DE1900245C3 - 5,6-Dihydro-3-hydrazinobenzo square bracket on square bracket for cinnolin and 3-hydrazinobenzocyclohepta square bracket on 5,6-c square bracket for pyridazine, process for their preparation and pharmaceuticals - Google Patents

Description

(H)

in which η has the meaning given in claim 1, is reacted with hydrazine hydrate in a manner known per se at a temperature between room temperature and about 130 ° C.

3. Medicament consisting of at least one compound according to claim 1 and one usual pharmaceutically acceptable carriers and / or auxiliaries.

40

The invention relates to 5,6-dihydro-3-hydrazinobenzo [h] cinnoline and 3-hydrazinobenzocyclohepta- [5, (i-c] pyridazine, a process for their preparation and medicines.

Hypertension is a fairly common and serious disease, especially among the elderly. High blood pressure, a consequence of hypertension, is a “widespread, serious disease. Hype Intension is often the cause of seizures that lead to paralysis, especially in the elderly, or from fatal strokes.

In the literature there are references to certain Hydrazinopyridazines with similar activity, so on hydralazine. The hydralazine that works as well Compound is known and used in hypertension in white learning scope, but leaves with regard to its hypotensive ability to be desired. As in detailed comparison entries has been found, the compounds of the present invention are relative to hydralazine The peak and duration of the hypotensive effect are also superior to those according to the invention Compounds have a lower toxicity than their counterparts : hssubstanz.

The invention is therefore based on the object of providing compounds and a process for their preparation and to create medicines that are useful in treating mild to severe hypertension in people and animals are useful and not the disadvantages of the prior art compounds exhibit.

This object is achieved according to the invention by the teaching according to claims 1 to 3.

In the process for preparing the compounds according to the invention, it is advantageous to use an excess to use on hydrazine hydrate.

As with most chemical reactions, temperatures can be higher or lower than this specifically described are applied. At significantly higher temperatures than those described however, the product yields can be returned due to a greater degree of side reactions, during temperatures which are considerably below the stated temperatures Due to reduced reaction rates, low yields or excessively long reaction times to lead. The most favorable temperature for the process according to the invention is about 130 ~ C.

Non-toxic salts that are pharmaceutically acceptable include e.g. B. the hydrochloride, Hydrobromides, hydroiodides, (low) -alkyl sulfates, (low) -alkyl and aryl sulfonates, phosphates, sulfates, Maleates, fumarates, succinates, tartrates, citrates.

The compounds of the invention are in any of the known pharmaceutical forms introduced for oral, parenteral or rectal administration. The compounds are in solid compositions for oral administration in unit dosage form as tablets, capsules, pills, granules or powder prepared. Solutions, emulsions or suspensions are also used for oral administration of connections established. For parenteral use, sterile suspensions or solutions are used manufactured. If desired, the compounds are presented in suppositories for rectal administration brought in.

The tablets or pills can be layered or otherwise compounded to form a to give a delayed release of the active compound. For example, the tablet or piile an inner part constituting a unit dose and an outer part constituting another unit dose represents, wherein the outer part is in the form of an envelope surrounding the inner part. The two parts can be separated by an enteric layer which serves to facilitate the release of the im to delay the active compound contained in the inner part by resisting destruction in the stomach, whereby it reaches the intestinal tract intact, where the enteric layer is destroyed and the active compound in the inner part is released. Such an enteric layer can be of a number consist of known substances, for example polymeric derivatives or mixtures thereof, Cellulose acetate, cetyl alcohol, shellac or cellulose acetate phthalate.

Examples of oral liquid dosage forms include aqueous solutions, aqueous alcoholic Solutions and aqueous or oily suspensions and emulsions, in which the product is pharmaceutical compatible carrier or vehicle is dissolved or dispersed. Flavors can be added to increase the palatability of the dosage form. Examples of vehicles are

Cottonseed oil, sesame oil, and peanut oil, and too acceptable dispersants for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, dextran and methyl cellulose.

Suppositories containing the compounds of the invention can readily be put into unit dosage form be prepared by adding the active ingredient to a commonly used suppository base, such as theobromo oil, gelatine treated with glycerine or a polyethylene glycol, mixed and then brought into a shape suitable for introduction into the rectum.

The following examples illustrate the invention. , ₅ Example 1

Preparation of 5,6-dihydro-3-hydrazinobenzo [h] cinnoline hydrochloride [1960]) and 0.6 g (0.012 mol) of hydrazine hydrate in 10 ml of 95% ethanol is heated to reflux for 2.5 hours. After cooling, the resulting precipitate is filtered off and washed with ice-cold 95% ethanol. 1.87 g (93.5%) of raw material are obtained. Recrystallization from acetonitrile lieferi the analytical sample having a melting point = 199-200 ⁰ C.

