WO2013134371A1 - Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives - Google Patents

Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives Download PDF

Info

Publication number
WO2013134371A1
WO2013134371A1 PCT/US2013/029346 US2013029346W WO2013134371A1 WO 2013134371 A1 WO2013134371 A1 WO 2013134371A1 US 2013029346 W US2013029346 W US 2013029346W WO 2013134371 A1 WO2013134371 A1 WO 2013134371A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methylene
bis
cyclohexane
amine
Prior art date
Application number
PCT/US2013/029346
Other languages
English (en)
Inventor
Wolfgang Wrasidlo
Original Assignee
Neuropore Therapies, Inc.
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 Neuropore Therapies, Inc. filed Critical Neuropore Therapies, Inc.
Publication of WO2013134371A1 publication Critical patent/WO2013134371A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to means and methods for treating, ameliorating and/or preventing diseases associated with abnormal accumulation of proteins.
  • AD Alzheimer's Disease
  • PD Parkinson's Disease
  • FTD fronto-temporal dementia
  • ALS amyotrophic lateral sclerosis
  • FID Huntington's Disease
  • ⁇ protein is a 38- 42 amino acid (aa) transmembrane peptide derived from the cleavage of the amyloid precursor protein (APP),
  • APP amyloid precursor protein
  • ⁇ and other APP metabolites might contribute to synaptic damage and neurodegeneration are currently under investigation.
  • Oligomers of ⁇ peptides can organize into dimers, trimers, tetramers, pentamers and other higher order arrays that can form annular structures. The levels of such oligomers in the brain are good predictors of the indices of dementia and synaptic loss in patients with AD.
  • ⁇ can complex to form higher molecular weight aggregates with a fibrillar organization that includes probably hundreds or thousands of ⁇ peptides.
  • fibrillar aggregates are the main component of the amyloid plaques, which are considered useful indicators for the neuropatbological diagnosis of AD.
  • the smaller circular oligomers are considered the toxic array, the fibrillar aggregates in the plaques are not directly toxic and might even represent an endogenous mechanism to isolate oligomers.
  • the existing state of the art includes inhibitors of ⁇ aggregates (fibrils, protofibrils and large oligomers) utilizing for this purpose thiofiavme T or equivalent assays to screen large libraries of existing molecules.
  • ⁇ aggregates fibrils, protofibrils and large oligomers
  • thiofiavme T or equivalent assays to screen large libraries of existing molecules.
  • the present invention relates to compounds having the general formula
  • X is an aliphatic group comprising 1 to 6 carbon atoms
  • Y is an aliphatic group comprising 1 to 6 carbon atoms
  • Ri, R.2, Rr and R 2 > are independently nil, hydrogen or an aliphatic group comprising 1 to 6 carbon atoms,
  • Gi, G 2 , G.3, G4, G5, G( > , G 7 , Gg, G9 and G3 ⁇ 4o are independently N or CH, wherein Gi, G 4 , G 7 and G 10 are C when R l s R 2 , R and R 2 - is an aliphatic group comprising 1 to 6 carbon atoms or hydrogen, or a pharmaceutically acceptable ester or salt thereof, wherein at least one of substituents Gj, G?, G 3 , G 4 , G 5 , Ge, G 7 , Gg, Go and Gio is an unsubstituted N.
  • the compounds of the present invention are unique in that they specifically block the early formation of toxic protein aggregation, e.g. the formation of ⁇ oligomers, in a human or animal body. These compounds specifically target very early toxic protein aggregations and have a high affinity to proteins which are known to be involved in protein aggregation in neurodegenerative disorder such as amyloid ⁇ . Furthermore the compounds of the present invention are stable in plasma and solution and are able to easily cross the blood brain barrier at high AUC brain/ blood ratios. The compounds of the present invention can be synthesized as shown below and with methods known in the art.
