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WO2017176040A1 - Composé hétérocyclique décomposant une protéine ras et utilisations correspondantes - Google Patents

Composé hétérocyclique décomposant une protéine ras et utilisations correspondantes Download PDF

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Publication number
WO2017176040A1
WO2017176040A1 PCT/KR2017/003704 KR2017003704W WO2017176040A1 WO 2017176040 A1 WO2017176040 A1 WO 2017176040A1 KR 2017003704 W KR2017003704 W KR 2017003704W WO 2017176040 A1 WO2017176040 A1 WO 2017176040A1
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methylene
nitrophenyl
alkyl
pyrazol
thiazolidin
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Korean (ko)
Inventor
최강열
한균희
차부현
김현태
이철호
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Industry Academic Cooperation Foundation of Yonsei University
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Industry Academic Cooperation Foundation of Yonsei University
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Priority to KR1020187029620A priority Critical patent/KR102304478B1/ko
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non 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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a compound which simultaneously degrades? -Catenin and Ras protein, a process for producing the same, and uses thereof.
  • Ras is a protein that regulates signal entry into key signaling systems related to cancer, such as PI3K and mTOR, and can be a good target for developing multi-target cancer drugs. Ras has an average of 30% mutation in cancer (72-90% in the case of K-Ras, 72-90% in the case of pancreatic cancer, 32-57% in colorectal cancer and 15-50% in lung cancer) There have been numerous efforts to do so.
  • FTIs farnesyltransferase inhibitors
  • GGTIs geranylgeranyltransferase inhibitors
  • Ras protein itself is degraded into a form dependent on polyubiquitination by inhibition of the Wnt / ⁇ -catenin signaling system.
  • Ras protein can be degraded by the inhibition of this signal transduction system through APC, Axin, and glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ), which are the voice regulators of the wint / beta-catenin signaling system.
  • APC Axin
  • GSK3 ⁇ glycogen synthase kinase 3 ⁇
  • Ras protein was phosphorylated by GSK3 ⁇ and ⁇ -TrCP E3 linker was involved and protein degradation proceeded.
  • a problem to be solved by the present invention is to provide a novel anticancer agent capable of solving the problems of existing anticancer drugs which do not exhibit anticancer effects due to Ras gene mutation, and which simultaneously decompose? -Catenin and Ras protein.
  • Another object to be solved by the present invention is to provide a pharmaceutical composition for treating cancer in a cancer patient having K-Ras mutant type comprising as an active ingredient a compound capable of simultaneously decomposing the? -Catenin and the Ras protein.
  • the present invention provides a compound capable of simultaneously decomposing ⁇ -catenin and Ras protein represented by the following formula (1).
  • Y is S or O
  • Z is S or NR x ;
  • R x is H, C 1- 6 alkyl or C 1- 3 alkyl, C 6 - 12 aryl;
  • X is a five to six membered heteroaryl containing from one to two nitrogen atoms, an eight to nine membered fused heteroaryl containing from one to two nitrogen atoms and a ten atom fused heteroaryl containing two nitrogen atoms, ; Said heteroaryl and fused heteroaryl being unsubstituted or N-substituted by a substituent selected from phenyl, benzyl and pyridyl or substituted with 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy, Gt; C-substituted < / RTI > Wherein said N-substituted phenyl, benzyl or pyridyl is unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;
  • R 1 is selected from the group consisting of hydrogen, 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH 2 ) n C (O) R 2 , (CH 2 ) m R 4 , (CH 2 ) n CONHR 5 , CHR 3 R 4 , (CH 2) m COONHR 3, CH 2 CR 3 R 6 R 7, -L 1 -C (O) NHR 3, naphthyl, (CH 2) m NHC ( O) R 3, (CH 2) m COR 7 or (CH 2) m NHSO 2 R 3 , and wherein the 4-6 heteroatom won the nitrogen of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C 1- 6 alkyl, C 1- 6 alkyl C 6 -12 aryl, C 6- 12 aryl C 1 - 6 alkyl, trifluoro C 2 - 6 alkyl, C 2- 6 alkenyl, -C (O) R
  • R 2 is selected from C 1- 6 alkyl, C 1- 6 alkoxy, dibenzyl amino carbonyl and C 1- 3 alkyl-piperazinyl,
  • R 3 is C 1- 6 alkyl
  • R 4 is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C 1- 3 alkyl-piperazinyl, mono- or di -C 1-3 alkylamino, C 1-3 alkyl-oxadiazolyl, pyridazinyl imidazole, triazolyl and C 6- 12 is selected from aryl, wherein C 6- 12 aryl is unsubstituted, or C 1- 6 alkoxy, nitrile, halogen, C 1- 6 alkyl, CF 3, C (O) C 1- 6 alkyl, -SC 1- 6 alkyl, hydroxy, OCF 3, dimethyl amino carbonyl and diisopropyl amino carbonyl substituent may be one to three substitutions selected from , if the substituents are plural, said substituents may be the same or different from each other, and the indolyl and benzo-o
  • R 5 is C 1- 6 alkyl, C 6- 12 aryl, C 6- 12 aryl C 1 - 6 alkyl, oxazole, pyridinyl C 1 - 3 alkyl or morpholino C 1 -3 alkyl;
  • R 6 is C 1- 6 alkyl
  • R 7 is (CH 2 ) m CONH (CH 2 ) mCH 3 , (CH 2 ) m COOH or C (O) NHR 3 ;
  • L 1 is phenylene
  • n is an integer of 0 to 5
  • n 1 to 5
  • Adjacent R < 3 > and R < 6 > are each independently present or bonded to each other to form a ring.
