FI65237B - OIL NATROPHENYLTHIONOCARBAMOYL CARBON MATERIAL - Google Patents

Description

ΓΒ1 / «« ANNOUNCEMENT ,, Λ, η jHTa lBJ (11) UTLÄCGNINGSSKRIFT OblOf • Jtfi & k 0 (4¾ Patent Lty 10 04 1934 ί%! # 7 Patent oeddelat VT ^ (51) IC * .lk.3 / lm.CI. 3 C 07 C 157/12 FINLAND (21) Pww «ii» k * mu · —pK * n «wetaiof T927U1 <B) H — M * -——- H o '·· 09 · T9 vr, , '(23) Alkuptlvt — Glttifhacadaf 16.09-76 (41) Tullut JuIMmM - BIIyK offuntllj oU.09.79

Date of publication of the patent and the register (44) Date of issue of the notice of publication. - 30 12 83

Patent and ocean reflex relay Anaftkan utbgd odi utijkr * ft «o publkurad (32) (33) (31) Pyyduttr uteoHcuus-Beflrd prtoritut 19.09.75

Federal Republic of Germany TVskland (DE) P 25 ^ 17 ^ 2.9 (71) Hoechst Aktiengesellschaft, Postfach 80 03 20, 6230 Frankfurt / Main 80, Federal Republic of Germany Förbundsrepubliken lyskland (DE) (72) Heinz Loevre, Kelkheim / Taunus, Josef Urbanietz, Schvalbach / Taunus,

Dieter Dihrel, Hofheim / Taunus, Reinhard Kirsch, Niederjosbach / Taunus,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7¾) Oy Kolster Ab (5 * 0 Process for the preparation of new therapeutically useful o-nitrophenylthionocarbamoylcarbamates Avdelad frän ansökan 762652

The present invention relates to a process for the preparation of o-nitrophenylthionocarbamoyl carbamates of the formula

> - C @

3 H-CS-NH-COOR 1 having alkyl of 1 to 4 carbon atoms, R 2 and R 2 independently of one another denote hydrogen, alkoxy of 1 to 4 carbon atoms, halogen, trifluoromethyl, 2 65237 alkyl having 1 to 4 carbon atoms or cyano and X is a group. -O-SO 2 - or -SO 2 -O-.

The invention is characterized in that a nitroaniline derivative of the formula wherein R 2, R 3 and X are as defined above is reacted with an alkyl isothiocyanatoformate of the formula S = C = N-COOR, (4) wherein R 1 is as defined above.

Suitable alkyl radicals for the substituents R 1, R 2 and R 2 are: methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tert-butyl. Suitable alkoxy groups for R2 and R3 are: methoxy, ethoxy, propoxy, isopropoxy and butoxy. Suitable halogen atoms in the substituents R2 and R3 are fluorine, chlorine, bromine and iodine.

To prepare the compound of formula (2), the o-nitroaniline derivative of formula (3) is reacted with an alkyl isothiocyanoformate for one to several hours at a temperature of 20 to 120 ° C, suitably using an excess of alkyl isothiocyanatoformate, that it also acts as a solvent. The reaction products are isolated by evaporating the excess alkyl isothiocyanato formate and extracting the residue as an inert solvent, suitably diluting the reaction mixture with water and shaking with an inert solvent which is immiscible with water. The reaction product enters an organic phase from which it can be obtained by evaporating off the solvent. Suitable solvents include, for example, ethyl acetate, diethyl ether, diisopropyl ether, methylene chloride, chloroform, benzene and the like.

Suitable alkyl isothiocyanato formates of the formula (4) are methyl ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl isothiocyanato formate.

3 65237

The o-nitroaniline derivatives of formula (3) required for the preparation of o-nitrophenylthionocarbamoyl carbamates of formula (2) are in turn obtained in the case where X is an -O-SO 2 group by giving the corresponding chloronitro compounds of formula (5), wherein and R 1 are as defined in formula (2), react with ammonia in a suitable solvent such as dioxane or methanol at elevated temperature and pressure. The chloro-nitro compounds of formula (5), on the other hand, are obtained by reacting 3-nitro-4-chloro-benzenesulfonic acid chloride of formula (6) with a phenol of formula (7) wherein R 2 and are as defined in formula (2), in an inert solvent in the presence of a base such as triethylamine.

