IL37235A

IL37235A - Pharmaceutical compositions containing (2-thiazolyl)thiourea derivatives

Info

Publication number: IL37235A
Application number: IL37235A
Authority: IL
Original assignee: Sparamedica Ag
Priority date: 1970-07-24
Filing date: 1971-07-05
Publication date: 1973-10-25
Also published as: IL37235A0; DE2137045A1; FR2100948B1; BE770403A; NL7108189A; ZA714076B; GB1330545A; FR2100948A1; AU3041671A

Description

37235/2 nitVin D» »3on mnpm * »w3n Pharmaceutical compositions containing {2-thiazolyl)thiourea derivatives SPARAHEDICA A.G» C. 35389 r The present invention relates to pharmaceutical preparations. More particularly, the invention is concerned with pharmaceutical preparations which possess antimalarial activity, an influence on amine metabolism or blood-pressure lowering propertie ch contain as the essential active ingredient a hiazol The pharmaceutical preparations provided by the present invention contain, as the essential active ingredient, 1,1- -diethyl-3-(2-thiazolyl)-2-thiourea, l-methyl-3-(2-thiazoly1 )- -2-thiourea, 1 , l-dimethyl-3-(4—methyl-2-thiazolyl )-2-thiourea and/or an acid addition salt of such a compound in admixture with a compatible pharmaceutical carrier.

It will be appreciated that the tautomeric forms of the three compounds mentioned hereinbefore can be present in the pharmaceutical preparations provided by this invent ionc The preferred pharmaceutical preparations provided by this invention contain as the essential active ingredient 1 ,l-diethyl-3-(2-thiazolyl)-2-thiourea, l-methyl-3-(2- -thiazolyl )-2-thiourea and/or an acid addition salt of such a compound., The pharmaceutical preparations provided by the present invention are particularly suitable for combatting malaria.

The antimalarial activity of the essential active ingredients aforesaid may, for example, be demonstrated in mice using the following experimental procedure: Six mice are each infected intraperitoneally with 10' mouse erythrocytes parasitised by Plasmodium berghei. The essential active ingredient aforesaid is administered per os for the first time ca · hours before the infection and then 24-, 4-8 and 72 hours after the infection. Twenty four hours after conclusion of the treatment, a blood smear is prepared from all the mice and coloured according to the method of Giemsa. The degree of infection is determined microscopically in comparison with untreated infected control mice. The dosage which in the treated mice is capable of reducing the number of parasitised erythrocytes to one-half is taken as the DEcr,.

Some exemplary results are summarised in Table I hereinafter„ Table I The acute toxicity of the essential active ingredients of the present pharmaceutical preparations in the mouse test lies, in general, at between 500 and 5000 mg/kg p.o.

In human medicine, the pharmaceutical preparations provided by the present invention can be administered by the oral, rectal or parenteral route. In this case, oral administration is suitable for prophylaxis and therapy, while parenteral administration is chiefly of significance for the therapy of severe cases.

In the case of daily administration of the present pharmaceutical preparations, the dosage administered at one time amounts to between 100 mg and 1000 mg (preferably between JOO mg and 600 mg) of the essential active ingredient in the case of an adult. In the case of injection for therapeutic purposes, the dosage is expediently higher, preferably between 500 mg and 1000 mg. Accordingly, the preferred pharmaceutical preparations of the present invention contain 100 mg to 1000 mg (especially 300 mg to 600 mg) of the essential active ingredient.

The essential active ingredients referred to earlier possess the advantage that they display no cross-resistance with known antimalarials and accordingly can also be employed for the treatment of this disease in countries in which known antimalarials fail.

Further, the essential active ingredients aforesaid influence amine metabolism. Thus, for example, they have an extraordinarily strong inhibiting action on the enzyme dopamine β-hydroxylase. It has also been found that compounds having this inhibitory action can bring about a lowering of the blood pressure.

