CN113979954A - Teninil antitumor drug compound and preparation method and application thereof - Google Patents

Teninil antitumor drug compound and preparation method and application thereof Download PDF

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CN113979954A
CN113979954A CN202111354228.7A CN202111354228A CN113979954A CN 113979954 A CN113979954 A CN 113979954A CN 202111354228 A CN202111354228 A CN 202111354228A CN 113979954 A CN113979954 A CN 113979954A
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tinib
cancer
drug compound
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CN113979954B (en
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张跃华
赵梦尧
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Nanjing Youyi Medical Technology Co ltd
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Abstract

The invention discloses a tinib antitumor drug compound with a systematic name of 4- [ bis (2-chloroethyl) amino]4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline amide which is a phenylalkyl acid having the general structural formula I, wherein n is an integer of 0 to 10. The invention also relates to a preparation, a preparation method and application of the tinib antitumor drug compound.
Figure DDA0003351273650000011

Description

Teninil antitumor drug compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of antitumor compound synthesis, and particularly relates to a novel tinib antitumor compound, a preparation method thereof, a preparation of the compound and application of the compound in preparation of an anticancer drug.
Background
The tumor is a disease seriously harming human life health, and is an abnormal pathological change formed by the loss of normal regulation and control of local tissue cells on the gene level under the action of carcinogenic factors of an organism, so that the clonal abnormal hyperplasia of the local tissue cells is caused, and the abnormal pathological change is expressed as the abnormal hyperproliferation and differentiation of the cells. Cancer has now become the first cause of death in humans, and represents the most serious threat to human survival.
The development of tinib antitumor drugs successfully brings cancer into the targeted therapy era, and the target is human epidermal growth factor tyrosine kinase receptor, which comprises the following steps: erbB1(EGFR, HER-1), erbB2(HER-2, neu), erbB3(HER-3), erbB4(HER-4) and the like, wherein the tinib medicaments greatly improve the life quality of a patient while prolonging the life time of the patient. Therefore, the development of novel high-efficiency low-toxicity targeted tinib antitumor drugs has important significance.
Disclosure of Invention
The invention aims to provide a novel targeted tinib antitumor drug compound which has the characteristics of high antitumor activity and low toxic and side effects.
The invention also aims to provide a synthesis method of the nylon antitumor drug compound.
The invention also aims to provide a preparation of the tinib antitumor drug compound, which comprises tablets, capsules, emulsions, micelle agents, liposomes, paste and the like.
Meanwhile, the invention also aims to provide the application of the tinib antitumor drug compound in preparing antitumor drugs.
The molecular formula of the tinib antitumor drug compound is shown as the general formula I:
Figure BDA0003351273630000011
wherein n is an integer of 0 to 10.
The compound has the systematic name of 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide.
The invention also relates to a preparation method of the tinib antitumor drug compound, which comprises the following steps:
1) preparing an intermediate 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5);
2)4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) and 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or derivative (6) thereof are subjected to acylation reaction to prepare the tinib antitumor drug compound (I), wherein the reaction formula is shown as the following formula 1
Figure BDA0003351273630000021
Wherein n is an integer of 0 to 10, X is OH, Cl, OR OCOR, and R is a hydrocarbon group.
The 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or the derivative (6) thereof is preferably 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid chloride.
Preferably, in the acylation reaction, the molar ratio of the 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) to the 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or the derivative thereof (6) is 1: 1 to 1.5.
Preferably, the condensing agent for the acylation reaction is selected from one or more of 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), Dicyclohexylcarbodiimide (DCC), N, N ' -Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) or Diisopropylcarbodiimide (DIC); the acid-binding agent is one or more selected from triethylamine, pyridine, diisopropylethylamine, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.
The preparation method of the intermediate 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) has been extensively studied and disclosed as an intermediate in the preparation of numerous tinib compounds in the prior art, for example, see the method disclosed in WO2005107758A 1.
Specifically and preferably, the preparation method of the tinib antitumor drug compound has a reaction formula shown as a formula 2:
Figure BDA0003351273630000031
the synthesis steps comprise:
(1) synthesizing 7-methoxy-6-nitro quinazoline-4 (3H) -ketone (2) by using 7-fluoro-6-nitro quinazoline-4 (3H) -ketone (1) as a raw material;
(2) reacting the 7-methoxy-6-nitro quinazoline-4 (3H) -ketone (2) obtained in the step (1) with phosphorus oxychloride to generate 4-chloro-7-methoxy-6-nitro quinazoline (3);
(3) 4-chloro-7-methoxy-6-nitroquinazoline (3) reacts with 3-chloro-4-fluoroaniline to produce 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-nitroquinazoline (4);
(4)4- (3-chloro-4-fluoroanilino) -7-methoxy-6-nitroquinazoline (4) reacts with iron powder to generate 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5);
(5)4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) reacts with 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or 4- [ bis (2-chloroethyl) amino ] phenylalkyl acyl chloride to produce the antitumor drug compound (I).
The invention also relates to a preparation of the tinib antitumor drug compound, namely a composition containing the tinib antitumor drug compound, wherein the composition contains an effective treatment amount of the tinib antitumor drug compound and pharmaceutically acceptable auxiliary materials.
The preparation of the tinib antitumor drug compound can be an oral preparation, an injection or an external preparation, and comprises tablets, capsules, liposome, emulsion or microemulsion, micelle, paste and the like. The tablet comprises the novel tinib antitumor drug compound and auxiliary materials. The capsule comprises the novel tinib antitumor drug compound and auxiliary materials. The liposome agent comprises the novel inventive antitumor drug compound of the tinib class, phospholipid (most typically lecithin and phosphatidylcholine), cholesterol and water phase. The emulsion comprises the novel inventive antitumor drug compound of the tinib class, one or more surfactants, an oil phase (lipophilic medium) and an aqueous phase. Emulsions may be of the oil-in-water or water-in-oil type. The micelle agent comprises the novel tinib antitumor drug compound, a cosolvent, one or more surfactants and a water phase. The ointment formula comprises the novel tinib antitumor drug compound and a matrix.
