WO2006081741A1 - Dérivés de quinazoline ou leurs sels de qualité pharmaceutique, synthèse et applications médicales desdites substances - Google Patents

Dérivés de quinazoline ou leurs sels de qualité pharmaceutique, synthèse et applications médicales desdites substances Download PDF

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Publication number
WO2006081741A1
WO2006081741A1 PCT/CN2006/000096 CN2006000096W WO2006081741A1 WO 2006081741 A1 WO2006081741 A1 WO 2006081741A1 CN 2006000096 W CN2006000096 W CN 2006000096W WO 2006081741 A1 WO2006081741 A1 WO 2006081741A1
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compound
group
pharmaceutically acceptable
acceptable salt
methoxy
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PCT/CN2006/000096
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Piaoyang Sun
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Piaoyang Sun
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to a quinazoline compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof, and the use of the compound alone or in combination with other drugs for the treatment of a cell proliferative disease such as cancer.
  • Background technique
  • the treatment of cell proliferative diseases such as psoriasis and cancer is mainly the use of compounds that inhibit DNA synthesis.
  • these compounds are highly toxic to cells.
  • Receptor tyrosine kinases are important in the transport of biochemical information, and this information can initiate cell replication. Depending on the type of growth factor linked to different receptor tyrosine kinases, it can be divided into different types of receptor tyrosine kinases, of which epidermal growth factor receptor tyrosine kinase is one of them. Epidermal growth factor receptor tyrosine kinase has been found in many human cancers (such as breast cancer, non-small cell lung cancer, gastric cancer, rectal cancer, leukemia, etc.), and studies have also found that epidermal growth factor is regulated in normal cells.
  • An object of the present invention is to provide a quinazoline compound or a pharmaceutically acceptable salt thereof; and another object of the present invention is to provide a process for preparing a quinazoline compound or a pharmaceutically acceptable salt thereof; The object is to provide the use of such a quinazoline compound or a pharmaceutically acceptable salt thereof, alone or in combination with other drugs, for the treatment of cell proliferative diseases such as cancer.
  • the object of the present invention is attained by the following technical means, and the present invention relates to a quinazoline compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a linear or branched fluorenyl group selected from hydrogen or 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms;
  • Q 2 is selected from an aryl or heterocyclic aryl group which is substituted or unsubstituted, and the number of the substituent groups is 1, 2 or 3; the substituent group is selected from the group consisting of hydrogen, halogen, hydroxyl group, amino group, cyano group, hydrazine Alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, aralkoxy, heteroaralkyloxy, arylalkyl, heteroarylalkyl, aryloxy Or a heteroaryloxy group, wherein the aryl or heteroaryl group may also be substituted by hydrogen, halogen, hydroxy, amino, cyano, alkyl or decyloxy;
  • the compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the Qi-(CH 2 ) nO- may be substituted at the 5, 6, 7 or 8 position of the quinazoline ring, preferably at the 6 or 7 position.
  • Substituted; ( ⁇ is selected from heterocyclic ring (11), wherein R 2 is selected from hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms or a cycloalkyl group of 3 to 6 carbon atoms, preferably 1 to 4 carbons A linear or branched alkyl group of an atom, more preferably a linear alkyl group of 1 to 4 carbon atoms.
  • the compound of the above formula (I) or a pharmacologically acceptable salt thereof of the present invention is selected from the group consisting of a heterocyclic ring (II), and in the heterocyclic (II) compound, the * carbon atom is a chiral carbon atom. Its configuration is in the form of a single enantiomer of (R) or (S) or enriched in one enantiomer.
  • the present invention further relates to a compound of the above formula (I) or a pharmaceutically acceptable salt thereof, wherein Qi-(CH 2 ) nO- may be substituted at the 5, 6, 7 or 8 position of the quinazoline ring, preferably at 6, Substituted at position 7; Q> is a heterocyclic (III) compound in which a *carbon atom is a chiral carbon atom and its configuration is a single pair of (S, S) or (R, R) The form is enriched or enriched in one enantiomeric form.
  • Q 2 may also be selected from substituted or unsubstituted aryl or heterocyclic aryl, preferably substituted aryl; substituent group The number is 1, 2 or 3, preferably 1 or 2.
  • the substituent group is selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, halodecyloxy, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, a heteroaralkyloxy, arylalkyl, heteroarylalkyl, aryloxy or heteroaryloxy group, wherein the aryl or heteroaryl group can also be hydrogen, halogen, hydroxy, amino, cyano, alkyl or alkoxy Substituted by the base.
