GB2061935A - Mercaptodihydroimidazopyridazinethione antifungal agents - Google Patents

Abstract

Antifungal agents of the formula:- <IMAGE> and their zinc complexes of the formula: <IMAGE> wherein R is a C1-C6 alkyl group, are disclosed, together with processes for their production and pharmaceutical compositions containing them.

Description

SPECIFICATION Antifungal agents This invention relates to certain mercaptodihydroimidazopyridazinethiones, and to their zinc complexes, which possess antifungal activity.

According to the invention there is provided a compound of the formula:

or a zinc complex thereof of the formula:

wherein R is a C1-C6 alkyl group.

The invention also provides a method of treating an animal; including a human being, having a fungal infection, which comprises administering to the animal an effective amount of a compound of the formula (I) or zinc complex of the formula (II), or a pharmaceutical composition comprising said compound or complex together with a pharmaceutically acceptable diluent or carrier.

The invention yet further provides a pharmaceutical composition comprising a compound of the formula (I) or zinc complex of the formula (II) together with a pharmaceutically acceptable diluent or carrier. The composition is preferably in unit dosage form.

By the term "unit dosage form" as used herein is meant a physically discrete unit containing an individual quantity of the active component in association with a pharmaceutically acceptable diluent or carrier, the quantity of active component being such that at least one unit or severable fraction of a unit is required for a single therapeutical administration.In the case of severable units, such as scored tablets, at least one severable fraction such as 1/2 or 1/4 of the unit may be all that is required for a single therapeutic administration It will be appreciated that the term "unit dosage form" does not include mere solutions except when the solutions are packaged in ingestible containers, e.g. soft capsules, or have been prepared so as to be suitable for parenteral administration, e.g. in vials of solution suitable for parenteral injection or in bottles for infusion.

R is preferably CH3 or C2H5.

The compounds and complexes of the invention may be prepared by the following routes: (1) The compounds can be prepared by the following scheme:

In the initial step, compound (III) and the dialkylaminoethyl chloride hydrochloride are heated together, e.g. under reflux, in the presence of potassium carbonate and in an alcoholic solvent, preferably ethanol.

Prolonged heating, e.g. up to 48 hours, is generally necessary. The product may then be isolated and purified by conventional procedures. Whilst the product is a single isomer, it is not known whether it has the structure (IVA) or (IVB).

In the second stage, compound (IVA) or (IVB) is heated, e.g. under reflux, with phosphorus pentasulfide in a suitable solvent, e.g. dry pyridine, typically for from 12 - 24 hours. The pyridine is then evaporated under reduced pressure, and the residue treated carefully with water. The mixture is then heated on a steam bath, cooled, and stirred with a large volume of chloroform whilst being acidified to about pHi with e.g.

hydrochloric acid. The aqueous and chloroform layers are then decanted from the resulting tarry residue, and the residue and aqueous layer separately extracted with chloroform. The chloroform extracts are combined, washed with water, dried and evaporated to the desired product.

(2) The zinc complexes can be prepared by heating, e.g. under reflux, a compound of the formula (I) with zinc dust in the presence of acetic acid, and in a suitable solvent, e.g. methanol. Generally, heating for 1 to 3 hours is necessary. The reaction mixture is cooled, filtered, and the resulting solid stirred with aqueous sodium hydroxide solution, filtered, and the residue washed with methanol, taken up in e.g. hot dimethylformamide, re-precipitated with water, and dried.

The in vivo evaluation of the compounds and complexes of the invention can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice which are inoculated with a strain of Candida albicans. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice following 48 hours observation. The dose level at which the compound provides 50% protection against the lethal effect of the infection (PD50) can be calculated.

Activity Results (PDSa. mglkg) p.o, i.v.

