DE1643965A1 - New carbamide derivatives and processes for their preparation - Google Patents

Description

Dr. Ing. 3arg2n Schmidt

Dr.r21.111. ::. Bruvc kekzner

pJtar, t .: r -; / i :: - i

8 Munich 2, Herniann-Sask-Str. 2

January 23, 1968

Re: Our reference: P-3268-1

Patent application for

Egyesält Gy & gyszer- es Tapszergyär, 30-38 Kereszturi ut, Budapest X (Hungary)

"concerning

New carbamide derivatives and processes for their production

• The invention relates to pharmacologically effective new Ihioharnetofi derivatives of the general formula I

Cl)

wherein R is a substituted or unsubstituted phenyl group, • a substituted or uneubstituted i'yridyl group, or a substituted or unsubstituted aralky group, and

62/86 old.

109829/1870

R ₁ denotes a straight-chain or branched »saturated or unsaturated alkyl group with 1-8 carbon atoms.

The subatituent B is two-fold 4-ethoxyphenyl, . 4-n-butoxy-phenyl-, 4-isoamyloxy-phenyl-, 4- (ß-dimethylamino) - ethoxyphenyl, 4-dimethylaminophenyl, 2,6-dimethylphenyl, 2,6-dichloro-phenyl-, 3-trlfluoromethyl-phenyl-, 4-carboxy-phenyl, JJ-Hydroxy ^ -oarboxy-phenyl, 2-pyridyl or a β-phenyl-isopropyl group.

The substituent R can conveniently be a * methyl, ethyl, Represent propyl, butyl, isoamyl or allyl group

The new compounds of general formula I can conveniently be prepared in such a way that a primary AmIn of the general formula II

R - NH ₂ (II;

wherein R has the above meanings with an isothlooyanate of the general formula III

R ₁ -OCN = CeS (III)

wherein R _{1 has} the above meanings, is implemented.

The reaction can be twofold in an indifferent Solvents such as acetone, benzene, etc., optionally under Heating, to be carried out

The starting compounds of the general formula III can in known catfish, e.g. by reacting the corresponding chlorocarbonic acid ester with a salt of rhodanic acid, e.g. with potassium or ammonium rhodanide will.

The invention relates to all stereoisomers of the compounds of the general formula I and the mixtures of the stereoisomers

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eboth in the form of the free baee ale also in the form of the acid salts *

The inventive new compounds of the general Formula I have valuable pharmacological properties. They thus have an anti-tuberculosis effect. Those derivatives in which the substituent R is a 4-alkoxyphenyl group and R is an alkyl group have a particularly advantageous tuberculosis effect. E.g. the l- (4 '- Ieoamyloxy-phenyl -) - 3-carbetoxy-thiourea and that 1- (4'-Isoamyloxy-phenyl) -3-carbo-n-propoxy-thioethanol in a concentration of 0.8 / ml the development of the tuberculo-bis-bacteria in vitro on Dubos nutrient medium Mice are observed.

A similar tuberculostatic effect is shown by, for example, 1- (3'-hydroxy-4'-carboxy-pheny1) -3-carbethoxy-thiourea ff and l- (3'-hydroxy-4'-carboxy-phenyl) -3- carbopropoxy-thiourea, the inhibitory effect of which comes into play at a concentration of 0.2-0.4 ^ f / ml.

The new compounds according to the invention of the general Formula I can be incorporated into medicinal preparations in a manner known per se, optionally together with other pharmacologically active substances Connections and / or carrier, binding, net, filling, geechnacks, etc. Means, in the form of tablets, pills, capsules, solutions, Emulsions, suspensions, suppositories etc. are transferred

The novel compounds according to the invention, as well as the Processes for producing the same are explained in more detail with reference to the following examples.

109829/1870

example 1

10 _{tons of} 7 g of 4-isoamyloxy-aniline in 35 ml of abs. Acetone dissolved »and while stirring a Lorning of 7» 85 g of carbethoxy thiocyanate in 15 ml of abs. Acetone was added dropwise in 30 minutes. The temperature calibration dee mildly warming up the mixture is maintained during the addition at 25-30 ⁰ C. The mixture is stirred for 2 hours at room temperature, filtered off with suction and then the precipitated crystalline precipitate and washed with a few ml of alcohol · There are obtained 11.4 g of l- ^(4-t -lsoamyloxy phenyl) -3-carbethoxy-thioharn8toff. This compound is after clarification with bone charcoal from 60 ml abs. Recrystallized alcohol. The product obtained melts at 122 ^° C. Further quantities of the product can be obtained by working up the mother liquors.

The well-known carbethoxyisothiocyanate used as starting material can according to the in Bull. Chern. Soc. Japan (£ 6, 1218/1963 /) described method.