Analysis C ₁₂ H ₁₂ N ₂ O:

Calculated ... C 71.98, H 6.04, N 13.99%; found .... C 72.27, H 6.15, N 14.01%.

B. 2,3,5,6-Tetrahydro-3-oxobenzo [h] cinnoline H

= O

NH - NH ₂ · HCl

A solution of 43.3 g (0,2MoI) of 5,6-dihydro-3-chlorobenzo [h] cinnolin in 500 ml of hydrazine hydrate is slowly heated with stirring to 13O ⁰ C 2,5Siunden long. After cooling slightly, crushed ice and then 300 ml of ice water are added. Thorough cooling and subsequent filtration and washing with cold water yields a yellowish solid material which is added to 400 ml of 15% strength aqueous hydrochloric acid and warmed very gently until it dissolves. If the solution is basic, more acid (concentrated) is added. The solution is then allowed to cool to room temperature, followed by thorough cooling in an ice bath. The crystallized product is collected and washed with 200 ml of ice water and once with 100 ml of isopropanol. After drying, the crude product is recrystallized from a solution of 410 ml of isopropanol, 120 ml of water and 10 ml of 5% strength aqueous hydrochloric acid. In this way, 42.9 g (86.5%) of product with a melting point = 196 ° C. (decomp.) Are obtained.

Analysis of C ₁₂ H ₁₂ N ₄ HCl:

Calculated ... C 57.95, H 5.27, N 22.53, Cl 14.26%; found .... C 57.68, H 5.30, N 22.70, Cl 14.18%.

20 A mixture of 26 g (0.13 mol) of 2,3,4,4 a, 5,6-hexahydro-3-oxobenzo [h] cinnolin in 195 ml of glacial acetic acid is heated untei stirring to 60 ⁰ C, until dissolution occurs . While heating continues, 20.8 g (0.13 mol) of bromine is carefully added with vigorous stirring. It is ^{heated to 70 °} C. for 2 hours. A precipitate is formed about 25 minutes after the addition of bromine, accompanied by a violent and copious evolution of hydrogen bromide gas. After cooling, the reaction mixture is poured into 400 ml of ice water. The solid is filtered off, washed thoroughly with cold water and once with cold ethanol and finally dried. In this way, 25.6 g (99.6%) of crude product are obtained. Recrystallization from ethanol provides the analysis sample with a temperature of 257 to 261 ° C.

Analysis C ₁₂ H ₁₀ N ₂ O:

Calculated ... C 72.71, H 5.09, N 14.13%; found .... C 72.87, H 5.04, N 13.93%.

C. 5,6-Dihydro-3-chlorobenzo [h] cinnoline

Preparation of the starting material 5,6-dihydro-3-chlorobenzo [h] cinnoline

A. 2,3,4,4 a, 5,6-hexahydro-3-oxobenzo [h] cinnoline H.

A solution of 2.04 g (0.01 mol) of 1-keto-tetrahydronaphthalene-2-acetic acid (W. H.Puterbaugh and R.L. Readshaw, J. Amer. Chem. Soc, 82, 3635 A suspension of 24.2 g (0.12 mol) 2,3,5,6-tetrahydro-3-oxobenzo [h] cinnoline in 200 ml phosphorus oxychloride is heated to 100 ° C for 1 hour. Dissolution occurs when heated. excess Phosphorus oxychloride is evaporated off under reduced pressure and ice is added to the residue. After basification with 5N sodium hydroxide and thorough extraction with chloroform, the Extracts washed first with water, dilute aqueous sodium hydroxide and brine, then dried over sodium sulfate, filtered and finally evaporated to dryness. The residue will dissolved in chloroform and stirred with activated charcoal for 1 hour. After filtering through filter aid and Evaporation to almost dryness will be colder

Petroleum ether, consisting essentially of η-hexane is (bp. 60 ° -80 ° C) was added and the resulting yellow precipitate is filtered off and washed with more η-hexane (bp. 60 to 80 ⁰ C). After drying, 21.5 g (81%> product with a mp = 151 to 154 ° C.) are obtained.

Analysis C ₁₂ H ₉ N ₂ Ci:

Calculated ... C 66.52, H 4.18, N 12.93, Cl 16.37%; found .... C 66.34, H 4.29, N 12.89, Cl 16.34%.

