WO2021201576A1 - Benzothiazole derivative compound - Google Patents
Benzothiazole derivative compound Download PDFInfo
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- WO2021201576A1 WO2021201576A1 PCT/KR2021/003954 KR2021003954W WO2021201576A1 WO 2021201576 A1 WO2021201576 A1 WO 2021201576A1 KR 2021003954 W KR2021003954 W KR 2021003954W WO 2021201576 A1 WO2021201576 A1 WO 2021201576A1
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- -1 Benzothiazole derivative compound Chemical class 0.000 title claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 21
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- 208000032839 leukemia Diseases 0.000 claims abstract description 16
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- 239000007787 solid Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 45
- 150000002431 hydrogen Chemical class 0.000 claims description 28
- 108091000080 Phosphotransferase Proteins 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 102000020233 phosphotransferase Human genes 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
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- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 14
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- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
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- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles 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
- A61K31/495—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to benzothiazole derivative compounds.
- the present invention relates to an Abl kinase inhibitor composition comprising a benzothiazole derivative compound and a pharmaceutical composition for preventing or treating abnormal cell growth disease.
- kinases that have been unequivocally implicated in the pathogenesis of various proliferative or myeloproliferative diseases, and therefore these members are important targets for the treatment of these diseases.
- Important examples of kinases that have been shown to cause or contribute to the pathogenesis of these diseases include the Abl kinase and the oncogenic fusion protein Bcr-Abl kinase.
- Abl kinase is an important non-receptor tyrosine kinase involved in cellular signaling and is involved in the regulation of the cell cycle, the cellular response to genotoxic stress, and the transmission of information about the cellular environment through integrin signaling. Overall, the Abl protein appears to play a complex role as a cellular module, integrating signals from a variety of extracellular and intracellular sources, and influencing decisions regarding the cell cycle and apoptosis.
- Abl-1A Abl-1A
- Abl-1B Abl-1B
- the N-terminal half of the Abl kinase is important for autorepression of the kinase domain catalytic activity (Pluk et al., Cell (2002) 108: 247).
- Abl kinase An aberrant dysregulated form of Abl kinase is formed from a chromosomal translocation event (also called the Philadelphia chromosome) (PC Nowell et al. Science (1960) 132: 1497; JD Rowley, Nature (1973) 243: 290).
- This abnormal chromosomal translocation leads to abnormal gene fusion between the Abl kinase gene and the breakpoint cluster region (BCR) gene, thereby encoding an abnormal protein called Bcr-Abl.
- Chimeric fusion (oncoprotein) Bcr-Abl with deregulated tyrosine kinase activity causes disease by overactivating cellular signaling.
- Bcr-Abl is responsible for the pathogenesis of 95% of chronic myelogenous leukemia (CML) and 10% of acute lymphocytic leukemia (AML). Therefore, Abl kinase inhibitors can be usefully used as targeted therapeutics for chronic myeloid leukemia, and targeted anticancer drugs have been released based on these studies.
- a representative example of such a targeted anticancer agent is STI-571 (Gleevec).
- Gleevec is effective by blocking the activity of Bcr-Abl, but recently, Gleevec resistance due to Bcr-Abl mutation has been reported.
- Some patients in the blast phase of CML are due to mutations in the Bcr-Abl kinase, and to date, more than 22 mutations have been reported. Among them, it has been reported that T315I (gate keeper residue mutation) is closely related to resistance of existing drugs.
- Tasigna and Sprycell which are second-generation drugs that improved Gleevec, have been developed, but so far they do not effectively act on mutant Abl (eg, T315I). No drugs were reported. Therefore, there is an urgent need to develop a drug capable of simultaneously inhibiting wild-type Abl kinase as well as mutant Abl (eg, T315I) kinase.
- the compounds according to the invention inhibit wild-type Abl kinases and mutant Abl kinases. Therefore, it is expected to develop as a drug that can overcome the resistance of existing anticancer drugs for leukemia as well as treatment for leukemia.
- Abl kinase is related to cell proliferation, there are many research reports that when overexpressed, it is involved in the development and metastasis of various solid cancers such as breast, lung, and ovarian cancer. For example, there is a study report that Abl kinase is overactivated in breast cancer or lung cancer (Arlinghaus et al., Oncogene (2008) 27, 4385), and the investigation result that the expression rate of Abl kinase is high also in epithelial ovarian cancer. There is a report that among stage 3 ovarian cancer patients, the Abl kinase-positive group showed a significantly lower survival rate than the negative group (Chang-Seok Kang et al. The Korean Journal of Pathology (2006) 40, 210).
- An object of the present invention is to provide a novel benzothiazole derivative compound, or a pharmaceutically acceptable salt thereof, capable of treating leukemia by inhibiting Abl kinase, and further, leukemia exhibiting resistance to existing anticancer agents.
- the present invention is to provide a pharmaceutical composition for inhibiting Abl kinase or a pharmaceutical composition for preventing and treating abnormal cell growth diseases, comprising a novel benzothiazole derivative compound or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide an anticancer agent for the treatment of leukemia or solid cancer comprising a novel benzothiazole derivative compound.
- the present invention relates to a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
- R 1 is alkyloxy having 1 to 6 carbon atoms or hydrogen
- R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 6 carbon atoms,
- R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;
- R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring,
- R 5 is amino, substituted or unsubstituted alkylamine having 1 to 6 carbon atoms, or imidazole.
- R 1 in Formula 1 is alkyloxy having 1 to 4 carbon atoms or hydrogen
- R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 4 carbon atoms,
- R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;
- R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;
- R 5 may be an alkylamine or imidazole having 1 to 6 carbon atoms which is unsubstituted or substituted with a heterocycle containing 1 or 2 hetero atoms selected from N, O and S.
- R 1 in Formula 1 is methyloxy, ethyloxy or hydrogen
- R 3 and R 4 are hydrogen and R 2 is hydrogen, fluoro, chloro, bromine, trifluoromethyl, methyl, ethyl, propyl or cyclopropyl;
- R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5-membered heterocyclic ring comprising an N atom,
- R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5-membered heterocyclic ring comprising N atoms,
- R 5 may be an alkylamine or imidazole having 1 to 4 carbon atoms substituted with a heterocycle containing 1 or 2 N atoms.
- R 1 in Formula 1 is methyloxy, ethyloxy or hydrogen
- R 3 and R 4 are hydrogen, R 2 is hydrogen, fluoro, chloro, methyl or ethyl,
- R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form pyrrole
- R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form pyrrole,
- R 5 may be any one of the substituents represented by the following Chemical Formulas 2 to 4:
- R 6 is an alkyl group having 1 to 6 carbon atoms or alkyloxy having 1 to 6 carbon atoms.
- the compound of the present invention may be, for example, any one of the following compounds of Formulas 5 to 15 and Formula 24, or a pharmaceutically acceptable salt thereof:
- the compound of Formula 1 according to the present invention may form a pharmaceutically acceptable salt.
- the compound of Formula 1 according to the present invention may be prepared from inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, maleic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid and the like;
- salts may be formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like.
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an inhibitory action on Abl kinase, for example, wild-type Abl kinase or mutant Abl(T315I) kinase.
- the present invention relates to a pharmaceutical composition for inhibiting Abl kinase or a pharmaceutical composition for preventing and treating abnormal cell growth diseases, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention relates to an anticancer agent for the treatment of leukemia or solid cancer comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention is for treating leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colorectal cancer, peritoneal cancer, peritoneal metastasis or pancreatic cancer It may be an anticancer agent.
- the present invention is an anti-cancer agent for the treatment of leukemia comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof, which is administered to a patient who develops resistance to other leukemia therapeutic agents that are already being administered to treat leukemia that can exhibit a therapeutic effect It relates to a composition for
- alkyl' refers to an aliphatic hydrocarbon radical, and is 'saturated alkyl' that does not contain an alkenyl or alkynyl moiety, or a 'saturated alkyl' containing at least one alkenyl or alkynyl moiety. It may be an unsaturated alkyl'.
- 'Alkenyl' refers to a group containing at least one carbon-carbon double bond
- 'alkynyl' refers to a group containing at least one carbon-carbon triple bond.
- Alkyl may be branched, cyclic or straight-chain, respectively, when used alone or in combination with alkylamines.
- Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.
- alkyl having 1 to 4 carbon atoms has 1 to 4 carbon atoms in the alkyl chain, and is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl. is selected from the group consisting of
- the compound of the present invention may be formulated into a formulation containing a pharmaceutically acceptable carrier or diluent for use as a pharmaceutical composition.
- the composition according to the present invention may be prepared according to a conventional method, and may be administered in a pharmaceutically appropriate formulation.
- it is administered orally in the form of tablets, capsules, sugar-coated tablets, film-coated tablets, solutions, suspensions, emulsions, etc., or injected subcutaneously, intramuscularly, intravenously or intraperitoneally. Alternatively, it may be administered parenterally through the method of injection.
- the dosage may be determined according to various factors including the age, weight and condition of the patient and the route of administration.
- the daily dosage can vary within wide limits and can be adapted to the individual requirements in each individual case.
- the dosage adopted for each route of administration may be in the range of 0.0001 to 50 mg/kg body weight.
- Such dosages may be administered to the patient, for example, 1 to 5 times per day.
- a suitable daily dose may be 0.0001 to 50 mg/kg body weight, and the daily dose may be administered as a single dose or according to a divided dose schedule.
- the compound of Formula 1 according to the present invention may be converted into a salt thereof by a conventional method known in the art.
- the compound of Formula 1 includes pharmaceutically acceptable salts thereof, and it should be understood that all of them are included in the scope of the present invention.
- such a salt may also be simply expressed as a compound of Formula 1.
- 2-amino-6-bromobenzothiazole of the following formula (16) is used, but the 6-position (C6 site) of benzothiazole is subjected to a Suzuki coupling reaction using palladium as a catalyst to form benzothiazole.
- a phenyl group at the 6-position of the thiazole an intermediate represented by the compound of Formula 17 is prepared.
- the benzothiazole compound of formula 18 can be prepared by introducing a urea functional group using carbonyldiimidazole to the 2-amino group:
- R 1 is alkyloxy having 1 to 6 carbon atoms or hydrogen
- R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 6 carbon atoms,
- R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;
- R 4 is hydrogen and R 2 and R 3 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring.
- the compound of Formula 16 is reacted with 1,4-dioxane and water (ratio 3:1) using a Suzuki-type coupling reaction using various phenylboronic acid, palladium catalyst (II), and potassium carbonate base. ) as a solvent and heating and stirring to 100° C., the phenyl group is substituted at the 6-position (C6 site, that is, the bromine site) of 2-amino-6-bromobenzothiazole of Formula 16.
- the phenyl-substituted benzothiazole compound was charged with anhydrous dimethylformamide as a solvent and nitrogen gas, and reacted with carbonyldiimidazole at room temperature to introduce a urea functional group at the C2 site of benzothiazole,
- the benzothiazole derivative compound of 9 can be prepared.
- R 1 , R 2 , R 3 and R 4 are as defined above.
- a substituted or unsubstituted alkylamine group may be introduced at the C2 site of benzothiazole to prepare the compound of Formula 1a:
- R 1 , R 2 , R 3 and R 4 are as defined above,
- R 5 ′ is a substituted or unsubstituted C 1 to C 6 alkylamine.
- the compound of Formula 18 is amide coupling (amide coupling) at room temperature in anhydrous dimethylformamide solvent together with triethylamine and piperazine in which aminoethyl groups and t-butoxycarbonyl groups are substituted on both nitrogen atoms, respectively.
- the compound of formula 19 was prepared by introducing piperazine additionally to the urea functional group, and then the t-butoxycarbonyl group substituted for piperazine was stirred at room temperature by adding trifluoroacetic acid in a dichloromethane solvent. Removal from piperazine can afford the compound of formula 20:
- R 1 , R 2 , R 3 and R 4 are as defined above.
- the compound of formula (18) was mixed with piperazine in which an aminoethyl group and an alkyl group (preferably an alkyl group having 1 to 6 carbon atoms) are substituted on both nitrogen atoms, together with triethylamine, in an anhydrous dimethylformamide solvent at room temperature under an amide couple.
- the compound of Formula 21 can be obtained by introducing piperazine additionally to the urea functional group through amide coupling.
- R 1 , R 2 , R 3 and R 4 are as defined above,
- R 6 is an alkyl group.
- the 2-amino-6-bromobenzothiazole compound of Formula 16 is first reacted with carbonyldiimidazole to prepare a compound of Formula 22, and the compound of Formula 22 is reacted with both nitrogen atoms Compound of Formula 23 by introducing piperazine, each substituted with an aminoethyl group and an alkyl group, with triethylamine at room temperature in anhydrous dimethylformamide solvent at room temperature to introduce piperazine additionally to the urea functional group can get Then, the compound of formula 22 can be reacted with various phenylboronic acids to prepare a compound of formula 21:
- R 1 , R 2 , R 3 , R 4 and R 6 are as defined above.
- the benzothiazole derivative compound or a pharmaceutically acceptable salt thereof according to the present invention can be used as an inhibitor for Abl kinase to treat diseases, particularly cancer, resulting from abnormal cell growth, function or behavior.
- 2 and 3 are graphs showing the results of measuring tumor size and tumor weight after administration of the compound of the present invention to animals, respectively.
- FIG. 4 is a photograph of a tumor extracted on the day of the end of the experiment after administration of the compound of the present invention to an animal.
- 5 is a graph showing the results of measuring tumor size after administration of the compound of the present invention to an animal.
- a benzothiazole derivative compound of Formula 1 according to the present invention was prepared according to the following general preparation method.
