IL42613A - Amino-5,6-dihydro-8,9-dialkoxy-imidazo or pyrazolo(1,5-a)isoquinolines their preparation and pharmaceutical compositions containing them - Google Patents

Description

42613/2 VTtT'B»K-»op'i ,?«,»Tt-9,8-i"iT'ri*n-6,5-i3*eK on is o^'aan r npn 'I'tcom Amino-5 »6^dihydro-8,9-dialkoxy-imidazo or pyrazolo l,5-a7isoquinolineB , their preparation and pharmaceutical compositions containing them CHINOIN GYOGYSZER ES VEO-YESZETI TERMEKEK OYARA RT.

» The present invention is directed to new amino-5,6 dihydro-8,9-dialkoxy-imidazo or of the general formula wherein A is an alkoxy group containing 1-4 carbon atoms, B represents a -N=C-NH-D -oarbamido group, wherein D stands for hydrogen, lower alkyl, benzyl, lower alkanoyl, inonohalo-lower-alkanoy1 , benzoyl, phenyl- lower-alkanoyl or a benzosulphonyl group optionally substituted with one or more lower alkyl groups and Y stands for hydrogen, cyano, lower alky1, carboxami do , phenyl group; and salts thereof.

It was found that compounds of the general formula I decrease the resistance of the coronary perfusion increase the perfusion, moderate the oxygen consumption of the heart muscle, improve the oxygenation of the heart, i.e the ratio of supply/O^ demand, and influence in an advan tageous manner the efficiency of the heart-labour.

The compounds of the general formula I are condensed amino imidazole or aminopyrazole derivatives.

The derivatives thereof obtained by condensation with isoquinoline rings are new.

The preparation of the compounds according to the present indention is effected in several cases by ·'ψ new methods.

According to one feature of the present invention aminoimidazole derivatives in which D in the group I -N=C-NHD is hydrogen are prepared by reacting an isoquinoline derivative of the general formula wherein X stands for halogen and A and Y have the same meaning as in formula I with an alkaline salt or an alkaline earth metal salt of cyanamide or with alkali-hydrogen- cyanamide to form an N-monosubstituted cyanamide intermediate which is converted by ring closure into a compound of the general formula la (Reaction scheme 1 ) I/.

The reaction may be carried out with compounds of the general formula II wherein the methylene group attached to the halogen is already substituted with Y, wherein Y stands for cyano or phenyl or with compounds of the general formula II, wherein Y is hydrogen.

The compounds of the general formula II are prepared by cyclizing the acylated derivative of the corresponding 2-phenyl-ethyl-amine , which latter was obtained by acylation with- halogen carboxylic acid by the Bischler-Napieralski reaction.

According tc a further feature of the invention the aminoimidazole derivative may also be prepared by acylating an amidoxime- of the general formula in a basic medium, to form the corresponding O-acyl- derivatives (Chem. Reviews, 62 155 (1962)). Some of these O-acyl-derivatives e.g. the tosylates are split off from the simple'amidoximes in the form of acid and form N- substituted cyanamides by Beckmann rearrangement (2. reaction scheme) . advantageous e.bodi- and as acylating agent sulfonic acid chloride, carboxyl ic acid chloride or carboxylic acid anhydride is used.

The preparation of the compounds of the gener al formula III is described in the Hungarian Patent Spe cification No. 156 811.

Where the aminoimidazoles of the general formula la are prepared by acylating the amidoximes of the general formula III, such compounds of the general formula la may be prepared by using the acylating agent in excess, -whereby the exocyclic amino group is acylated too (NH-Ac).

The ajnino-pvrazole derivative of the general formula lb 3.

HC C - Mj_ It is known that carbon dioxide is removed from the oxadiazole-5-one compounds (J. Heterocyclic Chem.259 .( 1 970,) ) , but the obtained product is very seldom homogeneous (Chem. Ber. lO^ 81 3 ( 1 972.) ) .

According to the present invention the reaction described above may be carried out with a good yield by heating in a melt, or in a non-polar solvent, -..particularly in xylene or tetraline. The reaction was carried out at a temperature above 1 00°C. The same products may be prepared by the alkaline hydrolysis of the compounds of the general formula IV (D=H) at the boiling point.

Compounds of the general formula IV may be prepared by cyclizing the corresponding N-( 2-phenethyl) -1 , 2 , 4-oxydiazolone-5 , 3-yl acetic acid amide derivatives by the Bischler-Uapieralski reaction.

Compounds of the general formula la and lb substituted in the exocyclic amino group are prepared in the following way: a) compounds of the formula la..'or lb containing an unsub- stituted amino group may be converted "e.g. by acylation, by reductive alkylation through a derivative of azomethine, or b) converting a 1 , 2 , 4-oxadiazole-5-one derivative of = general formula IV already substituted on (Reaction 42613/2. . scheme 4) D stands for an alkyl or benzyl group and Y and A are defined above.

It can be definitely proved whether a derivative substituted in the exocyclic nitrogen is an amino-imidazole la or an aminopyrazole lb when, as starting material, an unsubstituted compound of the general forraula la or lb of known structure is used, and the' exocyclic nitrogen is afterwards substituted with the group D e.g. by reductive condensation. In this case the product obtained from N -substituted-l , 2 , 4-oxadiazole- 5-one of the general formula IV may be identified.

In other cases it may be proved by proton-' magnetic jpe*±-&fea»ee if ' a compovind belongs to the la or lb compound group, if both condensed f ve - membered rings contain one C-H bond, this bond is attached to N in the group la and to C in the group lb and thus the position of the methine proton is characterist c for the structure.

According to another feature of the present in-v?ntion aminopyrazoles of the general formula lb and N--acyl derivatives thereof may be also ■ prepared from the compounds of the general formula V hprein R stands for alkyl, monohaloalkyl, phenyl or phenylalkyl, and Y has the same meaning as in formula I.

