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Serotonin 5-HI1A and dopamin D2 receptor ligands

A hydroxyl, phenylpiperazine technology, applied in the field of serotonin 5-HT1A and dopamine D2 receptor ligands, can solve the problem of not providing test data and so on

Inactive Publication Date: 2001-06-13
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] US Patent 3,374,237 discloses a group of 1-phenyl-3-(4-phenyl-1-piperazinyl-C 2-4 Alkyl)-2-imidazolidinones, which are said to be useful as sedatives, but no test data provided

Method used

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  • Serotonin 5-HI1A and dopamin D2 receptor ligands

Examples

Experimental program
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preparation example Construction

[0039] The present invention further relates to the preparation method of the new 4-phenylpiperazine compound of formula I, 4-phenylpiperidine compound and 4-phenyl-1,2,3,6-tetrahydropyridine compound, The method comprises: a) reacting a compound of formula II with a compound of formula III: where R 1 -R 5 , R 9 , R 10 , X, V, W, Z, n and dashed lines are as defined above, Y represents a suitable leaving group such as halogen, mesylate or tosylate; or b) reducing the amide carbonyl of formula IV Compound: where R 1 -R 5 , R 9 , R 10 , X, V, W, Z, n and dashed lines are as defined above; or c) make the compound of formula V where R 2 -R 5 , R 9 , R10 , X, V, W, Z, A and dashed lines are defined as above, with compound R 1 Y response, where R 1 is defined above and Y represents a suitable leaving group such as a halogen, mesylate or tosylate; or d) with an aldehyde R'CHO, a ketone R"R_CO or a carboxylic acid R'COOH (where R', R" and R_ are together with the nit...

Embodiment 1

[0052] Example 1 (similar method d) 1-(4-chloro-1-butyl)-3-cyclohexyl-2-imidazolidinone 1a

[0053] A mixture of 1-(4-chloro-1-butyl)-2-imidazolidinone (50 g) and cyclohexanone (83.3 g) in glacial acetic acid (1000 ml) was stirred at room temperature for 1 hour and the resulting mixture was cooled to 10-15°C and add NaBH in small batches within 5 hours 4 (42.4g). After stirring at room temperature overnight, the acetic acid was evaporated in vacuo. Add water (500ml) and dichloromethane (300ml) and by adding dilute NH 4 Aqueous OH solution adjusted the pH to greater than 9. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated in vacuo. The residual crude product was purified by silica gel column chromatography (eluting with ethyl acetate). Pure title compound 1a crystallized on standing. Yield: 33 g, mp: 30-35°C.

[0054] The following imidazolidinones were prepared according to the corresponding method: 1-(3-Ch...

Embodiment 2

[0055] Example 21-(4-chloro-1-butyl)-3-(4-fluorophenyl)-2-imidazolidinone 2a

[0056] To a solution of 2-aminoethanol (1100 g) in ethanol (1000 ml) was added 4-chlorobutanol (220 g), and the resulting mixture was refluxed for 4 hours. After cooling to 10°C, a solution of sodium methoxide in methanol (380ml) was added. The precipitate was filtered off and the volatiles were evaporated in vacuo. The remaining oil was distilled under reduced pressure. 4-[N-(2-Hydroxyethyl)amino]butanol was collected at 135-140° C. at 0.2-0.4 mmHg, yield: 106 g. Amino alcohol (25g) was dissolved in dichloromethane (150ml) and a solution of 4-fluorophenylisocyanate (26g) in dichloromethane (25ml) was added dropwise at 0-8°C. After reflux for 2 hours, the solvent was removed in vacuo to give crude 1-(2-hydroxyethyl)-1-(4-hydroxybutyl)-3-(4-fluorophenyl)urea as an oil, yield: 56 g . To a solution of all the crude urea derivatives and N,N-dimethylformamide (DMF, 1 ml) in dichloromethane (250 ml) ...

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Abstract

The present invention relates to a novel series of 4-phenylpiperazines, 4-phenyl-piperidines and 4-phenyl-1,2,3,6-tetrahydropyridines compound of general formula (I) wherein A is alkylene, alkenylene, alkynylene, and C3-7 cycloalkylene; R<1> is a C3-10 alkyl, alkenyl, or alkynyl group, cycloalk(en)yl, cycloalk(en)yl-alk(en / yn)yl, trifluoromethylsulfonyl, or alkylsulfonyl, R<2> - R<5> are optional substituents; R<9> and R<10> are hydrogen, alkyl or together form an ethylene or propylene bridge; W is O or S; V is O, S, CR<6>R<7>, or NR<8> wherein R<6>, R<7>, and R<8> are hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted arylalkyl or aryl, or R<6> and R<7> constitute a 3-7 membered spiroring; Z is -(CH2)m-, m being 2 or 3 or Z is -CH=CH-; X is N, C or CH; show effects on central serotonin 5-HT1A and dopamine D2 receptors. Thus the novel compounds are useful in the treatment of certain psychic and neurologic disorders in particular psychosis.

Description

field of invention [0001] The present invention relates to novel 4-phenylpiperazines, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridines. Due to central serotonin 5-HT 1A and dopamine D 2 Both receptors have effects, and the above-mentioned new compounds can be used to treat certain mental and neurological diseases. Background of the invention [0002] In the international patent application WO92 / 03426, a class of carbamoylalkyl or N-aryl groups having phenyl, naphthyl or quinolinyl at the 4-position and N-aryl substitution at the 1-position is disclosed. Substituted ureidoalkyl piperazine derivatives. The above-mentioned compounds are said to show effects on various receptors, such as 5-HT 2 , 5-HT 1A , affinity for alpha and dopamine receptors. [0003] EPAl 0376607 concerns as part of 5-HT 1A Agonists of certain 1-[4-(3-indolyl)butyl]-4-(2-hydroxyphenyl)piperazines. [0004] EPA1 0526434 discloses, among a series of other compounds, 1-[(4-phenyl-piperazi...

Claims

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Application Information

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IPC IPC(8): C07D233/34A61K31/415A61K31/4166A61K31/4427A61K31/445A61K31/4465A61K31/451A61K31/4523A61K31/4985A61P9/00A61P9/08A61P9/10A61P25/18A61P25/20A61P25/24A61P25/26A61P25/28A61P25/30C07D211/22C07D233/32C07D233/36C07D233/70C07D401/06C07D403/06
CPCC07D233/36C07D233/32C07D401/06A61P25/00A61P25/18A61P25/20A61P25/22A61P25/24A61P25/26A61P25/28A61P25/30A61P25/32A61P9/00A61P9/08A61P9/10
Inventor J·K·佩尔里加德E·K·莫尔岑
Owner H LUNDBECK AS
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