Field of the invention

The invention relates to p ridazinones, their preparation and use, and tnedicaments containing pyridaz¬ inones. Prior art 6-Ary l-3C2H3p ri dazi nones as starting materials or i ntermedi at es for the synthesis of pha rmaceut ca Ls and plant protection agents and processes for their prepara¬ tion are described, for exa ple, by Baddar et al. CJ.Che . Soc. 1965, 33421], Steck CJ .Heterocyc l. Chem. 11 (1974)755 , Albright et al. CJ .Heterocyc l . Chem. 15(1978)8813, Schreiber et al. CBu l l. Soc. Ch im. France 2(1973)6253, Pitarch et al. CEur.J .Med. Chem.-C imi ca Therapeutica 9(1974)6443 and Curran et al. CJ .Med. Chem. 17(1974)2733, or are known, inter alia, from the following desc ripti ons: German Offen legungsschri ft 2,435,244, German Offen legungsschri ft 2,445,681 and German Offen legungssc ri ft 2,757,923. 6-Ary 1-3 C2H3p ridaz i nones with a certain action are known, for example, from the following descri pt i ons : German Of en legungssch ri ft 2,427,943, German Offen legungs- schrift 2,810,267, German Offen legungssch ri ft 2,845,220, European Offen Legungss c ri ft 8,391, European Offen legungs- schrift 10,156, Japanese Preliminary Published Applica- tion 58,008,015 and U.S.Patent Spec i i cat i on 4,397,854.

6- (3,4-D i methoxypheny l) -3 2H3py ri daz i none is des¬ cribed by Pitarch et al. and in German Offen legungss ch ri ft 2,810,267. Sum ary of the invention

Certain 6-ary l-3C2H3pyri dazi nones of the general formula I now have an advantageous pharmacological action. The invention relates to 6-a ry 1-3 2H3p ri dazi nones of the general formula I ^"

2

1 - wherein one of the substituents 1 or R2 denotes a methoxy group and the other denotes an alkoxy group with 2 to 5 carbon atoms or an aLkenyloxy group with 3 to 5 carbon atoms and X denotes an oxygen atom or a sulfur atom, and their parmaco logi ca l ly acceptabie salts with bases .

Alkoxy and alkenyloxy are strai ght-chai n or branched. The double bond of alkenyloxy does not start from the carbon atom bonded to the oxygen atom. Examples of alkoxy and alkenyloxy which may be mentioned are n- butoxy, n-propoxy, ethoxy, amyloxy, 2,2-di methyIpropy l- oxy, i sopenty loxy, i sobutoxy, sec.-butoxy, isopropoxy, but en-2-yloxy, allyloxy and metha l ly loxy; preferred al¬ koxy radicals contain 3 or 4 carbon atoms. Possible salts are salts with inorganic and organic bases. Cations which are used for the salt foi— mation are, in particular, the cations of the alkali etals or alkaline earth metals, but the correspondi ng cations of organic nitrogen bases, such as amines or aminoa Ikaπo Is, aminosugars and the like, are also used. Examples which may be mentioned are the salts of sodium, magnesium, calcium, dimethylam ne, di ethy lam ne, ethanol- a ine, d ethano lami ne, tr ethanolami ne, glucamine, N- methylg luca ine, glucosamine and N-methy lg lucosam ne. 6-Ar l-3C2H3pyri dazi nones of the general formula

Ia

wherein

Ria denotes a methoxy group,

R2a denotes an alkoxy group with 2 to 4 carbon atoms or an alkenyloxy group with 3 or 4 carbon atoms and Xa denotes an oxygen atom, and their pha rma co log ca l ly acceptabie salts with bases,

OMPI

form an embodiment of the invention.

6-Ary 1-3C2H3p ri dazinones of the general formula Ib

5 wherein

Rlb de.notes an alkoxy grόup with 2 to 4 carbon atoms or an alkenyloxy group with 3 or 4 carbon atoms, R2b denotes a methoxy group and Xb denotes an oxygen atom,

10 and their pharmacologi cally acceptabie salts with bases, form another embodiment of the invention.

Preferred represe.ntatives of embodi ent Ia are those in which R2a represents an n-propoxy, isopropoxy or isobutoxy. group. Particularly preferre *.-.» t-,

15 compounds 6- (3-methoxy-4-.n-propoxyphenyl )-3 (2H) pyri dazi - none and 6- ⁽ 4-i sobutoxy-3-methoxyphen l ⁾ -3 (2H) pyπ ^* dazi- none.

Preferred representati es of the embodiment Ib are those in which Rlb represents an n-propoxy, isopro-

20 poxy, allyl or isobutoxy group. Particularly preferred representatives are the compounds 6- (3-i sobutoxy-4-me- thoxyphenyl)-3 [2Hlpyridazi none and 6- (4-methoxy-3-n-pro- poxyphenyl)-3C2H ^" lpyridazinone.

The invent on also relates to the use of the

25 compounds according to Claim 1 for the treat ent or pro- phylaxis of diseases which are based on disorders of the bronchi and/or cardiac i nsuff ci ency, or for strengthen- ing the heart, and to the appropriate medicaments.

The compounds 6-(3-methoxy-4-n-propoxyphenyl)- _jrj 3 f2H ^" ]py ridazi none, 6- (4-i sobutoxy-3-methoxyphenyl )-3 [2H ^" 1- pyridazinone and 6- (4-m.ethoxy-3- isopropoxyphenyl )-3 C2H] py- ridazinone are preferred for use for the treatment or prophylaxis of diseases which are based on disorders of the bronchi, and the two rst-mentioned compounds are

35 particularly preferred.

The compounds 6- ⁽ 3- sobutoxy-4-methoxyphenyl )- 3 £ H] pyridazinone, 6- ⁽ 4-methoxy-3-n-propoxyphenyl)-3[2H3- pyridazinone and 6- (3-al lyloxy-4-methox>phenyl)-3 f2Hl py- π ^' dazinone are preferred for use for the treatment p r prophylaxis of d seases which are based on cardiac i nsuffi ci ency, or for strengthening the heart, and the fi rst-mentioned compound is particularly preferred.

The preferred m-edicaments are_ those which contain compounds whose use is p>-e- ^e er ^r ? !.

The invention further ore relates to a process for the preparation of the 6-ar 1-3C2H3pyri dazi nones of the general formula I and their pharmaco logi ca lly accept¬ abie salts with bases, which is characteri zed in that a) a 6-ar l- etrahydropyri dazinone of the general formula II

wherein R1 and R2 have the abovementi oned meaning, is oxidized and, if desired, the resulting pyridazinone I (X = 0) is then converted into the pyri dazinethione I (X = S) and/or into the salt, or b) a morpholinobut ri c acid of the general formula III

wherein R1 and R2 have the abovementi oned meaning, is reacted with hydrazine and, if desired, the resulting

^≠ Wr _t

O PI

pyridazinone I (X = 0) is then converted into the pyrid- azinethione I (X = S ⁾ and/or into the salt, or c) an acrylic acid of the general formula IV

wherein R1 and R2 have the abovement i oned meaning, is reacted with hydrazine and, if desired, the resulting pyridazinone I (X = 0) is then ^' converted into the pyrid- azinethione I (X = S) and/or into the salt.