- Carbonyldiimidazole (2.5 equivalents) was added to the intermediate, and the mixture was stirred with anhydrous dimethylformamide solvent and nitrogen conditions for 15 hours. After completion of the reaction, all solvents in the mixture were blown off, and the resulting solid was filtered through a glass filter.
- R 1 , R 2 , R 3 and R 4 are as defined above.
- a new functional group is introduced into the compound obtained through the general preparation method 1 above. Specifically, t-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (1.1 equiv.) and triethylamine (3.0 equiv.) were added to the compound of Formula 18, and anhydrous dimethylformamide solvent and nitrogen condition were added. Stirred at room temperature for 3 hours. After completion of the reaction, an intermediate was obtained through column chromatography.
- the t-butoxycarbonyl substituent substituted with piperazine of the intermediate is removed from piperazine by stirring trifluoroacetic acid (30 equivalents) in a dichloromethane solvent at room temperature for 3 hours, and after completion of the reaction, the solvent is reduced The final urea solid is obtained.
- R 1 , R 2 , R 3 and R 4 are as defined above.
- Carbonyldiimidazole (1.1 eq) was added to 2-amino-6-bromobenzothiazole (1 eq) in DMF at room temperature, followed by stirring for 2 hours. The mixture was filtered and dried.
- the purified compound and phenylboronic acid having a substituent are placed in a dioxane solution, and a palladium catalyst (II) and a Cs 2 CO 3 solution are added thereto. After reacting while heating at 100°C overnight, it was cooled to room temperature and concentrated under reduced pressure.
- a palladium catalyst (II) and a Cs 2 CO 3 solution are added thereto. After reacting while heating at 100°C overnight, it was cooled to room temperature and concentrated under reduced pressure.
- R 1 , R 2 , R 3 , R 4 and R 6 are as defined above.
- N-methyl substituted 4-(2- ⁇ [(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]amino ⁇ ethyl)piperazine and (5-fluoro) in dioxane (4mL) Pd(dppf)Cl 2 was added to the rho-2-methoxyphenyl)boronic acid solution, and a solution of Cs 2 CO 3 in water (2mL) was added thereto. After reacting while heating at 100°C overnight, it was cooled to room temperature and concentrated under reduced pressure.
- benzothiazole derivative compounds specifically disclosed by the formulas 5 to 15 and 24 are shown in Tables 1 to 4 below.
- Ba/F3-Bcr-Abl-T315I Cells were placed in RPMI medium (Biowest, Kansas City, MO, USA) with 10% FBS (Biowest, Kansas City, MO, USA), 1% penicillin/streptomycin (Gibco, Grand Island, NY, USA) and then 5% Incubated at CO 2 /37°C.
- Ba/F3-Bcr-Abl- T315I cells were aliquoted in a 96-well plate at 8 ⁇ 10 3 per well, and the test compounds were treated at various concentrations.
- ponatinib (Ponatinib) drug Ba / F3-Bcr-Abl-T315I Since it strongly inhibits cell proliferation and also shows strong cytotoxicity in CHO-K1 and Hep G2 cells, side effects such as myelogenesis inhibition, pancreatitis, and cardiovascular disease may be induced.
- the compounds of the present invention are Ba/F3-Bcr-Abl-T315I It has a strong inhibitory activity to inhibit cell proliferation, and at the same time has weak inhibitory activity against CHO-K1 and Hep G2 cells, so it can be usefully used as a CML treatment drug without drug resistance and side effects.
- Ba/F3-Bcr-Abl-T315I Cells were treated with the compounds of Formulas 5 to 7 at a concentration of 1 ⁇ M, respectively, and after 0, 5, 10, 20, 30, and 60 minutes, the cells were collected to obtain proteins. Changes in phospho-BCR-ABL, phospho-AKT, phospho-STAT5 and phosphor-ERK, which may indicate the activity of BCR-ABL protein, were observed by Western blotting. It was also confirmed as a control to show that there was no effect.
- the compounds of Formulas 5 to 8 decreased the protein expression levels of phospho-BCR-ABL, phospho-STAT5, phospho-AKT and phosphor-ERK. Since there was no difference in the expression level of the BCR protein, it was confirmed that the drug did not affect the protein expressed in normal cells and caused a decrease only in the protein expressed in chronic myeloid leukemia (see FIG. 1 ).
- PK experiments were performed to measure the bioavailability of the compound of Formula 8 of the present invention when administered intravenously and orally to ICR mice. Each analysis was performed by LC-MS/MS analysis.
- mice Male 6-week-old mice were divided into an intravenous administration group and an oral administration group, and three mice were assigned to each group.
- intravenous administration group blood was collected over a total of 7 times, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1, 2, and 4 hours, and in the oral administration group, 0.25, 0.5, 1, 2, 3, 4, and 8 hours. Blood was drawn a total of 7 times.
- the collected blood is put in a heparin-treated (5 IU/mL) tube and mixed well. After blood collection, the blood is centrifuged at 5,000 rpm at 4°C for 10 minutes to separate plasma, and the separated plasma is collected by animal number and blood collection time. About 30-40 ⁇ L/tube was aliquoted into the marked tube, and stored in a cryogenic freezer (about -8°C).
- composition of each group is shown in Table 5 below.
- the compound of Formula 8 according to the present invention has a fairly good bioavailability of 62.7% when administered orally.
- the compounds of Formulas 5 and 8 of the present invention were administered intraperitoneally or orally for 15 days to determine whether tumor formation was inhibited at the animal level.
- an animal xenograft model was created by subcutaneously administering Ba/F3-Bcr-Abl-T315I cells (1 ⁇ 10 7 ) after a week of adaptation to nude mice (6 weeks old). After one week, when the tumor size reached about 80 mm 3 ) Oral administration, 25 mpk intraperitoneal administration) and the compound of Formula 8 (50 mpk oral administration, 30 mpk intraperitoneal administration) were divided into administration groups, and 5 animals were assigned to each group, and each substance was administered daily by intraperitoneal injection or oral administration. It was administered for 15 days by oral administration. Tumor size (long axis, short axis, thickness) was measured using a vernia caliper twice a week, and body weight was measured once a week. On the end of the experiment, tumors were removed and weights were compared between groups.
- the compound according to the present invention can be usefully used as an anticancer agent.
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Abstract
The present invention relates to an anticancer agent for treating leukemia or solid cancers, comprising a novel benzothiazole derivative compound or a pharmaceutically acceptable salt thereof, wherein the benzothiazole derivative compound inhibits Abl kinase, and thus can be effectively used for the treatment of leukemia, which exhibits resistance to conventional anticancer agents.
Description
본 발명은 벤조티아졸 유도체 화합물에 관한 것이다. 또한, 본 발명은 벤조티아졸 유도체 화합물을 포함하는 Abl 키나제 저해제 조성물 및 이상세포 성장 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to benzothiazole derivative compounds. In addition, the present invention relates to an Abl kinase inhibitor composition comprising a benzothiazole derivative compound and a pharmaceutical composition for preventing or treating abnormal cell growth disease.
단백질 키나제 패밀리의 몇몇 구성원은 각종 증식성 질환 또는 골수증식성 질환의 발병기전에 명백하게 관련되어 왔으며, 이에 따라 이들 구성원은 이들 질환의 치료를 위한 중요한 표적이 된다. 이들 질환의 발병기전을 일으키거나 이에 기여하는 것으로 밝혀져 온 키나제의 중요한 예에는 Abl 키나제 및 종양원성 융합 단백질 Bcr-Abl 키나제가 포함된다.Several members of the protein kinase family have been unequivocally implicated in the pathogenesis of various proliferative or myeloproliferative diseases, and therefore these members are important targets for the treatment of these diseases. Important examples of kinases that have been shown to cause or contribute to the pathogenesis of these diseases include the Abl kinase and the oncogenic fusion protein Bcr-Abl kinase.
Abl 키나제는 세포 신호 전달에 관여하는 중요한 비-수용체 티로신 키나제로서 세포 주기의 조절, 유전자독성 스트레스에 대한 세포 반응, 및 인테그린 신호전달을 통한 세포 환경에 관한 정보의 전달에 관여한다. 전체적으로, Abl 단백질은 다양한 세포외 및 세포내 출처로부터의 신호를 통합하고, 세포 주기 및 세포사멸(apoptosis)에 관한 결정에 영향을 미치는 세포 모듈로서의 복잡한 역할을 수행하는 것으로 보인다.Abl kinase is an important non-receptor tyrosine kinase involved in cellular signaling and is involved in the regulation of the cell cycle, the cellular response to genotoxic stress, and the transmission of information about the cellular environment through integrin signaling. Overall, the Abl protein appears to play a complex role as a cellular module, integrating signals from a variety of extracellular and intracellular sources, and influencing decisions regarding the cell cycle and apoptosis.
Abl 키나제에는 2개의 정상적인 이소형(isoform)이 있다(Abl-1A 및 Abl-1B). Abl 키나제의 N-말단 절반이 키나제 도메인 촉매 활성의 자가억제에 중요하다(Pluk et al., Cell (2002) 108: 247).There are two normal isoforms of Abl kinase (Abl-1A and Abl-1B). The N-terminal half of the Abl kinase is important for autorepression of the kinase domain catalytic activity (Pluk et al., Cell (2002) 108: 247).
Abl 키나제의 이상 조절장애 형태(aberrant dysregulated form)는 염색체 전좌 사건(필라델피아 염색체라 불리기도 한다)으로부터 형성된다(P.C. Nowell et al. Science (1960) 132: 1497; J.D. Rowley, Nature (1973) 243: 290). 이러한 비정상적인 염색체 전좌는 Abl 키나제 유전자와 BCR(breakpoint cluster region) 유전자 사이의 이상 유전자 융합에 이르게 하고, 이에 의해 Bcr-Abl이라 불리는 이상 단백질을 암호화하게 된다.An aberrant dysregulated form of Abl kinase is formed from a chromosomal translocation event (also called the Philadelphia chromosome) (PC Nowell et al. Science (1960) 132: 1497; JD Rowley, Nature (1973) 243: 290). This abnormal chromosomal translocation leads to abnormal gene fusion between the Abl kinase gene and the breakpoint cluster region (BCR) gene, thereby encoding an abnormal protein called Bcr-Abl.
탈조절된 티로신 키나제 활성을 갖는 키메라 융합체(종양단백질) Bcr-Abl는 세포 신호를 과활성화시킴으로써 질병을 야기한다. 특히 Bcr-Abl은 만성 골수성 백혈병(CML)의 95％ 및 급성 림프구성 백혈병(AML)의 10％의 발병에 있어서 발병 원인이 된다. 따라서 Abl 키나제 저해제는 만성 골수성 백혈병의 표적 치료제로 유용하게 사용될 수 있고, 이러한 연구에 기반하여 표적 항암제가 출시되었다. 이러한 표적 항암제의 대표적인 예가 STI-571(글리벡)이다.Chimeric fusion (oncoprotein) Bcr-Abl with deregulated tyrosine kinase activity causes disease by overactivating cellular signaling. In particular, Bcr-Abl is responsible for the pathogenesis of 95% of chronic myelogenous leukemia (CML) and 10% of acute lymphocytic leukemia (AML). Therefore, Abl kinase inhibitors can be usefully used as targeted therapeutics for chronic myeloid leukemia, and targeted anticancer drugs have been released based on these studies. A representative example of such a targeted anticancer agent is STI-571 (Gleevec).
글리벡은 Bcr-Abl의 활성을 차단하여 효과를 내지만 최근에 Bcr-Abl 돌연변이로 인한 글리벡 내성이 보고되고 있다. CML의 모구성 발증 단계에 있는 일부 환자는 Bcr-Abl 키나제에서의 돌연변이 때문에 발생하며, 현재까지 22종이 넘는 돌연변이가 보고되었다. 그 중, T315I(gate keeper residue mutation)가 기존 약물들의 내성과 밀접한 관련이 있음이 보고되었다.Gleevec is effective by blocking the activity of Bcr-Abl, but recently, Gleevec resistance due to Bcr-Abl mutation has been reported. Some patients in the blast phase of CML are due to mutations in the Bcr-Abl kinase, and to date, more than 22 mutations have been reported. Among them, it has been reported that T315I (gate keeper residue mutation) is closely related to resistance of existing drugs.
글리벡을 개선시킨 2세대 약제인 타시그나(Tasigna)나 스프라이셀(Sprycell) 등이 개발되었지만, 현재까지 돌연변이 Abl(예를 들어, T315I)에 효과적으로 작용하지 못하며, 현재까지 이 돌연변이에 사용할 수 있는 약물은 보고되지 않았다. 따라서 야생형 Abl 키나제뿐만 아니라, 돌연변이 Abl(예를 들어, T315I) 키나제도 동시에 저해할 수 있는 약물의 개발이 절실히 요구된다.Tasigna and Sprycell, which are second-generation drugs that improved Gleevec, have been developed, but so far they do not effectively act on mutant Abl (eg, T315I). No drugs were reported. Therefore, there is an urgent need to develop a drug capable of simultaneously inhibiting wild-type Abl kinase as well as mutant Abl (eg, T315I) kinase.
본 발명에 따른 화합물은 야생형 Abl 키나제 및 돌연변이 Abl 키나제를 억제한다. 따라서 백혈병의 치료뿐만 아니라, 기존의 백혈병 항암제의 내성을 극복할 수 있는 약물로서의 발전이 기대된다.The compounds according to the invention inhibit wild-type Abl kinases and mutant Abl kinases. Therefore, it is expected to develop as a drug that can overcome the resistance of existing anticancer drugs for leukemia as well as treatment for leukemia.