  • the compounds of the present invention have alternating hydrophobic and polar regions in their chemical structures that specifically target the earliest forms of amyloid ⁇ ( ⁇ ) oligomers, for instance, and prevent further accumulation of more toxic species.
  • These anti- ⁇ compounds work by preventing further docking of neighboring ⁇ peptides that can result in the formation of toxic oligomers. Therefore these compounds work by interfering at "early" stages the process of ⁇ oligomerization (e.g. dimer formation). They can also work by preventing already formed oligomers (e.g. trimers and tetramers) from growing further and forming ring like structures (e.g. pentamers, hexamers).
  • heterocyclic organic compounds described in this invention that block, among others, A
  • the heteroaromatic ring may comprise more than one nitrogen atom.
  • These further nitrogen atoms can either be free or connected to an alkyl group with 1-6 carbon atoms and being positively charged and thus forming a salt with negatively charged counter ions such as halogen, tosyiate, citrate, or any counter ion used in the formulation of drugs.
  • the heteroaromatic ring may either be unsubstituted or alternatively has attached to it in any position on the ring structure a hydrophobic group consisting of alkyl, alkoxy, fluorinated alkoxy. or halogen atoms including chlorine, bromine or iodide.
  • the heteroaromatic groups of the compound of the present invention can be identical in structure or can be distinct.
  • pharmaceutically acceptable salt relates to salts which are toxicologieally safe for human and animal administration.
  • suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric and sulfamic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, hydroxyrnaieic, fumaric, maleic, citric, lactic, gluconic, benzoic, succinic, methanesulphonic, oxalic, phenylacetic, toluenesulphonie, benezenesulphonic, salicyclic, sulphaniiic, aspartic, glutamic, edelic, stearic, palmi
  • X is selected from the group consisting of a methylene, ethylene and propylene group, preferably a methylene group.
  • Y is selected from the group consisting of a methylene, ethylene and propylene group, preferably a methylene group.
  • the carbon and/or nitrogen atoms of the heteroaromatic rings of the compound of the present invention can be substituted either with hydrogen or an aliphatic group comprising 1 to 6 carbon atoms.
  • a particularly preferred substituent of Ri is selected from the group consisting of a methyl, ethyl and propyl group, preferably a methyl group.
  • R 2 is preferably selected from the group consisting of a methyl, ethyl and propyl group, preferably a methyl group.
  • Rr is selected from the group consisting of a methyl, ethyl and propyl group, preferably a methyl group.
  • R.2- can be selected from the group consisting of a methyl, ethyl and propyl group, preferably a methyl group.
  • both heteroaromatic rings have the same structure and the same substituents.
  • the compound is selected from the group consisting of N,N'-((lr,4r)-cyciohexane ⁇ l,4- diylbis(methylene))bis(pyridin-2-amine), N,N'-((lr,4r)-cyclohexane-l,4- diylbis(methyl ene))bis(pyrazin-2-amine), N,N '-(( 1 r,4r)-cyclohexane- 1 ,4- diylbis(methylene))bis(pyridazin-3-amine), N,N'-((lr,4r)-cyclohexane-l ,4- diylbis(methylene))bis(pyrimidin-4 ⁇ amine), N,N'-(( 1 r,4r)-cyclohexane- 1,
  • the compounds of the present invention are preferably used in a method for treating and/or preventing diseases associated with abnormal accumulation of proteins, preferably amyloid and/or aipha-synuclein protein and/or lewy bodies, in organs.
  • amyloid protein is preferably amyloid beta.
  • the disease is preferably selected from the group consisting of Alzheimer's disease (AD), amyotrophic lateral sclerosis (A LS), Parkinson's disease (PD) and Huntington's Disease.
  • a LS amyotrophic lateral sclerosis
  • PD Parkinson's disease
  • Huntington's Disease Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of at least one compound according to the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of said compound or salt, and one or more pharmaceutically acceptable excipients.