The oxidation (dehydrogenat i on) according to pro- cess variant a) is carried out by methods which are known to the expert. For example, the dehydrogenat i on can be carried out in the presence of noble metals of sub-group 8, for example palladium or platinum CGerman Offen legungs- schrift 2,757,9233; with chromium tπ ^' oxide COverend et al. J. Chem. Soc. 1947, 2393 or with ni t robenzenesu Ifoni c acids o-r nitronaphtha lenesu Ifoni c acids, preferably with sodium or ammonium salts thereof CBritish Patent Specifi- cation 1,168,2913.

The react on according to process variant b) is carried out by a method analogous to that of Schreiber et al. CBul l. Soc. chim. France 2(1973 ⁾ 6253. For example, the morpholi nobuty r c acid III is reacted with hydrazine hydrate under reflux in a lower alkanol, for example n- butanol. A Ite rnat i e ly, the morpholinium salt, of the compound III, obtained by reaction of the correspondi ng acetophenone with glyoxylic acid and morpholine can be reacted with hydrazine hydrate in acid solution.

The reaction according to process variant c) is carried out by methods which are known to the expert. For example, the compounds IV are reacted, in a manner analogous to that in German Offen legungss ch ri ft 2,445,681, with ethanol or aqueous methanol at room temperature or slightly elevated temperature in the presence of basic compounds, such as alkali metal carbonates, hydroxides or lower alkanolates or tert ,-ami nes, the acid is libera-

O PI

ted from the salt formed and this acid is heated with 1 to 1.5 moles of hydrazine hydrate, at least a neutral medium, but preferably an acid medium, being maintained. The resulting arylpyridazi nones I (X = oxygen) are converted into the arylpyridazinethiones I (X = sulfur) by methods which are known to the expert. For example, the ar lp ri daz nones I are reacted, in a manner analogous to that of Albright et al. CJ .Heterocyc l.Chem. 15(1978)8813, with phosphorus oxyhalides at 80-120°C in the presence of a solvent, such as toluene, xylene or chlorinated hydrocarbons, but preferably without a sol¬ vent, to give the corre-sponding 6-aryl-3-ha logenopyri daz- ines, reaction of which (Jahine et al. Clnd.J.Chem. 16B (1978)1000-10033) with thiourea, for example by heating in a lower alkanol, such as n-butanol or methyl- or ethyl-cellosolve at 100 to 140°c for 5 - 10 hours, leads to the ar lpyridazinethiones I.

The 6-ar 1-3 2H3pyr daz nones I are converted into the s^lts .by methods which are known to the expert. That inorganic or organic base, the salt of which is desired, is used as the alkaline reactant. The salts are obtained, for example, by reacting the pyri dazinones I with the stoi ch ometr c equivalent of the corresponding base, for example sodium hydroxide or sodium methanolate, or by converting readily soluble salts into sparingly soluble salts by double decomposition.

For the preparation of the new compounds Ia and Ib, correspond ng starting compounds Ila, Ilb, lila, Illb, IVa or IVb

wherein Ria, Rlb, R2a and R2b have the abovementi oned meaning, are used.

The compounds II, III and IV are known, or they can be prepared by known processes.

The following examples serve to illustrate the invention in ore detail. m.p. denotes melting point and the temperatures are given in °C .

Example 1; 6- (4-n-Buto y-3-methox p eny l)-3C2H3py idazin- one

11.0 g of 6-(4-hydroxy-3-methoxypheny l) -4,5-di- hydro-3 C2H3pyri dazi none are heated under reflux together with 8.2 g of 1-bromobutane and 8.3 g of potassium car- bonate in 150 ml of anhydrous acetone for 20 hours. Thereafter, the starting compound can no longer be detec- ted by thin-layer chromatograph . The Suspension is fi l- tered hot, the filter cake is washed out with hot acetone and the fi ltrates are combined and evaporated in vacuo. The semi-solid residue C6-(4-n-butoxy-3-methoxypheny l) - 4,5-d hydro-3C2H3pyridazinone3 is taken up in 50 ml of ethanol, 10.0 g of sodium hydroxide in 200 ml of water and 14.6 g of sodium meta-ni trobenzenesu Ifonate are added and the m xture is heated under reflux for 2 hours.

After cooling, it is acidified to pH 1-2 with concentra- ted hydrochloric acid/ ^" the cr stalline solid is filtered off with suction and the solution is extracted several t mes with Chloroform. The residue from the Chloroform TO^

OMPI Λ

extract is combined with the crystals and the product is recrysta l li zed from e thano l /ethy l acetate. 8.7 g (63.7% of theory) of the title compound of m.p. 193 are obta ined.

The following are obtained analogously: 6-(4-allyloxy-3-methoxyphenyL -3C2Hlpyridaz none, m.p. 165' by reaction of 6- ⁽ 4-hydroxy-3-methoxyphe- nyl)-4,5-di hydro-3 L2Hlp.yridazi none with allyl bromide, and oxidation of the resulting 4,5-dihydro-3 [2H3pyridazi- none. ^•

Example 2; 6- ⁽ 4-Ethoxy-3-methoxyphenyl)-3C2H3pyr dazinone a) 4.5 g of 4-(4-ethoxy-3-tnethoxyphen l)-2-morphol- i no-4-oxobutyri c acid are boiled under reflux in 30 ml of 1-butanol with 6.7 g of 100% pure hydrazine hydrate for 8 hours. The reaction mixture is then evaporated in vacuo; the residue is bo led up in 100 ml of 2 N hydro- chloric acid, filtered off with suction and washed with water until free from acid. After drying, 2.1 g (65.6% of theory) of the title compound of m.p. 182-184° are obtained; after recrystal li zation from ethanol/ethyl acetate, the product has a melting point of 186°.

The following are obtained analogously: 6-(4-allyloxy-3-methoxyphenyl)-3[2H3.ρyridazinone, m.p. 165 ; 6-(3-methoxy-4-n-propoxyphenyl)-3 C2H] pyr - dazinone, -m.p ^~ . " 1 ^' 7'"2' ^* 6-(4-n-butoxy-3-methoxy- phenyl-3 f2Hlp ridazi none, m.p. 193°; 6-(4- ethoxy-3-methoxyphenyl)-3 C2H}pyri dazinone, m.p.

