+

WO2021137665A1 - Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation - Google Patents

Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation Download PDF

Info

Publication number
WO2021137665A1
WO2021137665A1 PCT/KR2020/095153 KR2020095153W WO2021137665A1 WO 2021137665 A1 WO2021137665 A1 WO 2021137665A1 KR 2020095153 W KR2020095153 W KR 2020095153W WO 2021137665 A1 WO2021137665 A1 WO 2021137665A1
Authority
WO
WIPO (PCT)
Prior art keywords
triazol
ethyl
dihydroxyphenyl
nmr
mhz
Prior art date
Application number
PCT/KR2020/095153
Other languages
English (en)
Korean (ko)
Inventor
류재상
이소윤
Original Assignee
이화여자대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020190178332A external-priority patent/KR102406246B1/ko
Priority claimed from KR1020190178450A external-priority patent/KR102406248B1/ko
Application filed by 이화여자대학교 산학협력단 filed Critical 이화여자대학교 산학협력단
Publication of WO2021137665A1 publication Critical patent/WO2021137665A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a 1,2,3-triazole derivative compound having heat shock protein 90 (HSP90) inhibitory activity, an optical isomer thereof, and a pharmaceutically acceptable salt thereof; their use for the manufacture of a medicament for treatment; treatment methods using them; pharmaceutical compositions containing them; and to a method for their preparation.
  • HSP90 heat shock protein 90
  • Heat shock protein 90 (Hsp90) chaperone is one of the most abundant molecular chaperones in eukaryotic cells, and is responsible for stabilizing and regulating the activity of various proteins related to cell growth, differentiation, and survival.
  • Hsp90 client proteins are tyrosine kinases, metastable signaling proteins (Akt, Raf-1, IKK), and mutated signaling proteins (p53, Kit, Flt3, v-Src). These client proteins bind to Hsp90 to form an intermediate complex. form them This intermediate complex is bound to co-chaperones such as Hsp70, Hsp40, Hip, and Hop, and when ATP is bound and hydrolyzed, Hsp90 is a mature complex containing p23, p50/cdc37, and immunophilins (IP). and catalyzes conformational maturation of the Hsp90 client protein.
  • co-chaperones such as Hsp70, Hsp40, Hip, and Hop
  • IP immunophilins
  • Hsp90 exists in an uncomplexed form with low affinity for Hsp90 inhibitors in normal cells. Therefore, Hsp90 inhibitors do not show sensitivity to normal cells and do not accumulate.
  • Hsp90 is involved in the folding and conformational maturation of the overexpressed oncoprotein, and exists in a complex form with the co-chaperon protein. This complexed Hsp90 shows a strong affinity for the Hsp90 inhibitor in cancer cells, and the Hsp90 inhibitor accumulates in the cancer cells. This is thought to be because the mutated proteins in cancer use more Hsp90 and the dependence on Hsp90 increases.
  • Hsp90 is recognized as an important target for selectively inhibiting the growth of cancer cells rather than normal cells in the development of new anticancer drugs.
  • the matrix protein which is a client protein of Hsp90, contains about 50 cancer-causing proteins, and when Hsp90 activity is inhibited, the Hsp90 client proteins are degraded by the proteasome. Therefore, Hsp90 activity inhibitors are receiving great attention as anticancer agents that can be applied to a wide range of cancers because they can simultaneously reduce various cancer-causing proteins.
  • HSP90 is involved in antigen presentation and activation of lymphocytes and phagocytes
  • HSP90 inhibitors inhibit the progression of autoimmune encephalomyelitis, rheumatoid arthritis, and systemic lupus erythematosus in an animal model.
  • neurodegenerative diseases such as senile dementia, Parkinson's disease, and polyglutamine (polyQ) disease have in common that they are accompanied by accumulation and aggregation of disease-causing proteins.
  • SBMA Spinal and bulbar muscular atrophy
  • Kennedy's disease is one of the nine polyQ diseases known to date, accompanied by muscle degeneration.
  • the disease is caused by a mutation in the androgen receptor that repeats 14 or more glutamine residues. Androgen receptor is a client protein of Hsp90, and it has been reported that the treatment of 17AAG, an Hsp90 inhibitor, alleviates the symptoms of SBMA.
  • HSP90 In addition to the intracellular HSP90, there is also a secreted HSP90, and the secreted HSP90 is increased in the blood of patients with chronic obstructive pulmonary disease (COPD), in which neutrophils and large phagocytic cells are increased. HSP90 is also known to be involved in the epithelial-mesenchymal transition (EMT), a mechanism involved in airway degeneration in asthma or COPD patients.
