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Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors

a technology of jun-n-terminal kinase and derivatives, which is applied in the field of arylsulfonamide derivatives, can solve the problems of defective regulation of the growth of the blood vessel wall, cell death and scar formation, renal failure or cerebral dysfunction,

Inactive Publication Date: 2010-02-04
LAB SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025]It is notably an objective of the present invention to provide chemical compounds which are able to modulate, preferably to down-regulate or to inhibit the JNK (Jun kinase) pathway so to be useful in method of treating diseases which involve the JNK pathway.

Problems solved by technology

Cardiovascular diseases, such as atherosclerosis and restenosis result from defective regulation of growth of the blood vessel wall.
Ischemia alone or coupled with reperfusion in the heart, liver, kidney or brain results in cell death and scar formation, which can ultimately lead to congestive heart failure, hepatic disorders, renal failure or cerebral dysfunction.
Thus, JNK inhibitors may block transformation and tumor cell growth.

Method used

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  • Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors

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examples

[0123]The invention will be illustrated by means of the following examples which are not to be construed as limiting the scope of the invention.

[0124]The compounds of the present invention may be synthesized according to the different synthesis pathways provided above. The following examples illustrate preferred methods for synthesizing the compounds according to formula I and determining their activities.

example i

5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride (1b) (compound of formula III)

a) 4-Chloro-N-thiophen-2-ylmethyl-benzamide (1a)

[0125]

[0126]A solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 mL dry CH2Cl2 was added over 30 min to a stirred solution of 2-aminomethyl-thiophene (0.137 mol) and iPr2NEt (0.25 mol) in CH2Cl2 (200 mL) at 0° C. A white solid was formed and the reaction was allowed to warm to room temperature over 1 h. The mixture was diluted with 200 mL of CH2Cl2, washed twice with HCl aq. (0.1N) and dried over MgSO4. Evaporation of the solvents afforded 28 g (98%) of the title benzamide (1a) as a white solid: m.p. 153-54° C., 1H NMR (CDCl3) δ 7.9 (d, J=8.67 Hz, 2H), 7.58 (d, J=8.67 Hz, 2H), 7.44 (dd, J=3.77, 1.13 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 7.16 (dd, J=3.39, 5.27 Hz, 1H), 6.62 (br d, 1H), 4.98 (d, J=5.65 Hz, 2H).

b) 5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride (1b)

[0127]

[0128]Chlorosulfonic acid ...

example ii

4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-3-ylsulfamoyl]-thiophen-2-ylmethyl}-benzamide (2)

[0129]The synthesis of the above compound (2) is a 3-step-synthesis (see scheme I).

Protocol I:

Step 1-N-Sulfonylation (Compound of Formula IV)

[0130]The mono protected diamine (+ / −)-3-Amino-1-N-Boc-Piperidine (compound of formula II) (0.4 g, 2 mMol, 1 eq), 5-(4-chlorobenzamidomethyl)thiophene-2-sulphonyl chloride (1b) (compound of formula III) (0.99 g, 2.4 mMol, 1.2 eq), and piperidine resin (2 g, 1.5 eq, loading of 1.5 mMol / g) are swirled in THF (50 ml) on orbital shaker overnight. Aminomethyl polystyrene (1.82 g, 1 eq, loading of 1.1 mMol / g) is added to the flask and contents swirled on orbital shaker overnight.

[0131]The resins are filtered and washed with a further 50 ml of THF. Filtrates are combined and solvent is evaporated under reduced pressure to yield quantitatively the corresponding sulfonamide (formula IV). No further purification is required at this stage.

Step 2—Removal ...

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Abstract

The present invention relates to sulfonamide derivatives of formula I notably for use as pharmaceutically active compounds, as well as to pharmaceutical formulations containing such sulfonamide derivatives. Said sulfonamide derivatives are useful in the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases. Furthermore, said sulfonamide derivatives are efficient modulators of the JNK pathway, they are in particular efficient and selective inhibitors of JNK2 and -3. The present invention is furthermore related to novel sulfonamide derivatives as well as to methods of their preparation.Ar1 is a substituted or unsubstituted aryl or heteroaryl group;X is O or S, preferably O;Ar2 a substituted or unsubstituted arylene or heteroarylene group;R1 and R2 are independently selected from the group consisting of hydrogen and a C1-C6-alkyl group;

Description

FIELD OF THE INVENTION[0001]The present invention is related to novel sulfonamide derivatives as well as to methods of their preparation. The present invention is further related to sulfonamide derivatives for use as pharmaceutically active compounds, as well as pharmaceutical formulations containing such sulfonamide derivatives. In particular, the present invention is related to sulfonamide derivatives useful in the treatment and / or prevention of apoptosis related disorders and inflammatory diseases. Furthermore, the present invention is related to sulfonamide derivatives displaying a substantial modulatory, notably an inhibitory, activity of the c-Jun-N-Terminal Kinases (JNKs) function or pathways respectively.BACKGROUND OF THE INVENTION[0002]Mammalian cells respond to some extracellular stimuli by activating signaling cascades which are mediated by various mitogen-activated protein kinases (MAPKs). Despite the differences in their response to upstream stimuli, the MAP kinase casc...

Claims

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Application Information

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IPC IPC(8): A61K31/381C07D409/12C07D333/34A61K31/4535A61P25/28A61P35/00A61P11/06A61K31/38A61K31/4025A61P1/04A61P1/16A61P9/04A61P9/10A61P13/12A61P19/00A61P19/02A61P25/00A61P25/16A61P27/02A61P29/00A61P37/00
CPCA61K31/38C07D409/12C07D333/34A61P1/04A61P1/16A61P11/06A61P13/12A61P19/00A61P19/02A61P25/00A61P25/16A61P25/28A61P27/02A61P29/00A61P35/00A61P37/00A61P9/04A61P9/10
Inventor RUECKLE, THOMASGOTTELAND, JEAN-PIERRETHOMAS, RUSSEL J.BIAMONTE, MARCO
Owner LAB SERONO SA
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