N-acyl derivative according to reaction scheme 5 may be formed in mild alkaline medium on heating in a melt or in a solvent, or compounds of the general formula lb wherein D stands for hydrogen are directly formed by strong alkaline hydrolysis. (kali Compounds of the general formula ί may be subsequently converted at the methine group of .he five memb ered condensed ring, as e.g. nitration, haiogehatioh Or forming of azo-compounds with diazonium compounds . Said process may be carried out with such representatives of the compounds of the general formula I wherein D is an acyi-protecting group and if desired after the introduction of Y the protecting group is removed by hydrolysis. By reduction of the azo-compounds according to a known method, compounds may be formed wherein YsNHj. Similarly in the case of la the same compounds (Y=NH«) are obtained by the reduction of Y=N0 compounds.

According to an embodiment of the present, invention compounds of the general formula I - wherein Y cyano stands for nitrilo group - may be hydrolized to form compounds of the general formula I wherein Y stands for carb- oxamido or alkoxycarbonyl group.

Acid additional salts of the compounds of the general formula I may be also prepared by reacting the compounds of the formula I with mineral .or organic acids or the corresponding basis are set free from the salts thereof.

The pharmacological tests were carried out in anaesthesized dogs CNembutal 25 mg/kg i.v.) according to the methods described as follows: 1. Effect on the arterial pressure. The arterial medium pressure was measured in the artery carotis of the dogs in a bloody way, by the insertion of a Statham measuring instrument with Hellige electromanometer and was registered by a Hellige multiscriptor continuously. The results are illustrated in table 1. 2. Coronary dilating effect. The coronary perfusion was measured by a thermodilutional process based on constant, steady cold liquid-infusion into the sinus coronarius CSzekeres L. , Papp J.Gy. , Fischer, E . : Acta Physiol. Acad. Sci. Hung. _33 , 115 /1969/) and was registered with the aid of a thermoelement, introduced also into the sinus coronarius on a KIPP Micrograph continuously and was expressed in a voluntary unit, as a ratio of the arterial medium pressure C'Hgmm and of the coronary perfusion, measur are summarized in the table II. 3. Effect on the oxygenization of the heart. In the course of the tests carried out in dogs simultaneously with the measuring of the coronary perfusion the oxygen saturation of the blood sample, sucked with steady speed with peristaltic pump through the KIPP Oxymeter from the sinus coronarius and let back to the branchial vein, was continuously registered. The oxygen saturation of the arterial blood and the haemoglobine content of the blood was also determined with the aid of a Zeiss haemometer. Knowing these data the oxygen consumption of the left heart ventricle was calculated Cml/lOOg . /min .3. To characterize the oxydative metabolism of the heart muscle and of the sufficiency of the oxygen supply the 02 supply/02 demand ratio was also calculated. Details can be found in Sze-keres , L. , Papp, J.Gy., Fischer, E.: European J. Pharmacol* » 1 '/1967/ . The results are shown in the table III. 4. Effect on the efficiency of the labour of the left heart ventricle . The extent of the effect on, the efficiency of the labour of the left heart ventricle was determined on the basis of the labour of the left heart ventricle, calculated from the cardiac output, registered according to the method cold liquid-infusion ( Szekeres ,L. , Papp, J.

Gy. , Fischer, E. : Acta¾Physiol. Acad. Sci. Hung., 33 , 115 /1969/ and from the arterial medium pressure, further-on knowing the oxygen consumption of the left ventricle, calculated as described above on the basis of the ratio of the labour of the left heart ventricle mkg. /min .) : and of the oxygen consumption of the left heart ventricle Cml. /min. /iOO g . The results are shown in the table IV. 5. Toxicity* The acute toxicity investigations were carried out in rats of a bodyweight 150-200 g. The dose Was injected in the caudal vein, within maximum 5 seconds in a volume of 0.2 ml./iOOg. The LD5o value arid the tolerance limits were determined on the basis of the number of the died animals within 24 hours , according to the method of Litchfield and Wilcoxoh C J. Pharmacol, exp. Ther. , 96 > 99 /1949/ .

According to a further feature of the present invention there are provided pharmaceoutical compositions containing as active ingredient a compound of the formula I or a salt thereof in admixture with pharmaceutically acceptable inert , non-toxic organic or inorganic carriers or diluents .

The products may be in form of tablets , capsules , suppositories etc. in semisolid form, e.g. ointment or in liquid form, solution, emulsion or suspension. The products may contain auxiliary materials as stabilizers, wetting, emulgating and suspending agents or salts or buffers causing the alteration of the osmotic pressure and further pharmaceutically acceptable excipients , arid/or further pharmaceutically active substances. 1 Further details of the present invention are, illustrated in the examples without limiting the scope of the invention to the examples. ' -12- 42613/2. { . ! Example la 6.0 g. of technical calcium cyanamide are suspended under heating in 15 ml. of water and 8.0 ml. of a 10% sodium hydroxide solution are added. The mixture is heated for 15 minutes at 50-60°C and the precipitate is filtered. 150 ml. of alcohol are added to the filtrate and the mixture is boiled under reflux. 2,7 g. of l-chbromethyl-6 ,7-dimethoxy-3 ,4-di- hydro-isoquinoline-hydrcchloride are added to the boiling solution within half an hour. Subsequently the reaction mixture is boiled for 4 hours and evaporated to- dryness in vacuo. 50 ml. of water are added to the residue, the and crystalline substance is filtered by suction, iried. 1.8 g. of 3-amino-5 ,6-dihydro-8 ,9-dimethoxy-imidazo- 15 , 1 -ajisoquinoline are obtained . Mp. : 232-236°C. The' product is purified by recrystallization from alcohol.