  • EMT epithelial-mesenchymal transition
  • novobiocin and cisplain inhibit Hsp90 by binding to the second ATP binding site thought to exist at the C-terminus of Hsp90.
  • Hsp90 present in tumor cells has higher ATPase activity than normal cells and has a high binding affinity with Hsp90 inhibitors, so that Hsp90 inhibitors can act specifically on tumor cells.
  • the anticancer activity of Hsp90 inhibitors has been verified in various in vitro and in vivo model systems, and 17-AAG is showing promising results as a therapeutic agent in clinical trials for various cancers.
  • 17-AAG has problems such as formulation, potential toxicity, and low water solubility, continuous development of Hsp90 inhibitors with improved pharmaceutical properties and efficacy is required.
  • the present researchers tried to find a substance with better anticancer activity by synthesizing a new inhibitor with a different backbone from the existing Hsp90 inhibitor structure.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a 1,2,3-triazole derivative compound having HSP90 inhibitory activity, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the same.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above compounds for the prevention or treatment of diseases related to HSP90 activity.
  • Another object of the present invention is to provide a use thereof for the manufacture of a medicament for the prophylaxis or treatment of diseases related to HSP90 activity.
  • Another object of the present invention is to provide a method for treating a disease associated with HSP90 activity comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising the above compounds.
  • the present inventors have completed the present invention by discovering a 1,2,3-triazole derivative compound having HSP90 inhibitory activity and using it to inhibit or treat HSP90 activity-related diseases.
  • the term -(C 1 -C 4 alkyl) refers to, for example, C 1 -C 4 such as methyl, ethyl, propyl, isopropyl, butyl. It means a straight or branched chain saturated hydrocarbon.
  • the term -O-(C 1 -C 4 alkyl) is, for example, methoxy, ethoxy, propoxy, isopropoxy, C 1 -C 4 of which oxygen is connected, such as butoxy. It refers to linear or branched saturated hydrocarbons.
  • -C 1 -C 4 haloalkyl is C 1 -C 4 C 1 -C 4 in which at least one hydrogen of a linear or branched saturated hydrocarbon is substituted with a halogen compound (ie, F, Cl, Br, or I) It refers to linear or branched saturated hydrocarbons.
  • a halogen compound ie, F, Cl, Br, or I
  • C 6 -C 12 aryl refers to an aromatic hydrocarbon containing 6 or 12 carbon atoms. monocyclic (eg, phenyl); ring systems such as bicyclic (eg, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl).
  • C 2 -C 12 heteroaryl refers to an aromatic hydrocarbon containing 2 to 12 carbon atoms wherein at least one of the ring carbon atoms is replaced with a heteroatom selected from oxygen, nitrogen and sulfur.
  • the heteroaryl group may be attached through a ring carbon atom, or, where valency permits, through a ring nitrogen, oxygen, or sulfur atom, and the like.
  • the heteroaryl is thiophenyl, quinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl pyridinyl, triazinyl, thiazolyl, furanyl, thiophenyl, indolyl, benzopyridinyl, pyra including, but not limited to, sleepiness.
  • C 2 -C 12 heterocycloalkyl refers to cycloalkyl containing 2 to 12 carbon atoms, each substituted by a heteroatom.
  • the heterocyclo group may be optionally substituted through a ring carbon atom, or, where valency permits, through a ring nitrogen, oxygen, or sulfur atom, and the like.
  • the present invention provides a 1,2,3-triazole derivative compound represented by the following formula (Ia), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • Y 1 to Y 3 are each independently -F, -Cl, -Br, -I, -CN, -OH or C 1 -C 4 alkyl;
  • R is a substituted or unsubstituted C 6 -C 12 aryl, or a substituted or unsubstituted C 2 -C 12 heteroaryl containing a heteroatom selected from oxygen, nitrogen and sulfur;
  • n is an integer of 1 to 4,
  • X is a substituted or unsubstituted C 6 -C 12 aryl, or a substituted or unsubstituted C 2 -C 12 heteroaryl containing a heteroatom selected from oxygen, nitrogen and sulfur, wherein Y is absent In case X is unsubstituted,
  • Z is -H, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 2 -C 12 heterocycloalkyl comprising a heteroatom selected from oxygen, nitrogen and sulfur, wherein C 6 When ⁇ C 12 aryl or C 2 ⁇ C 12 heterocycloalkyl is substituted, each substitution is independently -C 1 -C 4 alkyl, -F, -Cl, -Br, -I, -CN and -OH It is substituted with any one or more selected from.
