5-halo-tryptamine derivatives used as ligands of 5-HT 6 and/or 5-HT7 serotonin receptors

A 5-HT75-, 5-HT6 technology, applied in the field of 5-halotryptamine derivatives

Inactive Publication Date: 2004-10-06
SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, many psychotropic drugs (antidepressants, antipsychotics) are known to exhibit effects on 5-HT 6 High affinity, but not selective (Monsma, F.J. et al., Molecular Pharmacology (Molecular Pharmacology) 43.320-3...

Method used

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  • 5-halo-tryptamine derivatives used as ligands of 5-HT 6 and/or 5-HT7 serotonin receptors
  • 5-halo-tryptamine derivatives used as ligands of 5-HT 6 and/or 5-HT7 serotonin receptors
  • 5-halo-tryptamine derivatives used as ligands of 5-HT 6 and/or 5-HT7 serotonin receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (E)-5-Bromo-2-methyl-3-(2-nitrovinyl)-1H-indole

[0048] A solution of 0.58 g of 1-(dimethylamino)-2-nitroethylene (5 mmol) in 5 mL of trifluoroacetic acid was stirred and cooled to 0 °C, and 1.05 g (5 mmol) of 5-bromo-2-methyl -indole, and react the resulting mixture at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was then placed in an ice-water bath. The aqueous solution was extracted with ethyl acetate, and the combined organic phases were then washed with saturated bicarbonate solution, followed by water, and finally dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to leave a solid, orange residue which was then suspended in ethyl acetate-ether mixture and filtered.

[0049] Yield: 89%

[0050] R f =0.3 (cyclohexane / EtOAc:1)

[0051] M.p.: 196-198°C (decomposition)

[0052] 1H-NMR (200MHz) (DMSO-d 6 ): δ2.59(s, 3H), 7.34(m, 2H), 7.97(d, 1H, J=13.2Hz), 8.06(m, 1H), 8.26(...

Embodiment 2

[0067] According to the described method, and according to the above scheme and examples, the following compounds were prepared:

[0068] (E)-5-Chloro-2-methyl-3-(2-nitrovinyl)-1H-indole

[0069] orange solid

[0070] Yield: 85%;

[0071] M.p..191-193℃

[0072] 1 H NMR (200MHz, (acetone-d 6 ): δ2,68(s,3H), 7,21(dd,1H, J=1,95 and J=8,5Hz), 7,5(d,1H, J=8,5Hz), 7,85 (d, 1H, J=13,3Hz), 7,86 (d, 1H, J=1,95Hz), 8,30 (d, 1H, J=13,3Hz); EIMS: m / z 236 (M + ), 154(100).

[0073] 5-Chloro-2-methyltryptamine hydrochloride

[0074] From EtOH / Et 2 O Precipitated crystalline pale brown solid.

[0075] Yield: 72%

[0076] 1 H NMR (200MHz, (DMSO-d 6 ): δ2,33(s,3H), 6,97(dd,1H, J=1,9 and J=8,3Hz), 7,25(d,1H, J=8,3Hz), 7,52 (d, 1H, J=1,5Hz), 8,03(br,s,3H), 11,15(s,1H).

[0077] 5-chloro-2-methyl-N,N-dimethyltryptamine (ST 1936)

[0078] white solid;

[0079] Yield: 75%;

[0080] M.p.=126-127℃

[0081] 1 H NMR (200MHz, CDCl 3 ): δ2,35(s,6H), 2,38(s,3H), 2,44-2,52(m,2H), 2,79-2...

Embodiment 3

[0084]

[0085] Reactants: (a) t-BuLi, THF, -20°C; EtI, -78° to room temperature, 2h; (b) 2N NaOH, MEOH, reflux, 40h; (c) 1-(dimethylamino)- 2 Nitroethene, TFA, 0°C, 0,5h; (d) LiAlH 4 , THF, room temperature, 6h; (e) NaCNBH 3 , 40%, HCHO, MeOH, AcOH, room temperature, 2,5h.

[0086] N-(phenylsulfonyl)-5-chloro-2-ethylindole (2).

[0087] t-BuLi (3.7 mL of a 1.7 M solution in pentane) was added dropwise to N-(phenylsulfonyl)-5-chloroindole (1) in THF (35 mL) at -70 °C under nitrogen atmosphere (J. Org. Chem. (Journal of Organic Chemistry) 1981, 46, 3859) (1.5 g, 5.14 mmol). The mixture was stirred for 15 minutes, warmed to room temperature over 20 minutes, cooled to -70 °C, and treated with iodoethane solution (0.84 mL, 10.5 mmol) in anhydrous THF (5 mL). The mixture was stirred at -78 °C for 1 h, allowed to warm to room temperature, stirred for 2 h, poured into ice (15 g) and saturated NH 4 Cl aqueous solution, then extracted with diethyl ether (3 x 20 mL). The combin...

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Abstract

Compounds of Formula (I): (I); wherein: R1 and R2 either the same or different, are H or linear or branched C1-C6 alkyl; R3=linear or branched C1-C6 alkyl; R4=halogen, and pharmaceutically acceptable salts thereof are useful as active ingredients in the preparation of medicaments used as ligands of the 5-HT6 and/or 5-HT7 serotoninergic receptors.

Description

[0001] The invention described herein relates to the use of 5-HT 6 and / or 5-HT 7 Serotonin derivatives of ligands for serotonin receptors; processes for their preparation; their use as medicaments, in particular for the treatment of neurological pathological conditions associated with insufficient levels of serotonin, involving the cardiovascular system, Use of medicines for systemic pathological conditions of the gastrointestinal tract; and pharmaceutical compositions comprising them. Background of the invention [0002] Over the past 10 years, molecular cloning has revealed 14 serotonin subtypes, which have been grouped into seven subfamilies. The diversity of serotonin receptors has been proposed to be a direct result of the evolutionary era of the 5-HT system. In addition to 5-HT as a ligand-gated ion channel 3 With the exception of receptors, all receptors are members of the serotonin receptor superfamily, a large class of receptors linked to their effector functions v...

Claims

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Application Information

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IPC IPC(8): A61K31/4045A61K31/405A61P1/00A61P9/00A61P9/12A61P25/00A61P25/06A61P25/18A61P25/20A61P25/24C07D209/16
CPCA61K31/405C07D209/16A61P1/00A61P25/00A61P25/06A61P25/14A61P25/16A61P25/18A61P25/20A61P25/24A61P25/28A61P43/00A61P9/00A61P9/12A61K31/403
Inventor P·米内蒂M·A·迪切萨雷G·塔吉亚G·斯帕多尼
Owner SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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