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WO2008002039A1 - Quinazoline derivatives for inhibiting the growth of cancer cell - Google Patents

Quinazoline derivatives for inhibiting the growth of cancer cell Download PDF

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Publication number
WO2008002039A1
WO2008002039A1 PCT/KR2007/003061 KR2007003061W WO2008002039A1 WO 2008002039 A1 WO2008002039 A1 WO 2008002039A1 KR 2007003061 W KR2007003061 W KR 2007003061W WO 2008002039 A1 WO2008002039 A1 WO 2008002039A1
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WO
WIPO (PCT)
Prior art keywords
chloro
pyrrolidine
quinazolin
acryloyl
carboxyamide
Prior art date
Application number
PCT/KR2007/003061
Other languages
French (fr)
Inventor
Kwang-Ok Lee
Ji Hyeon Gong
Mi Young Cha
Chang Gon Lee
Young Hoon Kim
Kyuhang Lee
Tae Hun Song
Ji Yeon Song
Young-Jin Park
Eun Young Kim
Eunyoung Lee
Kyungik Lee
Maeng Sup Kim
Gwan Sun Lee
Original Assignee
Hanmi Pharm. Co., Ltd.
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Filing date
Publication date
Priority claimed from KR1020070047460A external-priority patent/KR100929146B1/en
Application filed by Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Publication of WO2008002039A1 publication Critical patent/WO2008002039A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof for inhibiting the growth of cancer cells induced by epithelial growth factor and its mutants, and a pharmaceutical composition comprising same as an active ingredient.
  • Protein tyrosine kinases play important roles in such cellular regulation, and their abnormal expression or mutation has been observed in cancer cells.
  • Protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on protein substrates.
  • Many growth factor receptor proteins function as tyrosine kinases to transport cellular signals. The interaction between growth factors and their receptors normally controls the cellular growth, but abnormal signal transduction caused by the mutation or overexpression of any of the receptors often induces tumor cells or cancers.
  • Protein tyrosine kinases have been classified into many families in terms of growth factors, and epithelial cell growth factor (EGF)-related EGF receptor (EGFR) tyrosine kinases have been intensely studied.
  • An EGFR tyrosine kinase is composed of a receptor and tyrosine kinase, and delivers extracellular signals to cell nucleus through the cellular membrane.
  • Various EGFR tyrosine kinases are classified based on their structural differences into EGFR (Erb-Bl), Erb-B2, Erb-B3 and Erb-B4, and each of the above members can form a homodimer- or heterodimer-signal delivery complex. Also, overexpression of more than one of the above mentioned homodimers is often observed in malignant cells. In addition, it is known that both EGFR and Erb- B2 significantly contribute to the formation of heterodimer-signal delivery complexes.
  • Gefitinib drugs for the inhibition of EGFR tyrosine kinases
  • Erlotinib drugs for the inhibition of EGFR tyrosine kinases
  • Lapatinib drugs for the inhibition of EGFR tyrosine kinases
  • drugs for the inhibition of EGFR tyrosine kinases have been developed, e.g., Gefitinib, Erlotinib, Lapatinib and the like.
  • Gefitinib or Erlotinib selectively inhibits EGFR
  • Lapatinib simultaneously inhibits EGFR and Erb-B2, thereby arresting the growth of tumors.
  • T790M a mutant of an EGFR tyrosine kinase, wherein threonine present at a position 790 in exon 20 region of EGFR tyrosine kinase is replaced with methionine (see [Plos Medicine 2005, 2(3), 225-235]), and also that it provides no substantial clinical effect on T790M variation patients.
  • Ri is 2- methoxyethoxy, (tetrahydrofuran-2-yl)methoxy, 2-morpholinoethoxy, (4- methylthiazol-5-yl)ethoxy or 2-(l/7-l,2,4-triazol-l-yl)ethoxy; and R 2 is 3- chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-bromo-3-chloro-2- fluorophenyl, 2,3,4-trifluorophenyl, 3,4-dichlorophenyl, 3,4-dichloro-2- fluorophenyl or 3-chloro-2,4-fluorophenyl, in the quinazoline derivative of formula (I).
  • 'halo' refers to fluoro, chloro, bromo or iodo, unless otherwise indicated.
  • Examples of more preferred compounds of formula (I) according to the present invention are: l) (2 1 S)-l-acryloyl-N-[4-[3-chloro-2-fluoro ⁇ henylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
  • Ri and R 2 have the same meanings as defined above.
  • a compound of formula (III) is subjected to a condensation reaction with N-(t ⁇ rt-Boc)-proline in an organic solvent to obtain a compound of formula (II).
  • the condensation agent which may be used in this reaction is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) or its acid- addition salt.
  • the organic solvent used in this reaction may be pyridine, tetrahydrofuran, methylene chloride or chloroform.
  • an organic or inorganic acid e.g., trifluoroacetic acid or heavy hydrochloric acid
  • an organic solvent e.g., CHCl 3
  • a compound of formula (III) is subjected to a reaction with a compound of formula (V) in an organic solvent (e.g., ethanol) in the presence of acetic acid and sodium cyanoborohydride to obtain a compound of formula (IV).
  • an organic solvent e.g., ethanol
  • a compound of formula (Ib) which corresponds to the inventive compound of formula (I) wherein A is -CH 2 -, is prepared by reacting the compound of formula (IV) with an organic or inorganic acid (e.g., trifluoroacetic acid or concentrated hydrochloric acid) in an organic solvent (e.g., CHCI 3 ) to induce the removal of the protective f-butoxycarbonyl group from the compound of formula (IV), followed by treatment with acryloyl chloride in an organic solvent (e.g., a mixture of tetrahydrofuran and water) in the presence of a base (e.g., sodium bicarbonate).
  • an organic or inorganic acid e.g., trifluoroacetic acid or concentrated hydrochloric acid
  • an organic solvent e.g., CHCI 3
  • acryloyl chloride e.g., a mixture of tetrahydrofuran and water
  • a base e.g., sodium bicarbonate
  • the compound of formula (I) of the present invention can also be used in the form of a pharmaceutically acceptable salt formed with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic
  • inventive compound or a pharmaceutically acceptable salt thereof selectively and efficiently inhibits the growth of cancer cells induced by epithelial growth factor and its mutants, and provides enhanced anticancer effects when combined with another anticancer agent.
  • inventive compound or a pharmaceutically acceptable salt thereof is useful for enhancing the effects of an anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents and antiandrogen.
  • the present invention provides a pharmaceutical composition for inhibiting cancer cell growth comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the inventive compound or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from about 0.01 to 100 mg/kg, preferably 0.2 to 50 mg/kg body weight per day in case of mammals including human in a single dose or in divided doses.
  • the dosage of the active ingredient may be adjusted in light of various relevant factors such as the condition of the subject to be treated, type and seriousness of illness, administration rate, and opinion of doctor. In certain cases, an amount less than the above dosage may be suitable. An amount greater than the above dosage may be used unless it causes deleterious side effects, and such amount can be administered in divided doses per day.
  • inventive pharmaceutical composition may be formulated in accordance with any of the conventional methods in the form of tablet, granule, powder, capsule, syrup, emulsion or microemulsion for oral administration, or for parenteral administration including intramuscular, intravenous and subcutaneous routes.
  • the inventive pharmaceutical composition for oral administration may be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent.
  • a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent.
  • a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent.