192 ; by reaction of the correspondi ng 4-aryl-2-morpho- lino-2-oxobuty i c acids with hydrazine hydrate. b) The 4-ar l-2-morpholino-4-oxobutyri c acids used are prepared as follows:

8.7 g of glyoxylic acid monohydrate are bo led up in 50 ml of ethanol until solution is complete, 16.5 g of morpholine and 18.5 g of 4-ethoxy-3-methoxyacetophen- one are then added and the mixture is stirred at 50 for 16 hours. The reaction mixture is evaporated in vacuo and the residue is digested with acetone, cooled, fil¬ tered off with suction and dried in vacuo. 9.9 g of

morpholinium 4-(4-ethoxy-3-methoxyphenyl)-2-morpholino-

4-oxobutyrate of m.p. 131° are obtained. To liberate the acid, the morpholinium salt is dissolved in 50 ml of water and the solution is acidified to pH 4.5 with acetic acid; the acid obtained as an oil is extra eted with Chloroform and the Chloroform extract is dried over sodium sulfate and evaporated. The residue is digested with ethyl acetate, fi ltered off with suction and dried in vaςuo. 4.9 g of the free acid of m.p. 157° are obtained.

In an analogous manner, morpholinium 4-(3-methoxy- 4-n-propoxyphen l)-2-morpholi no-4-oxobut ate, m.p. 110°; morpholinium 4-(4-n-butoxy-3-methoxypheny l)-2-morpho lino- 4-oxobutyrate, m.p. 120 ; 4- (4-a l ly loxy-3-methoxypheny D- 2-morpholino-4-oxobutyri c acid, m.p. 166°; morpholinium 4-(4-ethoxy-3-methoxyphenyl)-2-morpholino-4-oxobutyrate, m.p. 131 ; 4- (4-ethoxy-3-methoxypheny l ) -2-morpho l i no-4- oxobutyric acid, m.p. 157° are prepared from the corre- sponding a cetophenones . Example 3: 6- (3-methoxy-4-n-propoxyphen l )-3 2Hjpy ri daz- i none a) 10.6 g of 3-(3-methoxy-4-n-propoxybenzoy l) acry l i c acid and 6.1 g of potassium carbonate are dissolved in 100 ml of methanol and the solution s stirred overnight at room temperature. It is acidified with 7.4 ml of concentrated hydrochloric acid, 2.2 g of 100% pure hydrazine hydrate are added to the mixture and the mix¬ ture is boi led under reflux for 3 hours. It is then acidified to pH 1 with 1 ml of hydrochlori c acid and 75 ml of methanol are disti lle'd off in the course of 2 hours. The mixture is allowed to cool and the crystal mass is fi ltered off with suction, suspended several times in 50 ml of water each time, fi ltered off with suction and, finally, dried in vacuo. 6.6 g (63.7% of theory) of the title compound of m.p. 169-171° are obtained. After rec ysta 11 i zat i on from ethano l/ethy l acetate, the m.p. rises to 172°.

In an analogous manner, 6- (4-n-but oxy-3-methoxy¬ pheny l) -3 C2H3 yri daz i none, m.p. 193°; 6- (4-ethoxy-3

ethoxyphenyl) -3 H pyridazi none, m.p. 186 ; 6-(4-sec- butoxy-3-methoxyphenyl)-3 C2H]pyridazi none, m.p. 168 , 6- 4-(3-methyIbutoxy)-3-methoxypheny1 -3 H pyridaz none, m.p. 170°, are obtained from the correspondingly substitu- 5 ted 3-benzoylacryl c acids. b) The 3-benzoy lacryli c acids are prepared as follows:

10.4 g of ⁽ 3-methoxy-4-n-propoxy) acetophenone are mixed.with 9.2 g of glyoxylic acid monohydrate and the

10 mixture is heated at 110° in an oil bath for 1 hour. The mixture is then boiled up with 200 ml of water, cooled and extracted with Chloroform. For better phase Separation, the aqueous phase is saturated witfi sodium Chloride. After the Chloroform extract has been dried

15 over sodium sulfate and evaporated in vacuo, the orange¬ red residue is crystallized from acetone. 10.4 g (78.7% of theory) of 3-(3-methoxy-4-n-propoxybenzoyDacr l c acid of m.p. 158° are obtained.

In an analogous manner, 3-(4-n-butoxy-3-methoxy-

HH ber.zoyl) acryli c acid, m.p. 136 , 92.5% of theory; 3-(4- ethoxy-3-methoxybenzoyl) acr li c acid, m.p. 154 , 95.3% of theory; 3-(4-methoxy-3-n-prαpoxybenzoyl)acr l c acid, 3-(3-ethoxy-4-methoxybenzo l )-acryli c acid, 3-(3-allyl- oxy-4-methoxybenzo l) acr li c acid, 3- C3-(3-methyIbutoxy)- 25 4-methoxybenzoy acryl i c acid, 3-(4-sec .-butoxy-3-me- thoxybenzoyl)acryli c acid, m.p. 128 ; 96% of theory and 3- C -(3-methyIbutoxy)-3-methoxybenzoy acryli c acid, m.p. 110°; 93.1% of theory, are obtained from the correspond- ingly substituted acetophenones .

30 c ⁾ The substituted acetophenones are prepared as fo l lows:

50 g of 4-hydroxy-3-methoxyacetophenone are dis¬ solved in 100 ml of dimethyIformami de, 94 g of an 80% strength sodium hydride/mineral oil Suspension are added

35 m portions and 40.7 g of n-propyl bromide, dissolved in 200 ml of dimethy Iformami de, are added to the solution when the evolution of hydrogen has ended. The solution is stirred at 100° for 2 hours and freed from the sol-

vent in vacuo; the oi ly residue is partitioned between 2 N sodium hydroxide solution and methylene Chloride and the aqueous phase is extracted twice more with methylene Chloride. After the combined organic extracts have beeπ dried over potassium carbonate, they are evaporated in vacuo and the residue is crystallized from cyclohexane. 50.6 g (80.8% of theory) of 3-methoxy-4-n-p ropoxyaceto- phenone of m.p. 42° are obtained.

The following compounds are obtained in an analo- gous manner: 4-n-butoxy-3-methoxyacet ophenone, m.p. 45°, 82% of theory; 4-ethoxy-3-met hoxyacetophenone, m.p. 76", 90.8% of theory; 4-a l lyloxy-3-methoxyacetophenoπe, boi l- ing point 125 ^c /0.133 mbar, 92.3% of ^theory; 4-isopropyl- oxy-3-methoxyacetophenone, m.p. 111°, 79.7% of theory; 4-sec .-buty loxy-3-methoxyacetophenone, oi l, 95.5% of theory; 4- (3-methy Ibutoxy) -3-methoxya cetophenone, oi l, 95.8% of theory; 4-methoxy-3-n-propoxyacetophenone, m.p. 71°, 68.7% of theory; 3-ethoxy-4-methoxyacetophenone , m.p. 67°, ^" 74.3% of theory; 3-a l ly loxy-4-methoxy- acetophenone, m.p. 49°, 77% of theory; 3-i sopropy loxy-4- ethoxyacetophenone, m.p. 36 , 75.7% of theory; 3-(3- methy Ibutoxy)-4-methoxyacetophenone, oi l, 65% of theory; 3-i sobutoxy-4-methoxyacetophenone, m.p. 69 , 91.8% of theory, 4-i sobutoxy-3-methoxyacetophenone, m.p. 38 , 91.8% of theory.

