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WO2016006921A1 - Agent thérapeutique ciblant la leucémie myéloîde aiguë ayant des effets secondaires médicamenteux réduits - Google Patents

Agent thérapeutique ciblant la leucémie myéloîde aiguë ayant des effets secondaires médicamenteux réduits Download PDF

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Publication number
WO2016006921A1
WO2016006921A1 PCT/KR2015/007030 KR2015007030W WO2016006921A1 WO 2016006921 A1 WO2016006921 A1 WO 2016006921A1 KR 2015007030 W KR2015007030 W KR 2015007030W WO 2016006921 A1 WO2016006921 A1 WO 2016006921A1
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Prior art keywords
thieno
amino
pyrimidin
group
phenyl
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English (en)
Korean (ko)
Inventor
심태보
윤호종
허우영
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Korea Institute of Science and Technology KIST
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Korea Institute of Science and Technology KIST
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to acute myeloid leukemia targeted therapy with reduced drug side effects.
  • AML Acute myeloid leukemia
  • Fms-like tyrosine receptor kianse-3 FLT3
  • FLT3-ITD FLT3-ITD
  • FAK Fecal adhesion kinase
  • Patent Document 1 Korean Patent Publication No. 1,147,550
  • Patent Document 1 the 2,7-substituted thieno [3,2- d ] pyrimidine compound is ALK, Aurora A, EphA1, FAK, FLT3, Fms, Itk, KDR, Kit, Met, Ret, Src. It has been shown to inhibit the activity of various protein kinases of Syk, Tie2, and TrkB, and has been described as useful for the prevention and treatment of various tumor diseases.
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • the present inventors selected compounds having inhibitory activity against FLT3 point mutations in addition to the activity of inhibiting the proliferation of Molm14, an acute myeloid leukemia cell line, and confirmed through in vivo experiments that the selected compounds do not exhibit drug toxicity.
  • the present invention has been completed.
  • an object of the present invention is to provide a pharmaceutical composition useful for the treatment, prevention and alleviation of acute myeloid leukemia, which has an inhibitory activity against acute myeloid leukemia and an inhibitory activity against FLT3 point mutation.
  • the present invention is a drug containing a 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by the following formula (1) or a pharmaceutically acceptable salt as an active ingredient
  • a drug containing a 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by the following formula (1) or a pharmaceutically acceptable salt as an active ingredient Provided are pharmaceutical compositions for the treatment, prevention and alleviation of acute myeloid leukemia with reduced side effects.
  • X 1 is a nitrogen atom; Or -CH-R 3 , wherein R 3 is a hydrogen atom, a C 1 C 6 alkoxy group or a morpholino group,
  • X 2 represents a nitrogen atom
  • R 1 is a C 1 C 6 alkoxy group; Or a pentagonal or hexagonal heterocyclic group containing 1 to 2 heteroatoms selected from N and O, or a -C (O) -heterocyclic group, wherein the heterocyclic group is C 1 C 6 alkyl, piperidinyl and 1 -(C 1 C 6 alkyl) can be substituted or unsubstituted with a substituent selected from the group consisting of piperidinyl),
  • R 2 is a nitro group, a C 1 C 6 haloalkyl group, a C 1 C 6 alkoxy group, —NR 4 R 5 wherein R 4 and R 5 are the same as or different from each other and are a hydrogen atom, a C 1 C 6 alkyl group, C 1 C 6 is an alkylsulfonyl group), -COOR 6 , where R 6 is a hydrogen atom or a C 1 C 6 alkyl group, -CONR 7 R 8 , wherein R 7 and R 8 are the same or different and are hydrogen or C 1 C 6 alkyl group), or-(CH 2 ) k -OR 9, wherein k is an integer of 1 to 6 and R 9 is a hydrogen atom or a C 1 C 6 alkylcarbonyl group;
  • n is an integer from 1 to 5 substituents is substituted as the number of R 2.
  • the pharmaceutical composition of the present invention has a proliferative inhibitory activity against Molm14, an acute leukemia cell, and has a inhibitory activity against a gatekeeper mutant, D835 mutant, and ITD mutant, as a FLT3 point mutation.
  • the effect of treating, preventing and mitigating is excellent.
  • the pharmaceutical composition of the present invention has a very low drug toxicity, so that high doses can be administered, and thus the disease treatment effect is excellent.
  • the pharmaceutical composition of the present invention has an excellent effect of treating, preventing or alleviating acute myeloid leukemia while significantly reducing drug side effects.
