WO2018133756A1 - Agoniste d'autophagie ciblé et son application dans le traitement de maladies neurodégénératives - Google Patents

Agoniste d'autophagie ciblé et son application dans le traitement de maladies neurodégénératives Download PDF

Info

Publication number
WO2018133756A1
WO2018133756A1 PCT/CN2018/072575 CN2018072575W WO2018133756A1 WO 2018133756 A1 WO2018133756 A1 WO 2018133756A1 CN 2018072575 W CN2018072575 W CN 2018072575W WO 2018133756 A1 WO2018133756 A1 WO 2018133756A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
halogen
hydrogen
nmr
Prior art date
Application number
PCT/CN2018/072575
Other languages
English (en)
Chinese (zh)
Inventor
欧阳亮
刘博�
张岚
符雷蕾
魏于全
Original Assignee
四川大学
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
Application filed by 四川大学 filed Critical 四川大学
Publication of WO2018133756A1 publication Critical patent/WO2018133756A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton

Definitions

  • the invention relates to a targeted autophagy agonist and its application in the treatment of neurodegenerative diseases, and belongs to the technical field of therapeutic drug discovery of neurodegenerative diseases.
  • Neurodegenerative disease is a disease state in which cellular neurons of the brain and spinal cord are lost.
  • Typical neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Huntington's disease, are common neurodegenerative diseases in the elderly and are the most common extrapyramidal diseases in the elderly.
  • Parkinson's disease the number of patients in China is over one million. The prevalence rate of people over 65 years old is 1000/100,000. With the increase of age, men are slightly more than women. It is estimated that by 2030, the number of patients in China is close. 5000000.
  • the main clinical features of the disease resting tremor, slowness and reduction of movement, increased muscle tone, and instability of posture are the main features. At present, drug replacement therapy is still the main method of treatment nowadays.
  • levodopa replacement therapy can relieve the motor symptoms of most patients, but it can not prevent the apoptosis and necrosis of dopaminergic neurons. Decrease and the occurrence of side effects such as dyskinesia Therefore, it is of great clinical and social significance to elucidate the pathogenesis and to find effective interventions to develop early intervention and treatment of drugs to delay the development.
  • Neurodegenerative diseases are mainly manifested as motor symptoms, including resting tremor, bradykinesia, muscle rigidity and posture gait abnormalities. In addition, there are some non-motor symptoms such as constipation, olfactory disorders, depression, etc. .
  • Parkinson's disease the degeneration of dopaminergic neurons and the formation of Lewy bodies are the main pathological features. Among them, ⁇ -synuclein is the main component of Lewy bodies and one of the main markers of Parkinson's disease. .
  • Current studies have shown that autophagy can effectively promote the clearance of aggregated proteins in cells, so activation of autophagy may be a potential Parkinson's treatment strategy.
  • the technical problem solved by the present invention is to provide a novel compound as a ULK1 agonist.
  • the present invention provides a compound of formula I or formula II or a pharmaceutically acceptable salt thereof:
  • R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen
  • R 12 is hydrogen, alkyl, alkoxy or halogen
  • R 13 is hydrogen, alkyl, alkoxy or halogen
  • m is 1 or 2
  • y is 1 or 2
  • z is 1 or 2;
  • R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2;
  • X is O or S.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a neurodegenerative disease
  • the therapeutic drug for neurodegenerative diseases is preferably an anti-Parkinson drug.
  • the anti-Parkinson drug is preferably a ULK1 agonist drug, and the use thereof is for Parkinson's disease related treatment.
  • the present invention also provides a pharmaceutical composition which is a preparation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.
  • the compound prepared by the present invention or a pharmaceutically acceptable salt thereof can be used as a ULK1 agonist and has a more obvious Parkinson's therapeutic effect.
  • Fig. 1A shows that SH-SY5Y cells were treated with 5 ⁇ M BL-918 for 24 hours, and a picture of autophagosomes was detected by transmission electron microscopy.
  • Figure 1B shows that SH-SY5Y cells were treated with 5 ⁇ M BL-918 to detect the expression of ULK1, p-ULK1, mAtg13, p-mAtg13, FIP200, Atg101, LC3, Beclin-1 and SQSTM1/p62.
  • Figure 1C is an immunoprecipitation map of the ULK complex.
  • 1D shows that SH-SY5Y cells were transfected with GFP-LC3 and treated with siRNA-NC or siRNA-ULK1, and then incubated with 5 ⁇ M BL-918 for 24 hours, and the expression pattern of GFP-LC3 was observed using a fluorescence microscope.
  • Figure 1E shows that SH-SY5Y cells were transfected with siRNA-NC or siRNA-ULK1 and incubated with 5 ⁇ M BL-918 for 24 hours to detect ULK1, p-ULK1, mAtg13, p-mAtg13, FIP200, Atg101, LC3, Beclin-1 and SQSTM1 The expression level of /p62.
  • Figure 2A is a graph showing the protective effect of BL-918 on MPP+ injured cells by MTT cell survival assay.
  • Figure 2B shows that treatment of cells with si-ULK1 reverses the protective effect of BL-918, and cell viability is determined by MTT assay.
  • Figure 3A is a behavioral experiment of the time of rat swimming and climbing rod test.
  • Figure 3B is a determination of dopamine content in rat striatum.
  • Figure 3C is an immunofluorescence experiment of tyrosine hydroxylase in neurons.
  • the invention provides a compound of formula I or formula II:
  • R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen;
  • R 12 is hydrogen, alkyl, alkoxy or halogen;
  • R 13 is hydrogen, alkyl, alkoxy or halogen;
  • m is 1 or 2;
  • y is 1 or 2;
  • z is 1 or 2;
  • R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2;
  • X is O or S.
  • the chemical structure of the present invention is not required to be a chiral structure, and may be either R or S.
  • the structure is as shown in formula I, that is, the chemical formula is
  • X is O and R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen; R 12 is hydrogen, alkyl, alkoxy or halogen; R 13 is hydrogen, alkyl, alkoxy or halogen; m is 1 or 2; y is 1 or 2; z is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • X is O and R 1 is R 13 is alkyl, alkoxy or halogen; z is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • X is O and R 1 is R 13 is an alkyl group, an alkoxy group or a halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen.
  • X is O and R 1 is R 2 is More preferably, X is O and R 1 is R 2 is
  • X is O and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; y is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • X is O and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen. More preferably, X is O and R 1 is R 2 is More preferably, X is O and R 1 is R 2 is More preferably, X is O and R 1 is R 2 is