Example 4: 6-(3-Methoxy-4-n-propoxyphenyl)-3 [2H1 py ridaz- inethione. a) T3.9 g of 3-chloro-6-(3-methoxy-4-n-propoxy- pheny l) py ri dazi ne are boi led under reflux with 5.5 g of thiourea in 50 ml of ethylene glycol monomethyl ether for 8 hours. After cooling, the mixture is di luted with 250 ml of water and extracted three times i h Chloroform. The Chloroform extracts are dried over sodium sulfate and evaporated. The residue is crystallized from ethanol/ ethyl acetate. 4.8 g <-34.6% of theory) of the title com¬ pound of m.p. 174-176° are obtained.

The following com ounds are obtained in an analogous manner: 6- (3-ethoxy-4-methoxypheny l ) -3 C2H] - py ridazi nethione, m.p. 183°, 88.9% of theory; 6-(3-iso-

- r2 - propoxy-4-methoxyphenyl)-3 £ H _] pyridazi nethione, m.p. 168°, 93.4% of theory; 6-(3- sobutoxy-4-met oxyphenyl)- 3 C2H ] pyridazinethione, m.p. 170 , 66.7% of theory; 6- (4-i sobutoxy-3-methoxyphenyl)-3 C2H pyridazi nethione, m.p. 145°, 100% of theory. b ⁾ 29.9 g of 6-(3-methoxy-4-n-propoxypheny l)-3C2H3- pyridazinone are iπtroduced in portions into 65 ml of phosphorus ox de-tri chTori de, with stirring, and the mix¬ ture . s then stirred at 100° for 1 hour. The reaction mixture is concentrated to half in vacuo and poured onto ice, with thorough stirring. The crystals which deposit - are filtered off with suction, washed with water and dried in vaouo. 31.6 g of 3-ch loro-6-(3-methoxy-4-n- propoxyphenyDpyridazine are obtained. The following compounds are obtained in an analo¬ gous manner: 3-chloro-6- (3-ethoxy-4-methoxyphenyl)pyri- dazine, m.p. 141°, 63.9% of theory; 3-c loro-6-(3-i so- propoxy-4-methoxyphenyl)pyridazine, m.p. 144 , 94.9% of theory; 3-chloro-6-(3-isobutoxy-4-methoxyphenyl)pyrida- zine, m.p. 137°, 96.1% of theory; 3-ch loro-6-(4-i sobu- toxy-3-methoxyphenyUpy idazi ne, m.p. 116 , 95.8% of thecr .

Example 5: The sodium salt of 6-(3-methoxy-4-n-propoxy- p enyl)-3 2H3p ridazi none 26 g of 6-(3-methoxy-4-n-propoxyphenyl)-3C2H3- pyridazinone are stirred in 150 ml of methanol with 60 g of sodium methylate (97% pure) at 50° for 30 minutes and the mixture is then evaporated to dryness in vacuo. The colorless residue is extracted by boiling with etha- nol. After drying, 24.8 g (87.9% of theory) are obtained as a colorless solid which does not melt up to 280°. Example 6s 6-(3-Isopropoxy-4-methoxyphenyl)-3[2H 3pyridazinone

^' 9.1 g of 3-isopropoxy-4-methoxyacetophenone are mixed with 4.0 g of glyoxylic acid rnonohydrate, and the mix- ture is heated at 110° for 1.5 hours. After cooling to 50 C, the melt is diluted with 30 ml of water, and the mixture is made alkaline with 10 ml of concentrated aqueous ammonia solution. After addition of 2.2 g of

hydrazine hydrate, the solution is bo led under reflux for 2 hours, the title compound separating out as cry- stals. After cooling the Suspension, the latter is fil¬ tered off with suction, and the filter cake is washed with water to neutrality and dried in vacuo. After re¬ crysta l l i zati on from ethyl acetate, 8.5 g (75.2% of theory) of the title compound, of m.p. 160°, are ob- tai ned.

The following are obtained analogously: 6-(4- i sobütoxy-3-methoxypheny l)-3 L2H pyri.dazi none, m.p.

184 , 42.2% of theory, 6- (3-i sobutoxy-4-methoxypheny l )- 3 [2H pyridazinone, m.p. 186°, 58.4% of theory, 6-(3- ethoxy-4-methoxyphenyl ).-3[2H_] pyridazinone, m.p. 171°, 73.1% of theory and 6- (3-met oxy-4-n-propoxypheny L ) - 3£2H pyridazinone, m.p. 173°, 66.3% of theory.

Example 7: 6-[4-Methoxy-3-(3-methylbutoxy)phenylJ-3[2H3- pyridazi none

18 g of 4-methoxy-3- (3-methy Ibutoxy) acetophenone and 7.7 g of glyoxylic acid monohydrate are mixed and the mixture is heated at 110° for 1.5 hours. After cooling, the melt is dissolved in 50 ml of methanol, 11.6 g of potassium carbonate are added, and the mixture is stirred overnight at 20-25 . The mixture is then neutralized with 84 ml of 1 N hydrochloric acid, 4. g of hydrazine hydrate are added, and the mixture is boiled under reflux for 3 hours. Finally, it is acidified to pH 1 with 20 ml of concentrated hydrochloric acid, again briefly boiled up, and the reaction mixture is largely freed from methanol in vacuo. The resulting reaction product, which is partly an oil and partly crystalline, is extracted with Chloroform, and the combined extracts are dried over sodium sulfate and evaporated in vacuo. After re¬ crysta l li zation of the residue from isopropanol, 9.6 g (43.8% of theory) of the title compound, of m.p. 192 , are obtained. ►•.

The following are obtained analogously: 6- ⁽ 4- methoxy-3-n-propoxypheny l)-3 C2H 3 pyridazinone, m.p. 196°, 17.5% of theory, 6- (3-a l ly loxy-4-methoxypheny l ⁾ - 3 Ü H pyri dazinone, m.p. 175°, 16.3% of theory,

6- (3-ethoxy-4-methoxyphenyl ⁾ -3 [2H 3 p ridazinone, m.p. 171°,15.1% of theory and 6-(4- sopropoxy-3-methoxy- phenyl) -3 C2H pyridazinone, m.p. 200 , 26.4% of theory. Commercial usefulness ^' The 6-ar l-3C2H3pyri dazinones of the general for¬ mula I and those of e bodiments Ia or Ib have valuable properties which render them commerci a L ly useful. Sur- prisingly, they are distinguished by a bronchospasmolytic and/or cardiotonic action which is in some cases con- sider ^' ably superior to that of theophylline or theophyl- line-ethylenediam ne. They also have a more powerful bronchospasmolytic or positive inotropic action than 6- ⁽ 4-methoxyphenyl ⁾ -3C2H3p ridazinone.