  • the present invention also provides a pharmaceutical composition for treating cancer in a cancer patient having a K-Ras mutation type comprising the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cancer patient may be a cancer patient having a Wnt signal transduction system abnormality together.
  • the cancer is selected from the group consisting of colon cancer, stomach cancer, pancreatic cancer, brain tumor, lung cancer, bladder cancer, kidney cancer, thyroid cancer, rectal cancer, hematopoietic tumor, malignant melanoma, neuroblastoma, malignant melanoma and rhabdomyosarcoma .
  • the cancer may be a metastatic cancer.
  • the compounds according to the present invention bind to axin, a negative regulator of the Wnt / beta -catenin signaling system, to promote the binding of axin to the beta-catenin destruction complex, And Ras proteins, including K-Ras mutations, to regulate signal entry into key signaling pathways involved in cancer, thereby inhibiting cancer growth and killing cancer cells.
  • Ras proteins including K-Ras mutations
  • the present invention is also useful as a pharmaceutical composition for treating cancer.
  • FIGS. 1 to 3 show the results of comparing the degradation of ⁇ -catenin with that of Ras by treating the SW480 colon cancer cell line with APC and K- Ras mutations according to the embodiment of the present invention, with the comparative drug KYA1797K and its derivatives.
  • FIG. 4 shows the results of comparing the ability of the SW480 colon cancer cell lines with APC and K- Ras mutants to treat the comparative drug KYA1797K and derivatives according to the embodiment of the present invention.
  • the abnormal activation of the Wnt / ⁇ -catenin signaling system by the mutation of the genes involved in the Wnt / ⁇ -catenin signaling system is often the cause of cancer, so the discovery of inhibitors for this signal transduction system is key to cancer therapy .
  • a substance that primarily inhibits the Wnt / ⁇ -catenin signaling pathway is selected, it is not the overexpression of the ligand that activates the Wnt / ⁇ -catenin signal transduction system, but the key molecule such as APC or ⁇ -catenin ), It is important to identify low-molecular-weight compounds that target signal transduction agents that act in the cytoplasm or nucleus of the signal transduction system.
  • the present inventors have sought to find a substance that simultaneously inhibits the Wnt /? -Catenin signaling pathway system and the Ras / MAPK signal transduction system, thereby simultaneously degrading? -Catenin and Ras and Ras mutations, specifically K-Ras And found that these compounds are effective in the treatment of cancer in cancer patients who are resistant to conventional anticancer drugs, thereby completing the present invention.
  • the present invention provides a compound capable of simultaneously decomposing ⁇ -catenin and Ras protein represented by the following formula (1).
