CH638206A5 - 5,6-Dihydroimidazo[5,1-a]isoquinoline derivatives and processes for their preparation - Google Patents

Description

The invention relates to new 5,6-dihydro-imi-dazo (5, l-ä) isoquinoline derivatives of the general formula

(I)

where 35

R represents a hydrogen atom or an alkyl group containing 1-4 carbon atoms,

A is a nitrii or carbamoyl group,

B a lone pair of electrons or oxygen,

Y is hydrogen, alkyl containing 1-5 carbon atoms, 40 phenyl, hydroxyphenyl, aminophenyl, an optionally substituted furyl, alkoxyphenyl, halophenyl, an alkenyl group containing 2-4 carbon atoms optionally substituted by a substituted phenyl or, if B is different from oxygen, a hydroxyl - 45 means group and their salts formed with acids and bases.

If B means a lone pair of electrons, this pair of electrons cannot be clearly oriented to the nitrogen atom. If Y represents a hydroxyl group, then a keto-enol tautomerism arises where, in a boundary structure, the hydroxyl group in the place of Y changes into an oxo group bonded to the ring with a double bond, the double bond in the ring being rearranged at the same time (lactam structure).

The invention also relates to the acid addition salts of the compounds of the general formula I which are formed with bases, or with inorganic acids or, if Y is a hydroxyl group. The compounds of general formula I and their salts show a valuable pharmacological effect. The compounds have a selective broncholytic effect without affecting the myocardium. Those compounds of the general formula I which contain a methyl group at position R, a cyano group at position A, a lone pair of electrons at position B and a hydroxyl group at position Y show one of several orders of magnitude greater activity on the bronchus Muscle than on the myocardium.

The present invention also relates to the preparation of the compounds of the general formula I. The compounds of the formula (I) can be prepared by a) isonite-troso compounds of the general formula

(H)

OH

638206

4th

wherein R and A are as indicated above and the two Z represent hydrogen or a further carbon-nitrogen bond - with aldehydes of the general formula

Y-CHO

where Y is as above. V. X XI y is given and R1 is alkyl or aryl - reacted, or b) for the preparation of compounds of the general formula I wherein B represents a lonely pair of electrons, compounds of the general formula of the acids of the general formula Y-COOH - preferably with a Orthoesters, for example orthocarboxylic acid esters or orthocarbonic acid esters of the general formula

OR

10th

Y-C-OR

'OR1

(V)

(IV)

20th

A-C-NH.

wherein A and R are as indicated above - with a derivative

- in which Y is as indicated above and R1 is alkyl or aryl - or c) for the preparation of the compounds of the general formula I in which A is a nitrile group, ß-phenyl-ethyl-2s amides of the general formula

0 A 0

li i ii i

■ C-CH-NH-C-Y

(VI)

- wherein R and A are as indicated above and Y1 is either identical to Y or represents alkoxy or aryloxy - with inorganic acid chlorides, preferably with phosphoro-xychloride, optionally with dehydration of the carbamoyl group at the point of A, or d) for the preparation of the general formula I - in which B represents a lone pair of electrons, a compound of the general formula I in which B is oxygen, reduced, or e) for the preparation of the compounds in the general formula I in which B represents oxygen, a compound of the formula I. which represents a lonely pair of electrons at point B, oxidizes, or

0 for the preparation of the compounds of the general formula I in which A is a carbamoyl radical, compounds of the formula I in which A is a nitrile group, hydrogenated or g) for the preparation of the compounds of the general formula I in which A is a nitrile group, a compound of the general formula I, in which A denotes a carbamoyl group, is dehydrated and, if appropriate, a compound of the general formula I thus prepared which contains a Cm alkyl group in the place of R, is subject to ether cleavage and / or salt formation and / or compounds of the general formula I from their salts releases.

The compounds of the general formulas II and IV which serve as starting materials in the process according to the invention are known (Liebigs Ann. Chem., 1606/1973) and can be prepared by processes known per se. The compounds of general formula VI can e.g. be prepared from the corresponding ß-phenyl-ethylamine and from an N-acylaminocyanacetic acid ethyl ester.

If, in process variant a) according to the invention, such compounds of the general formula II are used as starting materials in which the two Z represent a second carbon-nitrogen bond, we obtain compounds of the general formula I in which Y denotes a hydroxyl group , if formaldehyde is used as the compound of formula III.

