the lipophilic medium accounts for 2% to 20% by weight of the formulation; preferably the lipophilic medium accounts for 4% to 12% by weight of the formulation; more preferably In the solution, the lipophilic medium accounts for 6% to 10% by weight of the formulation.
  • the lipophilic medium comprises soybean oil and the aqueous medium is water. In another embodiment of the emulsion and microemulsion, the lipophilic medium comprises an oil soluble vitamin E. In another embodiment of the emulsion or microemulsion, the lipophilic medium comprises an oil soluble vitamin E derivative.
  • the emulsion or microemulsion formulation may also include other ingredients commonly used in pharmaceutical emulsions and microemulsions, including surfactants and co-solvents.
  • Representative surfactants include nonionic surfactants such as Cremophor EL, Tween 80, polyethylene glycol vitamin E derivative surfactants and other surfactants. polymer.
  • Suitable polyethylene glycol vitamin E derivative surface activities include vitamin E succinic polyethylene glycol derivatives (such as vitamin E polyethylene glycol succinate), in the vitamin E derivative molecule, polyethylene glycol is Succinic acid is formed by linking the hydroxyl group of vitamin E.
  • the polyethylene glycol in the polyethylene glycol derivative of these vitamin E includes polyethylene glycol having various molecular weights (for example, 200, 300, 400, 600, 1000, etc.). alcohol.
  • vitamin E polyethylene glycol succinate such as D-alpha tocopherol polyethylene glycol 1000 succinate, TPGS, a nonionic surfactant
  • the surfactant is present in the formulation in an amount of from about 1% to about 10%, preferably from 2% to 6%, more preferably from 4% to 5% by weight.
  • the co-solvent comprises from about 0% to about 20% by weight of the formulation.
  • the present invention provides a micelle preparation of the chlorambucil derivative of the present invention comprising the chlorambucil derivative of the present invention, one or more surfactants, One or more co-solvents and an aqueous phase.
  • the pharmaceutical compound is present in the formulation in an amount of from about 0.005% to about 3.0% by weight, preferably the pharmaceutical compound is present in the formulation in an amount of from about 0.01% by weight to 2.5%; more preferably, the pharmaceutical compound is present in the formulation in an amount of from about 0.1% to about 1.0% by weight.
  • Suitable surfactants are present in the micellar formulations of the invention in an amount of from about 1% to about 10%, preferably from 2% to 6%, more preferably from 4% to 5% by weight.
  • the micelle formulation also includes other ingredients such as the cosolvents mentioned above.
  • the micelle formulation comprises polyethylene glycol and a lower alkyl alcohol (such as ethanol).
  • the co-solvent comprises from about 1% to about 20% by weight of the formulation.
  • the present invention provides a liposome agent of the chlorambucil derivative of the present invention comprising the chlorambucil derivative of the present invention, one or more phospholipids (including PEG) Phospholipids), one or more lipophilic mediators (such as cholesterol) and an aqueous phase.
  • a liposome agent of the chlorambucil derivative of the present invention comprising the chlorambucil derivative of the present invention, one or more phospholipids (including PEG) Phospholipids), one or more lipophilic mediators (such as cholesterol) and an aqueous phase.
  • the weight percentage of the pharmaceutical compound in the formulation From about 0.005% to about 5.0%, preferably the pharmaceutical compound is present in the formulation at a weight percent of from about 0.01% to about 2.5%; more preferably, the pharmaceutical compound is present in the formulation at a weight percent of from about 0.1% to about 1.5%.
  • Suitable phospholipids are present in the liposome formulation of the invention in an amount of from about 1% to about 10%, preferably from 2% to 6%, more preferably from 4% to 5% by weight.
  • the liposome formulation also includes other ingredients such as the lipophilic medium (e.g., cholesterol) as mentioned above.
  • the liposomal formulation comprises cholesterol or vitamin E.
  • cholesterol or vitamin E is about 0.1% to 20% by weight of the formulation.
  • the aqueous phase is included in the emulsion, microemulsion, micelle, and liposome formulations.
  • the aqueous phase comprises deionized water.
  • the aqueous phase comprises physiological saline.
  • the aqueous phase contains an acid such as succinic acid, citric acid, phosphoric acid) buffer.
  • the present invention provides a tablet of the chlorambucil derivative of the present invention comprising the chlorambucil derivative and the adjuvant of the present invention.