Formula (I), R = CH3 0.6 0.77 Formula(l),R=C2H5 0.82 asi Formula pl R= CH(CH3)2 1.02 0.46 Formula (11), R = C2H5 8.8 "Miconazole" 40.7 18.8 For human use, the anti-fungal compounds and complexes ofthe invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standardpharmaceuticalpractice.For example, they can be administered orally in the form oftablets containing such excipients as starch or lactose, orin capsules either alone orin admixture with excipients, orin the form of elixirs or suspensions containing flavouring or colouring agents, orin the form ofsuppositories orpessaries. The tablets are typicallypreparedby granulating the ingredients to geth er and compressing the resulting mixture to tablets of the desiredsize.

The capsules are typically prepared by granulating the ingredients together and filling them into hard gelatine capsules of the appropriate size to contain the ingredients. Similarly, the suppositories orpessaries may be prepared by conventional methods.

They can also be injectedparenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in the form ofa sterile aqueous solution which may contain othersolutes, for example, enough salts our glucose to make the solution isotonic. Such formulations may again be prepared by conventional techniques.

For oral and parenteral administration to human patients, it is expected that the daily dosage level of the anti-fungal compounds of the formula p) and complexes of the formula (ll) will be from 0.5 to 20 mglkg (in divided doses, when administered by the oral orparenteral route. Thus tablets, capsules or dosage units for parenteral administration (e.g. ampoules) containing the compounds can be expected to contain from 30 mg to 0.5g of active compound. The physician in any event will determine the actual dosage which will be most suitable for an individual patient bandit will vary with the age, weight and response of the particular patient.

The above dosages are exemplary of the average host. There can, of course, be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Alternatively, the anti-fungal compounds and complexes of the invention may be applied topically, e.g. in the form ofa cream or ointment For example there may be incorporated into a cream consisting ofan aqueous emulsion of polyethylene glycol or liquidparaffin, or they may be incorporated, at a concentration between 1 and 10%, into an ointment consisting ofa white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.

The following Examples illustrate the invention and the preparation of certain starting materials. All temperatures are given in "C.

Example A 4,-5-Dichloropyridazin-3-one (34 g), 2-diethylaminoethyl chloride hydrochloride (34.5 g) and anhydrous potassium carbonate (98 g) were heated under reflux in ethanol (1000 ml) for 46 hours.

The ethanol was then removed under reduced pressure and the residue partitioned between water (200 ml) and ethyl acetate (400 ml). The aqueous layer was extracted with a further portion of ethyl acetate (400 tml) and the organic layers combined, dried (MgS04), filtered and evaporated to an oil. This oil crystallised on trituration with petrol (b.p. 60 - 80 ). The crystalline solid was filtered off, washed with petrol and dried under vacuum at room temperature, 22.5 g, m.p. 67 - 70". The product was a single isomer, either ,4-chloro-2-(2-diethylaminoethyl)-5-ethoxypyridazine-3-one or 5-chloro-2-(2-diethylaminoethyl)-4 ethoxypyridazine-3-one.

Analysis %: Found: C,52.4, H.7.28, N,15.1 Calculated for C,2H20CIN3O2: C,52.6, H, 7.36, N, 15.3.

By a similar procedure, the corresponding 2-(dimethylaminoethyl) and 2-(diisopropylaminoethyl) compounds of respective m.p.'s 185 - 188 and 176 - 179 were prepared from 4,5-dichloropyridazine-3-one and, respectively, 2-dimethylaminoethylchloride hydrochloride and 2-diisopropylaminoethyl chloride hydrochloride. The products were isolated as the hydrochlorides by dissolving the crude product in ether and treating with hydrogen chloride gas.

Analysis % (dimethyl compound): Found: C, 43.1, H, 6.07, N,15.4 CalculatedforC10Hr6CIN302.HCi: C, 42.6, H, 6.07, N, 14.9.

Analysis% (diisopropyl compound): C,49.8, H,7.43, N,12.6 Found: CalculatedforC14H24CIN302.HCI: C,49.7, H, 7.45, N, 12.4.

Example 1 4,(5)-Chloro-2(2-diethylaminoethyl)-5(4)-ethoxypyridazine-3-one (22 g) and phosphorus pentasulphide (120 g) were heated under reflux for 18 hours in dry pyridine (1200 ml). The pyridine was evaporated under reduced pressure and the residue treated carefully with water (total amount 200 ml), in about 10 ml portions initially, when large quantities of hydrogen sulphide were evolved.