45 If formaldehyde is not used as the compound of the formula III, we obtain compounds of the general formula I which contain oxygen in the place of B. The reaction among the compounds of general formulas II and III is preferably carried out in the presence of an acidic catalyst. The acid can be used in an equivalent or excess amount. The reaction is generally carried out in the presence of a solvent. Examples of solvents are Alko-55 hole containing water or 1-4 carbon atoms and a mixture of the two in question. Suitable

Solvents include hydrocarbons, halogenated organic solvents, esters, ketones, acid amides, etc. The reaction is generally carried out at the boiling point of the reaction mixture, preferably between 70 60 and 120 ° C. The reaction product is isolated from the reaction mixture, preferably by filtration, and traces of the compounds of the general formula II can, if desired - if Y is not a hydroxyl group - be removed from the solution by washing with sodium carbonate solution.

Process variant a) can be carried out particularly advantageously in such a way that the product of the general formula II which has been prepared by isonitrosation is obtained

not isolated from the reaction mixture, but instead reacted with the corresponding aldehyde of the general formula III in the acidic reaction medium used.

When carrying out process variant b), the literature-known salts of the compounds of the general formula IV are used as starting materials. Preferably the sensitive compounds of formula IV are derived from their salts in the reaction mixture e.g. released with urea.

If an orthoester derivative of the general formula V - in which R1 is alkyl or aryl - of the acids of the general formula Y-COOH is used as the other reaction component, we preferably work in an alcohol medium containing 1-4 carbon atoms. If an acid chloride or acid anhydride is used as the derivative of the acids of the general formula Y-COOH, it is preferably the reaction in a non-acylating solvent, e.g. in a hydrocarbon, in a halogenated organic solvent, acid amide or pyridine. It is possible to work at room temperature or, if orthoesters are used, the reaction mixture can be heated for a short time (5-30 minutes).

The cyclization according to process variant c) takes place in a solvent, e.g. Chloroform, or hydrocarbon or in an excess of phosphorus oxychloride as a solvent. Phosphorus oxychloride can best be used as the cyclizing agent. The reaction is carried out between 60 and 110 ° C, generally at the boiling point of the reaction mixture. The compound of general formula I formed can be isolated by pouring the mixture onto ice water, onto ice. If the cyclization was carried out in an organic solvent, the compound of the formula I prepared can be separated from the organic phase after pouring on ice.

The reduction according to process variant d) can preferably be carried out with a dithionite in aqueous dimethylformamide as the reaction medium. E.g. the reduction can also be carried out with catalytically activated hydrogen.

In process variant e), hydrogen peroxide in an alkaline solution can serve as the oxidizing agent.

The hydration of the nitrile group according to process variant f) can e.g. by treatment with concentrated sulfuric acid, polyphosphoric acid or an alkali.

The compounds of the formula I which contain a carboxyl group instead of A can be converted, according to process variant g), to the compounds which contain a nitrile group in the place of A in such a way that the starting materials, e.g. dehydrated with thionyl chloride or phosphorus oxychloride.

The alkyl group means a straight or branched alkyl group containing 1-12 carbon atoms, preferably a straight or branched alkyl group containing 1-4 carbon atoms such as e.g. Methyl, ethyl, propyl, iso-propyl group and the various butyl groups. The aryl groups can contain 6-12 carbon atoms and are substituted or unsubstituted. The optionally substituted phenyl groups, particularly the unsubstituted phenyl group, are preferred. The aryl groups can be substituted by alkyl, nitro, amino, hydroxy, alkoxy or halogen. Aryl-substituted alkenyl group means a 2-4 carbon-containing alkenyl group substituted by phenyl group. The heteroaryl group contains 1-3 oxygen, sulfur or nitrogen atoms as the heteroatom, has 5-7 members and can be substituted by nitro, alkyl, amino, hydroxy.

5 638206

The reactions according to the invention are generally carried out at normal pressure, but it is optionally possible to work at higher or lower pressure.

The salts of the compounds of the general formula I, the release of the compounds of the general formula I from the salts and the ether cleavage of the -OR groups to -OH groups can be carried out by methods known from the literature.

The compounds of general formula I are effective as strong bronchodilators and can therefore be used as active ingredients in anti-asthmatic pharmaceutical preparations.