  • Y 1 may be C 1 -C 4 alkyl, and Y 2 and Y 3 may each independently be —OH.
  • the present invention provides a 1,2,3-triazole derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • R is a substituted or unsubstituted C 6 -C 12 aryl, or a substituted or unsubstituted C 2 -C 12 heteroaryl comprising a heteroatom selected from oxygen, nitrogen and sulfur;
  • n is an integer of 1 to 4,
  • X is a substituted or unsubstituted C 6 -C 12 aryl, or a substituted or unsubstituted C 2 -C 12 heteroaryl containing a heteroatom selected from oxygen, nitrogen and sulfur, wherein Y is absent In case X is unsubstituted,
  • Z is -H, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 2 -C 12 heterocycloalkyl comprising a heteroatom selected from oxygen, nitrogen and sulfur, wherein C 6 When ⁇ C 12 aryl or C 2 ⁇ C 12 heterocycloalkyl is substituted, each substitution is independently -C 1 -C 4 alkyl, -F, -Cl, -Br, -I, -CN and -OH It is substituted with any one or more selected from.
  • the 1,2,3-triazole derivative compound represented by the formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof may preferably be:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently CR a , CR b , CR c , CR d , CR e , CR f , CR g , O, N and S Any one selected from the group consisting of;
  • R a to R g are each independently -H, -F, -Cl, -Br, -I, -CN, -OH, -C 1 -C 4 alkyl, -O-(C 1 -C 4 alkyl), -NH 2 , and -NO 2 Any one selected from the group consisting of;
  • Z 8 is each independently any one selected from the group consisting of O, NH and S;
  • R 6 may be any one selected from the group consisting of H, -F, -Cl, -I, -Br, and -CN.
  • R is When , at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 is N, O, or S, and thus the ring may be heteroaryl.
  • At least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 is N, and more preferably, Z 1 may be N.
  • Z 1 is N
  • Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are CH.
  • Z 8 is preferably S.
  • R 6 is preferably any one selected from the group consisting of -F, -Cl, -I, -Br and -CN.
  • 1,2,3-triazole derivative compound represented by the formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof may preferably be:
  • X is It may be any one selected from the group consisting of.
  • any carbon position of X may be connected to the 1,2,3-triazole ring.
  • any carbon, O, N, or S position of X may be connected with Y.
  • 1,2,3-triazole derivative compound represented by the formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof may preferably be:
  • Z is -H, It may be any one selected from the group consisting of.
  • n is preferably 1.
  • Z when Z is a substituted C 6 -C 12 aryl, or a C 2 -C 12 heterocycloalkyl containing a heteroatom selected from substituted oxygen, nitrogen and sulfur, the substitution is each independently -C 1 ⁇ C 4 It may be composed of alkyl.
  • the compound represented by the formula (I) may preferably be a compound shown in Tables 1 and 2 below:
  • the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, Inorganic acid salts prepared from iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glue Organic acid salts prepared from conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, There are sulfonic acid,
  • the compounds represented by the formula (I) of the present invention may contain one or more asymmetric carbons and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. have.
  • Such isomers can be separated by conventional techniques, for example, the compound represented by formula (I) by column chromatography or resolution such as HPLC.
  • stereoisomers of each of the compounds represented by the formula (I) can be stereospecifically synthesized using optically pure starting materials and/or reagents of known configurations.
  • the present invention provides a method for preparing a 1,2,3-triazole derivative compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Preferred preparation of the 1,2,3-triazole derivative compound represented by the formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof is preferably carried out through the following methods.
  • Each of the synthesized azide compounds was referred to as 6a to 6c (the alphabet after each number corresponds to the alphabet after the finally synthesized number).
  • the synthesis was carried out through nucleophilic substitution using NaN 3 as a nucleophile from commercially available benzyl halides.
