CA1060344A - Antihypertonic agent - Google Patents
Antihypertonic agentInfo
- Publication number
- CA1060344A CA1060344A CA257,101A CA257101A CA1060344A CA 1060344 A CA1060344 A CA 1060344A CA 257101 A CA257101 A CA 257101A CA 1060344 A CA1060344 A CA 1060344A
- Authority
- CA
- Canada
- Prior art keywords
- etozolin
- antihypertonic
- dosage
- acid
- hypertensive
- 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.)
- Expired
Links
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
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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract of the Disclosure The present invention is concerned with the use of etozlin as an antihypertonic agent.
Description
~060344 Etozolin, i.e. 2-ethoxycarbonylmethylene-3-methyl-5-piperidino-4-thiazolidone, is an outstandingly compatible and potent diuretic disclosed in our United States Patent Specification No. 3,072,653, granted January 8th, 1963. Investigations on humans have shown that 400 mg. thereof have about the same diuretic effectiveness as 40 mg. of the known diuretic furo-semide, i.e. 4-chloro-N-furfuryl-5-sulphamoyl-anthranilic acid.
It is kno~n that all potent diuretics, such as furosemide and othacrynic acid, i.e. 2,3-dichloro-4-(2-methylene-butyryl)-phenoxyacetic acid, also excrt a considerable influence on the excretion of electrolytes. For 1~ this reason, that is in order to prevent an impoverishment in the organism of certain electrolytes and especially of potassium ions, strongly effective diuretics are used in dosages which are as low as possible. Thus, the usual furosemide dosage at the commencement of a diuretic treatment is 40 mg. once or twice daily. Subsequently, this dosage is adminis~ered only every other day (see Rote Liste, 1975; Editio Cantor, Aulendorf/Wurtt., No. 37038B). If, however, strongly effective diuretics are used for the treatment of high blood pressure, then these must be administered at high dosage levels over a com-paratively long period of time. Thus, the antihypertensively effective daily dosage for furosemide is about two to four times higher than the diuretically
It is kno~n that all potent diuretics, such as furosemide and othacrynic acid, i.e. 2,3-dichloro-4-(2-methylene-butyryl)-phenoxyacetic acid, also excrt a considerable influence on the excretion of electrolytes. For 1~ this reason, that is in order to prevent an impoverishment in the organism of certain electrolytes and especially of potassium ions, strongly effective diuretics are used in dosages which are as low as possible. Thus, the usual furosemide dosage at the commencement of a diuretic treatment is 40 mg. once or twice daily. Subsequently, this dosage is adminis~ered only every other day (see Rote Liste, 1975; Editio Cantor, Aulendorf/Wurtt., No. 37038B). If, however, strongly effective diuretics are used for the treatment of high blood pressure, then these must be administered at high dosage levels over a com-paratively long period of time. Thus, the antihypertensively effective daily dosage for furosemide is about two to four times higher than the diuretically
2~ e~fective dosage. Prolonged use at such a high dosage level is undesirable bec~use of the danger of too great a loss of electrolytes and fluids and, in the case of patients with normal or only slightly reduced kidney function is contraindicated under many circumstances.
Since etozolin belongs to the group of potent diuretics, it would be e~pected that it would behave in an analogous manner and that its prolonged use as an anti-hypertensive would, because of the influencing of the electro-lytes connected th~rewith and initiated by the high dosage, not result in any ad~antage as compared with the already known diuretics. For this reason, in United States Patent Specification No. 3,072,653, the therapeutic utilization
Since etozolin belongs to the group of potent diuretics, it would be e~pected that it would behave in an analogous manner and that its prolonged use as an anti-hypertensive would, because of the influencing of the electro-lytes connected th~rewith and initiated by the high dosage, not result in any ad~antage as compared with the already known diuretics. For this reason, in United States Patent Specification No. 3,072,653, the therapeutic utilization
3~ of the anti-hypertensive side effect, brought about in the case of potent ~060344 diuretics inter alia by increased water excretion, was not considered.
