EP0223811A1 - Use of nicorandil or pinacidil for the treatment of peripheral vascular disease - Google Patents
Use of nicorandil or pinacidil for the treatment of peripheral vascular diseaseInfo
- Publication number
- EP0223811A1 EP0223811A1 EP19860903470 EP86903470A EP0223811A1 EP 0223811 A1 EP0223811 A1 EP 0223811A1 EP 19860903470 EP19860903470 EP 19860903470 EP 86903470 A EP86903470 A EP 86903470A EP 0223811 A1 EP0223811 A1 EP 0223811A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- nicorandil
- treatment
- pinacidil
- peripheral vascular
- vascular disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 208000018262 Peripheral vascular disease Diseases 0.000 title claims abstract description 12
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 title claims description 18
- 229960002497 nicorandil Drugs 0.000 title claims description 17
- 229960002310 pinacidil Drugs 0.000 title claims description 15
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 title claims description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- IVVNZDGDKPTYHK-UHFFFAOYSA-N 1-cyano-2-(3,3-dimethylbutan-2-yl)-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)C(C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 17
- 239000000203 mixture Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 210000003205 muscle Anatomy 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 229960004132 diethyl ether Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000000810 peripheral vasodilating agent Substances 0.000 description 2
- 229960002116 peripheral vasodilator Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- -1 Nicorandil hydrochloride Compound Chemical class 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910004679 ONO2 Inorganic materials 0.000 description 1
- AFJCNBBHEVLGCZ-UHFFFAOYSA-N Pinacidil Chemical compound O.CC(C)(C)C(C)N=C(NC#N)NC1=CC=NC=C1 AFJCNBBHEVLGCZ-UHFFFAOYSA-N 0.000 description 1
- XSIZHTUSUPHZFF-UHFFFAOYSA-N [4-(2-phenylpropan-2-yl)phenyl] carbonochloridate Chemical compound C=1C=C(OC(Cl)=O)C=CC=1C(C)(C)C1=CC=CC=C1 XSIZHTUSUPHZFF-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- DDPMGIMJSRUULN-UHFFFAOYSA-N buphedrone Chemical compound CCC(NC)C(=O)C1=CC=CC=C1 DDPMGIMJSRUULN-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- AWLILQARPMWUHA-UHFFFAOYSA-M thiopental sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC([S-])=NC1=O AWLILQARPMWUHA-UHFFFAOYSA-M 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
Definitions
- 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.
- 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.
- 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
- 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.
- 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.
- nicorandil pinacidil or a pharmaceutically acceptable salt or a hydrate thereof 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.
- 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.
- 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.
- 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.
- 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.
- 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 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 (p ⁇ 2) of rat ischaemic gastrocnemius muscle.
- mice 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.
- the electrode current was continuously recorded. After a stabilisation period the muscle p ⁇ 2 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 ⁇ 2 frequency distribution was begun to be recorded. Each frequency distribution consisted of ⁇ 2 measurements from 90-120 different recording sites before and after compound administration in each animal.
- MABP mean arterial blood pressure
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Utilisation de nicorandile et de pinacidile ou d'un de leurs sels ou d'hydrates pharmaceutiquement acceptables dans la préparation d'un médicament pour le traitement des maladies vasculaires périphériques.Use of nicorandile and pinacidile or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment of peripheral vascular diseases.
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.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858512908A GB8512908D0 (en) | 1985-05-22 | 1985-05-22 | Treatment |
| GB8512908 | 1985-05-22 | ||
| GB8513551 | 1985-05-29 | ||
| GB858513551A GB8513551D0 (en) | 1985-05-29 | 1985-05-29 | Treatment |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0223811A1 true EP0223811A1 (en) | 1987-06-03 |
Family
ID=26289278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19860903470 Withdrawn EP0223811A1 (en) | 1985-05-22 | 1986-05-20 | Use of nicorandil or pinacidil for the treatment of peripheral vascular disease |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0223811A1 (en) |
| WO (1) | WO1986006960A2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE60601B1 (en) * | 1986-08-27 | 1994-07-27 | Chugai Pharmaceutical Co Ltd | Therapeutic agent for the treatment of disorders associated with cerebral ischemia |
| GB8801318D0 (en) * | 1988-01-21 | 1988-02-17 | Leo Pharm Prod Ltd | Pharmaceutical preparations |
| IT1256022B (en) * | 1992-06-08 | 1995-11-20 | STABLE PHARMACEUTICAL PREPARATIONS OF NICORANDIL | |
| AU2011347802B2 (en) | 2010-12-20 | 2015-05-07 | Dsm Ip Assets B.V. | Use of nitrooxy organic molecules in feed for reducing methane emission in ruminants, and/or to improve ruminant performance |
| US20200253926A1 (en) * | 2019-02-13 | 2020-08-13 | Supersalus, Inc. | Therapeutic combinations |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509591B2 (en) * | 1976-04-02 | 1980-05-15 | Chugai Seiyaku Kabushiki Kaisha | Pyridine derivatives |
-
1986
- 1986-05-20 EP EP19860903470 patent/EP0223811A1/en not_active Withdrawn
- 1986-05-20 WO PCT/GB1986/000282 patent/WO1986006960A2/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8606960A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1986006960A2 (en) | 1986-12-04 |
| WO1986006960A3 (en) | 1987-01-29 |
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Inventor name: ANGERSBACH, DIETER Inventor name: NICHOLSON, CHARLES, DAVID Inventor name: EVANS, JOHN, MORRIS |