DE1443397A1 - Process for the preparation of chemotherapeutically active thiosemicarbazones from aromatic oxo compounds - Google Patents

Description

Aktiebolaget KABI, Stockholm / Sweden

Process for the preparation of chemotherapeutically active thiosemicarbazones from aromatic oxo compounds.

The invention relates to methods of preparation chemotherapeutically active thiosemicarbazones from trialkyl-substituted aromatic oxo compounds which can be substituted in the thiosemicarbazone part.

The substances produced according to the invention are valuable therapeutic agents and act against viruses. A suitable one Test virus is viral influenza in mice. It works the substances also against several non-riah-related viruses and bacterial infections, however, viral pneumonia in mice is particularly suitable for studies of the type contemplated here, including due to the good reducibility.

In the search for chemotherapeutically effective compounds, one has a large number of thioseiaicarbazones manufactured. However, these known substances are generally not or only occasionally effective against viruses, none of these known thiosemicarbazones achieved

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but a satisfactory effect *

Erio semi carbazone thlos.emicarbasone of aromatic oxo-compounds as Benzaldehy & »in which the aromatic rope is trisubstittiiert symmetrically with the same or rerschiedenen alkyl, wad of Shiosemicarbazonteil _s preferably may be substituted by alkyl radicals combine a high chemotherapeutic activity with a low Toxisität and are characterized by favorable Absorption ratios in the case of oral administration from

The method of the invention consists in that one aromatic oxo compound symmetrically trisubstituted with alkyl radicals with a reactive thio-nitrogen compound, such as thodanide, thiosemicarbazide, aldehyde thiosemxcarbazon.

Instead of the symmetrically trisubstituted aromatic oxo compounds the corresponding functional derivatives, such as thioaldehydes, thaketones, acetals, halbacetals, Diacetals, mercaptals and bisulfite compounds, be used.

Instead of the thio-nitrogen derivative, corresponding nitrogen-containing compounds such as semicarbazide ver. be applied, then with a thio derivative is implemented. . BAD ORIGINAL

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H43397

Show particularly good chemotherapy efficacy such symmetrically trialkyl-substituted compounds, in which two alkyl radicals are the same, and on both sides of the different third alkyl substituent, the one ▼ may contain a branched chain.

By alkyl substitution in the thiosemicarbazone part Increased fat solubility of the compounds.

2,6-Dimethyl-4-iso-propylbenzaldehyde thiosemicarbazone has proven to be particularly suitable and its allyl- or isobutyl-substituted in the thiosemicarbazone part Derivatives, as well as 2,6-dimethyl-4- (sec./tert.) - butylbenzaldehyde thiosemicarbazone and its in the Thiosemicarba-. zonteil allyl or isobutyl substituted derivatives.

The method of administration of the new substances produced according to the invention is arbitrary.

The new chemotherapeutically active compounds are preferred for practical use in conjunction with suitable carrier substances are used. In the production of such preparations, the poor solubility must be of the compounds in water as well as the favorable therapeutic index, which allows many concentrations, is taken into account will. It is possible to choose the doses between 10 and 1000 mg. The doe scheme can be chosen be that a lower dose several times a day or

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a higher dose is given only once or twice a day.

example 1

A warm solution of 3.6 g of thiosemicarbazide in 50 ml of water is mixed with 7 g of 2,6-dimethyl-4-iso-propylbenzaldehyde in 70 ml of ethanol and the reaction mixture is boiled for 2 hours on the reflux condenser recrystallized from acetic acid, 2,6-dimethyl-4-iso-propylbenzaldehyde thiosemicarbazone being obtained. M.p. s 216c.

Example 2

A mixture of 12 g hydrazine sulfate and 6.5 g potassium carbonate in 75 nil ethanol is heated and with 9 g of potassium thiocyanate and 12 g of 2,6-dimethyl-4-sec-butylbenzalöehyd are added. The reaction mixture is boiled for 10 hours on a reflux condenser, the precipitate is deposited and washed with ethanol and slurried in water, laugh at the recrystallization acetic acid becomes 2,6-dimethyl-4-sec-butylbenzaldehyde thiosemicarbazone obtain. Pp, s 200 0.

Example ^

15 g of acetone thiosemicarbazone are dissolved in 150 ml of warm 50% acetic acid and mixed with 26.5 g of 2 _? 6-dimethyl-4-tert.-butybenzaldehyde is added in 40 ml of water, whereupon the semis is boiled for 1 hour on a reflux condenser and then.

