Technical field

Tlie present invention relates to new pyrimido/β,l-a/ isoquinolines, acid addition and quaternary ammonium salts thereof and process for the preparation thereof.

The new compounds can he characterized hy the general formula

- wherein R 1 and R2 stand for alkoxy containing 1 to 2 carbon atoms,

R stands for C-, ₇ alkyl, C,_ ₇ cycloalkyl, phenyl optionally substituted ^" by C-, , alkyl, C-, , alkoxy, hydroxy or a ino, or stands for naphtyl, phenyl-

C-, _ . alkyl optionally substituted on the phenyl group by C-,_, alkoxy, or a py idyl group.

Background art

It has been known that from l-cyanomethyl-3, -di- hydro-isoquinolines 3-N-substituted or. unsubsti uted 1- cyano-pyrimido/β,l-a/isoquinoline derivatives may be pre¬ pared by reacting same with formaldehyde or an amine

/Harsanyi K, Kiss P, Korbonits D. : J.Met,Chem. 10., 4-35 ^' /1973//. These pyrimido/β,l-a/isoquinoline derivatives show favourable effect on the heart and the circulation /Kiss P, Palosi E, Szegi J, Sze tmiklόsi J.: 7th Int. Symp. on Medicinal Chemistry Torremolinos /Spain 1980. Abstract Poster 71./

Hoechst prepared pyrimido/6,l-a/isoquinoline-4-one derivatives from l-cyanomethyl-3,4-dihydro-isoquinoline derivatives /BE-PS 862 785, GB PS 1 597 717, DE-PS 2720085/ and they also reported on the favourable activity of the compounds on the heart circulation../Lab; ^~ B; D'Sa A Domauer H; De Souza HJ 33th I t.Pharm.Cong ess, Jaipur, 1981/.

Both synthesis methods show the disadvantage that the substituents on the C atom of the molecule are constant. C atom forms a CH ₂ ~ group in method 1. and a CO group in method 2.

Disclosure of the invention

We wished to elaborate a new synthesis method in which the substituent of the C atom of the pyrimido/6,1-a/ isoquinoline ring system can be changed.

We have found that the compounds of the present invention can be prepared by a simple method in high purity and with an excellent yield by reducing a compound of the general formula

- -

or a salt thereof

1 2 ^~~

- wherein R and R are as given above and R^ is as defined above or benzyloxy- or nitro-subs tituted phenyl and dehydrating the obtained compound of the general formula

_TH.

^• wherein R 1 , R2 and R 3 are as given above - af ter isolation or without isolation and converting the obtained compound of th e general formula I to acid addition or quaternary ammoniu salt thereof or setting it free from the salt thereof .

Compounds of the general formula II can be pre¬ pared by the method disclo sed in HU-PS 167 240.

According to a pref erred embodiment of the proc ess of the invention compounds of the general f ormula II are reduc ed in an organic solvent or an aqueous-organic solvent medium or an aqueous medium by catalytic hydrogenation, or hydrogenation in situ or by chemical reducing agent.

When performing catalytic hydrogenation as a catalyst noble metal catalysts , such as palladium or ac tivated non- noble metal catalysts , such as Raney nickel can be used. As solvents or diluting agents water , organic solvents , pre¬ f erably methanol, ethanol, ethyl ac etate , dioxan or a water- organic solvent mixture may be employed.

Compounds of the general formula II can be used in the form of a base or salt. If the salt of the compounds of the .general formula II is used as starting material, the

- • -

dehydration of the compound of the formula III takes place spontaneously.

One may also proceed by acidifying the solution of the compounds of the general formula II in the form of 5 a base, i.e. the reductive condensation is carried out in an acidic medium. Acidification can preferably be conducted with aqueous inorganic acids /hydrochloric acid, sulfuric acid/ or organic acids /acetic acid, formic acid/.