In the case where X is a -SO 2 -O group, the corresponding o-nitroaniline derivatives of formula (3) are obtained by reacting 3-nitro-4-aminophenol (8) with benzenesulfonic acid chloride of formula (9). ), wherein R 1 and R 2 are as defined in formula (2), in an inert solvent in the presence of a base such as triethylamine.

Reaction costs are shown on page 4.

The o-nitrophenyl thionocarbamoyl carbaminates of the formula (2) act as antifungal drugs.

The active ingredients are administered orally or subcutaneously (transdermally) in combination with suitable pharmaceutical solvents or carriers, whichever is preferred, depending on the circumstances.

The active compounds of the formula (2) are always administered, depending on the condition of the patient, in a dose of 0.5 to 50 mg per kg of body weight for 1 to 14 days.

Suitable tablets for oral administration are tablets, granules, capsules, powders, granules or pastes containing the active ingredients together with customary excipients and carriers such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silicic acid. , with carboxymethylcellulose or similar substances.

(! 4 65237 RR5§H-cyclo-1-r3rN ° 1

3 I

(7) I (6) 5 © --- (sr (3): X = -O-SO - ^ nX '/ ^ SnH2 \ ^ "hST1

WNH-C-NH-COOR1 (2): X = -O-SO2-I

(D) -NO 2 -NH 2 J. (8) for "· (3): X = -SO 2 -O- V 2 RR 13 ° C ^ 1 ° -rsr1 K3 * VSs ^ A> NH-C-NH-COOR1: X = -SO2-O- 1 65237

PHARMACOLOGICAL COMPARATIVE TESTS

The anthelmintic activity of the compounds prepared in Examples 1, 12, 13 and 21 against Fasciola hepatica was studied in rats and ewe larvae against the effect of 2-nitro-5-phenylthiophenylthionocarbamoylmethylcarbamate (m.p. 144 ° 36) known from DE 38

For this purpose, rats were orally administered 15 Fasciola hepatica metaseroids and ewe lambs 200. After the period before the onset of the disease (the time between the puberty of the parasites, when the secretion of eggs and larvae begins, and the time of infection), the parasitic infection of each animal was confirmed by analyzing the faeces.

Test compounds were administered orally to experimental animals in a 2% by weight aqueous suspension of methylcellulose.

On days 7, 14, and 28 after treatment, the number of eggs per gram of feces was determined. On day 30, the animals were sacrificed and dissected for liver examination to ensure that no parasites were present when 100% potency of the test substance was found in the faecal analysis. The percentage reduction compared to the value obtained before treatment with the test substance was calculated and is shown in the following table and only on the 28th day of the effect of the test substance.

Compound Fasciola hepatica in rats Fasciola hepatica in ewe lambs Eg dose / mg / kg power% dose / mg / kg power% _body weight / _body weight / _ 1000 se. 100 30 p.o. 100 1000 p.o. 100 13 1000 se. 100 30 p.o. > 90 1000 p.o.

12 - 30 p.o. 100 21 1000 se. 100 30 p.o. > 95 _750 p.o._> 80____________

Known 1000 it. 0 30 p.o. 0 _1000 p.o._0 _______ s.c. = subcutaneously; po = orally.

65237

The results shown in the table show that the compounds according to the invention have a very good activity against parasites under the experimental conditions, while the reference compound has no activity at all.

EXAMPLES

1) 2-Nitro-4-phenoxysulfonyl-phenylthionocarbamoylmethylcarbamate is prepared by heating 29.4 g of 2-nitro-4-phenoxysulfonyl-aniline in 30 ml of methyl isothiocyanatoformate with stirring for 1 hour at 100 ° C. After cooling to 30 [deg.] C., a total of 200 ml of diisopropyl ether are gradually added, the mixture is cooled in an ice bath and the precipitated 2-nitro-4-phenoxysulfonyl-phenylthionocarbamoylmethylcarbamate is filtered off. It is clean enough for further processing. Yield 25 g, Jp. 137 ° C.