The bronchospasmolytic activity of the 6-aryl- ^' * ι ^" 2'---!_-/•"" - ä i - non_. * _" -3..s them to be used in human and vεteπnary medicine, where they are usad for the treat¬ ment and prophylaxis of diseases based on disorders of the bronchi. For example, chronic obstructive respiratory diseases of various origins (bronch tis or bronchial asthma) can be treated in humans and animals.

The positive inotropic activity of the 6-aryl- 3 C2H3pyridazi nones enables them to be used in human or veterinary medicine, where they are used for the treat¬ ment of diseases which are based on cardiac insuff ciency or for strengtheni ng the heart. For example, myocardial nsufficiency, cardiac insufficiency, geriatric heart, myocardial infarction, cardiovascu lar insufficiency, angina pectoris with deficient cardiac Output and coron- ary insufficiency are treated in humans and animals. The invention thus furthermore relates to a method of treating mammals suffering from one of the abovement oned diseases. The method is characterized in that a therapeut ca lly effective and pharmacologi cal ly acceptabie amount of one or more of the compounds accord- ing to the invention is administered to the diseased mamma l.

The invention also relates to medicaments con¬ taining one or more of the 6-ary1-3 2H3pyr dazi nones of

the general formula I or of embodiments Ia or Ib.

The medicaments are prepared by processes which are known per se, the compounds being used as such or, if appropriate, in combination with suitable pharmaceuti- cal excipients. If the new pharmaceut i ca l formulations contain pha rmaceut i ca l excipients in addition to the active compounds, the content of acti e compound in these mixtures is 0.5 to 95, preferably 15 to 75, per cent by weight of the total mixture.

The active compounds or the medicaments are used in any suitable formulation, provided that the establish- ment and maintenance of sufficient levels of active com¬ pound are ensured. This can be achieved, for example, by oral or parenteral admi ni st rat i on in suitable doses. The ph rnace« i ca l formulation of the active compound is usually in the form of unit doses appropriate for the desired admi ni st rat i on. A unit dose can be, for example, a tablet, a coated tablet, a capsule, a suppository or a measured volume of a powder, of a granulär material, of _a solution, of an emulsion or of a Suspension.

"Unit dose" in the context of the present inven¬ tion is understood as a physically discrete unit which contains an individual amount of the active constituent in combination with a pha rmaceut i ca l excipient, the con- tent of active compound in the unit dose corresponding to a fraction or multiple of a therapeutic individual dose. An individual dose preferably contains the amount of active compound which is given in one admi ni st rat i on and which usually corresponds to a whole dai ly dose or a half, one-third or one-quarter of the dai ly dose. If only a fraction, such as a half or one-quarter, of the unit dose is requi red for an individual therapeutic admi nist rat ion, the unit dose is advant ageous ly divisible, for example in the form of a tablet with a breaking groove.

When in the form of unit doses and intended, for example, for admi n i st rat i on to humans, the pha rmaceut i ca l formulations according to the invention can contain about

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5 to.250 mg, advantageous ly 10 to 200 mg and in particu¬ lar 20 to 100 mg, of active compound. Parenteral formu¬ lations can contain about 1 to 50 mg, advantageous ly 3 to 30 mg and in particular 5 to 25 mg, of active compound.

In human medicine, the active compound or com¬ pounds, when these are given orally, are in general administered in a daily dose of 0.1 to 10 mg/kg, prefer¬ ably 0.3 to 5 mg/kg and in particular 0.5 to 3 mg/kg of body .weight, if appropriate in the form of several, pre¬ ferably 1 to 3, individual admi ni strations, to achieve the desired results. An individual admini st rati on con¬ tains the active compound or compounds in amounts of 0.1 to 5 mg/kg, preferably 0.2 to 3 mg/kg and in particular 0.4 to 2 mg/kg of body weight. For admin strati on by inhalation, it is advantageous to administer the active compound or compounds in a daily dose of 0.1 to 10 mg, preferably 0.5 to 5 mg and in particular 1 to 3 mg, if appropriate in the form of several, preferably 1 to 3, individual doses.

Formulations for intravenous admi ni strati on are expedient, in particular, for acute treatment, for example emergency treatment.

The therapeutic admi nist rat on of the pharma- ceutical formulation can take place 1 to 4 times daily at fixed or varying points in time, for example before each meal and/or in the evening. However, it may be necessary to deviate from the dosages mentioned, and in particular to do so as a function of the nature, body weight and age of the individual to be treated, the nature and severity of the disorder, the type of formula¬ tion and of admi ni strat i on of the medicament, and the period or interval within which admi ni strat i on takes place. Thus, in some cases it may be sufficient to manage with less than the abovementi oned amount of active compound, whilst in ofher cases the abovementi oned amount of active compound must be exceeded. In acute cases, a higher dose is administered at the Start of the treatment. When the desired effect Starts, the dose is reduced to a

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■7' - lower. level. The Optimum dosage and type of administra- tion, of the active compounds, required in each particular ^" case can be determined by any expert on the basis of his expert knowledge.

The pharmaceuti ca l formulations as a rule consist of the active compounds according to the invention and non-toxic, pharmaceuti ca l ly acceptabie medicament excipi¬ ents, which are used as an ad ixture or diluent in solid, semi-solid or liquid form, or as a means of encasing, for example in the form of a capsule, a tablet coating, a sachet or some other Container for the therapeuti ca l ly active constituent. An excipient can, for example, serve as a promoter of the absorption of the medicament by the body, as a formulating auxiliary, as a sweetener, as a flavor correctant, as a colorant or as a preservat i ve.

Examples of forms which may be used orally are tablets, coated tablets, hard and soft capsules, for example made of ge.latin, dispersible powders, granules, aqueous and oily suspensions, emulsions, Solutions or si rups.

Tablets may contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating and dispersing agents, for example maize starch or alginates; binders, for example starch, gelatin or gum arabic; and lubricants, for example alum- inum stearate or magnesium stearate, talc or silicone oil. The tablets may additionally be provided with a coating, which can also be such that delayed dissolution and absorption of the medicament in the gast roi nt est i na l tract and hence, for example, better tolerance, a pro- tracted effect or a retarded effect are achieved. Gela¬ tin capsules can contain the medicament mixed w th a solid diluent, for example calcium carbonate or kaolin, or an oily diluent, for example olive oi l, groundnut oi l or paraffi n oil.