According to the present invention there is provided an anti-hypertonic composition in oral dosage unit form comprising etozolin and/or at least one pharmacologically acceptable salt thereof and a carrier, the amount of etozolin present being from 30 to 100 mg per dosage unit. Preferably etozolin is present in an amount between 40 and 90 mg per dosage unit. Dosage units containing from 50 to 75 mg of etozolin are particularly preferred.
Tllus, we have now found that etozolin is a highly effective anti-hyp~rtensive sgent and that this anti-hypertensive action is unexpectedly found 1~ 8t a dosage level which brings about practically no diuresis. The anti-hypcrtensive action of etozolin is completely new and unexpectedO Consequent-ly, in the 12 years which have elapsed since the publication of United States Patent Specification No. 3,072,653, during which etozolin has been extensively investigated, the valuable and important anti-hypertensive effectiveness of etozolin was not discovered and there has been no teaching of a pharmaceutical with this effectiveness Csee Arzneimittelforschung, 14 ~11), 1242/1964; Arch.
Exptl~ Pathol. Pharmacol., 249 (5), 432/1964; Klin. Wochenschr., 42 ~24), 1236/1964; Rev. Can. Biol., 23 ~2), 197/1964).
The results initially obtained from animal experiments have been ~0 confirmed on humans. According to these results, etozolin ac~s in an unfore-seeably low sub-diuretic dosage of 200 mg. per day, in an outstandingly anti-hypertensive manner. The blood pressure is significantly lowered and a diminution of the action was not found, even after several weeks of therapy.
Thus, eto201in behaves in a completely different manner from the previously known diuretics, the anti-hypertensive effect of which comes about essentially via the kidneys, i.e. by an increased excretion of electrolytes and water.
This can be seen from the fact that, with the previously known diuretics, an anti-hypertensive effect can only be achieved at all by the administration of high, strongly diuretically-effective dosages and that with the reduction of the extracellular volume of fluid, diuresis decreases correspondingly.
106(~344 In contradistinction thereto, the findings with etozolin indicate that this substance acts not only by renal action but also, surprisingly, by peripheral mechanisms which are more comparable with those of diazoxide, i.e. 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine l,l-dioxide (commercially available under the Trade Mark "hyperstat"; Physicians' Desk Reference, 29th edn., 1975, p. 1327). Therefore, it is to be assumed that etozolin, as com-parcd to the conventional diuretics, is also useul in the case of hyper-tensivc crises as a blood pressure lowering agent.
Thus, etozolin is a completely new type of anti-hypertensively ln Q~ective pharmaceutical. It acts in low dosages almost exclusively as an anti-hypertensive and manifests, in higher dosages, an additional diuretic e~ectiveness. There is thus provided the possibility, if desired, of combin-ing these two properties by a simple increase of the dosage. Thus, etozolin permits a departure from the previously conventional method of treatment, which consisted of a combination of a diuretic with an anti-hypertensive. This constitutes a considerable technical advance since, in modern therapy, the efort is increasingly made to achieve certain complex pharmaceutical effects by single substances with a suitable spec~rum of activity and thus to avoid the combination of several active materials in a single pharmaceutical com-position.
Furthermore, etozolin is characterized by a prolonged anti-l~pertensive action, an extraordinarily good compatibility and an extremely lo~ toxicity~ This also represents a technical advance since it is well documented that previously used anti-hypertensivespossess more or less marked side e~ects, some of which are of a serious nature~
Etozolin is, even in sub-diuretic dosages, an effective and non-toxic anti-hypertensive which is superior to the previously known substances having the same type of effect and thus represents a substantial improvement o~ the pharmacological art, which was previously unknown.
High blood pressure therapy is planned for years ahead and any ~C~6~)344 interruption, brought about by side effects, must be avoided, in order to avoid the dan~r of resistance (see, for example, Deutsche Med. Wochenschrift, 90, 549/1965). It is clear what importance is to be attributed to an anti-hypertensive therapy by means of a sin~Le substance without substantial side effects, especially without a ha~ul action upon the electrolyte and water metabolism of the body, and one which also has a low toxicity.