  • Y is S or O
  • Z is S or NR x ;
  • R x is H, C 1- 6 alkyl or C 1- 3 alkyl, C 6 - 12 aryl;
  • X is a five to six membered heteroaryl containing from one to two nitrogen atoms, an eight to nine membered fused heteroaryl containing from one to two nitrogen atoms and a ten atom fused heteroaryl containing two nitrogen atoms, ; Said heteroaryl and fused heteroaryl being unsubstituted or N-substituted by a substituent selected from phenyl, benzyl and pyridyl or substituted with 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy, Gt; C-substituted < / RTI > Wherein said N-substituted phenyl, benzyl or pyridyl is unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;
  • R 1 is selected from the group consisting of hydrogen, 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH 2 ) n C (O) R 2 , (CH 2 ) m R 4 , (CH 2 ) n CONHR 5 , CHR 3 R 4 , (CH 2) m COONHR 3, CH 2 CR 3 R 6 R 7, -L 1 -C (O) NHR 3, naphthyl, (CH 2) m NHC ( O) R 3, (CH 2) m COR 7 or (CH 2) m NHSO 2 R 3 , and wherein the 4-6 heteroatom won the nitrogen of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C 1- 6 alkyl, C 1- 6 alkyl C 6 -12 aryl, C 6- 12 aryl C 1 - 6 alkyl, trifluoro C 2 - 6 alkyl, C 2- 6 alkenyl, -C (O) R
  • R 2 is selected from C 1- 6 alkyl, C 1- 6 alkoxy, dibenzyl amino carbonyl and C 1- 3 alkyl-piperazinyl,
  • R 3 is C 1- 6 alkyl
  • R 4 is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C 1- 3 alkyl-piperazinyl, mono- or di -C 1-3 alkylamino, C 1-3 alkyl-oxadiazolyl, pyridazinyl imidazole, triazolyl and C 6- 12 is selected from aryl, wherein C 6- 12 aryl is unsubstituted, or C 1- 6 alkoxy, nitrile, halogen, C 1- 6 alkyl, CF 3, C (O) C 1- 6 alkyl, -SC 1- 6 alkyl, hydroxy, OCF 3, dimethyl amino carbonyl and diisopropyl amino carbonyl substituent may be one to three substitutions selected from , if the substituents are plural, said substituents may be the same or different from each other, and the indolyl and benzo-o
  • R 5 is C 1- 6 alkyl, C 6- 12 aryl, C 6- 12 aryl C 1 - 6 alkyl, oxazole, pyridinyl C 1 - 3 alkyl or morpholino C 1 -3 alkyl;
  • R 6 is C 1- 6 alkyl
  • R 7 is (CH 2 ) m CONH (CH 2 ) m CH 3 , (CH 2 ) m COOH or C (O) NHR 3 ;
  • L 1 is phenylene
  • n is an integer of 0 to 5
  • n 1 to 5
  • Adjacent R < 3 > and R < 6 > are each independently present or bonded to each other to form a ring.
  • the ring formed by combining R 3 and R 6 with each other may be cyclohexyl.
  • Alkyl means a straight chain (linear) or branched saturated hydrocarbon group generally having the specified number of carbon atoms.
  • alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and heptyl.
  • Heterocycloalkyl means a saturated or polycyclic hydrocarbon ring containing one to several heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the heteroatom of the heterocycloalkyl may be nitrogen.
  • Said heterocycloalkyl is unsubstituted, C 1- 6 alkyl, C 1- 6 alkyl, C 6 - 12 aryl, C 6- 12 aryl C 1 - to 6 alkyl, trifluoro C 2 - 6 alkyl, C 2- 6 Substituted with a substituent selected from -C (O) R 5 , -SO 2 R 3 , -COOR 3 , -SO 2 NHCOOR 3 , -SO 2 NH 2 and C (O) NR 2 R 3 or -COOC 1 - 6 alkyl, C 6 - 12 aryl may be substituted with a C-.
  • the definitions of R 2 , R 3 and R 5 are the same as those given above.
  • Halogen means < / RTI > fluoro, chloro, bromo and iodo.
  • the 5- to 6-membered heteroaryl may be selected from pyrrolyl, pyrazolyl and pyridyl.
  • the 8 to 9-atom condensed heteroaryl may be selected from benzoimidazolyl, indolyl, indazolyl and imidazolopyridyl.
  • the 10 atom-condensed heteroaryl may be quinoxalyl.
  • R 9 is hydrogen, phenyl, benzyl or pyridyl, and the phenyl, benzyl and pyridyl of R 9 is unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;
  • R 11 is halogen, nitrophenyl, pyridyl, trifluoromethyl or phenoxy;
  • a is an integer of 0 to 2;
  • the compound represented by the formula (1) may be selected from compounds represented by the following formulas (2) to (5).