  • the present invention is acute myeloid leukemia with reduced side effects of drugs containing 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by the following formula (1) or a pharmaceutically acceptable salt as an active ingredient
  • a pharmaceutical composition for treatment, prevention and alleviation is administered to patients containing 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by the following formula (1) or a pharmaceutically acceptable salt as an active ingredient
  • a pharmaceutical composition for treatment, prevention and alleviation is administered to reduce side effects of drugs containing 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by the following formula (1) or a pharmaceutically acceptable salt as an active ingredient
  • X 1 is a nitrogen atom; Or -CH-R 3 , wherein R 3 is a hydrogen atom, a C 1 C 6 alkoxy group or a morpholino group,
  • X 2 represents a nitrogen atom
  • R 1 is a C 1 C 6 alkoxy group; Or a pentagonal or hexagonal heterocyclic group containing 1 to 2 heteroatoms selected from N and O, or a -C (O) -heterocyclic group, wherein the heterocyclic group is C 1 C 6 alkyl, piperidinyl and 1 -(C 1 C 6 alkyl) can be substituted or unsubstituted with a substituent selected from the group consisting of piperidinyl),
  • R 2 is a nitro group, a C 1 C 6 haloalkyl group, a C 1 C 6 alkoxy group, —NR 4 R 5 wherein R 4 and R 5 are the same as or different from each other and are a hydrogen atom, a C 1 C 6 alkyl group, C 1 C 6 is an alkylsulfonyl group), -COOR 6 , where R 6 is a hydrogen atom or a C 1 C 6 alkyl group, -CONR 7 R 8 , wherein R 7 and R 8 are the same or different and are hydrogen or C 1 C 6 alkyl group), or-(CH 2 ) k -OR 9, wherein k is an integer of 1 to 6 and R 9 is a hydrogen atom or a C 1 C 6 alkylcarbonyl group;
  • n is an integer from 1 to 5 substituents is substituted as the number of R 2.
  • alkyl group' includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups are methyl, ethyl, normal propyl, isopropyl, cyclopropyl and normal butyl groups. , Isobutyl group, tert -butyl group, normal hexyl group, cyclohexyl group and the like.
  • Alkoxy group means an alkyl group of carbon connected to oxygen, wherein alkyl is as defined above.
  • a "haloalkyl group” includes 1 to 13 halogen atoms such as fluoro, chloro, bromo and iodo, and includes both linear and pulverized carbon chains having 1 to 6 carbon atoms, and the preferred haloalkyl group is fluorine. Chloromethyl group, trifluoromethyl group, 1,2-dichloroethyl group, 1,1-dichloroethyl group, pentafluoroethyl group and the like.
  • Heterocyclic group is a cycloalkyl group composed of 1 to 3 heteroatoms and carbon atoms composed of N and O, and includes piperidinyl, piperazinyl, morpholino, pyrrolidinyl, pyrazolidinyl, triazolidinyl, and the like. have.
  • X 1 is -CH-R 3 (wherein R 3 is a hydrogen atom, a C 1 C 6 alkoxy group or a morpholino group) );
  • X 2 represents a nitrogen atom;
  • R 1 is a morpholino group, 4- (C 1 C 6 alkyl) piperazinyl group, 1- (C 1 C 6 alkylpiperidin-4-yl) piperazinyl group, or -C (O)- Morpholino group;
  • R 2 is a nitro group, a C 1 C 6 haloalkyl group, a C 1 C 6 alkoxy group, -NR 4 R 5 (wherein R 4 and R 5 are the same as or different from each other, a hydrogen atom, a C 1 C 6 alkyl group, C 1 C 6 alkylsulfonyl group), -COOR 6 (wherein R 6 is a hydrogen atom or a C 1 C 6 alky
  • X 1 represents —CH—R 3 , wherein R 3 represents a C 1 C 6 alkoxy group; X 2 represents a nitrogen atom; R 1 represents a (C 1 C 6 alkyl) piperazinyl group; R 2 represents —NR 4 R 5 wherein R 4 and R 5 are the same as or different from each other and are a hydrogen atom, a C 1 C 6 alkyl group, a C 1 C 6 alkylsulfonyl group; N is a compound which shows the integer of 1-3 as a substitution number of substituent R ⁇ 2> .
  • the compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art.
  • non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfate, phosphoric acid, nitric acid, or propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfonic acid Together with non-toxic organic acids, salts of these pharmaceutically acceptable acids can be formed.
  • Scheme 1 below illustrates one embodiment of a typical method for preparing a 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by Chemical Formula 1.
  • the chloro compound represented by the following Chemical Formula 2 and the amine compound represented by the following Chemical Formula 4 are used as raw materials, and the above-described object of the present invention is achieved through a buckwald amination reaction using an organometallic compound.
