NO119270B - - Google Patents

Description

Process for the production of new, therapeutically effective substituted urea derivatives.

The present invention relates to a method for the production of new urea derivatives with valuable pharmacological properties.

It was found that they had hitherto not known urea derivatives of the general formula

where X means the methylene or ethylene group,

Y oxygen or sulphur,

and R 2 hydrogen, fluorine, chlorine or bromine, trifluoromethyl or lower alkyl or alkoxy groups and

n 0 or 1,

has outstanding antibacterial, particularly tuberculostatic, action. The biological properties characterize the compounds of the general formula I as active substances in disinfectants as well as in medicines for the treatment of tuberculosis and leprosy.

In the compounds of the general formula I, where and R 2 are lower alkyl and alkoxy groups, R 1 and R 2 are e.g. methyl-,

ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.butyl groups, acc. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy groups.

To prepare the new compounds of the general formula I, an amine of the general formula is reacted

where X and n have the meaning given under formula I, with a phenyl isocyanate or -isothiocyanate of the general formula or with a reactive functional derivative of a carbanilic acid or thiocarbanilic acid of the general formula

where Y, R^ and R» have the meaning given under formula I.

, as functional derivatives of acids with the general formula IV are suitable, e.g. their lower alkyl esters, phenyl esters, amides, N-nitro-amides, N-acetyl amides, N,N-diphenyl amides or especially when R 2 is present as a lower alkyl residue, also its chlorides.

The implementation of the turnover depends on the starting materials used. Reactions with phenyl isocyanates or isothiocyanates of the general formula III are carried out, e.g. at temperatures between 0° and 100°. Instead of isocyanates or isothiocyanates, compounds can also be used which, under the known reaction conditions, turn into such, such as e.g. 1,3,3-triphenylureas, whose phenyl residue in the 1-position, if desired, is substituted corresponding to the definition for R 1 and R t,-., In this case, higher reaction temperatures also occur up to approx. 250° in consideration. The reaction components can be used in stoichiometric quantities or an excess of a component can be selected. The order of addition is arbitrary, preferably, however, the isocyanate is added to the initial amine.

As solvents or diluents for both reaction components, depending on the required reaction temperature, e.g. benzene, toluene, xylene, chlorobenzene, chloroform, carbon tetrachloride, acetone, acetonitrile, tetrahydrofuran, dioxane or/and diethylene glycol dimethyl ether and for the amines also lower alkanols.

Reactions with lower alkyl esters or phenyl esters of carbanil acids or thiocarbanil acids of the general formula IV can be carried out at temperatures between 0° and 250° in the absence of solvents or in one of the above-mentioned solvents. Reactions with N-nitroamides, i.e. possibly corresponding to the definition for R^ and R^ substituted 1-phenyl-3-nitro-ureas are found e.g. place in water or an aqueous-organic medium, such as dioxane/water, at its boiling temperature, and such with the amides at temperatures up to approx. 200° in close

or absence of solvents, such as e.g. glacial acetic acid or phenol. For reactions of amines of the general formula II with the carbanilic acid chlorides or thiocarbanilic acid chlorides substituted according to the definition, the temperature range is between 0° and approx. 150° in consideration, whereby as an acid-binding agent an excess of the amines to be reacted, or a tertiary organic base, such as triethylamine, dimethylaniline or pyridine, or finally an inorganic base, such as sodium hydroxide, sodium or potassium carbonate, and as a solvent eg again

one of the above mentioned find application.

Following a second method related to the first mentioned, compounds of the general formula I are obtained by reacting an amine of the general formula

where and R2 has the meaning given under formula I, with an isocyanate or isothiocyanate of the general formula

where X, Y and n have the meanings specified under formula II and formula I respectively.

According to a third method, compounds of the general formula I are prepared by reacting a compound of the general formula

where X, R1, R2 and n have the meaning given under formula II or formula I respectively, with a compound of the general formula

where Y has the meaning given under formula I.