  • step (1-3) 300 mg of the compound prepared in step (1-3) was dissolved in 7 ml of pyridine. 356 mg of (25)-l-(ter?-butoxycarbonyl)pyrrolidine-2-carboxylic acid and 477 mg of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the resulting solution and stirred for 14 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent and the residue was washed with saturated sodium bicarbonate solution.
  • step (1-4) 476 mg of the compound prepared in step (1-4) was dissolved in 10 ml of methylene chloride. 10 ml of trifluoroacetic acid was added to the resulting solution and stirred for 5 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was added to the resulting residue to make it basic, followed by extraction with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain 320 mg of the title compound (82%).
  • step (1-5) 300 mg of the compound prepared in step (1-5) was dissolved in 7 ml of tetrahydrofuran, cooled to 0 ° C, and 70 ⁇ i of acrylic acid was added slowly thereto. 0.12 ml of pyridine and 249 mg of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride were added to the resulting solution, and stirred for 4 hrs while heating slowly to room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with chloroform.
  • Example 1 The procedure of Example 1 was repeated using 3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 600 mg of the title compound (28%).
  • Example 1 The procedure of Example 1 was repeated using 4-bromo-3-chloro-2- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 800 mg of the title compound (31%).
  • Example 1 The procedure of Example 1 was repeated using 2,3,4-trifluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 130 mg of the title compound (15%).
  • Example 1 The procedure of Example 1 was repeated using 3,4-dichlororoaniline in place of 3-chloro-2-fluoroaniline in step (1-I) 5 to obtain 140 mg of the title compound (12%).
  • Example 1 The procedure of Example 1 was repeated using 3-chloro-2,4- difluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 135 mg of the title compound (14%).
  • Example 1 The procedure of Example 1 was repeated using 3,4-dichloro-2- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 120 mg of the title compound (10%).
  • Example 1 The procedure of Example 1 was repeated using 3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and tetrahydrofuran-2-ylmethylalcohol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 50 mg of the title compound (11%).
  • Example 1 The procedure of Example 1 was repeated using 4-bromo-3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and tetrahydrofuran-2-ylmethylalcohol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 65 mg of the title compound (10%).
  • Example 10 Preparation of (25 r )-l-acryloyl-A/-r4-r4-bromo-3-chloro-2- fluorophenylamino1-7-(2-morpholinoethoxy)quinazolin-6-vnpyrrolidine-2- carboxyamide
  • Example 1 The procedure of Example 1 was repeated using 4-bromo-3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and 2- morpholinoethanol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 70 mg of the title compound (11%).
  • Example 1 The procedure of Example 1 was repeated using 2-(4-methylthiazol-5- yl)ethanol in place of 2-methoxyethanol in step (1-2), to obtain 65 mg of the title compound (34%).
  • Example 12 Preparation of (26 r )-l-acryloyl-N-(4-r3-chloro-2- fluorophenylaminol-7-r2- ⁇ /- r -1.2,4-triazol-l-yl ' )ethoxy "
  • Example 1 The procedure of Example 1 was repeated using 2-(l// ' -l,2,4-triazol-l- yl)ethanol in place of 2-methoxyethanol in step (1-2), to obtain 50 mg of the title compound (12%).
  • inventive compounds prepared in the Examples were formulated as follows:
  • Tablets for oral administration comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 1.
  • Injection formulations comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 3, wherein when a salt of the compound of formula (I) was used, the pH value was not manupulated.
  • Test Example 1 Inhibition of EGFR enzyme
  • 10 ⁇ i of EGFR (EGFR type 1 kinase) was added to each well of a 96- well microplate.
  • EGFR inhibitor 10 ⁇ l of a serially diluted solution of each of the compounds obtained in Examples 1 to 13, Iressa (Astrazeneca) or Lapatinib (Glaxo SmithKline) was added to each well, and the plate was incubated at room temperature for 10 mins.
  • 10 ⁇ l of Poly (GIu, Tyr) 4 : 1 (Sigma) and 10 ⁇ i of ATP were successively added thereto to initiate a kinase reaction, and the resulting mixture was incubated at room temperature for 1 hour.
  • 10 ⁇ i of 100 mM EDTA was added to each well and stirred for 5 mins to terminate the kinase reaction.
  • 30 ⁇ l of FP (fluorescence polarization) diluted buffer were added to the reacted mixture, followed by incubating in dark at room temperature for 30 mins.
  • the FP value of each well was determined with VICTORIII fluorescence meter (Perkin Elmer) at 488 nm, and IC 5O , the concentration at which 50% inhibition was observed, was determined, wherein the maximum (0% inhibition) value was set at the polarized light value measured for the well untreated with EGFR inhibitor and the minimum value corresponded to 100% inhibition.
  • the calculation and analysis of IC 50 were carried out by using Microsoft Excel. The results are shown in Table 5.
  • Test Example 2 Inhibition of EGFR mutant enzyme (T790M)
  • EGF mutant receptor (EGFR T790M kinase, Upstate) was added to each well of a 96- well microplate.
  • EGF mutant receptor EGFR T790M kinase, Upstate
  • Iressa Astrazeneca
  • Lapatinib GaxoSmithKline
  • Test Example 3 Test of cancer cell growth inhibition
  • a skin cancer cell line, A431 (ATCC: CRL- 1555), a breast cancer cell line, SK-Br3 (ATCC: HTB-30), and a colon/rectal cancer cell line, SW-620 (ATCC: CCL-227) were used to test the degrees of the inventive compounds in inhibiting the cancer cell growth using a culture medium, DMEM (Dulbecco's Modified Eagle's Medium) having 4.5 g/1 of glucose and 1.5 g/1 of sodium bicarbonate added and supplemented with 10% FBS (fetal bovine serum).
  • DMEM Dulbecco's Modified Eagle's Medium
  • the cancer cell lines stored in a liquid nitrogen tank were each quickly thawed at 37 ° C, and centrifuged to remove the medium.
  • the resulting cell pellet was mixed with a culture medium, incubated in a culture flask at 37 ° C under 5% CO 2 for 2 to 3 days, and the medium was removed.
  • the remaining cells were washed with DPBS (Dulbecco's Phosphate Buffered Saline) and separated from the flask by using Tripsin-EDTA.
  • the separated cells were diluted with a culture medium to a concentration of 100,000 A431 cells/ml, except that in case of SK-Br3, the dilution was carried out to 200,000 cells/ml. 100 ⁇ i of the diluted cell solution was added to each well of a 96-well plate, and incubated at 37 ° C under 5% CO 2 for 1 day.
  • the compounds obtained in Examples 1 to 13 as well as the conventional EGFR inhibitors, Iressa and Lapatinib were each dissolved in 99.5% DMSO to a concentration of 25 mM.
  • DMSO a small amount of 1% HCl was added thereto and treated in a 40 °C water bath for 30 mins until complete dissolution was attained.
  • the test compound solution was diluted with a culture medium to a final concentration of 100 ⁇ M, and then diluted 10 time serially to 10 "6 ⁇ M (final concentration of DMSO was less than 1%). The medium was removed from each well of the 96-well microplate.
  • a test compound solution 100 id of a test compound solution was added to each well holding the cultured cells, and the microplate was incubated at 37 ° C under 5% CO 2 for 72 hours. After removing the medium from the plate, 50 ⁇ i of 10% trichloroacetic acid was added to each well, and the plate was kept at 37°C for 1 hour to fix the cells to the bottom of the plate. The added trichloroacetic acid was removed from each well, the plate was dried, 100 ⁇ i of an SRB (Sulforhodamine-B) dye solution was added thereto, and the resulting mixture was reacted for 10 mins.