  • X is O and R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen; m is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • R 1 is R 111 is alkyl or alkoxy; R 112 is alkyl or alkoxy; R 2 is More preferably, X is O and R 1 is R 2 is
  • X is S;
  • R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen;
  • R 12 is hydrogen, alkyl, alkoxy or halogen;
  • R 13 is hydrogen, alkyl, alkoxy or halogen;
  • m is 1 or 2;
  • y is 1 or 2;
  • z is 1 or 2;
  • R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen;
  • n is 1 or 2.
  • R 1 is R 11 hydrogen, alkyl, alkoxy or halogen
  • R 12 is hydrogen, alkyl, alkoxy or halogen
  • m is 1 or 2
  • y is 1 or 2
  • R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen
  • n is 1 or 2.
  • X is S and R 1 is R 13 is alkyl, alkoxy or halogen; z is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • X is S, preferably, X is S, and R 1 is R 13 is an alkyl group, an alkoxy group or a halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen. More preferably, X is S and R 1 is R 2 is More preferably, R 1 is R 2 is More preferably, X is S and R 1 is R 2 is R 2 is
  • X is S and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; y is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • X is S and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen. More preferably, X is S and R 1 is R 2 is More preferably, X is S and R 1 is R 2 is More preferably, X is S and R 1 is R 2 is
  • X is S and R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen; m is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
  • X is S and R 1 is R 111 is alkyl or alkoxy; R 112 is alkyl or alkoxy; R 2 is More preferably, X is S and R 1 is R 2 is
  • the invention also provides pharmaceutically acceptable salts of the compounds of the invention.
  • the salt may be a nitrate, a hydrochloride, a sulfate or a phosphate or the like.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a neurodegenerative disease.
  • the neurodegenerative disease is preferably Parkinson's disease
  • the drug for treating neurodegenerative diseases is an anti-Parkinson drug.
  • the anti-Parkinson drug is preferably a ULK1 agonist drug for the related treatment of Parkinson's disease.
  • the present invention also provides a pharmaceutical composition which is a preparation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can be formulated into the following forms by methods known in the art: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, A suppository, a finely divided powder or aerosol or spray for inhalation, a sterile aqueous or oily solution or suspension or sterile emulsion for parenteral (including intravenous, intramuscular or infusion).
  • the liquid preparation can be prepared using sterile water or a water-propylene glycol solution as a solvent, and the active ingredient can also be formulated in an aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents as needed.
  • Aqueous suspensions for oral use can be dispersed in water by dispersing the finely divided active component with viscous materials such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose and other pharmaceutical fields. Known suspending agents.
  • the pharmaceutical composition can be in unit dosage form. In these forms, the composition is divided into unit doses containing appropriate quantities of the active ingredient.
  • the unit dosage form can be a packaged preparation, the package including a divided amount of preparation such as a packaged tablet, a capsule, and a powder in a vial or ampoule.
  • the unit dosage form can also be a capsule, cachet or tablet or it can be a suitable quantity of any such package.
  • the pharmaceutical composition of the present invention may be an active ingredient of only the compound of the present invention or may be combined with other anti-Parkinson compounds as an active ingredient.
  • the pharmaceutical composition of the present invention can be used in combination with other anti-Parkinson drugs.
  • this combination therapy can be achieved by administering the various therapeutic ingredients simultaneously, sequentially or separately.
  • Such combination products employ a compound of the invention within an effective dosage range and other pharmaceutically active agents within the approved dosage range.
  • the intermediate 3 (1 mol) was dissolved in 100 ml of tetrahydrofuran at -20 ° C, and after adding a nitrogen methylmorpholine (1 mol) and chloroformyl isobutyl ester (1 mol) for half an hour, the aniline derivative (1.2 mol) was added.
  • the reaction mixture was slowly added thereto, and after the reaction was kept for 2 hours, the reaction was quenched by taking 100 ml of a 5% aqueous sodium hydrogencarbonate solution. After stirring at room temperature for half an hour, it was extracted with methylene chloride (3 ⁇ 50 ml).
  • the purpose of this experiment was to test the activity of the compounds of the present invention on ULK1 enzyme activation in vitro and autophagy activity on cells.
  • BL-918 up-regulates the phosphorylation of ULK1 and mAtg13 and dephosphorylates the negative regulator mTOR upstream of the ULK complex. Further, it was found by immunoprecipitation experiments that the stability of BL-918 is a ULK complex (Fig. 1C). To verify whether compound BL-9184 induced autophagy was by targeting ULK1, siRNA was used to silence expression of ULK1. We found that the GFP-LC3 phosphor dot disappeared substantially (Fig. 1D, 1E). In summary, the compound BL-918 activated autophagy was achieved by targeting ULK1 to activate the ULK complex.
  • BL-918 has induced autophagy, it has cytoprotective activity.
  • MPP + induced SH-SY5Y cell injury model
  • BL-918 can reverse the death of SH-SY5Y cells induced by MPP + to some extent (Fig. 2A).
  • This protective activity can be reversed by the autophagy inhibitors 3-MA and si-ULK1 (Fig. 2B), further illustrating that BL-918 is a protective effect on cells by induction of autophagy.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agoniste d'autophagie ciblé et une application de celui-ci dans le traitement de maladies neurodégénératives, se rapportant au domaine technique de produits pharmaceutiques pour le traitement de maladies neurodégénératives. La solution selon la présente invention est de fournir un composé destiné à être utilisé en tant qu'agoniste d'ULK1. Le composé de l'invention, comprend un composé tel que présenté ou un sel pharmaceutiquement acceptable de celui-ci. Le composé ou le sel pharmaceutiquement acceptable de celui-ci de la présente invention peut être utilisé en tant qu'agoniste d'ULK1 et peut avoir une certaine activité contre des maladies neurodégénératives.
PCT/CN2018/072575 2017-01-18 2018-01-15 Agoniste d'autophagie ciblé et son application dans le traitement de maladies neurodégénératives WO2018133756A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710038351.5 2017-01-18
CN201710038351.5A CN106748892B (zh) 2017-01-18 2017-01-18 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用

