DD243931A5 - PROCESS FOR PREPARING 12-AMINO-PYRIAZINO (4 ', 5': 3,4) PYROLO (2,1-A) ISOCHINOLINE - Google Patents

Abstract

The invention relates to novel 12-amino-pyridazino (4,5: 3,4) -pyrrolo (2,1-a) isoquinolines of general formula I according to claim 1 and their physiologically acceptable Saeureadditionssalze. The new drugs are to be used in medicines to combat heart failure and cerebral metabolic disorders.

Description

(D

and their physiologically acceptable acid addition salts.

In this formula mean:

Ri and R ₂ , which may be the same or different, are hydrogen, C ₃ -C ₇ cycloalkyl, C ₂ -C ₅ alkenyl, phenyl (where the phenyl ring is optionally substituted once or twice by halogen or methoxy). Propargyl, a straight or branched chain, saturated or unsaturated alkyl radical having 1-5 carbon atoms, which may be substituted by hydroxy, alkoxy having 1-4 carbon atoms, halogen, NH ₂ , NH alkyl having 1-2 carbon atoms, Ν, Ν-dialkyl with 1-2 carbon atoms, NH-acyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, phenyl, (wherein the phenyl ring in turn may be further substituted by halogen, alkyl having 1-2 carbon atoms, alkoxy having 1-2 carbon atoms, NH-alkyl having 1-2 carbon atoms, Ν, Ν-dialkyl having 1-2 carbon atoms, NH ₂ , N-acyl having 2-3 carbon atoms or alkylsulfonylamino), furyl, thienyl, a nitrogen-containing heterocyclic 5- or 6-membered ring optionally as another heteroatom may contain an oxygen or sulfur atom (wherein the ring is optionally substituted by alkyl of 1-4 carbon atoms), R ₁ and R ₂ together with the nitrogen atom, a 3- to 7-membered ring, the given if another heteroatom may contain an oxygen or a nitrogen atom (where the ring is optionally substituted by phenyl [C ₁ -C ₄ ] alkyl [in which the phenyl ring is itself monosubstituted or disubstituted by halogen or methoxy]), R ₂ , if R _{1 is} hydrogen, an -NH ₂ , di (C ₁ -C ₂ ) alkylamino, acetonylamino, -NH (C ₂ -C ₃ ) acyl, alkylsulfonyl or alkoxycarbonyl radical each having 1-3 carbon atoms in the alkyl chain, the isopropylideneamino group

CH.

or a heterocyclic, a nitrogen atom and optionally as further heteroatom an oxygen, nitrogen or sulfur atom-containing 5- or 6-membered ring,

R ₃ , R ₄ and R ₅ , which may be the same or different, are hydrogen or an alkyl radical of 1-4 carbon atoms, R ₇ and Ra, which may be the same or different, hydroxy, alkoxy of 1-4 carbon atoms or alkylthio of 1 -4 carbon atoms and

Re and Rg, which may be the same or different, are hydrogen, hydroxy, alkoxy of 1-4 carbon atoms, alkylthio of 1-4 carbon atoms, or the balance

- N ^'X U

while

R ₁ O is hydrogen or alkyl of 1-4 carbon atoms and

R ₁ I is hydrogen or alkyl of 1-4 carbon atoms, where the alkyl radical may optionally be substituted by hydroxy, methoxy or furfuryl.

The invention further includes the physiologically acceptable acid addition salts of the compounds of the formula I.

Preferred compounds of the general formula I or their acid addition salts in which R ₁ and R ₂ , which may be identical or different, are hydrogen or a straight-chain or branched alkyl group having 1-5 carbon atoms or

R _{1 is} hydrogen and R _{2 is} amino, methylamino, dimethylamino, isopropylidenimino, dimethylaminoalkyl having 1-4 carbon atoms, methoxyalkyl having 1-4 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, phenyl, p-halophenyl, phenylethyl, where the phenyl ring is optionally or di-substituted by methoxy, or pyrazolyl,

or R ₁ and R ₂ together with the nitrogen atom mean a morpholino ring or a piperazine ring and R ₇ and Rg are methoxy.

The new compounds can be obtained by reacting a S, - di -hydroxy-methylmercapto-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline of the general formula

(II)

S-R

wherein R is alkyl having 1-5 carbon atoms or benzyl and the radicals R ₃ , R ₄ , R ₅ , Re, R ₇ , Re and R _{9 have} the abovementioned meaning, with a compound of general formula

HN^ < ""

wherein Ri and R _{2 have} the meaning given above.