  • Pd 2 (dba) 3 , Pd (OAc) 2 , PdCl 2 (PPh 3 ) 2 , Pd (PPh 3 ) 4, etc. may be used as the metal compound.
  • a ligand Xantphos (Cas number: 161265-03-8), Davephos (Cas number: 213697-53-1), Johnphos (Cas number: 224311-51-7), X-phos (Cas number: 564483-18-7 ), tert-Butyl Xphos (Cas 564483-19-8) and the like can be used.
  • reaction solvent a conventional organic solvent containing tetrahydrofuran, dioxane, N, N -dimethylformamide, N, N -dimethylsulfoxide, 2-butanol, 2-pentanol and the like can be used.
  • the reaction temperature is in the range from 50 to 200, preferably from 80 to 150.
  • the pharmaceutical composition according to the present invention has excellent proliferation inhibitory activity against acute leukemia cell Molm14.
  • various protein kinases such as ACK1, ALK, ARK5 / NUAK1, CAMK1d, CK2a, CLK1, DAPK1, DRAK1 / STK17A, DYPK1 / DYRK1A, FAK / PK2, FER, FES / FPS, FLT3, HIPK4, IGF1R, IR , IRR / INSRR, JAK2, LRRK2, MELK, MLCK / MYLK, MLK1 / MAP3K9, NEK1, PHKg1, PKCmu / PRKD1, PKN1 / PRK1, PLK1, PYK2, ROS / ROS1, RSK3, SIK2, STK16, TNK1, TNK1, Excellent inhibitory activity against, ULK1, ZIPK / DAPK3.
  • the pharmaceutical composition according to the present invention exhibits inhibitory activity against gatekeeper mutants, D835 mutants, and ITD mutants as FLT3 point mutations, and has low drug toxicity, thereby allowing targeted treatment of acute myeloid leukemia without drug side effects.
  • the pharmaceutical composition of the present invention contains a 2,7-substituted thieno [3,2- d ] pyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, solvate thereof, or a hydrate thereof as an active ingredient.
  • a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, etc. to this, oral administration such as tablets, capsules, troches, solutions, suspensions or the like in the pharmaceutical field, or It may be formulated into a parenteral preparation.
  • Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like.
  • lactose dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • the dosage of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. 0.01 to 1,000 mg / day, may be divided into once or several times a day at regular intervals, depending on the judgment of the doctor or pharmacist.
  • the compound of Example 1 was prepared through a 5-step synthesis process as follows.
  • 2,6-dichloro-3-nitropyridine (100 mg, 0.52 mmol) was dissolved in tetrahydrofuran (2 mL), followed by methanol (0.02 mL, 0.52 mmol) and sodium hydride (31 mg, 0.78 mmol, 60 % dispersion in mineral oil) was added. After stirring for 1 hour at room temperature, ethyl acetate was added and diluted, and the reaction was terminated with water. The organic layer was washed several times with water / salt, dried over magnesium sulfate, passed through a pad of celite, and concentrated after filtration.
  • Step 2 4- (6-methoxy-5-nitropyridin-2-yl) morpholine
  • Step 4 ethyl 4- (2-chlorothieno [3,2- d ] pyrimidin-7-yl) benzoate
  • Step 5 Ethyl 4- (2-((2-methoxy-6-morpholinopyridin-3-yl) amino) thieno [3,2- d ] pyrimidin-7-yl) benzoate
  • Example 5 4- (2 - ((2-methoxy-6-morpholinophenyl-3-yl) amino) thieno [3,2 -d] pyrimidin-7-yl) - N- (3 , 4,5-trimethoxyphenyl) benzamide
  • Example 7 4- (2-((2-methoxy-6-morpholinopyridin-3-yl) amino) thieno [3,2- d ] pyrimidin-7-yl) benzyl acetate
  • the compound of Example 12 was prepared through a five step synthesis process as follows.
  • Step 1 N- (3- (2-chlorothieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide
  • Step 2 N- (3- (2-chlorothieno [3,2- d ] pyrimidin-7-yl) phenyl) -N- methylmethanesulfonamide
  • N- (3- (2-chlorothieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide 212 mg, 0.624 mmol
  • dimethylformamide 3 mL
  • Sodium hydride 38 mg, 60% dispersion in mineral oil, 0.936 mmol
  • methyl iodide 0.05 mL, 0.749 mmol
  • water was slowly added dropwise to terminate the reaction.
  • Step 4 6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-amine
  • Step 5 N- Methyl- N- (3- (2-((6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-yl) amino) thier No [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide
  • the compound of Example 14 was prepared through a three step synthesis process as follows.