The mixture was then heated for two hours on a steam bath, cooled, and stirred with chloroform (1000 ml) whilst being acidified to pH 1 with hydrochloric acid (12 N). After stirring for 15 minutes the chloroform and aqueous layers were separated, and the remaining black tarry deposit was extracted with hot chloroform (500 ml) and the aqueous layer was also extracted with chloroform (500 ml). The chloroform extracts were then combined, washed with water (2 x 400 ml), dried (MgSO4), filtered and evaporated untii crystallisation occurred to give a brown crystalline solid, 10.2 g, m.p. 160 - 168", 1 -ethyl-8-mercapto-2,3-dihydro-7(1 H) imidazo (1,2-b)pyridazinethione.

Analysis %:- Found: C,44.9, H,5.29, N,19.4, S,31.3 C8H11N3S2requires: C,45.1, H, 5.20, N, 19.7, S,30.0.

Examples 2 and 3 By procedures similar to those of Examples 1, and starting from the corresponding dimethylaminomethyl and diisopropylaminoethyl compounds, the following products were prepared:

Example R M.P. Analysis % ( C) (Theoretical in brackets) C H N 2 CH3 282- 5 (d) 41.9 4.44 20.6 (42.2 4.55 21.1) 3 -CH(CH3)2 155-8 Mass spectra, MO = 227 (227) In Example 2, the product was isolated as in Example 1, except ethyl acetate was used instead of chloroform.

In this case removal of the ethyl acetate left a red gum, which was dissolved in sodium hydroxide solution (2 ml, 2N) and reprecipitated by addition of concentrated hydrochloric acid to pH 1, to give the product.

In Example 3, a similar procedure was used to that described in Example 2, except that after the final acid precipitation, the product was stirred with dry ether. Evaporation of the ether extract gave the product as a yellow solid.

Example 4 The imidazopyridazine product of Example 1 (0.6 g) and zinc powder (0.425 g) were heated under reflux fcr two hours in a mixture of glacial acetic acid (5.3 ml) and methanol (13 ml).

The reaction mixture was then cooled and filtered to give a yellow solid which was stirred in aqueous sodium hydroxide (2N) to pH 14, filtered off, washed with methanol, then taken up in hot dimethylformamide, re-precipitated with water, and dried at 60" under vacuum, to give 0.18 g of product, m.p. > 3000.

The product had the formula (II) in which R is C2H5.

Analysis %: Found: C, 39.2, H, 3.99, N, 17.1, S, 28.0 (C8H10N3S2)2.Zn requires: C, 39.2, H, 4.12, N, 17.2, S, 26.1.

Claims (8)

1. Acompound oftheformula:

our a zinc complex thereof of the formula:-

wherein R is a 01-0 alkyl group.

2. A compound or zine complex as claimed in claim 1 wherein R is OH3 or C2H5.

3. A process for preparing a compound of the formula (I) as claimed in claim 1, which comprises reaching a compound of the formula:

with a compound of the formula (R)2NCH2CH2CI wherein R is as defined in claim 1 in the presence of potassium carbonate in an alcoholic solvent, followed by reacting the resulting product with phosphoous pentasulfide.

4. A process for preparing a zinc complex as claimed in claim 1, which comprises reacting the corresponding compound of the formula (I) with zinc dust in the presence of acetic acid.

5. A process as claimed in claim 3 substantially as hereinbefore described in any one of Examples 1 to 3.

6. A process as claimed in claim 4 substantially as hereinbefore described in Example 4.

7. A compound of the formula (I) or zinc complex of the formula (Il) as claimed in claim 1 which has been prepared by a process as claimed in any one of claims 3 to 6.

8. A pharmaceutical composition comprising a compound of the formula (I) or zinc complex of the formula (II) as claimed in claim 1 or 7 together with a pharmaceutically acceptable diluent or carrier.