To prepare 2-nitro-4-phenoxysulfonylaniline, 54 g of 3-nitro-4-chloro-benzenesulfonic acid phenyl ester in 500 ml of dioxane are kept under an overpressure of gaseous ammonia 5 for 5 hours at 50 [deg.] C. and the solvent is then removed in vacuo. To the residue is added 200 ml of a mixture of equal parts of methanol and water, after which time a solid precipitate forms which is filtered off.

After recrystallization from methanol and benzene, 28 g of 2-nitro-4-phenoxysulfonylaniline are obtained, m.p. 104 ° C.

3-Nitro-4-chloro-benzenesulfonic acid phenyl ester is obtained by mixing 51 g of 3-nitro-4-chloro-benzenesulfonic acid chloride with 18.8 g of phenol in 120 ml of acetone and, under cooling, 28 ml of triethylamine at a temperature of not exceeding 10 ° C. Stir for a few more hours at room temperature and then add water to separate the oil which is extracted with ether. After recrystallization of the residue from methanol, 54 g of 3-nitro-4-chloro-benzenesulfonic acid phenyl ester, m.p. 71 DEG C., are obtained.

Correspondingly prepared using correspondingly modified starting materials: 2) from 3-nitro-4-chloro-benzenesulfonic acid 4-chloro-phenyl ester, m.p. 83 ° C m.p. 2-nitro-4- (4-chloro-phenoxysulfonyl) -aniline. Through 157 ° C 2-nitro-4- (4-chloro-phenoxysulfonyl) -phenyl-thionocarbamoylmethylcarbamate m.p. 146 ° C.

7,652,7 3) 3-Nitro-4-chloro-benzenesulfonic acid 3-chloro-phenyl ester m.p. 68 ° C 2-nitro-4- (3-chloro-phenoxysulfonyl) -aniline m.p. Through 127 ° C 2-nitro-4- (3-chloro-phenoxysulfonyl) -phenyl-thionocarbamoyl-methylcarbamate m.p. 153 ° C.

4) 3-Nitro-4-chlorobenzenesulfonic acid 2-chlorophenyl ester m.p. 87 ° C 2-Nitro-4- (2-chlorophenoxysulfonyl) phenyl thionocarbamoylmethylcarbamate m.p. 120 ° C.

5) 3-Nitro-4-chloro-benzenesulfonic acid 3,5-dichloro-phenyl ester m.p. 104 ° C 2-nitro-4- (3,5-dichloro-phenoxysulfonyl) -aniline m.p. 163 DEG C. 2-Nitro-4- (3,5-dichloro-phenoxysulfonyl) -phenyl-thionocarbamoylmethylcarbamate m.p. 158 ° C.

6) 3-Nitro-4-chloro-benzenesulfonyl acid-2,4-dichloro-phenyl ester m.p. 11 ° C 2-Nitro-4- (2,4-dichlorophenoxysulfonylamine) mp 154 ° C 2-Nitro-4- (2,4-dichlorophenoxysulfonyl) phenylthiocarbamoylmethylcarbamate mp 140 ° C.

7) 3-nitro-4-chlorobenzenesulfonic acid 3,4-dichlorophenyl ester m.p. 79 DEG C. 2-Nitro-4- (4,4-dichlorophenoxysulfonyl) -aniline m.p. 163 ° C 2-nitro-4- (3,4-dichlorophenoxysulfonyl) -phenylthionocarbamoylmethylcarbamate m.p. 174 ° C.

8) 3-Nitro-4-chloro-benzenesulfonic acid 4-methyl-phenyl ester m.p. 71 ° C 2-nitro-4- (4-methyl-phenoxysulfonyl) -aniline m.p. Through 135 ° C 2-nitro-4- (4-methylphenoxysulfonyl) -phenylthionocarbamoylmethylcarbamate m.p. 151 ° C.

9) 3-Nitro-4-chloro-benzenesulfonic acid 3-methyl-phenyl ester m.p. 57 ° C 2-nitro-4- (3-methyl-phenoxysulfonyl) -aniline m.p. 140 ° C 2-nitro-4- (3-methylphenoxysulfonyl) phenylthionocarbamoyl methyl carbamate m.p. 151 ° C.

