WO2005021506A1

WO2005021506A1 - Synthesis of 1-[4-(2-methoxyphenyl) piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane

Info

Publication number: WO2005021506A1
Application number: PCT/IB2003/003609
Authority: WO
Inventors: Gyan Chand Yadav; Somesh Sharma; Mohammad Salman
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2003-08-28
Filing date: 2003-08-28
Publication date: 2005-03-10
Anticipated expiration: 2006-02-28
Also published as: AU2003253173A1

Abstract

The present invention relates to syntheses of 1-[4-(2-methoxyphenyl)piperazin-1-yl]-(2,6-dioxopiperidin-1-yl)propane and its pharmaceutically acceptable salts, preferably hydrochloride having protracted uro-selective α1-adrenoceptor antagonistic activity. The compound holds promise for treating benign prostatic hyperplasia (BPH).

Description

SYNTHESIS OF l-[4-(2-METHOXYPHENYL) PIPERAZIN-l-YL]-3-(2,6- DIOXOPIPERIDIN-1-YL) PROPANE FIELD OF INVENTION

The present invention relates to syntheses of l-[4-(2-methoxyphenyl)piperazin-l- yl]-(2,6-dioxopiperidin-l-yl)propane and its pharmaceutically acceptable salts, preferably hydrochloride having protracted uro-selective cii -adrenoceptor antagonistic activity. The compound holds promise for treating benign prostatic hyperplasia (BPH). BACKGROUND OF INVENTION

A review in J. Med. Chem., 1997, V.40, No. 9, pp 1291-1315, describes pharmacological options available for the treatment of benign prostatic hyperplasia. Two successful therapies have been based on -adrenergic receptor antagonism and androgen levels modulation by 5α-reductase inhibitors. However, 5 -reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. On the other hand, c -antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore desirable modalities of treatment in the control of benign prostate hypertrophy. α Adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure. Thus, αi- adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.

The more important of the c^ -adrenoceptor antagonists which are currently used in the management of BPH are shown below:

PRAZOSIN

TERAZOSIN

DOXAZOSIN

(R)-(-)-TAMSULOSIN

AFLUZOSIN However, most of these known drugs are associated with vascular side effects (e.g. postural hypertension, syncope, dizziness, headaches, etc) due to lack of selectivity of action between prostatic and vascular αi-adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.

Various l-(4-arylpiperazin-l-yl)-ω-[N-(α, ω-dicarboxamido)]alkanes have been described in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,366 and 6,420,559. These compounds exhibit uro-selective αj-adrenoceptor antagonistic activity exceeding those of previously described compounds. These compounds exhibit significantly greater oci_A-adrenergic blocking potency than the known compounds in order to provide specific treatment for benign prostatic hyperplasia. This class of compounds are not associated with vascular side effects as they showed greater selectivity against _\ adrenoceptors, which thus offers selective relief for prostrate hypertrophy as well as essential hypertension.

It is seen that 2,6-dioxopiperidine group enhances the adrenoceptor blocking activity, and also greatly increases the selectivity for C^_A in comparison to αm- adrenoceptor blocking activity, which is believed desirable for the compounds to be good candidates for the treating of Benign Prostatic Hyperplasia (BPH).

1 -[4-(2-methoxyphenyl)piperazin- l-yl]-3-(2,6-dioxopiperidin- 1 -yl]propane of Formula I,

Formula I

a compound of this class showed greater selectivity against

adrenoceptors and it thus offers selective relief for prostrate hypertrophy as well as essential hypertension. This can be administered intravenously or intraduodenally.

Particular syntheses of l-[4-(2-methoxyphenyl)piperazin-l-yl-3-(2,6- dioxopiperidin-l-yl)propane of Formula I, is described by two methods in the U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,366 and 6,420,559.