Analysis: C1'^H15N3°2 calculated found 63.65 % 63,42 % 6.16 % 6.32 % 17.13 % 16.92 % The proton in the position- 1 appears at 6.70 ppm. in CDClg-DMSO solution in the NMR spectrum of the product .

Example lb 13.2 g. of [ 6 ,7-d imethoxy-3 , 4-dihydro-isoquin-oly1- / 1/ J-acet midoxime and 50 ml. of pyridine are mixed together, and while stirring and cooling 9.6 g. of tosyl- _13- 42613/2 . > chloride are added within 15 .inutes . The reaction fixture i. subsequently .ixed for 2 hours at 70°C and allowed to stand for one night in the refrigerator. The precipitated product is filtered by suction, washed with absolute alcohol and dried. 9.2 g. of 3-a.ino-B ,6-dihydro-B ,9- -din.ethoxy-i.idazo .l-aHsoauinoiine-hydrochloride are obtained. Mp. : 272-274 0 (from alcohol). The hydrochloride salt is dissolved in hot water to set free the base , and the solution is nade alkaline with 10$ sodium hydroxide solution.

A crystallized base is obtained, which is identical with the product of Example 1a.

Example 1 c According to the method described in Example 1b 25.6 g. of 3-amino-5 ,6-dihydro-8,9-dimethoxy-imidazo^5, 1 -a7isoquinor line-hydrochloride are obtained from 29.0 g. of β> ,7-dimethoxy-3,4-dihydro-isoquinolyl-(l 7-acetamidoxime and 13 ml. of benzoyl-dihydro-isoquinolyl-( 1 )-acetamidoxime and 13 ml. of benzoyl-chloride. The product is identical with that of Example 1b.

The same product is obtained if in the above reaction ethyl-chlorocarbonate is used instead of benzoyl- chloride .

Example 2. 14.56 g. of C 6 ,7-diethoxy-3 ,4-dihydro-isoquin-olyl-/l/H-acetamidoxime and 60 ml. of pyridine are mixed and while stirring and cooling 7.6 g. of benzoyl- chloride are added. Subsequently the mixture is stirred at 50-60°C, suspended in ethyl acetate and thus 12.65 g. of 3-amino- -5 ,6-dihydro-8 , 9-diethoxy-imidazo[5 ,1-al isoquinoline- -hydrochloride-rnonohydrate are obtained. Mp. : 206- 208°C (from alcohol).

Analysis: C15H22N3°3C1 Calculated: Found: C: 54.96 % 54.81 % H: ' i 6.77 % 6.64 % N: 12.81 % 12.76 % CI: 10.82 % 10.69 % dis The said hydrochloride s alt is/solved in 70 ml. of warm water, the solution is .clarified with charccal , 10% filtered and alkalized with/sodium hydroxide solution . 9.7 g. of 3-amino-5 ,6-dihydro-8 ,9- -diethoxy-irnidazo[5 , 1-a] isoquinoline are obtained. Mp . : 212-217°C Cfrom alcohol).

Analysis: ci5HigN3°2 calculated : found 65.91 ¾ 66.10 7.01 % 6.95 15.37 % Example 3 3.2 g. of technical calcium cyanamide are mixed in 9 ml. of a 10 sodium hydroxide solution for a quarter of an hour at 60-70°C and the mixture is filtered. 80 ml. of alcohol are added to the filtrate, i-.he mixture is boiled and 3.34 g. of 1- /1-chloroethy 1/ --6 , 7-dimethoxy- 3 , 4-dihydro- isoqu inol ne-hyd ochlorid e are. added to the boiling mixture (Arch, der Pharm. 277 , 177, -16- 42613/2 is filtered and alkalized with 10 sodium hydroxide solution. The crystallized product is filtered, washed with water and dried. Thus 3 g. of 2-amino-5 , 6-dihydro-8 , 9-dimethoxy- -pyrazolo- 5 , 1-aJ isoquinoline are obtained. Mp.: 216- -217°C (from alcohol .

Analysis: C^H^^O,, Calculated: Found: C: 63.65 63.45 % H: 6.16 '% 6.40 % N: 17.13 % 16.95 %.

The pro.ton in the position 1 appears at 5.85 ppm. in the NMR spectrum of the product.

Example 5b 65 ml. of. xylene are added to 13 g. of 3-C6,7- 2 -dimethoxy-3 ,4-dihydro-l-isoquinoly0 -methyl- A -1,2,4--oxadiazoline- 5-one and the reaction mixture is boiled under reflux for 3 hours . After .^cooling the precipitated crystals are filtered and dried. Thus 10 g. of 2-amino--5 , 6-dihydro- 8 , 9-dimethoxy-pyrazolo-C5 ,l-a3isoqinoline are obtained. The product is identical with the product de-scribed in Example 5a Upon addition of alcoholic hydrogen chloride to the 96% alcoholic solution of the product, the hydrochloride salt, 2-amino-5 , 6 -d ihydro- 8 , 9-dime thoxy-pyrazolo-C5 ^-a^iso-quinoline-hydrochloride-dihydrate is crystallized. Mp. : 128-130°C.

Analysis.. : C^H^N^Cl Calculated: Found: : 49.13 % 49.30 % Calculated : Found: /cont./ H: 6.34 % 6.11 % •N: 13.22 % 12.98 % CI: 11.16 % 11.27 % Example 5c 10% solution of 20 ml. of /sodium hydroxide in a oonoontration of 10-%- are added to 1.6 g. of 3-[6 ,7-dimethoxy-3 ,4-dihydro--l-isoquinolyr]-methyl-Δ2-1,2 ,4-oxadiazoline-5-one and the reaction mixture is boiled under reflux for 8 hours. After cooling 0.9 g. of 2-amino-5 , 6-dihydro-8 , 9-dimeth-oxy-pyrazolo-[5 ,l-a"]-isoquinoline is crystallized and the product is identical with the product described in the Example 5a. The LD5q value and the 95 % tolerance limits are 70 /34-148/ mg/kg.

