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Novel compounds as histone deacetylase inhibitors

a technology of histone deacetylase and compounds, which is applied in the field of new compounds as histone deacetylase inhibitors, can solve the problems of tumorigenic transformation, decrease of therapeutic doses, and destabilisation of the interaction of histones with dna, and achieve the effect of improving the condition of patients

Inactive Publication Date: 2005-08-11
4SC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0057] Therefore the compounds according to the invention and medicaments prepared therewith are generally useful to induce the differentiation and / or apoptosis of cells such as undifferentiated tumor cells. The therapeutic effect of the invention may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, cell activation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or to induce systemic changes in metabolism such as changes in sugar, lipid or protein metabolism, the inhibition of new blood vessel formation (anti-angiogenesis), the inhibition of tumor spread into other organs (anti-metastatic), the inhibition of tumor spread into neighboring normal structures (anti-invasive) or the promotion of programmed cell death (apoptosis).

Problems solved by technology

In the case of histone hyperacetylation, changes in electrostatic attraction for DNA and steric hindrance introduced by the hydrophobic acetyl group leads to destabilisation of the interaction of histones with DNA.
Disruption of these mechanisms gives rise to transcriptional misregulation and may lead to tumorigenic transformation.
Such combinatorial treatments could result in a decrease of the therapeutic doses of e.g. chemotherapeutic reagents required and could thus limit the currently observed, partly very serious side effects of frequently used therapies.

Method used

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  • Novel compounds as histone deacetylase inhibitors
  • Novel compounds as histone deacetylase inhibitors
  • Novel compounds as histone deacetylase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compound 1 (3-Cyclopentyl-N-hydroxy-propionamide)

[0085] To a solution of 3-Cyclopentyl-propionyl chloride (11.0 mL, 11.6 g, 72.0 mmol) in dichloromethane (50 mL) hydroxylamine hydrochloride (5.00 g, 72.0 mmol) and sodium bicarbonate (12.0 g, 144 mmol) were added. After stirring for 24 h at room temp. the reaction was quenched by addition of saturated ammonium chloride solution (50 mL). The layers were separated. The water layer was extracted with ethyl acetate (4×50 mL). The solvent of the combined organic layers was removed in vacuo. Precipitation of the crude product out of ethyl acetate by adding petroleum ether yielded the hydroxamate (5.25 g, 33.4 mmol, 46%) as a white solid. 1H NMR (300 MHz, [D6-DMSO]: δ=0.74-0.91 (m, 2H), 1.05-1.25 (m, 4H), 1.36 (q, J=7.4 Hz, 4H), 1.54-1.71 (m, 5H), 1.94 (t, J=7.6 Hz, 2H), 8.59 (s,1H) and 10.28 (s, 1H) (NH and OH). 13C NMR (75 MHz, [D6-DMSO]: δ=25.6, 26.0, 29.7, 32.4, 36.5, 169.2 (C(═O)NHOH). MS: m / z calcd for (C8H14NO2) [M+H]+...

example 2

Synthesis of Compound 2 (3-Cyclohexyl-N-hydroxy-propionamide):

[0086] To a solution of 3-Cyclohexyl-propionyl chloride (12.1 mL, 12.6 g, 72.0 mmol) in dichloromethane (50 mL) hydroxylamine hydrochloride (5.00 g, 72.0 mmol) and sodium bicarbonate (12.0 g, 144 mmol) were added. After stirring for 24 h at room temperature the reaction was quenched by addition of saturated ammonium chloride solution (50 mL). The layers were separated. The water layer was extracted with ethyl acetate (4×50 mL). The solvent of the combined organic layers was removed in vacuo. Precipitation of the crude product out of ethyl acetate by adding petroleum ether yielded the hydroxamate (7.21 g, 42 mmol, 58%) as a white solid. 1H-NMR (300 MHz, [D6-DMSO]: δ=0.95-1.12 (m, 2H), 1.38-1.69 (m, 6H), 1.62-1.77 (m, 3H), 1.94 (t, J=7.6 Hz, 2H), 8.58 (s, 1H) and 10.28 (s,1H) (NH and OH); 13C-NMR (75 MHz, [D6-DMSO]: δ=25.0, 31.8, 32.0, 32.3, 39.5, 169.5 (C(═)NHOH); MS: m / z calc. for (C9H17NO2) [M+H]+172; found 172.

example 3

Synthesis of Compound 3 (3-Cyclohexyl-N-hydroxy-acrylamide)

[0087] 3-Cyclohexyl-acrylic acid ethyl ester: to a cooled solution of oxalyl chloride (11.1 mL, 105 mmol) in dichloromethane (250 mL) was added at −78° C. a solution of dimethylsulfoxide (14.6 mL, 206 mmol) in dichloromethane (250 mL). After 5 min at the same temperature cyclohexylmethanol (10.8 mL, 87.5 mmol) and after additional 5 min triethylamine (60.7 mL, 438 mmol) were added. The reaction remained at −78° C. for two hours and then let warm to room temperature. The solvent was removed in vacuo. The resulting aldehyde was used for the next step without further purification. The crude cyclohexanecarbaldehyde was dissolved in toluene (200 mL) and ethanol (150 mL). After 15 min of stirring at 70° C. carbethoxy-methylene triphenylphosphorane (33.6 g, 96.5 mmol) was added in one portion. Stirring was continued for additional 24 hours. The solvent was removed in vacuo. The product was obtained by flash chromatography in 78% ...

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Abstract

The present invention is directed to compounds of the general formula (I) or pharmaceutical acceptable salts or physiologically functional derivatives thereof wherein: n is a non-aromatic ring system containing two to seven carbon atoms, wherein the ring system can contain one ore two double bonds; X is C, CH or CH2; Y is selected from C, CH, CH2, S, NR, CH2-CH2, H2C—CH, HC—CH2, C—CH2, H2C—C, or C—C; one or more of the hydrogen atoms can optionally be substituted by one or more substituents R′; each of the dotted lines means a single, a double or triple bond with the exclusion of a combination of a triple with triple bond and a double with a triple bond; R′ is independently H, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogene, haloalkyl, haloalkyloxy; R is H, an alkyl or cycloalkyl group; Z is CH, C, or P; p is 0 or 1.

Description

[0001] The present invention relates to compounds as inhibitors of enzymes having histone deacetylase activity, to the processes for the preparation of those compounds, and to their use for the treatment of diseases which are associated with hypoacetylation of histones and / or other molecules, or in which induction of hyperacetylation has a beneficial effect for example by inhibition of proliferation and / or induction of differentiation and / or induction of apoptosis in transformed cells, such as cancer. Furthermore, the compounds are useful for the treatment of other proliferative diseases, for therapy or prophylaxis of conditions associated with abnormal gene expression. BACKGROUND OF THE INVENTION [0002] Local remodeling of chromatin is a key step in the transcriptional activation of genes. Dynamic changes in the nucleosomal packaging of DNA must occur to allow transcriptional proteins to contact with the DNA template. One of the most important mechanisms influencing chromatin remod...

Claims

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Application Information

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IPC IPC(8): A61K31/19A61K31/66C07C259/04
CPCC07C259/04C07C2101/14C07C2101/08C07C2601/08C07C2601/14A61P35/00
Inventor MAURER, ALEXANDER B.HOEVELMANN, SASCHAMARTIN, ELKEHENTSCH, BERNDGASSEN, MICHAELKRAUS, JUERGENKRAUSS, ROLFVINCEK, ADAM-SPENCER
Owner 4SC
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