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is cooled. After neutralization with ammonia the precipitate is collected, recrystallized from moxan / water, where 2,6-dimethyl-4-tert. ~ biityl benzaldehyde thiosemicarbazone is obtained. Fp .: ^ 240 G.

Example 4

A mixture of 10 g of 2,6-dimethyl-4-iso-propyl-benzaldehyde in 70 ml of ethanol and 2 ml of acetic acid is mixed with 8 g of isobutylthiosemicarbazide in 60 ml of water, refluxed for 1 hour and then cooled. The crystals formed are separated off and recrystallized from alcohol-containing water, 2,6-dimethyl-4-isopropylbenzaldehyde-isobutylthiosemicarbazone being isolated. Mp 117 ⁰ C.

Example 5

A mixture of 21 g of 2,6-dimethyl-4-isopropyl-benzaldehyde in 200 ml of ethanol and 6 ml of acetic acid is mixed with 15.6 g of allyl thiosemicarbazide in 150 ml of water and the reaction mixture is refluxed for 3 hours and then cooled. The crystals formed are recrystallized from isopropanol, 2,6-dimethyl-4-isopropyl-benzaldehyde-allyl-thiosemicarbazone being obtained. Fp. °

The following compounds are obtained according to Examples 1-5:
1,3,5-tri-isopropylbenzaldehyde thiosemicarbazone, Pp.j.

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1,3,5-trimethylbenzaldehyde thiosemiearbazon, m.p. 237 ° C.

Example β

A tablet mass is made from 10 (3 g of a compound prepared according to the invention, 145 g of lactose granules (75 ropes of lactose, 25 parts of starch) and 5 g of magnesium stearate prepared. After sieving, tablets are made from this mass, which are 50 mg effective per tablet Contain substance.

Example 7

A powdery mixture is made from equal parts by weight of a chemotherapeutically active one produced according to the invention Compound and lactose prepares. After sieving, the mixture is filled into standard clear gelatin capsules so that the Amount of active substance is 200 mg per capsule. The sealed capsules are treated with talc or starch.

Example 8

A mixture containing 10 mg or ml of one produced according to the invention Containing chemotherapeutically active compound is prepared by adding 10 g of the active substance be suspended in 1000 ml of a solution consisting of 1 g of polyoxyethylene sorbitan monooleate, 7 g of sodium carboxymethyl-t cellulose, 750 g sorbital solution according to N.P, X., 8 g sodium cyclamate and consists of 325 g of water. The preparation contains raspberry or orange as a flavoring agent.

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Claims (1)

Claims 1. Process for the preparation of chemotherapeutically effective thiosemicarbazones from aromatic oxo compounds, thereby characterized in that an aromatic oxo compound which is symmetrically trisubstituted by alkyl radicals is known per se way ä) with a rhodanide or b) with a thiosemicarbazide or c) with an aldehyde thiosemicarbazone to oxo compounds with symmetrical trisubstitution Alkyl radicals in the aromatic part, it being possible for the alkyl radicals to be identical or different from one another, and optionally with substitution, in particular by alkyl radicals *, in the thiosemiearbazone part, preferably to 2,6-dimethyl-4-isopropylbenzaldehyde thiosemicarbazone and its in the thiosemicarbazone part allyl- / iso-butyl-substituted derivatives and to 2,6-dimethyl-4- (sec./tert.) - butylbenzaldehyde thiosemicarba- zon and its allyl / iso-butyl-substituted in the thiosemicarbazone part Implements derivatives. 2. The method according to claim 1, characterized in that that instead of the symmetrically trisubstituted aromatic oxo compounds, their functional derivatives, such as thioaldehydes, Thioketones, acetals, hemiacetals, diacetals, mercaptals, or J bisulfite bonds are used. the, change, ^. _v . 4. 9.! 937] 3 · The method according to claim 1, characterized in that instead of the thio-nitrogen derivative compounds such as
Semicarbazide with subsequent implementation with a
Thio derivative can be used. 4 · The method according to claim 1, 2 or 3 »characterized in that that as the starting material thiosemicarbazone clay benzaldehyde, in which the aromatic part is symmetrical is trisubstituted, can be used. 5. Method according to claim 1, 2, 3 or 4, characterized
characterized in that the starting material used symmetrically trialkyl-substituted oxoaromatic thiosemicarbazones, in particular of benzaldehyde, in which two alkyl radicals are the same, and on both sides of the different third alkyl substituent - which may contain a branched chain - are, preferably to increase the Pett solubility with one responsive
alkyl substituted thio nitrogen compound is reacted. 809803/1086