One of the typical representatives of the compounds according to the invention is the compound 1-cyano-5,6-dihydro-8,9-is dimethoxy-2H-imidazo (5, la) isoquinolin-3-one, which was prepared according to Example 12 and already at a concentration of 0.1-0.5 pg / ml, the guinea pig's trachea chain slackens. This effect is not inhibited by Inderai: (1-isopropyl-amino-3- / l-naphthyloxy / -propanol-2). The 20 compound produces a positive inotropic effect in cardiac muscle preparations (e.g. papillary muscle in cats) only at a concentration of 50 jxg / ml.

So the quotient of the concentration acting on the heart / concentration on breathing is about 25 100-500. This means that the compound according to the invention acts 100-500 times more on breathing than on cardiac activity. Under the same circumstances, the above quotient of a known preparation can be compared with the quotient of the compounds according to the invention and the selectivity of the new compounds can thereby be determined objectively.

The examination was carried out with terbutaline: [2-tert-butylamino-1 - (3,5-dihydroxyphenyl) ethanol] and the quotient was obtained from the concentration acting on the breathing 35 and ml the 0.1-0.5 ng / ml concentration affecting the heart: 10-50. This value is of an order of magnitude smaller than the value of the compound according to the invention. This means that the compound of the order of magnitude is more selective than terbutaline. This is all the more remarkable since the effect of terbutaline on the heart is 100 times smaller than the effect of izoprenaline: [DL-I- (3,4-dihydroxyphenyl) -2-isopropylaminoethanol] [j. Pharmacol. 26,999 (1974)]. The compound investigated according to the invention has 5000-45 50,000 times less effect on the papillary muscle than isoprene-naline. A large dose is required to have an effect on guinea pig ileum or gastric fundus.

The low toxicity of the compound according to the invention is also favorable, the toxicity corresponds to a value of 82 mg / body weight kg administered intravenously in a physiological salt solution.

The further details of the invention can be found in the following examples without limiting the invention in any sense.

55

example 1

2.61 g (10 mmol) and l- (isonitroso-cyano-methyl) -6,7-dimethoxy-l, 2,3,4-tetrahydro-isoquinoline are in a mixture of 18 ml of a 37% formaldehyde solution and <o 18 ml of 96% ethanol heated on a water bath. After about 15 minutes the reaction mixture becomes homogeneous, whereupon a solid material separates out after 2-3 hours. After boiling for 5 hours, the reaction mixture is cooled, filtered. 2.05 g of the l-cyano-5,6-dihydro-8,9-dimethoxy-imi-65 dazo (5, l-a) isoquinoline are obtained, melting point: 218-220 ° C. If desired, the product is recrystallized from butanol, acetonitrile, pyridine, dichloroethane or dimethylformamide, the product dissolves in aqueous acids,

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6

or do not leach. The molecular weight is determined by mass spectrography: 255.

Analysis:

Calc .: C 65.86% H 5.13% N 16.46%;

Found: C 65.75% H 5.05% N 16.26%.

Example 2

0.70 g (2.5 mmol) of 1- (amino-cyano-methylene) -6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline monohydrochloride and 0.16 g of urea are added in 5 ml of methanol is suspended, the mixture is heated to boiling with magnetic stirring and 0.5 ml (0.43 g) of ethyl orthoformate are added. After boiling for 5 minutes, the solution containing precipitate is cooled to -10 ° C. and filtered. 0.576 g of the product identical to the product of Example 1 is obtained. Melting point: 215-217 ° C. After recrystallization of butanol, the melting point becomes identical to the melting point of the product from Example 1.

Example 3

2.61 g (10 mmol) of l- (isonitroso-cyano-methyl) -6,7-dime-thoxy-l, 2,3,4-tetrahydro-isoquinoline are dissolved in 60 ml of 50% aqueous ethanol with 3 ml of benzaldehyde Heated for 6 hours. The excess of the benzaldehyde is then removed by steam distillation. 2.96 g of crude product are obtained, which can be filtered, and melts at 170 and 190.degree. After recrystallization of aceto-nitrile, 1.6 g of l-cyano-5,6-dihydro-8,9-dimethoxy-3-phenyl-imidazo (5, l-a) isoquinoline with a melting point of 226 ° C.

Analysis:

Calc .: C 72.49% H 5.17% N 12.68%;

Found: C 72.42% H 5.12% N 12.64%.

