AT278006B - Process for the preparation of new benzheterocyclic compounds and their salts - Google Patents

Description

  

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  Process for the preparation of new benzheterocyclic compounds and their salts
The invention relates to the preparation of new benzheterocyclic compounds having the ring structure of the formula
 EMI1.1
 
 EMI1.2
 

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   The aromatic part of the molecule can be unsubstituted or substituted by one or more identical or different substituents which can occupy any of the positions suitable for substitution. Substituents are e.g. B. lower alkyl such as the groups mentioned above, lower alkenyl groups such as the groups mentioned above, lower alkoxy groups such as the groups mentioned above, lower alkylenedioxy, such as methylenedioxy, aryloxy, such as phenyloxy groups, aryl-lower alkoxy, such as phenyl-lower alkoxy, z. B. benzyloxy groups, Niederalky1mercapto-, z. B. Methylmer- captogruppen, halogen atoms, such as the halogen atoms mentioned above, trifluoromethyl. Nitro, free or substituted amino groups, such as amino, lower alkylamino, e.g. B.

   Methylamine, ethylamino
 EMI2.1
    Isopropylamino, amoyamino or thiocarbamoyamino, or sulfonylamino, e.g. B. Phenylsu1fonylaminogruppen, úeie or functionally modified carboxyl groups, such as the radicals mentioned above, free or functionally modified sulfo groups, such as. B. Suifamoyl groups. or aryl or aryl lower alkyl. z. B. phenyl, benzyl or phenylethyl groups, or divalent aliphatic radicals, such as divalent aliphatic hydrocarbon radicals, which can preferably substitute adjacent positions of the aromatic part of the molecule, such as lower alkylene radicals, preferably with 4 carbon atoms, e.g. B. the 1,4-butylene radical, or lower alkenylene radicals, preferably with 4 carbon atoms, z.

   B. the l- or 2-buten-l, 4-ylene or especially the 1,3-butadien-1,4-ylene radical, such radicals, in particular aryl, such as phenyl groups, or divalent radicals, primarily a 1. 3-butadiene-1, 4-y1enrest, can be substituted in the manner mentioned above.



   Oxides of compounds in which X represents a sulfur atom are sulfoxides or primarily sulfones.



   The new compounds which are obtained according to the invention have valuable pharmacological properties. In addition to their effects against fungi, especially against Trichophyton species, they show antiviral effects such. B. against Sindbis virus, which can be detected by experiments on test animals such as hamsters, and primarily antifluenza effects, which can be particularly prophylactic in nature, e.g. B. against the influenza PR virus, which can be detected by means of experiments on test animals, such as mice, with subcutaneous or oral administration. They can therefore be used as pharmacologically, in particular antivirally, active agents, and they can be used before or after a corresponding infection.

   Furthermore, they can also be used as intermediates in the production of other valuable, in particular pharmacologically active compounds, such as. B. the corresponding compounds with the ring structure of the formula
 EMI2.2
 serve.
 EMI2.3
 fe are compounds of the formula
 EMI2.4
 wherein R is a reactive functionally modified carboxyl group such as a carboxylic lower alkoxy, e.g.

   Represents carbomethoxy or carbethoxy group or a cyano group, Rl is an aliphatic group
 EMI2.5
 Cyano group, or primarily a carbon-lower alkoxy group or a lower alkanoyl, especially an acetyl group, X is an oxygen or primarily a sulfur atom and Ar

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 represents an at most bicyclic o-arylene, in particular 1,2-phenylene and 1,2-naphthylene radical, optionally containing one or more of the above-mentioned substituents, or their tautomers and salts of such compounds.



   Compounds of the formulas are particularly valuable with regard to their antiviral and anti-influenza effects and as starting materials
 EMI3.1
 and
 EMI3.2
 wherein R 'represents a carbon lower alkoxy group or a cyano group, R * represents a lower alkyl radical or
 EMI3.3
    a lower alkanoyl group, particularly a lower alkyl, e.g. B. methyl, ethyl or n-propyl, a lower alkoxy, z. B. methoxy or ethoxy group, a halogen, z. B. fluorine, chlorine or bromine atom, a trifluoromethyl group, a nitro group, or a free or substituted amino, such as N-Mononiederalky1amino- or N, N-di-lower alkylamino, N-Acy1amino, z. B. N-lower alkanoylamino, N-carbamoylamino or N-sulfonylamino, e.g. B.

   N-phenylsulfonylamino group, such as one of the above-mentioned radicals, or their tautomers and salts of such compounds.