  • the SRB dye solution was prepared by dissolving SRB in 1% acetic acid to a concentration of 0.4%.
  • IC 50 the concentration at which 50% inhibition occurs, was evaluated based on the difference between the final concentration of the test cells and the initial concentration of the cells incubated in a well not-treated with the test compound which was regarded as 100%. The calculation of IC 50 was carried out by using Microsoft Excel, and the results are shown in Table 5.
  • each of the inventive compounds showed, at a low concentration thereof, an excellent anticancer activity by effectively inhibiting EGFR kinase and EGFR mutant kinase (T790M), arresting the growth of A431 and SK-Br3 haivng overexpressed EGFR and Erb-B2, respectively, while none of the inventive compounds inhibited the growth of SW-620 containing no overexpressed EGFR or Erb-B2.
  • the compounds of formula (I) of the present invention can selectively inhibit the growth of specific cancer cells induced by epithelial growth factor and its mutants without any side effect.

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Abstract

The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof for inhibiting the growth of cancer cells induced by epithelial growth factor and its mutants, and a pharmaceutical composition comprising same as an active ingredient.

Description

QUINAZOLINE DERIVATIVES FOR INHIBITING THE GROWTH OF CANCER CELL
FIELD OF THE INVENTION
The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof for inhibiting the growth of cancer cells induced by epithelial growth factor and its mutants, and a pharmaceutical composition comprising same as an active ingredient.
BACKGROUND OF THE INVENTION
There are many signal transduction systems in cells which are functionally linked to each other to control the proliferation, growth, metastasis and apoptosis of cells. The breakdown of the intracellular controlling system by genetic and environmental influences causes abnormal amplification or destruction of the signal transduction system leading to tumor cell generation.
Protein tyrosine kinases play important roles in such cellular regulation, and their abnormal expression or mutation has been observed in cancer cells. Protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on protein substrates. Many growth factor receptor proteins function as tyrosine kinases to transport cellular signals. The interaction between growth factors and their receptors normally controls the cellular growth, but abnormal signal transduction caused by the mutation or overexpression of any of the receptors often induces tumor cells or cancers.
Protein tyrosine kinases have been classified into many families in terms of growth factors, and epithelial cell growth factor (EGF)-related EGF receptor (EGFR) tyrosine kinases have been intensely studied. An EGFR tyrosine kinase is composed of a receptor and tyrosine kinase, and delivers extracellular signals to cell nucleus through the cellular membrane. Various EGFR tyrosine kinases are classified based on their structural differences into EGFR (Erb-Bl), Erb-B2, Erb-B3 and Erb-B4, and each of the above members can form a homodimer- or heterodimer-signal delivery complex. Also, overexpression of more than one of the above mentioned homodimers is often observed in malignant cells. In addition, it is known that both EGFR and Erb- B2 significantly contribute to the formation of heterodimer-signal delivery complexes.
Many drugs for the inhibition of EGFR tyrosine kinases have been developed, e.g., Gefitinib, Erlotinib, Lapatinib and the like. Gefitinib or Erlotinib selectively inhibits EGFR, and Lapatinib simultaneously inhibits EGFR and Erb-B2, thereby arresting the growth of tumors.
Meanwhile, it has been recently reported that Gefitinib has no effect on
T790M, a mutant of an EGFR tyrosine kinase, wherein threonine present at a position 790 in exon 20 region of EGFR tyrosine kinase is replaced with methionine (see [Plos Medicine 2005, 2(3), 225-235]), and also that it provides no substantial clinical effect on T790M variation patients.
Accordingly, there has continued to exist a need to develop a novel drug that is capable of giving an improved effect on a mutant of an EGFR tyrosine kinase, e.g., T790M, as well as bringing about no adverse side effects such as diarrhea and skin eruption.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a novel quinazoline derivative which selectively and efficiently inhibits cancer cell growth caused by epithelial growth factor and its mutants without any side effect.
It is another object of the present invention to provide a phamarceutical composition for inhibiting cancer cell growth comprising said quinazoline derivative as an active ingredient.
In accordance with one aspect of the present invention, there is provided a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
wherein,
Ri is Ci. g alkoxy substituted with a Ci.6 alkoxy or heterocyclic group, the heterocyclic group being a 5 or 6-membered heteroaromatic or non-aromatic moiety containing one to four of the elements selected from the group consisting of N, O and S; R2 is hydrogen or phenyl substituted with halogen; and A is -C(=O)- or -CH2-.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment of the present invention, Ri is 2- methoxyethoxy, (tetrahydrofuran-2-yl)methoxy, 2-morpholinoethoxy, (4- methylthiazol-5-yl)ethoxy or 2-(l/7-l,2,4-triazol-l-yl)ethoxy; and R2 is 3- chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-bromo-3-chloro-2- fluorophenyl, 2,3,4-trifluorophenyl, 3,4-dichlorophenyl, 3,4-dichloro-2- fluorophenyl or 3-chloro-2,4-fluorophenyl, in the quinazoline derivative of formula (I).
In the present invention, the term 'halo' refers to fluoro, chloro, bromo or iodo, unless otherwise indicated.
Examples of more preferred compounds of formula (I) according to the present invention are: l) (21S)-l-acryloyl-N-[4-[3-chloro-2-fluoroρhenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
2) (2»S)-l-acryloyl-N-[4-[3-chloro-2-fluorophenylamino]-7-methoxy- quinazolin-6-yl]pyrrolidine-2-carboxyamide;
3) (21S)-l-acryloyl-N-[4-[4-bromo-3-chloro-2-fluorophenylamino]-7-(2- methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
4) (25)-l-acryloyl-N-[4-[253,4-trifluorophenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
5) (25)-l-acryloyl-N-[4-[3,4-dichlorophenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
6) (2JS)-l-acryloyl-N-[4-[3-chloro-2,4-difluorophenylamino]-7-(2- methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide; 7) (2S)- 1 -acryloyl-N-[4-[354-dichloro-2-fluoroρhenylamino]-7-(2- methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
8) (25)-l-acryloyl-N-{4-[3-chloro-4-fluorophenylamino]-7- [(tetrahydrofuran-2-yl)methoxy]quinazolin-6-yl}pyrrolidine-2-carboxyamide;
9) (2>S)-l-acryloyl-N-{4-[4-bromo-3-chloro-4-fluorophenylamino]-7- [(tetrahydrofuran-2-yl)methoxy]quinazolin-6-yl}pyrrolidine-2-carboxyamide;
10) (2»S)-l-acryloyl-N-[4-[4-bromo-3-chloro-2-fluorophenylamino]-7- (2-morpholinoethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
11) (25)-l-acryloyl-N-{4-[3-chloro-2-fluoroρhenylamino]-7-[2-(4- methylthiazol-2-yl)ethoxy]quinazolin-6-yl}pyrrolidine-2-carboxy amide; 12) (2S)- 1 -acryloyl-N- {4-[3-chloro-2-fluorophenylamino]-7-[2-(l#-
1 ,2,4-triazol- 1 -yl)ethoxy]qυinazolin-6-yl}pyrrolidine-2-carboxyamide; or
13) (2S)- 1 -(2- { [4-(4-bromo-3-chloro-2-fluoroρhenylamino)-7-(2- methoxyethoxy)quinazolin-6-ylamino]methyl}pyrrolidine- 1 -yl)pro-2-pen- 1 - one.
