WO1996022096A1 - Compositions pharmaceutiques contenant bisaramil inhibant la production de radicaux, et leur procede de preparation - Google Patents

Compositions pharmaceutiques contenant bisaramil inhibant la production de radicaux, et leur procede de preparation Download PDF

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Publication number
WO1996022096A1
WO1996022096A1 PCT/HU1996/000003 HU9600003W WO9622096A1 WO 1996022096 A1 WO1996022096 A1 WO 1996022096A1 HU 9600003 W HU9600003 W HU 9600003W WO 9622096 A1 WO9622096 A1 WO 9622096A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
bisaramil
methyl
nonane
diazabicyclo
Prior art date
Application number
PCT/HU1996/000003
Other languages
English (en)
Inventor
Margit PELLIONISZ-PARÓCZAI
Egon Kárpáti
Katalin REGO^'S-SZABÓ
Erzsébet RO^'TH
Original Assignee
Richter Gedeon Vegyészeti Gyár Rt.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyészeti Gyár Rt. filed Critical Richter Gedeon Vegyészeti Gyár Rt.
Priority to AU44947/96A priority Critical patent/AU4494796A/en
Publication of WO1996022096A1 publication Critical patent/WO1996022096A1/fr

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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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine

Definitions

  • the invention relates to novel pharmaceutical compositions inhibiting the production of free radicals.
  • These compositions contain as active ingredient 3-methyl-7-ethyl-9 ⁇ -(4-chloro- benzoyloxy)-3,7-diazabicyclo[3,3, 1 ]nonane, a known compound (hereinafter: bisaramil) or its pharmaceutically acceptable salts.
  • the invention relates to a process for the prepara ⁇ tion of these compositions.
  • Bisaramil, preparation and effect thereof are disclosed in Hungarian patent No. 184,960.
  • the class of com ⁇ pounds including bisaramil is described to have antiarrhythmic
  • the invention is based on the newly observed effect of the known bisaramil to inhibit free radical production.
  • the recogni ⁇ tion of this new effect is surprising and cannot be concluded in any way from the earlier known effects of bisaramil on the im ⁇ pulse-forming and impulse-conducting systems of the heart.
  • a suspension rich of white blood cells was prepared from venous blood of healthy mongrel dogs.
  • the production of super ⁇ oxide radicals was stimulated by adding phorbol myristate ace ⁇ tate (chemically 4 ⁇ ,9 ⁇ , 12 ⁇ , 13 ⁇ ,20-pentahydroxytiglia-1 ,6-dien-3- -one 12 ⁇ -myristate 13-acetate) to the cell suspension containing polymorphous neutrophil granulocytes.
  • Fe 3+ ions being present in the ferricytochrome C complex were reduced to Fe 2+ ions.
  • the formed pink ferrocytochrome C complex containing Fe + ions made possible the spectrophotometric monitoring of the reaction at 550 nm.
  • the formation of the pink ferrocytochrome C complex is proportional to the amount of superoxide radicals formed.
  • the free radical-generating capacity vari ⁇ ous amounts of the active compound to be tested were added to the suspension in the form of bisaramil monohydrochloride, thereafter the suspension was incubated at 37 °C for 5 minutes and finally stimulation of free radical production was carried out.
  • Lidocaine ⁇ -diethylamino-2,6-dimethylacetanilide
  • Procainamide 4-amino-N-[2-(diethylamino)ethyl]benzamide
  • Sotalol N- ⁇ 4-[1 -hydroxy-2-(/1 -methylethyl/-amino)- ethyl]-phenylmethanesulfonamide
  • Amiodarone (2-butylbenzofuran-3-yl)- ⁇ 4-[2-(diethylamino)- ethoxy]-3,5-diiodophenyl ⁇ -ketone
  • Verapamil 5- ⁇ [2-(3,4-dimethoxyphenyl)-ethyl]- methylamino ⁇ -2-(3 ,4-dimethoxyphenyl)-2- isopropylvaleronitrile. It is obvious from the data of Table 2 that the known antiar ⁇ rhythmic drugs do not inhibit the free radical production of white blood cells, in contrary, they stimulate it in some cases.
  • Test No. 2 Study of the physical performance on m ice The swimming test was used for investigating the maximum physical performance. This test was carried out in such a way that male LATI/CFLP mice weighing 32 g were placed in a pool filled with water of 20 °C temperature. The water was made to undulate by air bubbling. A load of 2 g each was fixed to the tail of each animal to make the swimming more difficult. The time from placing the mice into the water up to the cessation of swimming movements was evaluated as the maximum perform ⁇ ance. For excluding the animals swimming well or wrongly, re ⁇ spectively, the performance of mice was tested once daily for two days. The experimental groups were selected from animals showing average values. Each group consisted of 10 mice.
  • the treatment was accomplished with bisaramil monohydrochloride dissolved in physiological saline solution and administered through a gastric tube one hour before the swimming test.
  • the control group received the same volume of saline solution only.
  • the performance of musculature is limited by the amount of available energy, accumulation of lactic acid and other metabo ⁇ lites, as well as the enhanced lipid peroxidation occurring due to the relative hypoxia which leads to the formation of toxic oxygen radicals [B iochem. Biophys. Res. Commun. 107. 1 198- 1205 (1981 )].
  • Test No. 4 Chronic occlusion in dogs treated orally with bisaramil A chronic occlusion was induced in Beagle dogs under ether anaesthesia by ligation of the descending branch of the left coro ⁇ nary artery (LAD ligation). This experiment lasted for 4 weeks. Bisaramil was administered first on the day of LAD ligation, then in the following three days as an intravenous infusion in a dose of 2 mg/kg/2 hours, then from the 5th day up to the 28th day orally in the form of bisaramil capsules in daily doses of 2 x 50 mg (about 2 x 5 mg/kg).
  • haemodynamic parameters heart rate, systemic arterial blood pressure, aorta flow
  • bisaramil at a dose of 2 mg/kg.
  • the antioxidant capacity of blood was diminished in each group as shown by the decrease of about 20 % in the reduced glutathione level and a decrease of about 25 to 30 % in the SOD activity. While a decreased GSH level could be measured in the control group after reperfusion for 60 minutes, whereas the GSH level of treated animals increased over the initial value (the initial plasma GSH level being 1 .53 ⁇ 0.32 nmol/l, and this increased to a value of 1 .82 ⁇ 0.3 nmol/l after a reperfusion for 60 minutes).