  • the present invention provides a method for preparing a 1,2,3-triazole derivative compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Preferred preparation of the 1,2,3-triazole derivative compound represented by the formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof is preferably carried out through the following methods.
  • 5-iodo-1,4-disubstituted-1,2,3-triazole is synthesized by linking alkyne with azide of various structures as a click-iodination reaction condition, and secondly, Suzuki cross coupling under palladium catalyst is used to synthesize 5-iodo-1,4-disubstituted-1,2,3-triazole.
  • Suzuki cross coupling under palladium catalyst is used to synthesize 5-iodo-1,4-disubstituted-1,2,3-triazole.
  • a 1,2,3-triazole derivative compound represented by Formula I is synthesized (Scheme 4).
  • one-pot iodide is introduced at position 5 of 1,2,3-triazole so that it can become a coupling partner for Suzuki cross-coupling while linking alkyne and azide through click chemistry.
  • the reaction condition of this one-pot click-iodination reaction is a method that was not used in previous studies and is an efficient method implemented for the first time in this study.
  • azide compounds were synthesized under the following conditions for synthesizing the compounds of Examples 40 to 59, respectively.
  • Each of the synthesized azide compounds was referred to as 12a to 12t (the alphabet after each number coincides with the alphabet after the number to be synthesized).
  • the synthesis was carried out through nucleophilic substitution using NaN 3 as a nucleophile from commercially available benzyl halides.
  • 1,2,3- triazole Compositions comprising derivative compounds, uses thereof, and methods of treatment using the same
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a 1,2,3-triazole derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a 1,2,3-triazole derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the present invention for use in the treatment and/or prevention of diseases related to heat shock protein 90 (HSP90) activity is a 1,2,3-triazole derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable provide salt.
  • the present invention provides a pharmaceutical composition for preventing or treating HSP90 activity-related diseases, comprising a 1,2,3-triazole derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • a pharmaceutical composition for preventing or treating HSP90 activity-related diseases comprising a 1,2,3-triazole derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • the pharmaceutical composition of the present invention exhibits a remarkable effect in preventing or treating diseases related to HSP90 activity.
  • Lung cancer pancreatic cancer, colorectal cancer, colorectal cancer, myeloid leukemia, thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancer, uterine cancer, ovarian cancer, brain cancer, stomach cancer, malignancies such as laryngeal cancer, esophageal cancer, bladder cancer, oral cancer, cancer of mesenchymal origin, sarcoma, teratocarcinoma, neuroblastoma, renal carcinoma, liver cancer, non-Hodgkin's lymphoma, multiple myeloma, and undifferentiated thyroid cancer;
  • metabolic diseases such as Wilson's disease, amyloidosis or diabetes
  • SMA spinal muscular atrophy
  • SCA spinal cerebellar ataxia
  • Degenerative neurological diseases or inflammatory diseases such as dementia, polyglutamine disease, Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth disease, sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy, amyotrophic lateral sclerosis, or multiple sclerosis neurological diseases, including neurological diseases;
  • digestive disorders such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease;
  • Inflammatory diseases of the musculoskeletal system and connective tissue such as rheumatoid arthritis, osteoarthritis, or systemic lupus erythematosus (SLE), etc., are also included, and in addition, symptoms or diseases related to the abnormal function of HSP90 are included.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a 1,2,3-triazole derivative compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for preventing or treating cancer comprising a 1,2,3-triazole derivative compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the lung cancer pancreatic cancer, colorectal cancer, colorectal cancer, myeloid leukemia, thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancer, uterine cancer, ovarian cancer, Any one selected from the group consisting of brain cancer, stomach cancer, laryngeal cancer, esophageal cancer, bladder cancer, oral cancer, cancer of mesenchymal origin, sarcoma, teratocarcinoma, neuroblastoma, renal carcinoma, liver cancer, non-Hodgkin's lymphoma, multiple myeloma, and undifferentiated thyroid cancer more than one
