WO2013007184A1 - Médicament antinéoplasique qui est un composé de tétrahydronaphtalène renfermant un groupe amide ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation - Google Patents

Médicament antinéoplasique qui est un composé de tétrahydronaphtalène renfermant un groupe amide ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2013007184A1
WO2013007184A1 PCT/CN2012/078422 CN2012078422W WO2013007184A1 WO 2013007184 A1 WO2013007184 A1 WO 2013007184A1 CN 2012078422 W CN2012078422 W CN 2012078422W WO 2013007184 A1 WO2013007184 A1 WO 2013007184A1
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group
pharmaceutically acceptable
compound
acceptable salt
tetrahydronaphthalene
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PCT/CN2012/078422
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English (en)
Chinese (zh)
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陈烨
王洋
卢红
邓晶晶
李文军
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Chen Ye
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicine, and in particular to a tetrahydronaphthylamine compound which inhibits tumor cell growth and exerts an antitumor effect, and a pharmaceutically acceptable salt thereof, a preparation method and use thereof.
  • Imatinib competitively inhibits the binding site of adenosine triphosphate (ATP) to a thymidine kinase (TK) receptor such as KIT, blocks TK phosphorylation, thereby inhibiting signaling, and inhibits KIT associated with kinase activity. Mutations (causing KIT receptor activation) and wild-type KIT.
  • ABL Abelson
  • KIT protein KIT protein
  • PDGF platelet-derived growth factor
  • Imatinib can reduce kinase phosphorylation of GIST-derived cell lines (GIST882) by functionally acquired KIT mutations that are independent of stem cell factor activation, and completely inhibit kinase phosphorylation at concentrations up to 1 ⁇ mol/L Chemical.
  • Imatinib approved by the FDA for the treatment of chronic myeloid leukemia (CML) in May 2001, was approved by the FDA in 2003 for the treatment of gastrointestinal stromal tumors (GIST).
  • Imatinib has significant adverse effects, and most patients experience some adverse reactions during their use, but most are mild to moderate.
  • transient hepatotoxicity such as elevated transaminases and hyperbilirubinemia, can occur.
  • an object of the present invention is to provide an antitumor drug tetralinamide which has superior antitumor activity and safety than imatinib and a therapeutic window width, and is pharmaceutically acceptable Salt.
  • Another object of the present invention is to provide a process for producing an antitumor drug tetralinamide type compound and a pharmaceutically acceptable salt thereof, and use thereof.
  • the compounds represented by [I] and [11] have extremely excellent antitumor activity, stability and safety.
  • the present invention relates to a compound represented by the general formula [I] and a pharmaceutically acceptable salt thereof:
  • D is selected from pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, or pyrazolyl, or each radical optionally substituted with 1, 2, 3, or R 2 is substituted, the R 2 is independently selected from halo, cyano, amino, C ⁇ 6 alkyl, d- 6 hydroxyalkyl, d — 6 haloalkyl, or — 6 cyanyl.
  • E is selected from pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, nitrogen Azyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quin Orolinyl, isoquinolyl, quinazolinyl, piperazinyl or morpholinyl, or each group optionally substituted by 1, 2, or 3 R 3 , said R 3 being independently selected Or halogen, cyano, amino, C ⁇ 6 alkyl, d- 6 hydroxyalkyl, d- 6 haloalkyl, or C ⁇ 6 cyanoalkyl.
  • R4 and R 5 are independently selected from a hydrogen atom, a cyano group, C ⁇ 6 alkyl, d- 6 hydroxyalkyl, d- 6 haloalkyl, d- 6 cyanoalkyl;
  • R 6 is independently selected from hydrogen atoms, C ⁇ 6 alkyl, C 2 - 6 hydroxyalkyl, C 2 - 6 haloalkyl, d- 6 cyanoalkyl, acyl and carboxylate;
  • p 0, 1, or 2.
  • D is a pyrimidinyl group
  • E is a pyridyl group, having the formula [III]
  • the compound represented by the above formula [III] and a pharmaceutically acceptable salt thereof preferably the compound 1 is: D is a pyrimidinyl group, E is a pyridyl group, R4 and R 5 are a hydrogen atom, and R 6 is a methyl group. , p is 1, and its structural formula is as follows: ,
  • D is a pyrimidinyl group
  • hydrazine is a pyrimidyl group, having a knot of the formula [IV]
  • the compound represented by the above formula [IV] and a pharmaceutically acceptable salt thereof preferably the compound 2 is: D is a pyrimidinyl group, hydrazine is a pyrimidinyl group, and R4 and R 5 p are 1, and the structural formula is as follows:
  • the above compound and a pharmaceutically acceptable salt thereof are used as an active ingredient in the preparation of a medicament for treating a tumor disease.