Example 4

13.05 g (50 mmol) of l- (isonitroso-cyanomethyl) -6,7-dime-thoxy-l, 2,3,4-tetrahydro-isoquinoline and 10 ml of salicylaldehyde are combined in 180 ml of 50% aqueous solution Ethanol heated for 6 hours. The reaction mixture remains heterogeneous throughout the cooking period. After filtering the reaction mixture, 15.84 g of 1-cyano-5,6-dihydro-8,9-dimethoxy-3- (2-hydroxyphenyl) -imi-dazo (5, la) isoquinoline are obtained, after recrystallization from nitromethane melts the product at 260 ° C.

Analysis:

Calcd .: C 69.16% H 4.93% N 12.10%;

Found: C 69.21% H 4.78% N 11.96%.

Example 5

7.65 g (30 mmol) of l-cyano-5,6-dihydro-8,9-dimethoxy-imi-dazo (5, la) isoquinoline are mixed in a mixture of 76 ml of 10% aqueous sodium hydroxide solution and 200 ml of 96 % Ethanol cooked for 5 hours. The alcohol is distilled off, whereupon the 7.92 g of 5,6-dihydro-8,9-dimethoxy-l-carbamoyl-imidazo (5, l-a) isoquinoline which precipitates out of the reaction mixture in crystalline form. Melting point: 250-252 ° C. After recrystallization from 50% aqueous ethanol, 7.06 g of the product is obtained, which shows the same melting point.

Analysis:

Calc .: C 61.52% H 5.53% N 15.37%;

Found: C 61.49% H 5.36% N 15.29%.

3.0 g of the above free base are dissolved in 50 ml of hot 2N hydrochloric acid solution. The hydrochloric acid solution is cooled, whereupon 3.11 g of the hydrochloride precipitate out, melting point during foaming: 280 ° C. (Decomposition)

Analysis:

Calc .: C 54.28% H 5.20% N 13.57% Cl 11.44%; Found: C 54.24% H 5.06% N 13.50% Cl 11.67%.

Similarly, the neutral sulfate dihydrate of 5,6-dihydro-8,9-dimethoxy-1-car-bamoyl-imidazo (5, 1-a) isoquinoline can be prepared with 2N sulfuric acid (C28H36N6O12S). Melting point during foaming: 215 ° C.

Analysis:

Calculated: C 49.40% H 5.33% N 12.34%;

Found: C 49.58% H 5.06% N 12.28%.

Example 6

2.73 g (10 mmol) of 5,6-dihydro-8,9-dimethoxy-l-carbamoyl-imidazo (5, l-a) isoquinoline are boiled for 1 hour with stirring with 14.5 ml of phosphorus oxychloride. The excess phosphorus oxychloride is distilled off and the residue is poured onto ice. The 1-cyano-5,6-dihydro-8,9-dimethoxy-imidazo (5, l-a) isoquinoline obtained is separated by filtration. 2.45 g of the product are obtained, melting point: 218 ° C. The physical constants of the product obtained correspond to the products according to Examples 1 and 2.

Example 7

5.1 g (20 mmol) l-cyano-5,6-dihydro-8,9-dimethoxy-imi-dazo (5, la) isoquinoline and 20.0 g pyridine hydrochloride are stirred at 200 ° C. for 2 hours 30 minutes heated. The mixture is then cooled and 100 ml of water are added. Filtration gives 4.25 g

1 -Cyano-5,6-dihydro-8,9-dihydroxy-imidazo (5.1-a) isoquinoline separated. After recrystallization from glacial acetic acid, 3.35 g of the pure product are obtained, melting point: 327-330 ° C.

Analysis:

Calculated: C 63.43% H 3.99% N 18.50%;

Found: C 63.21% H 4.11% N 18.25%.

Example 8

1.14 g (5 mmol) of l-cyano-5,6-dihydro-8,9-dihydroxy-imi-dazo (5, la) isoquinoline are added in portions to 3 ml of concentrated sulfuric acid with stirring and the reaction mixture is dissolved in overnight left in a refrigerator. Then ice is added and the precipitate formed is filtered. 1.70 g of 5,6-dihydro-8,9-dihydroxy-1-carbamoyl-imidazo (5,1-a) -isoquinoline-hydro dro-sulfate (C24H24N6O10S) are obtained, the product can be easily crystallized from water.

Analysis:

Calc .: 48.97% H 4.11% N 14.28%;

Found: 48.74% H 4.40% N 14.20%.