  • the significant increase of the plasma GSSG level in the control group has also an important role (the initial plasma GSSG level was found to be 0.5910.09 nmol/ml with a value of 1 .0 to 0.085 nmol/ml at the end of a reperfusion for 60 minutes), whereas the plasma GSSG level did not increase in the treated group (showing an initial plasma GSSG level of 0.67 ⁇ 0.14 nmol/ml and a value of 0.67 ⁇ 0.32 nmol/ml at the end of reperfusion).
  • the stimulated free radical-producing capacity of white blood cells isolated from the peripheral blood (PMN) was in ⁇ creased in the control group to about its twofold by the end of a reperfusion for 60 minutes (with an initial value of 1000 ⁇ 100.0 O 2 " /min/1 .5x10 4 PMN and final value of 2200 ⁇ 700.0 O 2 " /min%1 .5x10 4 PMN at the end of reperfusion).
  • the activity of antioxidant enzymes determined in the blood was characteristically altered not only in the early stage following LAD ligation but also later after ischaemia. This was positively influenced by chronic administration of bisaramil. Thus, neither the activity of SOD nor that of catalase diminished during a one- -month observation period, even an induction of the enzymes could be concluded.
  • the initial SOD activity of 395 ⁇ 60.0 l U/ml could be measured in the untreated group in the 3rd and 4th weeks, too, whereas the initial SOD activity of 564 ⁇ 60.0 lU/ml enhanced to 709 ⁇ 488.0 lU/ml on the 2nd week and 670 ⁇ 42.0 l U/ml, respectively, on the 3rd week.
  • the stimulated free radical-producing capacity of white blood cells isolated from peripheral blood was significantly dimin- ished after chronic bisaramil treatment from the 1 st week of the infarction up to the end of the observation period (4 weeks).
  • the stimulated free radical production of white blood cells isolated from peripheral blood was increased from the initially measured value of 15 ⁇ 2.0 nmol O 2 /min/1 .5 x 10 6 to 23 ⁇ 4.2 nmol 0 2 /min/1.5 x 10 6 in the first week; whereas in the bisaramil-treated group this value continued to be about the initial value of 9 ⁇ 1.5 nmol O 2 /min/1 .5 x 10 6 throughout the whole period.
  • the enhancement of lipid peroxidation activity was substan ⁇ tially lower in the myocardium homogenate of bisaramil-treated animals killed at the end of the 4th week than that of the control; this was demonstrated by the inhibition of increase in the MDA level.
  • the decrease in the endogenous GSH level was by about 15% lower and the decrease in SOD activity by about 10 % lower in the sample of the infarcted myocardium of treated animals than in those of untreated animals. This indicated be ⁇ sides the better preservation of endogenous glutathione also the effect of bisaramil on the free radical induced reactions.
  • bisaramil can be considered for the following diseases or disorders: bronchial asthma, spastic bronchitis, pulmonary fibrosis, Parkinson's disease, stroke, cra ⁇ nial trauma, rheumatic arthritis, arteriosclerosis, hypertension, thalassaemia, drepanocytosis, sclerosis multiplex, muscular dys ⁇ trophy, myocardial infarction, haemorrhagic shock, ischaemic in- testine or kidney diseases, cerebrovascular diseases, toxic liver injuries, cataract, ageing as well as tumorous diseases.
  • diseases or disorders bronchial asthma, spastic bronchitis, pulmonary fibrosis, Parkinson's disease, stroke, cra ⁇ nial trauma, rheumatic arthritis, arteriosclerosis, hypertension, thalassaemia, drepanocytosis, sclerosis multiplex, muscular dys ⁇ trophy, myocardial infarction, haemorrhagic shock, ischaemic in- testine or kidney diseases, cere
  • Bisaramil and its acid addition salts may be transformed to pharmaceutical compositions by mixing them with usual, pharma ⁇ ceutically acceptable nontoxic, inert solid or liquid carriers and/or additives useful for enteral or parenteral administration.
  • These pharmaceutical compositions may preferably contain 5 to 200 mg of active agent in one dosage unit.
  • the daily dose of a ⁇ - tive agent may be administered by introducing one or more dos ⁇ age unit(s).
  • the daily dose may be varied between 5 mg and 200 mg, however, depending on the condition and responsivity of the patient, as well as the severity of the clinical picture to be treated, the physician may prescribe higher or lower doses ac ⁇ cording to his knowledges.
  • carriers e.g.
  • the active agent may be formulated in the form of usual pharmaceutical compositions, particularly such as solid forms, e.g. tablets, lozenges, dragees, capsules (such as gela ⁇ tine capsules), pills, suppositories, etc.
  • the amount of the solid vehicle may be varied between wide limits, preferably it amounts to a value of about 50 mg to 1 g.
  • the compositions may contain usual pharmaceutical additives, such as preserva ⁇ tives, stabilizers, wetting and emulsifying agents etc.
  • compositions may be formulated by using conventional methods, e.g. in the case of solid compositions, the ingredients are sieved, mixed, granulated and compressed.
  • the compositions may be subjected to additional usual operations of pharmaceutical tech ⁇ nology, e.g. sterilization to obtain injectable solutions.
  • the aqueous phase was made alkaline by adding potassium carbonate, then ex ⁇ tracted 3 times with 60 ml of chloroform each, the combined chlo ⁇ roform phases were washed with 20 ml of saturated sodium chlo ⁇ ride solution, dried over anhydrous magnesium sulphate and the drying agent was filtered and washed twice with 5 ml of chloro ⁇ form each.
  • Corn-starch 71 g The above substances were wet-granulated in a generally known way and compressed to obtain tablets with a total weight of 200 mg each.
  • Example 3 Dragees weighing 225 mg with an active ingredient con ⁇ tent of 50 mg each
  • the tablets prepared as described above were coated with a layer consisting of sugar and talc in a known manner.
  • the dragees were polished by using a mixture of beeswax and car ⁇ nauba wax.