The build-up of water or hydrogen sulphide takes place easily when treated with water, diluted mineral acids or a mixture of water according to dilute mineral acids and a water-miscible organic solvent, such as tetrahydrofuran or dioxane, respectively by introducing hydrogen sulphide into a solution containing compounds of the general formula VII in an organic solvent, such as e.g. dioxane, or by treating such a solution with a hydrogen sulfide ion-releasing reagent, such as sodium hydrogen sulfide or sodium sulfide.

The aforementioned reactions are carried out according to the reactivity of the reagents used and the boiling temperature of any solvents or diluents used at temperatures between 0° and 150°.

A divisible allows certain compounds of the general formula I,

which is obtained according to one of the methods mentioned above, transfer to other compounds with this general formula.

In particular, one can convert thioureas, i.e. compounds

of the general formula I, where Y is sulfur and X, R^, R^

and n has the meaning given under formula I, to the corresponding urea substances.

Oxidizing agents, such as e.g. hydrogen peroxide in water-miscible solvents, sodium peroxide in alkaline-aqueous solution, potassium ferricyanide, ferric chloride, potassium permanganate, sodium or potassium hypochlorite in aqueous or aqueous-organic medium.

The starting substances with the general formula II, the 1-adamantanamine and the tricyclo[4,3,1,1 3 '8]undecan-3-amine (homoadamantan-1-amine) are known.

The administration of the new substituted urea derivatives

with the general formula I for the therapy of tuberculosis diseases as well as leprosy can take place in the usual dosage unit forms orally, as well as parenterally. Suitable forms of administration for oral use are e.g. tablets, dragees and gelatin capsules. For parenteral administration, e.g. solutions and dispersions in mixtures of water with suitable dissolution agents and/or emulsifiers, and in particular for intramuscular administration also solutions in suitable fatty oils in consideration. Of particular importance are the compounds of the general formula I in the local therapy of the aforementioned diseases, whereby non-single-dose administration forms, such as ointments, powders and aerosols, also come into question.

It is known from J.Med.Chem. 6, 452 - 455 (1963), that symmetric

and unsymmetrical diarylthioureas exhibit antibacterial activity. Thus, a whole range of investigated compounds show weight-reducing properties i.v. on in Youman's medium grown

Mycobacterium tuberculosis H 37 Rv Typ humanus, in concentrations of 5 - 100 ug/ml. In contrast, it can be shown that the compound 1-(1-adamantyl)-3-

ii (3,4-dichlorophenyl)-urea in an analogous experimental device already in a concentration of 0.3 µg/ml has a growth-inhibiting effect.

The tuberculostatic effect in vitro of the following compounds, which can be prepared according to the invention, and isonicotinic acid hydrazide are compared.

1) 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-urea

2) 1-(1-adamantyl)-3-(4-chlorophenyl)-urea

3) 1-(1-adamantyl)-3-(p-tolyl)-urea

4) 1-(1-adamantyl)-3-(α,α,α-trifluoro-4-chloro-m-tolyl)-urea

5) 1-(adamant-1-yl-methyl)-3-(3,4-dichlorophenyl)-urea

6) isonicotinic acid hydrazide.

Compounds 1-5 are dissolved in methylcellosolve and compound

6 in physiological saline solution. These compounds

is then further diluted with the corresponding solvents. The concentration of. the sample compounds in the solvent. is chosen so that when added to the nutrient bases, the desired final concentration is achieved.

The solution of the compounds is added to the still liquid nutrient medium (Youmans Semisolid) and filled to 5 ml in the culture tubes. After solidification, the tubes are inoculated with 0.1 ml tubercle bacterial suspensions of different strains of density McFarland 1. The inoculated tubes are cultured for 18 days at 37°. The lowest concentration is then determined, which completely inhibits the sample strain in the wick.

The acute toxicity is determined by a single oral administration of the test compound to white mice of both species. The animals are administered the test compound as a suspension in tragacanth solution per pharyngeal tube. A series of 5 mice is used per dose. The animals are then observed for 8 days and the percentage of fatalities per dose. DL5q, which occurs following the death of 50% of the animals, is then calculated by interpolation from the results obtained.