Example 9

2.61 g (10 mmol) of l- (isonitroso-cyano-methyl) -6,7-dime-thoxy-l, 2,3,4-tetrahydro-isoquinoline are added in 36 ml

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

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50% ethanol boiled for 6 hours with 2 ml of butyraldehyde. The starting materials gradually dissolve. After the reaction has ended, the reaction mixture is treated with activated carbon and filtered. 1 -Cyano-5,6-dihydro-8,9-dimethoxy-3-propyl-imidazo- (5,1-a) isoquinoline crystallizes from the filtrate. Melting point: 135-140 ° C. Yield: 2.75 g.

Example 10

0.87 g (2.5 mmol) of l-cyano-5,6-dihydro-8,9-dimethoxy-3- (2-hydroxyphenyl) imidazo (5, la) isoquinoline are mixed with 10 ml of 10% sodium hydroxide solution and 20 ml of 96% ethanol boiled under reflux for 5 hours. The alcohol is distilled off, the aqueous solution is neutralized to pH = 6.5 with 1N hydrochloric acid. 5,6-Dihydro-8,9-dimethoxy-3- (2-hydroxyphenyl) -1-carbamoyl-imidazo (5.1-a) -iso-quinoline is obtained as the product, yield: 0.91 g, Melting point: 245-247 ° C. The product can be recrystallized from 50% ethanol.

Analysis:

Calc .: C 65.76% H 5.24% N 11.50%;

Found: C 65.95% H 5.06% N 11.56%.

Example 11

1.1 g (3.33 mmol) of l-cyano-5,6-dihydro-8,9-dimethoxy-3-phenyl (5, la) isoquinoline are mixed with a mixture of 10 ml of 10% sodium hydroxide solution and 20 ml of 96% Ethanol heated under reflux for 8 hours. The reaction mixture does not become homogeneous even after the reaction time has elapsed, and the alcohol is distilled off. The residue obtained (0.90 g) melts over a period of 223 to 235 ° C, the product can be recrystallized from acetonitrile or 50% ethanol. The pure 5,6-dihydro-8,9-dimethoxy-3-phenyl-l-carbamoyl-imidazo (5, l-a) isoquinoline (0.71 g) melts at 229-230 ° C.

Analysis:

Calcd .: C 68.76% H 5.48% N 12.03%;

Found: C 68.92% H 5.27% N 11.87%.

Example 12

77.7 g (0.3 mol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are mixed with a mixture of 450 ml of water, 240 ml of 1N hydrochloric acid solution and 90 ml 37% formaldehyde solution heated in an apparatus provided with a stirrer for 2 hours. The solution discolors and an almost white precipitate is eliminated. Filtration can separate 81.55 g of the l-cyano-5,6-dihydro-8,9-dimethoxy-2H-imi-dazo (5, la) isoquinolin-3-one from the reaction mixture, melting point: 310-315 ° C. The product can be recrystallized from five times the amount of dimethylformamide. The product dissolves sharply in a 1N sodium hydroxide solution with sodium salt formation. (Melting point: 320-325 ° C.)

Analysis:

Calc .: C 61.89% H 4.83% N 15.49%;

Found: C 61.77% H 4.78% N 15.31%.

The sodium salt is preferably prepared by dissolving the product in a hot 2N sodium hydroxide solution. After the solution has cooled, the sodium salt crystallizes, which can be easily recrystallized from 96% ethanol. Solubility: 35 ml / g. The sodium salt dissolves excellently in the water.

The pharmacological tests were carried out with this product on guinea pig tracheal chains and on the papillary muscle of the cat.

s Example 13

2.59 g (10 mmol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are 3 hours in a mixture of 18 ml of 37% formaldehyde solution and 18 ml of 96% Cooked ethanol. The io crystalline product precipitates after only 2 hours. The reaction mixture is filtered. 2.6 g of the crystallizing from 15 ml of dimethylformamide

I-cyano-8,9-dimethoxy-2H-imidazo (5,1-a) isoquinolin-3-ones, melting point: 320-325 ° C are obtained.

The above product is not obtained in lye.

IS

Example 14

2.3 g (10 mmol) of l- (cyano-methylene) -6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline are mixed in a mixture of

II ml of 1N hydrochloric acid solution and 10 ml of water are suspended and the reaction mixture is cooled to 0-5 ° C. 0.70 g

Sodium nitrite in 6 ml of water are slowly added dropwise. The dropping takes longer than half an hour. The solution containing a purple precipitate is stirred at room temperature for a further 2 hours, 3 ml of 25 37% aqueous formaldehyde solution is added and the mixture is refluxed with stirring after slow heating. The solution discolors and a new beige-colored precipitate falls out. After filtering the reaction mixture, 2.8 g of l-cyano-5,6-dihydro-30 8,9-dimethoxy-2H-imidazo (5, l-a) isoquinolin-3-one are obtained. Melting point: 320-325 ° C. After recrystallization from 15 ml of dimethylformamide, 2.4 g of the product are obtained.

