WO2015160192A1 - Composition pharmaceutique permettant de traiter et de prévenir la leucémie, contenant un dérivé de thiénopyrimidine ou un sel pharmaceutiquement acceptable de celui-ci - Google Patents

Composition pharmaceutique permettant de traiter et de prévenir la leucémie, contenant un dérivé de thiénopyrimidine ou un sel pharmaceutiquement acceptable de celui-ci Download PDF

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WO2015160192A1
WO2015160192A1 PCT/KR2015/003807 KR2015003807W WO2015160192A1 WO 2015160192 A1 WO2015160192 A1 WO 2015160192A1 KR 2015003807 W KR2015003807 W KR 2015003807W WO 2015160192 A1 WO2015160192 A1 WO 2015160192A1
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alkyl
alkynyl
alkenyl
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unsubstituted
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Korean (ko)
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한균희
양지선
이철호
박준호
천광우
조보영
김현재
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Industry Academic Cooperation Foundation of Yonsei University
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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • the present disclosure relates to a pharmaceutical composition for treating and preventing leukemia, including thienopyrimidine derivatives or pharmaceutically acceptable salts thereof.
  • FLT3 Receptor tyrosine kinase 3
  • FLT3 is one of the receptor III tyrosine kinase families, including PDGFR, KIT and FMS.
  • FLT3 is commonly expressed in hematopoietic progenitor cells by hematopoietic stem cells and plays an important role in the expression of conventional stem cells and the immune system.
  • Abnormal overexpression and mutations of FLT3 are often observed in leukemia patients.
  • various mutations such as D835V, D835Y and internal tandem duplication (ITD) of FLT3 have been observed in acute myeloid leukemia (AML).
  • AML Acute myeloid leukemia
  • AML cells cause molecular defects, such as leukocyte proliferation, abnormalities of differentiation, and resistance to cell death. If the level of transcription of FLT3 is elevated in AML, this affects the phosphorylation of FLT3. Phosphorylation and activation of the FLT3 receptor activates downstream kinase pathways such as Ras / Mitogen-activated protein kinase (MAPK), which leads to abnormal cell growth and gene regulation.
  • MAPK mitogen-activated protein kinase
  • FLT3 has recently been considered as one of the most important targets from the therapeutic perspective of AML, and various studies on abnormal symptoms associated with FMS-like tyrosine kinase 3 (FLT3), RAS, and p53 genes for the treatment of AML. Is going on.
  • FLT3 TKD FLT3 TKD
  • Point mutations at residues of aspartate 835 (D835) replaced by various amino acids are one of the most common but less frequent than ITD mutations.
  • another major activity of FLT3 in AML is overexpression of wild type FLT3 protein. Overexpression of wt-FLT3 protein is relatively less frequent in AML cases, but even when FLT3 / ITD has not occurred, the overexpression has been found to act as an unfavorable prognostic factor.
  • FLT3 activation mutations are the most common mutations in AML, so inhibition of FLT3 is a major therapeutic target in AML.
  • FLT3 / ITD has been found to be a negative prognostic factor, and FLT3 / ITD is a key target in the treatment of AML.
  • Sorafenib (BAY-43-9006) [16], lestaurtinib (CEP-701) [17], sunitinib (SU11248) and tandutinib (MLN518) have been developed as first generation FLT3 inhibitors. Since they are not developed or optimized, they have the inhibitory activity of not only FLT3 but also many other kinases, and as a result, these compounds are very likely to cause side effects in AML treatment. Accordingly, quizartinib (AC220) was designed as an inhibitor of second generation FLT3. These inhibitors effectively inhibited FLT in the in vivo and cellular experiments of FLT3-ITD AML and were also active in clinical trials.
  • the thienopyrimidine derivative compounds of the present invention are not only effective in inhibiting inflammation and inhibiting cancer, but also provide thienopyrimidine derivatives as therapeutic agents targeted for the treatment and prevention of leukemia, particularly AML.
  • the thienopyrimidine derivatives of the present invention selectively exhibit excellent inhibitory activity against FLT3. Therefore, the thienopyrimidine compounds of the present invention, unlike the conventional FLT3 inhibitors, do not participate in other kinase pathways except for the FLT3 kinase pathway, and therefore, will have a very good therapeutic effect on AML caused by FLT3 / ITD mutation. It is predicted.