The title compound was synthesised by carrying out the reaction between glutaric anhydride and 3-[4-(2-methoxyphenyl)piperazin-l-yl]propylamine in pyridine at reflux temperature for 10 hours followed by the addition of acetic anhydride and refluxing the reaction mixture further for 5 hours. The product was purified by column chromatography, using chloroform-methanol (98:2) as eluent. The above mentioned methods in the prior art for the synthesis of compound of Formula I suffer from particular limitations and are not suitable for commercial production. The synthesis of pure compound via these two methods in the prior art involves the step of column chromatography for purification which is not commercially feasible. The use of chloroform in bulk for reaction work up and purification of the compound by column chromatography poses a problem of handling at a commercial level. Pyridine used in the reaction is highly toxic. During hydrochloride salt formation, use of diethylether or ethanolic HC1 is associated with the risk of fire. The reaction is time consuming and is completed in a time period of 15 hours. SUMMARY OF THE INVENTION

The present invention can solve problems associated with the prior art and can provide an improved method for synthesis of the compound of Formula I

Formula I

and its pharmaceutically acceptable salts, preferably hydrochloride, which method provides substantial benefits with respect to economics and convenience to operate at a commercial scale. More particularly, the present invention relates to a process for the preparation of the compound of Formula I and its pharmaceutically acceptable salts, for example, the hydrochloride salt, comprising reacting glutaric anhydride with the compound 3-[4-(2- methoxyphenyl) piperazine-l-yl]propylamine of Formula II

Formula II

to give the compound of Formula I

Formula I

which is further reacted with hydrochloric acid to give its hydrochloride salt.

The reaction of glutaric anhydride with the compound 3-[4-(2-methoxyphenyl) piperazine-l-yl]propylamine (synthesized by the procedure described in J Ind. Chem. Soc, LX, (1993), 874-876) of Formula II is carried out in a solvent which can be, for example, xylene, benzene or toluene.

The above reaction is completed in a time period ranging between 0.5-2 hours. It is efficiently accomplished in a time period of about 30-40 minutes. However, the length of time required will vary depending upon the factors as temperature of reaction and concentration.

In the following section preferred embodiments are described in a way to illustrate the process of this invention however, this does not limit the scope of the present invention. DETAILED DESCRIPTION

Preparation of l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl) propane hydrochloride

A solution of glutaric anliydride (0.5g, 4.38 mmole) and 3-[4-(2-methoxyphenyl) piperazinl-yl] propylamine (1.09g, 4.38mmole) in xylene (10ml) was refluxed for 30-40 minutes. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water (20ml) and extracted with ethyl acetate (2x15ml). The extract was dried over sodium sulphate and concentrated under reduced pressure to afford l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl) propane (1.2g) as an oil. The product was prepared in a yield of 80%. Infrared spectroscopy of the product yielded peaks at (DCM): 1723,1671.3 cm^"1. ¹HNMR spectra of the product showed peaks at (300 MHz, CDCl₃)δ: 1.80-1.91 (2H, m), 1.92-1.96 (2H, m), 2.53-2.58 (2H, m), 2.63- 2.68 (4H, m), 2.78 (4H, brs), 3.14 (4H, brs), 3.81-3.85 (5H, m), 6.84-7.03 (4H, m). The mass spectrum of the product showed a peak at 346 (M⁺+l). The hydrochloride salt was prepared in quantitative yield by the addition of isopropanolic hydrochloride solution to an isopropanolic solution of the free base and the resultant precipitate was collected by filtration to give a product with a melting point of 206-210°C. Column chromatography was not required in the purification of the product.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are within the scope of the present invention.

Claims

WE CLAIM:

1. A process for the synthesis of compound of Formula I

Formula I comprising reacting glutaric anhydride with the compound 3-[4-(2- methoxyphenyl)piperazine-l-yl Jpropylamine of Formula II

Formula II to yield the compound of Formula I.

2. The process of claim 1 , wherein the reaction of glutaric anhydride with the compound with the compound 3-[4-(2-methoxyphenyl)piperazine-l-yl]propylamine of Formula II to give the compound of Formula I is carried out in a solvent.

3. The process of claim 2, wherein the solvent is selected from xylene, benzene and toluene.

4. The process of claim 1, further comprising the preparation of the hydrochloride salt of Formula I, by reacting isopropanolic hydrochloric acid with the compound of Formula I.

5. The compound of Formula I, prepared by the process of claim 1.