A compound of formula (I) of the present invention may be prepared, for example, by the procedure shown in Reaction Scheme (I) (the compound of formula (Ia): A = -C(=O)-) or in Reaction Scheme (II) (the compound of formula (Ib): A = -CH2-) (see [J. Med. Chem., 1996; 39: 918]): <Reaction Scheme (I)>
Figure imgf000006_0001
Ia
<Reaction Scheme (II)>
Figure imgf000006_0002
wherein, Ri and R2 have the same meanings as defined above.
In Reaction Scheme (I), a compound of formula (III) is subjected to a condensation reaction with N-(tørt-Boc)-proline in an organic solvent to obtain a compound of formula (II). The condensation agent which may be used in this reaction is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) or its acid- addition salt. The organic solvent used in this reaction may be pyridine, tetrahydrofuran, methylene chloride or chloroform.
Subsequently, a compound of formula (Ia), which corresponds to the inventive compound of formula (I) wherein A is -C(=O)-5 is prepared by reacting the compound of formula (II) with an organic or inorganic acid (e.g., trifluoroacetic acid or heavy hydrochloric acid) in an organic solvent (e.g., CHCl3) to induce the removal of the protective ^-butoxycarbonyl group from the compound of formula (II), followed by a reaction with acryloyl chloride in an organic solvent (e.g., a mixture of tetrahydrofuran and water) in the presence of a base (e.g., sodium bicarbonate).
In Reaction Scheme (II), a compound of formula (III) is subjected to a reaction with a compound of formula (V) in an organic solvent (e.g., ethanol) in the presence of acetic acid and sodium cyanoborohydride to obtain a compound of formula (IV).
Subsequently, a compound of formula (Ib), which corresponds to the inventive compound of formula (I) wherein A is -CH2-, is prepared by reacting the compound of formula (IV) with an organic or inorganic acid (e.g., trifluoroacetic acid or concentrated hydrochloric acid) in an organic solvent (e.g., CHCI3) to induce the removal of the protective f-butoxycarbonyl group from the compound of formula (IV), followed by treatment with acryloyl chloride in an organic solvent (e.g., a mixture of tetrahydrofuran and water) in the presence of a base (e.g., sodium bicarbonate).
The compound of formula (I) of the present invention can also be used in the form of a pharmaceutically acceptable salt formed with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. The inventive compound or a pharmaceutically acceptable salt thereof selectively and efficiently inhibits the growth of cancer cells induced by epithelial growth factor and its mutants, and provides enhanced anticancer effects when combined with another anticancer agent. Namely, the inventive compound or a pharmaceutically acceptable salt thereof is useful for enhancing the effects of an anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents and antiandrogen.
Therefore, the present invention provides a pharmaceutical composition for inhibiting cancer cell growth comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
The inventive compound or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from about 0.01 to 100 mg/kg, preferably 0.2 to 50 mg/kg body weight per day in case of mammals including human in a single dose or in divided doses. The dosage of the active ingredient may be adjusted in light of various relevant factors such as the condition of the subject to be treated, type and seriousness of illness, administration rate, and opinion of doctor. In certain cases, an amount less than the above dosage may be suitable. An amount greater than the above dosage may be used unless it causes deleterious side effects, and such amount can be administered in divided doses per day.
The inventive pharmaceutical composition may be formulated in accordance with any of the conventional methods in the form of tablet, granule, powder, capsule, syrup, emulsion or microemulsion for oral administration, or for parenteral administration including intramuscular, intravenous and subcutaneous routes.
The inventive pharmaceutical composition for oral administration may be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent. Examples of the carrier employed in the injectable composition of the present invention are water, a saline solution, a glucose solution, a glucose-like solution, alcohol, glycol ether (e.g., polyethylene glycol 200), oil, fatty acid, fatty acid ester, glyceride, a surfactant, a suspension agent and an emulsifier. The following Examples are intended to further illustrate the present invention without limiting its scope.
Example 1 : Preparation of (2-Sr)-l-acryloyl-N-r4-r3-chloro-2-fluorophenyl- amino1-7-(2-methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide
(1-1) N-(3-chloro-2-fluorophenyl)-7-fluoro-6-nitroquinazoline-4-amine hydrochloride
1 g of 4-chloro-7-fluoro-6-nitroquinazoline hydrochloride was dissolved in 10 ml of isopropanol. 550 mg of 3-chloro-2-fluoroaniline was added to the resulting solution and stirred at 80 °C for 3 hrs. The reaction solution was cooled to room temperature and filtered under a reduced pressure.
The filtrate was condensed and the resulting residue was washed with isopropanol and air-dried to obtain 1.3 g of the title compound (97%). 1H-NMR (DMSOd6, 300MHz) δ : 9.45 (d, IH), 8.60 (s, IH), 7.80 (d,
IH)5 7.50 (m, 2H), 7.25 (t, IH).
( 1 -2) N-(3 -chloro-4-fluorophenyl)-7-(2-methoxyethoxy)-6-nitroquinazoline-4- amine 1 g of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazoline-4- amine hydrochloride was dissolved in 10 ml of dimethylsulfoxide (DMSO). 0.42 ml of 2-methoxyethanol and 1.5 g of potassium silanolate were added to the resulting solution and stirred at room temperature for 4 hrs. After completion of the reaction, ice was added to the reaction solution to induce the crystallization of the product. The solid thus obtained was washed with 150 ml of water, filtered under a reduced pressure, condensed, and the residue was air- dried to obtain 830 mg of the title compound (79%).
1H-NMR (DMSO-d6, 300MHz) δ : 10.30 (br s, IH), 9.08 (s, IH), 8.40 (s, IH), 7.45 (m, 3H), 7.20 (t, IH), 4.38 (m, 2H), 3.69 (m, 2H), 3.28 (s, 3H).
(1-3) iV^-(3-chloro-2-fluorophenyl)-7-(2-methoxyethoxy)quinazoline-4,6- diamine (the compound of formula (III))
590 mg of iron was dissolved in 10 ml of 50% ethanol. 0.07 ml of concentrated hydrochloric acid was added to the resulting solution, and the resulting mixture was heated to 100°C for activation. 830 mg of N-(3-chloro-2- fluorophenyl)-7-methoxy-6-nitroquinazoline-4-amine was added thereto, and the resulting mixture was refluxed. After completion of the reaction, the hot reaction solution was filtered through a celite pad under a reduced pressure, and then, the celite pad was washed with a mixture of chloroform and methanol. The wash solution was combined with the filtrate washed with saturated sodium bicarbonate solution. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain 727 mg of the title compound (95%).
1H-NMR(CDCI3-^CD3OD 1 drop, 300MHz) δ : 8.50 (s, IH), 8.30 (m, IH), 7.32 (s, 2H), 7.15 (m, 3H), 4.30 (m, 2H), 3.90 (m, 2H), 3.49 (s, 3H).
( 1 -4) (2S)-tert-buty\ 2-(4-(3-chloro-2-fluorophenylamino)-7-(2-methoxy- ethoxy)quinazolin-6-ylcarbamoyl)pyrrolidine-l-carboxylate (the compound of formula (H))
300 mg of the compound prepared in step (1-3) was dissolved in 7 ml of pyridine. 356 mg of (25)-l-(ter?-butoxycarbonyl)pyrrolidine-2-carboxylic acid and 477 mg of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the resulting solution and stirred for 14 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent and the residue was washed with saturated sodium bicarbonate solution. The organic layer was then dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain 470 mg of the title compound.