  • a pharmaceutical composition comprising a compound as described above, and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the use of a medicament for treating a tumor disease includes: leukemia, lung cancer, liver cancer, colon cancer, nerve Cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.
  • the beneficial effects of the present invention are: the antitumor drug tetralinamide compound obtained by the invention and the pharmaceutically acceptable salt thereof have better antitumor activity and safety, and can be used for treating leukemia, lung cancer,
  • the application of tumors such as colon cancer, ovarian cancer and kidney cancer has a wide anticancer spectrum and a wide therapeutic window, so it is very useful as an antitumor agent in the medical field.
  • FIG. 1 is a diagram showing the synthesis mechanism of a compound represented by the formula [I] of the present invention and a pharmaceutically acceptable salt thereof.
  • the compounds of the invention also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form which converts a basic group in the parent compound into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines (amino) groups.
  • the pharmaceutically acceptable salts can be prepared from inorganic or organic acids, which may include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids may include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almonds Acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable carrier includes any and all pharmaceutically acceptable solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, such media and agents are employed in pharmaceutically active materials, in It is well known in the art that unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition is contemplated, and the additional active ingredient may be incorporated into the compositions.
  • the pharmaceutical composition of the present invention can be used orally, by injection, by spray inhalation, for external use on the skin, for rectal administration, nasal, vaginal, intraperitoneal, or by implantation of a reservoir or a transdermal patch.
  • an important aspect of the present invention is that the present invention is useful for treating diseases involving tumors, including: leukemia, lung cancer, colon cancer, ovarian cancer, and renal cancer.
  • Another aspect of the invention relates to a process for the preparation of a compound of the general formula [I].
  • the compound of the general formula [I] can be produced by the following methods and processes.
  • 6-methoxy-1-tetralinone is refluxed in a 48% HBr solution to give intermediate 1-1
  • the phenolic hydroxyl group is protected with trifluoromethanesulfonic anhydride to give intermediate 1-2, 1-2 Reaction with CO in DMF, using palladium as a catalyst, such as palladium diacetate, 1,3-bis(phenylphosphine)propane (dppp) or bis(triphenylphosphine)palladium(II) chloride
  • II] [(PPh 3 ) 2 PdCl 2 ]
  • Intermediates 1-3 are obtained, which are reduced in an alcohol solvent (for example, ethanol) by a reducing agent (for example, sodium borohydride) to give Intermediate 1-4.
  • an alcohol solvent for example, ethanol
  • the hydroxy group of 1-4 is chlorinated under the action of a reagent such as thionyl chloride to give the chloro group of the intermediate 1-5, 1-5 substituted by a cyclic amino group (or cyclic amino group), using triethylamine or Potassium carbonate is used as a base to obtain intermediates 1-6, 1-6 in a solution of trimethylaluminum toluene with 6-methyl-! ⁇ -[(4-pyridin-3-yl)pyrimidin-2-yl]
  • the benzene-1,3-diamine is reacted to give a compound of the general formula [I].
  • Step C Synthesis of methyl 5-amino-5,6,7,8-tetrahydro-2-carboxylate
  • Step D Synthesis of 5-hydroxy-5,6,7,8-tetracarboxylic acid methyl ester
  • Step E Synthesis of methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate
  • Step F Synthesis of 5-(4-methylpiperazine-1-yl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester
  • Methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.41 g, 10 mmol) was dissolved in 20 mL of DMF solvent and potassium carbonate (2.78 g, 20 mmol) , N-methylpiperazine (2 g, 20 mmol), after reacting at 50 ° C for 5 hours, the reaction solution was added to ethyl acetate (80 ml), and the pH was adjusted to neutral with dilute aqueous hydrochloric acid.
