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Indol-3-Yl-cyclohexyl amide derivatives for treatment of depression (5-HT1 receptor antagonists)

A cyclohexyl and indole technology, which is applied in the field of various indol 3-yl-cyclohexylamine derivatives for the treatment of such diseases, can solve the problems of weakened curative effect and inability to fully explain the therapeutic activity

Inactive Publication Date: 2001-07-18
AMERICAN HOME PRODUCTS CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since SSRIs take several weeks to exert their full therapeutic effect, such a serotonin-blocking mechanism cannot fully explain its therapeutic activity
It is hypothesized that the two-week induction before the full antidepressant effect is observed is due to the involvement of the 5-HT1A autoreceptor, which inhibits the firing activity of serotonin neurons, causing attenuation of the therapeutic effect

Method used

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  • Indol-3-Yl-cyclohexyl amide derivatives for treatment of depression (5-HT1 receptor antagonists)
  • Indol-3-Yl-cyclohexyl amide derivatives for treatment of depression (5-HT1 receptor antagonists)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 (3,4-dihydro-benzo[1,4]oxazin-2-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-ring Hexa]-amine and (3,4-dihydro-benzo[1,4]oxazin-2-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl) -

[0073] Cyclohexyl]-amine

[0074] Trifluoroacetic acid (5 ml) was added to cis / trans-(tert-butyl-3,4-dihydro-benzo[1,4]oxazine-4-carboxylate-2-methanol at room temperature yl)-4-[5-fluoro-1H-indol-3-yl)-cyclohexyl]-amine in dichloromethane (15ml). After stirring the reaction mixture for 2 hours at room temperature, the solvent was removed. A small amount of methanol was added to the residue, and the solution was adjusted to pH >9 with 2N sodium hydroxide solution. The aqueous portion was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by chromatography (ethyl acetate / methanol / ammonia: 99 / 1 / 0.5) to obtain 0.41 g (35%) of the cis isomer as a white solid: mp 65...

Embodiment 2

[0082] Example 2 (3,4-dihydro-benzo[1,4]oxazin-3-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-ring Hexa]-amine and (3,4-dihydro-benzo[1,4]oxazin-3-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl) -

[0083] Cyclohexyl]-amine

[0084] 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.578g, 2.5mmol), 3-aminomethyl-1,4-benzoxazine (0.411g, 2.5mmol) , sodium triacetate borohydride (0.78g, 3.5mmol) and acetic acid (0.14ml, 2.5mmol) in 1,2-dichloroethane (11ml) was stirred at room temperature for 5 hours. The reaction was quenched with 1N sodium hydroxide and extracted with dichloromethyl. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by chromatography (ethyl acetate / methanol / ammonia: 99 / 1 / 0.5) to obtain 0.63 g (66%) of the cis isomer as an oil. The fumarate of the cis isomer was prepared in isopropanol: mp 208-209°C.

[0085] C 23 h 26 FN 3 O 0.5C 4 h 4 o 4 0.3H 2 Elemental analysis of O...

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Abstract

The invention provides compounds effective in treating disorders of the serotonin-affected neurological symptoms (5-HT1A receptor active), such compounds having formula (I), wherein: R1 and R5 are each, independently, hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or trifluoromethyl; R2 and R4 are each, independently, hydrogen, lower alkyl, phenyl, or substituted phenyl; R3 is hydrogen or lower alkyl; and X and Y are each, independently, O, NR6, or CH2, wherein R6 is hydrogen, lower alkyl, phenyl, or substituted phenyl; or pharmaceutically acceptable salts thereof.

Description

field of invention [0001] The compounds involved in the present invention are useful in the treatment of disorders of the nervous system affected by serotonin, such as depression and anxiety. More specifically, the present invention relates to various indol 3-yl-cyclohexylamine derivatives useful in the treatment of such diseases. Background of the invention [0002] Pharmaceutical compounds that enhance serotonin (serotonin) transmission are useful in the treatment of many psychiatric disorders including depression and anxiety. The first generation of drugs that non-selectively affected serotonin acted on multiple physiological functions, giving it many unwanted side effects such as blurred vision, dry mouth and sedation. The most recently described compounds are the selective serotonin reuptake inhibitors (SSRIs), whose main action is to inhibit the active removal of serotonin released at the synapse from the synaptic cleft by the presynaptic serotonin transporter. Since...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12A61K31/404A61K31/498A61K31/538A61P25/24C07D405/12
CPCC07D405/12A61P25/24
Inventor R·E·穆肖P·周
Owner AMERICAN HOME PRODUCTS CORPORATION
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