An anti-hypertensi.ve action can be achieved even with a dosage which is only 25% of the dluretically effective dosage, i.e. in a normal case with a dosage oE 100 mg. per day. me usual anti-hypertensive dosage is 100 - 200 mg. etozolin per day. In the case of 400 mg. etozolin per day, the anti-hypertensive effect is superimposed by a marked diuretic action.
me preparation of etozolin is achieved by reaction of 2-ethoxy-carbonyl~rethylene-3-nE?thyl-5-bro~4-thiazolidinone with piperidine and is described in ExaTple 4 of United States Patent Specification No. 3,072,653.
Etozolin is adm~nistered orally as an anti-hypertonic. As oral forms of a~ninistration, there can be used, for example, tablets, dragees, capsules and granulates. In the production of oral forms of administration, conventional, adauvant and carrier materials are employed in the usual man-ner, such as starch, lactose, m~nitol, methyl cellulose, talc, hi hly dis-20 persed silicic acids, high molecular wei~ht fatty acids (such as stearicacid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and veget-able fats and solid high molecular weight polymers (such as polyethylene glycol). If desired, the compositions can also contain additional flavoring materials as well as sweetening materials.
By pharmacologically compatible salts, is meant conventionally recognized salts of inorganic or organic acids which are nontoxic in the ~nounts administered, for example, hydrochloric acid, sulphuric acid, phos-plloric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid~ malonic acid, maleic acid, succinic acid or ascorbic acid.
1~ Thc salts can be prepared in the usual manner by neutralization of the free etozolin base with the desired acid in an appropriate solvent. The preferred salt is the hydrochloride, which has a melting point of 158 - 159C.
The following Example is given for the purpose of illustrating the present invention:
EXAMPLE
Hard gelatine capsule with a dosagè of`lOO`mg.`etozolin The following powdered active and adjuvant materials are homo-geneously mixed in the given amounts and placed in hard gelatine capsules of size ~:
~o etozolin 30 g.
lactose 31 g.
maize starch 31 g.
talc 1 g.
The weight of filling per capsule is 310 mg.
According to the present invention there is provided an anti-hypertonic composition in oral dosage unit form comprising etozolin and/or at least one pharmacologically acceptable salt thereof and a carrier, the amount of etozolin present being from 30 to 100 mg per dosage unit. Preferably etozolin is present in an amount between 40 and 90 mg per dosage unit. Dosage units containing from 50 to 75 mg of etozolin are particularly preferred.
Tllus, we have now found that etozolin is a highly effective anti-hyp~rtensive sgent and that this anti-hypertensive action is unexpectedly found 1~ 8t a dosage level which brings about practically no diuresis. The anti-hypcrtensive action of etozolin is completely new and unexpectedO Consequent-ly, in the 12 years which have elapsed since the publication of United States Patent Specification No. 3,072,653, during which etozolin has been extensively investigated, the valuable and important anti-hypertensive effectiveness of etozolin was not discovered and there has been no teaching of a pharmaceutical with this effectiveness Csee Arzneimittelforschung, 14 ~11), 1242/1964; Arch.
Exptl~ Pathol. Pharmacol., 249 (5), 432/1964; Klin. Wochenschr., 42 ~24), 1236/1964; Rev. Can. Biol., 23 ~2), 197/1964).
The results initially obtained from animal experiments have been ~0 confirmed on humans. According to these results, etozolin ac~s in an unfore-seeably low sub-diuretic dosage of 200 mg. per day, in an outstandingly anti-hypertensive manner. The blood pressure is significantly lowered and a diminution of the action was not found, even after several weeks of therapy.
Thus, eto201in behaves in a completely different manner from the previously known diuretics, the anti-hypertensive effect of which comes about essentially via the kidneys, i.e. by an increased excretion of electrolytes and water.
This can be seen from the fact that, with the previously known diuretics, an anti-hypertensive effect can only be achieved at all by the administration of high, strongly diuretically-effective dosages and that with the reduction of the extracellular volume of fluid, diuresis decreases correspondingly.