  • Step G Synthesis of 5-(4-methylpiperazin-1-yl)-5,7,8-tetrahydronaphthalene-2-carboxylic acid
  • Step H N- ⁇ 4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-amino]phenyl ⁇ -5-(4-methylpiperazin-1-yl)- Synthesis of 5,6,7,8-tetrahydronaphthalene-2-amide (Compound 1)
  • Methyl 5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.88 g, 10 mmol) and 6-methyl-! -[(4-Pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (3.32 g, 12 mmol) was suspended in 30 ml of toluene, and 2 M trimethylaluminum toluene solution was added. (5 ml, 10 mmol), the mixture was reacted at 10 CTC for 6 hours, and the solution was cooled. An aqueous solution of sodium potassium tartrate (50 ml) was added with stirring.
  • reaction solution was evaporated under reduced pressure of tetrahydrofuran, and ethyl acetate (50 ml) was added, and washed with brine (3, (60, 60, 30 ml), ethyl acetate phase dried over anhydrous sodium sulfate, filtered, Solvent, silica gel column chromatography was carried out under 50% ethyl acetate/dichloromethane/1% triethylamine mobile phase to give the desired product, Compound 1, 1.65 g, yield 61.8%.
  • the reaction flask was added to the compound 1 (5.33 g, 10 mmol), 100 ml of anhydrous methanol, methanesulfonic acid (1.01 g, 10.5 mmol), and refluxed at 70 ° C for 1 hour, then added pharmaceutically decolorized charcoal 2 g After refluxing for an additional 1 hour, it was suction filtered, and the filtrate was concentrated under reduced pressure.
  • Step A Synthesis of 4-[6-(methoxyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]piperazine-l-carboxylic acid tert-butyl ester
  • Methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate (22.4 g, 100 mmol), potassium carbonate (27.8 g, 200 mmol), tert-Butyl-1-carboxylic acid tert-butyl ester (20.5 g, 110 mmol) was added to 300 ml of DMF, stirred at 40 ° C for 5 hours, filtered, and filtrate was added to ethyl acetate (800 ml) with brine. 3 X 800 ml), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction was carried out in a hydrogen bromide solution at 100 ° C for 24 hours, and then cooled to room temperature.
  • the reaction solution was added to ice water and stirred to precipitate a large amount of solid.
  • the solid was filtered and rinsed with 5% aqueous sodium hydrogencarbonate and washed with deionized water until neutral.
  • Step B Synthesis of 5-(4-tert-butoxymethyl-piperidin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
  • Step C 4- ⁇ 6-[( ⁇ 4-methyl-3-[(4-Pyridin-3-ylpyrimidin-2-yl)amino]phenyl ⁇ amino)carbonyl]-1,2, Tert-butyl 3,4-tetrahydronaphthalen-1-yl ⁇ piperazine-1-carboxylate
  • Step B Synthesis of (2E)-3-(dimethylamino)succinimide (pyrimidin-5-yl)prop-2-enionone
  • Step D Synthesis of ! ⁇ -([4,5-dipyrimidin-2-yl)-6-methylbenzene-1,3-diamine
  • Step E N- ⁇ 4-methyl-3-[(4-pyrimidin-5yl)pyrimidin-2-amino]phenyl ⁇ -5-(4-methylpiperazin-1-yl)- Synthesis of 5,6,7,8-tetrahydronaphthalene-2-amide (Compound 2)
  • the reaction flask was added to the compound 2 (5.34 g, 10 mmol), anhydrous methanol 100 ml, methanesulfonic acid (1.01 g, 10.5 mmol), and refluxed at 70 ° C for 1 hour, then added pharmaceutically decolorized charcoal 2 g After refluxing for an additional 1 hour, it was suction filtered, and the filtrate was concentrated under reduced pressure.
  • Step B Synthesis of methyl 5-(3-methylimidazolidine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate
  • Step C Synthesis of 5-(3-methylimidazolidine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
  • Step D Synthesis of 5-(3-methylimidazolidine-1-yl)-1,2,3,4-tetrahydronaphthalene-5-acyl chloride hydrochloride
  • Step E N- ⁇ 4-Methyl-3-[(4-pyridin-3-yl)pyrimidin-2-amino]-phenyl ⁇ -5-(4-methylpiperazine small group)-5 Synthesis of 6,6,8-tetrahydronaphthalene-2-amide
  • Example 1 and Example 6 were test samples, and showed excellent antitumor effects as shown by the following pharmacodynamic tests.
