WO2012040754A2 - Nouveaux dérivés de thiazolamine comme accélérateurs de différenciation - Google Patents

Nouveaux dérivés de thiazolamine comme accélérateurs de différenciation Download PDF

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Publication number
WO2012040754A2
WO2012040754A2 PCT/AT2011/000393 AT2011000393W WO2012040754A2 WO 2012040754 A2 WO2012040754 A2 WO 2012040754A2 AT 2011000393 W AT2011000393 W AT 2011000393W WO 2012040754 A2 WO2012040754 A2 WO 2012040754A2
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WO
WIPO (PCT)
Prior art keywords
benzyl
arc
thiazolamine
aniline
ylidene
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/AT2011/000393
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German (de)
English (en)
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WO2012040754A3 (fr
Inventor
Marko D. Mihovilovic
Michael SCHNÜRCH
Birgit Waldner
Karlheinz Hilber
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Technische Universitaet Wien
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Technische Universitaet Wien
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Publication of WO2012040754A2 publication Critical patent/WO2012040754A2/fr
Publication of WO2012040754A3 publication Critical patent/WO2012040754A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel thiazolamine derivatives for use as accelerators of cell differentiation.
  • Molecules containing a thiazolamine moiety exhibit a number of interesting biological activities, depending on their substituents and the substitution pattern on the thiazole ring.
  • compounds of the formula below have been shown to be potent inhibitors of histone deacetylase and tyrosine kinase:
  • Ri and R 2 are selected from aryl, heteroaryl, hydrogen and acyl and R 3 is selected from aryl and heteroaryl
  • R 3 is selected from aryl and heteroaryl
  • N-phenylthiazolamine derivatives are also known as selective aurora kinase inhibitors (CB Andersen et al., ACS Chemical Biology 3 (3), 180-192 (2008)).
  • molecules of the formula below have been reported to induce autophagic cell death in renal cancer cells:
  • Ri and R 2 are selected from aryl and heteroaryl (MP Hay et al., J.Med.Chem. 53 (2), 787-797 (2010)). Due to the increasing importance of methods for influencing cell differentiation processes, attempts have been made to identify or synthesize molecules that have activity in promoting cell differentiation or undifferentiation. With regard to the use of thiazolamines for such purposes, N. Bouquier et al., Chem. Biol.
  • thiazolamine derivatives have the ability to Inhibition of the Trio / RhoG / Rac1 signaling pathway, inter alia, inhibits the differentiation of stimulated PC12 and C2C12 cells into neurites or myotubes.
  • the thiazolamine derivatives used for this purpose are in all cases two- or three-membered fused ring systems in which a nitrogen of the thiazolamine represents a bridgehead atom, the following structure being predominant:
  • R stands for variously substituted aryls or heteroaryls.
  • WO 2005/047524 A2 discloses molecules of similar size based on purines which induce the dedifferentiation of lineage-determined mammalian cells ("lineage-committed mammalian cells").
  • Molecules in such size ranges ie, molecular weights below about 1,000 g / mol, are often referred to as "small molecules", and the majority of all synthetic drugs are in this molecular weight range.
  • chemical compounds which promote the differentiation of cells for example in the form of such "small molecules” are desirable for numerous applications, for example for stem cell therapy. Examples here- for are hardly known.
  • a compound called the adhesin has been reported to be able to accelerate the differentiation of hippocampal neurons (Hoshino, M. et al., Biochemical Journal 427, 297 (2010)).
  • Wrenchnolol and Adhesamine are certainly complex compounds whose synthesis is associated with relatively high costs.
  • Another interesting compound is neuropathiazole, a 4-thiazolamine that has been reported to induce the differentiation of multipotential neural progenitor cells of the hippocampus into neurons in adults.
  • the object of the present invention was to produce further small molecules, in particular those based on thiazolamine, which are capable of accelerating the differentiation of mammalian cells and which are relatively easy to synthesize.
  • R 1 to R 3 are independently selected or absent from hydrogen, benzyl, aryl and heteroaryl, with at most one of the radicals R 1 to R 3 being hydrogen and R 4 being selected from benzyl, aryl and heteroaryl,
  • R 1 to R 4 are each independently optionally substituted with one or more substituents selected from halogen (F, Cl, Br, I), hydroxy, Ci -3 - alkyl, Ci -3 alkoxy, carboxy, C 1-3 alkylcarbonyl , d-3-alkoxycarbonyl, nitro, amino, mono- and di-Ci-3-alkylamino and cyano, in which the alkyl groups are optionally halogenated substituted;
  • n 0 to 2;
  • the above thiazolamine derivatives can be obtained in only three synthetic steps, whereby the cost and the cost of preparation compared to the compounds of the prior art can be significantly reduced.
  • such derivatives have been shown to be effective in promoting cell differentiation in a C2C12 mouse cell model.
  • the invention relates to the use of compounds of the above formula as cell differentiation accelerators.
  • Aryl and heteroaryl are to be understood here as mononuclear and polynuclear aromatic ring systems, preferably those having 5 to 10 ring atoms, more preferably aromatic rings having 5 or 6 ring atoms.