  • the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising a 1,2,3-triazole derivative compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the pharmaceutically acceptable salt is the same as described above for the pharmaceutically acceptable salt of the compound represented by Formula I of the present invention.
  • the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for administration.
  • the pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components. , and other conventional additives such as a bacteriostatic agent may be added.
  • compositions of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, and the like.
  • formulations can be prepared by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (the latest edition), Mack Publishing Company, Easton PA, and are formulated into various formulations according to each disease or component. can be
  • composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the weight, age, sex, and health status of the patient. , diet, administration time, administration method, excretion rate, and the severity of the disease, etc., the range varies.
  • the daily dose of the compound represented by the formula (I) of the present invention is about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg, and may be administered once to several times a day in divided doses.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for preventing or treating a disease related to HSP90 activity, comprising administering to a subject a therapeutically effective amount of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Suitable subjects according to the present invention include mammalian subjects.
  • a human is a suitable subject.
  • a human subject can be male or female and at any stage of growth.
  • terapéuticaally effective amount refers to an amount of the compound represented by Formula I effective for the prevention or treatment of HSP90 activity-related diseases.
  • the present invention provides a method for inhibiting HSP90 by administering a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a mammal, including a human.
  • the method for preventing or treating a disease related to HSP90 activity of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms by administering the compound represented by the formula (I).
  • the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered.
  • the dose and frequency of dose will vary with the age, weight and response of the individual patient.
  • a suitable dosage regimen can be readily selected by one of ordinary skill in the art taking these factors into account.
  • the method for preventing or treating a disease related to HSP90 activity of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful for disease treatment together with the compound represented by Formula I, and the additional active agent
  • the agents may exhibit a synergistic or adjuvant effect together with the compound of formula (I).
  • Another object of the present invention is to provide the use of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of HSP90 activity-related diseases.
  • the compound represented by the formula (I) for the manufacture of a medicament may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
  • composition comprising a compound represented by the above formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease related to HSP90 activity.
  • the present invention provides an HSP90 inhibitor comprising the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) of the present invention can selectively inhibit HSP90, so that the preventive or therapeutic effect on HSP90 activity-related diseases is remarkably excellent.
  • reagents and solvents mentioned below were purchased from Sigma-Aldrich, TCI, and Alfa aesar unless otherwise specified.
  • MPLC medium-pressure liquid chromatography
  • silica gel for column chromatography was Merck's 230400 mesh silica gel 60 system was used.
  • 1 H-NMR and 13 C-NMR data were measured using Varian Unity 400 MHz, and Mass Spectrum was performed using Agilent Technologies' 6220 TOF LC/MS spectrometer system.
  • a specific method for preparing the compound of Formula I is as follows.
  • POCl 3 (12 mL, 130.51 mmol) was dissolved in anhydrous DMF (22 mL) under argon gas, and stirred at 5° C. for 15 minutes.