The tablet of the anticancer drug compound in the tinib class comprises the following components:
(1) the tinib antitumor drug compound of the invention;
(2) and (5) auxiliary materials.
Commonly used excipients include: diluents (Diluents), such as starch, powdered sugar, dextrin, lactose, Pregelatinized starch (Pregelatinized starch), Microcrystalline cellulose (MCC), inorganic calcium salts, such as calcium sulfate, calcium hydrogen phosphate and calcium carbonate for pharmaceutical use, mannitol; (iv) binders (Adhesives) such as distilled water, ethanol, starch slurry, sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), Methylcellulose and Ethylcellulose (MC; ethcellulose, EC), hypromellose (hydroxypropyl cellulose, HPMC), other binders (5-20% gelatin solution, 50-70% sucrose solution, 3-5% aqueous or alcoholic solution of polyvinyl pyrrolidone (PVP)); (iii) Disintegrants (Disintegrants) such as dry starch, sodium Carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), crospovidone (also known as Cross-linked PVP), Croscarmellose sodium (CCNa is a Cross-linked Carboxymethyl cellulose ether (about 70% of the carboxyl groups are sodium salt type)), Lubricants (Lubricants) such as magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, Aerosil, talc, colorants, flavors, etc. whatever excipients are added, they should meet the pharmaceutical requirements, and should not react with, nor interfere with dissolution and absorption of the primary drug.
The tablet can be prepared by wet granulation and tabletting, dry granulation and tabletting and direct tabletting.
Or capsules of the anti-cancer medicine compound of the tinib class, including hard capsules and soft capsules. The components of the composition are as follows:
1) the tinib antitumor drug compound of the invention;
2) and (5) auxiliary materials.
Common adjuvants for hard gelatin capsules include, but are not limited to: the diluent is: for improving the physical properties of the contents and increasing the volume, often with some compressibility. Common diluents are mannitol, microcrystalline cellulose, lactose, pregelatinized starch 1500, corn starch, and the like. (ii) a lubricant: to prevent the adhesion of the powder to the metal material. Magnesium stearate, glyceryl monostearate, stearic acid, pulvis Talci, etc. are commonly used. ③ glidant: improve the fluidity of the contents. Silica powder, talc powder, etc. are commonly used. (iv) a disintegrant: ensuring the disintegration of the content. The common examples include crosslinked cellulose, corn starch, crospovidone, pregelatinized starch 1500, glycyl starch sodium, alginic acid, etc. Wetting agent: the wettability of the medicine and the dissolution medium is increased, and the efficacy of the preparation is ensured. Tween 80, sodium dodecyl sulfate, etc. are commonly used.
The adjuvant in the soft capsule content includes but is not limited to oily dispersion or PEG dispersion, and the content can be solution, suspension, emulsion, semisolid and the like. Oily dispersed (lipophilic) content adjuvants include: oily vehicle: soybean oil, castor oil, medium-chain fatty acids, and the like; ② the semisolid used for adjusting the viscosity includes hydrogenated castor oil, beeswax and the like; ③ surfactants such as phospholipids can improve the suspension stability of the suspension. Other stabilizers such as antioxidant BHT, etc. may also be added. PEG dispersed (hydrophilic) content adjuvants are usually PEG400 and PEG 600, and low molecular weight PEG200, 300 and high molecular weight PEG4000-10000 can be used together in semisolid.
The hard capsule shell is similar to soft capsule shell, and mainly contains gelatin, acacia, water, plasticizer (such as glycerol, and appropriate amount of propylene glycol and polyethylene glycol 200 can also be added, mannitol or sorbitol can replace glycerol to be used as plasticizer of rubber skin), antiseptic (such as potassium sorbate, nipagin, etc.), opacifier and pigment, etc., wherein water is used as solvent.
Alternatively, the ointment of the tinib antitumor compound comprises the following components:
1) the tinib antitumor drug compound of the invention;
2) a substrate.
Commonly used substrates include: hydrocarbons (such as vaseline, solid paraffin, liquid paraffin, and silicone), lipids (such as lanolin, beeswax and spermaceti wax, and dimethicone), and oils (such as animal and vegetable higher fatty acid glyceride and mixture thereof).
The tinib antitumor drug compound can be dissolved in a lipophilic medium, and suitable preparations also comprise a liposome agent, an emulsion or microemulsion agent, a micelle agent and the like.
Further, the tinib antitumor drug compound liposome preparation comprises the following components:
1) the tinib antitumor drug compound of the invention;
2) a phospholipid;
3) cholesterol or vitamin E and derivatives thereof;
4) an aqueous phase.
Or the emulsion or the microemulsion of the tinib antitumor drug compound comprises the following components:
1) an oil phase comprising:
a) the tinib antitumor drug compound of the invention;
b) a biocompatible lipophilic medium;
2) surfactants and cosolvents;
3) an aqueous phase.
Or, the tinib antitumor drug compound micelle agent comprises the following components:
1) the tinib antitumor drug compound of the invention;
2) a surfactant;
3) a cosolvent;
4) an aqueous phase.
The lipophilic medium (or carrier) may be any biocompatible lipophilic medium, representative biocompatible lipophilic media include:
1) oils and fats that can be used as lipophilic medium include fatty acids and esters of varying chain length, which are mostly linear but may also be branched, such as capric acid, caprylic acid, caproic acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and other saturated or unsaturated fatty acids and esters.
2) Fat-soluble vitamin E and derivatives thereof. Vitamin E refers to the natural or synthetic series of vitamin E commonly referred to as tocopherols and tocotrienols (tocophenols and tocotrienols), and tocopherols include alpha-tocopherol (D, DL, L), beta-tocopherol (D, DL, L), gamma-tocopherol (D, DL, L) and delta-tocopherol (D, DL, L). Tocotrienols are similar in structure to tocopherols, but tocotrienols have three double bonds in the carbon-2 side chain phytyl (phytyl). Tocotrienols include alpha-tocotrienol (D, DL, L), beta-tocotrienol (D, DL, L), gamma-tocotrienol (D, DL, L) and delta-tocotrienol (D, DL, L). The vitamin E derivatives include all derivatives of tocopherol and tocotrienol, such as vitamin E succinate, vitamin E acetate, etc.