According to the facts described above the product decreases the arterial blood pressure in a dose of 1-4 mg/kg i.v. , increases the coronary perfusion, decreases the coronary resistance, decreases the oxygen consumption of the heart muscle and improves i.e. increases the ratio 02 supply/02 demand expressing the oxygenation of the heart and influences favourably the efficiency of the heart labour. All these facts show, that under the circumstances of animal-tests the compound meets the requirements of antianginal agents .

Table I Table IV Example 6a a 10% solution of 50 ml. of alcohol and 10 ml. of/sodium hydroxide in a oonoontration of 10 % are added to 1.75 g. of 3- -[6 ,7-dimethoxy-3 ,4-dihydro-l-isoquinolyl}-methyl-5- -phenyl-1,2 ,4-oxadiazole and the reaction mixture is boiled under reflux for 3 hours. The alcohol is evaporated in vacuo and water is added to the residue. Thus 1,2 g. of 2-benzoyl amino-5 ,6-dihydro-8 ,9-dimethoxy-pyrazolo-[5 ,1-aJisoquinoline are obtained, the product is identical with the product described in Example 17.

Example 6b 10 ml. of xylene are added to 1 g. of 3-[6,7- dimethoxy- 3 , 4-dihydro- 1-isoquinolyΓ] -methyl- 5-phenyl- -1 ,2 ,4-oxadiazole and the reaction mixture is boiled under reflux for 8 hours. After cooling 0.9 g. of 2-benzoyl- amino-5,6-dihydro-8 ,9-dimethoxy-pyrazoloC5 ,1-a^isoquin- oline crystallizes , the product is identical with the product of the Example 6a.

Example 7 a 40% solution of 25 ml. of alcohol and 7 ml. of sodium hydroxide a oonoontpation of UP % are added to 1 g. of 3-^6,7--dimethoxy-3 ,4-dihydro-l-isoquinolyI]-jnethyl-5-phenyl--1,2, -oxadiazole and the reaction mixture is boiled under reflux for 8 hours. Subsequently the alcohol is evaporated in vacuo and water is added to the residue. 0.6 g. of 2-amino-5 ,6-dihydro-8 j 9-dimethoxy-pyrazolo [5 ,l-a~]iso-qUinoline are crystallized and the product is identical with the product described in Example 5.

Example 8a 2 g. of 3-('6 ,7-dimethoxy-3 ,4-dihydro-l-isoquin-olyl)-methyl-4-benzyl- ^2-l,2 ,4-oxydiazoline-5-one are melted oh a metal base of 170-180°C. After cooling the product is crystallized from benzene and thus 1.2 g. of 3-benzyl-amino-5 ,6-dihydro-8 , 9-dimethoxy-imidazo ['5 ,1-a]-isoquinoline are obtained. Mp. : 135°C.

Analysis: C20H2lN3°2 Calculated: Found: C: 71.62 % 71.52 % H: 6.31 % 5.98 % N: 12.53 % 12.42 % The proton in the position 1 appears at 6.85 ppm. in the NMR spectrum of the product...

Example 8b 10 ml. of xylene are adddd to 1.5 g. of 3-(6,7--dimethoxy-3 ,4-dihydro-l-isoquinolyl) -methyl-4-benzyl-- A -l» ,4-oxadiazoline-5-one and the mixture is boiled under reflux for 2 hours. After cooling 1.1 g. of 3-benz- described in Example 8a.

Example 8c 1.1 g. of benzaldehyde and 20 ml. of absolute alcohol are added to 2.3 g. of 3-amino-5 , 6-dihydro-8 , 9- -dimethoxy-imidazoL5 ,1-aJisoquinoline and the reaction mixture is boiled under reflux for 5 hours. After cooling 3.1 g. of 3-benzilidene-amino-5 ,6-dihydro-8 , 9-dimethoxy- -imidazo-[5 ,l-a]isoquinoline are crystallized. Mp. : 176°C (from alcohol).

Analysis: C H N 0 20 19 3 2 Calculated: Found: C: 72. o5 % 72.35 % H: 5.75 % 5.80% N: 12.61 % 12.69 % 1.6 g. of the saicf product are dissolved in 100 ml. of methanol and 0.5 g. of sodium borohydride are added to the solution within half an hour. Subsequently the solution is allowed to stand at room temperature whereafter the solvent is evaporated. Water is added to the residue which crystallizes. The product is filtered and dried. 1.7 g. of 3-benzylamino-5 ,6-dihydro-8 ,9-di-methoxy-imidazo[5 ,l-a"]isoquinoline are obtained and the product is identical with that of Example 8a. 1.7 g. of the above product are dissolved in methanolic hot methanol and the warm solution is acidified with^hydro- acid chloric methanol. After cooling l.H g. of 3-benzylamino--5 , 6-dihydro-8 ,9-dimethoxy-imidazo[ 5 ,'1-a isoquinoline--tfydrochlorid are crystallized. Mp.: 250-252 C.

. . Calculated: Found : C: 64.59 % 64.48 % H: 5.96 % 6.o2 % N: 11.31 % 11.50 % CI: 9.53 % 9.31 % The compound increases the contractility by 40% in a dose of 1-2 mg/kg. for 26-28 minutes. The cardiac output is increased by 30 % in narcotized dogs in a dose of 2 mg./kg., the duration of the effect is 16 minutes. The resistance of the pulmonal vascular system is decreased in a dose of 2 mg./kg. for 22 minutes. The compound improves the efficiency of the heart function of the narcotized dog. In a dose of 0.5 mg./kg. the compound causes an 77% increase of the femoral perfusion in arcot-ized dogs for 16 minutes. It increases the perfusion of the carotid system by 31 % for 24 minutes in a dose of 1 mg./kg. In the state of in situ the compound increased the electric fibrillar thershold of the cat-heart-atrial muscle-system by 104% in a dose of 2 mg./kg. The compound increased the electric fibrillar threshold of the cat--heart ventricle muscle-system in the state of in situ in a dose of 2 mg./kg. by 50% for 41 minutes and by 82% in a dose of 4 mg./kg.