  • 4-ethylresorcinol (1) (6.01 g, 43.50 mmol) was dissolved in anhydrous DMF (22 mL) and added to the solution, followed by stirring at room temperature for 19 hours.
  • the reaction mixture was cooled to 0 °C, adjusted to pH 10 by treatment with 10% aqueous NaOH solution, and stirred for 1 hour.
  • the mixture was adjusted to pH 4 by treatment with 1 M HCl.
  • the organic layer was separated, and the aqueous layer was extracted three times with CH 2 Cl 2 (3 ⁇ 500 mL).
  • 5-ethyl-2,4-dihydroxybenzaldehyde (2) (2.50 g, 15.0 mmol) and imidazole (4.09 g, 60.2 mmol) were dissolved in anhydrous DMF (8 mL) under argon gas, and TBDMSCl ( 6.80 g, 45.1 mmol) in anhydrous DMF (11 mL) was added. After stirring at room temperature for 2 hours, distilled water (30 mL) was added. The organic layer was separated, and the aqueous layer was extracted three times with a petroleum-ether:ether 9:1 solution (3 ⁇ 50 mL).
  • 1,2,3-triazole derivative compound 7a (30.4 mg, 45.0 ⁇ mol), 4-methoxyphenylboronic acid (10.3 mg, 68 ⁇ mol, 1.5 equiv.) and K 2 CO 3 (0.27 mmol, 3 equiv.) placed in a microwave vial.
  • Dioxane-water (3:1) (0.0225M) was added by syringe and Ar gas was bubbled through the reaction mixture for 5 min.
  • Pd(PPh 3 ) 4 (0.009 mmol, 0.1 eq) was added and the reaction mixture was irradiated with microwaves at 110° C. for 3 hours.
  • water (30 mL) was added and the reaction mixture was extracted with EtOAc (100 mL). The organic layer was dried over magnesium sulfate, filtered over EtOAc and concentrated in vacuo. Purification by column chromatography on silica gel gave the desired product 10a (17.8 mg, 93%) as an ivory solid.
  • the final compound was synthesized as follows by removing the TBS protecting group of the 1,2,3-triazole compound (14a-14t) having a TBS protecting group with TBAF.
  • Example 40 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(4-methylbenzyl)-1H-[1,2,3]triazole -4-yl]-6-ethylbenzene-1,3-diol (17a).
  • Example 41 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(4-methoxybenzyl)-1H-[1,2,3]tria zol-4-yl]-6-ethylbenzene-1,3-diol (17b).
  • Example 42 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(3-methoxybenzyl)-1H-[1,2,3]tria zol-4-yl]-6-ethylbenzene-1,3-diol (17c).
  • Example 43 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(4-nitrobenzyl)-1H-[1,2,3]triazole -4-yl]-6-ethylbenzene-1,3-diol (17d).
  • Example 44 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(3-nitrobenzyl)-1H-[1,2,3]triazole -4-yl]-6-ethylbenzene-1,3-diol (17e).
  • Example 45 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-fluoro-6-nitrobenzyl)-1H-[1,2 ,3]triazol-4-yl]-6-ethylbenzene-1,3-diol (17f).
  • Example 46 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(4-fluorobenzyl)-1H-[1,2,3]tria zol-4-yl]-6-ethylbenzene-1,3-diol (17 g).
  • Example 47 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-fluorobenzyl)-1H-[1,2,3]tria zol-4-yl]-6-ethylbenzene-1,3-diol (17h).
  • Example 48 4-[1-(2,3-difluorobenzyl)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1H-[1,2, 3]triazol-4-yl]-6-ethylbenzene-1,3-diol (17i).
  • Example 49 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-fluoro-5-trifluoromethylbenzyl)-1H-[ 1,2,3]triazol-4-yl]-6-ethylbenzene-1,3-diol (17j).
  • Example 50 4-[1-(2-chloro-5-trifluoromethylbenzyl)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1H-[1 ,2,3]triazol-4-yl]-6-ethylbenzene-1,3-diol (17k).
  • Example 51 4-[1-(3-chlorobenzyl)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1H-[1,2,3]triazole -4-yl]-6-ethylbenzene-1,3-diol (17l).
  • Example 53 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-(5-ethyl-2,4-dihydroxyphenyl)-[1, 2,3]triazol-1-ylmethyl]benzoic acid ethyl ester (17n).
  • Example 54 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(4-trifluoromethylbenzyl)-1H-[1,2,3 ]triazol-4-yl]-6-ethylbenzene-1,3-diol (17o).
  • Example 55 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-(5-ethyl-2,4-dihydroxyphenyl)-[1, 2,3]triazol-1-ylmethyl]benzonitrile (17p).
  • Example 57 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(3,4,5-trimethoxybenzyl)-1H-[1, 2,3]triazol-4-yl]-6-ethylbenzene-1,3-diol (17r).
  • Example 58 4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-quinolin-2-ylmethyl-1H-[1,2,3]triazole -4-yl]-6-ethylbenzene-1,3-diol (17s).
  • Example 59 4-[1-(5-chlorothiophen-2-ylmethyl)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1H-[1, 2,3]triazol-4-yl]-6-ethylbenzene-1,3-diol (17t).
  • the assay is based on competition of fluorescently labeled geldanamycin (FITC-GM) for binding to HSP90. Since FITC-GM binds to the ATP binding pocket of HSP90, this assay identified an inhibitor of ATP competition.