  • L may be NR 5 , a linear or branched fluorenyl group selected from hydrogen or 1 to 4 carbon atoms or 3 to 6 carbon atoms. Cyclodecyl, preferably hydrogen or a linear alkyl group of 1 to 4 carbon atoms.
  • the compound of the above formula (I) may form a salt with an acid selected from an organic acid or an inorganic acid.
  • the organic acid includes acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid and p-toluenesulfonic acid; and the inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, preferably hydrochloric acid.
  • Typical compounds of the formula (I) of the present invention include -
  • a further object of the invention is achieved by the following technical solution, which provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps -
  • Compound (VI) is obtained under acidic conditions or by hydrogenolysis of an amino protecting group to give compound (VII);
  • X refers to easy leaving
  • the group is preferably a halogen atom such as a chlorine, bromine or iodine atom.
  • the pharmaceutically acceptable salt can be prepared by mixing the compound (I) with a suitable acid by a conventional method, such as lyophilization or precipitation.
  • the base used is selected from an organic base (e.g., pyridine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, triethylamine, diisopropylethylamine).
  • organic base e.g., pyridine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, triethylamine, diisopropylethylamine.
  • an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • the solvent is selected from the group consisting of tetrahydrofuran, dimethyl sulfoxide, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, etc., preferably N, N-dimethylformamide; reaction temperature It is controlled at 0-100 ° C, preferably 20-80 ° C.
  • the acid to be used is selected from an organic acid (e.g., trifluoroacetic acid, trichloroacetic acid, acetic acid, etc.) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.), preferably trifluoroacetic acid.
  • organic acid e.g., trifluoroacetic acid, trichloroacetic acid, acetic acid, etc.
  • an inorganic acid e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • the molar amount of R 2 -X should be controlled to be equivalent to or lower than the amount of the compound (VII), and the base used is selected from an organic base (such as pyridine, Piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, triethylamine, diisopropylethylamine, etc.) or inorganic bases (such as sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium carbonate) , potassium carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), preferably pyridine and triethylamine.
  • organic base such as pyridine, Piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, triethylamine, diisopropylethylamine, etc.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium carbonate
  • potassium carbonate sodium methoxide, sodium e
  • a further object of the present invention is further achieved by the following technical scheme, in the preparation of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, which is characterized in that when the compound ( ⁇ ) in the form of R 2 is a methyl group, other Methylation methods, such as formaldehyde reduction, formaldehyde, formic acid methylation.
  • the invention further relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps -
  • R4 means an acyl group, including but not limited to the following: acetyl, propionyl, benzoyl, p-toluoyl; preferably benzoyl.
  • the dehydrating agent used is selected from a mixture of triphenyl p- and diazodicarboxylic acid di-Z1 ester or triphenylphosphine and azo.
  • a mixture of diisopropyl dicarboxylate or the like is preferably a mixture of triphenylphosphine and diethyl azodicarboxylate.
  • the invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a tyrosine kinase inhibitor, in particular for the preparation of a medicament for the treatment of a cell proliferative disorder.
  • the cell proliferative disorder includes cancer.
  • the present invention provides the use of such a quinazoline compound or a pharmaceutically acceptable salt thereof, alone or in combination with other drugs, for the treatment of a proliferative disease such as cancer.
  • Antitumor agents which can be used in combination with a compound provided by the present invention or a pharmaceutically acceptable salt thereof include, but are not limited to, at least one of the following classes: mitotic inhibitors (e.g., vinblastine, vindesine, and vinorelbine); tubulin Decomposition inhibitors (such as Taxol); alkylating agents (such as cisplatin, carboplatin and cyclophosphamide); antimetabolites (such as 5-fluorouracil, tegafur, methotrexate, cytarabine and hydroxyl Urea); insertable antibiotics (such as arrhenone, mitomycin and bleomycin); enzymes (such as aspartate); topoisomerase inhibitors (such as etoricin and camptothecin); Conditioner (such
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the composition consists of an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical composition provided by the present invention may be administered orally (such as tablets or capsules) or parenterally injected sterile solution (including intravenous injection, subcutaneous injection, intramuscular injection, intravascular injection or infusion) or topical (such as ointment). Or in the form of a rectum (such as a suppository).
  • parenterally injected sterile solution including intravenous injection, subcutaneous injection, intramuscular injection, intravascular injection or infusion) or topical (such as ointment).
  • topical such as ointment
  • a rectum such as a suppository
  • the compound of the present invention is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is controlled at 1-250 mg/kg, preferably 1-100 mg/kg, wherein "mg" represents an active group in a pharmaceutical composition.