3) The mono-, di-or triglycerides formed by the esterification of fatty acids with glycerol, whether synthetic or natural, can be used as lipophilic media, for example, glycerides such as soybean oil, cottonseed oil, rapeseed oil, fish oil, acetylated monoglycerides, glycerol monooleate, glycerol triacetate, and diacetyl tartrate, monoglycerides, castor oil, etc.
4) Fatty alcohols such as benzyl alcohol, stearyl alcohol, lauryl alcohol, etc., or their esters or ethers, such as benzyl benzoate.
Representative surfactants include:
1) polyethylene glycol surfactants such as polyoxyethylene castor oil EL (cremophor EL), Tween series surfactants, etc.
2) Phospholipid surfactants (phospholipids), such as lecithin (lecithin), soya lecithin (granulesten or soybean lecithin), polyethylene glycol phospholipids (pegylated phospholipids).
3) Polyethylene glycol vitamin E derivatives, such as vitamin E succinate polyethylene glycol (d-alpha-tocopherol 1000succinate, TPGS).
4) Polyoxyethylene polyoxypropylene block copolymer: block copolymers of POLOXAMERS or PLURONICS (H (OCH2CH2) a (OCH2CH2CH2) b (OCH2CH2) aOH).
Representative organic cosolvents include:
ethanol, polyethylene glycol, propylene glycol, glycerol, N-methylpyrrolidone, and the like. Polyethylene glycol (PEG) is hydrophilic and the chemical structure of the repeat unit is-CH2CH2O-is represented by the formula H- (CH)2CH2)n-OH, molecular weight generally ranging from 200 to 10000. For example, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like.
As used herein, "emulsion" refers to a heterogeneous liquid dispersion system in which one phase of liquid is dispersed in another phase of liquid in a droplet state by the action of a surfactant, such as droplets of oil and water, and the diameter thereof is generally 0.1 to 3.0 μm.
The emulsion may form a stable microemulsion. The term "microemulsion" refers to two immiscible liquids that form a thermodynamically stable isotropic, transparent or translucent dispersion, such as a microemulsion dispersion of oil and water, that is stabilized by an interfacial film formed by surfactant molecules. The average droplet diameter of the microemulsion is less than 200nm, and is generally 10-50 nm.
The emulsion or microemulsion comprises an oil phase and a water phase. The emulsion or microemulsion may be oil-in-water emulsion or water-in-oil emulsion.
The homogeneous and transparent solution containing the drug formed by mixing the oil phase, the nonionic surfactant and the co-emulsifier without water is called self-emulsifying drug delivery system (SEDDS), and the self-emulsifying drug delivery system forms an emulsion with the particle size of 100nm to 500nm, which can be used for improving the solubility and oral absorption of lipophilic drugs.
In one emulsion or microemulsion embodiment, the lipophilic medium comprises soybean oil and the aqueous medium is water. In another emulsion and microemulsion embodiment, the lipophilic medium comprises oil-soluble vitamin E. In another emulsion or microemulsion embodiment, the lipophilic medium comprises an oil-soluble vitamin E derivative.
In addition to the tinib-based anti-tumor compounds of the present invention, the emulsion or microemulsion formulations may also include other ingredients commonly used in pharmaceutical emulsions and microemulsions, including surfactants and cosolvents. Representative surfactants include nonionic surfactants such as polyoxyethylene castor oil EL (cremophor EL), Tween 80(Tween 80), polyethylene glycol vitamin E derivative surfactants, and other surfactant polymers.
Suitable polyethylene glycol vitamin E derivative surfactants include vitamin E succinic polyethylene glycol derivatives (e.g., vitamin E polyethylene glycol succinate) in which polyethylene glycol is formed by the attachment of succinic acid to the hydroxyl groups of vitamin E, and polyethylene glycols in these vitamin E polyethylene glycol derivatives include polyethylene glycols having various molecular weights (e.g., 200, 300, 400, 600, 1000, etc.). "vitamin E polyethylene glycol succinate" as used herein includes vitamin E polyethylene glycol succinate (e.g., D-alpha tocopheryl polyethylene glycol 1000succinate, TPGS, a nonionic surfactant (HLB ═ 16-18)) and various ester and ether derivatives of vitamin E polyethylene glycol.
The formulas of the various preparations comprise effective treatment amount of the tinib antitumor drug compound and auxiliary materials.
The tablet of the tinib antitumor drug compound comprises the antitumor drug compound and auxiliary materials. The content of the anti-tumor drug compound in each tablet can be 1 mg to 1000 mg, and the content of the anti-tumor drug compound in each tablet is 5mg to 500 mg in a preferred scheme; in a more preferred embodiment, the antitumor compound is contained in an amount of 10 mg to 250 mg per tablet.
The capsules of the tinib antitumor drug compound comprise the antitumor drug compound and auxiliary materials. The content of the anti-tumor drug compound in each capsule can be 1 mg to 1000 mg, and the content of the anti-tumor drug compound in each capsule is 5mg to 500 mg in a preferred scheme; in a more preferred embodiment, the antitumor compound is contained in an amount of 10 mg to 250 mg per granule.
In the emulsion or microemulsion of the tinib antitumor drug compound, the weight percentage of the antitumor drug compound in the preparation formula is 0.005-5.0%; preferably, the weight percentage of the anti-tumor drug compound in the preparation formula is 0.01 percent to 2.5 percent; in a more preferable scheme, the weight percentage of the anti-tumor drug compound in the preparation formula is 0.1 to 1.5 percent.