Example 9a 10% pi solution 70 ml. of/s <¾um hydroxide iji a oonoontration of and 400 ml. of alcohol are added to 10 g. of 3-(6,7- -dimethoxy-3 ,4-dihydro-l-isoquinolyl)-methyl-4-benzyl- _ Δ2-ι , 2 ,4-oxadiazoline-5-one and the reaction mixture the residue. 8 g. of 2-benzylamino-5 ,6-dihydro-e, methoxy-pyrazolo[.5,l-aj[isoquinoline are obtained. 156 °C ffrom alcohol).

Analysis: C^H^N^ Calculated: Found: 71.62 % 71.86 % 6.31 % 6.08 % 12.53 % 12.64 % Example 9b 0.6 g. of benzaidehyde and 10 ml. of absolute alcohol are added to 1.2 g. of 2-amino-5 , 6-dihydro-8 ,9- -dimethoxy-pyrazolo£5 ,1-aJisoquinoline and the reaction mixture is boiled under reflux for/hours. After cooling 1.1 g. of 2-behzylidene-amino-5 ,6-dihydro-8 ,9-dimethoxy--pyΓazolo-j;5,l-a' isoquinoline are obtained in crystallized form. Mp. : 163°C.

Analysis: C2oH19N3°2 Calculated 72.05 % 5.75 % 12.61 % Ό.9 g. of the above product are dissolved in 100 ml. of methanol and 0.2 g. of sodium borohydride are added to the solution. The solution ie allowed to stand for an hour whereafter the solvent is evaporated in vacuo. Water is added to the residue. Thus 0.8 g. of 2-benzyl--amino- 5 , 6-dihydro- 8 , 9-dimethoxy-pyrazolo[5 ,l-a]isoquin- e roduct is identical with that of -24- 42613/2 5.7 g. of the above product are dissolved in 80 ml. of acetone and the solution is acidified with anhydrous alcoholic hydrochloric acid. 5.5 g. of 2-benzylamino-5 ,6-dihydro-8 ,9-di- methoxy-pyrazolo[ 5 , l-ajisoquinoline-hydrochloride are / crystallized. Mp.: 206-20B °C.

Analysis: C^H^NgOjCl Calculated': Found: C: 64.59 % 64.70% H: 5.96 % 6.12 % N: 11.31 % 11.52 % CI: 9.53 % ' 9.38 % The proton in the position 1 appears at 5.73 ppm. in the NMR spectrum of the .product.

Example 10 14 ml. of 10 sodium hydroxide solution and 80 ml. of 'alcohol are added to 2 g. of 3-(6,7-d ethoxy-3 ,4-dihydro-l-isoquinolyl) -methyl- -benzyl- .Δ^--1 , 2 , 4-oxadiazoline- 5-one and the raction mixture is boiled under reflux for an hour. Subsequently the mixture is hess evaporated to dry/ and water is added to the residue. Thus 1,5 g. of 2-benzylamino-5 ,6-dihydro-8 , 9-diethoxy-pyrazolo- 5 , 1-a isoquinoline are obtained. Mp.: 130-131°C (f:oom butanoli .

Analysis: C„7H9 cH-O- Calculated : Found : 72.70 % 72.51 6.93 % 6.86 % 11.80 A ■ -25- Example 11 5 ml. of acetic acid anhydride are added to 1 g. of 2-amino-5 ,6-dihydro-8 ,9-dimethoxy-pyrazolo[5 ,l-a3iso- quinoline, the reaction mixture is heated on water bath for 10 minutes and allowed to stand for an hour. After pouring on ice 0.8 g. of 2-acetylamino-5 ,6-dihydro-8 , 9--dimethoxy-pyrazolo[5 ,l-a3isoquinoline are crystallized. Mp. : 223°C (from 75% alcohol).

Analysis: C1C.H, 7Νο0» Calculated : Found : 62.70 % 62.56 % 5.96 % 5.78 % 14.63 % 14.60 % Example 12 20 ml. of chloroform and 1,4 g. of potassium carbonate are added to 2.45 g. of 2-amino-5 ,6-dihydro--8 ,9-dimethoxy-pyrazoloC5 ,1-alisoquinoline and 1.15 g. of chlbrpacetyl chloride are added under stirring. Subsequently the mixture is stirred for 5 hours at room temperature and 20 ml. of water are added. The chloroformic phase is separated, dried over sodium sulphate and evaporated. 2 g. of 2-chloro-acetyl-amino-5 ,6-dihydro-8 ,9-di-methoxy-pyraz0loC5 ,l-a]isoquinoline are obtained. Mp. : 152-154°C Cfrom alcohol).

Analysis : C H N 0 CI 15 16 3 3 Calculated: Found: C: 55.99% 56.10% Example 13 30 ml. of acetic acid anhydride are added to 8 g. of 3-amino-5 ,6-dihydro-8 ,9-dimethoxy-imidazo[. ,l-a.| isoquinoline and the mixture is heated on water bath for half an hour. The mixture is poured on 150 ml. of icy water. The solution is neturalized with sodium carbonate and the precipitated crystals are filtered. Thus 6.2 g. o 3 -acetyl-amino- 5 ,6-dihydro- 8 ,9-dimethoxy-imidazol5 ,1-a] i quinoline are obtained. Mp. : 225°C Cfrom absolute alcohol) .

