CH547808A - PROCESS FOR PREPARING NEW CYCLOALKANE (C) PYRIDAZINE. - Google Patents

Description

  

  
 



   The invention relates to a process for the preparation of new compounds of the formula I in which n is an integer from 1 to 4, R is hydrogen or, if n is 1 or 2, is hydrogen, methyl or ethyl, R2 is hydrogen or methyl and R3 and R4 each represent a lower alkyl or together with the carbon atom to which they are bonded form a cycloalkylidene radical having 5 to 8 carbon atoms, and their acid addition salts.



   According to the invention, the new compounds of the formula I and their acid addition salts are obtained by reacting compounds of the formula Ia in which Rl, R2 and n have the above meaning with compounds of the formula V in which R3 and R4 have the above meaning and the compounds obtained of the formula I, if desired, converted into their acid addition salts.



   For example, the procedure is that a compound of formula Ia with a compound of formula V, if appropriate with the addition of an inert under the reaction conditions, preferably polar organic solvent such as a lower alcohol, eg. B. methanol, ethanol or isopropanol or an open-chain or cyclic ether, e.g. B.



     Diethylene glycol dimethyl ether, tetrahydrofuran or dioxane, if necessary, allow to react with heating by allowing the reaction mixture to react for 1/2 to 20 hours at temperatures of approx.



     Keeps OzC up to boiling point and then evaporates to dryness or lets the crude product crystallize out directly or after extensive concentration of the solution. The compounds of the formula I obtained can be isolated and purified by methods known per se. The free bases can be converted into their acid addition salts in the usual way and vice versa.



   If R3 and R4 are lower alkyl groups, these preferably contain 1 to 4 carbon atoms and are in particular methyl groups.



   The starting compounds can be made, for example, as follows:
Compounds of the formula Ia can be obtained by using compounds of the formula IIa in which R1 and n are as defined above and X is chlorine, bromine, the mercapto or an -SRs group, in which Rs is benzyl or lower alkyl Compounds of the formula III in which R2 is as defined above.



   It is preferred to use an excess of the compound of the formula III, for example 5 to 10 mol of a compound of the formula III based on 1 mol of a compound of the formula IIa, or one works in the presence of another basic agent which binds any acid formed during the reaction able, e.g. B. a tertiary amine or an alkali metal or alkaline earth metal hydroxide or carbonate. The reaction can, for example, in the presence of an inert under the reaction conditions, preferably polar organic solvent, for. B.



  a lower alcohol such as methanol, ethanol or isopropanol or an open-chain or cyclic ether such as dioxane, diethylene glycol dimethyl ether or tetrahydrofuran. Optionally, an excess of the compound of the formula III can also serve as a solvent.

  If compounds of the formula lib in which X 'stands for chlorine, bromine or the mercapto group and R, and n have the above meaning, are used, the reaction can be carried out, for example, by heating the compounds of formula IIb in hydrazine hydrate or methylhydrazine, optionally with the addition of one of the The above-mentioned solvents and / or basic condensing agents are carried out at normal pressure at temperatures between about 20 and about 150ob, preferably at temperatures between 80 and 120 ° C. or at the boiling point of the reaction mixture, and the reaction time can be between 1 and 20 hours.

  If a compound of the formula IIc, in which R1, Rs and n are as defined above, is used, the reaction with preferably an excess of hydrazine hydrate or methylhydrazine, optionally with the addition of one of the abovementioned solvents and / or basic condensing agents, is carried out in the autoclave at temperatures between 80 and 1500C carried out.



   Some of the compounds of the formula II are known.



   Compounds of the formula IId in which Rl and n have the above meanings and X'l is chlorine or bromine can, for. B.



  be obtained by compounds of the formula IV, in which R1 and n have the above meaning, with a suitable chlorinating or brominating agent, for. B. with phosphorus oxychloride, phosphorus tri- or pentachloride or phosphorus oxybromide, heated, preferably to temperatures up to approx.



     100'C or the boiling point of the reaction mixture.



   Compounds of the formula IIe, in which Rl and n have the above meanings, can, for. B. be obtained by reacting compounds of the formula IId with thiourea or, if appropriate, sodium sulfide. The reaction is preferably carried out in a polar organic solvent, e.g. B.



  a lower alcohol such as ethanol or dimethylformamide, at temperatures between approx. 30 and approx. 100oC and can take between approx. and 4 hours.



   Compounds of the formula IIc can be obtained, for example, by mixing compounds of the formula IIe with compounds of the formula VI, in which Rs and X11 have the above meanings, in the presence of an acid-binding agent, for example an alkaline earth metal or alkali metal carbonate or hydroxide. such as B. Potassium Carbonate. implements. The reaction is preferably carried out in a polar organic solvent. which has good solvency for the compounds of formula IIe, for example in dimethylformamide.