  • the tumor cells were trypsinized, dispersed into individual cells, and suspended in RPMI1640 medium containing penicillin (25 U/ml) and streptomycin (25 g/ml).
  • the cells were seeded in a 96-well culture plate (Corning Incorporated), cultured at 37 V, air containing 5% CO 2 at a relative humidity of 100% for 24 hours, and the culture solution was discarded, and a series of test samples were added.
  • the culture medium is set to parallel holes at each concentration. After culturing for 24 hours, the culture solution containing the test sample is discarded, and after adding the conventional culture solution for 48 hours, the culture solution is discarded, and then the thiazole blue (MTT) is replaced.
  • MTT thiazole blue
  • C indicates the OD value of the control cells.
  • T represents the OD value of the cells in the test sample group
  • T 0 represents the OD value of the control plate cells when the test sample is added
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
  • the nude mice xenografts were measured for the diameter of the transplanted tumor using a vernier caliper, and the animals were randomly divided into groups after the tumors were grown to 100 to 300 mm 3 .
  • the method of measuring the tumor diameter is used to dynamically observe the antitumor effect of the test substance.
  • the number of tumor diameters measured twice a week, and each mouse was weighed at the same time.
  • the experimental group was administered intravenously three times a week, and the positive control group was administered intravenously three times a week.
  • the negative control group was given the same amount of physiological saline at the same time.
  • the formula for calculating the tumor volume (TV) is:
  • RTV relative tumor volume
  • V Q the tumor volume measured at the time of sub-cage administration (g ⁇ d Q )
  • 1 ⁇ 4 the tumor volume at each measurement.
  • the evaluation index of antitumor activity is the relative tumor growth rate T / C (%), and the calculation formula is as follows:
  • TRTV experimental group RTV
  • C rtv negative control group RTV.
  • the P388 leukemia ascites inoculated in mice for 7 days was diluted 1:15 to adjust the number of leukemia cells to 1 X 10 7 /mL, 0.2 mL per mouse, and the next day was randomly divided into 6 groups.
  • Each of the compound 1 and compound 2 groups was administered intraperitoneally once a day for 10 days, and the imatinib group was administered intraperitoneally once every other day for 5 times.
  • the compound 1 and the compound 2 provided by the present invention are more excellent as shown by the above pharmacological test results as compared with the control compound imatinib. Inhibition of tumors.
  • mice The results of administration of circophentinib and etimicin in the tail vein of mice showed that both cimetidine and etimicin were toxic to the circulatory system, and the animals in the high-dose group were shocked 0.5 to 2 hours after administration. Jumping, then you can see the lack of energy, body tremor, less moving part of the mouse draining feces, there is light yellow thin feces pollution around the anus. The death occurred within 5 to 12 hours after administration. The dead mice were dissected, and the intestinal swell of the mice was visually observed. The contents of the water samples were cut open, the liver became white, and the other organs showed no abnormalities. Liver histopathology Examination showed hepatic cell spot necrosis. Surviving mice in each group were observed for 14 consecutive days. No abnormalities were observed in feeding, drinking water, general state and activity. After the observation period, the mice were sacrificed, and no abnormalities were observed in the liver and main organs by naked eyes.
  • Cyclobutinib is toxic to the respiratory system and causes respiratory failure in mice after administration. Its LD 50 is 420.6 mg / kg, and the 95 % confidence limit is 340.3 mg / kg ⁇ 500.9 mg / kg. The toxic target organ is mainly the liver.
  • Amphetamine is toxic to the respiratory system and causes respiratory failure in mice after administration. Its LD 50 is 463.5 mg / kg, and the 95 % confidence limit is 370.9 mg / kg ⁇ 556.1 mg / kg. The toxic target organs are mainly the lungs.
  • the compound of the present invention exhibits an excellent antitumor effect, and as an antitumor agent, it is effective for preventing and treating diseases, particularly cancer.
  • the compound of the present invention can be formulated into an effective amount and a pharmaceutically acceptable carrier or excipient containing the compound of the present invention.
  • the form of administration of the compound of the present invention as an antitumor agent can be selected from various forms, and examples thereof include an oral preparation such as a tablet, a capsule, a powder, a granule or a liquid, or, for example, a solution or suspension.
  • an oral preparation such as a tablet, a capsule, a powder, a granule or a liquid, or, for example, a solution or suspension.
