Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein junkinases

Abstract

The present invention is related to sulfonamide derivatives having a lipophilic moiety and which are substantially soluble. Said compounds are notably for use as pharmaceutically active compounds. The present invention also related to pharmaceutical formulations containing such sulfonamide derivatives. Said sulfonamide derivatives are efficient modulators of the JNK pathway, they are in particular efficient and selective inhibitors of JNK 2 and 3. The present invention is furthermore related to novel sulfonamide derivatives as well as to methods of their preparation. The compounds of formula (I) according to the present invention being suitable pharmaceutical agents are those wherein Ar1 and Ar2 are independently from each other substituted or unsubstituted aryl or heteroaryl groups, X is O or S, preferably O;R1 is hydrogen or a C1-C6-alkyl group, or R1 forms a substituted or unsubstituted 5-6-membered saturated or unsaturated ring with Ar1;n is an integer from 0 to 5, preferably between 1-3 and most preferred 1;Y within formula (I) is an unsubstituted or a substituted 4-12-membered saturated cyclic or bicyclic alkyl which is substituted with at least one ionisable moiety to which a lipophilic chain is attached and which is containing at least one nitrogen atom, whereby one nitrogen atom within said ring is forming a bond with the sulfonyl group of formula (I) thus providing a sulfonamide.

Description

technical field

[0001] The present invention relates to substantially soluble sulfonamide derivatives bearing lipophilic groups. The sulfonamide derivatives are mainly used as pharmaceutically active compounds. The invention also relates to pharmaceutical preparations containing such sulfonamide derivatives. In particular, the present invention relates to sulfonamide derivatives for use in the treatment and / or prevention of immune and nervous system diseases. In particular, the sulfonamide derivatives of the present invention have a marked modulatory effect, notably their inhibitory activity on JNK (Jun Kinase) function or pathway, respectively. Background technique

[0002] Apoptosis refers to the complex distortion of the cell membrane and organelles when cells undergo programmed cell death. In the process, the cell activates an intrinsic suicide program and systematically destroys itself. The following sequence of events can be observed:

[0003] • The cell surface b...

Examples

Embodiment 1

[0401] Example 1 (Protocole E; see Protocols 1, 3 and 6)

[0402] 3-Methoxy-N-{[5-({4-[(4-trifluoromethylbenzyl)amino]piperidin-1-yl}sulfonyl)thiophen-2-yl]methanol The preparation of base} benzamide (1)

[0403] {[(3-Methoxybenzoyl)amino]methyl}thiophene-2-sulfonyl chloride (1a)

[0404] To a solution of 2-aminomethylthiophene (10.6 mL, 103 mmol) and pyridine (9.1 mL, 104 mmol) in 100 mL of chloroform was added 3-methoxybenzoyl chloride (19.2 g, 103 mmol) in dichloromethane ( CH 2 Cl 2 ) solution. The reaction was warmed to room temperature over 1 hour and stirred for an additional 3 hours. Water was added when 3-methoxy-N-(thiophen-2-ylmethyl)benzamide (1b) (10.1 g) precipitated. The solid was filtered and washed with water. The remaining organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated to give (1b) (15.2g). The overall yield was 25.3 g (99.9%). (1b) was used directly in the next step without further purification....

Embodiment 63

[0415] Example 63 (Protocole A; see Protocols 1, 3 and 7)

[0416] Preparation of 4-chloro-N-[(5-{[4-(hexylamino)piperidin-1-yl]sulfonyl}-thiophen-2-yl)methyl]benzamide 4-Chloro-N-thiophen-2-ylmethyl-benzamide (63a)

[0417] 2-Aminomethyl-thiophene (0.137 mol) and i PR 2 A solution of NEt (0.25 mol) in dichloromethane (200 mL) was added to a solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 mL of anhydrous dichloromethane. A white solid formed and the reaction was warmed to room temperature over 1 hour. The mixture was diluted with 200 mL of dichloromethane, washed twice with aqueous hydrochloric acid (0.1 N), and dried over magnesium sulfate. After evaporation of the solvent, 28 g (98%) of a white solid, the title benzamide, was obtained: melting point 153-54°C, 1 H NMR (CDCl 3 )δ7.9(d, J=8.67Hz, 2H), 7.58(d, J=8.67Hz, 2H), 7.44(dd, J=3.77, 1.13Hz, 1H), 7.22(d, J=5.27Hz, 1H), 7.16 (dd, J=3.39, 5.27Hz, 1H), 6.62 (brd, 1H), 4.98 (d, J=5.65Hz, 2H).

[0418] 5-(...