  • R 9 is hydrogen, phenyl, benzyl or pyridyl, and the phenyl, benzyl and pyridyl of R 9 is unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;
  • R 11 is halogen, nitrophenyl, pyridyl, trifluoromethyl or phenoxy;
  • a is an integer from 0 to 2;
  • R x is H or C 1- 6 alkyl
  • R 1 is hydrogen, 4-6 membered heterocycloalkyl, carboxy-cyclohexyl, (CH 2) n C ( O) R 2, (CH 2) m R 4 or (CH 2) n CONHR 5, and said 4-6 the nitrogen source is a heteroatom of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C 6- 12 aryl C 1 - to 6 alkyl, -C (O) R 5, and the substituent is selected from -COOR 3 N- substituted, wherein C 6- 12 aryl C 1 - 6 alkyl which is unsubstituted or substituted one or more C 1- 6 alkoxycarbonyl, nitrile, halogen, C 1- 6 alkyl, CF 3, hydroxy, selected from OCF 3 Lt; / RTI >
  • R 2 is C 1- 6 alkyl, C 1- 6 alkoxy, or C 1- 3 alkyl-piperazinyl and;
  • R 3 is C 1- 6 alkyl
  • R 4 is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, morpholino, C 1- 3 alkyl-piperazinyl, mono- or di -C 1-3 alkylamino, C 1-3 alkyl-oxadiazolyl , an imidazolyl, triazolyl or C 6- 12 aryl, wherein C 6- 12 aryl is unsubstituted or C 1- 6 alkoxy, nitrile, halogen, C 1- 6 alkyl, CF 3, C (O) C 1- 6 alkyl, -SC 1- 6 alkyl, hydroxy, OCF 3, dimethyl amino carbonyl and diisopropyl amino, and carbonyl substituents can be one to three substitutions selected from the group consisting of, when the plurality of the substituent, the substituent be the same or different from each other, and the indolyl and benzo-oxazolyl is is unsubstituted or substituted by hydroxy
  • R 5 is C 1- 6 alkyl, C 6- 12 aryl, C 6- 12 aryl C 1 - 6 alkyl, oxazole, pyridinyl C 1 - 3 alkyl or morpholino C 1 -3 alkyl;
  • n is an integer of 1 to 4
  • m is an integer of 1 to 5.
  • the number of R 11 is two, and the two R 11 may be the same or different.
  • the compound of formula (1) may be selected from the following formulas (6) to (13).
  • Y is S or O
  • R 9 is hydrogen, phenyl or pyridyl, and the phenyl and pyridyl of R 9 are unsubstituted or substituted with one or more Nitro;
  • R < 11 > is nitrophenyl or trifluoromethyl
  • a is an integer of 1 to 2;
  • R 1 is hydrogen, 4-6 membered heterocycloalkyl, carboxy-cyclohexyl, (CH 2) n C ( O) R 2, (CH 2) m R 4 or (CH 2) n CONHR 5, and said 4-6
  • the heteroatom of the one heterocycloalkyl is nitrogen and the 4-6 membered heterocycloalkyl is unsubstituted or N-substituted by -COOR 3 ;
  • R 2 is C 1- 6 alkyl, C 1- 6 alkoxy, or C 1- 3 alkyl-piperazinyl and;
  • R 3 is C 1- 6 alkyl
  • R 4 is OH, COOH, morpholino, C 1- 3 alkyl-piperazinyl, mono- or di -C 1-3 alkyl amino or C 6- 12 aryl, wherein C 6- 12 aryl is unsubstituted;
  • R 5 is C 1- 6 alkyl, pyridinyl C 1 - 3 alkyl or morpholino C 1 - 3 alkyl;
  • n is an integer of 2 to 4
  • m is an integer of 2 to 5.
  • the compound represented by the formula (1) may be preferably selected from the following formulas (14) to (17).
  • Y is S or O
  • R 21 is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH 2 ) a R a or (CH 2 ) a C (O) R b ;
  • R < 22 &gt is hydrogen or nitro
  • R 23 is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen heteroatom which characters, (CH 2) a R a , (CH 2) b C (O) R c, (CH 2) c COOR d, ( CH 2 ) d CONHR e or (CH 2 ) e OH;
  • R 24 is heteroaryl, 4-6 membered heterocycloalkyl containing one nitrogen, (CH 2 ) b C (O) R d or (CH 2 ) d CONHR e ;
  • R a is OH, morpholino, C 1- 3 alkyl-piperazinyl or a mono- or di -C 1-3 alkyl amino;
  • R b is C 1- 3 alkyl-piperazinyl and
  • R c is C 1- 6 alkyl, C 1- 3 alkyl-piperazinyl or hydroxy
  • R d is C 1- 6 alkyl
  • R e is C 1- 6 alkyl or morpholino C 1 - 3 alkyl
  • a is an integer of 2 or 3
  • b is an integer of 2 to 5
  • c, d and e are each independently an integer of 2 to 4
  • f is an integer of 1 to 2.
  • the compound represented by the formula (1) may be more preferably selected from the following formulas (18) and (19).