  • the heteroatoms, of which one or more Others may be present, are preferably selected from nitrogen, sulfur and oxygen, with nitrogen and sulfur being particularly preferred and a single nitrogen heteroatom in the heteroaryl radical is more preferred.
  • nitrogen and sulfur being particularly preferred and a single nitrogen heteroatom in the heteroaryl radical is more preferred.
  • phenyl is preferred among the aryl and heteroaryl radicals.
  • an optional double bond shown in broken line in the formula is present, either endo or exocyclic, ie extending from C2 to either the thiazole or amine nitrogen.
  • R 1 to R 3 are preferably selected independently of one another from benzyl and phenyl, and on the two nitrogen atoms preferably only a total of two substituents are present. These two substituents are in particularly preferred embodiments each a phenyl and a benzyl group.
  • This radical is particularly preferably bonded to C 5 of the thiazole ring and is preferably selected from aryl and heteroaryl, more preferably from phenyl, thiophenyl and pyridinyl wherein phenyl is particularly preferred.
  • the optional substituents from R 1 to R 4 are preferably selected from fluoro, methyl, trifluoromethyl, nitro, carboxy and C 1-3 -alkoxycarbonyl, more preferably from fluoro, methyl and nitro.
  • the inventors of the present application believe that, in the presence of larger or even bulky substituents, the interaction of the thiazolamine derivatives of the invention with translation factors or other components of the cells essential to induce cell differentiation is hindered the effect of the invention would be impaired. Furthermore, it is believed that more electron attractive substituents are to be preferred because they appear to exert an activating effect.
  • Preferred thiazolamine derivatives of the invention are as follows
  • GC-MS measurements were taken on a Thermo Finnigan Focus GC / DSQ II using a standard capillary acid BGB 5 (30 mx 0.32 mm ID) and using one of the following standardized temperature profiles: STD 100-280 ° C Short method: 2 Minutes at 100 ° C, at 18 ° C / min to 280 ° C, 5 minutes at 280 ° C; or STD 100-280 ° C Long Procedure: 2 minutes at 100 ° C, at 6 ° C / min to 150 ° C, 3 minutes at 150 ° C, at 10 ° C / min to 280 ° C, 10 minutes at 280 ° C. Thin-layer chromatography was carried out with silica gel plates 60 F245 from Merck.
  • N-phenyl-2-thiazolamine 3 (30 mg, 0.17 mmol, 1.0 equiv.), Benzylbromide (38 mg, 0.22 mmol, 1.3 equiv.) And NaH (4.1 mg, 0). 17 mmol, 1.0 equiv) were dissolved in dry DMF (2 ml) and stirred at room temperature for 5 h. The reaction mixture was then diluted with EtOAc, concentrated on silica gel on a rotary evaporator and purified by MPLC (LP: EtOAc 85:15 + 5% TEA). The title compound 21 was obtained as a beige solid (30 mg, 66% of theory).
  • N-phenyl-2-thiazolamine 3 (264 mg, 1.50 mmol, 1.0 equiv.), Benzyl bromide (334 mg, 1.96 mmol, 1.3 equiv.) And triethylamine (152 mg, 1.50 mmol , 1.0 equiv) were dissolved at 0 ° C in dry dioxane (4 ml), allowed to warm slowly and stirred at 120 ° C on a heating block for 3 days. The reaction mixture was then diluted with EtOAc, concentrated on silica gel on a rotary evaporator and purified by MPLC (LP: EtOAc 85:15 + 4% TEA). The title compound 22 was obtained as a pale yellow solid (287 mg, 72% of theory).
  • the cell material was produced at the Institute of Pharmacology of the Medical University of Vienna.
  • C2C12 mouse cells were used as a model to determine the differentiation-promoting properties of the compounds prepared as described above.
  • the C2C12 cells were incubated for two days in culture dishes with growth medium (Dulbecco's modified Eagle's medium, DMEM, with 4.5 g / l glucose, 4 mM L-glutamine, 50 U / ml penicillin, 50 pg / ml streptomycin and 20% fetal calf serum) were incubated before the test compounds were added in differentiation medium (substantially identical to the growth medium, except that it contained 2% horse serum instead of fetal calf serum).
  • growth medium Dulbecco's modified Eagle's medium, DMEM, with 4.5 g / l glucose, 4 mM L-glutamine, 50 U / ml penicillin, 50 pg / ml streptomycin and 20% fetal cal
  • the compounds were first dissolved in DMSO, and these solutions were added to aliquots of the differentiation medium. As a comparison was pure DMSO dissolved in differentiation medium. First, 5 ⁇ solutions of the compounds were used, each experiment being carried out in duplicate.
  • the latter was removed, after which 3 ml of the above solutions of the respective compound and DMSO in differentiation medium were added to each cell culture. Subsequently, the cells were incubated at 37 ° C for 7 days. Meanwhile, the medium was exchanged twice, after 3 and 5 days. After 7 days, the cells were harvested, the medium was removed, and the cells were washed with PBS (phosphate buffered saline) to remove any residual differentiation medium. This is of essential importance as the medium contains proteins that could influence subsequent proteome analyzes.
  • PBS phosphate buffered saline
  • test compounds also developed more or less toxicity to the cells, as evidenced by dead cells. showed material in the samples. Both effects, ie acceleration of differentiation and toxicity, were enhanced during the following days.
  • the present invention provides a group of compounds capable of accelerating the differentiation of cells which are accessible in a relatively simple and inexpensive manner and which show little to no toxicity.