  • the compounds of the present mvention or a pharmaceutically acceptable salt thereof may be formulated by following any number of techniques known in the art of drug delivery.
  • the compounds or pharmaceutically acceptable salts thereof may of course be administered by a number of means keeping in mind that not all formulations not suitable for every route of administration. They can be administered in solid or liquid form.
  • the application may be oral, rectal, nasal, topical (including buccal and sublingual) or by inhalation.
  • the compounds of the invention or a pharmaceutically acceptable salt thereof may ⁇ be administered together with conventional pharmaceutically acceptable adjuvants, carriers and/or diluents.
  • the solid dosage forms comprise tablets, capsules, powders, pills, pastilles, suppositories, gels and granular forms of administration.
  • Liquid forms of administration include solutions, suspensions and emulsions. These may also be offered together with the above-mentioned additives.
  • Solutions and suspensions of the compounds of the invention or pharmaceutically acceptable salts thereof may be injected. If the suspension is too viscous for injection the pharmaceutical preparation may be implanted using devices designed for such purposes. Sustained release forms are generally administered via parenteral or enteric means. Parenteral administration is another route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • the administration of the compounds of the present invention may involve an oral dosage form. Oral dose formulations are preferably administered once or twice daily, three times daily in the form of a capsule or tablet, for instance, or alternatively as an aqueous based solution.
  • the administration may occur either daily, continuously, once a week or three times a week.
  • pharmaceutical compositions which in addition to the compounds of the present invention comprise other substances which are suited for treating, preventing or relieving the symptoms of synucleopathies and Parkinson's-like disorders. These combinations may be administered in solid or liquid form in a single formulation or composition or in separate formulations or compositions.
  • the pharmaceutical compositions contain from about 0.01 mg to about 5.0 g, preferably from about 0.05 mg to 2 g, more preferably from about 0.5 mg to 1 g, even more preferably from about 1 mg to 500 mg, of the compound of the present invention.
  • the compounds of the present invention can be administered to a patient in an amount of about 0.01 mg to about 5 g, preferably of about 0.05 mg to 2 g, more preferably from about 0.5 mg to 1 g, even more preferably from about 1 mg to about 500 mg per kg body weight.
  • the compounds of the present invention may also be provided as sustained release oral formulations. These formulations generally comprise the compounds of the invention having decreased solubility in order to delay absorption into the bloodstream. In addition, these formulations may include other components, agents, carriers, etc., which may also serve to delay absorption of the compounds. Microencapsulation, polymeric entrapment systems, and osmotic pumps, which may or may not be bioerodible, may also be used to allow delayed or controlled diffusion of the compounds from a capsule or matrix.
  • the term "effective amount" in the context of treating or preventing alpha-synucleopathies or Parkinson's-like disorders, especially PD, relates to the administration or addition of an amount of the compound of the present invention that is effective for the prevention and/or treatment of existing synucleopathies or Parkinson's-like disorder.
  • the effective amount will vary depending on the health and physical condition of the individual to be treated, the taxonomic group of the individual to be treated, the formulation of the composition, the assessment of the medical situations and other relevant factors.