Aqueous suspensions, which, if appropriate, are prepared at short notice, may contain suspending agents, for example sodium ca rboxymethy Lee l lu lose, methylcellu-

lose,- hydroxypropyLcel lulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth or gum arabic; dispersiπg agents and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycetanol, po lyoxyethylene- sorbitol monooleate, po lyoxyethylene sorbitan monooleate or lecithin; preservatives, for example methyl or propyl hydroxybenzoates; flavoring agents; and sweeteners, for example sucrose, lactose, sodium cyclamate, dextrose or inve-rt sugar syrup. Oily suspensions may contain, for example, groundnut oil, olive oil, sesame oil, coconut oil or paraffin o l, and thickeners, such as, for example, bees- wax, hard paraffin or cetyl alcohol; and furthermore sweeteners, flavoring agents and ant oxidants. Watei—dispersible powders and granules may con¬ tain the medicaments mixed with dispersing agents, wett¬ ing agents and suspending agents, for example those men¬ tioned above, as well as with sweeteners, flavoring agents and colorants. Emulsions may contain, for example, olive oil, groundnut oil or paraffin o l, in addition to emulsifying agents, such as, for example, gum arabic, gum tragacanth, phosphati des, sorbitan monooleate or polyoxyeth lene sorbitan monooleate, and sweeteners and flavoring agents. For rectal admini strati on of the medicaments, supposi tori es which are prepared with the aid of binders «which melt at the rectal temperature, for example cacao butter or polyethylene glycol, are used.

For parenteral admi ni strati on of the medicaments, steri le-i nj ectable aqueous suspensions, isotonic salt

Solutions or other Solutions, which, if appropriate, are to be prepared at short notice and which contain dispers¬ ing agents or wetting agents and/or pha r acologi ca lly acceptabie diluents, for example propylene glycol or butylene glycol, are used.

Oral admi ni strati on of the medicaments is pre¬ ferred.

For use as a bronchospasmolytic agent, adminis-

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- 49 - tration of the compounds according to the invention by inhalation is also preferred. These compounds are administered either di rectly as powders or by atomizing Solutions or suspensions containing the compounds accord-

₅ ing to the invention. Atomizing can thereby be effected in the conventional manner, for example by compressed air atomi zers or ultrasound atomizers. Administration from spray cans, especi a l ly .those with a conventional metering valve (metered aerosols) is particularly advantageous. By

•jη means of metered aerosols, it is possible to provide a defined amount of active compound per spray jet. So- called synchronous inhalers with which admi ni st rat i on of the active compound can be synchronized with Inhalation are of particular advantage here. Suitable synchronous

^c inhalation devices are disclosed, for example, in German

Patent Speci f i cat i on 1,945,257, German Patent Specifica- tion 1,917,911 and German Offen legungssch ri ft 2,055,734.

For inhalation purposes, the active compounds are preferably used in micronized form, particle sizes of 0 less than 10 μm being advantageous. For admi ni st rat i on from spray cans, the active compounds are dispersed in customary propellants, preferably with the aid of a dis- persing agent. Possible propellants are, in particular, mixtures of t ri ch lorof luoromethane (Frigeπ 11) and 5 di chlorodi f luoromethane (Fri gerhδ l 2) , it being possible for all or some of the t ri ch lorof luoromethane to be replaced by 1 ,1 ,2-t ri ch lorot ri f luoroethane (F ri geιτδ-^113 ) . Possible dispers ing agents are, in particular, the soi— bitan esters customary for these purposes (Spanen from 0 Atlas GmbH) and lecithin. The dispersing agent is dis¬ solved in the propellant co ponent of lower volati lity, which has been initially introduced in cooled form. The micronized active compound is sti rred or the micronized active compounds are stirred into the solution. The 5 dispers ion is fi lled _^ into spray cans. After crimping, the more highly volati le propellant component is forced i n.

The active compound or compounds can also be in

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mi crd-encapsulated form, if appropriate together with one or more of the excipients or additives mentioned. Tablets containing 100 mg of 6- (4-isopropoxy-3-methoxy- phenyl ⁾ -3 C2H3pyridaz none 40 kg of active compound, 24 kg of lactose and

16 kg of maize starch are granulated with 4 kg of poly- vinyIpyrrolidone (molecular weight /*- ^• 25,000) in 5.5 liters of water and the granules are forced through a sieve of 1.25 mm mesh width. After drying, 10 kg of carboxy- methylcel lulose, 4 kg of talc and 2 kg of magnesium stearate are added. The granules are compressed to tablets 9 mm in diameter, 250 mg in weight and with a hardness of 4 to 5 kg on a cam-type machine.

Capsules containing 15 mg of 6-(3-methoxy-4-n-propoxy- phenyl)-3C2H3pyr dazinone

150 mg of active compound, 845 mg of micro- crystalline cellulose and 5 mg of amorphous silica are finely powdered, the powder is mixed thoroughly and size 4 hard gelatin capsules are filled with the mixture. Metered aerosol formulation containing 6- ⁽ 4- sobutoxy- 3-methoxypheπyl)-3r2Hlpyridazinone aroma are 0.270 g of micronized active compound are stirred into the solution and 24 ml cans are filled with the mixture. After crimp- ing, 14.971 g are forced in. With a chamber voLume of the metering valve of 125 ul, 1.6 mg of active compound are released as an aerosol per valve st roke. Siological nvesti ations

The 6-ary 1-3C2H3p ridazi nones of the general formula I have a bronchospasmolytic and/or cardiotonic action which in some cases is considerably superior to that of theophylline o theophyl li ne-eth lenedi amine. In addition, they have a more powerful bronchospasmolytic or positive inotropic action than 6-(4-methoxyphen D- 3 2H3pyr dazi none, as the co parison on known experi- mental designs shows.

The relax ing action of the 6-aryl-3[ H3pyridazi- nones I has been tested in vitro on a chain of tracheal rings (Tr.) of guinea pigs. The positive inotropic ac¬ tion was tested in vitro on the electrically stimulated left atrium of rats (L.a.). The quotient of

^CEC 40pot eft atrium ^{and [EC} 50 ³ 1 rachea ^{serves as a mea"} sure of the organ-select i ve activity. The quotients of the rεc _{cn 4} . . valu-es and CEC _{/ n} . ] . . _t _. . va-

^L 50 ^J trachea * ^■ 40pot. left atrium

Lues or theophylline and the tested compound are repor- ted as a measure of activity.