또한, Abl 키나제는 세포의 증식과 관련이 있기 때문에, 과발현된 경우, 유방암, 폐암, 난소암 등의 다양한 고형암의 발달과 전이에 관여한다는 많은 연구 보고가 있다. 예를 들어, Abl 키나제가 유방암이나 폐암에서도 과활성화된 경우가 있다는 연구 보고가 있으며(Arlinghaus et al., Oncogene(2008) 27, 4385), 상피성 난소암에서도 Abl 키나제의 발현율이 높다는 조사결과가 있고, 난소암 3기 환자 중 Abl 키나제가 양성인 군이 음성인 군에 비해 유의하게 낮은 생존율을 보였다는 보고가 있다(강창석 et al. The Korean Journal of Pathology(2006) 40, 210).In addition, since Abl kinase is related to cell proliferation, there are many research reports that when overexpressed, it is involved in the development and metastasis of various solid cancers such as breast, lung, and ovarian cancer. For example, there is a study report that Abl kinase is overactivated in breast cancer or lung cancer (Arlinghaus et al., Oncogene (2008) 27, 4385), and the investigation result that the expression rate of Abl kinase is high also in epithelial ovarian cancer. There is a report that among stage 3 ovarian cancer patients, the Abl kinase-positive group showed a significantly lower survival rate than the negative group (Chang-Seok Kang et al. The Korean Journal of Pathology (2006) 40, 210).
이러한 연구 결과들은, Abl이 세포증식과 밀접하게 연관되어 있으므로, 악성으로의 변화 및 질병의 진행과도 관련되어 있기 때문이라고 해석할 수 있다.The results of these studies can be interpreted because Abl is closely related to cell proliferation, and thus is also related to malignant change and disease progression.
본 발명은 Abl 키나제를 억제하여 백혈병을 치료하고, 더 나아가서 기존의 항암제에 대하여 내성이 나타난 백혈병을 치료할 수 있는 신규의 벤조티아졸 유도체 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하기 위한 것이다.An object of the present invention is to provide a novel benzothiazole derivative compound, or a pharmaceutically acceptable salt thereof, capable of treating leukemia by inhibiting Abl kinase, and further, leukemia exhibiting resistance to existing anticancer agents.
또한, 본 발명은 신규의 벤조티아졸 유도체 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 Abl 키나제 저해용 약학 조성물 또는 이상세포 성장 질환의 예방 및 치료용 약학 조성물을 제공하기 위한 것이다.In addition, the present invention is to provide a pharmaceutical composition for inhibiting Abl kinase or a pharmaceutical composition for preventing and treating abnormal cell growth diseases, comprising a novel benzothiazole derivative compound or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 신규의 벤조티아졸 유도체 화합물을 포함하는 백혈병 또는 고형암 치료용 항암제를 제공하기 위한 것이다.Another object of the present invention is to provide an anticancer agent for the treatment of leukemia or solid cancer comprising a novel benzothiazole derivative compound.
본 발명은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염에 관한 것이다:The present invention relates to a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
상기 식에서,In the above formula,
R1은 탄소수 1 내지 6의 알킬옥시 또는 수소이고,R 1 is alkyloxy having 1 to 6 carbon atoms or hydrogen,
R3 및 R4는 수소이고, R2는 수소, 할로겐, 할로알킬 또는 탄소수 1 내지 6의 직쇄, 환 또는 분지쇄의 알킬기이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 6 carbon atoms,
R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 5원 또는 6원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;
R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 5원 또는 6원 헤테로사이클릭 고리를 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring,
R5는 아미노, 치환 또는 비치환된 탄소수 1 내지 6의 알킬아민 또는 이미다졸이다.R 5 is amino, substituted or unsubstituted alkylamine having 1 to 6 carbon atoms, or imidazole.
본 발명의 일 실시예에서, 상기 화학식 1의 R1은 탄소수 1 내지 4의 알킬옥시 또는 수소이고,In one embodiment of the present invention, R 1 in Formula 1 is alkyloxy having 1 to 4 carbon atoms or hydrogen,
R3 및 R4는 수소이고, R2는 수소, 할로겐, 할로알킬 또는 탄소수 1 내지 4의 직쇄, 환 또는 분지쇄의 알킬기이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 4 carbon atoms,
R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 N, O 및 S로부터 선택된 1개 또는 2개의 헤테로 원자를 포함하는 5원 또는 6원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;
R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 N, O 및 S로부터 선택된 1개 또는 2개의 헤테로 원자를 포함하는 5원 또는 6원 헤테로사이클릭 고리를 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;
R5는 N, O 및 S로부터 선택된 1개 또는 2개의 헤테로 원자를 포함하는 헤테로사이클로 치환되거나 또는 비치환된 탄소수 1 내지 6개의 알킬아민 또는 이미다졸일 수 있다.R 5 may be an alkylamine or imidazole having 1 to 6 carbon atoms which is unsubstituted or substituted with a heterocycle containing 1 or 2 hetero atoms selected from N, O and S.
본 발명의 다른 실시예에서, 상기 화학식 1의 R1은 메틸옥시, 에틸옥시 또는 수소이고,In another embodiment of the present invention, R 1 in Formula 1 is methyloxy, ethyloxy or hydrogen,
R3 및 R4는 수소이고, R2는 수소, 플루오로, 클로로, 브롬, 트리플루오로메틸, 메틸, 에틸, 프로필 또는 사이클로프로필이거나,R 3 and R 4 are hydrogen and R 2 is hydrogen, fluoro, chloro, bromine, trifluoromethyl, methyl, ethyl, propyl or cyclopropyl;
R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 N 원자를 포함하는 5원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5-membered heterocyclic ring comprising an N atom,
R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 N 원자를 포함하는 5원 헤테로사이클릭 고리를 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5-membered heterocyclic ring comprising N atoms,
R5는 1개 또는 2개의 N 원자를 포함하는 헤테로사이클로 치환된 탄소수 1 내지 4개의 알킬아민 또는 이미다졸일 수 있다.R 5 may be an alkylamine or imidazole having 1 to 4 carbon atoms substituted with a heterocycle containing 1 or 2 N atoms.
본 발명의 또다른 실시예에서, 상기 화학식 1의 R1은 메틸옥시, 에틸옥시 또는 수소이고,In another embodiment of the present invention, R 1 in Formula 1 is methyloxy, ethyloxy or hydrogen,
R3 및 R4는 수소이고, R2는 수소, 플루오로, 클로로, 메틸 또는 에틸이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, fluoro, chloro, methyl or ethyl,
R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 피롤을 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form pyrrole,
R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 피롤을 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form pyrrole,
R5는 하기 화학식 2 내지 4로 나타낸 치환기 중 어느 하나일 수 있다:R 5 may be any one of the substituents represented by the following Chemical Formulas 2 to 4:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
상기식에서, R6은 탄소수 1 내지 6의 알킬기 또는 탄소수 1 내지 6의 알킬옥시이다.In the above formula, R 6 is an alkyl group having 1 to 6 carbon atoms or alkyloxy having 1 to 6 carbon atoms.
본 발명의 화합물은 예를 들어, 하기 화학식 5 내지 15 및 화학식 24의 화합물 중 어느 하나인 화합물 또는 이의 약학적으로 허용 가능한 염일 수 있다:The compound of the present invention may be, for example, any one of the following compounds of Formulas 5 to 15 and Formula 24, or a pharmaceutically acceptable salt thereof:
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
[화학식 8][Formula 8]
[화학식 9][Formula 9]
[화학식 10][Formula 10]
[화학식 11][Formula 11]
[화학식 12][Formula 12]
[화학식 13][Formula 13]
[화학식 14][Formula 14]
[화학식 15][Formula 15]
[화학식 24][Formula 24]
본 발명에 따른 화학식 1의 화합물은 약학적으로 허용 가능한 염을 형성할 수 있다. 예를 들어, 본 발명에 따른 화학식 1의 화합물은 황산, 염산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산; 타르타르산, 포름산, 시트르산, 아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 젖산, 말론산, 말레산, 말산, 살리실산, 숙신산, 옥살산, 프로피온산, 아스파르트산, 글루탐산, 구연산 등과 같은 유기산; 또는 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 나프탈렌설폰산 등과 같은 설폰산 등과 염을 형성할 수 있다.The compound of Formula 1 according to the present invention may form a pharmaceutically acceptable salt. For example, the compound of Formula 1 according to the present invention may be prepared from inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, maleic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid and the like; Alternatively, salts may be formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like.
본 발명에 따른 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염은 Abl 키나제, 예를 들어 야생형 Abl 키나제 또는 돌연변이형 Abl(T315I) 키나제에 대한 억제 작용을 갖는다.The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an inhibitory action on Abl kinase, for example, wild-type Abl kinase or mutant Abl(T315I) kinase.
따라서, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 Abl 키나제 저해용 약학 조성물 또는 이상세포 성장 질환의 예방 및 치료용 약학 조성물에 관한 것이다.Accordingly, the present invention relates to a pharmaceutical composition for inhibiting Abl kinase or a pharmaceutical composition for preventing and treating abnormal cell growth diseases, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 백혈병 또는 고형암 치료용 항암제에 관한 것이다. 구체적으로, 본 발명은 백혈병, 뇌종양, 신장암, 위암, 피부암, 방광암, 유방암, 자궁암, 폐암, 결장암, 전립선암, 난소암, 간암, 대장암, 복막암, 복막전이암 또는 췌장암을 치료하기 위한 항암제일 수 있다.In addition, the present invention relates to an anticancer agent for the treatment of leukemia or solid cancer comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof. Specifically, the present invention is for treating leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colorectal cancer, peritoneal cancer, peritoneal metastasis or pancreatic cancer It may be an anticancer agent.
또한, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 백혈병 치료용 항암제로서, 이미 투약 중인 다른 백혈병 치료제에 대하여 내성이 발생한 환자에게 투여되어 치료 효과를 나타낼 수 있는 백혈병 치료용 조성물에 관한 것이다.In addition, the present invention is an anti-cancer agent for the treatment of leukemia comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof, which is administered to a patient who develops resistance to other leukemia therapeutic agents that are already being administered to treat leukemia that can exhibit a therapeutic effect It relates to a composition for
본 명세서에서 사용되는 용어 '알킬’은 지방족 탄화수소 라디칼을 의미하며, 알케닐이나 알키닐 부위를 포함하지 않는 '포화알킬(saturated alkyl)'이거나, 적어도 하나의 알케닐 또는 알키닐 부위를 포함하는 '불포화알킬(unsaturated alkyl)'일 수 있다. '알케닐(alkenyl)'은 적어도 하나의 탄소-탄소 이중결합을 포함하는 그룹을 의미하며, '알키닐(alkynyl)'은 적어도 하나의 탄소-탄소 삼중결합을 포함하는 그룹을 의미한다. 알킬은 단독으로 또는 알킬아민과 같이 조합하여 사용되는 경우에 각각 분지형, 환 또는 직쇄형일 수 있다.As used herein, the term 'alkyl' refers to an aliphatic hydrocarbon radical, and is 'saturated alkyl' that does not contain an alkenyl or alkynyl moiety, or a 'saturated alkyl' containing at least one alkenyl or alkynyl moiety. It may be an unsaturated alkyl'. 'Alkenyl' refers to a group containing at least one carbon-carbon double bond, and 'alkynyl' refers to a group containing at least one carbon-carbon triple bond. Alkyl may be branched, cyclic or straight-chain, respectively, when used alone or in combination with alkylamines.
전형적인 알킬 그룹에는 메틸, 에틸, 프로필, 이소프로필, 사이클로프로필, n-부틸, 이소부틸, t-부틸, 펜틸, 헥실, 에테닐, 프로페닐, 부테닐 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 예를 들어, 탄소수 1 내지 4의 알킬은 알킬쇄에 1 내지 4 개의 탄소 원자를 가지며, 메틸, 에틸, 프로필, 이소프로필, 사이클로프로필, n-부틸, 이소-부틸, sec-부틸 및 t-부틸로 이루어진 그룹에서 선택된다.Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like. . For example, alkyl having 1 to 4 carbon atoms has 1 to 4 carbon atoms in the alkyl chain, and is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl. is selected from the group consisting of
본 발명의 화합물은 약학적 조성물로 사용하기 위하여, 약학적으로 허용 가능한 담체 또는 희석제를 함유하는 제형으로 제제화할 수 있다. 본 발명에 따른 조성물은 통상적인 방법에 따라 제조될 수 있으며, 약학적으로 적절한 제형으로 투여할 수 있다.The compound of the present invention may be formulated into a formulation containing a pharmaceutically acceptable carrier or diluent for use as a pharmaceutical composition. The composition according to the present invention may be prepared according to a conventional method, and may be administered in a pharmaceutically appropriate formulation.
본 발명의 바람직한 실시예에 의하면, 정제, 캡슐, 당-코팅 정제, 필름-코팅 정제, 액제, 현탁제, 유화제 등의 형태로 경구적으로 투여되거나, 피하, 근육내, 정맥내 또는 복강내 주사 또는 주입의 방법을 통하여 비경구적으로 투여될 수도 있다.According to a preferred embodiment of the present invention, it is administered orally in the form of tablets, capsules, sugar-coated tablets, film-coated tablets, solutions, suspensions, emulsions, etc., or injected subcutaneously, intramuscularly, intravenously or intraperitoneally. Alternatively, it may be administered parenterally through the method of injection.
