IL28607A - Therapeutic compositions based on n-(n',n'-dimethyl-dithio-carbamyl)-succinimide - Google Patents

Description

C O H E N Z S P I S B A C H EG O. PAT E N T AT TO R N E YS 24, LE VON TIN STR., f. O. B. 1169 T E L - A V I V , - P A'T E N T.S & D E S I G N S O R D I N A N C E 16930/67 SPECIFICATION THERA PEUT IG COMPOS IT IONS BA SEP ON N- (H ' , ' - D IMETHYL-D ITHIO-CA BBAMYL)-SUCCINIMIDE -^'ηη'η-Ν» TN» ) -N "71 ητοοταοπ ητηεπη mansn We, ROUSSEL-UCIAF, a French Societe Anonyme, of 35» Boulevard des Invalides, Par is, 7a > Prance, DO HEREBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement: 0 manifest outstanding local antifungal and antibacterial activities, superior to that of the knownproducts. For example, the bactericidal effect and the bacteriostatic effect with reference to the pathogenic staphylococci of the new compositions are definitely superior to those of compositions based on sodium diethyl-dithiocarbamate , tetraethylthiuram tetra-sulfide or other antibacterial agents. Moreover, for example, with reference to Candida albicans, the local antifungal activity of the new composition is definitely superior to that of compositions based on nystatine, amphotericin B, sodium undecylenate , sodium The residual oil was taken up in ethanol. Crystall f-zation was initiated by allowing the ethanol-oil mixture to stand or 1 hour at room temperature and then completed in an ice bath.

The crystals formed were vacuum filtered, washed with iced ethanol and dried under vacuum, thus obtaining 59 gm of the desired N-(N' ,Ν' -dimethyl-dithio-carbamyl )-succinimide. The product had a melting point of 166° to l67° C, after recrystallization, first from 3 volumes of acetone, then from 5 volumes of methanol.

Analysis C7H10N2°2'S2; molecular weight = 218.3 Calculated C 38.51$ H 4.62$ N 12.83$ S 29.38$ Found 38. 5 .6 12.5 29.2 As it has been previously stated, the therapeutic compositions, based on Ν-(Ν' ,Ν' -dimethyl-dithio-carbamyl )-succinimide, can be utilized for the treatment of mycosis and of microbiological infections of the skin and mucous membranes .

N-(N' ,Ν' -dimethyl-dithio-carbamyl )-succinimide can be utilized locally as a topic application on the skin or mucous membranes preferably in form of a typical topical preparation containing from about 0.05$ to 10$ of the active principle. The typical topical preparation containing the active principle is applied directly and locally to the infected areas of the skin and/or mucous membranes of warm-blooded animals infected with mycosis or microbio-logical infections of the skin or mucous membranes .The topical preparations are applied in sufficient quantity so that the Infected area of the skin or mucous membranes is in contact with the preparation containing the active TABLE II Thus, it was ascertained that the bacteriostatic and the bactericidal effects of the studied product were distinctly superior to those of the two compounds tested in comparison. 2. Local antibacterial activity An agar culture was Inoculated with the bacteria to be studied. The agar culture was perforated and a circular lamella of 1 cm diameter was lifted out. Into the cavity thus obtained a specific quantity of the studied j product was introduced in the form of a 1$ ointment. (The j controls received only the excipient of the ointment.) j The culture medium was kept in the incubator for 18 hours ! i at 37°C. Ar'ound the cavity a circular zone of inhibition appeared. The diameter of this zone of inhibition was measured and was proportional to the activity of the product: This experiment was effected on three different j pathogenic strains of Staphylococcus aureus and on- one j pathogenic strain of Klebsiella pneumoniae. The agar cul- | tures used were the D.S.T. media (Oxoid) with a pH of 7. , and the blood agar base media (Oxoid) with a pH of 7.4, enriched with 1 of deflbrinated human blood.