The compounds are identified in the Tables which follow by a serial number, as follows: 1 : 6-(4-isopropoxy-3-methoxyphenyl)-3[ _. 2H pyridazinone 2: 6- (3-methoxy-4-n-p ropoxypheny l) -3 2H] pyri dazi none 3: 6-(4-n-butoxy-3-methoxypheny l )-3 H1 py ridazi none 4: 6- (4-et hoxy-3-methoxypheny l )-3 C2H 3 pyridazinone 5: 6-(4-allyloxy-3-methoxyphenyl)-3C2H pyridazinone 6: 6- C3-methoxy-4- (3-meth Ibutoxy) -pheny 13 -3 [2 H] pyri - dazinone 7: 6-(4-sec .-butoxy-3-methoxypheny l )-3 C2H p ri dazi none 8: 6- (3-ethoxy-4-methoxyphenyl)-3[2H3 pyri dazi none 9: 6-(3-allyloxy-4-methoxyphenyl)-3C2H pyπ ^' dazinone 10: 6-(4-methoxy-3-n-propoxyphenyl -3 2H3pyridazinone 11 : 6- (4-methoxy-3-isopropoxyphenyl)-3C!2H3 pyri dazi none 12: 6- C4-methoxy-3-G-methylbutoxy ) -pheny 1 -3 [2HJ pyri dazi - none 13: 6-(3-methoxy-4-n-propoxyphenyl -3 2H3pyri dazinethione 14: 6-(3-ethoxy-4-methoxyphenyl -3tT H pyridazi nethione 15: 6-(4-methoxy-3-isobutoxyphenyl)-3t2 3. pyridazinone 16: 6-(3-methoxy _r 4-isobutoxypheny 1 )-3 [i2H ] pyri daz - none 17: 6-(4-methoxy-3-isopropoxyphenyl)-3r_2H ρyHdazi nethione 18: 6-(3-isobutoxy-4-methoxyphenyl)-3C H pyridazi nethione 19: 6-(4-methoxyphenyl)-3C2H|pyridazinone

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Tab le 1 : Bronchospasmoly ic and positive inotropic action, toxicity

Colu n A -igrE _{5Q trachea} Column B -igCεc _{40pot ^} i _{Left atrium} Column C Column D ^l - ^εC 50- ¹ theophylline ^{7 l} " ^EC 5θ ^"i substance Column E

40pot . theophy lline ^L 40pot . ^■ * substance Column F Approximate L ^, ouse p.o., values with * are data on the tolerated dose.

The bronchospasmolyt c act on of the compounds on the chain of tracheal rings of the guinea pig was tested n vitro:

Four para l le l chains of tracheal rings, each consisting of 6 ndividual rings, of guinea pigsCcT and ς>, 430-600 g ⁾ in an organ bath ζ.5 ml, Krebs-Henseleit solution with added phentolamine (10 mol /l), 37 C, initial tension of the organs 2 g, gass.ing with carbogenj develop a stable, spontaneous tonic contraction after about 20 to 30 minutes. Relaxation of these permanently contracted organs can be caused, under isometric measurement condi- tions, by application of the test substance in cumulatively- semi logari thmi cal ly increasing concent ra ion (for example 1x1θ ^"6 + 2x10~ ⁶ + 7x1θ ^"6 + 2x10~ ⁵ etc. mol/l), a con- stant relaxation response being waited for after each individual dose of the test substance before the next higher concentrati on is administered. Over a period of 20 to 30 minutes, a complete dose/action curve of the test substance is thus obtained. The particular relaxa- tion is expressed as a percentage fraction of the maximum relaxation which can be achieved by administrat ion of (-)isoprenaline (10 mol/l). The concentration of the test substance which causes 50% of the maximum relaxation w ich can be achieved, expressed by the negati e loga- rithm of the EC ₅ Q mol/l: -IgCECggl! is a measure of the bronchodi lator activity.

The positive inotropic action of the compounds was tested in vitro on the electrically stimulated left atrium of rats. Isometric contractions (HSE force sensor K-30;

Watanabe recorder. Linear Corder Mark 5) of isolated, left atria from rats Cd*, 250-300. g) in an organ bath ⁽ 10 ml, Tyrode nutrient solution, 31°C, gassing with carbogen, in tial tension of the organs 0.25 g) under electrical Stimulation (HSE stimulator, 7 V, 3 ms, 2 Hz) were recorded. After an equi librat ion time of 30 minutes, a dose-dependent increase in the contraction force can be caused by application of the test substance in cumula- t i ve ly-semi logari thmi ca l ly increasing concentrat on (for

example 1x1θ ^"6 + 2x10 ^"6 + 7x10 ^"6 + 2 X 10~ ⁵ etc. mol/l ⁾ , a constant inotropic response being waited for after each individual dose of the test sub¬ stance before the next higher concentration is administered. The particular ncrease in the contraction force is expressed in % of the starting value before adnrinistration of the substance. The concentration of the test sub¬ stance which potentiate.s the contraction force of the atrium by 40% compared with the starting value

<_ CEC θp' ₀ t. ^rno1 -/ 13, expressed by the negative loga- rithm of the CEC Q _pot mo1/ l_J : -lgCEC 0 _pot 3 serves as a measure of the cardiotonic activity.

The toxicity studies are carried out on female NHRI mice Cbody weight 23-30 g) . The animals C5 animals per dose) receive food and water ad libitum. Various doses of the substances are administered once as a Sus¬ pension in methocel via a gavage. The period of observation lasts 7 days. The tolerated dose (TD), that is to say the highest dose at which as yet none of the animals die, is determined by observation. The average lethal dose (LD _5Q ), that is to say the dose at which 50% of the animals die, is determined from the dose/action curve by means of linear regression.

The in vitro findings are supported by the results of in vivo studies, as can be seen from measure- ments of bronchospasmolysi s in guinea pigs and cardiac contracti lity in guinea pigs and cats.

Table II shows the results of testing of the in- hibition of histamine-induced bronchospasm in anesthetized guinea pigs. Compounds 2, 11,15and 16 prove to be s ignifi cant ly more effective than theophylline.

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Table I : Percentage inhibition of histamine-induced bronchospasm

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Vmax maximum flow rate of the respiratory air duriπi inspiration

Vmax maximum flow rate of the respiratory air duriπg _ expi ration B , ••• breath volume

A method for s imu Ltaneous ly recording pharmaco- dynamic and toxic effects on internal sens i t i ve receptors. on the respiration and .the cardi ovascu lar System of guinea pigs was used [U.Kilian, E. Müller, E. Ch . ttmann 0 and J.'Hamacher, Arzneimittel-Forschung 28 (II) 1699-1708, 19783. The pneumotachogram of anesthetized (ethylure- thane, 1.25 g/kg i.p.), monovagotomi zed, spontaneous ly breathing guinea pigs (0", 350-450 g) was recorded. To characterize the bronchospasm induced by histamine (0.09- 5 0.18 ^j mol /kg i.V.), the maximum flow rate of the res¬ piratory air during inspiration (Vmax .) and expiration (Vmax ) and the breath volume (BV^) were measured. A histamine spasm before adm n st ration of the substance was compared with several histamine spasms after adminis- 0 tration of the substance. The test substances were administered i ntravenous ly (i .v.) and/or i nt raje j una l ly (i.j.) . 5 to 10 animals were used per measurement, and the arith etic mean was calculated from the re¬ sults. 5 Table III: Protective effect against a cetyl choline- induced bronchospasm in conscious guinea pigs

*) Administered in 4% strength methocel Suspension **) fest 45 min. after admi n st rat i on : 5(5) ***) Test 45 min. after adm ni st rat i on : 3(2) The figure in parentheses indicates the number out of > 10 animals in which the latency period more than tripled. The latency period is to be understood to be the time from the Start of acety l cho l i ne-atomi zat i on until clear signs of asth a appeared.