  • R 21 is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH 2 ) a R a or (CH 2 ) a C (O) R b ;
  • R < 22 &gt is hydrogen or nitro
  • R 23 is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen heteroatom which characters, (CH 2) a R a , (CH 2) b C (O) R c, (CH 2) c COOR d, ( CH 2 ) d CONHR e or (CH 2 ) e OH;
  • R a is OH, morpholino, C 1- 3 alkyl-piperazinyl or a mono- or di -C 1-3 alkyl amino;
  • R b is C 1- 3 alkyl-piperazinyl and
  • R c is C 1- 6 alkyl, C 1- 3 alkyl-piperazinyl or hydroxy
  • R d is C 1- 6 alkyl
  • R e is C 1- 6 alkyl or morpholino C 1 - 3 alkyl
  • a is an integer of 2 or 3
  • b is an integer of 2 to 5.
  • the compound represented by the formula (1) can be specifically selected from the following compounds or pharmaceutically acceptable salts thereof.
  • the compound represented by the formula (1) can be preferably selected from the following compounds or pharmaceutically acceptable salts thereof.
  • the compound represented by the formula (1) may be more preferably selected from the following compounds or pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt is not particularly limited as long as it is ordinarily used in the art, and specific examples thereof include non-toxic inorganic acids such as hydrochloric acid, sulfuric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid and nitric acid, , Salicylic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, para toluenesulfonic acid, ethanesulfonic acid and methanesulfonic acid.
  • non-toxic inorganic acids such as hydrochloric acid, sulfuric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid and nitric acid, , Salicylic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, para toluenesulfonic acid, ethanesulfonic acid and methanesulfonic acid.
  • the Ras protein may be a wild type Ras protein or a Ras mutant protein, and the Ras mutant protein is preferably a K-Ras mutant type protein.
  • the compound represented by Formula 1 according to the present invention may be one which binds to Axin to degrade ⁇ -catenin or Ras protein, and preferably decomposes ⁇ -catenin and Ras protein simultaneously .
  • the compound represented by Formula 1 according to the present invention can inhibit the Wnt / beta -catenin signal transduction system and inhibits the growth of cancer cells on invitro and invivo by simultaneously degrading beta -catenin and Ras protein,
  • the present invention can be used as a pharmaceutical composition for cancer treatment of cancer patients having a cancer patient, preferably a cancer patient having a Ras mutation type, more preferably a K-Ras mutant type and showing no therapeutic effect on conventional anticancer drugs.
  • Ras is composed of K, N, and H-Ras. Among them, K-Ras has many mutations in colorectal cancer, lung cancer, metastatic cancer, etc. and acts as an important tumor regulator in such cancer.
  • the compound represented by the above formula (1) according to the present invention is characterized by decomposing the Ras protein which is not the activity of the Ras protein and decreasing the amount thereof.
  • the Ras protein is characterized not only by the wild-type Ras but also by the K-Ras mutation, and thus exhibits an anticancer effect against cancer having a K-Ras mutation, particularly cancer that is resistant to antibody / anticancer drugs targeting EGFR And clinically confirmed that the anticancer effect was remarkably excellent in colorectal cancer, lung cancer, stomach cancer, metastatic cancer and the like which are resistant to conventional anticancer drugs.
  • the compound represented by Formula 1 according to the present invention can inhibit Ras / PI3K / Akt signal transduction system as well as the lower Ras / ERK signal transduction system by inhibiting Ras protein.
  • the cancer according to the present invention may be an abnormality of the Wnt /? - catenin signal transduction system or a cancer caused by Ras protein.
  • the cancer may be cancer of the colon, stomach cancer, pancreatic cancer, brain tumor, lung cancer, bladder cancer, renal cancer, Tumor, malignant melanoma, neuroblastoma, malignant melanoma, and rhabdomyosarcoma.
  • the cancer according to the present invention may also be a metastatic cancer.
  • the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable carrier in addition to the compound represented by the formula (1), and may be appropriately selected according to techniques known in the art.
  • a pharmaceutically acceptable carrier means a known pharmaceutical excipient that is useful when formulating the pharmaceutically active compound for administration and is substantially non-toxic and non-sensitive under the conditions of use.
  • the exact ratio of such excipients is determined by standard pharmaceutical practice, as well as the solubility and chemical properties of the active compound, the route of administration chosen.
  • the pharmaceutical composition of the present invention may be formulated into a form suitable for a desired administration method using suitable and physiologically acceptable excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants, .
  • the pharmaceutical composition according to the present invention may be formulated into tablets, capsules, pills, granules, powders, injections or solutions.
  • Formulations suitable for oral administration include solid preparations such as tablets, microparticles, capsules containing liquid or powder, pills, granules, powders, lozenges (including liquid-filled ones), chews, Gels, solid solutions, liposomes, films (including mucosal-tackiness), ovules, sprays and liquids.