환자의 연령, 체중 및 상태와 투여경로를 비롯한 각종 요인에 따라 투여량이 결정될 수 있다. 1일 투여용량은 광범위한 한도치 내에서 변할 수 있으며, 각각의 개별 경우에서 개인적 요건에 맞게 조정될 수 있다. 일반적으로, 본 발명의 화합물을 성인에게 단독 투여하는경우, 투여 경로별로 채택된 투여용량은 0.0001 내지 50 mg/kg 체중의 범위일 수 있다.The dosage may be determined according to various factors including the age, weight and condition of the patient and the route of administration. The daily dosage can vary within wide limits and can be adapted to the individual requirements in each individual case. In general, when the compound of the present invention is administered alone to an adult, the dosage adopted for each route of administration may be in the range of 0.0001 to 50 mg/kg body weight.
이러한 투여 용량은 예를 들면 1일 1 내지 5 회로 환자에게 투여될 수 있다. 정맥내 주사의 경우, 적절한 1일 용량은 0.0001 내지 50 mg/kg 체중일 수 있으며, 1일 투여용량은 단일 투여분으로서 또는 분할 용량 스케줄에 따라 투여될 수 있다.Such dosages may be administered to the patient, for example, 1 to 5 times per day. For intravenous injection, a suitable daily dose may be 0.0001 to 50 mg/kg body weight, and the daily dose may be administered as a single dose or according to a divided dose schedule.
본 발명에 따른 화학식 1의 화합물은 본 발명이 속하는 기술분야에 알려진 통상적인 방법에 의해 그의 염으로 전환될 수 있다. 본 명세서에서는 별도의 설명이 없는 한, 화학식 1의 화합물에는 약학적으로 허용 가능한 그의 염도 포함되며, 이들은 모두 본 발명의 범주에 포함되는 것으로 이해되어야 한다. 설명의 편의를 위하여, 본 명세서에서는 이러한 염도 화학식 1의 화합물로 간단히 표현될 수 있다.The compound of Formula 1 according to the present invention may be converted into a salt thereof by a conventional method known in the art. In the present specification, unless otherwise specified, the compound of Formula 1 includes pharmaceutically acceptable salts thereof, and it should be understood that all of them are included in the scope of the present invention. For convenience of explanation, in the present specification, such a salt may also be simply expressed as a compound of Formula 1.
본 명세서에서 사용된 그 밖의 용어와 약어들은 달리 정의되지 않는 한 본 발명이 속하는 기술 분야의 당업자에게 통상적으로 이해되는 의미로서 해석될 수 있다.Unless otherwise defined, other terms and abbreviations used herein may be interpreted as commonly understood by those skilled in the art to which the present invention belongs.
이하에서는, 화학식 1의 화합물의 제조방법을 설명한다.Hereinafter, a method for preparing the compound of Formula 1 will be described.
1. 제조방법 A1. Manufacturing method A
출발물질로서 하기 화학식 16의 2-아미노-6-브로모벤조티아졸을 사용하되, 벤조티아졸의 6번 자리(C6 자리)에 팔라듐을 촉매로 하는 스즈키 커플링(Suzuki Coupling) 반응을 시켜 벤조티아졸의 6번 위치에 페닐 그룹을 도입하여, 화학식 17의 화합물로 표시되는 중간체를 제조한다. 2-아미노 그룹에는 카르보닐디이미다졸을 이용하여 유레아 작용기를 도입함으로써 화학식 18의 벤조티아졸 화합물을 제조할 수 있다:As a starting material, 2-amino-6-bromobenzothiazole of the following formula (16) is used, but the 6-position (C6 site) of benzothiazole is subjected to a Suzuki coupling reaction using palladium as a catalyst to form benzothiazole. By introducing a phenyl group at the 6-position of the thiazole, an intermediate represented by the compound of Formula 17 is prepared. The benzothiazole compound of formula 18 can be prepared by introducing a urea functional group using carbonyldiimidazole to the 2-amino group:
[화학식 16][Formula 16]
[화학식 17][Formula 17]
[화학식 18][Formula 18]
상기 식에서,In the above formula,
R1은 탄소수 1 내지 6의 알킬옥시 또는 수소이고,R 1 is alkyloxy having 1 to 6 carbon atoms or hydrogen,
R3 및 R4는 수소이고, R2는 수소, 할로겐, 할로알킬 또는 탄소수 1 내지 6의 직쇄, 환 또는 분지쇄의 알킬기이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 6 carbon atoms,
R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 5원 또는 6원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;
R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 5원 또는 6원 헤테로사이클릭 고리를 형성한다.R 4 is hydrogen and R 2 and R 3 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring.
보다 구체적으로 설명하면, 먼저 다양한 페닐보론산과 팔라듐 촉매(Ⅱ), 탄산칼륨 염기를 사용하는 스즈키 타입의 커플링 반응을 이용하여, 화학식 16의 화합물을 1,4-다이옥산과 물(비율 3:1)을 용매로 하여 100℃로 가열 및 교반함으로써, 화학식 16의 2-아미노-6-브로모벤조티아졸의 6번 자리(C6 자리, 즉 브롬 자리)에 페닐 그룹을 치환시킨다. 이후, 페닐로 치환된 벤조티아졸 화합물을 무수 디메틸포름아마이드를 용매로 하고 질소 기체로 충전한 뒤, 실온에서 카르보닐디이미다졸과 반응시켜 벤조티아졸의 C2 자리에 유레아 작용기를 도입함으로써, 화학식 9의 벤조티아졸 유도체 화합물을 제조할 수 있다.More specifically, first, the compound of Formula 16 is reacted with 1,4-dioxane and water (ratio 3:1) using a Suzuki-type coupling reaction using various phenylboronic acid, palladium catalyst (II), and potassium carbonate base. ) as a solvent and heating and stirring to 100° C., the phenyl group is substituted at the 6-position (C6 site, that is, the bromine site) of 2-amino-6-bromobenzothiazole of Formula 16. Thereafter, the phenyl-substituted benzothiazole compound was charged with anhydrous dimethylformamide as a solvent and nitrogen gas, and reacted with carbonyldiimidazole at room temperature to introduce a urea functional group at the C2 site of benzothiazole, The benzothiazole derivative compound of 9 can be prepared.
상기 제조방법에 따른 반응스킴은 하기 반응식 A와 같이 표시할 수 있다:The reaction scheme according to the preparation method can be represented as in Scheme A below:
[반응식 A][Scheme A]
상기 식에서, R1, R2, R3 및 R4는 상기 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 and R 4 are as defined above.
2. 제조방법 B2. Method B
또한, 상기 제조방법 A에서 제조된 화학식 18의 화합물에 추가적인 반응을 진행함으로써, 벤조티아졸의 C2 자리에 치환 또는 비치환된 알킬아민기를 도입하여 화학식 1a의 화합물을 제조할 수 있다:In addition, by performing an additional reaction on the compound of Formula 18 prepared in Preparation Method A, a substituted or unsubstituted alkylamine group may be introduced at the C2 site of benzothiazole to prepare the compound of Formula 1a:
[화학식 1a][Formula 1a]
상기 식에서,In the above formula,
R1, R2, R3 및 R4는 상기 정의한 바와 같고,R 1 , R 2 , R 3 and R 4 are as defined above,
R5'은 치환 또는 비치환된 탄소수 1 내지 6의 알킬아민이다.R 5 ′ is a substituted or unsubstituted C 1 to C 6 alkylamine.
예를 들어, 화학식 18의 화합물을, 양쪽 질소 원자에 각각 아미노에틸기 및 t-부톡시카보닐기가 치환되어 있는 피페라진을 트리에틸아민과 함께 무수 디메틸포름아마이드 용매 하에 실온에서 아마이드 커플링(amide coupling)을 진행하여, 유레아 작용기에 추가적으로 피페라진을 도입함으로써 화학식 19의 화합물을 제조하고, 이후 피페라진에 치환되어 있는 t-부톡시카보닐기는 디클로로메탄 용매 하에 트리플루오로아세트산을 넣어 실온에서 교반하여 피페라진으로부터 제거시켜, 화학식 20의 화합물을 얻을 수 있다:For example, the compound of Formula 18 is amide coupling (amide coupling) at room temperature in anhydrous dimethylformamide solvent together with triethylamine and piperazine in which aminoethyl groups and t-butoxycarbonyl groups are substituted on both nitrogen atoms, respectively. ), the compound of formula 19 was prepared by introducing piperazine additionally to the urea functional group, and then the t-butoxycarbonyl group substituted for piperazine was stirred at room temperature by adding trifluoroacetic acid in a dichloromethane solvent. Removal from piperazine can afford the compound of formula 20:
[화학식 19][Formula 19]
[화학식 20][Formula 20]
상기 식에서, R1, R2, R3 및 R4는 상기 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 and R 4 are as defined above.
또한, 화학식 18의 화합물을, 양쪽 질소 원자에 각각 아미노에틸기 및 알킬기(바람직하게는 탄소수 1 내지 6의 알킬기)가 치환되어 있는 피페라진을 트리에틸아민과 함께 무수 디메틸포름아마이드 용매 하에 실온에서 아마이드 커플링(amide coupling)을 진행하여, 유레아 작용기에 추가적으로 피페라진을 도입함으로써 화학식 21의 화합물을 얻을 수 있다.In addition, the compound of formula (18) was mixed with piperazine in which an aminoethyl group and an alkyl group (preferably an alkyl group having 1 to 6 carbon atoms) are substituted on both nitrogen atoms, together with triethylamine, in an anhydrous dimethylformamide solvent at room temperature under an amide couple. The compound of Formula 21 can be obtained by introducing piperazine additionally to the urea functional group through amide coupling.
[화학식 21][Formula 21]
상기 식에서,In the above formula,
R1, R2, R3 및 R4는 상기 정의한 바와 같고,R 1 , R 2 , R 3 and R 4 are as defined above,
R6은 알킬기이다.R 6 is an alkyl group.
3. 제조방법 C3. Manufacturing method C
상기 제조방법 A와 달리, 화학식 16의 2-아미노-6-브로모벤조티아졸 화합물을 카르보닐디이미다졸과 먼저 반응시켜 화학식 22의 화합물을 제조하고, 상기 화학식 22의 화합물을, 양쪽 질소 원자에 각각 아미노에틸기 및 알킬기가 치환되어 있는 피페라진을 트리에틸아민과 함께 무수 디메틸포름아마이드 용매 하에 실온에서 아마이드 커플링(amide coupling)을 진행하여, 유레아 작용기에 추가적으로 피페라진을 도입함으로써 화학식 23의 화합물을 얻을 수 있다. 이후, 상기 화학식 22의 화합물을 다양한 페닐보론산과 반응시켜 화학식 21의 화합물을 제조할 수 있다:Unlike Preparation A, the 2-amino-6-bromobenzothiazole compound of Formula 16 is first reacted with carbonyldiimidazole to prepare a compound of Formula 22, and the compound of Formula 22 is reacted with both nitrogen atoms Compound of Formula 23 by introducing piperazine, each substituted with an aminoethyl group and an alkyl group, with triethylamine at room temperature in anhydrous dimethylformamide solvent at room temperature to introduce piperazine additionally to the urea functional group can get Then, the compound of formula 22 can be reacted with various phenylboronic acids to prepare a compound of formula 21:
[화학식 22][Formula 22]
[화학식 23][Formula 23]
[화학식 21][Formula 21]
상기 식에서, R1, R2, R3, R4 및 R6은 상기 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 , R 4 and R 6 are as defined above.
본 발명이 속한 기술분야에서 통상의 지식을 가진 자라면, 화학식 1의 구조를 바탕으로 하여 상기와 같이 기재된 제조방법 외의 다른 다양한 방법에 의해서도 화학식 1의 화합물을 제조할 수 있음을 이해할 수 있다.Those of ordinary skill in the art to which the present invention pertains can understand that the compound of Formula 1 can be prepared by various methods other than the above-described preparation method based on the structure of Formula 1 .
본 발명에 따른 벤조티아졸 유도체 화합물 또는 이의 약학적으로 허용 가능한 염은 Abl 키나제에 대한 저해제로서 비정상적 세포 성장, 기능 또는 거동으로부터 야기되는 질환, 특히 암을 치료하는데 사용할 수 있다.The benzothiazole derivative compound or a pharmaceutically acceptable salt thereof according to the present invention can be used as an inhibitor for Abl kinase to treat diseases, particularly cancer, resulting from abnormal cell growth, function or behavior.
도 1은 본 발명의 화합물에 대하여 BCR-ABL 활성의 변화를 알아보기 위해 웨스턴 블럿(western blotting)을 시행한 결과를 도시한 것이다.1 shows the results of western blotting to determine the change in BCR-ABL activity with respect to the compound of the present invention.
도 2 및 도 3은 각각 본 발명의 화합물을 동물에 투여한 후 종양 크기 및 종양 무게를 측정한 결과를 도시한 그래프이다.2 and 3 are graphs showing the results of measuring tumor size and tumor weight after administration of the compound of the present invention to animals, respectively.
도 4는 본 발명의 화합물을 동물에 투여한 후, 실험 종료일에 적출한 종양을 촬영한 사진이다.4 is a photograph of a tumor extracted on the day of the end of the experiment after administration of the compound of the present invention to an animal.
도 5는 본 발명의 화합물을 동물에 투여한 후 종양 크기를 측정한 결과를 도시한 그래프이다.5 is a graph showing the results of measuring tumor size after administration of the compound of the present invention to an animal.
이하, 본 발명의 바람직한 실시예와 Abl 저해 활성 효과를 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것일 뿐이며, 본 발명의 사상이나 범위가 이에 한정되는 것은 아니다.Hereinafter, preferred examples of the present invention and the effect of Abl inhibitory activity will be described in detail. However, these examples are only for explaining the present invention in more detail, and the spirit or scope of the present invention is not limited thereto.