  • Step 2 6- (4-ethylpiperazin-1-yl) -2-methoxypyridin-3-amine
  • Step 3 N- (3- (2-((6- (4-ethylpiperazin-1-yl) -2-methoxypyridin-3-yl) amino) thieno [3,2- d ] pyrimidine -7-yl) phenyl) -N- methylmethanesulfonamide
  • the compound of Example 17 was prepared through a three step synthesis process as follows.
  • Step 1 1- (6-methoxy-5-nitropyridin-2-yl) -4- (1-methylpiperidin-4-yl) piperazine
  • Step 2 2-methoxy-6- (4- (1-methylpiperidin-1-yl) piperazin-1-yl) pyridin-3-amine
  • Step 3 N- (3- (2-((2-methoxy-6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-yl) amino) Thieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide
  • Example 18 The compound of Example 18 was prepared through the four steps of synthesis as follows.
  • Step 2 4- (6-isopropoxy-5-nitropyridin-2-yl) morpholine
  • Step 4 N- (3- (2-((2-isopropoxy-6-morpholinopyridin-3-yl) amino) thieno [3,2- d ] pyrimidin-7-yl) phenyl) Methanesulfonamide
  • the compound of Example 19 was prepared through a three step synthesis process as follows.
  • Step 2 6- (4-ethylpiperazin-1-yl) -2-isopropoxypyridin-3-amine
  • Step 3 N- (3- (2-((6- (4-ethylpiperazin-1-yl) -2-isopropoxypyridin-3-yl) amino) thieno [3,2- d ] pyridine Midin-7-yl) phenyl) methanesulfonamide
  • the compound of Example 20 was prepared through a three step synthesis process as follows.
  • Step 1 1- (6-isopropoxy-5-nitropyridin-2-yl) -4- (1-methylpiperidin-4-yl) piperazine
  • Step 2 2-isopropoxy-6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-amine
  • Step 3 N- (3- (2-((2-isopropoxy-6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-yl) amino ) Thieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide
  • the compound of Example 21 was prepared through a two step synthesis process as follows.
  • Step 2 N- (3- (2-((2-methoxy-4- (morpholin-4-carbonyl) phenyl) amino) thieno [3,2- d ] pyrimidin-7-yl) phenyl Methanesulfonamide
  • the compound of Example 22 was prepared through the four steps of synthesis as follows.
  • Step 2 4- (6-methoxy-3-nitropyridin-2-yl) morpholine
  • Step 4 N- (3- (2-((6-methoxy-2-morpholinopyridin-3-yl) amino) thieno [3,2- d ] pyrimidin-7-yl) phenyl) methane Sulfonamide
  • novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.
  • EDTA ethylenediamine tetraacetic acid
  • lance detection buffer 5 ⁇ L of ethylenediamine tetraacetic acid (EDTA, final concentration of 40 mM) diluted in the lance detection buffer was added and allowed to stand at room temperature for 5 minutes to stop the reaction, again diluted with 4X Eu-anti- 5 ⁇ L of a selective phosphorylated antibody of phospho-Tyr (PT66) was added to a final concentration of 1 uM and allowed to react at room temperature for 60 minutes.
  • the signal was measured with an EnVision multilabel reader after adjusting to detect the energy transfer (TR-FRET) of fluorescence reflection over time at a stimulus wavelength of 320 nm and an emission wavelength of 665 nm.
  • TR-FRET energy transfer
  • Table 1 shows N- (3- (2-((6- (4-ethylpiperazin-1-yl) -2-methoxypyridin-3-yl) amino) thieno [3,2- d ] pyridine This is a list of kinases that show at least 80% inhibition when the sample is treated with midin-7-yl) phenyl) methanesulfonamide (Example 16 compound) at a concentration of 1 uM.
  • the GI 50 values calculated by measuring the proliferation inhibitory ability of the acute leukemia cell line Molm14 (FLT3-ITD mt / FLT3-wt overexpressing cells) with respect to the compounds synthesized in Examples 1 to 23 are shown in Table 2 below.

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Abstract

Cette invention concerne un agent thérapeutique ciblant la leucémie myéloïde aiguë ayant des effets secondaires médicamenteux réduits, et qui est utile pour traiter, prévenir et soulager la leucémie myéloïde aiguë grâce à son activité inhibitrice contre la leucémie myéloïde aiguë et à son activité inhibitrice contre les espèces portant une mutation ponctuelle FLT3.
PCT/KR2015/007030 2014-07-07 2015-07-07 Agent thérapeutique ciblant la leucémie myéloîde aiguë ayant des effets secondaires médicamenteux réduits Ceased WO2016006921A1 (fr)

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