  • the conventional thienopyrimidine derivatives inhibit the activity of I ⁇ B kinase- ⁇ (IKK ⁇ or IKK-2), thereby inhibiting the activity of nuclear factor kappa B (NF- ⁇ B), and NF- ⁇ B It has been found that it can be used for the prevention and treatment of diseases associated with activity, in particular for the treatment of inflammatory diseases such as rheumatoid and cancer, but the therapeutic effect on leukemia, in particular AML is not known.
  • the present invention provides a pharmaceutical composition comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof, which is excellent in FLT3 inhibitory activity, for the treatment and prevention of acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • One embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof having excellent therapeutic and prophylactic effects on leukemia, including myeloid leukemia (AML).
  • AML myeloid leukemia
  • a pharmaceutical composition comprising a thienopyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof has not only good anticancer activity but also has excellent therapeutic and prophylactic effects against leukemia, especially acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the present invention comprises a pharmaceutical composition for preventing or treating leukemia, comprising thienopyrimidine derivatives or pharmaceutically acceptable salts thereof having excellent therapeutic and prophylactic effects on myeloid leukemia (AML). More specifically, the thienopyrimidine derivative is a thieno [2,3-d] pyrimidine derivative and is represented by the following Chemical Formula 1.
  • R 1 is H; Linear or triturated C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl; -(CH 2 ) n -COOR; -O- (CH 2 ) n -NRR '; -(CH 2 ) n -OH; -(CH 2 ) n -OR; -Y- (CH 2 ) n -MR; C 5 -C 20 heteroaryl unsubstituted or substituted with C 1 -C 10 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or halogen, selected from the group consisting of S, O and N atoms Or a C 5 -C 20 heteroaryl group containing two hetero atoms; or Is;
  • R 3 is H; -OH; -CN; Linear or triturated C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl; -(CH 2 ) n -COOR; -CONH- (CH 2 ) n -NRR '; -O- (CH 2 ) n -NRR '; -CO- (CH 2 ) n -NRR '; -(CH 2 ) n -OH; -(CH 2 ) n -OR; C 6 -C 20 aryl unsubstituted or substituted with C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or halogen; C 5 -C 20 heteroaryl unsubstituted or substituted with C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkyny
  • R 2 is H; -OH; -NRR '; Linear or ground C 1 -C 10 alkyl; C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl; -(CH 2 ) n -Z; -Y- (CH 2 ) n -Z; -(CH 2 ) n -C 3 to C 7 cycloalkyl; C 1 -C 3 alkyl; C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or a halogen-substituted or unsubstituted by C 5 -C 20 heteroaryl comprising one or two heteroatoms selected from the group consisting of S, O and N atoms C 5 -C 20 heteroaryl; Substituted or unsubstituted C 6 -C 20 aryl; or Is;
  • R 4 and R 5 are each independently H, linear or triturated C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, -NR'R ", -Y- (CH 2 ) n -NR'R ", -Y- (CH 2 ) n -Z, , , , Or S, O and N atoms, wherein R 4 and R 5 are bonded to each other and substituted or unsubstituted with C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or halogen To form a C 3 -C 20 heterocyclyl group comprising one or two hetero atoms selected from the group;
  • Z is —NR′R ′′; substituted or unsubstituted C 5 -C 20 heteroaryl or heterocyclyl, including one to three hetero atoms selected from the group consisting of S, O and N atoms; Pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 2- or 3-oxo-pyrroli substituted or unsubstituted with C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or halogen Dine, 2-, 3- or 4-oxo-piperidine, oxazole, triazole, pyridine, imidazole, imidazolidine, 2,5-dioxo-pyrrolidine, 2- or 3-oxo- Piperazine, 2-oxo-imidazolidine, 4,4-ethylenedioxy-piperidine, 2- or 3-thienyl, 2- or 3-furyl; Is;
  • R 6 is H; halogen; -OH; -OR; -COOR; (CH 2 ) n -OR; Linear or ground C 1 -C 5 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl; -NO 2 ; -Y- (CH 2 ) n -Z; Or -Y- (CH 2 ) n -NR'R ";
  • R 7 is H; Or linear or triturated C 1 -C 5 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl;
  • R 8 is H; Linear or triturated C 1 -C 5 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl,-(CH 2 ) n -NR'R ";-(CH 2 ) n -OR or-(CH 2 ) n -OH;
  • R 9 is H; halogen; -OH; -OR; -NO 2 ; -COOR; -(CH 2 ) n -OR; -(CH 2 ) n -NR'R "; linear or triturated C 1 -C 5 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl; -Y- (CH 2 ) n -Z; Y- (CH 2 ) n -NR'R "; -Y- (CH 2 ) n -M- (CH 2 ) n -OR; -Y- (CH 2 ) n -M- (CH 2 ) n -ph; Or -Y- (CH 2 ) n -M- (CH 2 ) n -NR'R ";
  • R 11 and R 12 are each independently H; Linear or ground C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl; Substituted or unsubstituted C 6 -C 20 aryl which is halogen or R 11 and R 12 are bonded to each other; Substituted or unsubstituted C 3 -C 7 cycloalkyl; Or N; To form a C 5 -C 20 heterocycle comprising one or two hetero atoms selected from the group consisting of O and S;
  • R 13 is -Y- (CH 2 ) n -Z,-(CH 2 ) n -Z, or-(CH 2 ) n -NR'R ";
  • R, R 'and R are each independently H; linear or milled C 1 -C 5 alkyl;-(CH 2 ) n -C 6 H 6 ;-(CH 2 ) n -OH; or -CH 2 CF 3 Is;
  • Y is O, S, -NH-, -NH-CO-, or -CO-NH-;
  • M is O, S, -NH-, -NH-CO-, or -CO-NH-;
  • n is an integer of 0-6.