106(~344 In contradistinction thereto, the findings with etozolin indicate that this substance acts not only by renal action but also, surprisingly, by peripheral mechanisms which are more comparable with those of diazoxide, i.e. 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine l,l-dioxide (commercially available under the Trade Mark "hyperstat"; Physicians' Desk Reference, 29th edn., 1975, p. 1327). Therefore, it is to be assumed that etozolin, as com-parcd to the conventional diuretics, is also useul in the case of hyper-tensivc crises as a blood pressure lowering agent.
Thus, etozolin is a completely new type of anti-hypertensively ln Q~ective pharmaceutical. It acts in low dosages almost exclusively as an anti-hypertensive and manifests, in higher dosages, an additional diuretic e~ectiveness. There is thus provided the possibility, if desired, of combin-ing these two properties by a simple increase of the dosage. Thus, etozolin permits a departure from the previously conventional method of treatment, which consisted of a combination of a diuretic with an anti-hypertensive. This constitutes a considerable technical advance since, in modern therapy, the efort is increasingly made to achieve certain complex pharmaceutical effects by single substances with a suitable spec~rum of activity and thus to avoid the combination of several active materials in a single pharmaceutical com-position.
Furthermore, etozolin is characterized by a prolonged anti-l~pertensive action, an extraordinarily good compatibility and an extremely lo~ toxicity~ This also represents a technical advance since it is well documented that previously used anti-hypertensivespossess more or less marked side e~ects, some of which are of a serious nature~
Etozolin is, even in sub-diuretic dosages, an effective and non-toxic anti-hypertensive which is superior to the previously known substances having the same type of effect and thus represents a substantial improvement o~ the pharmacological art, which was previously unknown.
High blood pressure therapy is planned for years ahead and any ~C~6~)344 interruption, brought about by side effects, must be avoided, in order to avoid the dan~r of resistance (see, for example, Deutsche Med. Wochenschrift, 90, 549/1965). It is clear what importance is to be attributed to an anti-hypertensive therapy by means of a sin~Le substance without substantial side effects, especially without a ha~ul action upon the electrolyte and water metabolism of the body, and one which also has a low toxicity.
An anti-hypertensi.ve action can be achieved even with a dosage which is only 25% of the dluretically effective dosage, i.e. in a normal case with a dosage oE 100 mg. per day. me usual anti-hypertensive dosage is 100 - 200 mg. etozolin per day. In the case of 400 mg. etozolin per day, the anti-hypertensive effect is superimposed by a marked diuretic action.
me preparation of etozolin is achieved by reaction of 2-ethoxy-carbonyl~rethylene-3-nE?thyl-5-bro~4-thiazolidinone with piperidine and is described in ExaTple 4 of United States Patent Specification No. 3,072,653.
Etozolin is adm~nistered orally as an anti-hypertonic. As oral forms of a~ninistration, there can be used, for example, tablets, dragees, capsules and granulates. In the production of oral forms of administration, conventional, adauvant and carrier materials are employed in the usual man-ner, such as starch, lactose, m~nitol, methyl cellulose, talc, hi hly dis-20 persed silicic acids, high molecular wei~ht fatty acids (such as stearicacid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and veget-able fats and solid high molecular weight polymers (such as polyethylene glycol). If desired, the compositions can also contain additional flavoring materials as well as sweetening materials.
By pharmacologically compatible salts, is meant conventionally recognized salts of inorganic or organic acids which are nontoxic in the ~nounts administered, for example, hydrochloric acid, sulphuric acid, phos-plloric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid~ malonic acid, maleic acid, succinic acid or ascorbic acid.
1~ Thc salts can be prepared in the usual manner by neutralization of the free etozolin base with the desired acid in an appropriate solvent. The preferred salt is the hydrochloride, which has a melting point of 158 - 159C.