[제조 실시예][Production Example]
본 발명에 따른 화학식 1의 벤조티아졸 유도체 화합물을 하기의 일반적 제조방법에 따라 제조하였다.A benzothiazole derivative compound of Formula 1 according to the present invention was prepared according to the following general preparation method.
<일반적 제조방법 1><General manufacturing method 1>
2-아미노-6-브로모벤조티아졸(1 당량), 페닐보론산(1.1 당량), 탄산칼륨(3당량), 비스(디페닐포스핀)페로센-팔라듐(Ⅱ)(0.1당량)을 마이크로웨이브 반응 바이알에 넣고, 1,4-디옥산과 물의 비율이 3 : 1인 용액 하에 혼합물을 100℃에서 3시간 동안 마이크로웨이브 반응기에서 가열하였다. 반응 종료 후, 셀라이트 필터를 통해 고체를 제거하였으며, 컬럼 크로마토그래피를 통해서 C6 위치에 원하는 페닐 그룹이 도입된 벤조[d]티아졸-2-아민 중간체를 얻었다.2-amino-6-bromobenzothiazole (1 eq.), phenylboronic acid (1.1 eq.), potassium carbonate (3 eq.), bis(diphenylphosphine)ferrocene-palladium (II) (0.1 eq.) It was placed in a wave reaction vial, and the mixture was heated in a microwave reactor at 100° C. for 3 hours under a solution in which the ratio of 1,4-dioxane to water was 3:1. After completion of the reaction, the solid was removed through a Celite filter, and a benzo[d]thiazol-2-amine intermediate in which a desired phenyl group was introduced at the C6 position was obtained through column chromatography.
상기 중간체에 카르보닐디이미다졸(2.5당량)을 넣고 무수 디메틸포름아마이드 용매와 질소 조건하에 15시간 동안 교반하였다. 반응 종료 후 혼합물의 용매를 전부 날린 후, 유리필터를 통해 생성된 고체를 걸렀다.Carbonyldiimidazole (2.5 equivalents) was added to the intermediate, and the mixture was stirred with anhydrous dimethylformamide solvent and nitrogen conditions for 15 hours. After completion of the reaction, all solvents in the mixture were blown off, and the resulting solid was filtered through a glass filter.
상기 제조방법에 따른 반응식 A는 다음과 같다:Scheme A according to the above preparation method is as follows:
[반응식 A][Scheme A]
상기 식에서, R1, R2, R3 및 R4는 상기 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 and R 4 are as defined above.
<일반적 제조방법 2><General manufacturing method 2>
상기 일반적 제조방법 1을 통하여 얻은 화합물에 새로운 작용기를 도입한다. 구체적으로, 화학식 18의 화합물에 t-부틸 4-(2-아미노에틸)피페라진-1-카복실레이트(1.1 당량) 및 트리에틸아민(3.0 당량)을 넣고, 무수 디메틸포름아마이드 용매와 질소 조건 하에 실온에서 3시간동안 교반하였다. 반응 종료 후, 컬럼 크로마토그래피를 통해서 중간체를 얻었다.A new functional group is introduced into the compound obtained through the general preparation method 1 above. Specifically, t-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (1.1 equiv.) and triethylamine (3.0 equiv.) were added to the compound of Formula 18, and anhydrous dimethylformamide solvent and nitrogen condition were added. Stirred at room temperature for 3 hours. After completion of the reaction, an intermediate was obtained through column chromatography.
상기 중간체의 피페라진에 치환되어 있는 t-부톡시카보닐 치환기는 트리플루오로아세트산(30 당량)을 디클로로메탄 용매 하에 실온에서 3시간 동안 교반하여 피페라진에서 제거되며, 반응 종료 후 용매를 감압하여 최종 유레아 고체를 얻는다.The t-butoxycarbonyl substituent substituted with piperazine of the intermediate is removed from piperazine by stirring trifluoroacetic acid (30 equivalents) in a dichloromethane solvent at room temperature for 3 hours, and after completion of the reaction, the solvent is reduced The final urea solid is obtained.
상기 제조방법에 따른 반응식 B는 다음과 같다:Scheme B according to the preparation method is as follows:
[반응식 B][Scheme B]
상기 식에서, R1, R2, R3 및 R4는 상기 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 and R 4 are as defined above.
<일반적 제조방법 3><General manufacturing method 3>
실온에서 DMF 중의 2-아미노-6-브로모벤조티아졸(1 당량)에 카르보닐디이미다졸(1.1당량)을 가하고, 2시간 교반하였다. 혼합물을 여과하고, 건조하였다.Carbonyldiimidazole (1.1 eq) was added to 2-amino-6-bromobenzothiazole (1 eq) in DMF at room temperature, followed by stirring for 2 hours. The mixture was filtered and dried.
여기에, 4-(2-아미노에틸)피페라진-1-카복실산의 N을 알킬기로 치환시킨 화합물을 실온에서 가하고, 1시간 교반하였다.A compound in which N of 4-(2-aminoethyl)piperazine-1-carboxylic acid was substituted with an alkyl group was added thereto at room temperature, followed by stirring for 1 hour.
잔사에 물을 붓고, 에틸 아세테이트로 추출하였다. 황산마그네슘으로 유기층의 수분을 제거하고, 감압 농축하였다. 혼합물을 컬럼크로마토그래피로 정제하였다.Water was poured into the residue, and extraction was performed with ethyl acetate. Moisture in the organic layer was removed with magnesium sulfate and concentrated under reduced pressure. The mixture was purified by column chromatography.
상기 정제된 화합물 및 치환기를 갖는 페닐보론산을 다이옥산 용액에 넣고, 팔라듐 촉매(II) 및 Cs2CO3 용액을 가한다. 밤새도록 100℃로 가열하면서 반응시킨 후, 실온으로 냉각시키고, 감압 농축하였다.The purified compound and phenylboronic acid having a substituent are placed in a dioxane solution, and a palladium catalyst (II) and a Cs 2 CO 3 solution are added thereto. After reacting while heating at 100°C overnight, it was cooled to room temperature and concentrated under reduced pressure.
잔사에 물을 붓고, 에틸 아세테이트로 3회 추출한 후, 유기층의 수분을 황산마그네슘으로 제거하고, 감압 농축하여 최종 생성물을 수득하였다.Water was poured into the residue, and after extraction with ethyl acetate three times, moisture in the organic layer was removed with magnesium sulfate and concentrated under reduced pressure to obtain a final product.
상기 제조방법에 따른 반응식 C는 다음과 같다:Scheme C according to the above preparation method is as follows:
[반응식 C][Scheme C]
상기 식에서, R1, R2, R3, R4 및 R6은 상기 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 , R 4 and R 6 are as defined above.
이하에서는, 본 발명의 구체적인 화합물의 제조 실시예를 설명한다.Hereinafter, preparation examples of specific compounds of the present invention will be described.
<실시예 1> 6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-아민<Example 1> 6- (5-fluoro-2-methoxyphenyl) benzo [d] thiazol-2-amine
하기 반응식 D에 따라, 2-아미노-6-브로모벤조티아졸(500 mg, 1당량), (5-플루오로-2-메톡시페닐)보론산(408 mg, 1.1당량), 탄산칼륨(905 mg, 3당량), 비스(디페닐포스핀) 페로센-팔라듐(Ⅱ) (178 mg, 0.1 당량)을 넣고 상기 일반적 제조방법 1에 따라 반응을 수행하였다. 셀라이트 필터를 실시한 뒤, 남은 용액은 헥산과 아세트산에틸을 이용한 컬럼 크로마토그래피를 실시하여 6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-아민을 얻었다. (수율: 86%)According to Scheme D below, 2-amino-6-bromobenzothiazole (500 mg, 1 equiv), (5-fluoro-2-methoxyphenyl)boronic acid (408 mg, 1.1 equiv), potassium carbonate ( 905 mg, 3 equivalents), bis(diphenylphosphine) ferrocene-palladium(II) (178 mg, 0.1 equivalents) were added, and the reaction was carried out according to the general preparation method 1 above. After performing Celite filter, the remaining solution was subjected to column chromatography using hexane and ethyl acetate to obtain 6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-amine. (Yield: 86%)
[반응식 D][Scheme D]
1H NMR (599 MHz, Methanol-d 4) δ 7.73 (s, 1H), 7.41 - 7.36 (m, 2H), 7.10 - 6.98 (m, 3H), 3.78 (s, 3H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.73 (s, 1H), 7.41 - 7.36 (m, 2H), 7.10 - 6.98 (m, 3H), 3.78 (s, 3H).
<실시예 2> N-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-1H-이미다졸-1-카복스아마이드<Example 2> N-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide
하기 반응식 E에 따라, 6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-아민(480mg, 1 당량)과 카르보닐디이미다졸(709mg, 2.5 당량)을 넣고, 상기 일반적 제조방법 1에 따라 반응을 수행하였다. 얻어진 고체를 거름종이를 통해 필터링하고 디클로로메탄으로 세척함으로써 N-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-1H-이미다졸-1-카복스아마이드을 얻었다. (수율: 93%)According to Scheme E below, 6- (5-fluoro-2-methoxyphenyl) benzo [d] thiazol-2-amine (480 mg, 1 eq.) and carbonyldiimidazole (709 mg, 2.5 eq.) were added. , the reaction was carried out according to the general preparation method 1 above. N-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-1H-imidazole-1- Carboxamide was obtained. (Yield: 93%)
[반응식 E][Scheme E]
1H NMR (599 MHz, Methanol-d 4) δ 7.96 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.53 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (dd, J = 9.3, 2.9 Hz, 1H), 7.09 - 7.01 (m, 4H), 3.79 (s, 3H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.96 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.53 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (dd, J = 9.3, 2.9 Hz, 1H), 7.09 - 7.01 (m, 4H), 3.79 (s, 3H).
<실시예 3> t-부틸 4-(2-(3-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)유레이도)에틸)피페라진-1-카복실레이트<Example 3> t-Butyl 4-(2-(3-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)ureido)ethyl)piperazine- 1-carboxylate
하기 반응식 F에 따라, N-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-1H-이미다졸-1-카복스아마이드(600 mg, 1 당량)과 t-부틸 4-(2-아미노에틸)피페라진-1-카복실레이트(411 mg, 1.1 당량), 트리에틸아민(494 mg, 3.0 당량)을 넣고, 상기 일반적 제조방법 2에 따라 반응을 수행하였다. 반응 종료 후, 메탄올과 디클로로메탄을 사용한 컬럼 크로마토그래피를 통해 t-부틸 4-(2-(3-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)유레이도)에틸)피페라진-1-카복실레이트를 얻었다. (수율: 55%)According to Scheme F below, N-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (600 mg, 1 equiv), t-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (411 mg, 1.1 equiv), and triethylamine (494 mg, 3.0 equiv), and react according to General Method 2 above. was performed. After completion of the reaction, t-butyl 4-(2-(3-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazole-2- 1) ureido) ethyl) piperazine-1-carboxylate was obtained. (Yield: 55%)
[반응식 F][Scheme F]
1H NMR (599 MHz, Methanol-d 4) δ 7.92 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (dd, J = 9.1, 2.8 Hz, 1H), 7.09 - 7.02 (m, 2H), 3.79 (s, 3H), 3.48 (s, 4H), 3.44 (t, J = 6.3 Hz, 2H), 2.59 (t, J = 6.2 Hz, 2H), 2.50 (s, 4H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.92 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H) , 7.11 (dd, J = 9.1, 2.8 Hz, 1H), 7.09 - 7.02 (m, 2H), 3.79 (s, 3H), 3.48 (s, 4H), 3.44 (t, J = 6.3 Hz, 2H), 2.59 (t, J = 6.2 Hz, 2H), 2.50 (s, 4H).
<실시예 4> 1-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-3-(2-(피페라진-1-일)에틸)유레아<Example 4> 1-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea
하기 반응식 G에 따라, t-부틸 4-(2-(3-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)유레이도)에틸)피페라진-1-카복실레이트(300mg, 1.0 당량)를 디클로로메탄에 녹인 뒤, 트리플루오로아세트산(1.93 mg, 30 당량)을 넣고 상기 일반적 제조방법 2에 따라 반응을 진행하였다. 이후, 용매를 감압하여 1-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-3-(2-(피페라진-1-일)에틸)유레아를 얻었다. (수율: 94%)According to Scheme G, t-butyl 4-(2-(3-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)ureido)ethyl)piperazine -1-carboxylate (300 mg, 1.0 equiv) was dissolved in dichloromethane, trifluoroacetic acid (1.93 mg, 30 equiv) was added thereto, and the reaction was carried out according to General Method 2 above. Then, the solvent was reduced under reduced pressure to 1-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-3-(2-(piperazin-1-yl)ethyl) got urea. (Yield: 94%)
[반응식 G][Scheme G]
1H NMR (599 MHz, Methanol-d 4) δ 7.91 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H), 7.09 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 - 7.01 (m, 2H), 3.78 (s, 3H), 3.49 (t, J = 6.0 Hz, 2H), 3.33 - 3.30 (m, 4H), 2.96 (s, 4H), 2.81 (t, J = 6.1 Hz, 2H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.91 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H) , 7.09 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 - 7.01 (m, 2H), 3.78 (s, 3H), 3.49 (t, J = 6.0 Hz, 2H), 3.33 - 3.30 (m, 4H) ), 2.96 (s, 4H), 2.81 (t, J = 6.1 Hz, 2H).