Compounds of the general formula I can preferably

10 be formed after acidifying the ethanol solutions of the compounds of the general formula II with a mixture of water and hydrochloric acid at 20-25 °C under atmospheric pressure in the presence of palladium /active coal catalyst. After removing the catalyst by filtration and evaporating the

15 solvent the hydrochloride salt of the compounds of the general formula I is obtained.

If the reduction of the compounds of the general formula II is conducted with hydrogen in situ, one may pre¬ ferably proceed by developing hydrogen by reacting a suit-

20 able metal /zinc, tin, iron/ with an aqueous acid. As acids hydrochloric acid, sulfuric acid, acetic acid may be used, preferably in aqueous or aqueous-organic, particularly in aqueous ethanolic medium.

As chemical reducing agent acid type reactants,

25 such as ferrosulphate may be employed, preferably in aqueous mineral acid medium.

Compounds of the general formula I show on the basis of tests performed on test animals significant pharmacodynamic effects. According to rabbit tests the

30 compounds show a significant antianginal activity in pre¬ venting coronary insufficiency caused by vasopressin /EKG

T wave elevation/, particularly those compounds are effi-

^* 5 cient, wherein R ^* ^ stands for phenyl, substituted phenyl, phenyl-alkyl, substituted phenyl-alkyl, pyridyl, and

~~

35 ppaarrttiiccuullaarrllyy aaccttiivvee aarree those compounds wherein stands for phenyl, or pyridyl.

According to tests performed on dogs the compounds significantly increase the contractility of the left heart chamber at a dose of 0.5-1.0 mg/kg i,v., they improve the minute/volume labour of the heart, decrease the coronary resistance, i.e. improve the blood perfusion _β According to cat-tests the compounds also show a significant anti- arrythmic activity, and they also show a lasting hypo- tensive activity. According to experiments carried out on isolated rabbit-heart the favourable effect of the compounds is also due to the direct heart effect.

The compounds also exhibit a considerable activity in the human blood in inhibiting the platelet aggregation caused by ADP and arachidonic acid.

On the basis of said effects the compounds of the general formula I can favourable be used in human therapy for curing diseases of heart circulation.

The compounds of the general formula I and salts thereof can be used in therapy in the form of pharmaceutical compositions containing the active ingredient and non-toxic inert, pharmaceutically acceptable organic and inorganic carriers. The compositions may be formulated into solid form, such as tablets, film coated dragees, enterosolvent dragees, pills, capsules or into liquid form, such as suspen¬ sions, solutions or emulsions. As carriers e.g. talc, starch, gelatine, water, polyalkylene glycols etc. ^' may be used.

The compositions can optionally contain other ex- cipients, such as wetting agents, emulsifiers or suspending agents, salts and buffers, promoting the change of osmotic pressure, disintegrating agents and/or other ^* pharmaceutically active agents _»

Further details of the invention can be found in the following Examples which serve merely for illustration and not for limitation.

- -

Examples

The preparation of the starting material

1-24,7 0,075 mole of oc -_T- .2-/3,4-dialkoxy-phenyl/-ethyl/] - carbamoyl-acetamidoxime /HU-PS 167240/ are dissolved in 300 ml of anhydrous ethanol and to the solution 0,15 mole of

3 ethyl carboxylate of the general formula R C0 C _o H _r and ά <

0,075 mole of sodium ethylate prepared of 1.73 g metal sodium and 75 ml of anhydrous ethanol are added. The mix¬ ture is heated under reflux for 6 hours. After cooling alcohol is distilled off and the residue is triturated with water and distilled off by suction, washed with water and dried, and crystallized from ethanol, Melting points of the thus obtained phenyl/-ethyl-/l/-carbamoyl7-methyl-5-substituted-l,2,4- oxadiazoles are enlisted in Table 1, /Compounds of the general formula

25-48,/ 0,06 mole of the oxadiazole derivatives prepared according to a/ are dissolved hot in 200 ml chloroform and under boiling 0,36 mole of phosphoroxy chloride are slowly added dropwise, whereafter the mix ^* t re is boiled for further 3 hours under reflux. The solvent and the excess phosphoroxychloride are distilled off at reduced

- -

pressure. The residue is dissolved in chloroform, alka-. lized cautiously with a 25 % ammonium hydroxide solution, the solution is washed with water and dried above magnesium- sulphate. The solvent is distilled off and the residue is crystallized from acetonitrile.