  • Liquid preparations include, for example, suspensions, solutions, syrups and elixirs.
  • the tablets generally contain a disintegrant in addition to the drug.
  • Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrant, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropylcellulose or carboxy Cellulose such as methyl cellulose, alginate such as sodium alginate or alginic acid, cross-linked cellulose such as croscarmellose sodium, gums such as guar gum and xanthan gum, cross-linking such as crospovidone, A polymer, a boiling agent such as sodium bicarbonate, citric acid or the like may be mixed and used.
  • the disintegrant will include, but is not limited to, from about 1% to about 25% by weight of the dosage form, preferably from about 2% to about 10% by weight of the dosage form.
  • Binders are generally used to impart tack to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, starch, copovidone, highly disperse silica, mannitol, lactose , Hydroxypropylcellulose, and hydroxypropylmethylcellulose. Generally, the binder will comprise from about 1% to about 40% by weight of the dosage form, preferably from about 2% to about 25% by weight of the dosage form, but is not limited thereto.
  • the tablets may be, for example, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol and dicalcium phosphate as diluents.
  • the diluent will comprise from about 1% to about 70% by weight of the dosage form, preferably from about 2% to about 50% by weight of the dosage form, but is not limited thereto.
  • Tablets may also optionally contain a surfactant, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surfactant may comprise from about 0.2% to about 5% by weight of the tablet, and the glidant may comprise from about 0.2% to about 1% by weight of the tablet.
  • a surfactant such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • the surfactant may comprise from about 0.2% to about 5% by weight of the tablet, and the glidant may comprise from about 0.2% to about 1% by weight of the tablet.
  • lubricants there may also be mentioned lubricants such as talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, magnesium stearate, sodium lauryl sulfate, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, glyceryl monostearate Polyethylene glycol 4000, and the like can be used.
  • the lubricant generally comprises from about 0.25% to about 5%, preferably from about 0.5% to about 3% by weight of the tablet.
  • ingredients include antioxidants, colorants, flavors, preservatives and taste-masking agents.
  • Tablet formulations can be pressed directly or squeezed with a roller to form tablets.
  • the tablet formulation or a portion of the formulation may be wet, dry, melt-granulated, melt congealed or extruded prior to tableting.
  • the final formulation may comprise one or more layers, may be coated or uncoated, and may be encapsulated.
  • Solid preparations for oral administration can be formulated in immediate release and / or modified release form.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release types.
  • the pharmaceutical composition of the present invention may be a tablet. Tablets may optionally be film coated.
  • the total amount of the drug per unit dose may be an amount that provides a convenient size dosage form to the patient.
  • the pharmaceutical compositions of the invention may be formulated in the form of sustained release tablets.
  • a matrix polymer selected from an enteric polymer, a hydrophobic substance, and a hydrophilic polymer may be used as the matrix base.
  • enteric polymer examples include a mixture of at least one selected from the group consisting of polyvinyl acetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, Eudragit L and Eudragit S Can be used.
  • the hydrophobic substance may be a polyvinyl acetate, a polymethacrylate copolymer, a poly (ethyl acrylate, methyl methacrylate) copolymer, a poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate, Ethylcellulose and cellulose acetate, fatty acid and fatty acid esters, fatty acid alcohols, waxes and inorganic substances can be selected.
  • fatty acid and fatty acid esters include glyceryl palmitostearate, Fatty acid alcohols such as glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid; waxes such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; carnauba wax, beeswax and microcrystalline wax As an inorganic substance, talc, precipitated carbon Can be used to select one or more selected from calcium, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and bigeom.
  • Fatty acid alcohols such as glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid
  • waxes such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol
  • carnauba wax beeswax and micro
  • the hydrophilic polymer may be selected from saccharides, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers.
  • Specific examples of the hydrophilic polymer include dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinozaylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin, and the like can be selected.
  • cellulose derivative hydroxypropylmethylcellulose , Hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxyethylmethylcellulose and the like can be used.
  • casein or zein may be selected as the protein, and polyvinyl alcohol such as polyvinyl alcohol may be used as the polyvinyl derivative , Polyvinylpyrrolidone and polyvinyl acetal diethylaminoacetate.
  • polymethacrylate copolymer poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate ), Poly (methacrylic acid, methyl methacrylate) copolymer, poly (methacrylic acid, ethyl acrylate) copolymer and the like can be selected and polyethylene glycol, polyethylene oxide and the like can be selectively used as a polyethylene derivative And carbomers can be used as the carboxyvinyl polymer.