<실시예 5> N-(6-브로모)-1,3-벤조티아졸-2-일)-1H-이미다졸-1-카복스아마이드<Example 5> N-(6-bromo)-1,3-benzothiazol-2-yl)-1H-imidazole-1-carboxamide
하기 반응식 H에 따라, 실온에서 DMF(15㎖) 중의 2-아미노-6-브로모벤조티아졸(3mmol)에 1-(1H)-이미다졸-1-카보닐)-1H-이미다졸 (3.3mmol)을 가하고, 2시간 교반하였다. 혼합물을 여과하고, 건조하여, N-(6-브로모)-1,3-벤조티아졸-2-일)-1H-이미다졸-1-카복스아마이드를 제조하였다. 이 화합물에 대하여 정제 과정 없이 그대로 다음 반응을 진행시켰다:1-(1H)-imidazole-1-carbonyl)-1H-imidazole (3.3) in 2-amino-6-bromobenzothiazole (3 mmol) in DMF (15 mL) at room temperature according to Scheme H mmol) was added and stirred for 2 hours. The mixture was filtered and dried to give N-(6-bromo)-1,3-benzothiazol-2-yl)-1H-imidazole-1-carboxamide. For this compound, the following reaction proceeded as it was without purification:
[반응식 H][Scheme H]
<실시예 6> N-메틸 치환된 4-(2{[(6-브로모-1,3-벤조티아졸-2-일)카바모일]아미노}에틸)피페라진<Example 6> N-methyl substituted 4-(2{[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]amino}ethyl)piperazine
하기 반응식 I에 따라, DMF (5mL)중의 N-(6-브로모)-1,3-벤조티아졸-2-일)-1H-이미다졸-1-카복스아마이드 (1mmol) 용액에 1-(2-아미노에틸)-4-메틸피페라진을 가하였다. 실온에서 1시간 동안 교반하면서 반응시키고, 잔사를 물(10mL)에 넣은 후, 에틸 아세테이트로 추출하였다. 화합물을 실온에서 가하고, 1시간 교반하였다.1- To a solution of N-(6-bromo)-1,3-benzothiazol-2-yl)-1H-imidazole-1-carboxamide (1 mmol) in DMF (5 mL) according to Scheme I (2-Aminoethyl)-4-methylpiperazine was added. The reaction was stirred at room temperature for 1 hour, and the residue was taken up in water (10 mL) and extracted with ethyl acetate. The compound was added at room temperature and stirred for 1 hour.
잔사에 물을 붓고, 에틸 아세테이트로 추출하였다. 황산마그네슘으로 유기층의 수분을 제거하고, 감압 농축하였다. 혼합물을 컬럼크로마토그래피로 정제하여, N-메틸 치환된 4-(2-{[(6-브로모-1,3-벤조티아졸-2-일)카바모일]아미노}에틸)피페라진을 수득하였다.Water was poured into the residue, and extraction was performed with ethyl acetate. Moisture in the organic layer was removed with magnesium sulfate and concentrated under reduced pressure. The mixture was purified by column chromatography to obtain N-methyl substituted 4-(2-{[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]amino}ethyl)piperazine did.
[반응식 I][Scheme I]
<실시예 7> 3-[6-(5-플루오로-2-메톡시페닐)-1,3-벤조티아졸-2-일]-1-[2-(4-메틸피페라진-1-일)에틸]우레아<Example 7> 3-[6-(5-fluoro-2-methoxyphenyl)-1,3-benzothiazol-2-yl]-1-[2-(4-methylpiperazine-1- work) ethyl] urea
디옥산 (4mL) 중의 N-메틸 치환된 4-(2-{[(6-브로모-1,3-벤조티아졸-2-일)카바모일]아미노}에틸)피페라진 및 (5-플루오로-2-메톡시페닐)보론산 용액에 Pd(dppf)Cl2 를 가하고, 물 (2mL) 중의 Cs2CO3 용액을 가하였다. 밤새도록 100℃로 가열하면서 반응시킨 후, 실온으로 냉각시키고, 감압 농축하였다.N-methyl substituted 4-(2-{[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]amino}ethyl)piperazine and (5-fluoro) in dioxane (4mL) Pd(dppf)Cl 2 was added to the rho-2-methoxyphenyl)boronic acid solution, and a solution of Cs 2 CO 3 in water (2mL) was added thereto. After reacting while heating at 100°C overnight, it was cooled to room temperature and concentrated under reduced pressure.
잔사를 물(10mL)에 넣고, 에틸 아세테이트 10mL로 3회 추출한 후, 유기층의 수분을 황산마그네슘으로 제거하고, 감압 농축하여 최종 생성물인 3-[6-(5-플루오로-2-메톡시페닐)-1,3-벤조티아졸-2-일]-1-[2-(4-메틸피페라진-1-일)에틸]우레아를 수득하였다.The residue was placed in water (10 mL), extracted three times with 10 mL of ethyl acetate, and the organic layer was removed with magnesium sulfate and concentrated under reduced pressure to obtain the final product, 3-[6-(5-fluoro-2-methoxyphenyl). )-1,3-benzothiazol-2-yl]-1-[2-(4-methylpiperazin-1-yl)ethyl]urea was obtained.
[반응식 J][Scheme J]
1H NMR (400 MHz, DMSO) d 12.01 (br, 1H), 10.88 (Br, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.63 (d, J=9.2Hz, 2H), 7.49 (dd, J=8.4Hz, 1H), 7.22-7.11(m, 3H), 7.02 (s, 1H), 6.80 (br, 1H), 3.76 (s, 3H), 3.28(q, J=5.9Hz, 2H), 2.43 (m, 3H), 2.34 (m, 3H), 2.17 (s, 3H), LC/MS (M+H)-(m/z)=444.2 1H NMR (400 MHz, DMSO) d 12.01 (br, 1H), 10.88 (Br, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.63 (d, J=9.2Hz, 2H), 7.49 (dd , J=8.4Hz, 1H), 7.22-7.11(m, 3H), 7.02 (s, 1H), 6.80 (br, 1H), 3.76 (s, 3H), 3.28 (q, J=5.9Hz, 2H) , 2.43 (m, 3H), 2.34 (m, 3H), 2.17 (s, 3H), LC/MS (M+H) - (m/z)=444.2
상기 실시예에 기재되어 있지 않은 치환기를 포함하는 화합물에 대해서도 상기의 본 발명에 따른 실시예의 반응 원리 및 조건이 적용될 수 있으며, 따라서 통상의 기술자라면 실시예의 개시내용 및 당업계의 기술상식에 기초하여 이들 치환기를 포함하는 화합물을 용이하게 제조할 수 있다.The reaction principles and conditions of Examples according to the present invention can be applied to compounds containing substituents not described in the above Examples, and therefore, those skilled in the art can Compounds containing these substituents can be easily prepared.
본 발명에서 화학식 5 내지 화학식 15 및 화학식 24로 표시하여 구체적으로 개시하고 있는 벤조티아졸 유도체 화합물을 아래 표 1 내지 4에 나타내었다.In the present invention, the benzothiazole derivative compounds specifically disclosed by the formulas 5 to 15 and 24 are shown in Tables 1 to 4 below.
| 화합물compound | 구조structure | 이름name | NMRNMR | |
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화학식 5chemical formula 5 |
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1-(6-(2-메톡시페닐)벤조[d]티아졸-2-일)-3-(2-(피페라진-1-일)에틸)유레아1-(6-(2-methoxyphenyl)benzo[d]thiazol-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea | 1H NMR (599 MHz, Methanol-d 4) δ 7.89 (s, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 (dt, J = 8.3, 1.7 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 3.81 (d, J = 1.7 Hz, 3H), 3.54 (t, J = 6.0 Hz, 2H), 3.40 - 3.33 (m, 4H), 3.07 (s, 4H), 2.91 (t, J = 6.0 Hz, 2H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.89 (s, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 (dt, J = 8.3, 1.7 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 3.81 (d, J = 1.7 Hz, 3H), 3.54 (t, J = 6.0) Hz, 2H), 3.40 - 3.33 (m, 4H), 3.07 (s, 4H), 2.91 (t, J = 6.0 Hz, 2H). | |
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화학식 6chemical formula 6 |
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1-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-3-(2-(피페라진-1-일)에틸)유레아1-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea | 1H NMR (599 MHz, Methanol-d 4) δ 7.91 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H), 7.09 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 - 7.01 (m, 2H), 3.78 (s, 3H), 3.49 (t, J = 6.0 Hz, 2H), 3.33 - 3.30 (m, 4H), 2.96 (s, 4H), 2.81 (t, J = 6.1 Hz, 2H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.91 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H) , 7.09 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 - 7.01 (m, 2H), 3.78 (s, 3H), 3.49 (t, J = 6.0 Hz, 2H), 3.33 - 3.30 (m, 4H) ), 2.96 (s, 4H), 2.81 (t, J = 6.1 Hz, 2H). | |
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화학식 7chemical formula 7 |
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N-(6-(2-메톡시-5-메틸페닐)벤조[d]티아졸-2-일)-1H-이미다졸-1-카복사마이드N-(6-(2-methoxy-5-methylphenyl)benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide | 1H NMR (599 MHz, Methanol-d 4) δ 7.92 (d, J = 1.7 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.51 (dd, J = 8.4, 1.7 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.05 (s, 2H), 6.97 (d, J = 8.3 Hz, 1H), 3.77 (s, 4H), 2.32 (s, 4H). 1 H NMR (599 MHz, Methanol- d 4 ) δ 7.92 (d, J = 1.7 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.51 (dd, J = 8.4, 1.7 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.05 (s, 2H), 6.97 (d, J = 8.3 Hz, 1H), 3.77 (s, 4H), 2.32 (s, 4H). | |
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화학식 24chemical formula 24 |
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N-(6-(5-플루오로-2-메톡시페닐)벤조[d]티아졸-2-일)-1H-이미다졸-1-카복사아마이드N-(6-(5-fluoro-2-methoxyphenyl)benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide | 1H NMR (599 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.53 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (dd, J = 9.3, 2.9 Hz, 1H), 7.09 - 7.01 (m, 4H), 3.79 (s, 3H). 1 H NMR (599 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.53 (dd, J = 8.4) , 1.8 Hz, 1H), 7.11 (dd, J = 9.3, 2.9 Hz, 1H), 7.09 - 7.01 (m, 4H), 3.79 (s, 3H). | |
| 화합물compound | 구조structure | 이름name | NMRNMR |
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화학식 8chemical formula 8 |
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3-[6-(5-플루오로-2-메톡시페닐)-1,3-벤조티아졸-2-yl]-1-[2-(4-메틸피페라진-1-일)에틸]우레아3-[6-(5-fluoro-2-methoxyphenyl)-1,3-benzothiazol-2-yl]-1-[2-(4-methylpiperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 12.01 (br, 1H), 10.88 (Br, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.63 (d, J=9.2Hz, 2H), 7.49 (dd, J=8.4Hz, 1H), 7.22-7.11(m, 3H), 7.02 (s, 1H), 6.80 (br, 1H), 3.76 (s, 3H), 3.28(q, J=5.9Hz, 2H), 2.43 (m, 3H), 2.34 (m, 3H), 2.17 (s, 3H), LC/MS (M+H)-(m/z)=444.21H NMR (400 MHz, DMSO) d 12.01 (br, 1H), 10.88 (Br, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.63 (d, J=9.2Hz, 2H), 7.49 (dd , J=8.4Hz, 1H), 7.22-7.11(m, 3H), 7.02 (s, 1H), 6.80 (br, 1H), 3.76 (s, 3H), 3.28 (q, J=5.9Hz, 2H) , 2.43 (m, 3H), 2.34 (m, 3H), 2.17 (s, 3H), LC/MS (M+H)-(m/z)=444.2 |
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화학식 9chemical formula 9 |
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3-[6-(1H-인돌-4-일)-1,3-벤조티아졸 -2-일]-1-[2-(피페라진-1-일)에틸]우레아3-[6-(1H-indol-4-yl)-1,3-benzothiazol-2-yl]-1-[2-(piperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 11.31 (s, 1H), 11.22 (br, 1H), 9.12 (br, 2H), 8.15 (d, J=1.2Hz, 1H), 7.70 (q, J=10.0Hz, 2H), 7.42 (m, J=10.8Hz, 2H), 7.19 (m, J=7.6Hz, 2H), 7.11 (d, J=0.8Hz, 1H), 6.59 (t, J=2Hz, 1H), 3.47 (s, 2H), 3.22-2.95 (m, 4H), LC/MS (M+H)-(m/z)=421.21H NMR (400 MHz, DMSO) d 11.31 (s, 1H), 11.22 (br, 1H), 9.12 (br, 2H), 8.15 (d, J=1.2Hz, 1H), 7.70 (q, J=10.0Hz) , 2H), 7.42 (m, J=10.8Hz, 2H), 7.19 (m, J=7.6Hz, 2H), 7.11 (d, J=0.8Hz, 1H), 6.59 (t, J=2Hz, 1H) , 3.47 (s, 2H), 3.22-2.95 (m, 4H), LC/MS (M+H)-(m/z)=421.2 |
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화학식 10chemical formula 10 |