  • the weight unit of the minute, "kg” indicates the weight of the human body.
  • the dosage of the drug depends on a number of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's Gender, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; additionally, optimal treatment modalities such as mode of treatment, daily dose of compound (I) or pharmaceutically acceptable salt
  • optimal treatment modalities such as mode of treatment, daily dose of compound (I) or pharmaceutically acceptable salt
  • the type can be verified according to traditional treatment options.
  • the compound obtained by the present invention 4-(3'-ethynyl-anilino)-7-methoxy-6-[(2' S) - (N- Methylazetidin-2-(methoxy)quinazoline (No.: Compound 2), 4-(3'-chloro-4'-fluoro-anilino)-7-methoxy-6 -[ (2' R) - (N-methylazetidinyl-2-) methoxy]quinazoline (number: compound 3), 4-(3'-ethynyl-anilino)-7- Methoxy-6-[(2' R) - (N-methylazetidin-2-yl)methoxy]quinazoline (number: compound 4) and 4-(3'-ethynyl) -anilino)-7-methoxy-6- ⁇ 2-[(1R, 4R)-2-oxo-5-azabicyclo[2.2.1]heptyl-5-
  • Figure 1 Inhibition of EGFR receptor by Iressa series of compounds.
  • Figure 2 Effect of HH-IR-4, Tarceva on human epithelial carcinoma A431 nude mice xenografts.
  • Figure 3 Effect of HH-IR-4, Tarceva on body weight of tumor-bearing nude mice.
  • Figure 4 Effect of HH-IR-4, Tarceva on human epithelial carcinoma A431 nude mice xenografts. Tumor photograph.
  • Figure 5 Mean plasma concentration-time curve after Beagle was orally administered with 20 mg/kg TARCEVA or HH-IR-4 hydrochloride. detailed description
  • L-aspartic acid diisopropyl ester hydrochloride (76.2 g 0.3 mmol) was added to a mixture of toluene (400 ml) and trimethylchlorosilane (32.7 g, 0.3 mmol) under a nitrogen atmosphere. After cooling to 5-10 V, triethylamine (63.8 g, 0.63 mmol) was added dropwise, and the mixture was naturally allowed to react to room temperature for 1 hour.
  • the preparation method is the same as that in the first embodiment except that 4-(3'-chloro-4'-fluoro-anilino)-7-methoxy-6-[(2'S)-(N-tert-butoxy) is prepared.
  • the carbonyl azetidinyl-2-)methoxy]quinazoline was changed to 4-(3'-chloro-4'-fluoro-anilino)-7-methoxy-6-[ (2' R - (N-tert-Butoxycarbonylazetidin-2-yl)methoxy]quinazoline.
  • the preparation method is the same as that in the first step of the first embodiment, except that (S)-N-tert-butoxycarbonylazetidin-2-one methanesulfonate is changed to (R)-N-tert-butoxy Carbonyl azetidinyl-2-methanol mesylate.
  • the preparation method was the same as that in the first step of Example 1, except that L-aspartate was changed to D-aspartate.
  • Embodiment 3 is the same as that in the first step of Example 1, except that L-aspartate was changed to D-aspartate.
  • the preparation method is the same as that in the first embodiment except that 4-(3'-chloro-4'-fluoro-anilino)-7-methoxy-6-[(2')
  • the preparation method is the same as that in the first embodiment except that 4-(3'-chloro-4'-fluoro-anilino)-7-methoxy-6-[(2' S) - (N-tert-butoxy) is used.
  • the carbonyl azetidinyl-2-) methoxy] quinazoline was changed to 4-(3'-ethylidene-anilino)-7-methoxy-6-[ (2' S) - (N- Tert-Butoxycarbonylazetidin-2-(methoxy)quinazoline.
  • the preparation method is the same as that in the first step of the first embodiment, except that 4-(3'-chloro-4'-fluoro-anilino)-6-hydroxy-7-methoxyquinazoline is changed to 4-(3). '-ethynyl-anilino)-6-hydroxy-7-methoxyquinazoline.
  • 6-Acetoxy-7-methoxy-3,4-dihydroquinazoline (preparation method refers to WO 96/33980 Example 1 15 g), thionyl chloride (215 ml) and DMF (4.3 ml) It was placed in a reaction flask and reacted at 90 ° C for 4 hours. After cooling, the thionyl chloride was removed under reduced pressure to give 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride.