  • R 1 is H; C 1 -C 5 alkyl; -(CH 2 ) n -COOR; -O- (CH 2 ) n -NRR '; -(CH 2 ) n -OH; -(CH 2 ) n -OR; -Y- (CH 2 ) n -MR; C 5 -C 20 heteroaryl unsubstituted or substituted with C 1 -C 10 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or halogen, selected from the group consisting of S, O and N atoms Or a C 5 -C 20 heteroaryl group containing two hetero atoms; or Is,
  • R 3 is H; -OH; -CN; Linear or triturated C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl; -(CH 2 ) n -COOR; -CONH- (CH 2 ) n -NRR '; -O- (CH 2 ) n -NRR '; -CO- (CH 2 ) n -NRR '; -(CH 2 ) n -OH; -(CH 2 ) n -OR; C 6 -C 20 aryl unsubstituted or substituted with C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or halogen; C 5 -C 20 heteroaryl unsubstituted or substituted with C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkyny
  • R 2 is H, —OH, —NRR ′, linear or triturated C 1 -C 10 alkyl,-(CH 2 ) n -Z, -Y- (CH 2 ) n -Z,-(CH 2 ) n -C C 5 -C 20 heteroaryl unsubstituted or substituted with 3 to C 7 cycloalkyl, C 1 -C 3 alkyl, or halogen, containing one or two hetero atoms selected from the group consisting of S, O and N atoms C 5 -C 20 heteroaryl; Or substituted or unsubstituted C 6 -C 20 aryl or Is;
  • R 4 and R 5 are each, independently, H, or linear or triturated C 1 -C 5 alkyl, —NR′R ′′, —Y— (CH 2 ) n —NR′R ′′, —Y— (CH 2 ) n -Z, , , , Or; Or C 3 -C comprising one or two hetero atoms selected from the group consisting of S, O and N atoms, wherein R 4 and R 5 are bonded to each other to be substituted or unsubstituted with C 1 -C 3 alkyl; Forms a 20 heterocyclyl group;
  • Z is -NR'R "; pyrrolidine, piperidine, piperazine, morph, unsubstituted or substituted with C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or halogen Pauline, thiomorpholine, 2- or 3-oxo-pyrrolidine, 2-, 3- or 4-oxo-piperidine, oxazole, triazole, pyridine, imidazole, imidazolidine, 2,5 -Dioxo-pyrrolidine, 2- or 3-oxo-piperazine, 2-oxo-imidazolidine, 4,4-ethylenedioxy-piperidine, 2- or 3-thienyl, 2- or 3-furyl; Is;
  • R 6 is H; -OH; -OR; -COOR; (CH 2 ) n -OR; Linear or ground C 1 -C 5 alkyl; -NO 2 ; -Y- (CH 2 ) n -Z; Or -Y- (CH 2 ) n -NR'R ";
  • R 7 is H; Or linear or milled C 1 -C 5 alkyl;
  • R 8 is H; Linear or ground C 1 -C 5 alkyl; -(CH 2 ) n -NR'R ";-(CH 2 ) n -OR or-(CH 2 ) n -OH;
  • R 9 is H; halogen; -OH; -OR; -NO 2 ; -COOR; -(CH 2 ) n -OR; -(CH 2 ) n -NR'R "; linear or triturated C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl; C 1 -C 3 alkyl; C 2 -C 3 Pyrrolidine substituted or unsubstituted with alkenyl, C 2 -C 3 alkynyl or halogen; piperidine; piperazine-Y- (CH 2 ) n -Z; -Y- (CH 2 ) n -NR ' R "; -Y- (CH 2 ) n -M- (CH 2 ) n -OR; -Y- (CH 2 ) n -M- (CH 2 ) n -ph; Or -Y- (CH 2 ) n -M
  • R 11 and R 12 are each independently H; Linear or ground C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl; Halogen; Or R 11 and R 12 combine with each other to form a substituted or unsubstituted C 6 -C 20 aryl; Substituted or unsubstituted C 3 -C 7 cycloalkyl; Or N; A group which forms a C 5 -C 20 heterocycle comprising one or two hetero atoms selected from the group consisting of O and S;
  • R 13 is —Y— (CH 2 ) n —Z; -(CH 2 ) n -Z or-(CH 2 ) n -NR'R ";
  • R; R ′ and R ′′ are each independently H; linear or triturated C 1 -C 5 alkyl; — (CH 2 ) n —C 6 H 6 ; — (CH 2 ) n —OH; or —CH 2 CF 3 ;
  • Y is O, S, -NH-, -NH-CO-, or -CO-NH-;
  • M is O; S -NH-; -NH-CO- or -CO-NH-;
  • n is an integer of 0-3.