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3-[6-(2-메톡시페닐)-1,3-벤조티아졸-2-일]-1-[2-(4-메틸피페라진-1-일)에틸]우레아3-[6-(2-methoxyphenyl)-1,3-benzothiazol-2-yl]-1-[2-(4-methylpiperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 10.85 (s, 1H), 7.95 (d, J=1.6Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 7.46 (d, J=8.4Hz, 1H), 7.34 (m, 2H), 7.12 (d, J=8.0Hz, 1H), 7.04 (m, 1H), 6.80 (s, 1H), 3.77 (s, 1H), 3.36 (s, 2H), 3.28 (m, 2H), 2.40 (m, 8H), 2.18 (s, 3H), LC/MS (M+H)-(m/z)=426.21H NMR (400 MHz, DMSO) d 10.85 (s, 1H), 7.95 (d, J=1.6Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 7.46 (d, J=8.4Hz, 1H) ), 7.34 (m, 2H), 7.12 (d, J=8.0Hz, 1H), 7.04 (m, 1H), 6.80 (s, 1H), 3.77 (s, 1H), 3.36 (s, 2H), 3.28 (m, 2H), 2.40 (m, 8H), 2.18 (s, 3H), LC/MS (M+H)-(m/z)=426.2 |
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화학식 11chemical formula 11 |
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3-[6-(1H-인돌-4-일)-1,3-벤조티아졸-2-일]-1-[2-(4-메틸피페라진-1-일)에틸]우레아3-[6-(1H-indol-4-yl)-1,3-benzothiazol-2-yl]-1-[2-(4-methylpiperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 12.03 (br, 1H), 11.28 (s, 1H), 10.55 (br, 1H), 8.15 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.66 (dd, J=6.4Hz, 2H), 7.41 (m, 2H), 7.19 (t, J=7.6Hz, 1H), 7.12 (d, J=5.4Hz, 1H), 7.03 (m, 1H), 6.83 (s, 1H), 6.60 (m, 1H), 3.36 (s, 2H), 3.29 (m, 2H), 2.39 (m, 8H), 2.17 (s, 3H), LC/MS (M+H)-(m/z)=435.21H NMR (400 MHz, DMSO) d 12.03 (br, 1H), 11.28 (s, 1H), 10.55 (br, 1H), 8.15 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.66 (dd, J=6.4Hz, 2H), 7.41 (m, 2H), 7.19 (t, J=7.6Hz, 1H), 7.12 (d, J=5.4Hz, 1H), 7.03 (m, 1H), 6.83 (s, 1H), 6.60 (m, 1H), 3.36 (s, 2H), 3.29 (m, 2H), 2.39 (m, 8H), 2.17 (s, 3H), LC/MS (M+H)- (m/z)=435.2 |
| 화합물compound | 구조structure | 이름name | NMRNMR |
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화학식 12chemical formula 12 |
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3-[6-(1H-인돌-5-일)-1,3-벤조티아졸-2-일]-1-[2-(피페라진-1-일)에틸]우레아3-[6-(1H-indol-5-yl)-1,3-benzothiazol-2-yl]-1-[2-(piperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 11.53 (s, 1H), 9.83 (s, 3H), 8.28 (s, 1H), 7.79 (m, 3H), 7.56 (m, 2H), 7.30 (m, 3H), 3.48 (m, 8H) LC/MS (M+H)-(m/z)=421.21H NMR (400 MHz, DMSO) 11.53 (s, 1H), 9.83 (s, 3H), 8.28 (s, 1H), 7.79 (m, 3H), 7.56 (m, 2H), 7.30 (m, 3H) , 3.48 (m, 8H) LC/MS (M+H)-(m/z)=421.2 |
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화학식 13chemical formula 13 |
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3-[6-(1H-인돌-6-일)-1,3-벤조티아졸-2-일]-1-[2-(피페라진-1-일)에틸]우레아3-[6-(1H-indol-6-yl)-1,3-benzothiazol-2-yl]-1-[2-(piperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 10.91 (s,1H) 9.76 (s, 3H), 8.14 (s, 1H), 7.67 (m, 5H), 7.56 (m, 2H), 7.39 (m, 2H), 3.56 (m, 8H) LC/MS (M+H)-(m/z)=421.21H NMR (400 MHz, DMSO) d 10.91 (s, 1H) 9.76 (s, 3H), 8.14 (s, 1H), 7.67 (m, 5H), 7.56 (m, 2H), 7.39 (m, 2H), 3.56 (m, 8H) LC/MS (M+H)-(m/z)=421.2 |
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화학식 14chemical formula 14 |
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3-[6-(1H-인돌-7-일)-1,3-벤조티아졸-2-일]-1-[2-(피페라진-1-일)에틸]우레아3-[6-(1H-indol-7-yl)-1,3-benzothiazol-2-yl]-1-[2-(piperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 10.73 (s, 1H), 9.83 (s, 3H), 8.12 (d, J=1.6Hz, 1H), 7.76 (m, 1H), 7.68 (m, 1H), 7.51 (m, 2H), 7.15 (d, J=6.0Hz, 1H), 7.01 (t, J=7.6Hz, 1H), 3.52 (m, 12H) LC/MS (M+H)-(m/z)=421.21H NMR (400 MHz, DMSO) d 10.73 (s, 1H), 9.83 (s, 3H), 8.12 (d, J=1.6Hz, 1H), 7.76 (m, 1H), 7.68 (m, 1H), 7.51 (m, 2H), 7.15 (d, J=6.0Hz, 1H), 7.01 (t, J=7.6Hz, 1H), 3.52 (m, 12H) LC/MS (M+H)-(m/z) =421.2 |
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화학식 15chemical formula 15 |
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3-[6-(1H-인돌-7-일)-1,3-벤조티아졸-2-일]-1-[2-(4-메틸피페라진-1-일)에틸]우레아3-[6-(1H-indol-7-yl)-1,3-benzothiazol-2-yl]-1-[2-(4-methylpiperazin-1-yl)ethyl]urea | 1H NMR (400 MHz, DMSO) d 11.04 (s, 1H), 8.14 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.63 (dd, J=8.4Hz, 1H), 7.56 (d, J=7.6Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.13 (m, 2H), 6.54 (m, 1H), 3.44 (m, 4H), 2.83 (s, 3H) LC/MS (M+H)-(m/z)=435.21H NMR (400 MHz, DMSO) d 11.04 (s, 1H), 8.14 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.63 (dd, J=8.4Hz, 1H), 7.56 (d , J=7.6Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.13 (m, 2H), 6.54 (m, 1H), 3.44 (m, 4H), 2.83 (s, 3H) LC/ MS (M+H)-(m/z)=435.2 |
이하에서는, 본 발명에 따른 화학식 1로 표시되는 벤조티아졸 화합물 또는 이의 약학적으로 허용 가능한 염의 Abl 키나제의 저해 활성 효과를 확인하는 실험을 수행하였다.Hereinafter, an experiment was conducted to confirm the inhibitory activity of the Abl kinase of the benzothiazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention.
실험예 1. Ba/F3-Bcr-Abl-T315I 세포 증식에 대한 억제활성 측정Experimental Example 1. Measurement of inhibitory activity against Ba/F3-Bcr-Abl-T315I cell proliferation
Ba/F3-Bcr-Abl-T315I 세포를 RPMI 배지(Biowest, Kansas City, MO, USA)에 10% FBS(Biowest, Kansas City, MO, USA), 1% 페니실린/스트렙토마이신(Gibco, Grand Island, NY, USA)을 넣은 후 5% CO2/37℃에서 배양하였다. Ba/F3-Bcr-Abl- T315I 세포를 웰(well)당 8 × 103개로 96 웰 플레이트에 분주 후 다양한 농도로 실험 화합물을 처리하였다. Ba/F3-Bcr-Abl-T315I Cells were placed in RPMI medium (Biowest, Kansas City, MO, USA) with 10% FBS (Biowest, Kansas City, MO, USA), 1% penicillin/streptomycin (Gibco, Grand Island, NY, USA) and then 5% Incubated at CO 2 /37°C. Ba/F3-Bcr-Abl- T315I cells were aliquoted in a 96-well plate at 8 × 10 3 per well, and the test compounds were treated at various concentrations.
화합물 처리 시에는 10 mM의 원료용액을 준비하였으며, 순차적으로 희석하여 첨가하였다 (최종농도 DMSO 0.1%). 세포 생존율을 측정하기 위하여 MTS 활성 검색법(CellTiter 96 Assay, Promega)을 사용하였다. 한 개의 웰(well) 당 20 ㎕ 염료를 넣고, 2시간 배양한 다음, 흡광도를 측정하였다. GloMax Discover Microplate Reader(Promega)를 사용해 490 nm 파장에서 판독하였으며, IC50값 및 CC50값은 GraphPad Prism 8.0 소프트웨어를 사용하여 계산하였다. 그 결과는 하기 표 4와 같다:In the case of compound treatment, a 10 mM raw material solution was prepared and added after sequential dilution (final concentration of DMSO 0.1%). In order to measure the cell viability, MTS activity assay (CellTiter 96 Assay, Promega) was used. 20 μl of dye was added per well, incubated for 2 hours, and then absorbance was measured. Readings were made at 490 nm wavelength using a GloMax Discover Microplate Reader (Promega), and IC 50 values and CC 50 values were calculated using GraphPad Prism 8.0 software. The results are shown in Table 4:
[표 4][Table 4]
상기 표 4의 결과에 의하면, 포나티닙(Ponatinib) 약물은 Ba/F3-Bcr-Abl-T315I 세포 증식을 강하게 억제함과 동시에 CHO-K1 및 Hep G2 세포에서도 강한 세포 독성을 보이므로 골수생성억제, 췌장염, 심혈관질환 등의 부작용이 유발될 수 있다.According to the results of Table 4, ponatinib (Ponatinib) drug Ba / F3-Bcr-Abl-T315I Since it strongly inhibits cell proliferation and also shows strong cytotoxicity in CHO-K1 and Hep G2 cells, side effects such as myelogenesis inhibition, pancreatitis, and cardiovascular disease may be induced.
그러나, 본 발명의 화합물들은 Ba/F3-Bcr-Abl-T315I 세포 증식을 억제하는 강한 억제활성을 가지며, 동시에 CHO-K1 및 Hep G2 세포에 대해서는 억제활성이 미약하므로 약물 내성 및 부작용이 없는 CML 치료약물로 유용하게 사용될 수 있다However, the compounds of the present invention are Ba/F3-Bcr-Abl-T315I It has a strong inhibitory activity to inhibit cell proliferation, and at the same time has weak inhibitory activity against CHO-K1 and Hep G2 cells, so it can be usefully used as a CML treatment drug without drug resistance and side effects.
실험예 2. 합성한 화합물의 BCR-ABL 활성 측정Experimental Example 2. Measurement of BCR-ABL activity of the synthesized compound
본 발명에 따른 화합물에 의한, 만성 골수성 백혈병 세포 증식에 필수적인 BCR-ABL 활성의 변화를 알아보기 위해 웨스턴 블럿(western blotting)을 시행하였다. Western blotting was performed to examine the change in BCR-ABL activity essential for chronic myeloid leukemia cell proliferation by the compound according to the present invention.
Ba/F3-Bcr-Abl-T315I 세포에 화학식 5 내지 7의 화합물을 각각 1μM 농도로 처리한 후 0, 5, 10, 20, 30, 60분 후에 세포를 각각 모아 단백질을 획득하였다. Western blotting 방법으로 BCR-ABL 단백질의 활성을 의미할 수 있는 phospho-BCR-ABL, phospho-AKT, phospho-STAT5 및 phosphor-ERK의 변화를 관찰하였고, 정상 혈구 세포에도 존재하는 BCR 단백질은 정상세포에 영향을 주지 않는다는 것을 보여주기 위해 대조군으로서 같이 확인하였다. Ba/F3-Bcr-Abl-T315I Cells were treated with the compounds of Formulas 5 to 7 at a concentration of 1 μM, respectively, and after 0, 5, 10, 20, 30, and 60 minutes, the cells were collected to obtain proteins. Changes in phospho-BCR-ABL, phospho-AKT, phospho-STAT5 and phosphor-ERK, which may indicate the activity of BCR-ABL protein, were observed by Western blotting. It was also confirmed as a control to show that there was no effect.
그 결과 화학식 5 내지 8의 화합물은 phospho-BCR-ABL, phospho-STAT5, phospho-AKT 및 phosphor-ERK의 단백질 발현양이 감소됨을 확인하였다. BCR 단백질의 발현량은 차이가 없는 것으로 보아 정상세포에서 발현하는 단백질에 영향을 미치지 않고 만성 골수성 백혈병에서 발현하는 단백질에만 감소를 유발하는 약물임을 확인하였다(도 1 참조).As a result, it was confirmed that the compounds of Formulas 5 to 8 decreased the protein expression levels of phospho-BCR-ABL, phospho-STAT5, phospho-AKT and phosphor-ERK. Since there was no difference in the expression level of the BCR protein, it was confirmed that the drug did not affect the protein expressed in normal cells and caused a decrease only in the protein expressed in chronic myeloid leukemia (see FIG. 1 ).
실험예 3. 마우스에서의 약물동력학 실험Experimental Example 3. Pharmacokinetic experiment in mice
본 발명의 화학식 8의 화합물을 ICR 마우스에 정맥내투여 및 경구투여를 하였을 때의 각각의 생체이용률을 측정하기 위하여 약물동력학(PK) 실험을 하였다. 각 분석은 LC-MS/MS 분석법으로 실시하였다.Pharmacokinetics (PK) experiments were performed to measure the bioavailability of the compound of Formula 8 of the present invention when administered intravenously and orally to ICR mice. Each analysis was performed by LC-MS/MS analysis.
수컷 6주령 마우스를 정맥내 투여군 및 경구투여군으로 나누어, 각 군당 3마리씩 배정하였다. 정맥투여 군은 5분, 10분, 15분, 30분, 1, 2, 4시간의 총 7회에 걸쳐 채혈하였고, 경구투여 군은 0.25, 0.5, 1, 2, 3, 4, 8시간의 총 7회에 걸쳐 채혈하였다.Male 6-week-old mice were divided into an intravenous administration group and an oral administration group, and three mice were assigned to each group. In the intravenous administration group, blood was collected over a total of 7 times, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1, 2, and 4 hours, and in the oral administration group, 0.25, 0.5, 1, 2, 3, 4, and 8 hours. Blood was drawn a total of 7 times.
