NO762821L - - Google Patents

Abstract

Process for the preparation of new organic compounds.

Description

The present invention relates to a method for the production of new compounds of formula I

in which R^, R 2 and R^ independently of each other stand for hydrogen, halogen, nitro, cyano, hydroxy, alkyl, alkoxy or alkylthio, the alkyl groups having 1-4 carbon atoms, and their tautomeric forms.

In the compounds of formula I, halogen in the individual case means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine. Alkyl, alkoxy and alkylthio preferably contain 1-2 carbon atoms. Preferably, one or two of the substituents R^, Rg or R^ means hydrogen. R^ specifically stands for halogen. R^ means in particular hydrogen, halogen or methyl. stands for hydrogen, methyl or chlorine in particular.

The compounds of formula I may exist in their tautomeric form, which is represented by formula Ia

for the sake of simplicity, the compounds of formula I and Ia are summarized under formula I. The same applies to the starting compounds of formula II and III mentioned below.

The peculiarity of the method according to the invention for producing the compounds of formula I is that compounds of formula II

wherein R^, R^ and R^ have the above meaning, and either A

stands for hydrogen and B, Z and: X, together with the carbon atom to which they are attached, stands for the group -C=N, or A and B together mean a second bond between the nitrogen and carbon atoms, and X and Z

stand in each case independently of each other for a cleavable group, or their tautomeric form. are reacted with ethylenediamine.

The compounds of formula I which can be prepared by the method according to the invention can be transferred into their salts and vice versa.

The method can be carried out on a for the production of

analogous compounds in a known manner, e.g. the procedure according to DOS 2,322,880.

X and Z are either the same or different and mean appropriately

an R4S-, an R^NH-, an R40- or C^NHN group.^wherein R4 stands for hydrogen or an alkyl group with 1-3 carbon atoms, or they mean chlorine in the individual case. Preferably, X stands for SCH^ and Z for NH2.

An acid addition salt of the compounds of formula II is preferably used, e.g. the hydroiodide, and ethylenediamine in the form of the free base, or L"is the compound with formula II in the form of the free base and a monoacid addition salt of the ethylenediamine, e.g. the tosylate.

The procedure is suitably carried out at temperatures

between 0 and 200°C, preferably between 60 and 160°C. Suitable solvents are alcohols with 1-8 carbon atoms, such as methanol, ethanol or n-pentanol, dioxane, nitrobenzene or xylene.

The compounds of formula I can be isolated and purified in and for

known way.

It is assumed that the method according to the invention forms intermediate compounds of formula III in which R^, R^, R^°9Z have the above-mentioned meaning, or their tautomers, which form the compounds of formula I by ring closure.

A special case of the method according to the invention

is thus a method for preparing compounds of formula I by cyclization of compounds of formula III.

The method can be carried out in a manner known for ring closure reactions. E.g. the above stated preferred values for Z, solvent and temperatures can be used. The compounds of formula III are preferably formed in situ from compounds of formula II

but can also be produced from other compounds.

The starting compounds of formula II can be prepared analogously to

per se known methods, e.g. the method according to DOS 2,322,880 using 5-amino-2,1,3-benzothiadiazole derivatives.

The basic compounds of formula -.1 can be converted into their acid addition salts by reaction with suitable inorganic or organic acids. For. this is suitable as inorganic acids, e.g. hydrochloric acid and as organic acids, e.g. acetic acid eyi maleic acid, etc.: The compounds of formula I which can be prepared by the method according to the invention are distinguished by their pharmacodynamic properties. In particular, the compounds of formula I act against rigor and myotonolytic.

The compounds of formula I can also be supplied in the form of

their acid addition salts, which have the same degree of activity as the free bases.

N

The supply of the compounds of formula I respectively their salts

can take place either orally in the form of tablets, granules, capsules or dragees or parenterally in the form of injection solutions.

In the following examples, the temperatures are indicated in °C and are

uncorrected.

EXAMPLE 1 : 4-chloro-5-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole

A solution of 9.5 g of S-methyl-N-(4-chloro-2,1,3-benzothiadiazol-5-yl)-isothiuronium iodide in 70 ml of methanol is added with 1.7 ml of ethylenediamine and the mixture is heated to boiling for 1 hour . The solvent is then evaporated, 10 ml of n-pentanol is added to the residue and heated for 1 hour at 15_0°C. The cooled mixture is diluted with 100 ml of ether, the precipitate is filtered and washed with a little ether. The residue is dissolved in 70 ml of methanol, the solution is treated with activated charcoal, filtered, made alkaline with 2N aqueous sodium hydroxide solution. diluted with 100 ml of water and evaporated to half the volume. After cooling, the precipitate formed is filtered off, washed with water and boiled with 200 ml of methanol, upon cooling the compound mentioned in the title is reached with a melting point of 232-235°C.

The starting material used in this example is obtained in the following way:

A solution of 6 g of ammonium rhodanide in 200 ml of acetone is added

ice bath 7 ml benzoyl chloride and stir for 10 min. To this solution is added a solution of 6 g of 4-chloro-5-amino-2,1,3-benzothiadiazole in 200 ml of methanol and the mixture is heated to boiling for 2 hours and cooled

then, hvprved N-benzoyl-N'-(4-chloro-2,1,3-benzothiadiazol-5-yl)-thiourea (m.p. 220-222°C from methanol) precipitates. The precipitate is filtered off and quickly brought to the boil with 100 ml',

of a 2N aqueous sodium hydroxide solution. After 5 minutes of boiling, the solution is cooled, filtered and slightly acidified with glacial acetic acid. The resulting cake/precipitate is filtered, washed with water, boiled off with a little methanol and washed with ether. The thus obtained N-(4-chloro-2,1,3-benzothiadiazol-5-yl)-thiourea (melting point 210-213°C) is heated to boiling for 1 hour with 5 g of methyl iodide in 100 ml of methanol and the mixture is then evaporated to dryness, whereby crude S-methyl-N-(4-chloro-2,1,3-benzothiadiazol-5-yl)-isothiuronium iodide (m.p. 175-179°C from methanol) is obtained which is used without further purification in the preceding reaction.

EXAMPLE 2

Analogous to example 1 and using corresponding starting materials in approximately equivalent quantities, the following compounds of formula I can be arrived at: a) 5-(2-imådazolin_2-yl-amino)-2,1,3-benzothiadiazole with melting point 200-201 °C,

b) 4-bromo-5-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole

with melting point 234-236°C.

Claims (2)

1. Process for the preparation of compounds of formula I. in which R,, R„ and R in the individual case independently stand for hydrogen <3> , halogen, nitro, cyano, hydroxy, alkyl, alkoxy or alkylthio, where the alkyl groups in each case have 1-4 carbon atoms, and their tautomeric forms, characterized in that compounds of formula II in which R^ , R^ and R^ have the above meaning, and either A stands for hydrogen and B , Z and X together with the carbon atom to which they are bound stand for the group -C=N, or A and B together mean a second bond between the nitrogen and carbon atom, and X and Z in the individual case independently stand for a leaving group, or their tautomeric form is reacted with ethylenediamine. 2.. Process for preparing compounds with the formula I mentioned in claim 1, characterized in that compounds with formula III in which R^ , R^, R^ and Z have the meaning specified in claim 1, is subject to a circular conclusion.