35

Example 15

12.95 g (50 mmol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are stirred for 40 hours in a mixture of 40 ml of 1N hydrochloric acid solution and 40 ml and 100 ml of water boiled with 10 ml salicylaldehyde. The solution with the precipitate is filtered cold, the precipitate is washed with 3 x 15 ml of absolute ethanol. 12.97 g of l-cyano-5,6-dihydro-8,9-dimethoxy-3- (4-hydroxyphenyl) imidazo (5, la) isoquinoline-2-oxide are obtained, 45 melting point: 270-273 ° C.

The product is recrystallized from 380 ml of nitromethane, whereupon an analytically pure product is obtained. From the mother liquor of the original reaction mixture, 3.23 g of the likewise analytically pure product can thus be obtained.

Analysis:

Calc .: C 66.12% H 4.72% N 11.57%;

SS Found: C 66.40% H 4.92% N 11.35%.

Example 16

12.95 g (50 mmol) of l- (isonitroso-cyano-methyl) -3,4- «o dihydro-6,7-dimethoxy-isoquinoline are reacted with 10 ml of benzaldehyde in the manner given in Example 15. 12.06 g of l-cyano-5,6-dihydro-8,9-dimethoxy-3-phenyl-imi-dazo (5, l-a) isoquinoline-2-oxide are obtained. Melting point: 260-262 ° C. After recrystallization from nitrome-65 than 10.41 g of the product are obtained. Melting point: 268-270 ° C.

Another 2.0 g of the product can be obtained from the mother liquor.

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8th

Analysis:

Calc .: C 69.19% Found: C 69.45%

H 4.93% H 5.14%

N 12.09%; N 12.31%.

Example 17

5.18 g (20 mmol) of 1 - (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are reacted with 4.0 ml of butyraldehyde in the manner given in the example analysis: 15.

A dark solution is obtained which is treated with activated charcoal: C 63.15% and filtered, the filtrate is sown with 30 ml. Gef .: C 63.20% aqueous sodium hydroxide solution the crude 1 -Cyano-5,6-dihydro-8,9-dimethoxy-3-propyl-imidazo (5,1-a) -isoquinoline-2-oxide. The crude product 4.54 g is recrystallized from 25 ml of absolute ethanol. Yield: 4.02 g. is The melting point of the pure product: 208 ° C.

dehydrated, 16 ml of 1N hydrochloric acid and 20 ml of water are added, the mixture is boiled under reflux for 4 hours. 4.04 g of l-cyano-5,6-dihydro-8,9-dimethoxy-3-methylimidazo (5.1-a) isoquinoline-2-oxide are obtained, melting point: 192 ° C. After recrystallization from acetonitrile, the product melts at 204 ° C.

H 5.3% N 14.73%; H 5.6% N 14.84%.

Example 18

7.77 g (30 mmol) of 1- (isonitroso-cyano-methyl) 3,4-dihydro 6,7-dimethoxy-isoquinoline are combined with 5.44 g (40 mmol) of ani-20 analysis: saldehyde, as described in the example 15, implemented. After filtering the reaction mixture, a crude sample is obtained: C 66.89% which contains a substantial amount of isonitroso derivative F .: C 66.84%. The crude product is boiled with 10% sodium carbonate solution, whereby the isonitroso derivative is removed. The purified product is 1-cyano-5,6-dihydro-8,9-dimethoxy-3- (4-methoxyphenyl) imidazo (5.1-a) isoquinoline-2-oxide (2.47 g, melting point : 262 ° C with decomposition).

Example 23

2.65 g of l- (isonitroso-cyano-methyl) -6,7-dimethoxy-l, 2,3,4-tetrahydro-isoquinoline are boiled with 10 ml of 20% aqueous acetaldehyde with the addition of alcohol for 2 hours. 1.0 g of 1-cyano-5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo (5,1-a) isoquinoline is obtained. Melting point: 204 ° C.

H 5.62% H 5.57%

N 15.60%; N 15.60%.