The following Example is given for the purpose of illustrating the present invention:
EXAMPLE
Hard gelatine capsule with a dosagè of`lOO`mg.`etozolin The following powdered active and adjuvant materials are homo-geneously mixed in the given amounts and placed in hard gelatine capsules of size ~:
~o etozolin 30 g.
lactose 31 g.
maize starch 31 g.
talc 1 g.
The weight of filling per capsule is 310 mg.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An antihypertonic composition in oral dosage unit form comprising etozolin and/or at least one pharmacologically compatible salt thereof and a carrier, the amount of etozolin and/or pharmacologically compatible salt present being from 30 to 100 mg. per dosage unit.
2. An antihypertonic composition according to Claim 1, which con-tains etozolin and/or at least one pharmacologically compatible salt thereof in an amount of from 40 to 90 mg. per dosage unit.
3. An antihypertonic composition according to Claim 1, which contains etozolin and/or at least one pharmacologically compatible salt thereof in an amount of from 50 to 75 mg. per dosage unit.
4. An antihypertonic composition according to Claim 1, in the form of a tablet, dragee, capsule or granulate.
5. An antihypertonic composition according to Claim 1, wherein the etozolin is used in the form of its hydrochloride.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2532180A DE2532180C2 (en) | 1975-07-18 | 1975-07-18 | Use of Etozolin in the fight against hypertension |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1060344A true CA1060344A (en) | 1979-08-14 |
Family
ID=5951852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA257,101A Expired CA1060344A (en) | 1975-07-18 | 1976-07-16 | Antihypertonic agent |
Country Status (11)
| Country | Link |
|---|---|
| AU (1) | AU503445B2 (en) |
| BE (1) | BE844210A (en) |
| CA (1) | CA1060344A (en) |
| DD (1) | DD126756A5 (en) |
| DE (1) | DE2532180C2 (en) |
| GB (1) | GB1550393A (en) |
| GR (1) | GR61353B (en) |
| IE (1) | IE43611B1 (en) |
| LU (1) | LU75396A1 (en) |
| PH (1) | PH13059A (en) |
| ZA (1) | ZA763981B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU531659B2 (en) * | 1979-03-22 | 1983-09-01 | Goedecke Aktiengesellschaft | (+)-(3-methyl-4-oxo - 5n-piperidinothiazolidin-2-ylidene) acetic acid esters |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3072653A (en) * | 1961-03-06 | 1963-01-08 | Warner Lamber Pharmaceutical C | 5-amino derivatives of 4-thiazolidinones and process therefor |
-
1975
- 1975-07-18 DE DE2532180A patent/DE2532180C2/en not_active Expired
-
1976
- 1976-07-05 ZA ZA763981A patent/ZA763981B/en unknown
- 1976-07-13 GR GR51250A patent/GR61353B/en unknown
- 1976-07-14 GB GB29336/76A patent/GB1550393A/en not_active Expired
- 1976-07-16 LU LU75396A patent/LU75396A1/xx unknown
- 1976-07-16 CA CA257,101A patent/CA1060344A/en not_active Expired
- 1976-07-16 DD DD193930A patent/DD126756A5/xx unknown
- 1976-07-16 IE IE1580/76A patent/IE43611B1/en unknown
- 1976-07-16 BE BE168970A patent/BE844210A/en not_active IP Right Cessation
- 1976-07-16 AU AU15959/76A patent/AU503445B2/en not_active Expired
- 1976-07-16 PH PH18693A patent/PH13059A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PH13059A (en) | 1979-11-21 |
| BE844210A (en) | 1976-11-16 |
| DE2532180C2 (en) | 1986-12-18 |
| AU1595976A (en) | 1978-01-19 |
| DD126756A5 (en) | 1977-08-10 |
| IE43611B1 (en) | 1981-04-08 |
| GB1550393A (en) | 1979-08-15 |
| LU75396A1 (en) | 1977-02-28 |
| GR61353B (en) | 1978-10-26 |
| DE2532180A1 (en) | 1977-02-10 |
| ZA763981B (en) | 1977-05-25 |
| AU503445B2 (en) | 1979-09-06 |
| IE43611L (en) | 1977-01-18 |
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