In this case, a starting compound of the general formula II is dissolved in a high-boiling inert solvent, for example dimethylformamide, dimethylacetamide, chlorobenzene, hexamethylphosphoric trisamide, etc. and heated with the amine component of the general formula III under reflux until the reaction is complete. The reaction time is between about 1 to 15 hours and depends on the starting components used. For reactive amines and alcohols or tetrahydrofuran can be used as a solvent; Under certain circumstances, a reaction in an autoclave can be advantageous.

If the amines used are liquid and sufficiently high-boiling, the reaction may also be in excess of the amine without additional solvent (e.g., aniline, morpholine, phenylethylamine), optionally under a nitrogen atmosphere.

In some cases, a reactant can also be used which serves as a solvent in the reaction as well as by cleavage during the reaction provides the required amine, for. B. dimethylformamide. The 12-amino-pyridazino-pyrazoloisoquinolines according to the invention are bases and can be converted in the usual way with inorganic or organic acids into any physiologically acceptable acid addition salts. Examples of suitable acids for salt formation are hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, phosphoric, nitric, acetic, propionic, butyric, caproic, valeric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid and the like.

By the method described above, for. B. the following end products are obtained:. 3,4-dihydro-6,7-dimethoxy-12-N, N-dimethylaminoethyl-amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride;

S ^ -dihydro-e ^ dimethoxy - ^ - dimethylamino -pyridazino-H'.S'iS ^ lpyrrolotS.I-alisochinolin hydrochloride; 3,4-dihydro-6,7-dimethoxy-12-morpholino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride; [4 ', 5': 3,4] 3,4-dihydro-6,7-dimethoxy-isoquinolin-pyridazino 12 acetonylhydrazon pyrrolo [2,1-a]; 3,4-dihydro-6,7-dimethoxy-12-anilino-pyridazino [4 ', 5': 3,4] pyrrolo [2, l-a] isoquinoline hydrochloride; 3,4-dihydro-6,7-dimethoxy-12-methylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-alisochinolin hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-ethylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-diethylamino-pyridazinot4 ', 5 ^r: 3,4] pyrrolo [2, la] isoquinoline hydrochloride.

SADihydro-ej-dimethoxy - ^ - cyclopropylamino-pyridazinoK '^' -. S ^ ^ .i lpyrrolo aJisochinolin hydrochloride.

SADihydro-e ^ dimethoxy - ^ - ^ isopropylamino-pyridazinoK'.S'iS lpyrrolo ^ .i aJisochinolin hydrochloride.

3,4-Dihydro-6,7-dimethoxy-12-butylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride 3,4-dihydro-6,7-dimethoxy -12-N, N-dimethylhydrazinopyridazino [4 ', 5 ^r: 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- (2-methoxyethyl) -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoch1nolin hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [2- (3,4-dimethoxyphenyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline · HCL.

S ^ -dihydro-dimethoxy e ^ - ^ - O-aminopyrazolylJ-pyridazinoK '^' ^ iS ^ i-Jpyrrolo aJisochinolin hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-cyclopentylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

S ^ -dihydro-ej-dimethoxy - ^ - cyclohexylmethylaminopyridazinoH '^' iS ^ lpyrroloß.i-alisochinolin hydrochloride.

SADihydro-e ^ dimethoxy - ^ - -propargylamino-pyridazinoH'.B '^^ lpyrrolo ^ .i alisochinolin hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- {2- [2- (1-methyl) pyrrolidinyl] ethyl} -amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1 -aJisoquinoline · HCl.

3,4-Dihydro-6,7-dimethoxy-12- [2- (1-piperidinyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline HCl.

3,4-dihydro-6,7-dimethoxy-12-pyrrolidinyl-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-n-propylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

12-allylamino-3,4-dihydro-6,7-dimethoxy-pyridazino [4 ', 5': 3,4] pyrroloi2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [4- (2-methoxyphenyl) piperazinyl] -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- (3-dimethylaminopropyl) -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-Dihydro-6,7-dimethoxy-12- [2- (1-morpholinyl) -ethyl] -aminopyridazino [% ', 5': 3,4] pyrrolo [2,1-a] isoquinoline HCI.