  • the preparation method is the same as that in the first embodiment except that 4-(3'-chloro-4'-fluoro-anilino)-7-methoxy-6-[(2'S)-(N-tert-butoxy) is prepared. Carbonylazetidin-2-) methoxy]quinazoline was changed to 4-(3'-ethynyl-anilino)-7-methoxy-6-[ (2' R) - (N - tert-Butoxycarbonylazetidin-2-)methoxy]quinazoline.
  • N-tert-butoxycarbonyl-L-hydroxyindole ammonia methanol (4.94 g 22.7 mmol) was dissolved in pyridine (90 ml), cooled to -10 ° C, benzoyl chloride (3.19 g, 22.7 mmol) was added dropwise to give a white precipitate. , naturally rise to room temperature and react overnight.
  • Methanesulfonyl chloride (2.58 g, 22.7 mmol) was added dropwise, and the residue was evaporated to dryness eluted eluted eluted eluted eluted -N-tert-Butoxycarbonyl-L-hydroxyprolinol benzoate.
  • the preparation method is the same as that in the fifth embodiment except that 6-(hydroxyethyleneoxy)-7-methoxy-4-(3'-chloro-4'-fluoro-anilino)quinazoline is changed to 6 - (Hydroxyethyleneoxy)-7-methoxy-4-(3'-ethynyl-anilino)quinazoline.
  • the preparation method is the same as that in the fifth embodiment except that (IS, 4S)-2-oxo-5-azabicyclo[2.2.1]heptane hydrochloride is changed to (1R, 4R)-2-oxo-5- Nitrobicyclo[2.2.1]heptane hydrochloride ( 1R, 4R) -2-oxo-5-azabicyclo[2.2.1]heptane hydrochloride
  • the acid anhydride (81.6 g) and acetic acid (240 ml) were mixed and heated to 50 ° C, and L-hydroxyproline (20 g 0.15 mol) was added thereto, and the mixture was heated to reflux for 5.5 h.
  • the solution was concentrated, and the obtained concentrate was added to EtOAc (2N 280 ml), and the mixture was refluxed for 3 hr, and 5 g of activated carbon was refluxed for 15 min, and filtered through Celite.
  • the filtrate was concentrated to 60 ml, allowed to stand, and a needle-like solid was precipitated, filtered, and dried to obtain a needle-like crystal D-path valine hydrochloride.
  • N-tert-butoxycarbonyl-D-hydroxyindole methanol N-tert-butoxycarbonyl-D-hydroxyprolinol (2.0 g 9.2 mmol) triphenylphosphine (2.66 g 10 mmol) was dissolved in dichloromethane (200 ml) and cooled to 0 ° C in an ice salt bath.
  • the preparation method is the same as that in the fifth embodiment. The difference is that 6-(hydroxyethyleneoxy)-7-methoxy-4-(3'-chloro-4'-fluoro-anilino)quinazoline is changed to 6-(hydroxyethyleneoxy) -7-Methoxy-4-(3'-ethynyl-anilino)quinazoline, modified (1S, 4S)-2-oxo-5-azabicyclo[2.2.1]heptanyl hydrochloride Is (1R, 4R)-2-oxo-5-azabicyclo[2.2.1]heptane hydrochloride.
  • Example ten 6-(hydroxyethyleneoxy)-7-methoxy-4-(3'-chloro-4'-fluoro-anilino)quinazoline is changed to 6-(hydroxyethyleneoxy) -7-Methoxy-4-(3'-ethynyl-anilino)quinazoline, modified (1S, 4S)-2-oxo-5-azabicyclo[2.2.1]
  • Vanillin 90 g, 0.59 mol
  • absolute ethanol 400 ml
  • potassium carbonate 80 g, 0.59 mol
  • benzyl bromide 114 g, 0.9 mol
  • the upper intermediate (16 g, 0.053 mol) and glacial acetic acid (320 ml) were placed in a reaction flask and heated to 90 °C.
  • Add iron powder (14.8 g, 0.265 mol) in 20 minutes continue to react for 45 minutes after the addition, filter, insoluble materials washed with hot acetic acid, combine the filtrate, rush into 10% hydrochloric acid (560 nil), filter, filter cake Wash with hot water, cool the filtrate, adjust the pH to alkaline with 15% sodium hydroxide, crystallize, filter, wash with isopropanol, and dry to give 4-benzyloxy-5-methoxy-2-aminobenzamide : 9.7 grams.
  • HH-IR-4 4-(3'-ethynyl-anilino)-7-methoxy-6-[(2' R) - (N-methylazetidin-2-) Oxy] quinazoline.
  • mice BALB/cA-nude nude mice
  • Feeding environment SPF level.
  • HH-IR-4 significantly inhibited the growth of human epithelial carcinoma A431 nude mice, and the inhibition was dose-dependent.