  • the solid preparation may be directly prepared in the form of a tablet, a capsule, a granule or a powder, but may also be produced using a suitable additive.
  • suitable additive include sugars such as lactose and glucose, and starches such as corn, wheat, and rice, and fatty acids such as stearic acid, such as magnesium metasilicate aluminate or anhydrous calcium phosphate.
  • Inorganic salt case A synthetic polymer such as polyvinylpyrrolidone or polyalkylene glycol, for example, a fatty acid salt such as calcium stearate or magnesium stearate, or an alcohol such as stearyl alcohol or benzyl alcohol, such as methyl fiber.
  • Synthetic cellulose derivatives such as carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose, and other additives which are generally used, such as gelatin, talc, vegetable oil, gum arabic, and the like.
  • the solid preparation of these tablets, capsules, granules, powders and the like may usually contain 0.1 to 99% (w/w), preferably 0.1 to 50% (w/w) of the active ingredient.
  • the liquid preparation can be produced in the form of a liquid, an alcohol or a liquid preparation such as soybean oil, peanut oil or sesame oil in a form of a suspension, a syrup, an injection or a drip, using a suitable additive which is usually used.
  • intravenous injection or subcutaneous injection for example, distilled water for injection, physiological saline, aqueous glucose solution, ethanol, polyethylene glycol, or the like may be mentioned.
  • a liquid for intravenous injection for example, an aqueous solution of citric acid and sodium citrate
  • an electrolyte solution for intravenous and intravenous injection, or the like, or a mixed solution of these.
  • injection solutions may usually contain 0.1 to 20% (w/w), preferably 0.5 to 5% (w/w) of the active ingredient.
  • a dosage form of a suspending agent, a syrup or the like for oral administration may usually contain 0.5 to 10% (w/w) of an active ingredient.
  • the preferred amount of the compound of the present invention can be administered depending on the kind of the compound to be used, the type of the compound to be compounded, the frequency of application and the specific site to be treated, the severity of the condition, the age of the patient, the diagnosis of the doctor, and the tumor.
  • the type varies, but as a general target, for example, the dose per one adult per day can be in the range of l to 300 mg at the time of oral administration, and in the case of parenteral administration, at the time of intravenous injection. Preferably, it is in the range of from l to 150 mg per day.
  • the number of administrations varies depending on the administration method and symptoms, but it is 1 to 3 times a day. Further, an administration method such as intermittent administration such as administration every other day or administration for two days may be used.

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Abstract

La présente invention porte sur un nouveau composé qui est un composé de tétrahydronaphtalène renfermant un groupe amide tel que représenté par la formule générale I, ou un sel pharmaceutiquement acceptable de celui-ci, servant de médicament antinéoplasique. L'invention porte également sur un procédé de préparation du composé, sur une composition pharmaceutique comprenant le composé, sur un résultat d'effet antinéoplasique exosomatique et endosomatique et sur une étude sur la toxicité aiguë. Le médicament antinéoplasique qui est un composé de tétrahydronaphtalène renfermant un groupe amide de la présente invention est doté d'une meilleure activité antinéoplasique et d'une meilleure innocuité. Il peut être utilisé pour traiter des tumeurs telles qu'une leucémie, un cancer du poumon, un cancer du côlon, un cancer de l'ovaire et un cancer du rein et similaire, présentant donc une large fenêtre thérapeutique et une haute valeur d'application en tant qu'agent antinéoplasique dans le domaine pharmaceutique.
PCT/CN2012/078422 2011-07-12 2012-07-10 Médicament antinéoplasique qui est un composé de tétrahydronaphtalène renfermant un groupe amide ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation WO2013007184A1 (fr)

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CN201110193137XA CN102295635B (zh) 2011-07-12 2011-07-12 抗肿瘤药物四氢化萘酰胺类化合物及其药学上可接受的盐及制备方法和应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045632A (zh) * 2014-06-03 2014-09-17 辽宁大学 抗肿瘤药物苯并二氢吡喃（噻喃）酰胺类化合物及其药学上可接受的盐及制备方法和应用
WO2018187894A1 (fr) * 2017-04-10 2018-10-18 师健友 Médicament pour le traitement de maladies tumorales, et ayant des effets antibactériens, antiviraux et anti-inflammatoires

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