In the emulsion or microemulsion, the weight percentage of the lipophilic medium in the preparation formula is 2 to 20 percent; preferably the lipophilic medium is present in the formulation in an amount of from 4% to 12% by weight; more preferably, the lipophilic medium is present in the formulation in an amount of 6 to 10% by weight.
The emulsion or microemulsion contains about 1 to 10%, preferably 2-6%, and more preferably 4-5% by weight of the surfactant in the formulation.
In the emulsion or microemulsion, the cosolvent accounts for 0-20% of the weight of the formula.
The micelle formulation of the anticancer drug compound of the tinib class as described above comprises the anticancer drug compound of the tinib class of the present invention, one or more surfactants, one or more cosolvents and an aqueous phase.
In the micelle agent of the tinib antitumor drug compound, the weight percentage of the drug compound in the formula is about 0.005-3.0%, preferably the weight percentage of the drug compound in the formula is about 0.01-2.5%; more preferably, the pharmaceutical compound is present in the formulation in an amount of about 0.1% to about 1.0% by weight.
Suitable surfactants may be present in the micelle formulation of the present invention in an amount of about 1 to 10% by weight, preferably 2-6% by weight, more preferably 4-5% by weight.
Micelle formulations may also include other ingredients, such as the co-solvents mentioned above. In one embodiment, the micelle formulation comprises polyethylene glycol and a lower alkyl alcohol (e.g., ethanol). The cosolvent in the micelle agent accounts for about 1 to 20 percent of the weight of the formula.
The liposome agent of the tinib antitumor drug compound comprises the antitumor drug compound, one or more phospholipids (including PEGylated phospholipid), one or more lipophilic media (such as cholesterol) and a water phase.
In the liposome preparation of the tinib antitumor drug compound, the weight percentage of the drug compound in the formula is about 0.005-5.0%, and preferably the weight percentage of the drug compound in the formula is about 0.01-2.5%; more preferably, the pharmaceutical compound is present in the formulation in an amount of about 0.1% to about 1.5% by weight.
Suitable phospholipids may be present in the liposomal formulation of the present invention in an amount of about 1 to about 10% by weight, preferably 2-6% by weight, and more preferably 4-5% by weight.
The liposomal formulation may also include other ingredients such as the lipophilic vehicles mentioned above (e.g., cholesterol). In one embodiment, the liposomal formulation comprises cholesterol or vitamin E. The liposome formulation comprises cholesterol or vitamin E in an amount of about 0.1% to about 20% by weight of the formulation.
The above emulsion, microemulsion, micelle and liposome formulations contain an aqueous phase. In one embodiment, the aqueous phase comprises deionized water. In another embodiment, the aqueous phase comprises physiological saline. In another embodiment, the aqueous phase comprises a buffer of an acid (e.g., succinic acid, citric acid, phosphoric acid).
The ointment of the tinib antitumor drug compound comprises the tinib antitumor drug compound and one or more matrixes.
The weight percentage of the anti-tumor drug compound in the ointment of the tinib anti-tumor drug compound is about 0.01 to 30 percent, and the weight percentage of the drug compound in the formula is preferably about 0.05 to 20 percent; more preferably, the pharmaceutical compound is present in the formulation in an amount of about 0.1% to about 10% by weight.
The invention also provides application of the novel tinib antitumor drug compound in preparation of an anticancer drug. Such cancers include, but are not limited to (i) cancers of the blood and lymphatic system, such as leukemia, lymphoma, myeloma; ② solid tumor cancer, such as breast cancer, ovarian cancer, pancreatic cancer, colon cancer, rectal cancer, non-small cell lung cancer, bladder cancer, gastric cancer, liver cancer, etc., sarcoma, skin cancer and glioma, etc.
The tinib antitumor drug compound can be used for treating cancers including blood and lymphatic system, such as leukemia, lymphoma, myeloma; and solid tumor cancers such as breast cancer, ovarian cancer, cervical cancer, pancreatic cancer, esophageal cancer, colon cancer, rectal cancer, lung cancer, bladder cancer, stomach cancer, liver cancer, skin cancer, sarcoma, glioma, etc.
The therapeutic efficacy and toxicity of the tinib-based drug compounds of the present invention are determined by in vitro cell or in vivo animal experiments, such as ED50 (50% effective dose: the amount of drug that results in a positive reaction in 50% of the subjects), LD50 (50% lethal dose, the amount that kills half of the subjects), and GI50 (the concentration of drug that inhibits the growth of the i-cancer drug at the growth of the half of the subjects by 50%). The ratio of half lethal dose (LD 50)/half effective dose (ED50) is usually referred to as 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 novel tinib antitumor drug compound aims at improving the treatment index and the safety of the drug and simultaneously improving the treatment effect. The drug dose obtained from in vitro cell experiments and in vivo animal experiments can be used to formulate a range of doses for use in humans. The dosage of such compounds is preferably within the range of ED50, which is less or not at all toxic. Dosage will generally vary depending upon the dosage form employed, the sensitivity of the patient, the route of administration, and the like. Reference will generally be made to conventional dosages of the same or similar drugs.