  • a further aspect of the present invention relates to the use of a compound according to the present invention for the manufacture of a medicament for treating and/or preventing diseases associated with abnormal accumulation of proteins, preferably amyloid and/or alpha-syn clevn protein and/or lew)' bodies, in organs.
  • proteins preferably amyloid and/or alpha-syn clevn protein and/or lew
  • Another aspect of the present invention relates to a method for treating, ameliorating and/or preventing diseases associated with abnormal accumulation of proteins, preferably amyloid and/or alpha-synuclein protein and/or lewy bodies, in organs by administering to an individual suffering or being at risk to suffer from said diseases an effective amount of a compound or a pharmaceutical preparation according to the present invention.
  • proteins preferably amyloid and/or alpha-synuclein protein and/or lewy bodies
  • Fig. 1 shows a general reaction scheme to obtain the compounds of the present invention.
  • Fig. 2 shows that compound 7 reverses oligomeric-mediated increases in calcium mobilization.
  • Fig. 3 shows that compound 7 reverses oligomeric-mediated decreases in calcein fluorescence.
  • Fig. 4 shows that compound 7 reduces Abeta-protein dirners in a cell free preparation.
  • Figs, 5 A and 5B show the most preferred compounds of the present invention.
  • Example i Synthesis of Compound 1 (N,N'-((lr,4r)-cycIohexane-l,4- diylbis(methylene))his(pyridin-2-amine))
  • Example 8 Synthesis of Compound 9 ( , '-((ir,4r)-cycIohexane-l,4- diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine))
  • Recombinant Abeta-protein (American Peptide Company) was prepared at a concentration of ⁇ and incubated for either 16 hours at 37°C (monomer control) or 37°C+56°C for 16 + 6 hours (oligomer control).
  • Compound 7 (N,N'-((lr,4r)-cyclohexane- l ,4-diylbis(methylene))bis(3-methyipyriditi-2-amine); NPT 420-7) was co-incubated at concentrations from 0 to 12 ⁇ , and resulting control and compound oligomeric solutions were used in subsequent cell based assays (calcium and calcein mobilization assays) or cell free western blots.
  • Fig. 2 The data in Fig. 2 are presented as (A) mean relative fluorescent unit (RFU) values ⁇ standard error of the mean (SEM), and (B) as % reversal of oligomeric mediated increases in calcium fluorescence.
  • REU mean relative fluorescent unit
  • SEM standard error of the mean
  • B % reversal of oligomeric mediated increases in calcium fluorescence.
  • Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by post hoc Tukey- Kramer tests (Prism Graph Pad Software, San Diego, CA, USA). The significance level was set at p ⁇ 0.05, and denoted as ***p ⁇ 0.001 versus vehicle control (No Abeta) group or ### pO.001 vs. compound 7 Control (No Abeta).
  • Calcein Assay Assessment of calcein fluorescence was carried out following the calcium mobilization assay procedure described above with modifications including use of calcein AM fluorescent indicator dye (Life Technologies, Carlsbad, CA; #C3100MP and a different cell plating density (30K vs. 25 K cells per 96 well plate). Briefly, plated B103 cells were treated with prepared vehicle or Abeta-protein monomer and oligomeric solutions (as described above) for 16 hours at 37°. Calcein solution was prepared in phenol red free media with DMSO. 200uL of the resultant solution was added to each well and the plates were incubated at 37° for 2 hour.
  • the fluorescence was read with excitation/emission filter at 470- 495/515- 575 nm on a DTX 880 Multimode Detector (Beckman Coulter, Ful!erton, CA).
  • the data are presented in Figure 3 as (A) mean relative fluorescent unit (RFU) values ⁇ standard error of the mean (SEM), and (B) as % reversal of oligomeric mediated increases in calcein fluorescence.
  • Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by post hoc Tukey-Kxamer tests (Prism Graph Pad Software, US A). The significance level was set at p ⁇ 0.05, and denoted as #p ⁇ 0.05 vs. NPT-420-7 Control (No Abeta).