  • the effect of HH-IR-4 was very significant. When administered at 25 mg/kg, the T/C was 6.5%. Tumors barely grow, and their efficacy is superior to Tarceva (T/C% 15.9%).
  • the effect of HH-IR-4 and Tarceva was comparable when administered at 12.5 mg/kg. The mice were well tolerated by both HH-IR-4 and Tarceva with no apparent toxicity. (See Table 2, Figure 2, Figure 3, Figure 4 for specific results) Table 2.
  • HH-IR-4 25 5 5 16.2 17.1 140 ⁇ 25 121 ⁇ 44 0 ⁇ 9 ⁇ 0.3 6.5* dO : time of administration in a cage; dn: 21 days after the first administration. *P ⁇ 0.01 vs control 4.
  • HH-IR-4 significantly inhibited the growth of human epithelial carcinoma A431 nude mice xenografts.
  • the efficacy of HH-IR-4 is better than that of Tarceva
  • HPLC-UV method for determining the concentration of TARCEVA and its analogue HH-IR-4 in Beagle dog plasma was established. The method was applied to determine the plasma concentration of plasma in Beagle dogs after oral administration of the hydrochloride of two compounds. The samples were subjected to liquid-liquid extraction (LLE) and chromatographed to determine two compounds in plasma.
  • LLE liquid-liquid extraction
  • TARCEVA Erlotinib hydrochloride, batch number 20050826;
  • Fig. 5 The blood concentration-time curve of HH-IR-4 and TARCEVA after oral administration is shown in Fig. 5.
  • Pharmacokinetic parameters DAS2.0 software using Beagle dogs after oral administration of the two compounds fit compartmental model drugs in vivo pharmacokinetic behavior, and calculate the pharmacokinetic parameters, C wa3 ⁇ 4, t, " ⁇ preclude the use Found , while comparing the pharmacokinetic behavior of the two compounds.

Abstract

La présente demande concerne des dérivés de quinazoline de formule (I) ou leurs sels de qualité pharmaceutique, les valeurs de R1, Q1, Q2, m et n étant détaillées dans la description. La présente invention concerne également un procédé de synthèse ainsi que des préparations thérapeutiques contenant une dose active des composés de formule (I) ou de leurs sels. Il a été montré que les composés de formule (I) ou leurs sels pouvaient traiter les maladies cellulaires prolifératives telles que le cancer, par inhibition du récepteur de facteur de croissance épidermique de la surface cellulaire.
PCT/CN2006/000096 2005-02-05 2006-01-20 Dérivés de quinazoline ou leurs sels de qualité pharmaceutique, synthèse et applications médicales desdites substances WO2006081741A1 (fr)

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CN102796109A (zh) * 2011-05-23 2012-11-28 复旦大学 4-氨基喹唑啉化合物及其制备方法和用途
US9181277B2 (en) 2011-11-14 2015-11-10 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use

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CN1356990A (zh) * 1999-06-21 2002-07-03 贝林格尔英格海姆法玛公司 双环杂环化合物,含有该化合物的药物组合物,该化合物的用途及其制备方法
CN1406232A (zh) * 2000-02-26 2003-03-26 歌德克有限责任公司 制备(3－氯－4－氟苯基)－[7－(3－吗啉－4－基丙氧基)－6－硝基喹唑啉－4－基]－胺或(3－氯－4－氟苯基)－[7－（3－吗啉－4－基丙氧基)－6－氨基喹唑啉－4－基]－胺的简单方法
CN1434821A (zh) * 2000-06-06 2003-08-06 阿斯特拉曾尼卡有限公司 ***用的喹唑啉衍生物
CN1481370A (zh) * 2000-12-20 2004-03-10 ���ָ��Ӣ��ķ�������Ϲ�˾ 喹唑啉衍生物,含该化合物的药物组合物,其用途及其制备方法
WO2003040108A1 (fr) * 2001-11-03 2003-05-15 Astrazeneca Ab Derives quinazoline utilises en tant qu'agents antitumoraux
WO2003082290A1 (fr) * 2002-03-30 2003-10-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg 4-(n-phenylamino)-quinazolines / quinolines en tant qu'inhibiteurs de la tyrosine kinase

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CN102796109A (zh) * 2011-05-23 2012-11-28 复旦大学 4-氨基喹唑啉化合物及其制备方法和用途
CN102796109B (zh) * 2011-05-23 2015-10-07 复旦大学 4-氨基喹唑啉化合物及其制备方法和用途
US9181277B2 (en) 2011-11-14 2015-11-10 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use

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