채혈된 혈액은 헤파린이 처리된 (5 IU/mL) 튜브에 담아 잘 섞어주고, 채혈 후 혈액은 4℃ 5,000 rpm에서 10분간 원심 분리하여 혈장을 분리한 후, 분리된 혈장을 동물번호 및 채혈시간이 표시된 튜브에 약 30~40μL/tube씩 분주하여 담아, 초저온 냉동고(약 -8℃)에 보관하였다.The collected blood is put in a heparin-treated (5 IU/mL) tube and mixed well. After blood collection, the blood is centrifuged at 5,000 rpm at 4°C for 10 minutes to separate plasma, and the separated plasma is collected by animal number and blood collection time. About 30-40 μL/tube was aliquoted into the marked tube, and stored in a cryogenic freezer (about -8°C).
각 군의 구성은 하기 표 5와 같다.The composition of each group is shown in Table 5 below.
| 시험군test group | 처리물질material to be treated | 부형제excipient | 투여 경로route of administration |
투여 용량Dosage
(mg/kg)(mg/kg) |
투여량Dosage
(mL/kg)(mL/kg) |
군당military party
마리수Marisu |
| G1G1 |
8번 화합물number 8 compound |
DMSO : saline = 5 : 95DMSO:saline= 5:95 |
IVIV | 1One | 55 | 33 |
|
G2 | POPO | 1010 | 1010 | 33 |
분석 결과는 하기 표 6과 같다:The analysis results are shown in Table 6:
[표 6][Table 6]
분석 결과, 본 발명에 따른 화학식 8의 화합물은 경구 투여시의 생체이용률이 62.7%로서 상당히 양호함을 알 수 있다.As a result of the analysis, it can be seen that the compound of Formula 8 according to the present invention has a fairly good bioavailability of 62.7% when administered orally.
실험예 4. Ba/F3-Bcr-Abl-T315I 세포 마우스 모델에서 종양억제 확인Experimental Example 4. Confirmation of tumor suppression in Ba/F3-Bcr-Abl-T315I cell mouse model
본 발명의 화학식 5 및 8의 화합물을 Ba/F3-Bcr-Abl-T315I 세포를 이용하여 마우스 모델을 만든 후에 15일간 복강 또는 경구 투여하여 종양 생성 억제 여부를 동물 수준에서 확인하였다.After making a mouse model using Ba/F3-Bcr-Abl-T315I cells, the compounds of Formulas 5 and 8 of the present invention were administered intraperitoneally or orally for 15 days to determine whether tumor formation was inhibited at the animal level.
구체적으로, 누드 마우스(6 주령) 반입 후 일주일의 적응기를 거친 후 Ba/F3-Bcr-Abl-T315I 세포(1 × 107)를 피하로 투여하여 동물 이종이식 모델을 만들었다. 일주일에 거쳐 종양 크기가 80 mm3 정도 되었을 때, 대조군(DMSO:PEG 400:Saline=5:50:45), Imatinib(양성대조물질), 화학식 5의 화합물(100 mg/kg(이하 mpk로 표기) 경구투여, 25mpk 복강투여) 및 화학식 8의 화합물(50 mpk 경구투여, 30 mpk 복강투여)의 투여 그룹으로 나누어, 각 군 당 5마리씩 배정하고, 각 물질을 매일 복강주사(intraperitoneal injection) 또는 경구투여(oral administration)로 15일간 투여하였다. 일주일에 2번 버니아 캘리퍼스를 이용하여 종양의 크기(장축, 단축, 두께)를 측정하였고, 체중은 일주일에 1번 측정하였다. 실험 종료일에 종양을 적출하여 군 간의 무게를 비교하였다.Specifically, an animal xenograft model was created by subcutaneously administering Ba/F3-Bcr-Abl-T315I cells (1 × 10 7 ) after a week of adaptation to nude mice (6 weeks old). After one week, when the tumor size reached about 80 mm 3 ) Oral administration, 25 mpk intraperitoneal administration) and the compound of Formula 8 (50 mpk oral administration, 30 mpk intraperitoneal administration) were divided into administration groups, and 5 animals were assigned to each group, and each substance was administered daily by intraperitoneal injection or oral administration. It was administered for 15 days by oral administration. Tumor size (long axis, short axis, thickness) was measured using a vernia caliper twice a week, and body weight was measured once a week. On the end of the experiment, tumors were removed and weights were compared between groups.
도 2 내지 도 5에 나타낸 바와 같이, 15일간 화학식 5 및 8의 화합물을 복강 또는 경구 투여한 경우, 종양 크기(부피) 및 종양 무게가 대조군에 비해 통계적으로 유의하게 감소하여 항암 효능을 보이고 있었다.2 to 5, when the compounds of Formulas 5 and 8 were administered intraperitoneally or orally for 15 days, the tumor size (volume) and tumor weight were statistically significantly reduced compared to the control group, thereby showing anticancer efficacy.
본 발명에 따른 화합물은 항암제로서 유용하게 사용될 수 있다.The compound according to the present invention can be usefully used as an anticancer agent.
Claims (9)
- 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염:A compound of Formula 1 or a pharmaceutically acceptable salt thereof:[화학식 1][Formula 1]
상기 식에서,In the above formula,R1은 탄소수 1 내지 6의 알킬옥시 또는 수소이고,R 1 is alkyloxy having 1 to 6 carbon atoms or hydrogen,R3 및 R4는 수소이고, R2는 수소, 할로겐, 할로알킬 또는 탄소수 1 내지 6의 직쇄, 환 또는 분지쇄의 알킬기이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 6 carbon atoms,R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 5원 또는 6원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 5원 또는 6원 헤테로사이클릭 고리를 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring,R5는 아미노, 치환 또는 비치환된 탄소수 1 내지 6의 알킬아민 또는 이미다졸이다.R 5 is amino, substituted or unsubstituted alkylamine having 1 to 6 carbon atoms, or imidazole. - 제 1 항에 있어서,The method of claim 1,R1은 탄소수 1 내지 4의 알킬옥시 또는 수소이고,R 1 is alkyloxy having 1 to 4 carbon atoms or hydrogen,R3 및 R4는 수소이고, R2는 수소, 할로겐, 할로알킬 또는 탄소수 1 내지 4의 직쇄, 환 또는 분지쇄의 알킬기이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, halogen, haloalkyl, or a linear, cyclic or branched alkyl group having 1 to 4 carbon atoms,R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 N, O 및 S로부터 선택된 1개 또는 2개의 헤테로 원자를 포함하는 5원 또는 6원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 N, O 및 S로부터 선택된 1개 또는 2개의 헤테로 원자를 포함하는 5원 또는 6원 헤테로사이클릭 고리를 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5 or 6 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;R5는 N, O 및 S로부터 선택된 1개 또는 2개의 헤테로 원자를 포함하는 헤테로사이클로 치환되거나 또는 비치환된 탄소수 1 내지 6개의 알킬아민 또는 이미다졸인 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염.R 5 is an unsubstituted or substituted heterocycle containing 1 or 2 heteroatoms selected from N, O and S, an alkylamine having 1 to 6 carbon atoms, or imidazole, a compound of Formula 1 or a pharmaceutically acceptable compound thereof salt.
- 제 1 항에 있어서,The method of claim 1,R1은 메틸옥시, 에틸옥시 또는 수소이고,R 1 is methyloxy, ethyloxy or hydrogen,R3 및 R4는 수소이고, R2는 수소, 플루오로, 클로로, 브롬, 트리플루오로메틸, 메틸, 에틸, 프로필 또는 사이클로프로필이거나,R 3 and R 4 are hydrogen and R 2 is hydrogen, fluoro, chloro, bromine, trifluoromethyl, methyl, ethyl, propyl or cyclopropyl;R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 N 원자를 포함하는 5원 헤테로사이클릭 고리를 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form a 5-membered heterocyclic ring comprising an N atom,R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 N 원자를 포함하는 5원 헤테로사이클릭 고리를 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form a 5-membered heterocyclic ring comprising N atoms,R5는 1개 또는 2개의 N 원자를 포함하는 헤테로사이클로 치환된 탄소수 1 내지 4개의 알킬아민 또는 이미다졸인 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염.R 5 is an alkylamine or imidazole having 1 to 4 carbon atoms substituted with a heterocycle containing 1 or 2 N atoms, or a pharmaceutically acceptable salt thereof.
- 제 1 항에 있어서,The method of claim 1,R1은 메틸옥시, 에틸옥시 또는 수소이고,R 1 is methyloxy, ethyloxy or hydrogen,R3 및 R4는 수소이고, R2는 수소, 플루오로, 클로로, 메틸 또는 에틸이거나,R 3 and R 4 are hydrogen, R 2 is hydrogen, fluoro, chloro, methyl or ethyl,R3는 수소이고, R2 및 R4는 이들이 부착된 원자와 함께 피롤을 형성하거나,R 3 is hydrogen and R 2 and R 4 together with the atoms to which they are attached form pyrrole,R4는 수소이고, R2 및 R3는 이들이 부착된 원자와 함께 피롤을 형성하며,R 4 is hydrogen, R 2 and R 3 together with the atoms to which they are attached form pyrrole,R5는 하기 화학식 2 내지 4로 나타낸 치환기 중 어느 하나인 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염:R 5 is any one of the substituents represented by the following formulas 2 to 4 of the compound of Formula 1 or a pharmaceutically acceptable salt thereof:[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
상기식에서, R6은 탄소수 1 내지 6의 알킬기 또는 탄소수 1 내지 6의 알킬옥시이다.In the above formula, R 6 is an alkyl group having 1 to 6 carbon atoms or alkyloxy having 1 to 6 carbon atoms. - 제 1 항에 있어서, 하기 화학식 5 내지 15 및 화학식 24의 화합물 중 어느 하나인 화합물 또는 이의 약학적으로 허용 가능한 염:The compound according to claim 1, which is any one of the compounds of Formulas 5 to 15 and Formula 24, or a pharmaceutically acceptable salt thereof:[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
[화학식 8][Formula 8]
[화학식 9][Formula 9]
[화학식 10][Formula 10]
[화학식 11][Formula 11]
[화학식 12][Formula 12]
[화학식 13][Formula 13]
[화학식 14][Formula 14]
[화학식 15][Formula 15]
[화학식 24][Formula 24]
- 제1항 내지 제5항 중 어느 한 항에 따른 화합물을 포함하는 Abl 키나제 저해용 의약 조성물.A pharmaceutical composition for inhibiting Abl kinase comprising the compound according to any one of claims 1 to 5.
- 제1항 내지 제5항 중 어느 한 항에 따른 화합물을 포함하는 암 치료용 조성물.A composition for treating cancer comprising the compound according to any one of claims 1 to 5.
- 제7항에 있어서, 상기 암은 백혈병 또는 고형암인 것을 특징으로 하는 암 치료용 조성물.The composition for treating cancer according to claim 7, wherein the cancer is leukemia or solid cancer.
- 제1항 내지 제5항 중 어느 한 항에 따른 화합물을 포함하는 백혈병 치료용 항암제로서, 이미 투약 중인 타 백혈병 치료제에 대하여 내성이 발생한 환자에게 투여되는 것을 특징으로 하는 백혈병 치료용 조성물.An anticancer agent for the treatment of leukemia comprising the compound according to any one of claims 1 to 5, wherein the composition for treatment of leukemia is administered to a patient who has developed resistance to other leukemia therapeutic agents already being administered.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030153568A1 (en) * | 2000-02-07 | 2003-08-14 | Basf Aktiengesellschaft Ludwigshafen, Germany | Benzothiazole derivatives |
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2021
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20030153568A1 (en) * | 2000-02-07 | 2003-08-14 | Basf Aktiengesellschaft Ludwigshafen, Germany | Benzothiazole derivatives |
Non-Patent Citations (4)
| Title |
|---|
| HONG SEUNGHEE, KIM JINHEE, YUN SUN-MI, LEE HYUNSEUNG, PARK YOONSU, HONG SOON-SUN, HONG SUNGWOO: "Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 56, no. 9, 9 May 2013 (2013-05-09), US, pages 3531 - 3545, XP055855402, ISSN: 0022-2623, DOI: 10.1021/jm301891t * |
| LIN WEI-CONG, TAN SHE-PEI, ZHOU SHENG-FU, ZHENG XIAO-JIE, WU WEN-JUAN, ZHENG KANG-CHENG: "Binding Mechanism and Molecular Design of Benzimidazole/Benzothiazole Derivatives as Potent Abl T315I Mutant Inhibitors", HUAXUE-WULI-XUEBAO = CHINESE JOURNAL OF CHEMICAL PHYSICS, vol. 30, no. 4, 27 August 2017 (2017-08-27), pages 429 - 442, XP055855496, ISSN: 1674-0068, DOI: 10.1063/1674-0068/30/cjcp1704066 * |
| PARK HWANGSEO, HONG SEUNGHEE, KIM JINHEE, HONG SUNGWOO: "Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 135, no. 22, 5 June 2013 (2013-06-05), pages 8227 - 8237, XP055855497, ISSN: 0002-7863, DOI: 10.1021/ja311756u * |
| YUN SUN-MI; JUNG KYUNG HEE; KIM SOO JUNG; FANG ZHENGHUAN; SON MI KWON; YAN HONG HUA; LEE HYUNSEUNG; KIM JINHEE; SHIN SANGHYE; HONG: "HS-438, a new inhibitor of Imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia", CANCER LETTERS, NEW YORK, NY, US, vol. 348, no. 1, 18 March 2014 (2014-03-18), US, pages 50 - 60, XP028664384, ISSN: 0304-3835, DOI: 10.1016/j.canlet.2014.03.012 * |
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