   The compounds of the formulas show particularly pronounced antiviral and anti-influenza effects
 EMI3.4
 and

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 EMI4.1
 
 EMI4.2
 

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   Depending on the reaction conditions, the new compounds are obtained in free form or in the form of their salts, the preparation of which is also encompassed by the invention. So you get, depending on the substituents z. B. basic, neutral, acidic or mixed salts, it being possible for hemi-, mono-, sesqui- or polyhydrates to be formed. The salts of the new compounds can be converted into the free compounds as well as into other salts in a manner known per se, acid addition salts z. B. by treatment with basic agents such as alkaline reagents or ion exchangers, salts with bases by treatment with acidic agents such as acids, a compound with free carboxyl group can salts, especially non-toxic salts with bases, e.g. B. alkali metal, alkaline earth metal or ammonium salts, e.g.

   B. by treating with metal hydroxides, especially alkali metal or alkaline earth metal, such as sodium, potassium or calcium hydroxides or with Al
 EMI5.1
 
Hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or with organic acids such as aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, e.g.

   B. ant, vinegar, propionic, amber, glycol, milk, apple, wine, lemon, maleic, hydroxymaleic, pyruvic, phenyl acetic, benzoin, p-aminobenzoic, anthranil -, p-Hydroxybenzoic, salicylic, p-aminosalicylic, Embon, methanesulfon, ethanesulfon, hydroxyethanesulfon, ethylensulfon, halobenzenesulfon, toluenesulfon, naphthalenesulfon, N-cyclo-hexylsulfamine, or Methionine, tryptophan, lysine or arginine and ascorbic acid.



   The above-mentioned and other salts of the new compounds, such as. B. their picrates can optionally be used to purify the free compounds obtained, converting the free compound into a salt thereof, isolating the latter and reconstituting the free compound therefrom, or to characterize them. As a result of the close relationships between the new compounds in free form and in the form of their salts, in the preceding and in the following the free compounds or salts are to be understood, meaningfully and appropriately, also the corresponding salts or free compounds.



   The new compounds can be in the form of drugs, e.g. B. in the form of pharmaceutical preparations, which they contain in free form or in the form of their salts together with organic or inorganic, solid or liquid pharmaceutically acceptable carriers, and which are suitable for enteral, e.g. B. suitable for oral or parenteral administration. Substances which are inert to the new compounds are used as carriers, such as. B.
 EMI5.2
    Gelatine, sugar such as lactose or glucose, starches such as wheat or corn starch, stearyl alcohols, salts to regulate the osmotic pressure or buffers and, if appropriate, therapeutically valuable compounds; they are produced in a manner known per se.



   The new compounds can also be used in veterinary medicine, e.g. B. in one of the above forms or as an additive to feed, e.g. B. be used together with the usual diluents and feed.



   The invention is described in more detail in the following example. The temperatures are given in degrees Celsius.



   Example: A mixture of 6.44 g of N-Pheny1-N'- (2, 2-dicarbethoxyvinyl) thiourea in 50 ml of dry chloroform and 4 g of bromine in 100 ml of dry chloroform is refluxed for 6 hours. The solvent is removed under reduced pressure and the residue is taken up in water. The aqueous mixture is with 2-n. aqueous sodium hydroxide solution made basic, the solid material is filtered off, washed with water and crystallized from ethanol; the N- (2-benzthiazolyl) aminomethylene malonic acid diyl ester thus obtained melts from 106 to 1070.



   The starting material can be made as follows:
A mixture of 13.5 g of phenyl isothiocyanate and 18.1 g of aminomethylene malonic acid diethyl ester is heated for 12 h at 160 to 1700, then cooled and triturated with benzene. The solid material is filtered off and crystallized from benzene, giving the N-phenyl-N '- (2,2-dicarbethoxyvinyl) thiourea, which is processed further without further purification.

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 EMI6.1
 

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Claims (1)

<Desc / Clms Page number 7> the formula EMI7.1 EMI7.2 EMI7.3 used as starting materials, where R is a hydrogen atom, an aliphatic or cycloaliphatic hydrocarbon radical or an aryl group, R2 is a cyano, carbon lower alkoxy or lower alkanoyl group, X is an oxygen or a sulfur atom, and Ar is optionally one or more Lower alkyl, lower alkenyl, lower alkoxy, lower alkylenedioxy, aryloxy, aryl-lower alkoxy, lower alkyl mercapto, trifluoromethyl, nitro, free or substituted amino, free or functionally modified carboxy, aryl or aryl lower alkyl groups or substituted halogen atoms, at most bicyclic or the like -Arylene residue. 5. The method according to any one of claims 1 to 3, characterized in that one <Desc / Clms Page number 8> connections of the formulas EMI8.1 and EMI8.2 EMI8.3 EMI8.4 <Desc / Clms Page number 9> EMI9.1 EMI9.2 EMI9.3 EMI9.4