  • R 1 is R 1 is H, -Me, -Et, -ph, -ph-F, -CH 2 -ph, -ph-OH, -CH 2 OH , thiophenyl, -CH 2 -ph-OMe, -ph -OME, -ph-ME, -CONH 2, -COOME, -COOEt, -CH 2 -COOEt, -ph-OC 2 H 5 -NR'R " , -CH 2 -ph-OC 3 H 7 -NR'R ”,
  • R 3 is H, -OH, -CN, -Me, -Et, -COOH, -COOME, -CONH 2 , -CONH-CH 2 CH 2 -N (CH 2 ) 3 , -ph, -ph-F, -CH 2 -ph, -ph-OH, -CH 2 -ph-OH, -ph-NO 2 , -ph-ME, -CH 2 OH, -C 2 H 5 OH, -ph-OME, -ph- ME, -ph-OC 2 H 5 -NH-CH 2 -ph, ph-OC 2 H 5 -NH-C 3 H 7- (CH 2 ) 3 , -ph-OC 2 H 5 -NR 2 , -ph -C 2 H 5 -NH-C 2 H 5 -OR, -ph-NO 2 , -ph-C 2 H 5 -NH 2 ,
  • R 1 and R 3 combine with each other to form a piperidine substituted or unsubstituted with C 1 -C 3 alkyl
  • R 2 is -Me, -Et, propyl, tert-butyl, thiophenyl, -NH 2 , -ph-NH 2 , -ph-OMe, -ph-NR'R ”, -ph, -ph-OH,- ph-F, -ph-OC 2 H 5 -NRR ',
  • R 4 and R 5 are each independently H, —CH 2 —ph, —NH 2 , —C 2 H 5 —NH, —NH—C 2 H 5 —NH, Can be selected from.
  • the compound represented by Formula 1 may be any one of the following formula.
  • Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating leukemia, comprising a thienopyrimidine derivative represented by Formula 2 below or a pharmaceutically acceptable salt thereof.
  • the compounds represented by the formula (1) of the present invention may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art, and further include pharmaceutically acceptable carriers, excipients, diluents or combinations thereof. It can be included as.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like. It doesn't work.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salts, but is not limited thereto.
  • Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of Formula 1 include salts of acidic or basic groups which may be present in compounds of Formula 1 unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like. It can be manufactured through the manufacturing process.
  • the compound of Formula 1 since the compound of Formula 1 has an asymmetric center, it may exist in different enantiomeric forms, and all optical isomers and R or S type stereoisomers of the compound of Formula 1 and mixtures thereof are also included within the scope of the present invention.
  • the present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.
  • the present invention provides a method for preparing a thienopyrimidine derivative of Chemical Formula 1.
  • the thienopyrimidine derivative of Formula 1 may be chemically prepared by the method shown in the following schemes, but is not limited to those prepared by such a method.
  • those skilled in the art will fully understand that the thienopyrimidine derivatives of Formula 1 of the present invention may be prepared by various methods using techniques well known in the art.
  • reaction schemes represent the preparation method of the representative compounds according to the present invention in stages, and various compounds of the present invention change the reagents, solvents, and reaction sequences used during the preparation of ⁇ Scheme 1> to ⁇ Scheme 3>, and the like. It can be manufactured by the change or modification of.
