The invention relates to a process for the synthesis of l-(4-arylpiperazin-l-yl)-to-(2,6-dioxopiperidin-l-yl)alkanes as α1-adrenoreceptor blockers useful for the treatment of hypertension and benign prostatic hyperplasia (BPH).
The novel 1 -(4-arylpiperazin-l-yl)-α-(2,6-dioxopiperidin-l-yl)alkanes prepared by the process of Ihe present invention having formula III, as shown in the drawing accompanying this specification, where R represents groups like chlorophenyl, fluorophenyl, methylphenyl, mcthoxyphenyl, pyridyl, pyrimidyl, 3, 4 - dimethylphenyl and trifluoromethylphenyl and n=2-4. These compounds have selective a,-adrenoreceptor blocking activity and would therefore be useful for the treatment of disorders controllable by a,- adrenoreccptor antagonism such as hypertension and benign prostatic hyperplasia. The main objective of the present invention is to provide a process for the synthesis of the compound of the formula III as defined above which would be useful for disease conditions amenable to treatment with α1-adrenoreceptor blocking
agents.
A number of established a,- adrenoreccptor antagonists such as prazosin and terazosin having formulae VIII and IX, as shown in the accompanied drawings, are currently used in the management of BPH. However, this class of drugs are associated with vascular events (postural hypertension, syncope, dizziness, headaches etc.) due to thin margins in selectivity of action. Thus, there is a need to discover a prostate-selective a,- adrenoreceptors which will confer liiodynamic improvement without the accompanying vascular side effects associated with existing drugs. The compounds of the present invention offer this possibility.
The compounds of the present invention may be prepared by methods well known in the art and familiar to a well versed synthetic organic chemist. The process used for the preparation of the compounds-of formula III, according to the present invention, are illustrated in the "Reaction Scheme" as shown in the accompanied drawing.
This method comprises condensing 2,6-dioxopiperidine (glutarimide) of the formula I with l-(4-arylpipera/in-l-yl)--chloroalkanes of the formula II in the presence of potassium carbonate and a suitable solvent such as acetone or dimethylformamide at temperatures ranging upto 150oC for a period varying between 8-24 hours to produce the corresponding l-(4-arylpiperazin-l-yl)--(2,6-dioxopiperidin-l-yl)alkanes of the formula III where R represents groups like chlorophenyl, fluorophenyl, methylphenyl, methoxyphenyl. pyridyl, pyrimidyl, 3,4-dimethylphenyl and trifluoroniethylphenyl and n=2-4.
It was observed that the reaction time was significantly reduced by the addition of phase transfer catalysts such as tetrabutylammonium bromide and potassium iodide.
In the above synthesis, where specific bases, acids, solvents, phase transfer catalysts etc. are mentioned, it is to be understood that the other acids, bases, solvents, phase transfer catalysts etc.
may be used. Similarly, the reaction temperature and duration of the reaction may be adjusted according to the desired needs.
Preferred compounds according to the invention and capable of being produced by the reaction sequences described above are given below. The following examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
Preparation of l-[4-(2-Methoxyphenyl)piperazin-l-yl]-3-[2,6-dioxopiperidin-l-yl) - propane of the formula III, where R=2-OCH3C6H4
EXAMPLE 1
A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol) and l-[4- (2-methoxyphenyl)piperazin-l-yl]-3-chloropropane (6.18 g, 23.02 mmol), K2CO3 (2.38 g, 17.27 mmol) and tetrabutylammoniuin
bromide (1.48 g , 4.60 mmol) in acetone ( 80 ml) was refluxed for 16 hours at 80°C with stirring. The solvcnl was evaporated off in vacuo and the residue suspended in water (60 ml), extracted with chloroform (3x40 ml) and the organic layers combined, washed with water (2x40 ml), dried over anhydrous Na,SO4 and evaporated in vacuo to give the title compound having formula III. The
product was purified by column chromatography over flash silica gel using chloroform-methanol (98:2) as ekient; yield 3.58 g (45%),oil. The hydrochloride salt was prepared in the quantitative yield by the addition of ethereal hydrogen chloride solution to a methanolic solution of the free base and collected by filtration of the resultant precipitate, m.p. 219-22 T'C.