3,4-dihydro-6,7-dimethoxy-12-n-pentylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-cyclohexylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [4- (2-phenylethyl) piperazinyl] -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-furfurylamino-pyridazino [4 ', 5': 3,4] pyrrolot2,1-a] isochinQlin hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- (3-methoxypropylamino) -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dtmethoxy-12-isopentylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-Dihydro-6,7-dimethoxy-12- [2- (1-pyrrolidinyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline * HCl ,

3,4-dihydro-6,7-dimethoxy-12- (2-hydroxyethyl) -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-Dihydo-6,7-dimethoxy-12- (4-fluoroanilino) -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [2- (4-pyridinyl) ethyl] -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [2- (2-pyridinyl) ethyl] -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-aJisochinolin hydrochloride.

12- (4-amino-1-benzyl-piperidinyl) -3,4-dihydro-6,7-dimethoxy-pyridazino (4 ', 5': 3,4] pyrrolo [2,1-a] isochinolinHCI.

3,4-dihydro-6,7-dimethoxy-12- [2- (3-thieno] ethyl] -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [2- [2- (1-methyl) pyrrolyl] ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2, 1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12- [4- (2-phenylethyl) piperazinyl] -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

SADihydro-ej-dimethoxy - ^ - isobutylamino-pyridazinoH '^' iS ^ lpyrrolo ^ .i-aJisoquinoline hydrochloride.

3,4-dihydro-6,7-dimethoxy-12-benzylamino-py.ridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

The starting materials of the general formula II can be prepared starting from a compound of the general formula

(IV)

COOR

wherein

R denotes a lower alkyl radical having 1-4 carbon atoms and the radicals R3, _{R4, R5,} Re, R7, Re and _R9 have the meaning indicated above, by reaction mitHydrazinhydrat, converting the thus-obtained 3,4,11,12 -Tetrahydropyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinolinone- (12) of the general formula

(V)

wherein the radicals R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , Re and R 9 have the abovementioned meaning, with the aid of phosphorus pentasulfide in the corresponding thione of the general formula

(Vl)

wherein the radicals R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R _{9 have} the abovementioned meaning, and conversion of the thione compound into the corresponding methylmercapto of the general formula

(II)

S-R

wherein R is alkyl of 1-5 carbon atoms or benzyl and the radicals R ₃ , R ₄ , R 5, Re, R 7, Rs and R _{9 have} the meaning given above by means of dimethylacetamide / methyl iodide.

The starting materials of general formula IV can be obtained according to the information in German Patent Application P 3401018.1 by base-catalyzed rearrangement of the literature known 1- (3-furyl) -3,4-dihydroisoquinolines.

The new 12-amino-pyridazino [4 ', 5': 3,4lpyrrolo [2,1-a] isoquinolines of the general formula I have valuable therapeutic properties both as bases and in the form of their salts in animal experiments. Thus, they show a strong binding to the muscarinic receptor; This is an experiment in which a homogenate from different brain areas of the rat is incubated with tritium-N-methylscopolamine and displaced by adding the substance to be examined, the radioligand. Displacement gives a measure of the affinity of the substance to the muscarinic cholinergic receptor (see Watson, M., et al., Live Science, Vol.32, p.3001-3011 [1983] and R. Hammert et al., Nature, Vol. 283, p.90-92 [1980]). Also in a test for cardiotonic activity on the isolated auricle of the guinea pig, compounds of the general formula I have proven to be very effective. In this experiment, spontaneously beating isolated atria are used; the quantitatively measured positive inotropic effect is a measure of the influence on contractility. EC _S0 is the amount of active substance in mg / kg which causes a 50% increase in contractility (see R. Reichl, W. Traunecker, A. Engelhardt: Proceedings of the 12th meeting of the European Society for the Study of Drug Toxicity, Uppsala, June 1970, Excerpta Medica, International Cong. Series No. 220 - Isolated Atrium)

On the basis of these findings, the compounds of the general formula I or their acid addition salts are to be used as active ingredients for medicaments for heart failure and cerebral metabolic disorders. The compounds can be administered both enterally and parenterally. As a dose for oral administration, 5 to 500, preferably 20 to 250mg of active ingredient per dose, for i.v. application, 0.5 to 150, preferably 5 to 50mg per dose proposed.

Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions, aerosols or dispersible powders. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or Achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in dragee casings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee wrapper may also consist of several layers to achieve a depot effect, wherein the auxiliaries mentioned above in the case of the tablets may be used. Juices of the inventive active ingredients or active compound combinations may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a taste-improving agent, for. B. flavoring, such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection solutions are in the usual manner, for. B. with the addition of preservatives, such as p-hydroxybenzates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, prepared and filled into injection bottles or ampoules.

The capsules containing one or more active ingredients or active compound combinations can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.

Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

embodiment

The following examples serve to explain the invention in more detail:

Example 1 a ^ Dihydro-ej-dimethoxy-1Z-N, N-dimethylaminoethylamino-pyridazinoH'''is-1-pyrrolo-1-iisoquinoline hydrochloride 8g 3,4-Dihydro-6,7-dimethoxy-12-methylmercapto-pyridazino [4 ' 5 ': 3,4] pyrrolo [2,1-a] isoquinoline and 15 ml of (N, N-dimethylaminoethyl) -amine are heated to boiling point in 100 ml of dimethylacetamide for 2 hours. After cooling to room temperature, the orange-yellow solution is concentrated in vacuo, the oily residue taken up in methylene chloride, extracted with water and dried over sodium sulfate. After the solvent has been stripped off, the residue is purified by means of an Al ₂ O.sub.youta (Al ₂ O ₃ neutral, Fa. Woelm, activity stage III, eluent: methylene chloride / methanol [100: 8]). The reaction product is dissolved in ethanol and precipitated by the addition of ethanolic hydrochloric acid as the hydrochloride. Yield: 6.6 g (73% of theory); Mp> 250 ^° C.

Example 2

5 g of S ^ -dihydro-ej-dimethoxy-1-methylmercapto-pyridazinoH'.S'-1-pyrrolofoi-alisoquinoline are heated to boiling point in 200 ml of ethanol with 10 ml of hydrazine hydrate for 2 hours. After completion of the reaction, concentrated in vacuo, the residue is stirred with water, filtered off and crystallized from the filter residue of ethanol / ether. The title compound is obtained in a yield of 3.4 g (71% of theory); Mp 254-257 ⁰ C.

Example 3 S, 1-Dihydro-ej-dimethoxy-1-dimethylamino-pyridazinoH, S'isylpyrrolo ^, i-a-jisoquinoline hydrochloride 5g a-dihydro-ej-dimethoxy-1-methylmercapto-pyridazinoH'.S '. -α ^ Ipyrrolo ^ .i-alisoquinoline are heated to boiling temperature in 100 ml of dimethylformamide for 15 hours. After completion of the reaction is evaporated, the residue slurried in methylene chloride and filtered with suction. After dissolving the filter residue in hot methanol, the base is added by adding ethanolic hydrochloric acid in the Hydrochloric! convicted and pleases.

Yield of title compound: 3.6 g (72% of theory); Mp 264 ° C.

Analogously to Example 3 were obtained:

Starting from 3,4-dihydro-6,7-dimethoxy-12-methylmercaptopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline by reaction with formamide, the 3,4-dihydro-6, 7-dimethoxy-12-amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride, mp 271 ⁰ C..

Starting from 3,4-dihydro-6,7-dimethoxy-12-methylmercaptopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline by reaction with methylformamide, the 3,4-dihydro-6,7- dimethoxy-12-methylaminopyridazino [4'-5 ': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride, m.p. 260-265 ° C.

Example 4 3,4-Dihydro-6,7-dimethoxy-12-dimethylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride 5g SADihydro ^ J-dimethoxy - ^ - methylmercaptopyridazinoW.S'isylpyrrolo ^, alisoquinoline are heated to 120 ° C in 50 ml of dimethylacetamide with 20 ml of dimethylamine in an autoclave for 10 hours. After completion of the reaction, the solvent is removed in vacuo, the residue is purified on silica gel (eluent: methylene chloride / methanol [100: 10]), the hydrochloride is formed and crystallized from methanol.

Yield: 3.1 g (63% of theory); Fp.264 ° C.

Following the procedure described above, the following compounds were further prepared:

3,4-dihydro-6,7-dimethoxy-12-methylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.2 g (67% of theory); Mp.> 250X.

SADihydro-ej-dimethoxy - ^ - ^ ethylamino-pyridazinoH'.S'iS jpyrroloti.i-alisochinolin hydrochloride.