The compounds 1-5 produced according to the method according to the invention inhibit, at low toxicity, the isonicotinic acid-hydrazide-resistant and -sensitive human tubercle bacteria strains A 5 and H 37 Rv.

The following examples describe the preparation of the new substituted urea derivatives of the general formula I and of previously unknown intermediates. The temperature ranges are indicated in degrees Celsius.

EXAMPLE 1 '

5.5 g (36.5 mmol) of 1-adamantanamine in 100 ml of absolute benzene and 6.25 g (33.3 mmol) of 3,4-dichlorophenyl isocyanate in 100 ml of the same solvent are combined, whereby heating and

in crystallization takes place. Mano ppheats the mixture for 1 hour to 80°, cools and filters. The filter material is stirred for 1 hour in lOO ml 1-n hydrochloric acid, filtered, washed neutrally with water and dried over phosphorus pentoxide, after which 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-urea with a melting point of 220 - 221° is obtained .

Analogously, using the correspondingly substituted phenyl isocyanates and .1-adamantanamine acc. N-methyl-1-adamantanamine acc. tricyclo]4,3,1,1 3 ' 8Jundecan-3-amine the following ureas: . a) 1-(1-adamantyl)-3-(p-tolyl)-urea, m.p. 252 - 256°; b) 1-(1-adamantyl)-3-(p-chlorophenyl)-urea, m.p. 242 - 243°; c) 1-(1-adamantyl)-3-(2,4-dichlorophenyl)-urea f-, m.p. 221 - 222°; d) 1-(1-adamantyl)-3-(6-chloro-α,α,α-trifluoro-m-tolyl)-urea, m.p. 233 - 234°; e) 1-(1-adamantyl)-3-(p-methoxyphenyl)-urea, m.p. 234 - 236°; f) 1-(1-adamantyl)-3-(p-methoxyphenyl)-urea, m.p. 235 - 238°;

g) 1-(1-adamantyl)-3-(2,5-dimethoxyphenyl)-urea, m.p.

240 - 242°; h) 1-(tricycloph4,3,1,1<3>'<8>]undec-3-yl)-3-(3,4-dichlorophenyl)-urea, m.p. 233 - 236°.

EXAMPLE 2

5.0 g (33 mmol) of 1-adamantanamine in 50 ml of absolute toluene is added to 5.70 g (28 mmol) of 3,4-dichlorophenyl isothiocyanate in 50

ml of absolute toluene, whereby heating and crystallization take place. It is heated for 1 hour on a steam bath, cooled, filtered and washed with ether. The solid phase is then stirred in 100 ml 1-n hydrochloric acid and 20 ml methanol, filtered off, washed neutrally with water and then recrystallized from dioxane/ethanol: 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-2- thiourea, m.p. 193 - 195°.

Analogously, e.g. using the correspondingly substituted phenylisothiocyanates and 1-adamantanamine the following 2-thioureas: a) 1-(1-adamantyl)-3-(p-chlorophenyl)-2-thiourea, m.p. 172 - 173°;

b) 1-(1-adamantyl)-3-(2,4-dichlorophenyl)-2-thiourea, m.p.

181 - 183°;

c) 1-(1-adamantyl)-3-(4-chloro-α,α,α-trifluoro-m-tolyl)-2-thiourine, m.p. 169 - 171°. in

EXAMPLE 3

A solution of 1.13 g (6 mmol) of 3,4-dichlorophenyl isocyanate in 10 ml of absolute toluene is added to a solution of 0.99 g

(6 mmol) 1-adamantanemethylamine. After 2 hours of heating in a steam bath, it is cooled, whereby crystals separate out. These are filtered off, washed with toluene and recrystallized

from ethanol. The thus obtained 1-(1-adamantanemethyl)-3-(3,4-dichlorophenyl)-urea melts at 189 - 191°.

EXAMPLE 4

885 g (5 mmol) of 1-adamantane isocyanate and 535 mg (5 mmol) of p-toluidine are dissolved in 25 ml of absolute benzene and boiled for 15 hours under reflux. The crystals that separate are sucked off after cooling to room temperature and washed with benzene. 1-(1-adamantyl)-3-(p-tolyl)-urea melts at 254 - 255°.