  • the pharmaceutical composition can be administered orally or parenterally in any desired dosage form, depending on the kind of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, The effective amount can be adjusted depending on various factors including time, route of administration and minute of composition, duration of treatment, concurrent medication, and the like.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered at a dose of 4000 mg / day at intervals of one to several times, .
  • composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient can be used in combination with the second anticancer drug.
  • the second anticancer agent according to the present invention can be any known anticancer agent.
  • known chemotherapeutic agents such as alkylating agents, metabolic antagonists, natural agents, hormones and antagonists, and biological agents such as immunotherapies and gene therapy agents may be included.
  • Examples of the second anticancer agent according to the present invention include nitrogene mustard, imatinib, oxaliplatin, erlotinib, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, cisplatin, viscum alum, But are not limited to, nadir, tretinoin, hydroxycarbamide, dasatinib, estramermin, gemtuzumab ozogamicin, ibritumomat cetane, heptaplatin, methylaminelebulinic acid, amsacrine, proccarbazine, , Holmium nitrate chitosan, gemcitabine, doxifluridine, femetrexed, tegafur, capecitabine, gimeracin, atheracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and a combined preparation comprising a second anticancer drug.
  • the kind of the second anticancer agent is as exemplified above.
  • Indazole 3-carboxylic acid (1 eq.) was dissolved in tetrahydrofuran, stirred at 0 ° C, and a solution of 1M lithium aluminum hydride (1.05 eq.) In tetrahydrofuran was slowly added thereto. Lt; / RTI > When the reaction was completed, water was added to remove remaining lithium aluminum hydride, and extraction with ethyl acetate was carried out. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture containing indazole-3-methyl alcohol. The residue was dissolved in dimethylmethane and pyridine dichromic acid (2 eq.) Was added.
  • Yl ⁇ methylene] -2,4-dioxothiazolidin-3-yl] butanoic acid was prepared from (Z) -4- [5- 0.1 M methanol solution was prepared, and 1 M potassium hydroxide methanol solution (1 eq.) was added dropwise while stirring at 60 ⁇ , followed by stirring at 60 ⁇ for 1 hour. Then, the temperature was lowered to room temperature, and the formed precipitate was stirred and washed with methanol 2-3 times to obtain the desired compound (yield: 76%).
  • SW480 cells were obtained from the American Type Culture Collection (ATCC, Manassas, Va.).
  • HEK293 reporter cells HEK293 cells with TOPflash gene chromosome
  • Oh Sang Taek Kel Min University, Seoul, Korea.
  • HEK293 reporter cells were cultured in DMEM (Gibco) supplemented with 10% fetal bovine serum (FBS; Gibco).
  • SW480 cells were cultured in RPMI 1640 medium containing 10% FBS.
  • the activity of the TOPflash reporter of A2731, A3249, A4280, A4297, A3249, A2483, A3461 and A3011 was similar to or lower than that of the TOPflash reporter of the comparative compound KYA1797K. It was experimentally confirmed that the compounds of the present invention are superior to the comparative compound KYA1797K in inhibiting the Wnt /? - catenin signal transduction system.
  • the changes in the amount of each protein were observed using anti-pan-Ras, anti- ⁇ -catenin and anti- ⁇ -tubulin antibodies and quantification of each pan-Ras and ⁇ - , And normalized to a relative value with the gain of the control group (DMSO) set to 1, and the graphs are shown in Figs. 1 to 3.
  • the compounds A3249, A4365 and A4365H showed cytotoxicity and the compounds A3004, A2698, A2725, A3250, A4267, A4278, A4267, A4283, A4284, A4352, A4353, A4354, A4363, Or [beta] -catenin, respectively.
  • These compounds have been experimentally confirmed to be capable of simultaneously inhibiting the Wnt / ⁇ -catenin signal transduction system and Ras.

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Abstract

La présente invention concerne un composé qui dégrade simultanément la ß-caténine et une protéine Ras comprenant une mutation K-Ras. Le composé selon la présente invention induit l'inhibition de la prolifération cancéreuse et la mort de cellules cancéreuses par la régulation d'une entrée de signal dans un système de transduction de signal clé impliqué dans le cancer, présentant ainsi un effet sur le traitement du cancer chez des patients atteints d'un cancer montrant une résistance aux agents anticancéreux classiques en raison d'une anomalie de transduction du signal Wnt et d'une mutation du gène de Ras.