Example 19 30

1.74 g (5 mmol) l-cyano-5,6-dihydro-8,9-dimethoxy-3-phenyl-imidazo (5, la) isoquinoline-2-oxide are suspended in 35 ml dimethylformamide and a solution of 1 , 85 g of sodium dithionite in 10 ml of water is added. The reaction mixture is heated with stirring on a boiling water bath. After 6 hours of cooking it will

Filtered mixture. 1.47 g l-cyano-5,6-dihydro-8,9-dime calc .: C 62.91%

Thoxy-3-phenyl-imidazo (5, l-a) isoquinoline are separated from the filtrate: C: 63.10% of the filtrate, melting point: 224-226 ° C.

Example 24

2.59 g (0.01 mol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are mixed with 1.5 ml

0-Chlorobenzaldehyde reacted in aqueous hydrochloric acid with boiling. The reaction product is separated with filtration and is recrystallized from alcohol

1-Cyano-5,6-dihydro-8,9-dimethoxy-3- (o-chlorophenyl) imidazo (5.1-a) -isoquinolin-2-oxide obtained (0.68 g), melting point: 260 ° C.

H 4.22% H 4.37%

N 11.01% N 11.21%

Cl 9.29%; Cl 9.32%.

Example 20

2.59 g (0.01 mol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline and 2.65 g of o-nitrocinnamic aldehyde are mixed in a mixture of 8 ml 1N hydrochloric acid and 20 ml of water boiled for 4 hours. The product (3.71 g) is separated by filtration. After recrystallization from 50 ml of dimethylformamide, a pure product is obtained (1.74 g, melting point: 268-270 ° C. with decomposition): 1-cyano-5,6-dihydro-8,9-dimethoxy-3- (ß- o-nitro-styryl) -imidazo (5,1-a) isoquinoline-2-oxide.

45

Example 25

5.18 g (0.02 mol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are boiled for 4 hours with 4.23 g of nitro-furfural in aqueous hydrochloric acid. The crude product (6.44 g) is isolated by filtration. After recrystallization from dimethylformamide, the pure 1-cyano-5,6-dihydro-8,9-dimethoxy-3- (5-nitro-2-furyl) imidazo (5,1-a) isoquinoline-2-oxide is obtained. Melting point: 259 ° C.

50

Analysis:

Calc .: C 63.15% Found: C 62.89%

Analysis:

Calc .: C 56.55% Found: C 56.78%

N 3.69% N 3.83%

N 14.65%; N 14.80%.

H 4.34% H 4.19%

H 13.39%; N 13.20%.

Example 21

5.18 g (0.02 mol) of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline are mixed with 4.5 g (0.06 mol) of glyoxylic acid in 40 ml of water for 2 hours cooked with stirring. 5.0 g of l-cyano-5,6-dihydro-8,9-dimethoxy-2H-imidazo (5, l-a) isoquinolin-3-one are obtained. The product corresponds with all physical constants to the product prepared with formaldehyde according to Examples 12, 13 and 14.

Example 22

5.18 g of l- (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dime-thoxy-isoquinoline are mixed with 20 ml of 20% aqueous acetal

Example 26

ss 5.18 g of 1 - (isonitroso-cyano-methyl) -3,4-dihydro-6,7-dime-thoxy-isoquinoline and 4.5 g of p-dimethylaminobenzaldehyde are reacted in aqueous hydrochloric acid at the boiling point, 8.26 g of the crude product are isolated, from which the inson troso starting compound is removed by boiling with aqueous 60 soda. 1-Cyano-5,6-dihydro-8,9-dimethoxy-3- (4-dimethylaminophenyl) imidazo (5.1-a) isoquinoline-2-oxide (3.4 g) is obtained. After recrystallization from nitromethane, the product melts at 263 ° C.

65 Analysis:

Calc .: C 67.68% Found: C 67.92%

H 5.68% H 5.87%

N 14.35%; N 14.10%.

Example 27

1- (Isonitroso-cyano-methyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline and cinnamaldehyde are reacted by boiling in aqueous hydrochloric acid, the product can be recrystallized from acetic acid. l-cyano-5,6-dihydro-8,9-dimeth-oxy-3- (β-phenyl-styryl) -imidazo (5, l-a) isoquinoline-2-oxide

9 638 206

is produced (melting point: 290 ° C).

Analysis:

s Calc .: C 70.76% H 5.13% N 11.25%;

Found: C 70.52% K 5.18% N 11.45%.