  • the chlorambucil derivative of the present invention may be contained in an amount of from 1 mg to 1000 mg per tablet. In a preferred embodiment, the chlorambucil derivative of the present invention has a content of 10 mg per tablet. Up to 500 mg; in a more preferred embodiment, the chlorambucil derivative of the present invention is contained in an amount of from 20 mg to 250 mg per tablet.
  • the present invention provides a capsule of the chlorambucil derivative of the present invention comprising the chlorambucil derivative and the adjuvant of the present invention.
  • the content of the chlorambucil derivative of the present invention may be from 1 mg to 1000 mg per capsule.
  • the content of the chlorambucil derivative of the present invention in each capsule is 10 mg to 500 mg; in a more preferred embodiment, the chlorambucil derivative of the present invention is contained in an amount of 20 mg to 250 mg per one.
  • the present invention provides a cream of the chlorambucil derivative of the present invention comprising the chlorambucil derivative of the present invention, one or more matrices.
  • the phenylbutyric acid mustard derivative of the present invention is present in an amount of from 0.01% to 30% by weight in the paste, preferably from 0.05% to 20% by weight of the pharmaceutical compound in the formulation; more preferably, The pharmaceutical compound is present in the formulation in an amount of from about 0.1% to about 10% by weight.
  • the invention also provides the use of the newly invented pharmaceutical compound, that is, the use of the chlorambucil derivative of the invention in the preparation of an anticancer drug.
  • the pharmaceutical compounds of the invention are useful in the manufacture of a medicament for the treatment of cancer.
  • the pharmaceutical compound of the present invention can be used for the treatment of cancer including the blood system such as leukemia, lymphoma, myeloma; and non-blood cancer such as solid tumor cancer (such as breast cancer, ovarian cancer, pancreatic cancer, colon cancer, rectal cancer, non- Small cell lung cancer, bladder cancer, stomach cancer, liver cancer, etc.), meat Tumor, skin cancer and glioma.
  • the blood system such as leukemia, lymphoma, myeloma
  • non-blood cancer such as solid tumor cancer (such as breast cancer, ovarian cancer, pancreatic cancer, colon cancer, rectal cancer, non- Small cell lung cancer, bladder cancer, stomach cancer, liver cancer, etc.), meat Tumor, skin cancer and glioma.
  • the efficacy and toxicity of the pharmaceutical compounds of the present invention are determined by in vitro cell or in vivo animal experiments, for example, ED50 (50% effective dose, half effective amount: 50% of the dose when the subject is positive), LD50 (50% lethal) Dose, half-lethal dose, killing half of the test subject) and GI50 (concentration of the anti-cancer drug that inhibits the growth of cancer cells by 50%, inhibiting the concentration of the drug in 50% of the subjects).
  • the ratio of the median lethal dose (LD50) / half effective dose (ED50) is usually referred to as the therapeutic index to indicate the safety of the drug. Drugs with a large therapeutic index are safer than drugs with a small therapeutic index.
  • the newly invented anticancer drug compound aims to improve the therapeutic index and the safety of the drug while also improving the therapeutic effect.
  • the dose of the drug obtained from in vitro cell experiments and in vivo animal experiments can be used to formulate a dose range for the human body.
  • the dose of such a compound is preferably in the range of ED50 with little or no toxicity.
  • the dosage change will generally depend on the dosage form employed, the sensitivity of the patient, and the route of administration.
  • a conventional dose of topotecan is 0.2-1.5 mg/m 2
  • a conventional dose of irinotecan is 100 mg-350 mg/m 2 .
  • the pharmaceutical compounds of the invention may be used alone or in combination with one or more other therapeutic agents.
  • these pharmaceutical compounds can be used with the following therapeutic agents including, but not limited to, androgen inhibitors such as flutamide and luprolide; antiestrogens, such as Tamoxifen; antimetabolites and cytotoxic drugs such as daunorubicin, fluorouracil, floxuridine, interferon alpha, Methotrexate, plicamycin, mecaptopurine, thioguanine, adriamycin, carmustine, lomustine Lomustine), cytarabine, cyclophosphamide, doxorubicin, estramustine, altretamine, hydroxyurea, ifosfamide (ifosfamide), procarbazine, mutamycin, busulfan, mitoxantrone, carboplatin, cisplatin, streptozotocin (streptozocin),
  • therapeutic agents including, but
  • the liquid chromatogram of XBB-001 is shown in Figure 3, purity: 99.07%; chromatographic conditions: column: C18 column (5 ⁇ m, 150 mm ⁇ 5 mm); mobile phase: CH 3 CN: IPA: HAc (95: 5: 0.1); detection wavelength: 254 nm; flow rate: 1.0 ml/min; injection amount: 5 ⁇ L; column temperature: 40 °C.