The tinib antitumor drug compound can be used alone or together with one or more other therapeutic drugs. For example, in the treatment of cancer, these pharmaceutical compounds may be used with the following therapeutic agents, including but not limited to: androgen inhibitors such as flutamide (flutamide) and lupperoid (luprolide); antiestrogens, such as tamoxifen (tomoxifen); antimetabolites and cytotoxic drugs such as daunorubicin (daunorubicin), pentafluorouracil (fluorouricin), floxuridine (floxuridine), interferon-alpha (interferon alpha), methotrexate (methotrexate), mithramycin (plicamycin), thiopurine (mecapture), thioguanine (thioguanine), adriamycin (adriamycin), carmustine (carmustine), lomustine (lomustine), cytarabine (cytarabine), cyclophosphamide (cyclophosphamide), adriamycin (doxorubicin), estramustine (estramustine), altretamine (altramine), hydroxyurea (hydroyurea), ifosfamide (ifosfamide), procarbazine (procarbazine), promycin (mitomycin), cyanamide (sultrine), mitomycin (butomycin), mitomycin (bleomycin), mitomycin (imidazole), and platinum (epothilone), carboplatin (cisplatin); hormones, such as megestrol (medroxyprogesterone), ethinylestradiol (ethinyl estradiol), estradiol (estradiol), leuprolide (leuprolide), megestrol (megestrol), octreotide (octreotide), diethylstilbestrol (diethylstilbestrol), chloroestrene (chlorotrianisene), etoposide (etoposide), podophyllotoxin (podophyllotoxin) and goserelin (goserelin); nitrogen mustard derivatives, such as mechlorethamine phenylpropionate (melphalan), chlorambucil (chlorambucil), and thiotepa (thiotepa); steroids, such as betamethasone (betamethasone); and other antitumor agents such as live Mycobacterium bovis (live Mycobacterium bovis), dacarbazine (dicarbazine), asparaginase (aspargine), leucovorin (leucovorin), mitotane (mitotane), vincristine (vincristine), vinblastine (vinblastine), and docetaxel (taxotere), and the like.
Has the advantages that: the tinib antitumor drug compound has good anticancer activity and can be used for preparing drugs for treating cancers of blood and lymphatic systems and solid tumor cancers.
The present invention will be described in detail with reference to specific examples. It is intended that the scope of the invention be limited not by this detailed description, but rather by the claims appended hereto.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an antitumor drug compound 4- [ bis (2-chloroethyl) amino ] phenylbutyrate 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline amide (YY-058-5).
FIG. 2 is a mass spectrum of an antitumor drug compound 4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline amide (YY-058-5).
Detailed Description
The following examples are intended to illustrate the synthesis, formulation, in vivo pharmacodynamics, etc. of the novel antitumor compounds of the present invention. The examples are set forth to aid in the understanding and practice of the invention and are not intended to limit the invention.
EXAMPLE 14 Synthesis of- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5)
The synthesis of the 4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) comprises the following steps:
(1) synthesis of 7-methoxy-6-nitroquinazolin-4 (3H) -one (2)
The reaction formula is shown as the following formula:
Figure BDA0003351273630000111
adding about 50ml of methanol into a 100ml round-bottom flask, adding 0.760g (20mmol) of sodium methoxide, stirring until the methanol is dissolved, adding 1.046g (5mmol) of 7-fluoro-6-nitroquinazolin-4 (3H) -one (1), heating and refluxing for 2H, adding 30% glacial acetic acid to adjust the pH to 6-7, adding 50ml of water, stirring for 20min, and filtering to obtain 1.087g of light yellow solid with the yield of 98.26%.
1H NMR(500MHz,DMSO-d6):δppm:12.4696(s,1H),8.5111(s,1H),8.2161(s,1H), 7.4157(s,1H),4.0382(s,3H)。
(2) Synthesis of 4-chloro-7-methoxy-6-nitroquinazoline (3)
The reaction formula is shown as the following formula:
Figure BDA0003351273630000112
1.039g (4.70mmol) of 7-methoxy-6-nitroquinazolin-4 (3H) -one (2) and 30mL of phosphorus oxychloride are added into a 100mL round bottom flask, the mixture is heated and refluxed until the reaction is finished, the excess phosphorus oxychloride is removed by reduced pressure distillation, about 150mL of ethyl acetate is added for stirring, saturated sodium bicarbonate aqueous solution is added, the pH is adjusted to be neutral, the organic phases are combined, after the organic phases are washed by saturated saline for 3 times, anhydrous sodium sulfate is dried, the ethyl acetate is removed by reduced pressure distillation, and 1.12g of yellow solid product is obtained and is directly used for the next reaction.
(3) Synthesis of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-nitroquinazoline (4)
The reaction formula is shown as the following formula:
Figure BDA0003351273630000121
in a 250mL round bottom flask, 1.12g (4.674mmol) of 4-chloro-7-methoxy-6-nitroquinazoline (3), 1.40g (9.618mmol) of 3-chloro-4-fluoroaniline and 100mL of isopropanol were added, stirred, and after concentrated HCl 4 was added dropwise, the mixture was heated under reflux at 100 ℃ for 1 hour, cooled to room temperature, adjusted to pH 7 to 8 with Triethylamine (TEA), and the isopropanol was distilled off under reduced pressure, and a silica gel column layer was separated to obtain 1.110g of a yellow solid product with a yield of 68.10%.
MS(Positive ESI):m/z(M+H+)＝349.05373，MS(Negative ESI):m/z(M-H+)＝347.03710。
1H NMR(500MHz,DMSO-d6):δppm:10.1139(s,1H),9.2010(s,1H),8.6671(s,1H), 8.1602-8.1415(m,1H),7.8129-7.7813(m,1H),7.4714-7.4352(m,2H),4.0615(s,3H)。
(4) Synthesis of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5)
The reaction formula is shown as the following formula:
Figure BDA0003351273630000122
1.90g (5.448mmol) of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-nitroquinazoline (4), 30mL of ethanol and 15mL of water are placed in a 250mL round-bottomed flask, stirred, and then 1.50g (26.860mmol) of iron powder (which was washed and activated with 1N HCl before use) is added, then 850. mu.l of glacial acetic acid is added, the mixture is heated to 100 ℃ and refluxed for 1 hour, then the hot reaction solution is basified with 25% aqueous ammonia, then filtered by heating, the filtrate is cooled to room temperature, hydrochloric acid is added to adjust the pH of the reaction solution to 6, and NaHCO is used to adjust the pH of the reaction solution to 63The reaction solution was adjusted to pH 7 to 8, the solvent ethanol was distilled off under reduced pressure, and water was added thereto and filtered to obtain 1.33g of a yellow solid product, which was used in the next reaction in a yield of 76.6%.
