WO1986006960A2

WO1986006960A2 - Use of nicorandil or pinacidil for the treatment of peripheral vascular disease

Info

Publication number: WO1986006960A2
Application number: PCT/GB1986/000282
Authority: WO
Inventors: Charles David Nicholson; Dieter Angersbach; John Morris Evans
Original assignee: Beecham Group P.L.C.; Beecham-Wuelfing Gmbh & Co. Kg.
Priority date: 1985-05-22
Filing date: 1986-05-20
Publication date: 1986-12-04
Also published as: WO1986006960A3; EP0223811A1

Abstract

The use of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof in the preparation of a medicament for the treatment of peripheral vascular disease.

Description

USE OF NICORANDIL OR PINACIDIL FOR THE TREATMENT OF PERIPHERAL VASCULAR DISEASE j -

The present invention relates to a method for the treatment of peripheral vascular disease and to the use of compounds in the preparation of medicaments for the treatment of peripheral vascular disease. 0

German Offenlegungsschrift 2 714 713 discloses the compound N-[2-(Nitrooxy)ethyl]-3-pyridinecarboxamide and, in Example 1, a process by which it can be prepared. The compound, which is referred to herein by 5 its common name, nicorandil, is described in the patent as a peripheral vasodilator, demonstrated by its activity in increasing blood flow in the femoral artery of the anaesthetised healthy dog.

0 United Kingdom Patent No. 1489879 discloses the compound N' '-Cyano- N-4-pyridyl-N' -1,2,2-trimethyl- propylguanidine and, in Example 47, a process by which it can be prepared. The compound, which is referred to herein by its common name, pinacidil, is described in 5 the patent as a hypotensive compound. In ' 'Drugs of the Future' ¹ Vol. VI(3), 149, 1981, pinacidil is described as a vasodilator.

Peripheral vasodilators in general are known not to 0 increase the nutritional blood flow to ischaemic tissues, and in particular not to increase the oxygen tension of ischaemic tissues

It has now been discovered that nicorandil and 5 pinacidil are unexectedly and surprisingly active in increasing the oxygen tension in ischaemic skeletal muscle. This property reflects an increase in the nutritional blood flow through ischaemic skeletal muscle which in turn indicates that nicorandil and pinacidil are of potential use as agents for the treatment of peripheral vascular disease such as intermittent claudication.

Accordingly, the present invention provides a method for the treatment of peripheral vascular disease in human or non-human mammals, which method comprises administering an effective, non-toxic amount of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof, to human or non-human mammals in need of such treatment.

The administration may be by way of oral, sub-lingual, transdermal or parenteral administration.

An effective amount of nicorandil pinacidil or a pharmaceutically acceptable salt or a hydrate thereof ( 'the compound" ) may be determined in accordance with the usual factors, such as the nature and severity of the condition and the weight of the subject requiring treatment. However it is believed that an amount of from 0.01 to 50 mg/kg, more preferably 0.01 to 10mg/kg, per day should be sufficient for effective treatment.

Within this dosage range no adverse toxicological effects are indicated with the compound.

It is preferred that the compound is administered in the form of a unit-dose pharmaceutical composition in which it is combined with a pharmaceutically acceptable carrier; such as a unit-dose oral or parenteral composition.

Examples of oral and sub-lingual compositions include tablets and capsules which generally contain conventional excipients, such as a binding agent, filler, lubricant, and disintegrating agent. An oral composition may also be in the form of a liquid, such as an aqueous or oily suspension, a solution, emulsion, syrup or elixir, or it may be in the form of a dry product for reconstitution with water or any other pharmaceutically acceptable liquid vehicle. Such liquid compositions generally contain conventional additives where appropriate, such as a suspending agent, emulsifying agent, preservative or flavouring agent.

Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.

Examples of parenteral compositions include suspensions and solutions which generally contain a surfactant or wetting agent and one or more adjuvants, such as a local anaesthetic, preservative or buffering agent. A parenteral solution may be prepared by dissolving the compound in an aqueous or non-aqueous vehicle and filter sterilizing it prior to filling into a vial or ampoule and sealing. A parenteral suspension may be prepared in much the same manner except that the compound is suspended, rather than dissolved, in the vehicle and that sterilization is carried out prior to suspension by exposure of the compound or salt to ethylene oxide. A unit-dose composition preferably contains from 0.1 to 1000 mg, such as 0.5 to 500 mg of the compound. Such unit-dose compositions may be administered from one to six times per day such that the total daily dose is in the range mentioned hereinbefore for effective treatment.