Example 2

Production of 3-hydrazinobenzocycloheptaf_5,6-c] pyridazine hydrochloride

NH - NH ₂ ■ HCl

A solution of 21.8 g (0.10MoI) benzosuber-1-one-2-acetic acid (W. J. Horton, H.W. Johnson and J. L. Zollinger, J. Amer. Chem. Soc, 76, 4587 [1954]) and 6.0 g (0.12 mol) of hydrazine hydrate in 100 ml absolute alcohol is refluxed for 2.0 hours. After cooling, filtering and washing the material is dried with cold ethanol. 20.1 g (94%) of product are obtained. Recrystallization from ethanol provides the analysis sample with a F. = 186.5 to 187 ° C.

Analysis C ₁₃ H ₁₄ N ₂ O:

Calculated ... C 72.87, H 6.59, N 13.08%;
found .... C 72.72, H 6.48, N 13.20%.

B. 2,3-Dihydro-3-oxobenzocyclohepta [5,6-c] pyridazine

A mixture of 2.95 g (0.012 mol) 3-chlorobenzocyclohepta [5,6-c] pyridazine in 50 ml of hydrazine hydrate is slowly heated to 130 ° C with stirring, and it is kept at this temperature for 3 hours. After cooling, water is added, and the solid which separates out is filtered off and washed with cold water. After drying 3.25 g of free hydrazine base are obtained, consisting of ethyl acetate / n-hexane (b.p. 60 to 80 ° C) is recrystallized. The free hydrazine base is dissolved in ether / ethanol solution, which is then added dropwise a saturated solution of hydrochloric acid in ether is added with stirring. Which The solid which separates out is collected, washed with ether and dried. Be that way 2.16 g (68.5%) of product were obtained. Recrystallization from isopropanol provides the analysis sample with a F. = 242 to 244 ° C.

Analysis C ₁₃ H ₁₄ N ₄ HCl:

Calculated ... C 59.43, H 5.75, N 21.33, Cl 13.49%; found .... C 59.59, H 5.98, N 21.19, Cl 13.67%.

Production of the starting material
3-chlorobenzocyclohepta [5,6-c] pyridazine

A. 2,3,4,4a-Tetrahydro-3-oxobenzocyclohepta [5,6-c] pyridazine

A 250 ml three-neck, flame-dried round-bottom flask, equipped with a stirrer, cooler and dropping funnel with pressure compensation, is added with 24.6 g (0.115MoI)

2,3,4,4a - Tetrahydro - 3 - oxobenzocyclohepta [5,6 - c] pyridazine in 170 ml of glacial acetic acid and placed under a nitrogen atmosphere. The mixture is heated to 75 ° C until dissolution is complete. after which 18.4 g (0.115 mol) bromine are added dropwise over 30 minutes. The temperature is then held at 75 ^° C. for 1.5 hours. After cooling, the reaction mixture is poured into ice, triturated and filtered. The collected solid is washed well with water. After drying, 23.9 g (94%) of raw material are obtained. Recrystallization from acetonitrile provides the analysis sample with a F. = 235 to 239 ° C.

Analysis C ₁₃ H ₁₂ N ₂ O:

Calculated ... C 73.56, H 5.70, N 13.20%;
found .... C 73.32, H 5.86, N 13.41%.

C. 3-Chlorobenzocyclohepta [5,6-c] pyridazine

Cl

A solution of 5.0 g (0.0236 mol) of 2,3-dihydro-3-oxobenzocyclohepta [5,6-c] pyridazine in 50 ml of phosphorus oxychloride is heated to reflux for 30 minutes. After removing the excess Phosphorus oxychloride, the residue is poured into ice water with thorough stirring. The aqueous phase is made basic with concentrated ammonium hydroxide to pH 8 to 9, and the solids which separate out are extracted with methylene chloride. The combined extracts are made with water and brine washed and dried over sodium sulfate. Filtration and removal of the solvent gives a solid residue which, after recrystallization from ethyl acetate with activated charcoal, 4.41 g (81.2%) Product supplies. Further recrystallization provides the analysis sample with a F. = 156.5 to 158 ° C.

Analysis C ₁₃ H ₁₁ N ₂ Cl:

Calculated ... C 67.67, H 4.81, N 12.14, Cl 15.37%; found .... C 67.72, H 4.80, N 12.01, Cl 15.65%.

Claims (2)

Patent claims: 1. 5,6 - dihydro - 3 - hydrazinobenzo [h] cinnoline and 3-hydrazinobenzocyclohepta [5,6-c] pyridazine of formula I. (D in which π denotes the number 1 or 2, as well as their non-toxic, pharmaceutically acceptable acid addition salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that a compound of the general formula 11