Yield: 3.1 g (63% of theory); Fp.273 ° C.

S ^ -dihydro-e.T-dimethoxy - ^ - ^ diethylamino-pyridazinoH'.S'iS lpyrrolo ^ .i alisochinolin hydrochloride.

Yield: 3.4 g (67% of theory); Fp.276 ° C.

3,4-dihydro-6,7-dimethoxy-12-cyclopropylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 2.4 g (46% of theory); Mp.> 260 ° C.

Example 5 3,4-Dihydro-6,7-dimethoxy-12-morpholino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride 5g 3,4-dihydro-6, 7-dimethoxy-12-methylmercapto-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-alisoquinoline and 20 ml of morpholine are heated to boiling point in 100 ml of dimethylacetamide for 1.5 hours. After completion of the reaction is concentrated in vacuo, the residue triturated with methylene chloride and filtered with suction. The reaction product is dissolved in a methylene chloride / methanol mixture, converted into the hydrochloride by addition of ethanolic hydrochloric acid and crystallized. The yield of title compound is 3.5 g (63% of theory); Fp.267 ⁰ C. Analogously to the procedure described above were prepared:

3,4-dihydro-6,7-dimethoxy-12-isopropylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 3.0 g (57% of theory); Fp.238 ° C.

3,4-dihydro-6,7-dimethoxy-12-butylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 4.2 g (78% of theory); Mp .257 ⁰ C.

S ^ -dihydro-ej-dimethoxy - ^ - N, N-dimethylhydrazino-pyridazinoH'.S'iS ^ ^ .i Ipyrrolo alisochinolin hydrochloride. Yield: 4.5 g (87% of theory); Mp.> 265X.

3,4-dihydro-6,7-dimethoxy-12- (2-methoxyethyl) amino-pyridazino [4 ', 5': 3,4lpyrrolo [2,1-a] isoquinoline-hydrochloride. Yield: 3.6 g (67% of theory); Fp.252 ° C.

3,4-dihydro-6,7-dimethoxy-12- [2- (3,4-dimethoxyphenyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline · HCl. Yield: 5.5 g (78% of theory); Fp.257 ° C.

3,4-dihydro-6,7-dimethoxy-12- (3-aminopyrazolyl) -pyridazino [4 ', 5': 3,4] pyrrolot2,1-a] isoquinoline hydrochloride. Yield: 4.1 g (68% of theory); Mp.> 260 ° C.

3,4-dihydro-6,7-dimethoxy-12-cyclopentylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 3.1 g (56% of theory); Fp.265 ° C.

3,4-dihydro-6,7-dimethoxy-12-cyclohexylmethylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 5.2 g (87% of theory); Fp.262 ° C.

3,4-dihydro-6,7-dimethoxy-12-propargylamino-pyridazino [4 ', 5'3,4] pyrrolot2,1-a] isoquinoline hydrochloride. Yield: 3.7 g (73% of theory); Fp.247 ° C.

3,4-dihydro-6,7-dimethoxy-12- {2- [2- (1-methyl) pyrrolidinyl] ethyl} -amino-pyridazino [4 ', 5': 3,4lpYrrolo [2,1- a] isoquinoline · HCl. Yield: 4.3 g (69% of theory); Fp.256-258 ° C.

3,4-Dihydro-6,7-dimethoxy-12- [2- (1-piperidinyl) -ethyl] -aminopyridazino (4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline) HCl Yield: 3.3 g (53% of theory) mp 248-251 ° C.

3,4-dihydro-6,7-dimethoxy-12-pyrrolidinyl-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 3.1 g (59% of theory); Fp.277-278 ° C.

3,4-dihydro-6,7-dimethoxy-12-n-propylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 3.7 g (72% of theory); Fp.258 ° C.

12-allylamino-3,4-dihydro-6,7-dimethoxy-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride. Yield: 2.7 g (53% of theory); Fp.260-263 ° C.

3,4-dihydro-67-dimethoxy-12- [4- (2-methoxyphenyl) piperazinyl] -pyndazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 4.8 g (66% of theory); Fp.250-252 ⁰ C.