1H-NMR(CDCI3^OOMHZ) δ : 9.10 (s, IH), 8.95 (m, IH), 8.69 (s, IH), 8.40 (m, IH), 7.28 (s, IH), 7.15 (d, 2H), 4.35 (m, 3H), 3.90 (m, 2H)5 3.50 (m, 2H), 3.48 (s, 3H), 1.99 (m, 4H), 1.47 (m, 9H). (1-5) (2S)-N-(4-(3 -chloro-2-fluorophenylamino)-7-(2-methoxyethoxy)- quinazolin-6-yl)pyrrolidine-2-carboxyamide
476 mg of the compound prepared in step (1-4) was dissolved in 10 ml of methylene chloride. 10 ml of trifluoroacetic acid was added to the resulting solution and stirred for 5 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was added to the resulting residue to make it basic, followed by extraction with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain 320 mg of the title compound (82%).
1H-NMR(CDCI31 SOOMHZ) δ : 9.12 (s, IH), 8.68 (s, IH), 8.35 (m, IH), 7.55 (br s, IH), 7.15 (m, 2H), 4.35 (m, 2H), 3.93 (m, IH), 3.89 (m, 2H), 3.51 (s, 3H), 3.10 (m, 2H), 2.20 (m, 2H), 2.13 (m, 2H).
(1-6) (2.S)-l-acryloyl-N-[4-[3-chloro-2-fluoroρhenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide (the compound of formula
(Ia))
300 mg of the compound prepared in step (1-5) was dissolved in 7 ml of tetrahydrofuran, cooled to 0°C, and 70 βi of acrylic acid was added slowly thereto. 0.12 ml of pyridine and 249 mg of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride were added to the resulting solution, and stirred for 4 hrs while heating slowly to room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (eluent- ethyl acetate : methanol = 10 : 1) to obtain 35 mg of the title compound (10%).
Figure imgf000011_0001
δ : 9.99 (s, IH), 9.07 (s, IH), 8.68 (s, IH),
8.39 (dd, IH), 7.53 (s, IH), 7.14 (d, 2H), 6.55 (d, IH), 6.53 (s, IH), 5.82 (dd, IH)3 4.94 (d, IH), 4.34 (m, 2H)5 3.96 (m, 2H)5 3.77 (td, IH)5 3.62 (m, IH)5 3.50 (s5 3H)5 2.64 (m, IH)5 2.14 (m, 2H)5 1.95 (m, IH).
Example 2: Preparation of r2ιSf)-l-acryloyl-N-r4-r3-chloro-2-fluorophenyl- amino1-7-methoxyquinazolin-6-yllpyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 600 mg of the title compound (28%). 1H-NMR(DMSO^6, 300MHz) δ : 9.83 (s, IH), 9.52 (s, IH)5 8.81 (s,
IH), 8.06 (m, IH), 7.73 (m, IH), 7.38 (m, IH), 7.27 (s, IH), 6.67 (m, IH), 6.20 (m, IH), 5.74 (m, IH), 4.73 (m, IH), 4.30 (m, 2H), 3.63 (m, 2H)5 3.61 (m, 2H)5 3.32 (s5 3H)5 2.09 (m, 2H)5 1.95 (m, 2H).
Example 3: Preparation of (2>Sr)-l-acryloyl-N-['4-[4-bromo-3-chloro-2- fluoroρhenylaminol-7-('2-methoxyethoxy)quinazolin-6-yllpyrrolidine-2- carboxy amide
The procedure of Example 1 was repeated using 4-bromo-3-chloro-2- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 800 mg of the title compound (31%).
1H-NMR (CDCl3, 300MHz) δ : 9.99 (s, IH)5 9.05 (s, IH), 8.65 (s, IH)5 8.20 (t, IH), 7.70 (bs, IH), 7.43 (dd, IH)5 7.25 (s, IH)5 6.55 (m, 2H)5 5.83 (m, IH), 4.94 (m, IH), 4.32 (m, 2H)5 3.94 (m, 2H), 3.78 (m, IH)5 3.60 (m, IH), 3.50 (s, 3H), 2.61 (m, IH), 2.10 (m, 3H).
Example 4: Preparation of (2S)-l-acryloyl-N-r4-[2,3,4-trifluorophenylaminol- 7-(2-methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 2,3,4-trifluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 130 mg of the title compound (15%).
1H-NMR (CDCl3, 300MHz) δ : 9.87 (s, IH), 8.97 (s, IH)5 8.55 (s, IH)5
7.80 - 7.74 (m, 2H)5 7.16 (s, IH)5 6.95 - 6.92 (m, IH)5 6.52-6.48 (m, 2H)5 5.81
- 5.76 (m, IH)5 4.91 - 4.89 (m, IH)5 4.22 - 4.27 (m, 2H), 3.91 - 3.86 (m, 2H)5 3.76 - 3.73 (m, IH)5 3.60 - 3.58 (m, IH)5 3.45 (s, 3H)5 2.80 (br S5 IH), 2.55 (br s, IH)5 2.09 - 1.94 (m, 2H).
Example 5: Preparation of (2-Sf)-l-acryloyl-N-r4-[3,4-dichlorophenylaminol-7-
(2-methoχyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 3,4-dichlororoaniline in place of 3-chloro-2-fluoroaniline in step (1-I)5 to obtain 140 mg of the title compound (12%).
1H-NMR (CDCl3, 300MHz) δ : 9.92 (s, IH)5 9.58 (s, IH), 8.87 (s, IH)5 8.55 (s, IH), 8.20 (d, IH)5 7.84 (dd, IH)5 7.60 (d, IH)5 7.30 (s, IH)5 6.67 (m,
IH)5 6.21 (m, IH)5 5.74 (m, IH)5 4.76 (m, IH), 4.34 (t, 2H)5 3.76 (m, 2H)5 3.60
(m, 2H)5 3.32 (s, 3H), 2.10 (m, 4H).
Example 6: Preparation of (2£)-l-acryloyl-N-[4-[3-chloro-2,4- difluorophenylamino1-7-(2-methoxyethoχy)quinazolin-6-yl1pyrrolidine-2- carboxyamide
The procedure of Example 1 was repeated using 3-chloro-2,4- difluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 135 mg of the title compound (14%).
1H-NMR (CDCl35 300MHz) δ : 9.95 (s, IH)5 9.03 (s, IH)5 8.60 (s, IH), 8.06 (m, IH)5 7.62 (bs, IH), 7.21 (s, IH), 7.01 (m, IH)5 6.53 (m, 2H)5 5.82 (m, IH)5 4.94 (m, IH)5 4.30 (m, 2H)5 3.94 (m, 2H), 3.76 (m, IH)5 3.62 (m, IH)5 3.49 (s, 3H)5 2.58 (m, IH)5 2.33 (m, IH), 2.13 (m, 2H), 1.95 (m, IH).
Example 7: Preparation of (2Sr)-l-acryloyl-N-r4-r3,4-dichloro-2- fluorophenylaminol-7-(2-methoxyethoxy)quinazolin-6-yllpyrrolidine-2- carboxyamide
The procedure of Example 1 was repeated using 3,4-dichloro-2- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 120 mg of the title compound (10%).