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

Abstract

L'invention concerne l'utilisation d'un dérivé de thiazolamine pour accélérer la différenciation de cellules, caractérisée en ce que l'on utilise un dérivé de 2-thiazolamine de la formule générale suivante : dans laquelle R1 à R3 sont choisis indépendamment les uns des autres parmi l'hydrogène, le benzyle, un aryle et un hétéroaryle ou bien sont absents, au maximum un des restes R1 à R3 étant un hydrogène, et R4 est choisi parmi le benzyle, un aryle et un hétéroaryle, les restes R1 à R4 pouvant être substitués indépendamment les uns des autres par un ou plusieurs substituants choisis parmi un halogène (F, Cl, Br, I) ou un groupe hydroxy, alkyle en C1-3, alcoxy en C1-3, carboxy, alkylcarbonyle en C1-3, alcoxycarbonyle en C1-3, nitro, amino, mono- et dialkylamino en C1-3 ainsi que cyano, dans lequel les groupes alkyle peuvent être halogénés ; - - - (aa) représente respectivement une liaison simple ou une liaison double ; n = 0 à 2 et, lorsque n = 1, le reste R4 peut être rattaché dans la position 4 ou dans la position 5 du noyau cyclique thiazole et, lorsque n = 2, les restes R4 sont rattachés dans les positions 4 et 5 du noyau cyclique thiazole.
PCT/AT2011/000393 2010-09-27 2011-09-26 Nouveaux dérivés de thiazolamine comme accélérateurs de différenciation Ceased WO2012040754A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA1614/2010 2010-09-27
AT16142010A AT510456B1 (de) 2010-09-27 2010-09-27 Thiazolamin-derivate als zelldifferenzierungsbeschleuniger

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WO2012040754A2 true WO2012040754A2 (fr) 2012-04-05
WO2012040754A3 WO2012040754A3 (fr) 2012-06-21

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12030875B2 (en) 2018-09-07 2024-07-09 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
US12157731B2 (en) 2020-03-03 2024-12-03 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
US12157732B2 (en) 2021-08-25 2024-12-03 PIC Therapeutics, Inc. eIF4E inhibitors and uses thereof
US12234231B2 (en) 2021-08-25 2025-02-25 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047524A2 (fr) 2003-11-10 2005-05-26 The Scripps Research Institute Compositions et procedes pour induire la differenciation cellulaire
WO2007064891A1 (fr) 2005-12-01 2007-06-07 The Scripps Research Institute Compositions et procédés servant à induire la différenciation neuronale

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5369108A (en) * 1991-10-04 1994-11-29 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US9234178B2 (en) * 2008-10-31 2016-01-12 Janssen Biotech, Inc. Differentiation of human pluripotent stem cells
EP2251010A1 (fr) * 2009-05-08 2010-11-17 Sygnis Bioscience GmbH & Co. KG Utilisation de tiabendazole et dérivés correspondants pour la thérapie de conditions neurologiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047524A2 (fr) 2003-11-10 2005-05-26 The Scripps Research Institute Compositions et procedes pour induire la differenciation cellulaire
WO2007064891A1 (fr) 2005-12-01 2007-06-07 The Scripps Research Institute Compositions et procédés servant à induire la différenciation neuronale

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
C.B. ANDERSEN ET AL., ACS CHEMICAL BIOLOGY, vol. 3, no. 3, 2008, pages 180 - 192
D. JUNG ET AL., J. AM. CHEM. SOC., vol. 131, 2009, pages 4774 - 4782
M. HOSHINO ET AL., BIOCHEMICAL JOURNAL, vol. 427, 2010, pages 297
M.P. HAY ET AL., J. MED. CHEM., vol. 53, no. 2, 2010, pages 787 - 797
N. BOUQUIER ET AL., CHEM. BIOL., vol. 16, 2009, pages 657 - 666
S. MAHBOOBI ET AL., J. MED. CHEM., vol. 52, no. 8, 2009, pages 2265 - 2279

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12030875B2 (en) 2018-09-07 2024-07-09 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
US12157731B2 (en) 2020-03-03 2024-12-03 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
US12157732B2 (en) 2021-08-25 2024-12-03 PIC Therapeutics, Inc. eIF4E inhibitors and uses thereof
US12234231B2 (en) 2021-08-25 2025-02-25 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof

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Publication number Publication date
AT510456B1 (de) 2012-11-15
AT510456A1 (de) 2012-04-15
WO2012040754A3 (fr) 2012-06-21

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