Analysis: ci5H 7N3°3 Calculated: Found: C: 62.70% 62.40% H: 5.96 5.90% N: 14.63% 14.69% Example 14 30 ml. of chloroform and 1.4 g, of potassium carbonate are added to 2.45 g. of 3 -amino-5 ,6-dihydro- 8 , -dimethoxy-imidazo 5 ,1-aJisoquinoline and under stirring 1.15 g. of chloroacetyl chloride are added. The mixture is stirred at room temperature for 5 hours and 20 ml. of water are added. The chloroformic solution is separated, dried over sodium sulphate and evaporated. 1.4 g. of 3-chloro-aCetylamino-5 ,6-dihydro-8 ,9-dimeth ar-imidazo-[5 ,l-a]isoquinoline are obtained. Mp. : 251°C Cfrom alcohol.) .

Analysis: C15H16N303C1 Calculated: Found: Calculated: Found: /Cont./ H: 5.ol% 4.93% N: 13.o6% 12.84% CI: ll.o2% 11.16% Example 15 1 g. of technical caldum cyanamide are sus nn; · 10 ed in 5 ml. of luke warm water and 1.4 ml. of/sodium solution hydroxide/ re added in a oonoontration of 10 % . -The mixture B stirred at 50 to 60°C for a quarter of an hour and the precipitate is filtered. 50 ml. of alcohol are added to the filtrate and the mixture is boiled. 1 g. of c -bromo-6 ,7-dimethoxy-3 ,4-dihydro-l-isoquinolyl aceto- nitrile are added to the boiling solution. The reaction mixture is boiled for 4 hours and is evaporated to dryness. Water is added to the residue. Thus 0.6 g. of 1- ai. -3-amino-5 ,6-dihydro-8 ,9-dimethoxy-imidazoC5 ,1-a^iso- quinoline are obtained. Mp.: 236°C Cfrom alcohol).

Analysis: εΐ4Ηΐ4Ν4°2 Calculated: Found: C: 62.21% 61.61% H: 5.22% 5.30% N: 2o.73% 2o.41% Example 16 15.ml. of water and 0.7 g. of benzoyl chloride are added to 1 g. of 3-amino-5 ,6-dihydro-8 ,9-dimethoxy-,-imidazo[5 ,l-a]J isoquinoline and the pH value of the reaction mixture is held under stirring and cooling at a value 10% of 10-11 by adding. absolution of sodium hydroxide in a aminQ-5,6-dihydro-ai.,'9-4'imethoxy-imida2oC:5 ,l-a^isoqu^.noli are obtained. Mp. : 258°C (from alcohol^..

Analysis: ¾Η19Ν303 Calculated: Found: C: ,. , : ., .68.75% 68.60% H: 5.48% 5.74% N: ' 12.o3% 12;o5% Example' 1-7 0.7 g. of benzoyl chloride are reacted with 1 g. of 2-amino-5 ,6-dihydro-8 , 9-dimethoxy-pyrazolo- 5 ,1-a]- isoquinoline according to the method described in Example 15 and thus 1 g. of 2-benzoyl-amino-5 ,6-dihydro-8 ,9-di-methoxy-pyrazolo 5 ,1-a] isoquinoline are obtained. Mp. : 185°C (from alcohol).

Analysis: C2o¾gN3°3 Calculated: Found: C: , 68.75% . 68.52% H: 5.48% 5.65% 12.o3% 11.83% Example 18 10 ml. of 2-h/-hydrochloric acid solution are added to 0.5 g. of 2-acetylamino-5 ,6-dihydro-8 ,9-dimeth-oxy-pyrazoXo [5 ,l-a3isoquinoline and the reaction mixture is boiled under reflux for half an hour. On cooling 0.5 g. of 2-amino-5 ,6-dihydro-8 ,9-dimethoxy-pyrazolo 5,1-a iso-quinoline-hydrochloride-dihydrate are crystallized, the product is identical with the product of the Example 5. -29- 42613/2 ' Example 19 15 ml. of a 5 sodium hydroxide solution are added to 1.3 g. of 3-acetylamino- ,-5,6-dihydro-8,9-dimethoxy-imidazo(5,l-aJisoquinoline and the reaction mixture is boiled for an hour under reflux. On cooling 0.8 g. of 3-amino-5 ,6-dihydro-8 , 9-dimethoxy- -imidazot.5 ,1-a"] ieoquinoline are crystallized, the product is identical with the product of the Example l.-Mp.: 234-236°C.

Example 20 10 ml. of xylene are added to 1.0 g. of 3- (6 ,7- -dimethoxy-3 ,4-dihydro-l-isoquinolyl) -methyl-5-propyl- -1»2 ,4-oxidiazole and the reaction mixture is boiled for 8 hours under reflux. The solvent is evaporated in vacuo and the residue is recrystallized from aqueous alcohol. 0.7 g. of 2-butiryl-amino-5 ,6-dihydro-8 ,9-dimethoxy- s pyrazolo [5yl-aUisoquinoline-hemihydrate are obtained.

Mp.: 125-127°C.

Analysis: 1 2H20 Calculated: Found: C: 62.94% 62.80 H: 6.84% 6.71c> N: 12.96% 12.75? Example 21 140 mg. of 3-(6 ,7-dimethoxy-3 ,4-dihycro-l- 2 -isoquinolyl) -methyl-4-ethyl- A -1 ,2 ,4-oxadiazoli;-e-5--one are mixed with 4 ml. of alcohol end.1' ml. of a 10/» nd the reaction mixture -3o- is evaporated in vacuo and water is added to the residue. 81 mg. of 2-ethylami.no- 5 , 6-dihydro-8 j9-dimethoxy-pyrazolo Γδ jl-alisoquinoline are obtained. Hp.: 114~1160c ·..' ί: ».·οηι alcohol benzinelCd^") .