The inhibitory action of the aforementioned essential active ingredients on the enzyme dopamine β-hydroxylase may be demonstrated in vivo using the following experimental procedure: The essential active ingredient is administered five times per os during 2.5 days to groups each consisting of 6 male rats weighing 150-180 g. Three hours after the last administration, the alterations in the brain given in Table II hereinafter in % (control = 100%) are ascertained: Table II The compatible pharmaceutical carrier present in the pharmaceutical preparations provided by this invention can be a non-toxic, inert, solid and/or liquid carrier and/or excipient suitable for therapeutic administration which is usual in pharmacy. Further, the compatible pharmaceutical carrier can be an organic or inorganic carrier. Especially suitable pharmaceutical carriers for oral and parenteral application include, for example, starches, lactose, magnesium stearate, talc, vegetable oils, organic solubilisers such as polyalkylene glycol or glycerine formal, water as well as organic and inorganic bases. The harm c utic l r arati ns c n b m d in sol d form (e.g. as tablets, dragees, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). They may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They can also contain therapeutically valuable substances other than the essential active ingredients aforesaid.

The following Examples illustrate the invention: Example 1 Tablets of the following composition are manufactured: 1 ) 1, l-Diethyl-3-(2-thiazolyl)-2-thiourea 25Ο mg Corn starch 278 mg Lactose 70 mg Magnesium stearate 2 mg 600 mg 2) l-Methyl-3-(2-thiazolyl)-2-thiourea 25Ο mg Corn starch 278 mg Lactose 70 mg Magnesium stearate 2 mg 600 mg The essential active ingredient and a part of the aforementioned carriers are granulated with a corn-starch paste. After drying, a powder of corn starch and magnesium stearate is added and the mixture is compressed on a tabletting machine to tablets of 13 mm thickness, 600 mg weight and a hardness of 6-8 SCE.

Example 2 An injection solution of the following composition is manufactured: l,l-Diethyl-3-(2-thiazolyl)-2-thiourea 500 mg Glycerine formal 0.5 ml Diethanolamine 0.076 ml Water 0.5 ml The solution is prepared according to usual procedures, filtered and either treated with a preservative and filled into ampoules in an inert atmosphere or filled into ampoules under an inert gas without preservative and sterilised.

Claims

Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is:

1. A process for the manufacture of a pharmaceutical preparation having antimalarial activity, an influence on amine metabolism or blood-pressure lowering properties, which process comprises compounding l,l-diethyl-3-(2-thiazolyl)-2-thiourea, l-methyl-3- (2-thiazolyl )-2-thiourea, 1, 1-dimethyl-3- ( -methyl-2-thiazolyl )-2-thiourea and/or an acid addition salt of such a compound as essential active ingredient with a compatible pharmaceutical carrier.

2. A process according to Claim 1, wherein said essential active ingredient is l,l-diethyl-3- (2-thiazolyl ) -2-thiourea, l-methyl-3- (2-thiazolyl )-2-thiourea and/or an acid addition salt of such a compound.

3· A process according to Claim 1 substantially as herein before described with reference to the foregoing Examples.

4. A pharmaceutical preparation having antimalarial activity, an influence on amine metabolism or blood-pressure lowering properties containing as essential active ingredient l,l-diethyl-3- (2-thiazolyl) -2-thiourea, l-methyl-3- (2-thiazolyl) -2-thiourea, l,l-dimethyl-3-( -methyl-2-thiazolyl)-2-thiourea and/or an acid addition salt of such a compound in admixture with a compatible pharmaceutical carrier.

wherein said essential active ingredient is 1, l-diethyl-3-(2-thiazolyl ) -2-thiourea, l-methyl-3- (2-thiazolyl ) -2-thiourea and/or an acid addition salt of such a compound.

6. A pharmaceutical preparation according to Claim 4 or Claim 5 which contains 100 mg to 1000 mg of said essential active ingredient.

7· A pharmaceutical preparation according to Claim 6 which contains 300 mg to 600 mg of said essential active ingredient .

8. A pharmaceutical preparation according to Claim 4, substantially as hereinbefore described with reference to the foregoing Examples.