(5) Synthesis of 4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5)
The reaction formula is shown as the following formula:
Figure BDA0003351273630000131
100mg (0.328mmol) chlorambucil, 286mg (0.752mmol)2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 175. mu.l (1.254mmol) Triethylamine (TEA) and 10ml DMF were charged in a 50ml round bottom flask, stirred at room temperature for 1h, then 100mg (0.314mmol)4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) were added, heated to 50 ℃ and stirred until the reaction was complete, and the silica gel column was separated to give 150mg of solid product in 78.9% yield.
The hydrogen nuclear magnetic resonance spectrum and the mass spectrum of the synthesized compound (YY-058-5) are shown in FIGS. 1 and 2.
MS(Positive ESI):m/z(M+H+)＝604.15087，MS(Negative ESI):m/z(M-H+)＝ 602.12823。
1H NMR(500MHz,CDCl3):δppm:9.0137(s,1H),8.6174(s,1H),8.0317(s,1H)， 7.8930-7.8753(m,1H),7.5395-7.5089(m,1H),7.2759(s，1H)，7.1457-7.0867(m，3H)， 6.6481(s,1H),6.6310(s,1H),4.0553(s,3H),3.7094-3.6818(t,4H,J＝6.9Hz),3.6229-3.5956(t,4H, J＝6.8Hz),2.6683-2.6388(t,2H,J＝7.4Hz),2.4986-2.4690(t,2H,J＝7.4Hz),2.2717(s,1H), 2.0910-2.0320(m,2H)。
EXAMPLE 24 Synthesis of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide- [ bis (2-chloroethyl) amino ] benzoate
4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) was produced in the same manner as in steps (1) to (4) of example 1.
(5) Synthesis of 4- [ bis (2-chloroethyl) amino ] benzoic acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide
The reaction formula is shown as the following formula:
Figure BDA0003351273630000141
in a 50ml round bottom flask, 85mg (0.3270mmol) of 4- [ bis- (2-chloroethyl) -amino ] -benzoic acid, 286mg (0.752mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 175. mu.l (1.254mmol) of Triethylamine (TEA) and 10ml of DMF were added, stirred at room temperature for 1h, then 0.10g (0.314mmol) of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) was added, heated to 50 ℃ and stirred until the reaction was complete, and the column layer of silica gel was separated to give 130mg of solid product, 70.6% yield.
EXAMPLE 34 Synthesis of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide- [ bis (2-chloroethyl) amino ] benzeneoctanoic acid
4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) was produced in the same manner as in steps (1) to (4) of example 1.
(5) Synthesis of 4- [ bis (2-chloroethyl) amino ] benzene octanoic acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline amide
The reaction formula is shown as the following formula:
Figure BDA0003351273630000142
the reaction steps are as follows:
in a 50ml round bottom flask were added 319 mg of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5), 167. mu.l (1.2mmol) of Triethylamine (TEA) and 10ml of DMF and stirred at room temperature for 1h, followed by 379 mg (1.1mmol) of 8- {4- [ bis- (2-chloroethyl) -amino ] -phenyl } -octanoyl chloride, which was heated to 50 ℃ and stirred until the reaction was complete, and the column layer was separated over silica gel to give 518.6mg of solid product in 78.5% yield.
EXAMPLE 4 formulations of (4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5), including tablets, capsules, emulsions, micelles, liposomes and paste formulations
In this example, formulations of tablets, capsules, emulsions, micelles, liposomes and pastes of the antitumor compound (YY-058-5) were included.
(1)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) capsule (Wet granulation)
YY-058-5 in the amount prescribed is mixed with sodium starch glycolate, lactose and magnesium stearate in the amount prescribed, and then wet granulation is carried out after adding Tween 80 aqueous solution in the amount prescribed, the prepared wet material is dried in a fluidized bed, a drying tray or other suitable dryer, the dried granules are milled to a suitable particle size distribution and then mixed with other components in the amount prescribed, and finally the mixture is filled into two pieces of hard gelatin capsule shells.
Components Content of each capsule (mg) Percentage of each component (%)
YY-058-5 25 25
Tween 80 2.5 2.5
Lactose 25 25
Magnesium stearate 2.5 2.5
Sodium starch glycolate 45 45
The total weight of each capsule 100
(2)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) tablet (Wet granulation)
Granulating a prescribed amount of an aqueous solution of sodium lauryl sulfate with a prescribed amount of YY-058-5, sodium starch glycolate, magnesium stearate and microcrystalline cellulose, drying the resulting wet material in a fluidized bed, drying pan or other suitable dryer, milling the dried granules to the desired particle size distribution, and compressing the mixture into tablets.
Figure BDA0003351273630000151
Figure BDA0003351273630000161
(3)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) tablet (dry granulation)
Firstly, raw material YY-058-5 is crushed and sieved, the particle size is controlled to be less than 80 μm, then the YY-058-5 with the prescription amount is mixed with aerosil, the starch, cane sugar and croscarmellose sodium with the prescription amount are added, the mixture is mixed, dry granulation is carried out, the magnesium stearate with the prescription amount is added after granulation, the mixture is mixed, tabletting and film coating are carried out.
Components Content per tablet (mg) Percentage of each component (%)
YY-058-5 10 50
Starch 5 25
Sucrose 1.5 7.5
Croscarmellose sodium 1.5 7.5
Silica gel micropowder 1.5 7.5
Magnesium stearate 0.5 2.5
The total weight of each capsule 20
(4)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) emulsion
YY-058-5 is dissolved in a mixture of soybean oil, Tween 80 and polyethylene glycol PEG (200), deionized water (DI water) is added, and then stirred and emulsified by ultrasound or by a homogenizer, and the composition of the produced emulsion is as follows:
Figure BDA0003351273630000162
the resulting emulsion drug was filtered through a filter with a pore size of 0.2 μm and filled into a sterile glass bottle.
(5)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) emulsion
YY-058-5 is dissolved in a mixture of D-alpha-tocopheryl acetate, D-alpha-tocopheryl polyethylene glycol 1000succinate (TPGS) and polyethylene glycol PEG (200), and deionized water (DI water) is added, followed by stirring and ultrasonic emulsification or emulsification with a homogenizer to produce an emulsion having the following composition:
Figure BDA0003351273630000171
the resulting emulsion drug was filtered through a filter with a pore size of 0.2 microns and filled into sterile glass vials.