  • Some compounds of the present invention have been prepared according to processes not included in the scope of Scheme 1 to Scheme 3, and detailed preparation procedures for these compounds are described in detail in their respective examples.
  • Scheme 1 will illustrate a method for preparing compounds of one embodiment of the present invention by the scheme in which compounds 8a to 8e are prepared from 2-acetylthiophene.
  • Scheme 1 first, Knoevenagel condensation reaction of 2-acetylthiophene with malononitrile in the presence of NH 4 OAc and AcOH yields 2- [1- (thiophene n-2-yl) ethylidene] malononitrile 2. This is then treated with sulfur and piperidine to give thiophene 3a. Thereafter, compound 3a is heated with formamide at 180 ° C.
  • Compounds 11a to 11i can be synthesized simply by heating the carboxylate compounds 10a to 10i with appropriate carbonnitrile under acidic conditions and chlorinated with POCl 3 at 100 ° C. to give 4-chloro-thieno [2, 3-d] pyrimidine 12a to 12i.
  • Thieno [2,3-d] pyridin-4-amine derivatives 13a to 13m are first heated with compound 5a to 5d or compound 12a to 12i with hydrazine hydrate followed by 3-methylfuran-2,5-dione. It can be obtained by heating.
  • the present invention provides a pharmaceutical composition for preventing or treating leukemia disease, comprising a thienopyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof, and in a preferred embodiment,
  • the pharmaceutical composition described above may further comprise a suitable carrier, excipient or diluent according to conventional methods.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
  • compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose, lactose ( lactose), gelatin and the like can be mixed and prepared.
  • lubricants such as magnesium stearate, talc can also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include various excipients other than commonly used simple diluents such as water and liquid paraffin, such as wetting agents, sweeteners, fragrances, and preservatives.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used.
  • Preferred dosages of the compounds according to the invention depend on the condition and body weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art.
  • the compound of formula 1 of the present invention can be administered in an amount of 0.0001-500 mg / kg, preferably 0.01-300 mg / kg divided once to several times daily.
  • Compound of Formula 1 in the composition of the present invention may be combined in an amount of 0.0001 to 50% by weight relative to the total weight of the composition.
  • the pharmaceutical dosage forms of the compounds according to the invention may be in the form of their pharmaceutically acceptable salts, and may also be used alone or in combination with other pharmaceutically active compounds as well as in suitable combinations.
  • the pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • Example 11 general preparation of 3-methyl-1- (thieno [2,3-d] pyrimidin-4-ylamino) -1 H-pyrrole-2,5-dione derivative (13a-m)
  • kinase panel test (KinaseProfiler TM, Merck Millipore, UK) was performed on the following 22 kinases, including the IKK ⁇ kinase test.
  • the evaluation method of the representative kinase FLT3 (h) of the 22 kinases is as follows, wherein the compound 13k and 17a synthesized in the above examples were used as test compounds.
  • test compounds 13k and 17a did not inhibit kinase activity such as IKK ⁇ in other signaling pathways, while excellent inhibitory activity against FLT3 (8% at 10 ⁇ M treatment, respectively). And 4% residual activity).
  • the test compound since the test compound is not involved in other kinase pathways, it is expected that side effects are unlikely to occur in the treatment of AML, and the treatment and prevention effect of AML by abnormal overexpression and mutation is expected to be excellent.
  • Flt3 (h) consists of 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 ⁇ M EAIYAAPFAKKK, 10 mM magnesium acetate (MgAcetate) and [ ⁇ -33P-ATP] (a concentration of approximately 500 cpm / pmol is required for specific activity). Incubated together. The reaction was started by adding MgATP, and after 40 minutes of incubation at room temperature, the reaction was terminated by adding 3% phosphoric acid solution. 10 ⁇ L of the reaction solution was filtered through a P30 filter mat, washed three times with 75 mM phosphoric acid and once with methyl alcohol for 5 minutes, then dried and aggregated via scintillation. Each compound was treated with Flt3 (h) at five concentrations (10, 1, 0.1, 0.01, and 0.01 ⁇ M) with 10 ⁇ M ATP to obtain IC 50 values. Meanwhile, AC220 and MLN518 were used as controls.
  • Human cancer cells (ACHN, HCT15, MDA-MB-231, NCI-H23, NUGC-3, PC-3, MV4-11, THP-1, K562, and HL-60) that were distributed by the American Type Culture Collection (ATCC) Used. Cancer cell lines were used in the experiment after incubation for 72 hours in 37 °C, 5% carbon dioxide incubator by adding 10% FBS to RPMI 1640 culture.