Analysis: c 5Hi9N3°2 Calculated: Found: C: 65.91% .65.92% H: . 7.ol% 6.93% .

N: 15.38% . 15.13% Example 22 · · ' i 10 ml of pyridine and 1,9 g of p-toluene sulphonic acid chloride are added to 2,45 g of 2-amino-5,6- -dihydro-8, 9-dimethoxy-pyrazolo/5 , 1-a/isoquinoline , the reaction mixture is ¾eated o a water bath for five minutes. After pouring into water 33 g 2- (4-toluol- sulphonylarr.i no,)-5 , 6-dihydro-8 , 9-dime thoxy-pyrazolo/5 , 1-a/- isoquinoline are obtained. After cry stalli spti on the rcp. is 259-261 °C (from dioxan)'.

Analysis: Calculated found C: 60,13.1* 59,94 * H: 5,29 5 ,45 5i K: 10,52 ·ί 10,36 Example 23 0,7 g of l-cyano-3-anino-5 , 6-dih dro-8, 9-dimethoxy- -inidazo- 5 , 1-a/isoquinoline are added in portions to 4, 0 ml of cone, sulphuric acid with stirring; and the reaction mixture is allowed to stand for a day at room temperature. After pouring into ice the precipitated crystals- are— filtered- off— and— 15 ml -of -hot- Avater- are added.

After washing the solution alkaline 0, g of -3-anino-5, 6-dihydro-8, 9-diraethoxy-imidazo/5 , 1-a/isoquinoline are obtained.

Kp.: I43-I4 °C ( from alcohol) Analysis: C-^H^N^ ' Calcula ed found * » C: 58,32 58,05 H: 5,59 ^ 5,33 ' .

N: 19,43 # ' 19,27 , £ o e n ove product are disso ved in 10 '.ml of a ,5 N hot hydrochloric acid solution. After cooling .0, 45 g l-cartoxanido-3-amino-5 , G-dihydro-8 ,'"9-dimethoxy--imidazo 5 , -a/isoquinoline h'/drochloride crystallise.

Iv'.p. : 300-305 °C.

Analysis: -^^H^^N^O^Cl calculated found 0: ' 51,77 co 51,55 ?S N: 17,25 ^ 16,95 i Cl: 10,92 11,08 # Example 24 1,5 g of sodiuiQ-hydrogen-cyananide are dissolved in 30 ml of hot anhydrous ethanol and 1,25 g of l-0( -chlorobenzyl--6,7-diraethoxy-3,4-dihydro-i3oquinoline are added to the solution, subsequently the reaction mixture is oi- ed for 6 hours and evaporated to dryness in vacuo. Benzene is added to the residue, the benzene phase, is separated and dried over sodium sulphate and evaporated and ethyl acetat is added to the residue. 0,3 g of l-phenyl-3-arino-5 -dihydro-8,9-direthoxy-imidazo/5,l-¾/isoquinoline are crystallized. I.lp. : 235-236 °C (from ethanol) .

Analysis: -^Η-^Ν^^ Calculated found C: 7l,0l : . 70,78 K: 5,96 5,74 5* : 13,08 ■ 13,00 si

Claims (1)