The results obtained are compiled in Table III. 4. Local n i n l activity The activity of N- (N1 jN'-dimethyl-dithic-carbamyl)- succinimide, utilized as an ointment containing 1 of active principle, was studied in comparison with diverse pathogenic strains by employing the method described in 2 above. (local antibacterial activity). a) Action on the pathogenic fungi A dextrose agar culture of Sabouraud, pH of 5.2, was inoculated with diverse strains of Candida. The ointment was introduced into the cavity obtained, and the culture was kept in the incubator for 48 hours at 37°C.

The following results were obtained: TABLE VII It can be ascertained from these results that the zones of inhibition were very large.

In a different test, conducted under the same experimental conditions, the local antifungal, activity of the studied product with reference to Candida albicans was determined in comparison with nystatin, sodium dinethyl- dithiocarbamate, sodium undecylenate and amphotericin B, each of these compounds being utilized in the form of ointment containing 1% of active principle.

Table VIII represents a compilation of the results obtained.

TABLE VIII These results showed that the antifungal activity of N- (N1 jN'-diraethyl-dithio-carbamylJ-succinimide with reference to diverse strains of Candida albicans was distinctly superior to that of each of the other antifungal compounds. b) Action on the pathogenic fungi The activity of N- (N' , N«-dimethyl-dithio-carbamyl )■ succinimide utilized in the form of a 1% ointment, with reference to various strains of fungi was determined under the same test conditions as previously described. In a dextrose agar Sabouraud media, pH of 5.2, after incubating for 12 days at 24°C, the following results were obtained as shown in Table IX.

Accordingly, it can be ascertained that the zones of inhibition were very large.

In a different test, the antifungal. . activity of the studied product with reference to three strains of Mucors was determined after incubating for 12 days at 24°C. The test was conducted for comparison with sodium diethyl- dithiocarbamate under identical experimental conditions.

The results are compiled in Table X.

TABLE X These results showed clearly the fungistatic and fungicidal effectiveness of N- (N1 ,Ν'-dimethyl-dithio-car- bamyl)-succinimide with reference to the Mucor strains. This activity was very superior to that of sodium diethyl- dithiocarbamate .

. Local tolerance Male rats, each weighing 220 gra, were shaved on the dorso-lumbar area. After 48 hours of rest, the animals were divided into two groups: i Group A; The animals received an application Ν-ΐΝ',Ν'- I dimethyl-dlthio-carbarayl)-succinimide in the I . form of a 1% ointment every day for a period of ; 3 days.

! I Group B: A sangiheous sore was induced on the shaved part i of the body. Then every day for a period of 3 days, the animals received an application of the i ; ointment onto this wound.

I For both groups the cutaneous tolerance was ! excellent. The regrowth of the hair was complete after 20 ;'. days, covering the entire surface previously shaved. In I ■j Group B, the wound presented an aspect of a slightly re- tracted scab. After 8 to 10 days, the scab disappeared, I j leaving a supple, smooth and glossy skin. j For the second test, a group of rats, each animal ! weighing 280 to 300 gm, received a daily application of ! 200 mg of an ointment containing 1% of N-(N' ,N1'-dimethy1-i dithio-carbamyl)-succinimide on the shave part of the body j over a period of two weeks. A second group of rats received a daily application of 200 mg of the excipient alone. At the end of the test, the general condition of both groups of animals was very satisfactory, and no local irritation at all was observed, nor was any difference in the weight between the animals receiving the studied product and those receiving only the excipient observed. Consequently, the local tolerance is thus satisfactory.

Claims (1)

1. HAVING NOW particularly described and tained the nature of our said invention and in what manner the same is to he we declare that is A therapeutic composition the treatment of mycosis and microbiological infections of the skin and mucous membranes of animals which comprises from about to of and the remainder a pharmaceutical vehicle The therapeutic composition of claim 1 wherein said is present in an amount of between to DATED 5th day of Se insufficientOCRQuality