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  • 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

Nouvelles compositions pharmaceutiques inhibant la production de radicaux libres et renfermant, à titre d'ingrédient actif, du 3-méthyl-7-éthyl-9α-(4-chlorobenzoyloxy)-3,7-diazabicyclo[3,3,1]-nonane préparé de manière connue en soi, ou son sel thérapeutiquement acceptable, ainsi que des charges, des diluants et d'autres additifs connus en soi favorisant la formulation et étant couramment utilisés dans la préparation de compositions pharmaceutiques. On décrit également un procédé de préparation de ces compositions, et leur utilisation dans la préparation de compositions pharmaceutiques inhibant la production de radicaux libres, et dans un procédé de traitement chez les malades d'affections cliniques dues à l'agression oxydative ou à l'affaiblissement ou l'épuisement des défenses anti-oxydantes endogènes de l'organisme.
PCT/HU1996/000003 1995-01-20 1996-01-18 Compositions pharmaceutiques contenant bisaramil inhibant la production de radicaux, et leur procede de preparation WO1996022096A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44947/96A AU4494796A (en) 1995-01-20 1996-01-18 Pharmaceutical compositions containing bisaramil inhibiting radical production and process for preparing same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9500167 1995-01-20
HU9500167A HUT75093A (en) 1995-01-20 1995-01-20 New anti-radical pharmaceutical compositions and process for producing them

Publications (1)

Publication Number Publication Date
WO1996022096A1 true WO1996022096A1 (fr) 1996-07-25

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AU (1) AU4494796A (fr)
HU (1) HUT75093A (fr)
WO (1) WO1996022096A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032487A1 (fr) * 1997-12-18 1999-07-01 Glaxo Group Limited ANTAGONISTES DE Kv2.1

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Antiarrythmic effects of bisaramil in canine models of ventricular arrythmias", EUR.J.PHARMACOL., vol. 233, no. 1, 1993, pages 1 - 6, XP000572020 *
"Bisaramil, a new class I antiarrythmic agent", CARDIOVASC.SURG., vol. 11, no. 4, 1993, pages 516 - 24, XP002004313 *
"Investigations to characterize a new antiarrythmic drug bisaramil", PHARMACOL.RES., vol. 24, no. 2, 1991, pages 149 - 62, XP000572024 *
"Pharmacokinetic study of bisaramil in man", ACTA PHARM.HUNG., vol. 63, no. 6, 1993, pages 327 - 33, XP000572039 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032487A1 (fr) * 1997-12-18 1999-07-01 Glaxo Group Limited ANTAGONISTES DE Kv2.1
US6589934B1 (en) 1997-12-18 2003-07-08 Smithkline Beecham Corporation Kv2.1 antagonists

Also Published As

Publication number Publication date
HUT75093A (en) 1997-04-28
AU4494796A (en) 1996-08-07
HU9500167D0 (en) 1995-03-28

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