1. - 33 - 42613/2 CLAIMS: 1. Amino-5 , 6-dihydro-8, 9-dialkoxy-imidazo or pyrazolo [1,5-a] isoquinolints of the general formula wherein A is an alkoxy group containing 1-4 carbon atoms , B represents a -N=C-NH-D carbamido group, wherein D stands for hydrogen, lower alkyl, benzyl, lower " alkanoyl, monohalo-lower-alkanoyl, benzoyl, phenyl- lower-alkanoyl or a benzosulphonyl group optionally substituted with one or more lower alkyl groups and Y stands for hydrogen, cyano, lower alkyl, carboxamido , or phenyl group', and salts thereof. 2. 3-amino-5 , 6-dihydro- 8 ,9-dimethoxy-imidazo- [5 ,l-a]isoquinoline and salts thereof. 3; 3-amino-5 , 6-dihydro- 8 , 9-diethoxy-imidazo-[5 jl-alisoquinoline and salts thereof. 4. l-methyl-3-amino-5 , 6-dihydro-8 ,9-dimethoxy--imidazo Γ5 ,l-alisoquinoline and salts thereof. 5. 2-phenyl-acetyl-amino-5 , 6-dihydro- 8 ,9--dimethoxy-pyrazolo Q5 ,1-alisoquinoline and salts thereof. 6. 2-amino-5 ,6-dihydro-8 , 9-dimethoxy-pyrazolo-[5 ,l-a"]isoquinoline and salts thereof. 7. 3-benzylamino- 5 , 6-dihydro- 8 , 9-dimethoxy- -imidazo [5 ,l-a]isoquinoline and salts thereof. - 34 - 42613/2 8. 2-benzylamino-5 ,6-dihydro-8 ,9-dimethoxy- aid salts thereof. 9. 2-benzylamino-516--dlhydro-8)9-diethoxy- · -pyra;iolo[5 ,1-al .isoquinoli ne nd u.^lts tbf-.roof.. 10. 2-acetyl ;-unino~5 ,G--dihydro~8 , 9~d inethoxy- -pyrazolo[5 ,i-a1isoquinoline and salts thereof. . . 11. 2-chloi',o,icetylamino-5 ,6-dihydro-8 ,9-d.i.inet; oxy-pyrazolo[5 ,1-alisoquinoline and salts thereof. . 12. 3-acety.lamino-5 ,6-dihydro-8 , 9-d.imethoxy- -i .idazoC5 , l-ajisoquinoline and salts thereof. 13 3-chloroacetyl-amino-5 ,6-dihydro-8 ,9-di- methoxy-imidazo[5,l-alisoquinoline and salts thereof. 14. l-cyano-3-amino-5 , 6-d.ihydro-8 , 9-dim thoxy- -imidazo [5 , 1-alisoquinoline and salts thereof. 15. 3-benzolyamino-5 ,6-dihydro-8 ,9-dimethoxy- -imidazoC5 ,l-a7isoquinoline and salts thereof. IB. 2-benzoylamino-5 ,6-dihydro-8 , 9-dirnethoxy- -pyrazolo[5 ,1-a.!isoquinoline and salts thereof. 17. 2-but rylamino-5 ,6-dihydro-8 ,9-dimethoxy-—pyrazolo£5 ,l-a3isoquinoline-hemiydrate and salts thereof 18. 2-ethylamino-5 ,6-dihydro-8 ,9-d.imethoxy-— yrazolo£.5 ,1-alisoquinoline and salts thereof. 19. A process for the preparation of 3-amino- imidazo [5 ,1-a] isoquinoline derivatives of formula I in Claim 1 in which D in the group -N=C-NHD is hydrogen and A and Y have the same meaning as in Claim 1 which comprises reacting a compound of the general formula II - 35 - 42613/3 or the acid addition salt thereof, wherein A' and Y are as defined above arm X is halogen, with an alkaline salt or an alkaline earth metal salt of cyanami de or with alkali-hydrogen-cyanamide . 20. Process for the preparation of the 3-ajnino- -imidazo [5 , l-a] isoguinoline derivatives of the general formula I in Claim 1 in which D in the group -N=C-NHD has' benzyl,; A has the same meaning as in Claim 1 and Y stands for hydrogen," carboxamido, alkyl or phenyl, which comprises reacting an isoquinolyl-acetamidoxi e of the general formula wherein A and Y are as defined above, with a sulfonic r acid halide in equimoi ar amount or in excess or with a carboxylic acid chloride or anhydride as acylating ageirt. - 36 - 42613/2 21. A process for the preparation of compounds of the general formula I in Claim 1 wherein A is as defined in Claim 1, D in the group -N=C-NHD is other than hydrogen, lower alkyl or benzyl and Y has the same—meaning—as -in _ a compound of the general formula I in Claim 1 wherein A and Y are as defined above and D is hydrogen with a sulfonic acid halide or a carboxylic acid derivative. 22. A process for the preparation of pyrazolo- [5 ,1-a] isoquinoline derivatives of the general formula I in Claim 1 wherein A is as defined in Claim 1, Y is as defined in Claim 20 and D is hydrogen, which comprises subjecting a compound of the general formula wherein A, Y and D are as defined above, to heating in a solvent ..or in a -melt or—tO-aqueo.us_ o -alkaline hydrolys 23. Process according to Claim 22 wherein xylene or tetraline are used as a solvent. 24. Process according to Claim 22 wherein the reaction is carried out at above 100°C. I 25. Process according to Claim 22 wherein the reaction is effected by boiling the compound IV with aqueous alkali. - 37 - 42613/2 26. Process for the preparation of compounds of formula I in Claim 1 in which A and D are as defined in Claim 20 and Y is as defined in Claim 21, which comprises converting a compound of the general formula wherein Y is as defined in Claim 20 and. R is alkyl, monohaloalkyl, phenyl or phenylalkyl in mild alkaline medium, in a solvent or in the form of a melt. 27. Process for the preparation of compounds of formula I in Claim 1 in which D is hydrogen and Y is as defined in Claim 20, which comprises subjecting a compound of the general formula V wherein Y and R are as defined in Claim 26 to strong alkaline effect. 28. Process for the preparation of pyrazolo- in Claim 1, wherein A is as defined in Claim 1, Y is as defined in Claim 20 and D represents an alkyl or benzyl group, which comprises subjecting a compound of the general formula IV in Claim 22 wherein A, Y and D are as defined above, to alkaline hydrolysis. - - 29· Process for the preparation of compounds of the general formula I in Claim' 1 wherein A is as defined in Claim 1, Y stands for hydrogen, carboxamido, alkyl or phenyl and D stands for alkyl or benzyl, which comprises subjecting a compound of the general formula I wherein A and Y are as defined above and D stands for hydrogen, to reductive condensation with aldehydes containing a lower alkyl or phenyl-lower-alkyl group and simultaneously reducing or, if desired, isolating the reaction product and then reducing it. 30. Process for the preparation of· ircidazo- [5,1-aJisoquinoline derivatives of the general formula I in Claim 1 wherein Λ is ac defined in Claim 1, Y is as defined in Claim 20 and D stands for alkyl or benzyl, which comprises heating a compound of the general forir.ula IV wherein A, Y and D are as defined above at a temperature above 100°C in a solvent or in the form of a melt. 31. Process for the preparation of compounds of the general formula I in Claim 1 wherein Λ and D are as defined in Claiia 1 and Y stands for a carboxamido group, which comprises subjecting a cor.pound of the general formula I wherein A and D are as defined above and Y is a cyano group to hydrolysis or alcoholysis. 32. Process for the preparation of cor.pounis of the general formula I in Claim 1 wherein A and Y are as defined in Claim 1 and D is hydrogen, which coicprises subjecting a corresponding compound of formula I in which D is an acyl group to hydrolysis. 33. Process for the preparation of the acid addition salts of the compounds of the general formula I in Claim 1 which comprises reacting a compound of formula I with a mineral or organic acid and, if desired, setting free the bas.tr, of the general formula I from the salts thereof. 34. Pharmaceutical compositions containing as active ingredient a compound of the general formula I in or Claim 1/an acid addition salt thereof in admixture with pharmaceutically suitable inert, non-toxic diluents or carriers. 35. Pharmaceutical compositions according to Claim 34 comprising at least one compound enumerated in the Examples as active ingredient.