B

Claims (12)

638206 PATENT CLAIMS 1. 5,6-Dihydro-imidazo (5, l-a) isoquinoline derivatives of the general formula (I) wherein R denotes hydrogen or alkyl containing 1-4 carbon atoms, A is nitrii or carbamoyl, B represents a lone pair of electrons or oxygen and Y represents hydrogen, alkyl containing 1-5 carbon atoms, phenyl, hydroxyphenyl, aminophenyl, an optionally substituted furyl, alkoxyphenyl, halophenyl, an alkenyl group containing 2-4 carbon atoms optionally substituted by a substituted phenyl, or if B is different from oxygen, means a hydroxyl group and its formed with acids and bases 20th 25th 30th Salts. 2. 1-cyano-5,6-dihydro-8,9-dimethoxy-2H-imidazo- (5,1-a) isoquinoline-3-one as a compound according to claim 1. 3rd 638 206 3. Pharmaceutical preparations with selective broncho-further activity, characterized by a content of a compound of general formula I, wherein R, A, B, Y have the meaning given in claim 1, or a salt thereof. 4. A process for the preparation of 5,6-dihydro-imi-dazo (5, l-a) isoquinoline derivatives of the general formula (I) according to claim 1, characterized in that compounds of the general formula (II) OH wherein R and A are as indicated above and the two Z represent hydrogen or a further carbon-nitrogen bond - with aldehydes of the general formula Y-CHO (HI) wherein Y has the meaning given above, and / or forms salt from the compounds obtained using acids or bases and / or releases the compound of the general formula (I) from the salts obtained. 5. The method according to claim 4, characterized in that one carries out the reaction in the presence of a solvent, preferably aqueous-alcoholic alkanol, acid reamide, hydrocarbon or liquid halogenated hydrocarbon. 6. The method according to claim 4, characterized in that the reaction is carried out at 60-120 ° C. 7. The method according to claim 4, characterized in that the reaction is carried out in an acidic medium, in the presence of an acid catalyst. 8. Process for the preparation of 5,6-dihydro-imi-dazo (5,1-a) isoquinoline derivatives of the general formula (I) according to Claim 1, which contain a lone pair of electrons at the position of B and in which R, A and Y have the meaning given above, characterized in that a compound of the formula (I) which contains a oxygen atom at the position of B is characterized and wherein R, A and Y have the meaning given above, according to the process according to claim 4 and the compound thus obtained is reduced and / or forms salts from the compounds obtained using acids or bases and / or from the salts obtained Releases compound of general formula (I). 9. A process for the preparation of 5,6-dihydro-imi-dazo (5, la) isoquinoline derivatives of the general formula (I) according to claim 1, which contain an oxygen atom 60 in the place of B and wherein R, A and Y are the have the meaning given above, characterized in that a compound of the general formula (I) in which B is a lonely pair of electrons and R, A and Y have the meaning given above, according to the process according to claim 4 65 and the compound thus obtained oxidized and / or from the compounds obtained using acids or bases forms salt and / or from the salts obtained releases the compound of general formula (I). 10. A process for the preparation of 5,6-dihydro-imi-dazo (5, la) isoquinoline derivatives of the general formula (I) according to claim 1, wherein A is carbamoyl and R, B and Y have the meaning given above, characterized that a compound of the general formula (I), in which A represents a nitrile group and R, B and Y have the meaning given above, is prepared by the process according to claim 4 and the compound thus obtained is hydrated and / or from the compounds obtained under Use of acids or bases forms salt and / or releases the compound of general formula (I) from the salts obtained. 11. A process for the preparation of 5,6-dihydro-imi-dazo (5,1-a) isoquinoline derivatives of the general formula (I) according to Claim 1, in which A is nitrii and R, B and Y have the meaning given above, characterized in that a compound of the general formula (I), in which A is carbamoyl and R, B and Y have the meaning given above, is prepared by the process according to claim 4 and the compound thus obtained is dehydrated and / or from the compounds obtained using acids or bases forms salt and / or releases the compound of general formula (I) from the salts obtained, s 12. A process for the preparation of 5,6-dihydro-imi-dazo (5, la) isoquinoline derivatives of the general formula (I) according to claim 1, wherein R is hydrogen and A, B and Y have the meaning given above, characterized that a compound of the general formula (I) in which R is an alkyl containing 1-4 carbon atoms is prepared according to the process of claim 4 and the compound thus obtained is subjected to ether cleavage and / or from the compounds obtained using acids or bases forms salt and / or i5 releases the compound of general formula (I) from the salts obtained.