Abstract

La présente invention concerne un composé de formule générale suivante. Les composés de l'invention bloquent spécifiquement la formation précoce d'agrégation de protéines toxiques, par exemple la formation d'oligomères Αβ, dans un corps humain ou animal. Ces composés ciblent spécifiquement les agrégations très précoces de protéines toxiques et possèdent une affinité élevée pour les protéines connues pour être impliquées dans les agrégations protéiques lors d'un trouble neurodégénératif, tel que l'amyloïde β. En outre, les composés sont stables dans le plasma et en solution et sont capables de traverser la barrière hémato-encéphalique à des rapports SSC élevés cerveau/sang.
PCT/US2013/029346 2012-03-06 2013-03-06 Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives WO2013134371A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261607304P 2012-03-06 2012-03-06
US61/607,304 2012-03-06

Publications (1)

Publication Number Publication Date
WO2013134371A1 true WO2013134371A1 (fr) 2013-09-12

Family

ID=47892062

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/029346 WO2013134371A1 (fr) 2012-03-06 2013-03-06 Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives

Country Status (1)

Country Link
WO (1) WO2013134371A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015116663A1 (fr) 2014-01-29 2015-08-06 Neuropore Therapies, Inc. Amides hétéroaryles comme inhibiteurs de l'agrégation protéique
WO2016040780A1 (fr) * 2014-09-11 2016-03-17 Neuropore Therapies, Inc. Composés tricycliques à liaison animométhyle et méthyloxy utilisés en tant qu'inhibiteurs de l'agrégation de protéines
WO2017020010A1 (fr) 2015-07-29 2017-02-02 Neuropore Therapies, Inc. Dérivés bis-hétéroaryliques en tant que modulateurs de l'agrégation des protéines
WO2017093363A1 (fr) 2015-11-30 2017-06-08 Universität Wien Composé destiné à être utilisé dans la prévention et le traitement de maladies neurodégénératives
EP3207925A1 (fr) 2016-02-22 2017-08-23 Universität Wien Composé destiné à être utilisé dans la prévention et le traitement de maladies neurodégénératives
WO2018138086A1 (fr) 2017-01-26 2018-08-02 Ucb Biopharma Sprl Dérivés bis-hétéroaryliques utilisés en tant que modulateurs de l'agrégation de protéines
WO2018138088A1 (fr) 2017-01-26 2018-08-02 Ucb Biopharma Sprl Dérivés bis-hétéroaryliques bicycliques utilisés en tant que modulateurs de l'agrégation des protéines
WO2018138085A1 (fr) 2017-01-26 2018-08-02 Ucb Biopharma Sprl Dérivés bis-hétéroaryliques d'alcoxy utilisés en tant que modulateurs de l'agrégation de protéines

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239808A1 (en) * 2002-05-10 2005-10-27 Thomas Schrader Active substances for the treatment, diagnosis and prophylaxis of diseases in which abnormal protein structures occur
WO2008061796A2 (fr) * 2006-11-24 2008-05-29 Ac Immune Sa Nouveaux composés destinés au traitement de maladies associés à des protéines amyloïdes ou de type amyloïde

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239808A1 (en) * 2002-05-10 2005-10-27 Thomas Schrader Active substances for the treatment, diagnosis and prophylaxis of diseases in which abnormal protein structures occur
WO2008061796A2 (fr) * 2006-11-24 2008-05-29 Ac Immune Sa Nouveaux composés destinés au traitement de maladies associés à des protéines amyloïdes ou de type amyloïde

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9738635B2 (en) 2014-01-29 2017-08-22 Neuropore Therapies, Inc. Heteroaryl amides as inhibitors of protein aggregation
EP3348556A1 (fr) 2014-01-29 2018-07-18 UCB Biopharma SPRL Amides hétéroaryles comme inhibiteurs de l'agrégation des protéines
WO2015116663A1 (fr) 2014-01-29 2015-08-06 Neuropore Therapies, Inc. Amides hétéroaryles comme inhibiteurs de l'agrégation protéique
US11078196B2 (en) 2014-01-29 2021-08-03 UCB Biophama SRL Heteroaryl amides as inhibitors of protein aggregation
US10358443B2 (en) 2014-01-29 2019-07-23 Ucb Biopharma Sprl Heteroaryl amides as inhibitors of protein aggregation
WO2016040780A1 (fr) * 2014-09-11 2016-03-17 Neuropore Therapies, Inc. Composés tricycliques à liaison animométhyle et méthyloxy utilisés en tant qu'inhibiteurs de l'agrégation de protéines
US10975066B2 (en) 2015-07-29 2021-04-13 UCB Biopharma SRL Bis-heteroaryl derivatives as modulators of protein aggregation
WO2017020010A1 (fr) 2015-07-29 2017-02-02 Neuropore Therapies, Inc. Dérivés bis-hétéroaryliques en tant que modulateurs de l'agrégation des protéines
WO2017093363A1 (fr) 2015-11-30 2017-06-08 Universität Wien Composé destiné à être utilisé dans la prévention et le traitement de maladies neurodégénératives
US11179358B2 (en) 2015-11-30 2021-11-23 Universität Wien Compound for use in the prevention and treatment of neurodegenerative diseases
EP3207925A1 (fr) 2016-02-22 2017-08-23 Universität Wien Composé destiné à être utilisé dans la prévention et le traitement de maladies neurodégénératives
WO2018138088A1 (fr) 2017-01-26 2018-08-02 Ucb Biopharma Sprl Dérivés bis-hétéroaryliques bicycliques utilisés en tant que modulateurs de l'agrégation des protéines
US10913735B2 (en) 2017-01-26 2021-02-09 UCB Biopharma SRL Bis-heteroaryl derivatives as modulators of protein aggregation
US10889584B2 (en) 2017-01-26 2021-01-12 UCB Biopharma SRL Bicyclic bis-heteroaryl derivatives as modulators of protein aggregation
WO2018138085A1 (fr) 2017-01-26 2018-08-02 Ucb Biopharma Sprl Dérivés bis-hétéroaryliques d'alcoxy utilisés en tant que modulateurs de l'agrégation de protéines
US11091474B2 (en) 2017-01-26 2021-08-17 UCB Biopharma SRL Alkoxy bis-heteroaryl derivatives as modulators of protein aggregation
WO2018138086A1 (fr) 2017-01-26 2018-08-02 Ucb Biopharma Sprl Dérivés bis-hétéroaryliques utilisés en tant que modulateurs de l'agrégation de protéines