3,4-dihydro-6,7-dimethoxy-12- (3-dimethylaminopropyl) amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 2.4 g (43% of theory); Mp.> 250 ° C.

a ^ Dihydro-ej-dimethoxy - ^ - K -timorpholinyl-ethyl-amino-pyridazino-W.S'iS ^ Ipyrrolo ^ i-a-jisoquinoline • HCl.

Yield: 3.4 g (54% of theory); Mp.> 260 ° C.

3,4-dihydro-6,7-dimethoxy-12-n-pentylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 4.9 g (87% of theory); Mp. 259 to 261 ⁰ C.

3,4-dihydro-6,7-dimethoxy-12-cyclohexylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.8 g (66% of theory); Fp.253 ° C.

3,4-dihydro-6,7-dimethoxy-12- [4- (2-phenylethyl) piperazinyl] -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.8 g (53% of theory); Fp.264 ° C.

3,4-dihydro-6,7-dimethoxy-12-furfurylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-alisochinolin hydrochloride.

Yield: 3.2 g (56% of theory); Fp.243-246 ° C.

3,4-dihydro-6,7-dimethoxy-10- (3-methoxypropylamino) -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.6 g (65% of theory); Mp.> 250 ° C.

3,4-dihydro-6,7-dimethoxy-12-isopentylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.2 g (58% of theory); Mp. 259 ⁰ C.

3,4-Dihydro-6,7-dimethoxy-12- [2- [1-pyrrolidinyl] -ethyl] -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline HCI.

Yield: 3.3 g (55% of theory); Mp.> 260 ° C.

3,4-dihydro-6,7-dimethoxy-12- (2-hydroxyethyl) -aminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 4.2 g (80% of theory); Fp.259 ° C.

Example 6 S ^ -dihydro-ej-dimethoxy-pyridazinoH'.S'isylpyrrolo ^, i-alisoquinoline-^-acetonylhydrazone 1 g of 3,4-dihydro-6,7-dimethoxy-12-hydrazino-pyridazino [4 ' , 5 ': 3,4] pyrrolo [2,1-a] isoquinoline are dissolved in 50 ml of acetone and heated to boiling for Ѵг hour. It is concentrated in vacuo and sucks off the precipitated crystals in the cold. Yield: 5.1 g (95% of theory); Mp 173-175 ° C.

Example 7 3,4-Dihydro-6,7-dimethoxy-12-anilino-pyradizinot4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride 5g SADihydro-ej-dimethoxy-1-methylmercapto pyridazinoH '^' .- S ^ Jpyrrolo ^ i-aJisoquinoline are heated to boiling point in 50 ml of aniline under nitrogen protection for 6 hours. Excess aniline is removed in vacuo, the residue is triturated with methylene chloride, filtered off with suction and recrystallized from methanol / methylene chloride.

Yield: 3.0 g (53% of theory); Mp.> 250 ° C.

Analog were produced:

3,4-dihydro-6,7-dimethoxy-12- (4-fluoroanilino) -pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 4.0 g (67% of theory); Mp> 270 ^° C.

3,4-dihydro-6,7-dimethoxy-12- [2- (4-pyridinyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 4.1 g (70% of theory); Mp.> 260 ° C.

3,4-dihydro-6,7-dimethoxy-12- [2- (2-pyridinyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.7 g (62% of theory); Mp> 26O ⁰ C.

12- (4-Amino-1-benzyl-piperidinyl) -3,4-dihydro-6,7-dimethoxy-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline • HCl.

Yield: 3.9 g (56% of theory); Mp.> 250 ° C.

3,4-dihydro-6,7-dimethoxy-12- [2- (3-thieno) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 4.0 g (65% of theory); Mp> 280 ° C.

3,4-dihydro-6,7-dimethoxy-12- [2- [3- (1-methyl) pyrrolyl] ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2, 1-a] isoquinoline hydrochloride.

Yield: 3.6 g (61% of theory); Mp 256-258 ° C.

3,4-dihydro-6,7-dimethoxy-12- [2- (1-piperidinyl) ethyl] amino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride.

Yield: 3.6 g (58% of theory); Mp. 250 ° C.

3,4-dihydro-6,7-dimethoxy-12-isobutylamino-pyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride, mp 250 ⁰ C..

3,4-Dihydro-6,7-dimethoxy-12-benzylaminopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline hydrochloride, m.p. 257 ° C.