The following compounds may in a similar manner from the corresponding amine of the general formula II and from carbethoxy isothiocyanate in acetone or benzene prepared werdent l-U'-Athoxy-phenylM-carbethoxy-thiourea (Γ.ρ. »$ 141-142 ⁰ Ο l- (4 ^l -n-butoxy-phenyl) -3-carbethoxy-thiourea (Pp il28 ° C) \ l- (4 ^f - / fJ-dimethyl amino / -ethoxy-phenyl) -3-carbethoxy-thiourea ( pp: 125-126 ⁰ C);
1 - (4 '^ Dimethylaminophenyl) -3-carbethoxy- thiourea (Pp >> 193 ⁰ C) j

l- (2 », 6'-dimethyl-phenyl) -3-carbäthoxy-thioharnetoff (Pp ι 205-206 ⁰ C) \

1 0 9 8 2 * 0 / Γ8 7 0

1- (2 ", δ'-dichlorophenylM-earbethoxy-thiourea (Pp t 2O5 ° C) j 1- (3" -trifluoromethyl-phenyl) -3-carbethoxy-thiourea (M.p.t 99 ° C) |

l-Cß-Bienyl-ieopropyl ^ -carbethoxy-thiourea (m.p .: 57 ⁰ C) f l- (2'-pyridyl) -3-carbothoxy-thiourea (m.p. 102 ° C) t l- (5 ', 6' benzo-1 ', 4'-dioxan-yl-2') - methyl-3-oarbäthoxy-thioharnetoff (Fpi 116 ⁰ C).

With 4-isoamyloxy-ajiilin and n-l-topoxyrcarbonyl-ieothiocyanate, the l - ^ '- isoamyloxy-phenyli-Sn-carbo-propoxy-thioharnetoff can also be produced in the above-described whiteness; Melting point ⁴ 91 0 O.

The n-propoxy-carbonyl-isothiocyanate was similar Way how the carbethoxy-iothiocyanate is made; Boiling point ι 35-39 ° C / O, 3 mm Hg.

Example 2

A suspension of 7.6 g of 4-aminosalicylic acid in 30 ml of abs. Acetone or abs. Benzene is a solution of 6.5 g of carb ~ ethoxy-ieothlocyanat in 10 ml of abs. Acetone or abs. Benzene dripped in within an hour. The reaction mixture is ^{stirred at 50 °} C. for 2 hours. When it cools down, it is excreted "

Sucked off the product and washed with 2 × 10 ml of ethanol. According to Kltt-

tion with bone coal and Umkrlstallisierung from ethanol to obtain 6 »β 3 l- (3 ^{f-hydroxy-4'-carboxy-pheny1)} -3-carboethoxy-thiourea having a melting point of 224 ⁰ C (with decomposition) ·

Similarly, 1- (4'-carboxy-phenyl) -3-n-propoxy-carbonyl-thioharnetoff (Schmelzpunktι 215 ⁰ C) of 4-aminosalicylic acid, and are prepared n-propoxy-carbonyl isothiocyanate may ·

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Claims (6)

Claims 1. Thiourea derivatives of the general formula I R-HH-Jj-NH-JOR ₁ Cl) S 0 in which R is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, or means a substituted or unsubstituted aralkyl group ^ and R ^ is a straight-chain or branched, saturated or unsaturated alkyl group with 1 to 8 carbon atoms 109829/1870 2. Process for the preparation of the new thiourea derivatives of the general formula I. H-NH-C-NH-GOR ₁ (i) ß 0 in which R is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, or a substituted or unsubstituted aralkyl group, and R _{1 is} a straight-chain or branched, saturated or unsaturated alkyl group with 1 to 8 carbon atoms, characterized in that a primary amine is the general formula II R - NH ₂ (II) in which R has the above meanings, with an isothiocyanate of the general formula III -N = C = S (HI) in which R _{1 has} the above meanings, is implemented. 3. The method according to claim 2, characterized in that 4-1boamyloxy-phenyl-aniline with Garbfithoxy-ieothiocyanat is implemented. 4. The method according to claim 2, characterized in that 4-isoamyloxy-phenyl-aniline with n-carbon -propoxy-isothiocyanate is implemented. 5. The method according to any one of claims 2 to 4, characterized marked that the reaction in an indifferent solvent is carried out. 6. The method according to any one of claims 2 to 5, characterized characterized that the reaction occurs under heating is carried out. - 7 -109829/1870 Further development of the method according to claim 1 for the production of medicinal preparations with an anti-tuberculosis effect, characterized in that a new thiourea derivative of the general formula I, in which R and R _{1 have} the meanings given in claim 1, optionally together with other pharmaceutically active compounds and / or carrier, binding, wetting, filling, flavoring, etc. agents, in the form of tablets, pills, capsules, solutions, emulsions, suspensions, suppositories, etc., are converted into pharmaceutically usable products in a manner known per se . 109829/187 0