  • Fig. 4 The nuclear magnetic resonance spectrum of XBB-002 is shown in Fig. 4, and the mass spectrum is shown in Fig. 5.
  • the liquid chromatogram of XBB-002 is shown in Figure 6, purity: 98.8%; chromatographic conditions: column: C18 column (5 ⁇ m, 150mm ⁇ 5mm); mobile phase: acetonitrile: water (70:30); detection wavelength: 254 nm; flow rate: 1.0 ml/min; injection amount: 5 ⁇ L; column temperature: 40 °C.
  • the column layer was separated, and 100-200 mesh silica gel was used as a stationary phase, and a mixture of dichloromethane and ethyl acetate was used as a eluent to give a pale yellow solid (0.462 g).
  • the XBB-003 nuclear magnetic resonance spectrum is shown in Fig. 7, and the mass spectrum is shown in Fig. 8.
  • the liquid chromatogram of XBB-003 is shown in Figure 9, purity: 94.55%; chromatographic conditions: column: C18 column (5 ⁇ m, 150mm ⁇ 5mm); mobile phase: acetonitrile: water (80:20); detection wavelength: 254 nm; flow rate: 1.0 ml/min; injection amount: 5 ⁇ L; column temperature: 40 °C.
  • the liquid chromatogram of XBB-004 is shown in Figure 12, purity: 96.82%; chromatographic conditions: column: C18 column (5 ⁇ m, 150 mm ⁇ 5 mm); mobile phase: acetonitrile: water (85: 15); detection wavelength: 254 nm; flow rate: 1.0 ml/min; injection amount: 5 ⁇ L; column temperature: 40 °C.
  • Example 5 Formulation of the chlorambucil derivative of the present invention, including emulsion, micelle, liposome, tablet, capsule and ointment formulation
  • an emulsion, a micelle, a liposome, a tablet, a capsule, and a paste formulation of the chlorambucil derivative of the present invention are included.
  • the emulsion, micelle, liposome, tablet, capsule and ointment formulation contains the chlorambucil derivative of the present invention, optionally one or more of the compounds of formula I, II or III .
  • the prepared emulsion drug was filtered through a 0.2 micron filter and placed in a sterile glass bottle.
  • the resulting emulsion drug was filtered through a 0.2 micron filter and placed in a sterile glass vial.
  • XBB-001 4-[Bis(2-chloroethyl)amino]phenylbutyric acid camptothecin (XBB-001) is dissolved in a mixture of soybean oil, Tween 80 and polyethylene glycol PEG (200), and then deionized water is added. (DI water), then stirred and emulsified or emulsified with a homogenizer.
  • DI water deionized water
  • the prepared emulsion drug was filtered through a 0.2 micron filter and placed in a sterile glass bottle.
  • XBB-003 4-[Bis(2-chloroethyl)amino]benzophenone 10-hydroxy acid camptothecin (XBB-003) is dissolved in a mixture of soybean oil, Tween 80 and polyethylene glycol PEG (200), and then added Deionized water (DI water), then stirred and emulsified or emulsified with a homogenizer.
  • DI water Deionized water
  • the prepared emulsion drug was filtered through a 0.2 micron filter and placed in a sterile glass bottle.
  • the prepared emulsion drug was filtered through a 0.2 micron filter and placed in a sterile glass bottle.
  • the prepared micelle drug was filtered through a 0.2 micron filter and used.
  • the prepared micelle drug was filtered through a 0.2 micron filter and used.
  • the prepared micelle drug was filtered through a 0.2 micron filter and used.
  • the prepared micelle drug was filtered through a 0.2 micron filter and used.
  • the prepared micelle drug was filtered through a 0.2 micron filter and used.
  • each capsule Percentage of each component (%) XBB-002 100 40 Tween 80 5 2 lactose 50 20 Magnesium stearate 5 2 Sodium starch glycolate 90 36 Total weight of each capsule 250
  • This experiment compares the chlorambucil derivative of the present invention with the anticancer drug irinotecan to inhibit A549 (human non-small cell lung cancer), BGC-823 (human gastric adenocarcinoma), HepG2 cells (human liver cancer cells). ), GI50 values of K562 cells (human chronic myeloid leukemia cells), HT-29 cells (human colon cancer cells) (drug concentrations inhibiting 50% growth of cancer cells), and evaluation of in vitro cytotoxicity of the drug compounds.