  • reaction buffer 20 mM HEPES, pH 7.5, 50 mM NaCl, 10 mM MgCl 2 , 0.02% Brij 35, Add fresh: 2 mM DTT, 0.02 mg/ml BSA, 1% DMSO
  • the compounds dissolved in DMSO were mixed with the enzyme mixture using Echo550 from Acoustic Technology and incubated for 10 minutes. The reaction was initiated by mixing the FITC-GM mixture. Incubated for 2 hours at room temperature with gentle mixing.
  • the IC 50 value was determined by measuring the fluorescence polarization and calculating the mP value.
  • Example compound Compound IC50* ( ⁇ M): HSP90a
  • Example 1 10a 0.00970
  • Example 2 10b 0.00524
  • Example 3 10c 0.03211
  • Example 4 10d 0.12310
  • Example 5 10e 1.13700
  • Example 6 10f 0.06657
  • Example 7 10g 0.25830
  • Example 8 10h 0.89930
  • Example 9 10i 0.18370
  • Example 11 10k 0.04301
  • Example 12 10l 0.05460
  • Example 13 10n 0.04161
  • Example 14 10n 0.32570
  • Example 16 10p 0.02453
  • Example 17 10q 0.02268
  • Example 18 10r 0.10200
  • Example 19 10s 0.08332
  • HSP90 inhibitory ability was assayed based on the binding ability to HSP90a and HSP90b of Examples 20 to 39 similarly to the above Examples. The results are shown in Table 9.
  • Example compound Compound IC 50 ( ⁇ M): HSP90a HSP90b Example 20 11a 0.05638 0.32640 Example 21 11b 0.02485 0.15590 Example 22 11c 0.01206 0.03620 Example 23 11d 0.03571 0.10520 Example 24 11e 0.03530 0.20280 Example 25 11f 0.04407 0.16160 Example 26 11g 0.03576 0.37860 Example 27 11h 0.01149 0.06182 Example 28 11i 0.00602 0.03211 Example 29 11j 0.04022 0.31510 Example 30 11k 0.04369 0.50130 Example 31 11l 0.02463 0.12280 Example 32 11m 0.01186 0.03336 Example 33 11n 0.02408 0.20110 Example 34 11o 0.04234 0.20060 Example 35 11p 0.04804 0.23120 Example 36 11q 0.07434 0.42530 Example 37 11r 0.01726 0.12660 Example 38 11s 0.02450 0.06859 Example 39 11t 0.05738 0.34710
  • Example 61 HSP90 ⁇ inhibition assay of Examples 40 to 59 (IC50 measurement)
  • the assay is based on competition of fluorescently labeled geldanamycin (FITC-GM) for binding to HSP90. Since FITC-GM binds to the ATP binding pocket of HSP90, this assay identified an inhibitor of ATP competition.
  • reaction buffer 20 mM HEPES, pH 7.5, 50 mM NaCl, 10 mM MgCl 2 , 0.02% Brij 35, Add fresh: 2 mM DTT, 0.02 mg/ml BSA, 1% DMSO
  • the compounds dissolved in DMSO were mixed with the enzyme mixture using Echo550 from Acoustic Technology and incubated for 10 minutes. The reaction was initiated by mixing the FITC-GM mixture. Incubated for 2 hours at room temperature with gentle mixing.
  • the IC50 value was determined by measuring the fluorescence polarization and calculating the mP value.
  • Example compound Compound IC 50 ( ⁇ M): Example 40 17a 0.2033 Example 41 17b 0.2544 Example 42 17c 0.2074 Example 43 17d 0.2491 Example 44 17e 0.1781 Example 45 17f 0.06993 Example 46 17g 0.1538 Example 47 17h 0.2354 Example 48 17i 0.1394 Example 49 17j 0.4800 Example 50 17k 4.216 Example 51 17l 0.5185 Example 53 17m 0.1222 Example 53 17n 0.1156 Example 54 17o 0.7274 Example 55 17p 0.2138 Example 56 17q 0.07528 Example 57 17r 14.5 Example 58 17s 0.2188 Example 59 17t 0.1112
  • the example compounds according to the present invention exhibited an excellent HSP90 inhibitory effect. Considering these results, the compound according to the present invention exhibits excellent effects in preventing, treating, and ameliorating diseases related to HSP90 activity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne : un composé dérivé de 1,2,3-triazole ayant une activité inhibitrice de la protéine de choc thermique 90 (HSP90), un isomère optique, et un sel pharmaceutiquement acceptable de celui-ci ; ainsi qu'une utilisation correspondante pour préparer un médicament thérapeutique ; une méthode de traitement l'utilisant ; une composition pharmaceutique le contenant ; et un procédé de préparation associé. Le composé représenté par la formule chimique I, l'isomère optique, ou le sel pharmaceutiquement acceptable de celui-ci, selon la présente invention peut inhiber de manière sélective la HSP90 ce qui permet d'obtenir un excellent effet de prévention ou de traitement d'une maladie associée à l'activité de HSP90.
PCT/KR2020/095153 2019-12-30 2020-12-29 Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation WO2021137665A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1020190178332A KR102406246B1 (ko) 2019-12-30 2019-12-30 Hsp90 억제제로서의 1,2,3-트리아졸 유도체 화합물 및 이의 용도
KR10-2019-0178332 2019-12-30
KR1020190178450A KR102406248B1 (ko) 2019-12-30 2019-12-30 Hsp90 억제제로서의 1,2,3-트리아졸 유도체 화합물
KR10-2019-0178450 2019-12-30

