Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use

a technology of tetrahydropyridine and piperazine, which is applied in the field of piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use, and can solve the problems of patients withdrawing from treatment, ssris and all other antidepressants currently available, and several weeks of treatmen

Inactive Publication Date: 2002-11-21
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0218] Reactions according to method o) is performed by use of standard conditions for nitrile hydrolysis and reductions according to method o) is conveniently performed in an inert solvent such as e.g., diethyl ether or tetrahydrofuran using lithium aluminium hydride or alane.

Problems solved by technology

The side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.
SSRIs and all other antidepressants currently available suffer from a serious drawback in that several weeks of treatment are necessary to produce the therapeutic effect.
The late onset of action is a significant problem, particularly in the treatment of patients with severe depression and suicide potential.
Further, one in three patients are not responsive to SSRIs.

Method used

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  • Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use
  • Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use
  • Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0223] 1a, 1-[1,4-Benzodioxan-]5-yl-4-[-(inden-1-yl)-4-butyl]piperazine, oxalate

[0224] A mixture of 4(1-indenyl)butyl methanesulfonate (1.2 g, prepared as described in U.S. Pat. No. 5665725), 1-(1,4-benzodioxan-5-yl)piperazine (1.2 g), and potassium carbonate (0.8 g) in 3-methyl-2-pentanone (50 mL) was refluxed for 16 h. Cooling, filtration, and removal of solvent in vacuo gave an oil which was applied to silica gel flash chromatography (eluent: heptane / methylene chloride / triethylamine 70:26:4). The obtained oil was converted to the title oxalate salt (0.7 g) from acetone by addition of oxalic acid. Mp 130-31.degree. C. .sup.1H NMR (DMSO-d.sub.6): 1.60-1.90 (m, 4H); 2.55 (t, 2H); 3.05 (t, 2H); 3.15 (s, 8H); 3.35 (s, 8H); 3.35 (s, 2H); 4.15 4.35 (m, 4H); 6.30 (s, 1H); 6.50 (t, 1H); 6.60 (s, 1H); 6.75 (t, 1H); 7.20 (t, 1H); 7.25(t, 1H); 1H); 7.40 (d, 1H); 7.50 (d, 1H). MS m / z (%):391 (MH+, 79%), 218 (37%), 162 (50%), 129 (100%)

[0225] The following compounds were prepared analogously (...

example 2

[0230] 2a, 1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]pi-perazine, oxalate

[0231] A solution of 5-fluorobenzofuran-3-carboxylic acid (56 g) and saturated etheral solution of hydrochloric gas (300 mL) in methanol (600 mL) was stirred for 16 h at room temperature. Further etheral HCl was added (300 mL) followed by stirring for 24 h. Concentration in vacuo gave a dark crystalline material, methyl 5-fluorobenzofuran-3-carboxylate (58 g). Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55.degree. C. during the addition. After stirring for 2 h the reaction was quenched successively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipit...

example 3

[0241] 3a, 1-[Benzofuran-7-yl]-4-[2(5-fluorobenzofuran-3-yl)ethyl]piprazin-e, fumarate

[0242] A solution of 5-fluorobenzofuran-3-ylacetic acid (4.6 g, prepared as described in Example 2) in dry tetrahydrofuran (200 mL) was added dropwise to a suspension of lithium aluminium hydride (4.5 g) in dry tetrahydrofuran (150 mL) at room temperature. After reflux for 2 h the reaction was quenched by successive additions of water (9.2 mL), 15% aq. sodium hydroxide (4.6 mL), water (23 mL). Filtration and removal of solvent in vacuo gave an oil, 2-(5-fluorobenzofuran-3-yl)ethanol (4.3 g).

[0243] A solution of 2-(5-fluorobenzofuran-3-yl)ethanol (5.2 g) and tetrabromomethane (11.6 g) in acetonitrile (175 mL) was treated with tnrphenylphosphine (8.3 g) at 0.degree. C. After stirring for 15 min, the mixture was concentrated in vacuo an the resulting oil was applied to a silica gel flash column (eluent: heptaneiethyl acetate 65:35) resulting in an oil, 3(2-bromoethyl)-5-fluorobenzofuran (7.4 g).

[0244]...

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Abstract

A piperidine, tetrahydropyridine or piperazine derivative having formula (I), any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein B is C1-10-alkylene, C1-10-alkenylene or C1-10-alkynylene; X is -O-, -S-, or CR4R5-; and Y is -CR6R7, -CR6R7-CR8R9, or CR6=CR7-; or X and Y together form a group -CR4=CR5, or -CR4-CR5-CR6R7-; Z is -O-, or -S-; W is N, C, or CH, and the dotted line is an optional bond; A is a bicyclic ring selected from (Ia) or (Ib) wherein E1, E2 and E3 are selected from O, S, N, NR11, C, CR12 and CHR13, and the dotted line indicates an optional bond, provided that E2 and E1 and / or E3 may not simultaneously be O, or S. The compounds of the invention are considered useful for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.

Description

[0001] The present invention relates to novel piperidine, tetrahydropyridine and piperazine derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use thereof for the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake. The compounds of the invention also possess antagonistic activity at 5-HT.sub.1A receptors and are considered to be particularly useful for the treatment of depression.[0002] Selective serotonin (or 5-HT) reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step forward in the treatment of depression because they have fewer and less severe side effects compared to first generation antidepressant (tricyclics and non-selective MAO inhibitors). The side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.[0003] SSRIs and all other antid...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496A61P25/18A61P25/22A61P25/24A61P43/00C07D307/81C07D319/18C07D319/20C07D405/12C07D405/14C07D407/12C07D413/12
CPCC07D307/81C07D319/18C07D413/12C07D405/14C07D407/12C07D405/12A61P25/00A61P25/18A61P25/22A61P25/24A61P43/00
Inventor MOLTZEN, EJNER KNUDKROG-JENSEN, CHRISTIANBJORNHOLM, BERITH
Owner H LUNDBECK AS
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