1H-NMR (CDCl3, 300MHz) δ : 10.03 (s, IH)5 9.06 (s, IH), 8.67 (s, IH), 8.36 (t, IH), 7.52 (s, IH)5 7.30 (dd, IH), 7.24 (s, IH), 6.55 (m, 2H)5 5.83 (m, IH)5 4.95 (m, IH), 4.33 (m, 2H), 3.95 (m, 2H), 3.76 (m, IH), 3.62 (m, IH)5 3.51 (s5 3H)5 2.61 (m, IH), 2.13 (m, 2H)5 1.97 (m, IH).
Example 8: Preparation of (2>y)-l-acryloyl-N-(4-r3-chloro-4- fluorophenylaminol-7-[(tetrahydrofuran-2-yl)methoxy]quinazolin-6-yU- pyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and tetrahydrofuran-2-ylmethylalcohol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 50 mg of the title compound (11%). 1H-NMR (CDCl35 300MHz) δ : 9.93 (s, IH)5 8.54 (s, IH)5 8.20 (s, IH),
7.86 (dd, IH), 7.65 (m, IH), 7.11 (t, IH), 6.99 (s, IH)5 6.55 (dd, IH), 6.45 (dd, IH)5 5.75 (dd5 IH), 5.00 (d, IH)5 4.30 (m, IH)5 3.86 (m, 4H), 3.65 (m, 2H), 2.50 (m, IH)5 2.13 (m, 4H), 1.97 (m, 2H), 1.65 (m, IH).
Example 9: Preparation of f2.SVl-acryloyl-N-(4-r4-bromo-3-chloro-4- f.uorophenylamino'1-7- [(tetrahydiOfuran-2-yl)methoxy]quinazolin-6-yl ) - Pyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 4-bromo-3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and tetrahydrofuran-2-ylmethylalcohol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 65 mg of the title compound (10%).
1H-NMR (CDCl3, 300MHz) δ : 9.92 (m, IH), 9.03 (m, IH), 8.63 (m, IH), 8.20 (m, IH), 7.74 (bs, IH)5 7.43 (m, IH), 7.22 (m, IH), 6.51 (m, 2H), 5.79 (m, IH), 4.93 (m, IH), 4.47 (m, IH), 4.14 (m, 3H), 3.92 (m, 2H), 3.81 (m, IH), 3.63 (m, IH), 2.61 (m, IH), 2.18 (m, 4H), 1.88 (m, 2H).
Example 10: Preparation of (25r)-l-acryloyl-A/-r4-r4-bromo-3-chloro-2- fluorophenylamino1-7-(2-morpholinoethoxy)quinazolin-6-vnpyrrolidine-2- carboxyamide
The procedure of Example 1 was repeated using 4-bromo-3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and 2- morpholinoethanol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 70 mg of the title compound (11%). 1H-NMR (CDCl3, 300MHz) δ : 10.08 (s, IH), 9.05 (s, IH), 8.64 (s, IH),
8.17 (m, IH), 7.71 (bs, IH), 7.40 (dd, IH), 7.19 (s, IH), 6.52 (m, 2H), 5.82 (m, IH), 4.94 (m, IH), 4.29 (m, 2H), 3.76 (m, 5H), 3.62 (m, IH), 3.08 (m, IH), 2.97 (m, IH), 2.63 (m, 6H), 2.21 (m, IH), 1.97 (m, IH).
Example 11 : Preparation of (26r)-l-acryloyl-N-(4-r3-chloro-2- fluorophenylamino]-7-[2-(4-methylthiazol-5-yl)ethoxylquinazolin-6-yU- pyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 2-(4-methylthiazol-5- yl)ethanol in place of 2-methoxyethanol in step (1-2), to obtain 65 mg of the title compound (34%).
1H-NMR (CDCl3, 300MHz) δ : 10.07 (s, IH), 9.06 (s, IH)5 8.66 (s, IH), 8.61 (s, IH), 8.31 (m, IH), 7.70 (br S5 IH), 7.23 (s, IH), 7.16 (m, 2H), 6.48 (dd, IH), 6.45 (dd, IH), 5.76 (dd, IH), 4.93 (d, IH), 4.37 (t, 2H), 3.71 (m, IH), 3.63-3.44 (m, 3H), 2.55 (m, IH), 2.48 (s, 3H), 2.16 (m, 2H)5 1.95 (m, IH). Example 12: Preparation of (26r)-l-acryloyl-N-(4-r3-chloro-2- fluorophenylaminol-7-r2-π/-r-1.2,4-triazol-l-yl')ethoxy"|quinazolin-6-vU- pyrrolidine-2-carboxyamide
The procedure of Example 1 was repeated using 2-(l//'-l,2,4-triazol-l- yl)ethanol in place of 2-methoxyethanol in step (1-2), to obtain 50 mg of the title compound (12%).
1H-NMR (CDCl3, 300MHz) δ : 10.37 (s, IH)5 8.99 (s, 2H), 8.59 (t, IH), 8.10 (t, IH), 7.98 (s, IH), 7.13 (s, IH), 7.08 (m, 2H), 6.54 (dd, IH), 6.48 (dd, IH), 5.84 (dd, IH), 4.94 (m, 2H), 4.70 (d, IH), 4.55 (t, IH), 4.40 (m, IH), 3.70 (m, IH), 3.55 (m, IH), 2.60 (m, IH), 2.15 (m, 2H), 1.85 (m, IH).
Example 13: Preparation of (2,SM-f2-(r4-(4-bromo-3-chloro-2- fluorophenylamino)-7-(2-methoxyemoxy)quinazolin-6-ylamino]methyU- pyrrolidine- 1 -yl)pro-2-pen- 1 -one
(13-1) Λ^-(4-bromo-3-chloro-2-fluoroρhenyl)-7-(2-methoxyethoxy)- quinazoline-4,6-diamine (the compound of formula (III))
The procedures of steps (1-1) to (1-3) of Example 1 were repeated using 4-bromo-3-chloro-4-fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 0.78 g of the title compound (82%).
(13-2) (2S)-tert-butyl 2- { [(4-(4-bromo-3 -chloro-2-fluoroρhenylamino)-7-(2- methoxyethoxy)quinazolin-6-ylamino]methyl}pyrrolidine- 1 -carboxylate (the compound of formula (IV))
600 mg of the compound prepared in step (13-1) and 0.47 g of (S)-tert- butyl-2-formylpyrrolidine-l -carboxylate were dissolved in a mixture of 8 ml of acetic acid and 8 ml of ethanol. 270 mg of sodium cyanoborohydride was added to the resulting solution and stirred at room temperature for 3 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was added to the resulting residue to make it basic, followed by extraction with methylene chloride. The organic layer thus obtained was dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (eluent- ethyl acetate : methylene chloride : methanol = 7 : 7 : 1) to obtain 0.56 g of the title compound (66%).
1H-NMR (CDCl3, 300MHz) δ : 8.51 (s, IH), 8.19 (s, IH), 7.96 (s, IH), 7.92 (UH), 7.45 (m, IH), 7.12 (s, IH), 5.12 (bt, IH), 4.32 (t, 2H)5 4.29 (m, IH), 3.85 (m, 2H), 3.61 (m, IH), 3.47 (s, 3H), 3.46 (m, IH), 3.25 (m, IH), 3.05 (m, IH), 1.80 (m, 4H), 1.42 (s, 9H).
(13-3) (2.S)-N¥-(4-bromo-3-chloro-2-fluorophenyl)-7-(2-methoxyethoxy)-N5- (pyrrolidin- 1 -ylmethyl)quinazoline-4,6-diamine
0.56 g of the compound prepared in step (13-2) was dissolved in 10 ml of methylene chloride. 10 ml of trifluoroacetic acid was added to the resulting solution and stirred for 1 hr. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was added to the resulting residue to make it basic, which was extracted with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain 404 mg of the title compound (86%).
