bis(8-hydroxyquinolinium) sulphate

Originator

Hydroxystilbamidin,Merrell National,US,1954

Indications

Used in the treatment of nonprogressive blastomycosis of the skin and other mycoses.

Background

Hydroxystilbamidine isethionate is used in the therapy of some patients with nonprogressive blastomycosis of the skin, and pulmonary or systemic blastomycosis in children, with fewer side effects than amphotericin B. Hydroxystilbamidine isethionate is also used in pathology for diagnostic purposes.

Definition

ChEBI: Hydroxystilbamidine is a stilbenoid.

Manufacturing Process

Preparation of 2-Nitro-4,4'-Dicyanostilbene: 10 grams of 2-nitro-ptolunitrileand 8.1 grams of 4-cyano-benzaldehyde were heated to 170° to 180°C, 1.2 and 0.6 cc of piperidine were added at quarter-hour intervals, heating was continued for a further one and a quarter hours, the product cooled, triturated with glacial acetic acid and filtered. The residue was crystallized from glacial acetic acid as yellow needles, MP 290°C.
Preparation of 2-Amino-4,4'-Dicyanostilbene: 10.0 grams of 2-nitro-4,4'- dicyanostilbene thus prepared were suspended in 200 cc of glacial acetic acid and a hot solution of 50 grams of stannous chloride (SnCl2 · 2H2O) in 50 cc of concentrated hydrochloric acid was quickly added. Rapid reaction occurred and the boiling was continued for a further 4 minutes, the reaction mixture was cooled, filtered, and the stannous chloride residue decomposed with 25% aqueous caustic soda solution. The liberated amine crystallized from glacial acetic acid as yellow needles, MP 232°C.
Preparation of 2-Hydroxy-4,4'-Dicyanostilbene: 10 grams of 2-amino-4,4'- dicyanostilbene thus prepared were dissolved in 400 cc of boiling glacial acetic acid and 200 cc of dilute sulfuric acid added; the solution was suddenly chilled and diazotized over one and a half hours at 5° to 10°C with sodium nitrate (3.0 grams/15 cc H2O). The diazonium salt solution was decomposed by boiling for 15 minutes with 600 cc of 55% aqueous sulfuric acid solution; the solution was diluted, cooled and filtered. The residue crystallized from ethyl alcohol as lemon yellow prismatic needles, MP 296°C
Preparation of 2-Hydroxy -4,4'-Diamidinostilbene Dihydrochloride: 10 grams of 2-hydroxy-4,4'-dicyanostilbene were suspended in 250 cc of absolute ethyl alcohol and the mixture saturated with dry hydrogen chloride at 0°C. The whole was left for eight days at room temperature. The imino-ether hydrochloride formed was filtered off, washed with dry ether and dried in the air for a short time. It was then added to 250 cc of 10% ethyl alcoholic ammonia and the whole heated for 5 hours at 45°C. The 2-hydroxy-4,4'- diamidinostilbene dihydrochloride which separated was crystallized from 10% hydrochloric acid. It forms pale yellow needles, MP 357°C (decomposition).
Preparation of the Final Isethionate Product: The diisethionate may be produced by treating a solution of the dihydrochloride with alkali carbonate, separating and dissolving the resultant base in aqueous isethionic acid and precipitating the diisethionate with acetone. The product may be purified by dissolving in hot methyl alcohol containing a trace of water followed by precipitation by the cautious addition of acetone. The diiseihionate has a MP of 286°C.

Therapeutic Function

Fungicide

Pharmacokinetics

Hydroxystilbamidine isethionate is a member of the diamidines, a large family of biochemially and pharmacologically interesting compounds. It has a rather unusual combination of properties, exhibiting antitrypanosomal, antimaliarial, antifungal and carcinostatic activities. It also appears to act as an immunosuppressant. This drug may be used in the treatment of blastomycosis, a disease cased by the dimorphic fungus or mold called Blastomyces dermatitids. Blastomycosis is a pulmonary infection that can lead to fever, cough and (rarely) symptoms similar to tuberculosis. Hydroxystilbamidine has largely been replaced with amphotericin B.

Metabolism

Not Available