Publications (1)

Publication Number Publication Date
WO2021137665A1 true WO2021137665A1 (fr) 2021-07-08

Family

ID=76686961

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/095153 WO2021137665A1 (fr) 2019-12-30 2020-12-29 Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation

Country Status (1)

Country Link
WO (1) WO2021137665A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114671861A (zh) * 2022-04-12 2022-06-28 安徽医科大学 一种汉黄芩素衍生物及其制备方法与应用
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030013712A1 (en) * 2001-04-30 2003-01-16 Tullis Joshua Spector Triazole compounds useful in treating diseases associated with unwanted cytokine activity
US20030100558A1 (en) * 2001-04-30 2003-05-29 Tullis Joshua Spector Triazole compounds useful in treating diseases associated with unwanted cytokine activity
KR20090023614A (ko) * 2006-05-18 2009-03-05 메르크 파텐트 게엠베하 트리아졸 유도체 ⅱ
US20140329812A1 (en) * 2010-12-20 2014-11-06 Sigma-Tau Research Switzerland S.A. Aryl triazole compounds with antitumoural activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030013712A1 (en) * 2001-04-30 2003-01-16 Tullis Joshua Spector Triazole compounds useful in treating diseases associated with unwanted cytokine activity
US20030100558A1 (en) * 2001-04-30 2003-05-29 Tullis Joshua Spector Triazole compounds useful in treating diseases associated with unwanted cytokine activity
KR20090023614A (ko) * 2006-05-18 2009-03-05 메르크 파텐트 게엠베하 트리아졸 유도체 ⅱ
US20140329812A1 (en) * 2010-12-20 2014-11-06 Sigma-Tau Research Switzerland S.A. Aryl triazole compounds with antitumoural activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI SHUANG-JUN; LIU QIAN; HE XIAO-BIN; LIU JIN-PING; LIU XIAO-LIU; HU JIE; TANG ZHI-PENG; PENG QING-YUN; CUI LIAN-JIE; ZHANG HUA-NI: "Pyrola incarnata demonstrates neuroprotective effects against β-amyloid-induced memory impairment in mice", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 30, no. 2, 4 December 2019 (2019-12-04), XP086033983, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2019.126858 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114671861A (zh) * 2022-04-12 2022-06-28 安徽医科大学 一种汉黄芩素衍生物及其制备方法与应用
CN114671861B (zh) * 2022-04-12 2023-11-24 安徽医科大学 一种汉黄芩素衍生物及其制备方法与应用
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras

Similar Documents

Publication Publication Date Title
WO2021137665A1 (fr) Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation
WO2011043568A2 (fr) Nouveaux composés efficaces comme inhibiteurs de la xanthine oxydase, leur procédé de préparation et composition pharmaceutique les contenant
AU2019381113B2 (en) Novel compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof
WO2017188694A1 (fr) Composé hétéroaryle comprenant de l'azote et son utilisation
WO2018139903A1 (fr) Composé pyrimidine et son utilisation pharmaceutique
WO2017142325A1 (fr) Nouveau composé thiophène substitué en 2,3,5 utilisé en tant qu'inhibiteur de la protéine kinase
WO2020096372A1 (fr) Nouveau dérivé de pipéridine-2,6-dione et utilisation associée
WO2014109530A1 (fr) Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer
AU2019217094B2 (en) Compounds for inhibiting TNIK and medical uses thereof
WO2014065575A1 (fr) Dérivé de 4,5-dihydro-1h-pyrazole ou ses sels et composition pharmaceutique les comprenant
WO2023054759A1 (fr) Dérivé de 2-aminoquinazoline et composition antivirale le comprenant
WO2020022787A1 (fr) Nouveau dérivé d'imidazole présentant une activité inhibitrice de jnk et composition pharmaceutique le comprenant
WO2011122815A2 (fr) Nouveaux dérivés de quinoxaline
WO2019074241A1 (fr) Inhibiteur de l'interaction entre pd-1 et pd-l1, comprenant un dérivé de phénylacétylène
WO2016006975A2 (fr) Nouveaux dérivés imidazotriazinone ou imidazopyrazinone et leur utilisation
EP3060549A1 (fr) Nouveau dérivé oxodihydropyridinecarbohydrazide antifongique
WO2020101450A1 (fr) Composés dérivés d'azilsartan, leurs intermédiaires, leur procédé de préparation et composition pharmaceutique les comprenant
WO2021172887A1 (fr) Composés dérivés de 1,3,4-oxadiazole utilisés comme inhibiteurs d'histone désacétylase 6, et composition pharmaceutique les comprenant
WO2019235879A1 (fr) Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor
WO2010032986A2 (fr) Nouveaux dérivés de 5-(4-aminophenyl)-isoquinoline, leurs sels pharmaceutiquement acceptables, procédé de production associé et composition contenant les dérivés comme principe actif pour la prophylaxie et le traitement d'états pathologiques induits par l'hyperactivité de la kinase raf
WO2015016511A1 (fr) Nouveau dérivé de biphényle, et son procédé de préparation
WO2012157900A2 (fr) Précurseur marqué au 18-f pour substances radioactives à usage médical utilisées en tomographie par émission de positons et son procédé de préparation
WO2022086110A1 (fr) Dérivé de thiobenzimidazole ou sel pharmaceutiquement acceptable de celui-ci, et leur utilisation
WO2018021762A1 (fr) Nouveau composé, son procédé de préparation, et composition pharmaceutique le contenant
WO2022119090A1 (fr) Dérivés de biphénylpyrrolidine et de biphényldihydroimidazole permettant d'inhiber l'activité du récepteur 5-ht7 de la sérotonine, et composition pharmaceutique le comprenant comme principe actif

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20910161

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20910161

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载