1H-NMR (CDCl3, 300MHz) δ : 8.50 (s, IH), 8.25(t, IH), 7.40 (m, IH), 7.04 (s, IH), 6.73 (s, IH), 5.21 (bs, IH), 4.28 (m, 3H)5 3.82 (m, 2H)5 3.57 (m, IH)5 3.45 (s, 3H), 3.32 (m, IH), 3.05 (m, 2H)5 2.03 (m, IH), 1.87 (m, 2H)5 1.62 (m, IH).
(13-4) (2S)- 1 -(2- { [(4-(4-bromo-3 -chloro-2-fluoroρheny lamino)-7-(2- methoxyethoxy)quinazolin-6-ylamino]methyl}pyrrolidin- 1 -yl)pro-2-pen- 1 -one (the compound of formula (Ib)) 383 mg of the compound prepared in step (13-3) was dissolved in a mixture of 5 ml of tetrahydrofuran and 1 ml of distilled water. 184 mg of sodium bicarbonate and 0.06 ml of acryloyl chloride were added to the resulting solution in order, and stirred at room temperature for 2 hrs. After completion of the reaction, saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (eluent- ethyl acetate : methylene chloride : methanol = 5 : 5 : 1) to obtain 177 mg of the title compound (42%).
1H-NMR (CDCl3, 300MHz) δ : 8.67 (s, IH), 8.54 (s, IH), 8.33 (s, IH), 8.10 (t, IH), 7.44 (dd, IH), 7.14 (s, IH), 6.47 (m, 2H), 5.75 (m, IH), 5.13 (bt, IH), 4.64 (m, IH), 4.32 (t, 2H), 3.85 (m, 2H)5 3.71 (m, 2H), 3.52 (m, IH), 3.48 (s, 3H), 3.10 (m, IH), 2.05 (m, 2H), 1.97 (m, 2H).
The inventive compounds prepared in the Examples were formulated as follows:
Preparation Example 1
Tablets for oral administration comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 1.
<Table 1>
Figure imgf000018_0001
Preparation Example 2 Gelatin capsules for oral administration comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 2.
<Table 2>
Figure imgf000019_0001
Preparation Example 3
Injection formulations comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 3, wherein when a salt of the compound of formula (I) was used, the pH value was not manupulated.
<Table 3>
Figure imgf000019_0002
Preparation Example 4
Injection formulations comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 4. <Table 4>
Figure imgf000020_0001
Test Example 1 : Inhibition of EGFR enzyme
10 μi of EGFR (EGFR type 1 kinase) was added to each well of a 96- well microplate. As an EGFR inhibitor, 10 μl of a serially diluted solution of each of the compounds obtained in Examples 1 to 13, Iressa (Astrazeneca) or Lapatinib (Glaxo SmithKline) was added to each well, and the plate was incubated at room temperature for 10 mins. 10 μl of Poly (GIu, Tyr) 4 : 1 (Sigma) and 10 μi of ATP were successively added thereto to initiate a kinase reaction, and the resulting mixture was incubated at room temperature for 1 hour. 10 μi of 100 mM EDTA was added to each well and stirred for 5 mins to terminate the kinase reaction. 10 μl of 10 X anti-phosphotyrosine antibody (Pan Vera), 10 μl of 10 X PTK (protein tyrosine kinase) green tracer (Pan Vera) and 30 μl of FP (fluorescence polarization) diluted buffer were added to the reacted mixture, followed by incubating in dark at room temperature for 30 mins. The FP value of each well was determined with VICTORIII fluorescence meter (Perkin Elmer) at 488 nm, and IC5O, the concentration at which 50% inhibition was observed, was determined, wherein the maximum (0% inhibition) value was set at the polarized light value measured for the well untreated with EGFR inhibitor and the minimum value corresponded to 100% inhibition. The calculation and analysis of IC50 were carried out by using Microsoft Excel. The results are shown in Table 5.
Test Example 2 : Inhibition of EGFR mutant enzyme (T790M)
10 μl of EGF mutant receptor (EGFR T790M kinase, Upstate) was added to each well of a 96- well microplate. As an EGFR inhibitor, 10 μl of a serially diluted solution of each of the compounds obtained in Examples 1 to 13, Iressa (Astrazeneca) or Lapatinib (GlaxoSmithKline) was added to each well, and the plate was incubated at room temperature for 10 mins. Hereinafter, the procedure of Test Example 1 was repeated. The results are shown in Table 5.
Test Example 3: Test of cancer cell growth inhibition
A skin cancer cell line, A431 (ATCC: CRL- 1555), a breast cancer cell line, SK-Br3 (ATCC: HTB-30), and a colon/rectal cancer cell line, SW-620 (ATCC: CCL-227) were used to test the degrees of the inventive compounds in inhibiting the cancer cell growth using a culture medium, DMEM (Dulbecco's Modified Eagle's Medium) having 4.5 g/1 of glucose and 1.5 g/1 of sodium bicarbonate added and supplemented with 10% FBS (fetal bovine serum).
The cancer cell lines stored in a liquid nitrogen tank were each quickly thawed at 37°C, and centrifuged to remove the medium. The resulting cell pellet was mixed with a culture medium, incubated in a culture flask at 37°C under 5% CO2 for 2 to 3 days, and the medium was removed. The remaining cells were washed with DPBS (Dulbecco's Phosphate Buffered Saline) and separated from the flask by using Tripsin-EDTA. The separated cells were diluted with a culture medium to a concentration of 100,000 A431 cells/ml, except that in case of SK-Br3, the dilution was carried out to 200,000 cells/ml. 100 μi of the diluted cell solution was added to each well of a 96-well plate, and incubated at 37°C under 5% CO2 for 1 day.
The compounds obtained in Examples 1 to 13 as well as the conventional EGFR inhibitors, Iressa and Lapatinib were each dissolved in 99.5% DMSO to a concentration of 25 mM. In case that the test compound was not soluble in DMSO, a small amount of 1% HCl was added thereto and treated in a 40 °C water bath for 30 mins until complete dissolution was attained. The test compound solution was diluted with a culture medium to a final concentration of 100 μM, and then diluted 10 time serially to 10"6 μM (final concentration of DMSO was less than 1%). The medium was removed from each well of the 96-well microplate.
100 id of a test compound solution was added to each well holding the cultured cells, and the microplate was incubated at 37 °C under 5% CO2 for 72 hours. After removing the medium from the plate, 50 βi of 10% trichloroacetic acid was added to each well, and the plate was kept at 37°C for 1 hour to fix the cells to the bottom of the plate. The added trichloroacetic acid was removed from each well, the plate was dried, 100 μi of an SRB (Sulforhodamine-B) dye solution was added thereto, and the resulting mixture was reacted for 10 mins. The SRB dye solution was prepared by dissolving SRB in 1% acetic acid to a concentration of 0.4%. After removing the dye solution, the plate was washed with water, and dried. When the dye solution was not effectively removed by water, 1% acetic acid was used. 150 μJL of 10 mM trisma base was added to each well, and the absorbance at 570 nm was determined with a microplate reader. IC50, the concentration at which 50% inhibition occurs, was evaluated based on the difference between the final concentration of the test cells and the initial concentration of the cells incubated in a well not-treated with the test compound which was regarded as 100%. The calculation of IC50 was carried out by using Microsoft Excel, and the results are shown in Table 5.