10) 3-nitro-4-chlorobenzenesulfonic acid 2,4-dimethylphenyl ester m.p. 81 ° C 2-nitro-4- (2,4-dimethylphenoxysulfonyl) -aniline m.p. Via 105 ° C 2-nitro-4- (2,4-dimethylphenoxysulfonyl) -phenylthionocarbamoylmethylcarbamate m.p. 136 ° C.

11) 3-Nitro-4-chloro-benzenesulfonic acid 4-methoxy-phenyl ester m.p. 86 ° C 2-nitro-4- (4-methoxy-phenoxysulfonyl) -aniline m.p. Through 143 ° C 2-nitro-4- (4-methoxy-phenoxysulfonyl) -phenylthionocarbamoylmethylcarbamate m.p. 152 ° C.

12) 3-Nitro-4-chloro-benzenesulfonic acid 3-methoxy-phenyl ester m.p. 74 ° C 2-nitro-4- (3-methoxy-phenoxysulfonyl) -aniline m.p. 116 ° C 2-Nitro-4- (3-methoxy-phenoxysulfonyl) -phenyl-thionocarbamoylmethylcarbamate m.p. 133 ° C.

8 65237 13) from 3-nitro-4-chloro-benzenesulfonic acid 3-cyano-phenyl ester m.p. 119 ° C 2-nitro-4- (3-cyano-phenoxysulfonyl) -aniline mp 182 ° C. 2-Nitro-4- (3-cyano-phenoxysulfonyl) -phenyl-thionocarbamoylmethylcarbamate m.p. 142 ° C.

14) 3-nitro-4-chloro-benzenesulfonic acid 3-trifluoromethyl-phenyl ester, m.p. 65 ° C via 2-nitro-4- (3-trifluoroethyl-phenoxysulfonyl) -aniline m.p. 131 ° C and 2-nitro-4- (3-trifluoromethylphenoxysulfonyl) phenylthionocarbamoyl methylcarbamate m.p. 157 ° C.

15) 2-Nitro-4-phenylsulfonyloxyphenylthiocarbamoylmethylcarbamate is prepared by heating 29.4 g of 2-nitro-4-phenylsulfonyloxyaniline in 30 ml of methyl isothiocyanatoformate for 1 h at 100 ° C with stirring. Cool to 30 ° C and slowly add 200 ml of diisopropyl ether to the mixture, which is cooled in an ice bath and the precipitated 2-nitro-4-phenylsulfonyloxy-phenylthionocarbamoylmethylcarbamate is filtered off with suction. The product is recrystallized from a mixture of methyl glycol and methanol to give 30 g of the title compound, m.p. 134 ° C. To prepare 2-nitro-4-phenylsulfonyloxyaniline, 15.4 g of 3-nitro-4-aminophenol dissolved in 100 ml of acetone are mixed with 14 ml of triethylamine and 17.6 g of benzenesulfonic acid chloride dissolved in 30 ml of acetone are added dropwise while stirring in an ice bath. so that the temperature of the mixture does not rise above 20 ° C. The mixture is stirred for a further 3 h at room temperature, the triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The residue is triturated with 50 ml of methanol and filtered. The precipitate is washed with methanol and dried to give 18.2 g of 2-nitrophenylsulfonyloxyaniline, m.p. 140 ° C.

16) As in Example 15, 2-nitro-4- (3-trifluoromethylphenylsulfonyl) aniline is prepared m.p. 132 ° C 2-Nitro-4- (3-trifluorophenylsulfonyloxy) phenylthionocarbamoylmethylcarbamate, m.p. 126 ° C.

Claims (1)

Claim: A process for the preparation of novel therapeutically useful o-nitrophenylthionocarbamoyl carbamates of the formula R 2 -No 2) © - (βΓ m R 3 \ NH-CS-NH-COOR 1) with alkyl having 1 to 4 carbon atoms, R 2 and R 2 independently represent hydrogen, alkoxy of 1 to 4 carbon atoms, halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms or cyano and X is a group -O-SO 2 - or -SO 2 -O-, characterized in that the o-nitroaniline derivative, of the formula: R 3 \ nh 2 wherein R 2, R 1 and X are as defined above, is reacted with an alkyl isothiocyanatoformate of the formula: S = C = N-COOR 1 (4) wherein is as defined above.