  • ATCC American Type Culture Collection
  • MV4-11 and THP1 are mutant cell lines of FLT3 / ITD observed in AML, and the excellent growth inhibitory activity on the cells suggests the excellent therapeutic and prophylactic effects of AML.
  • most test compounds had better FLT3 / ITD and wt-FLT3 inhibitory activity compared to AC220, which is known as a selective inhibitor.
  • Flt3 (D835Y) (h) has a concentration of 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 ⁇ M EAIYAAPFAKKK, 10 mM magnesium acetate (MgAcetate) and [ ⁇ -33P-ATP] (approximately 500 cpm / pmol for specific activity). Incubation). The reaction was started by adding MgATP, and after 40 minutes of incubation at room temperature, the reaction was terminated by adding 3% phosphoric acid solution. 10 ⁇ L of the reaction solution was filtered through a P30 filter mat, washed three times with 75 mM phosphoric acid and once with methyl alcohol for 5 minutes, then dried and aggregated via scintillation.
  • This experiment measured the IC50 for the kinase domain mutation FLT3_D835Y on the 10 compounds. It can be seen that all of these compounds have excellent IC50 values at 46 nM to 591 nM. In particular, among them, the formulas 128, 134, 137, 49, and 92 described in Table 5 were found to have excellent inhibitory activity against D835Y compared to A220 and MLN518. The experimental results indicate that the thienopyrimidine derivative compounds of the present invention also have inhibitory activity against TKD mutations, suggesting that the problem of treatment resistance of mutations to conventional inhibitors can be solved.

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Abstract

L'invention concerne une composition pharmaceutique permettant de prévenir ou de traiter la leucémie, contenant un dérivé de thiénopyrimidine représenté par la formule chimique 1 suivante, ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/KR2015/003807 2014-04-15 2015-04-15 Composition pharmaceutique permettant de traiter et de prévenir la leucémie, contenant un dérivé de thiénopyrimidine ou un sel pharmaceutiquement acceptable de celui-ci Ceased WO2015160192A1 (fr)

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GB2575196A (en) * 2015-08-17 2020-01-01 Univ Holy Ghost Duquesne Thieno pyridimine compounds and manufacture of the same
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10961216B2 (en) * 2017-07-28 2021-03-30 Massachusetts Institute Of Technology Small molecule modulators of the androgen receptor
WO2022219172A1 (fr) * 2021-04-15 2022-10-20 Novelyeast Bv Inhibiteurs de l'absorption du glucose utilisés dans le traitement du cancer et d'autres maladies
EP3971190A4 (fr) * 2019-05-17 2023-06-14 Voronoi Inc. Dérivé de pyrimidine condensé avec un hétérocycle et son utilisation
US12391705B2 (en) 2018-12-19 2025-08-19 Shy Therapeutics, Llc Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

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GB2575196A (en) * 2015-08-17 2020-01-01 Univ Holy Ghost Duquesne Thieno pyridimine compounds and manufacture of the same
GB2575196B (en) * 2015-08-17 2020-06-03 Univ Holy Ghost Duquesne Thieno pyridimine compounds and manufacture of the same
US11078214B2 (en) 2015-08-17 2021-08-03 Duquesne University Of The Holy Spirit Monocyclic thieno, pyrido, and pyrrolo pyrimidine compounds and methods of use and manufacture of same
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US12168668B2 (en) 2015-12-22 2024-12-17 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
KR20180066985A (ko) 2016-12-11 2018-06-20 연세대학교 산학협력단 티에노피리미딘 유도체 및 이의 용도
US11026930B1 (en) 2017-06-21 2021-06-08 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10961216B2 (en) * 2017-07-28 2021-03-30 Massachusetts Institute Of Technology Small molecule modulators of the androgen receptor
US12391705B2 (en) 2018-12-19 2025-08-19 Shy Therapeutics, Llc Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
EP3971190A4 (fr) * 2019-05-17 2023-06-14 Voronoi Inc. Dérivé de pyrimidine condensé avec un hétérocycle et son utilisation
WO2022219172A1 (fr) * 2021-04-15 2022-10-20 Novelyeast Bv Inhibiteurs de l'absorption du glucose utilisés dans le traitement du cancer et d'autres maladies
US20240252508A1 (en) * 2021-04-15 2024-08-01 Novelyeast Bv Novel glucose uptake inhibitors for use in the treatment of cancer

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