Publications (1)

Publication Number Publication Date
WO2018133756A1 true WO2018133756A1 (fr) 2018-07-26

Family

ID=58943394

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/072575 WO2018133756A1 (fr) 2017-01-18 2018-01-15 Agoniste d'autophagie ciblé et son application dans le traitement de maladies neurodégénératives

Country Status (2)

Country Link
CN (1) CN106748892B (fr)
WO (1) WO2018133756A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024030332A1 (fr) * 2022-08-01 2024-02-08 Verge Analytics, Inc. Méthodes de traitement de troubles neurologiques avec des activateurs de la kinase 1 d'activation de l'autophagie de type unc51 (ulk1)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112057442A (zh) * 2020-08-27 2020-12-11 四川大学 一种硫脲类化合物的抗肌萎缩侧索硬化作用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6391917B1 (en) * 1998-01-21 2002-05-21 Zymogenetics, Inc. Dialkyl ureas as calcitonin mimetics
WO2004022528A2 (fr) * 2002-09-09 2004-03-18 Nps Allelix Corp. Derives d'arylglycine et leur utilisation comme inhibiteurs du transport de la glycine
WO2004022534A1 (fr) * 2002-09-09 2004-03-18 Nps Allelix Corp. Derives d'arylglycine utilisables comme inhibiteurs de transport de glycine
WO2006063113A2 (fr) * 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Urees utilisees comme inhibiteurs du facteur xa
WO2006063293A2 (fr) * 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Thiourees utilisees comme inhibiteurs du facteur xa