   Compounds of formula IV can, for. B. be obtained by compounds of the formula VII, wherein Rl and n have the above meaning, in a solvent inert under the reaction conditions, for. B. a lower alcohol such as ethanol in the presence of at least equivalent amounts of glacial acetic acid with hydrazine hydrate or a salt of hydrazine, optionally under an inert gas atmosphere by heating to temperatures between 70 to 110sCe, preferably to the boiling point of the reaction mixture, cyclized and the compounds of formula VIII formed, wherein Rl and n have the above meaning. oxidized, preferably with bromine using a halogenated hydrocarbon such as chloroform or ethylene chloride as a solvent.



   Compounds of the formula VII can be obtained by reacting compounds of the formula IX, wherein Rl and n have the above meaning, with a secondary amine, preferably a cyclic amine such as. B. pyrrolidine, morpholine or piperidine, preferably in an inert organic solvent under the reaction conditions, e.g. B.

 

  an aromatic hydrocarbon such as benzene, to an enamine of the formula X, wherein R1 and n have the above meaning and Y stands for a secondary amino group, converts this with alkyl bromoacetate in the presence of an organic solvent which is inert under the reaction conditions, e.g. B. an aromatic hydrocarbon such as benzene, a halogenated hydrocarbon such as chloroform or an ether or dimethylformamide is added at room temperature, the reaction mixture is heated for several hours, preferably to boiling temperature, and with the resulting reaction product of the formula XI, in which R1, n and Y have the above meaning, the enamine group cleaves again by heating with water.



   The compounds of the formula I and their pharmacologically acceptable acid addition salts have not yet been described in the literature. They are characterized by interesting pharmacodynamic properties and can therefore be used as remedies.



   As shown in experiments on the hypertensive Grollmann rat, the compounds have antihypertensive effects.



   The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. In general, however, satisfactory results are obtained in test animals at a dose of 0.1 to 10 mg / kg body weight; If necessary, this dose can be administered in 2 to 3 portions or as a sustained release form. For larger mammals, the daily dose is around 5 to 500 mg.



  For oral administration, the partial doses contain about 2 to 250 mg of the compound of the formula I in addition to solid or liquid carrier substances.



   Due to their antihypertensive effect, the substances can be used in high pressure therapy.



   The compounds of the formula I or



  their physiologically tolerable acid addition salts are administered alone or in a suitable pharmaceutical form with pharmacologically inert adjuvants.



   If the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to those described here or analogously to processes known per se.



   In the following examples, which illustrate the invention in more detail but are not intended to restrict its scope in any way, all temperatures are given in degrees Celsius.



   Example 1 5,6,7,8,9,10-hexahydro-3-isopropylidene hydrazino-cycloocta [c] pyridazine
A solution of 0.5 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta [c] pyridazine in 15 ml of absolute ether is heated on a water bath for 1 hour. After cooling, the precipitated crystals are filtered off and dried.



  The analytically pure compound mentioned in the title of melting point 165-1670 is obtained.



   The starting material can be obtained as follows:
A mixture of 11.7 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta [c] pyridazine and 60 ml of hydrazine hydrate in 50 ml of absolute alcohol is refluxed at a bath temperature of 110 ° for 17 hours with stirring heated. The orange solution is completely concentrated, the remaining crystalline residue is filtered off and washed with water. The still moist crude product is recrystallized from 100 ml of absolute alcohol and gives the analytically pure 3 hydrazino-5,6,7,8,9,10-hexahydrocycloocta [c] pyridazine of melting point 145-1480 (decomposition).

 

   Example 2 3-Cyclohexylidenehydrazino-5,6,7,8,9,10-hexahydro-cycloocta [c] pyridazine
A solution of 10.0 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta [c] pyridazine in 100 ml of cyclohexanone is refluxed at a bath temperature of 180 for 1½ hours. The batch is concentrated in vacuo to a crystalline residue and this is recrystallized once from isopropanol. This gives the analytically pure compound named in the title and having a melting point of 160 to 162 (decomposition)
EMI2.1
  
EMI3.1
  
EMI4.1
 

 

Claims (1)

PATENT CLAIMS I. A process for the preparation of new cycloalkane [c] pyridazines of the formula I in which n is an integer from 1 to 4, Rl is hydrogen or, if n is 1 or 2, is hydrogen, methyl or ethyl, R2 is hydrogen or methyl and R3 and R4 each stand for a lower alkyl or together with the carbon atom to which they are bonded form a cycloalkylidene radical with 5 to 8 carbon atoms, and their acid addition salts, characterized in that compounds of the formula Ia, in which Rl, R2 and n have the above meaning with compounds of the formula V in which R3 and R4 have the above meaning, and the compounds of the formula I obtained are converted, if desired, into their acid addition salts. II. Cycloalkane [c] pyridazines of the formula I and their acid addition salts prepared by the process according to claim I.