Similar Documents

Publication Publication Date Title
WO2013134371A1 (fr) Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives
RU2722179C2 (ru) Лечение состояний, ассоциированных с гиперинсулинемией
RU2535667C2 (ru) Энантиомеры спиро-оксиндольных соединений и их применение в качестве терапевтических средств
US20110124675A1 (en) The hydrosulfate of prasugrel, its pharmaceutical combination and use thereof
US10772884B2 (en) Sulphate salts of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine, preparation thereof and use of the same
TWI415613B (zh) Anti-cancer agent resistance to overcome the agent
CN115884965A (zh) 用于治疗ApoL1相关疾病的组合物
UA116466C2 (uk) Кристалічні форми інгібіторів тирозинкінази та їх солей
JP6735810B2 (ja) 置換１０ｈ−フェノチアジン−３，７−ジアミン化合物の化学合成方法
CN111372579B (zh) 取代的苯基磺酰基苯基三唑硫酮和其用途
US20220064120A1 (en) Solid state forms of a selective potassium channel modulator
EP2325187A1 (fr) Hydrogénosulfate de prasugrel, son composé médicinal et son utilisation
UA113302C2 (xx) Кристалічний поліморф 1-(3-трет-бутил-1-п-толіл-1h-піразол-5-іл)-3-(5-фтор-2-(1-(2-гідроксіетил)-1н-індазол-5-ілокси)бензил)сечовини гідрохлориду
WO2018233483A1 (fr) Préparation et utilisation de dérivés de phénylquinolinone et de flavonoïde
TW201922690A (zh) 環－amp反應元素結合蛋白的抑制劑
CA2969699A1 (fr) Composes, compositions et procedes d'utilisation associes
WO2019215937A1 (fr) Cristaux de dérivé de tétrahydronaphtyle urée
WO2013070911A1 (fr) Composés et méthodes de traitement d'une fibrose kystique
WO2007082472A1 (fr) Composé de quinolone anti-infectueux, son procédé de préparation et son utilisation
JP7134983B2 (ja) テトラヒドロナフチルウレア誘導体の結晶
CN113666895B (zh) 卤代2-苯并[c]呋喃酮类化合物及其应用
CN108069833B (zh) 苯并四环衍生物及其制备方法和在医药上的应用
WO2015186144A2 (fr) Procédé d'inhibition de la bêta-sécrétase au moyen de bis-o-déméthylcurcumine pour la prévention, la prise en charge et le traitement de maladies neurodégénératives
CA3166527A1 (fr) Compositions et methodes de traitement de troubles neurodegeneratifs, neurodeveloppementaux, myodegeneratifs et du stockage lysosomal
WO2024036243A2 (fr) Sels d'inhibiteurs hétérocycliques du transporteur 4 de monocarboxylate pour le traitement d'une maladie

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: 13710260

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: 13710260

Country of ref document: EP

Kind code of ref document: A1