(6)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) micelle agent
YY-058-5 is dissolved in a mixture of D-alpha-tocopheryl polyethylene glycol 1000succinate (TPGS), ethanol and polyethylene glycol PEG (200) to obtain a transparent liquid, a proper amount of normal saline is added before use, and then stirring and ultrasonic stirring are carried out to obtain a clear liquid, wherein the produced micelle agent comprises the following components:
Figure BDA0003351273630000172
the prepared micelle agent medicine is filtered by a filter with the pore diameter of 0.2 micron for standby.
(7)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) micelle agent
YY-058-5 is dissolved in the mixture of polyoxyethylene castor oil EL (cremophor EL), ethanol and polyethylene glycol PEG (200) to obtain transparent liquid, and a proper amount of deionized water (DI water) is added before use, and then stirring and ultrasonic stirring are carried out to obtain clear liquid, wherein the produced micelle agent has the following composition:
Figure BDA0003351273630000173
the prepared micelle agent medicine is filtered by a filter with the pore diameter of 0.2 micron for standby.
(8)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) micelle agent
YY-058-5 is dissolved in the mixture of polyoxyethylene castor oil EL (cremophor EL), ethanol and polyethylene glycol PEG (200) to obtain transparent liquid, and a proper amount of deionized water (DI water) is added before use, and then stirring and ultrasonic stirring are carried out to obtain clear liquid, wherein the produced micelle agent has the following composition:
Figure BDA0003351273630000181
the prepared micelle agent medicine is filtered by a filter with the pore diameter of 0.2 micron for standby.
(9)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) micelle agent
YY-058-5 is dissolved in a mixture of Tween 80(Tween 80), ethanol and polyethylene glycol PEG (200) to obtain a transparent liquid, a proper amount of deionized water (DI water) is added before use, then stirring and ultrasonic stirring are carried out to obtain a clear liquid, and the produced micelle agent comprises the following components:
Figure BDA0003351273630000182
filtering the obtained micelle preparation with a filter with a pore size of 0.2 μm
(10)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) liposome agent
In a round bottom flask, 100mg YY-058-5, 1600 mg phospholipids (lecithin, phosphatidylcholine) and 110 mg cholesterol were dissolved in 15mL chloroform (CHCl)3) Slowly heating to 40 deg.C, evaporating solvent under reduced pressure with rotary evaporator to form a thin lipid membrane, vacuum drying overnight, further removing chloroform from the lipid membrane, adding 50ml of 5% sucrose solution, stirring and ultrasonic stirring, filtering the obtained liposome solution with a filter with pore size of 0.2 μm, filling into a sterile glass bottle, freezing with dry ice and acetone, and freeze drying for 24 hr to obtain 4- [ bis (2-chloroethyl) amino acid]4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline phenylbutylate (YY-058-5) as a liposome formulation.
11)4- [ bis (2-chloroethyl) amino ] phenylbutyric acid 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazolinamide (YY-058-5) paste
Heating and melting appropriate amount of YY-058-5, stearic acid, glyceryl monostearate, liquid paraffin, polyethylene glycol 200(PEG 200), and tween-80; heating appropriate amount of glycerol and water to 70-80 deg.C, adding into oil phase under stirring, and stirring to form paste with the following composition:
Figure BDA0003351273630000191
example 6 pharmacodynamic test of YY-058-5 on growth inhibition of transplanted tumor of lung cancer cell LLCI mouse
(1) The preparation method of the medicine comprises the following steps:
preparation method of YY-0-58-5
The preparation method comprises the following steps: weighing 15.52mg of YY-058-5 powder medicine, adding 2ml of medicinal Tween, fully dissolving to be slightly transparent, adding 18ml of CMCNa aqueous solution (volume ratio is 0.5 percent), and stirring to be fully dissolved. The administration volume was 0.2ml/20g, i.e., the administration dose was 7.72 mg/kg.
② preparation method of positive control drug Dacomitinib
The preparation method comprises the following steps: weighing 12mg of dacomitinib powder, adding 2ml of medicinal Tween, fully dissolving to be slightly transparent, adding 18ml of CMCNa aqueous solution (volume ratio is 0.5%), and stirring to be fully dissolved. The administration volume was 0.2ml/20g, i.e., the administration dose was 6 mg/kg.
(2) Source, species and strain of experimental animal
Strain and source: c57BL/6 mice, supplied by shanghai slek laboratory animals llc, laboratory animals production licenses: SCXK (Shanghai) 2017-. Weight: 18-22g, sex: female, feeding conditions: air-conditioning room, temperature 18-24 deg.C, relative humidity 40-70%.
(3) Grouping of laboratory animals
Blank control group (model control group) 8
Dacromicinib (positive control drug) 8
YY-058-58
(4) Experimental methods
ICR mice are taken and inoculated with ascites tumor according to the transplantation tumor research method (ascites is taken under aseptic operation, PBS solution is diluted according to 1:2, cell suspension is prepared, the container is placed on ice cubes, the ice cubes are used for suction by using an empty needle, the cells are uniformly mixed before each suction, 0.2ml of right forelimb armpit subcutaneous inoculation is carried out on each mouse, the weight of the mouse is weighed 24 hours after the inoculation, the mouse is randomly divided into 3 groups, and each administration group is inoculated 24 hours later (d)1) The first administration. The administration is performed by intragastric administration, 1 time/1 day, and 7 times in total. The administration volumes were all 0.2ml/20 g. On day 8 after inoculation (d)8) Tumor-bearing mice were sacrificed and the tumor masses were weighed, and the data were statistically processed (t-test).
(5) Results of the experiment
Results show that compared with a model control group, YY-058-5 and a positive control drug dacomitinib have obvious inhibition effects on the growth of tumors transplanted by mouse lung cancer cells LLCI (P <0.01), but YY-058-5 is stronger than dacomitinib on tumors transplanted by lung cancer cells LLCI under the same molar concentration.