Embodiment 122

[0428] Example 122 (Protocole L; see Schemes 2 and 7)

[0429] 2-{[4-(Hexylamino)piperidin-1-yl]sulfonyl}-5-{[(3-methoxy-benzoyl)amino]methyl}thiophene-3- Preparation of Ethyl Carboxylate (122)

[0430] Diallyl-thiophen-2-ylmethylamine (122a)

[0431] 2-Aminomethyl-thiophene (51.4 g, 956 mmol) and i-Pr 2 NEt (140 g, 1081 mmol) in dichloromethane (1 L). Allyl bromide (115.7 g, 454 mmol) was added and reflux temperature was reached automatically after 2 hours of mildly exothermic reaction. The mixture was stirred overnight (16 hours), washed (saturated sodium bicarbonate solution; brine), dried (magnesium sulfate) and concentrated. The resulting oil was filtered through silica gel (ethyl acetate:hexane 1:4). The filtrate was concentrated and filtered repeatedly to obtain 70.3 g (80%) of brown oil, namely the title diallylamine. Determined by NMR: 1 H NMR (CDCl -3 )δ7.25 (br.d, J=5.9Hz, 1H), 6.98 (br.dd, J=5.1, 2.8Hz, 1H), 6.94-6.92 (m, 1H), 5.99-5.86 (m, 2H) , 5.29...

technical field

[0001] The present invention relates to substantially soluble sulfonamide derivatives bearing lipophilic groups. The sulfonamide derivatives are mainly used as pharmaceutically active compounds. The invention also relates to pharmaceutical preparations containing such sulfonamide derivatives. In particular, the present invention relates to sulfonamide derivatives for use in the treatment and / or prevention of immune and nervous system diseases. In particular, the sulfonamide derivatives of the present invention have a marked modulatory effect, notably their inhibitory activity on JNK (Jun Kinase) function or pathway, respectively. Background technique

[0002] Apoptosis refers to the complex distortion of the cell membrane and organelles when cells undergo programmed cell death. In the process, the cell activates an intrinsic suicide program and systematically destroys itself. The following sequence of events can be observed:

[0003] • The cell surface b...

Examples

Embodiment 1

[0401] Example 1 (Protocole E; see Protocols 1, 3 and 6)

[0402] 3-Methoxy-N-{[5-({4-[(4-trifluoromethylbenzyl)amino]piperidin-1-yl}sulfonyl)thiophen-2-yl]methanol The preparation of base} benzamide (1)

[0403] {[(3-Methoxybenzoyl)amino]methyl}thiophene-2-sulfonyl chloride (1a)

[0404] To a solution of 2-aminomethylthiophene (10.6 mL, 103 mmol) and pyridine (9.1 mL, 104 mmol) in 100 mL of chloroform was added 3-methoxybenzoyl chloride (19.2 g, 103 mmol) in dichloromethane ( CH 2 Cl 2 ) solution. The reaction was warmed to room temperature over 1 hour and stirred for an additional 3 hours. Water was added when 3-methoxy-N-(thiophen-2-ylmethyl)benzamide (1b) (10.1 g) precipitated. The solid was filtered and washed with water. The remaining organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated to give (1b) (15.2g). The overall yield was 25.3 g (99.9%). (1b) was used directly in the next step without further purification....

Embodiment 63

[0415] Example 63 (Protocole A; see Protocols 1, 3 and 7)

[0416] Preparation of 4-chloro-N-[(5-{[4-(hexylamino)piperidin-1-yl]sulfonyl}-thiophen-2-yl)methyl]benzamide 4-Chloro-N-thiophen-2-ylmethyl-benzamide (63a)

[0417] 2-Aminomethyl-thiophene (0.137 mol) and i PR 2 A solution of NEt (0.25 mol) in dichloromethane (200 mL) was added to a solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 mL of anhydrous dichloromethane. A white solid formed and the reaction was warmed to room temperature over 1 hour. The mixture was diluted with 200 mL of dichloromethane, washed twice with aqueous hydrochloric acid (0.1 N), and dried over magnesium sulfate. After evaporation of the solvent, 28 g (98%) of a white solid, the title benzamide, was obtained: melting point 153-54°C, 1 H NMR (CDCl 3 )δ7.9(d, J=8.67Hz, 2H), 7.58(d, J=8.67Hz, 2H), 7.44(dd, J=3.77, 1.13Hz, 1H), 7.22(d, J=5.27Hz, 1H), 7.16 (dd, J=3.39, 5.27Hz, 1H), 6.62 (brd, 1H), 4.98 (d, J=5.65Hz, 2H).

[0418] 5-(...

Embodiment 122

[0428] Example 122 (Protocole L; see Schemes 2 and 7)

[0429] 2-{[4-(Hexylamino)piperidin-1-yl]sulfonyl}-5-{[(3-methoxy-benzoyl)amino]methyl}thiophene-3- Preparation of Ethyl Carboxylate (122)

[0430] Diallyl-thiophen-2-ylmethylamine (122a)

[0431] 2-Aminomethyl-thiophene (51.4 g, 956 mmol) and i-Pr 2 NEt (140 g, 1081 mmol) in dichloromethane (1 L). Allyl bromide (115.7 g, 454 mmol) was added and reflux temperature was reached automatically after 2 hours of mildly exothermic reaction. The mixture was stirred overnight (16 hours), washed (saturated sodium bicarbonate solution; brine), dried (magnesium sulfate) and concentrated. The resulting oil was filtered through silica gel (ethyl acetate:hexane 1:4). The filtrate was concentrated and filtered repeatedly to obtain 70.3 g (80%) of brown oil, namely the title diallylamine. Determined by NMR: 1 H NMR (CDCl -3 )δ7.25 (br.d, J=5.9Hz, 1H), 6.98 (br.dd, J=5.1, 2.8Hz, 1H), 6.94-6.92 (m, 1H), 5.99-5.86 (m, 2H) , 5.29...

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