EXAMPLE 2
A mixture of 1 -chloro-3-(2,6-dioxopiperidin-l-yl)propane (22.09 g, 116.40 mmol), l-(2-niethoxyphenyl)piperazine (21.90 g., 114.07 mmol), potassium carbonate (16.06g, 116.40 mmol) and potassium iodide (1.16g, 6.98 mmol) in N, N-dimethylformamide (90 ml.) was heated at 100oC for I 7 hrs. and the solvent was evaporated under reduced pressure. Residue was dissolved in ethyl acetate (400 ml), washed with water (5 x 100 ml.) and dried over Na2SO4 and concentrated to give an oil which was purified by column chromatography over silicagel using chloroform -methanol (99:1) as eluent; yield 33.8 g., (85%), oil. The hydrochloride salt of this product was formed in the manner described above.
l-('hloro--(2,6-dioxopiperidin-l-yl)alkanes can be prepared by the reaction of respective 1-bromo--chloroalkanes with 2,6-dioxopiperidine in the presence of tctrabutylammonium bromide and potassium carbonate in acetone at room temperature.
An illustrative list of the compounds of the invention synthesised by the above described methods is given below:
l-|4-(4-Fluorophenyl)piperazin-l-yl|-3-(2,6-dioxopiperidiii-l-yI)propane of the formula III, where R=4-FC6H4, m.p. 200-202oC
1 -[4-(4-ChlorophenyI)piperazin-l-yl|-3-(2,6-dioxopiperidin-1 -yl)propane hydrochloride of the formula HI, where R=4-ClC6H4, m.p. 206-208oC
1 -[4-(3-TrifluoromethylphenyI)piperazin-1 -yl|-3-(2,6-dioxopiperidin-1 -yI)propane hydrochloride of the formula III, where R=3-CF3C6H4, m.p. 228-229'C
l-|4-(2-Fluorophenyl)piperazin-l-yl|-3-(2,6-dioxopiperidiii-l-yI)propane hydrochloride of the formula III , where R=2-FC6H4, m.p. 215-216OC
l-|4-(2-Methylphenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride of the formula III, where R=2-CH3C6H4, m.p. 206-207'C
l-|4-(2-Pyridyl)piperazin-l-yl)-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride of the formula III, where R=2-pyridyl, m.p. 244-245°C
1 - |4- (3-Chlorophenyl)piperazin -l-yI|-3 -(2, 6 - dioxopiperidin -1 - yl) propane hydrochloride of the formula III, where R = 3-CIC6H4, m.p. 214-215°C
l-|4-(3,4-Dimethylphenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride of the formula III, where R = 3, 4-diCH3C6H3, low melting hygroscopic
1 - |4 - (2 - Pyrimidyl) piperazin - 1 - yl] - 3 - (2, 6 - dioxopiperidin - 1 - yl) propane hydrochloride of the formula III, where R -2 -pyrimidyl, m.p. 195-196"C
l-|4-(3-methoxyphenyl)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride of the formula III, where R = 3-OCH3C()H4, m.p. 196-197'C.
i-|4~(4-methoxyphenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride of the formula III, where R = 4-OCH3C6H4, m.p. 218-220°C.
l-|4-(2-methoxyphenyl)piperazin-l-yl|-4-(2,6-dioxopiperidin-l-yl)butane hydrochloride of the formula III, where R = 2-OCH3C6H4, m.p. 190-192°C.
All the melting points reported above are uncorrected and taken by an open capillary method using Buehi 535. .

We Claim:
1. A process for the preparation of 1 -(4-arylpiperazin-1 -yl)--(2,6-dioxopiperidin-1 -yl) alkanes of Formula III, as selected α1-adrenoceptor blockers useful for the treatment of benign prostatic hyperplasia (BPH) and hypertension, as shown in the accompanied drawings, wherein R represents group like chlorophenyl, fluorophenyl, methylphenyl, methoxyphenyl, pyridyl, pyrimidyl, di-methylphenyl and trifluoromethylphenyl and n=2-4, which comprises condensing 2,6-dioxopiperidine of Formula I with 1-(4-arylpiperazin-l-yl)-co-chloro-alkanes of Formula II, as shown in the accompanied drawings, wherein R and n have the same meanings as defined above, in the presence of a base and a phase transfer catalyst tetrabutyl ammonium bromide and potassium iodide in an organic solvent at a temperature ranging up to 150°C.
2. A process for the preparation of l-(4-aryl piperazin-l-yl)--(2,6-dioxopiperidin-1-yl) alkanes of Formula III, substantially as herein described with reference to example.