<Table 5>
Figure imgf000023_0001
As shown in Table 5, each of the inventive compounds showed, at a low concentration thereof, an excellent anticancer activity by effectively inhibiting EGFR kinase and EGFR mutant kinase (T790M), arresting the growth of A431 and SK-Br3 haivng overexpressed EGFR and Erb-B2, respectively, while none of the inventive compounds inhibited the growth of SW-620 containing no overexpressed EGFR or Erb-B2.
Therefore, the compounds of formula (I) of the present invention can selectively inhibit the growth of specific cancer cells induced by epithelial growth factor and its mutants without any side effect.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000024_0001
wherein,
Ri is C i.6 alkoxy substituted with a Ci_6 alkoxy or heterocyclic group, the heterocyclic group being a 5 or 6-membered heteroaromatic or non-aromatic group containing one to four of the elements selected from the group consisting ofN, O and S;
R2 is hydrogen or phenyl substituted with halogen; and A is -C(=O> or -CH2-.
2. The compound of claim 1, wherein Ri is 2-methoxyethoxy, (tetrahydrofuran-2-yl)methoxy, 2-morpholinoethoxy, (4-methylthiazol-5- yl)ethoxy or 2-(lH-l,2,4-triazol-l~yl)ethoxy; and R2 is 3-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-bromo-3-chloro-2-fluorophenyl, 2,3,4- trifluorophenyl, 3,4-dichlorophenyl, 3,4-dichloro-2-fluorophenyl or 3-chloro- 2,4-fluorophenyl.
3. The compound of claim 1, which is selected from the group consisting of: (2iS)-l-acryloyl-N-[4-[3-chloro-2-fluorophenylamino]-7-(2-methoxyethoxy)- quinazolin-6-yl]pyrrolidine-2-carboxyamide; (2iS)-l-acryloyl-iV-[4-[3-chloro-2-fluorophenylamino]-7-methoxyquinazolin-6- yl]pyrrolidine-2-carboxyamide;
(25)-l-acryloyl-N-[4-[4-bromo-3-chloro-2-fluorophenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide; (2,S)-l-acryloyl-N-[4-[2,3.4-trifluorophenylamino]-7-(2-methoxyethoxy)- quinazolin-6-yl]pyrrolidine-2-carboxyamide;
(2ιS)-l-acryloyl-N-[4-[3.4-dichlorophenylamino]-7-(2-methoxyethoxy)- quinazolin-6-yl]pyrrolidine-2-carboxyamide; (2S)-l-acryloyl-N-[4-[3-chloro-2,4-difluorophenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
(2<Sf)-l-acryloyl-N-[4-[354-dichloro-2-fluorophenylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
(2>S)-l-acryloyl-N-{4-[3-chloro-4-fluorophenylamino]-7-[(tetrahydrofuran-2- yl)methoxy]quinazolin-6-yl}pyrrolidine-2-carboxyamide;
(2S)- 1 -acryloyl-N- {4-[4-bromo-3-chloro-4-fluorophenylamino]-7-[(tetrahydro- furan-2-yl)methoxy]quinazolin-6-yl}pyrrolidine-2-carboxyamide;
(2<S)-l-acryloyl-N-[4-[4-bromo-3-chloro-2-fluorophenylamino]-7-(2- morpholinoethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide; (2S)- 1 -acryloyl-N- {4-[3-chloro-2-fluoroρhenylamino]-7-[2-(4-methylthiazol-2- yl)ethoxy]quinazolin-6-yl}pyrrolidine-2-carboxyamide;
(2S)- 1 -acryloyl-N- {4-[3-chloro-2-fluoroρhenylamino]-7-[2-(l#- 1 ,2,4-triazol- 1 - yl)ethoxy]quinazolin-6-yl}pyrrolidine-2-carboxyamide; and
(2S)- 1 -(2- { [4-(4-bromo-3 -chloro-2-fluoropheny lamino)-7-(2-methoxy ethoxy)- quinazolin-6-ylamino]methyl}pyrrolidine-l-yl)pro-2-pen-l-one.
4. A pharmaceutical composition for inhibiting the growth of cancer cells comprising the quinazoline derivative or its pharmaceutically acceptable salt of claim 1 as an active ingredient.
5. The pharmaceutical composition of claim 4, which is administered in combination with an anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents and antiandrogen.
PCT/KR2007/003061 2006-06-28 2007-06-25 Quinazoline derivatives for inhibiting the growth of cancer cell WO2008002039A1 (en)

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US8466283B2 (en) 2006-12-05 2013-06-18 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
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US10231973B2 (en) 2015-03-20 2019-03-19 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Salts of quinazoline derivative and method for preparing the same
CN113278012A (en) * 2020-02-19 2021-08-20 郑州泰基鸿诺医药股份有限公司 Compounds useful as kinase inhibitors and uses thereof
CN114437046A (en) * 2022-01-28 2022-05-06 遵义医药高等专科学校 5-fluorouracil spliced 4-aniline quinazoline compound and preparation method and application thereof
CN114437161A (en) * 2022-01-27 2022-05-06 遵义医药高等专科学校 Zidovudine spliced 4-aniline quinazoline compound as well as preparation method and application thereof

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KR100929146B1 (en) 2006-06-28 2009-12-01 한미약품 주식회사 Quinazolin derivatives have cancer cell growth inhibitory effect
US8466283B2 (en) 2006-12-05 2013-06-18 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
USRE46856E1 (en) 2006-12-05 2018-05-22 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
EP3050880A4 (en) * 2013-09-28 2017-04-26 Chia Tai Tianqing Pharmaceutical Group Co.,Ltd Quinazoline derivative and preparation method therefor
JP2016531937A (en) * 2013-09-28 2016-10-13 正大天晴薬業集団股▲分▼有限公司Ｃｈｉａ Ｔａｉ Ｔｉａｎｑｉｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ Ｃｏ．， Ｌｔｄ． Quinazoline derivative and method for producing the same
US9725439B2 (en) 2013-09-28 2017-08-08 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Quinazoline derivative and preparation method therefor
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CN107556295A (en) * 2013-09-28 2018-01-09 正大天晴药业集团股份有限公司 Quinazoline derivant and preparation method thereof
CN105555782A (en) * 2013-09-28 2016-05-04 正大天晴药业集团股份有限公司 Quinazoline derivatives and preparation methods thereof
US10231973B2 (en) 2015-03-20 2019-03-19 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Salts of quinazoline derivative and method for preparing the same
CN113278012A (en) * 2020-02-19 2021-08-20 郑州泰基鸿诺医药股份有限公司 Compounds useful as kinase inhibitors and uses thereof
WO2021164793A1 (en) * 2020-02-19 2021-08-26 郑州同源康医药有限公司 Compound used as kinase inhibitor and use thereof
CN113278012B (en) * 2020-02-19 2022-07-12 郑州同源康医药有限公司 Compounds useful as kinase inhibitors and their applications
CN114437161A (en) * 2022-01-27 2022-05-06 遵义医药高等专科学校 Zidovudine spliced 4-aniline quinazoline compound as well as preparation method and application thereof
CN114437161B (en) * 2022-01-27 2023-09-12 遵义医药高等专科学校 Zidovudine spliced 4-aniline quinazoline compound and preparation method and application thereof
CN114437046A (en) * 2022-01-28 2022-05-06 遵义医药高等专科学校 5-fluorouracil spliced 4-aniline quinazoline compound and preparation method and application thereof
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