As used herein the terms 'pharmaceutical composition' and 'pharmaceutically acceptable' embrace compositions and ingredients for both human and veterinary use.

Examples of pharmaceutically acceptable salts of nicorandil and pinacidil include the hydrochloride and hydrobromide.

The present invention also provides the use of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof in the preparation of a medicament for the treatment of peripheral vascular disease. Such treatment may be carried out in the manner as described hereinbefore.

The present invention further provides a pharmaceutical composition for use in the treatment of peripheral vascular disease which comprises an effective amount of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof and a pharmaceutically acceptable carrier. Such composition may be prepared in the manner as described hereinbefore.

The following Example describes the preparation of nicorandil and the following pharmacological data illustrates the invention. EXAMPLE :

Preparation of N-[2-(Nitroxy)ethyl]-3-pyridinecarb- oxamide hydrochloride

6g (4 ml) nitric acid were cooled with ice in a three-necked flask equipped with stirrer, thermometer and dropping funnel. 3.47g (3.4 ml) ethanolamine were dropped in carefully and the mixture stirred for 30 minutes. 40ml diethylether were added, the liquid phase decanted from the precipitate which was then washed twice with diethylether. The precipitate was rapidly dissolved in 30 ml water and the remaining ether removed in a separating funnel. The aqueous solution was transferred to a three necked flask with 10 g sodium bicarbonate and 40 ml methylene chloride. Over 30 minutes 5 g nicotinoylchloride hydrochloride was added to the mixture in the flask maintained at 0° to 5°C by ice cooling. After 30 minutes stirring the organic phase was separated and the aqueous phase extracted twice with methylene dichloride. The combined organic layers were extracted with aqueous a2 CO3 then water, dried over N 2S04 and evaporated to dryness. The residue was dissolved in ethanol and treated with ethanolic HC1. Evaporation to dryness yielded N-[2-(Nitrooxy)ethyl]-3-pyridinecarboxamide as the hydrochloride, which was recrystallized from ethanol, and the crystals filtered by suction and washed with diethylether. Yield: 1.5g M.pt: 130°C

IR: NH 3280 cm"¹

CO 1675 cm"¹ ONO2 1640 cm^-1

The sample of nicorandil prepared as the hydrochloride in the above Example was used in the following test: - 6 - The effect of test compounds on the oxygen tension (pθ2) of rat ischaemic gastrocnemius muscle.

(a) Animal preparation

Male rats (300 to 350g), in which the femoral artery of the hindlimb had been ligated 6 weeks previously in order to induce hypoxia, were anaesthetized with sodium-thiopentone (100 mg/kg) . The arterial blood pressure was recorded from a carotid artery.

(b) Measurement

An incision was made through the skin on the inside of the hypoxic limb. The fascia covering the surface of the gastrocnemius muscle was removed carefully and a multiwire oxygen sensitive electrode was placed on the muscle.

The electrode current was continuously recorded. After a stabilisation period the muscle pθ2 frequency distribution was recorded by repeatedly altering the position of the electrode on the muscle surface. The test compound was then administered and 15 min later a second muscle θ2 frequency distribution was begun to be recorded. Each frequency distribution consisted of θ2 measurements from 90-120 different recording sites before and after compound administration in each animal.

The change in the mean muscle θ2» produced by test compound administration, was calculated for each animal. - 7 - The results are shown in Table 1.

TABLE 1

Compound A Nicorandil hydrochloride Compound B Pinacidil (monohydrate)

i.d. intraduodenal administration

MABP mean arterial blood pressure

Claims

1. The use of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof in the preparation of a medicament for the treatment of peripheral vascular disease.

2. The use according to claim 1 wherein the salt is the hydrochloride or the hydrobromide.

3. The use according to claim 2 of nicorandil hydrochloride.

4. The use according to claim 1 of pinacidil monohydrate.

5. A pharmaceutical composition for use in the treatment of peripheral vascular disease which comprises an effective amount of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof and a pharmaceutically acceptable carrier.

6. A method for the treatment of peripheral vascular disease in human or non-human mammals, which method comprises administering an effective, non-toxic amount of nicorandil or pinacidil or a pharmaceutically acceptable salt or a hydrate thereof, to human or non-human mammals in need of such treatment.