TABLE 1 effect of YY-058-5 on mouse Lung cancer cell LLCI transplanted tumor growth (X + -SD, n ═ 8)
Figure BDA0003351273630000201
In comparison with the blank set, the results,*P＜0.05，**P＜0.01
example 7 pharmacodynamic experiment of YY-058-5 on human Lung cancer cell A549 nude mouse transplanted tumor
(1) The preparation method of the medicine comprises the following steps:
the same as in example 6.
(2) Source, species and strain of experimental animal
Source, species, strain: balb/c nude mice, available from Shanghai Slek laboratory animals, Inc. Production license of experimental animal: SCXK (Shanghai) 2017-; the certification number is as follows: 20170005052791, respectively; license for use of experimental animal: SYXK (threo) 2017-0040; the age in days: 4-5W; sex: and (4) male.
(3) Grouping of laboratory animals
Model control group: 6 are
6 dacomitinib
YY-058-5: 6 are
(4) Experimental methods
Preparation of model
Collecting cultured human lung cancer A549 cell suspension with concentration of 1X107One/ml, 0.1ml each, was inoculated subcutaneously in the right axilla of mice.
② grouping and administering
The diameter of the mouse graft tumor was measured with a vernier caliper, and 21 days after the inoculation, the tumor grew to 100mm3Animals were randomly grouped into groups of 6 animals each. At the same time, each group of mice was started to administer the drug according to the administration schedule shown in the group and administration schedule of table 2, and the antitumor effect of the test sample was dynamically observed using the method for measuring tumor size. After the experiment was completed, the mice were sacrificed immediately and the tumor mass was removed by surgery and weighed.
Observation index
The formula for Tumor Volume (TV) is:
TV＝1/2×a×b2
wherein a and b represent length and width, respectively.
Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows:
RTV＝Vt/V0
wherein V0When administered separately from the cage (i.e. d)0) Measurement of the resulting tumor volume, VtFor the tumor volume at each measurement.
Evaluation indexes of antitumor activity: the relative tumor proliferation rate T/C (%) was calculated as follows:
Figure BDA0003351273630000211
TRTV: treatment group RTV; cRTV: model set RTV
Evaluation indexes of antitumor activity: the tumor growth inhibition (%) is calculated as follows:
Figure BDA0003351273630000212
fourthly, statistical treatment
The mean values are represented by X + -SD, the analysis between groups is statistically processed by t-test, and the results are statistically analyzed using SPSS (statistical Package for the Social science) 17.0.
Experimental results
Results show that YY-058-5 and a positive control drug dacomitinib have obvious inhibition effect on the growth (P <0.01) of the nude mouse transplanted tumor of the human lung cancer cell A549 compared with a model control group, but YY-058-5 has stronger tumor than the dacomitinib of the nude mouse transplanted tumor of the human lung cancer cell A549 under the same molar concentration.
TABLE 2 effect of YY-058-5 on tumor growth of human lung carcinoma cell A549 in nude mouse (X + -SD, n ═ 6)
Figure BDA0003351273630000221
P <0.05 × P <0.01 × P <0.001 was compared to the model control group.

Claims (10)

1. A tinib antitumor drug compound has a structural general formula shown in the following formula I:
Figure FDA0003351273620000011
wherein n is an integer of 0 to 10.
2. A method for preparing a tinib antitumor compound according to claim 1, comprising the steps of:
1) preparing an intermediate 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5);
2)4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) and 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or derivative (6) thereof are subjected to acylation reaction to prepare the tinib antitumor drug compound (I), wherein the reaction formula is shown as the following formula:
Figure FDA0003351273620000012
wherein n is an integer of 0 to 10, X is OH, Cl, OR OCOR, and R is a hydrocarbon group.
3. The process for producing an antitumor drug compound of the tinib type according to claim 2, wherein the 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or derivative thereof (6) is 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid chloride.
4. The method for preparing the tinib antitumor drug compound according to claim 2, wherein the condensing agent for the acylation reaction is one or more selected from 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, N, N ' -carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or diisopropylcarbodiimide; the acid-binding agent is one or more selected from triethylamine, pyridine, diisopropylethylamine, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.
5. The method for preparing a tinib antitumor drug compound according to claim 2, wherein the molar ratio of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6-aminoquinazoline (5) to 4- [ bis (2-chloroethyl) amino ] phenylalkyl acid or its derivative (6) in the acylation reaction is 1: 1 to 1.5.
6. The use of the antineoplastic compounds of the tinib class according to claim 1 for the preparation of anticancer drugs.
7. Use according to claim 6, wherein the cancer is of the blood and lymphatic system and solid tumors.
8. The use of claim 7, wherein the cancer is leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, cervical cancer, pancreatic cancer, esophageal cancer, colon cancer, rectal cancer, lung cancer, bladder cancer, gastric cancer, liver cancer, sarcoma, skin cancer, or glioma.
9. An antitumor pharmaceutical composition, comprising a therapeutically effective amount of the tinib antitumor compound of claim 1 and a pharmaceutically acceptable excipient.
10. The antitumor pharmaceutical composition as claimed in claim 9, wherein the pharmaceutical composition is in the form of tablet, capsule, emulsion, micelle, liposome or paste.
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CN115850248A (en) * 2022-12-09 2023-03-28 南京友怡医药科技有限公司 Teninil antitumor drug compound and preparation method and application thereof
CN115925712A (en) * 2022-12-09 2023-04-07 南京友怡医药科技有限公司 Targeted antitumor drug compound and preparation method and application thereof
CN115850248B (en) * 2022-12-09 2024-07-02 南京友怡医药科技有限公司 Tinich antitumor drug compound and preparation method and application thereof
CN115925712B (en) * 2022-12-09 2024-08-09 南京友怡医药科技有限公司 Targeted antitumor drug compound and preparation method and application thereof

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