It is clear from Table III, that compounds 1, 2, 10, 13, 15 and 16 produce a greater protective effect against the bronchospasm in conscious guinea pigs caused by acetyl cho l i ne-atom zat ion than does the comparison substance theophylline.

The test procedure was derived from that of T. Olsson, Acta AI lergologi ca 2_6, 438-447(1971): guinea pigs (250-350 g ⁾ in a closed plexiglass cylinder (voLume 5 l) are exposed to a mist of a cety l chol ine (0.06% in 0.9% sodium Chloride solut i on; Heyer Use 77 ultrasonic atomi- zer) twice at an interval of 20 minutes. The time from the Start of atomization to the onset of clear respira¬ tory exertion (in certain c i rcu stances, hypoxic convul- sion in the lateral position) is measured, and is denoted the latency period.

In the control test (without ad ni st rat i on of the substance), the latency period is 2 minutes. The test substance is administered orally by gavage (Standard dose 100 μmol/kg, volume 1 ml of 4% strength methocel Suspension in 0.9% strength sodium chlori de solution/kg). After 30 minutes, the animals are again exposed to the acetyl chol i ne mist, and the latency periods are measured. Prolongation of the latency period to at least twice its length is regarded as a protective effect.

Table IV below shows the results obtained on Langendorff guinea pig hearts -with substances according to the invention compared with theophyll ne, amrinone and 6-(4-methoxyphenyl)-3 [2H ^' l pyridazinone ⁽ serial no. 19) .

Table IV: Percentage increase in the left-ventri cu Lar pressure and the heart rate in guinea pig hearts isolated and perfused by the Langen- dorff method.

* ⁾ EC,„: is not reached

20

EC 20 dose which leads to a 20% increase in the left- ventricular pressure max Maximum percentage increase in the left-ventri- cular pressure which can be reached with the indicated dose of the test substance The compounds according to the invention show a considerably greater increasing effect on the left-ven- tricular pressure than do the comparison substances. In this context, it is particularly important that the in¬ crease in the heart rate is only i nconsiderable.

The measurement of the left-ventri cular pressure, the heart rate and the coronary flow was carried out on isolated and perfused hearts (Langendorff hearts) of guinea pigs ((T and <j>, 400-500 g). After the animals have been sacrificed by a biow to the neck and exsanguination through the carotid arteries, the thoracic cavity is opened, and the aorta is exposed and looped up with a thread. A cannula, which is attached by tubing to the

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apparatus from which the nutrient solution slowly drops, is introduced in the direction of the heart and the heart is, quickly after removal from the thorax, connected to the perfusion apparatus. A balloon probe, connected to a Statham pressure sensor, is advanced through a cut through the left atrium into the left ventricle, and is provided with an initial pressure of ^' 40 mm Hg. Coronary perfusion is carried out at constant pressure (60 cm H ₇ 0) from a Mariott flask containing Krebs-Henselei t solution (37°C, ^' gassing with carbogen). The nutrient solution flowing freely from the coronary sinus into the right atrium is measured with a flow meter (Grefe, Ludenscheid) and, together with the change in the left-ventπ ^* cular pressure and the heart rate determined from this, is re- corded on a Watanabe recorder. The substances are ad¬ ministered in a volume of 0.1 ml of nutrient solution, in the dosage indicated in Tab. IV, within 2 sec, into the perfusion tubing close to ^' the heart, successively in increasing doses to 5 hearts per substance and dose. Table V below shows the results of measurement of the maximum rate of pressure rise in the right ventri¬ cle of guinea pigs.

Table V: Percentage change in the heart funct on dP/dt of gu nea max pigs

Amrinone 0 3 33 8 13

1 40 21 15

3 66 13 20

10 101 39 29

- 30 141 78 69

Theo¬ 10 59 12 20 phylline 30 92 53 67

100 147 135 112 ^'

dP/dt : Maximum rate of pressure rise in the max ri ght vent ri c Le .

It is clear from the values in Table V that the compounds according to the invention which were investi- gated have stronger positive inotropic effects (increase in dP/dt ) than do the co parison substances amrinone max and theophylline.

The effect of the substances on the cont ract i li ty of the heart of guinea.pigs is tested on animals (ό, 400 to 1000 g) under urethane anesthesia. The change in pressure in the right ventricle of the heart is measured with a tip catheter introduced through the right jugular

- 31 - vein and the maximum rate of pressure rise (dP/dt ) is determined from max this. The heart rate is derived from the pressure waves. — No noticeable increases in the heart rate were found. The test substances were administered intravenously. 5- 7 animals were used for each measurement, and the aπ'th- met ^' ic mean was calculated from the results.

Table VI below shows the results of measurement of the percentage maximum rate of pressure rise in the left ventric le of cats. The comparison compounds inves- tigated were amrinone and t heophy 11 i ne-ethy lenedi ami ne . Table VI : Percentage change in the heart function dP/dtmax in the cat

dP/dtmax: Maximum rate of pressure rise in the left ventricle.

The stated dose for t eophy l l i ne-ethy lenedi ami ne relates to the content _^ of theophyll ne.

Substances 2, 5 and 7 have stronger positive inotropic effects (increase in dP/dtmax) than do the comparison compounds, without leadiπg to any considerable increase in the heart rate or end-di asto l i c ventricular

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p ressure .

The effect of the substances on the cont ract i li ty of the heart in cats was tested on animals (0, +, 3.2 to 5.2 kg) under anesthesia with ch lora lose/urethane. The change in pressure in the left ventricle of the heart was measured with a tip catheter introduced through the right carotid artery, the R peak in the ECG (bipolar ehest lead) initiating-a Signal to record the end-dia- stolic pressure; in addition, the maximum rate of pres- sure rise (dP/dtmax) was determined from the change in pressure. The heart rate was derived from the pressure waves. The test substances were administered intra- venously. 2-6 animals were used per measurement, and the arithmetic mean was calculated from the results.

Measurements of blood pressure and heart rate after admini stration of compounds according to the in¬ vention to anesthetized rats showed no adverse findings.

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