The preparation of the starting compounds is described using the example of 3,4-dihydro; 6,7-dimethoxy-12-methylmercaptopyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinoline.

a) 3,4,11,12-Tetrahydro-6,7-dimethoxy-pyridazino [4 ', 5': 3,4] -pyrrolo [2,1-a] isoquinolin-12-one

8.25 g of ethyl 1-formyl-5,6-dihydro-8,9-dimethoxypyrofo [2,1-a] -isoquinoline-2-carboxylate and 7 ml of hydrazine hydrate are stirred for 3 hours in 40 ml of boiling pyridine. After cooling, the crystalline precipitate is filtered off with suction and freed by washing with methanol from adhering pyridine. The resulting product is analytically pure and is used without further purification for the next stage. Yield: 7.1 g (95.4% of theory); Mp> 285 ° C.

b) 3,4,11,12-Tetrahydro-6,7-dimethoxy-pyridazino [4 ', 5': 3: 4] -pyrrolo [2,1-a] isoquinoline-12-thione

To a suspension of 404 g of 3,4,11,12-tetrahydro-6,7-dimethoxypyridazino [4 ', 5': 3,4] pyrrolo [2,1-a] isoquinolin-12-one in 2.81 Pyridine are introduced rapidly with stirring at room temperature 302 g of phosphorus pentasulfide in portions. With slight increase in temperature to max. 60 ⁰ C forms a yellow solution from which orange yellow crystals precipitate after a short time. The reaction mixture is heated under reflux for about 4 hours, allowed to cool to room temperature and the crystals are filtered off with suction. This is digested in a mixture of 11 water and 200 ml of ethanol and dried after vacuuming at 60 ⁰ C in a vacuum. The product is processed further without further purification. For analysis, a sample of ethanol / methylene chloride is crystallized. Yield: 392 g (92% of theory); Mp 294 ⁰ C.

с) a ^ -dihydro-e ^ -dimethoxy-ia-methylmercapto-pyridazinol ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 1-liter pyrrolo-1-alisoquinoline-1-thione in 600 ml of dimethylacetamide is treated with 20 ml of methyl iodide at room temperature with stirring. After about 20 minutes of stirring at room temperature, an orange-yellow solution forms, which precipitates after a further 15 minutes orange crystals.

The mixture is stirred for a further hour, the crystals are filtered off with suction and washed with methylene chloride. A second fraction is obtained from the mother liquor after evaporation and trituration with methylene chloride. The resulting product is pure by NMR spectroscopy and is processed without further purification steps. A sample was recrystallized from dimethylacetamide for analysis.

Yield: 99.8 g (96% of theory); Mp 254 ⁰ C.

formulation Examples

a) dragees

1 drag core contains:

Active substance according to the invention 150.0 mg

Lactose 50.0 mg

Corn starch 22.0 mg

Gelatin 2.0mg

Magnesium Stearate 1.0mg

225.0 mg production

The mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with 1 mm mesh size, dried at 40 ⁰ C and again driven through a sieve. The granules thus obtained are mixed with magnesium stearate and pressed. The cores thus obtained are coated in a conventional manner with a sheath, which is applied by means of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragees are polished with beeswax

 Dragee final weight: 200 mg

b) tablets

Active substance according to the invention 100.0 mg

Lactose 40.0 mg

Corn starch 44.0 mg

soluble starch 5.0 mg

Magnesium stearate 1.0 mg

190.0 mg production

Active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules dried and intimately mixed with lactose and corn starch. The mixture is then compressed into tablets of 100 mg in weight, each containing 10 mg of active ingredient.

c) Suppositories

1 suppository contains:

Active substance according to the invention 120.0 mg

Suppository mass 1680.0 mg

manufacturing

The finely powdered substance is stirred with the aid of an immersion homogenizer in the molten and cooled to 4O ⁰ C Zäpfchemasse. The mass is poured at 35 ⁰ C in slightly pre-cooled molds.

d) Ampoules composition:

Active substance according to the invention 50.0 parts by weight

Sodium pyrosulfite 1.0 parts by weight

Disodium salt of ethylenediaminetetraacetic acid

Sodium chloride 8.5 parts by weight

Double distilled water ad 1000.0 parts by weight

manufacturing

The active ingredient and the excipients are dissolved in a sufficient amount of water and brought to the desired concentration with the necessary amount of water. The solution is filtered and filled under aseptic conditions in 1 ml ampoules. Finally, the ampoules are sterilized and sealed. Each vial contains 50.0 mg of active ingredient.