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20020276A1 (es) * 2000-06-30 2002-04-06 Elan Pharm Inc COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER
DE60112942T2 (de) * 2000-06-30 2006-06-22 Elan Pharmaceuticals, Inc., South San Francisco Verbindungen zur behandlung der alzheimerischen krankheit
EP1558606A4 (fr) * 2002-10-02 2008-05-07 Bristol Myers Squibb Co Diaminoalkyle contenant du lactame, acides amines beta, acides amines alpha et leurs derives utilises en tant qu'inhibiteurs du facteur xa
FR2937973B1 (fr) * 2008-11-04 2010-11-05 Galderma Res & Dev Modulateurs des recepteurs de la melanocortine, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6391917B1 (en) * 1998-01-21 2002-05-21 Zymogenetics, Inc. Dialkyl ureas as calcitonin mimetics
WO2004022528A2 (fr) * 2002-09-09 2004-03-18 Nps Allelix Corp. Derives d'arylglycine et leur utilisation comme inhibiteurs du transport de la glycine
WO2004022534A1 (fr) * 2002-09-09 2004-03-18 Nps Allelix Corp. Derives d'arylglycine utilisables comme inhibiteurs de transport de glycine
WO2006063113A2 (fr) * 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Urees utilisees comme inhibiteurs du facteur xa
WO2006063293A2 (fr) * 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Thiourees utilisees comme inhibiteurs du facteur xa

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024030332A1 (fr) * 2022-08-01 2024-02-08 Verge Analytics, Inc. Méthodes de traitement de troubles neurologiques avec des activateurs de la kinase 1 d'activation de l'autophagie de type unc51 (ulk1)

Also Published As

Publication number Publication date
CN106748892B (zh) 2018-09-18
CN106748892A (zh) 2017-05-31

Similar Documents

Publication Publication Date Title
CN102883607B (zh) 用于治疗癌的化合物
KR101441146B1 (ko) Ｎｐｙ ｙ5 수용체 길항 작용을 갖는 아민 유도체
AU2010229144B2 (en) P2X3, receptor antagonists for treatment of pain
CA3149900A1 (fr) Composes inhibiteurs de rip1 et leurs procedes de fabrication et d'utilisation
EP3275440B1 (fr) Nouveau dérivé d'oxadiazole et produit pharmaceutique en contenant
CN111936139B (zh) 6-氨基异喹啉的单(酸)盐及其用途
TW200406375A (en) Aminotetralin-derived urea modulators of vanilloid VR1 receptor
JP2009531365A (ja) セラミドキナーゼ調節
JP7026787B2 (ja) ヒストン脱アセチル化酵素１および／または２（ｈｄａｃ１－２）の選択的阻害剤としての新規なヘテロアリールアミド誘導体
CN101896457A (zh) 组蛋白脱乙酰基酶抑制剂
WO2016155653A1 (fr) Isomères à chiralité axiale, leurs procédés de préparation et leurs utilisations pharmaceutiques
WO2018133716A1 (fr) Composé d'urée hétérocyclique, composition pharmaceutique de celui-ci et application associée
JP6905597B2 (ja) Ｎ−置換イミダゾールカルボン酸エステル系化合物とその調製方法及び用途
TW406077B (en) 7-(2-imidazolinylamino)quinoline compounds useful as alpha-2 adrenoceptor agonists
WO2018133756A1 (fr) Agoniste d'autophagie ciblé et son application dans le traitement de maladies neurodégénératives
JP2010523627A (ja) Ｇｐｂａｒ１アゴニストとしてのピリダジン誘導体、ピリジン誘導体およびピラン誘導体
JPH11269140A (ja) 分化誘導剤
WO2024099478A1 (fr) Thiazide cyclique aromatique inhalable et analogue, composition pharmaceutique contenant la thiazine cyclique aromatique inhalable, et utilisation de la thiazine cyclique aromatique inhalable comme anti-inflammatoire et anti-tumoral
WO2008068170A1 (fr) Inhibiteurs de l'hdac
WO2015085860A1 (fr) Composé hétérocyclique d'acide hydroxamique, composition pharmaceutique et application associées
US8829002B2 (en) Substituted methyl amines, serotonin 5-HT6 receptor antagonists, methods for production and use thereof
ES2708563T3 (es) Derivados de sulfonamida como moduladores de receptores de quimiocinas
JPH0859458A (ja) インダン誘導体を含有する高脂血症治療剤
CA2752199A1 (fr) Derives de 3-benzofuranyl-indol-2-one substitues en position 3, leur preparation et leur application en therapeutique
PL231063B1 (pl) Pochodne 1-(podstawionej sulfonylo)-2-aminoimidazoliny jako środki przeciwnowotworowe

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: 18742187

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18742187

Country of ref document: EP

Kind code of ref document: A1