  • Adherent cells adopt SRB method, suspension cells adopt CCK-8 law.
  • the IC50 values are shown in Table 1.
  • Table 1 The experimental results show that the chlorambucil derivatives of the present invention have obvious proliferation inhibition effects on the above five kinds of cancer cells, and the inhibitory activities are higher than that of irinotecan, especially XBB-002. It has a strong inhibitory activity on cancer cells.
  • the IC50 value of irinotecan at 48 hours is about 10 ⁇ M, while the IC50 value of XBB-002 is about 0.1 ⁇ M, which is much lower than the IC50 value of irinotecan, indicating that the inhibitory activity of XBB-002 on cancer cells is much higher than that of irinotecan.
  • XBB-002 has a high inhibition rate of 100% at high concentrations, which can kill cancer cells.
  • the suspension cells were added with CCK-8, 10 ⁇ L/well, and after incubation at 37 ° C for 2 hours, the absorbance at 450 nm was read to calculate the inhibition rate;
  • Adherent cells were fixed with trichloroacetic acid (TCA), and each well was fixed with 25 ⁇ L of pre-cooled 50% TCA solution (the final concentration of TCA was 10%). When adding TCA, it must be gently added to the surface of the culture solution. After standing for 5 min, the plate was moved to 4 ° C for 1 h, so that the cells were fixed at the bottom of the culture well;
  • TCA trichloroacetic acid
  • SRB was formulated into a 0.4% solution with 1% acetic acid, 100 ⁇ L of RBRB solution was added to each well, and allowed to stand at room temperature for 10 min. SRB not bound to protein was washed 5 times with 1% acetic acid and air dried;
  • the IC50 values are shown in Table 2.
  • the experimental results show that the chlorambucil derivatives of the present invention have a significant proliferation inhibitory effect on human colon cancer cell Caco-2, and the cells are increased with the increase of drug concentration. The proliferation inhibition is enhanced and cancer cells can be killed.
  • the Caco-2 cell line was cultured to a good state and viable, and the log phase cells were collected, seeded on a 96-well culture plate, and plated so that the density of the cells to be tested was 8 ⁇ 10 3 per well, and the marginal wells were filled with sterile PBS. Incubate in a 5% CO 2 , 37 ° C cell incubator, and start testing after the cells are attached to 60%-70% of the cells.
  • Each group was given a blank control group, a negative control group and a drug administration group.
  • the blank control group contained no cells, the negative control group did not add the drug, and the concentration (final concentration) gradient of the administration group was set as shown in 3.1.
  • each compound After dissolving each compound, it was sterilized by filtration and diluted to the corresponding concentration with a medium.
  • the injection volume per well was 150 ⁇ L (the control DMSO content was 0.5% in the final volume), and 6 replicate wells were set for each administration dose.
  • the drug-containing hole media was aspirated, washed twice with PBS, sterile filtered after adding 200 ⁇ L of MTT solution (0.5mg / mL), placed in cell culture Continue to culture for 4 hours in the box. Stop the culture and discard the supernatant.
  • 150 ⁇ L of DMSO was added to each well, and the mixture was shaken at 37 ° C for 10 min at a low speed to sufficiently dissolve the methyl violet crystal, and the OD value was measured at a wavelength of 490 nm.

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Abstract

La présente invention concerne un dérivé de chlorambucil présentant une structure de formule I, II, ou III, et un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne également un procédé de préparation du composé précédent, une préparation et une utilisation associées.
PCT/CN2015/071322 2014-01-23 2015-01-22 Dérivé de chlorambucil, procédé de préparation et utilisation Ceased WO2015110040A1 (fr)

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CN105859570A (zh) * 2016-04-14 2016-08-17 梯尔希（南京）药物研发有限公司 一种苯丁酸氮芥衍生物的制备方法
CN106588946B (zh) * 2017-01-25 2019-01-22 郑州大学 10-羟基喜树碱衍生物、合成方法及其应用
CN109384730B (zh) * 2017-08-10 2022-02-18 南京友怡医药科技有限公司 1-{3-[对-双-(2-氯乙基)胺基]苯丙胺基}甲酰-5-氟脲嘧啶及制备和应用
CN118878468A (zh) * 2024-07-11 2024-11-01 贵州大学 一种含苯基氮芥片段的二氨基嘧啶类化合物及其制备方法与应用

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