Claims (1)

Invention claim: wherein Ri and R ₂ , which may be the same or different, are hydrogen, C ₃ -C ₇ cycloalkyl, Cz-Cs alkenyl, phenyl (wherein the phenyl ring is optionally substituted once or twice by halogen or methoxy). Propargyl, a straight or branched, saturated or unsaturated alkyl radical having 1-5 carbon atoms which may be substituted by hydroxy, alkoxy of 1-4 carbon atoms, halogen, NH ₂ , NH-alkyl of 1-2 carbon atoms, N, N-dialkyl with 1-2 carbon atoms, NH-acyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, phenyl, (wherein the phenyl ring in turn may be further substituted by halogen, alkyl having 1-2 carbon atoms, alkoxy having 1-2 carbon atoms, NH-alkyl having 1-2 carbon atoms, Ν, Ν-dialkyl having 1-2 carbon atoms, NH ₂ , N-acyl having 2-3 carbon atoms or alkylsulfonylamino), furyl, thienyl, a nitrogen-containing heterocyclic 5- or 6-membered ring optionally as another heteroatom may contain an oxygen or sulfur atom (wherein the ring is optionally substituted by alkyl having 1-4 carbon atoms), or R, and R ₂ together with the nitrogen atom, a β-7-membered ring, the optionally as further heteroatom, an oxygen or a nitrogen atom may contain (wherein the ring is optionally substituted by phenyl (C ₁ -C ₄ ) alkyl (wherein the phenyl ring in turn is mono- or di-substituted by halogen or methoxy), or R ₂ when R _{1 is} hydrogen, an -NH ₂ , di (C ₁ -C ₂ ) alkylamino, acetonylamino, -NH (C ₂ -C ₃ ) acyl, alkylsulfonyl or alkyloxycarbonyl radical each having 1-3 carbon atoms in the alkyl chain, the isopropylidenimino group CH. or a heterocyclic, a nitrogen atom and optionally as further heteroatom an oxygen, nitrogen or sulfur atom containing 5 or 6 ring, R ₃ , R ₄ and R ₅ , which may be identical or different, denote hydrogen or an alkyl radical having 1-4 carbon atoms, R ₇ and R ₈ , which may be the same or different, are hydroxy, alkoxy of 1-4 carbon atoms or alkylthio of 1-4 carbon atoms, and R ₆ -Rg, which may be the same or different, represent hydrogen, hydroxy, alkoxy of 1-4 carbon atoms, alkylthio of 1-4 carbon atoms or the remainder - N while R 1 is hydrogen or alkyl of 1-4 carbon atoms and R 6 is alkyl of 1-4 carbon atoms, where the alkyl radical may optionally be substituted by hydroxy, methoxy or furfuryl, and their physiologically acceptable acid addition salts, characterized in that a SADihydro - ^ - methylmercapto-pyridazino- (4 ', 5': 3,4) -pyrolo (2,1-a) isoquinoline of the general formula wherein SCH. R is alkyl having 1-5 carbon atoms or benzyl and the radicals R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , Rs and Rs have the meanings given above, with a compound of the general formula HN (III) R. wherein Ri and R _{2 have} the abovementioned meaning, and that an end product thus obtained is optionally converted in a manner known per se into a physiologically tolerated acid addition salt. Field of application of the invention The invention relates to a process for the preparation of 12-amino-pyridazino (4 ', 5': 3,4) -pyrolo (2,1-a) isoquinolines having valuable pharmacological properties. The compounds according to the invention are used as medicaments, for example for the treatment of cardiac insufficiency and cerebral metabolic disorders. Characteristic of the known technical solutions There is no information available on which compounds have so far been used to treat heart failure and cerebral Metabolic disorders were applied. There is also no information available on processes for the preparation of 12-amino-pyridazino (4 ', 5': 3,4) -pyrolo (2,1- alisochinolinen. Object of the invention The aim of the invention is the provision of novel compounds with valuable pharmacological properties that can be used, for example, for the treatment of heart failure and cerebral metabolic disorders. Explanation of the essence of the invention The invention has for its object to provide novel compounds with the desired properties and methods for their To find a production " The invention relates to novel 12-amino-pyridazino [4 ', 5': 3,4] -pyrrolo [2,1-a] isoquinolines of the general formula