EXAMPLE 5

To the suspension of 710 mg of 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-thiourea in 10 ml of methanol is added 680 mg of 30% hydrogen peroxide, dissolved in 10 ml of methanol. The mixture is heated under reflux, whereby a clear dissolution occurs after 30 minutes. After a further 30 minutes, 10 ml of water is added dropwise to the hot solution. The precipitated product, 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-urea, is filtered off hot and recrystallized from 80% ethanol, m.p. 218 - 221°.

EXAMPLE 6

Dissolve 1.77 g (5 mmol) 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-thiourea at 30° in 180 ml pure dioxane, then add 18 ml water and finally 9 g lead oxide (PbO) (40 mmol). First

stirred for 15 hours at room temperature and then for 3 hours at reflux temperature. The reaction mixture is filtered hot through "Hyflo". The hot filtrate is added until boiling water (220 ml). On cooling, crystals separate;

after recrystallization from ethanol, the 1-(1-adamantyl)-3-(3,4-dichlorophenyl)urea melts at 215 - 220°.

EXAMPLE 7

200 mg (0.62 mmol) of 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-carbodiimide, 15 ml of dioxane and 5 ml of 0.1-n hydrochloric acid are boiled together for 1 hour under reflux. After cooling, a little water is added, and the crystals that stand out as a result are filtered off. Recrystallization from ethanol gives 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-urea with m.p. 220 - 224°.

The 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-carbodiimide required for the reaction described above is prepared as follows: 5.32 g (15 mmol) 1-(1-adamantyl)-3-( 3,4-dichlorophenyl)-thiourea is dissolved at room temperature in 600 ml of absolute dioxane. 6 g (50 mmol) of anhydrous magnesium sulfate and finally 26.8 g (120 mmol) of lead oxide (PbO) are then added. The whole is stirred for 15 hours at 60°, then cooled and filtered through Hyflo. The clear, colorless filtrate is concentrated in vacuo to dryness. The oil-like residue is taken up in 300 ml of pentane. The clear solution is made clear by means of filtration through activated carbon and concentration, whereby crude 1-(1-adamantyl)-3-(3,4-dichlorophenyl)-carbodiimide crystallizes out. After recrystallization from pentane at -15°, pure product with m.p. 60 - 61°.

EXAMPLE 8

Into the boiling solution of 321 mg (1 mmol) of 1-(1-adamantyl)-3-(3,4-dichlorophenyl)carbodiimide in 10 ml of absolute dioxane, hydrogen sulfide is introduced for 3 hours. The yellow reaction solution is concentrated to dryness. The yellow residue is washed twice each time with 5 ml of ethanol, after which the undissolved part, 1-(1-adamantyl)-3-(3,4-dichloro-phenyl)-thiourea is crystallized, m.p. 189 - 192°.

Claims (1)

Process for the production of new therapeutically effective substituted urea derivatives with antibacterial and especially tuberculostatic effect with the general formula where X means the methylene or ethylene group, Y oxygen or sulphur, and R^ hydrogen, fluorine, chlorine or bromine, trifluoromethyl or lower alkyl or alkoxy groups and n 0 or 1, characterized in that mana) reacts an amine with the general formula where X and n have the meaning given under formula I, with a phenyl isocyanate or -isothiocyanate with the general or with a reactive functional derivative of a carbanilic acid or thiocarbanilic acid of the general formula where Y, and R^ have the meaning given under formula I, or b) that one reacts an amine with the general formula where R 1 and R 2 have the above meaning, with an isocyanate or isothiocyanate of the general formula where X, Y and n have the meaning stated above, or c) that one converts a compound with the general formula where X, R^ , R^ and n have the above meaning, with a compound of the general formula i where Y has the above meaning, or d) that a thiourea derivative with the general formula I is converted in a known manner into the corresponding urea derivative. Cited publications: J. Med. Chem. 6, pp. 452-55 (1963)