PCT/KR2017/003704 2016-04-04 2017-04-04 Composé hétérocyclique décomposant une protéine ras et utilisations correspondantes Ceased WO2017176040A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209083A1 (fr) * 2018-04-26 2019-10-31 재단법인 의약바이오컨버젼스연구단 Nouveau composé utilisé en tant qu'inhibiteur de mtor et utilisation associée
WO2019235879A1 (fr) * 2018-06-08 2019-12-12 재단법인 의약바이오컨버젼스연구단 Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor
WO2023121184A1 (fr) * 2021-12-21 2023-06-29 (주)메디픽 Composé dérivé de thiazolidinedione substitué et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102620902B1 (ko) * 2020-04-24 2024-01-04 가천대학교 산학협력단 신규 알파-시누클레인 방사성 리간드 및 이를 포함하는 신경퇴행성 질환 진단용 조성물

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003073999A2 (fr) * 2002-03-01 2003-09-12 Pintex Pharmaceuticals, Inc. Composes de modulation de pin1 et procedes d'utilisation correspondant
US20040214872A1 (en) * 2002-09-26 2004-10-28 Pintex Pharmaceuticals, Inc. Pin1-modulating compounds and methods of use thereof
US20090227624A1 (en) * 2008-01-28 2009-09-10 Ramanuj Dasgupta Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
US9056862B2 (en) * 2011-05-10 2015-06-16 National University Corporation Kobe University Thioxothiazolidine derivative having Ras function inhibitory effect

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102078318A (zh) * 2009-11-27 2011-06-01 华东理工大学 5-取代-2，4-噻唑烷二酮类化合物在制备igf1r功能调节药物中的应用
KR101404185B1 (ko) * 2012-03-09 2014-06-11 연세대학교 산학협력단 Ｗｎｔ／β-카테닌 신호전달계와 관련된 질병의 예방 및 치료용 약학 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003073999A2 (fr) * 2002-03-01 2003-09-12 Pintex Pharmaceuticals, Inc. Composes de modulation de pin1 et procedes d'utilisation correspondant
US20040214872A1 (en) * 2002-09-26 2004-10-28 Pintex Pharmaceuticals, Inc. Pin1-modulating compounds and methods of use thereof
US20090227624A1 (en) * 2008-01-28 2009-09-10 Ramanuj Dasgupta Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
US9056862B2 (en) * 2011-05-10 2015-06-16 National University Corporation Kobe University Thioxothiazolidine derivative having Ras function inhibitory effect

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHA, P.-H.: "Small-molecule binding of the axin RGS domain promotes [beta]-catenin and Ras degradation", NATURE CHEMICAL BIOLOGY, vol. 12, no. 8, August 2016 (2016-08-01), pages 593 - 600, XP055601388 *

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Publication number Priority date Publication date Assignee Title
US11649231B2 (en) 2018-04-26 2023-05-16 Medicinal Bioconvergence Research Center Compound as mTOR inhibitor and use thereof
CN112368279B (zh) * 2018-04-26 2024-05-28 医药生命融合研究团 作为mTOR抑制剂的新化合物及其用途
JP7491510B2 (ja) 2018-04-26 2024-05-28 メディシナル バイオコンバージェンス リサーチ センター ｍＴＯＲ阻害剤としての新規化合物及びその用途
CN112368279A (zh) * 2018-04-26 2021-02-12 医药生命融合研究团 作为mTOR抑制剂的新化合物及其用途
WO2019209083A1 (fr) * 2018-04-26 2019-10-31 재단법인 의약바이오컨버젼스연구단 Nouveau composé utilisé en tant qu'inhibiteur de mtor et utilisation associée
JP2021527629A (ja) * 2018-04-26 2021-10-14 メディシナル バイオコンバージェンス リサーチ センター ｍＴＯＲ阻害剤としての新規化合物及びその用途
KR102297501B1 (ko) * 2018-06-08 2021-09-02 재단법인 의약바이오컨버젼스연구단 신규 mTOR 저해제를 포함하는 암 예방 또는 치료용 조성물
KR20190139637A (ko) * 2018-06-08 2019-12-18 재단법인 의약바이오컨버젼스연구단 신규 mTOR 저해제를 포함하는 암 예방 또는 치료용 조성물
WO2019235879A1 (fr) * 2018-06-08 2019-12-12 재단법인 의약바이오컨버젼스연구단 Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12433910B2 (en) 2020-12-03 2025-10-07 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
WO2023121184A1 (fr) * 2021-12-21 2023-06-29 (주)메디픽 Composé dérivé de thiazolidinedione substitué et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant
EP4455143A4 (fr) * 2021-12-21 2025-10-29 Medific Inc Composé dérivé de thiazolidinedione substitué et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems

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