The melting points of the obtained compounds of the formula II and of the hydrochlorides thereof formed in ethyl acetate are summarized in Table 2,

Exam-pie 49

A mixture of 3.49 g /0.01 mole/ of 3-/73,4-dihydro-6,7- dimethoxy-isoquinolin-l-yl/-methy±7-5-phenyl-l,2,4-oxadiazo le and 350 ml of ethanol, 10 ml of a 10 % aqueous hydrochloric acid solution and 0.5 g 8 % active coal-palladium are hydrated at 20 C under atmospheric pressure under stirring. . - ■ <-■ Hydration ceases after the consumption of 1 mole equivalent hydrogen gas. The mixture is filtered, washed with ethanol and thus the catalyst is removed and the solvent is distilled off at reduced pressure. The residual crystals /obtained in 100 % yield/ are recrystallized from water and 3,28 g of 9.10-dimethoxy-4-phenyl-6,7-dihydro-2H-2- imino-pyrimido _t l~a7isoquinoline-hydrochloride monohydrate are obtained, melting point: 231-232 C.

Examples 50-75

Process for the preparation of the compounds of the general formula I,

0,01 mole of 3-/73, -dihydro-6,7-dialkoxy-isoquinoline-l- yl/-methyl7-5-substituted-l,2,4-oxadiazole of the general formula II is hydrated with a mixture of ethanol at an amount of 100 times the weight of said compound, 10 ml 10 % aqueous hydrochloric acid, 0.5 g 8 % active coal-palladium at room temperature under atmospheric pressure. The mixture is then filtered and the residue is crystallized from

water, aqueous ethanol or ethanol and thus hydrochlorides of the compounds of the general formula I are obtained. Melting points of the obtained compounds are included in Table 3.

Example 7

7.86 g /0.02 mole/ 3-/73,4-dihydro-6,7-dime uhoxy-iso- quinolin-l-yl/-methyl7-5-/4-methyl-phenyl/-l,2, -oxadi- azole are hydrated in 300 ml of dioxan with 2 g Raney-nickel -catalyst at 25 C under overpressure. The catalyst is removed by filtration, evaporated, treated with activated charcoal and the residue is heated to boiling with 200 ml of 2 % hydrochloric ^' acid. Upon cooling 7.1 g of 9,10-dimethoxy- 4-/4-methyl-phenyl/-6,7-dihydro-2H-2-imino-pyrimido_6,l-a7 isoquinolin-hydrochloride-monohydraτe are obtained. M.p.: 258 °C /under decomposition/

Example 75

On 4.2 g iron dust 0.8g 5 N hydrochloric acid is added dropwise and the mixture is- stirred until the intensive bubbling ceases whereupon the mixture is boiled with 10 ml water for half an hour. After adding 1*5 ml water under stirring at 65 °C 5.74 g /0.02 mole/ of 3- 3,4-dihydro- 6,7-dimethoxy-isoquinolin-l-yl/-meth l7-5-methyl-l,2,4- oxadiazole and 40 ml of ethanol are added to the mixture. The mixture is boiled under stirring for 15 minutes, filtered by suction and the precipitate is washed with 20 ml ethanol. 5.77 g of crystallized 9,10-dimethoxy-4- methyl-6,7-dihydro-2H-2-imiho-pyrimido /6,l-a7 isoquinoline hydrochloride are obtained. M.p.: 274-275 °C. After crystallization from 96 % ethanol the produc-t melts at 277-278 °C.

Table 1

Compounds of the general formula IY

-

Continuation of Table 1

- 11 -

Table 2

• Compounds of the gemsral formula II

- 12 -

Continuation of Table 2

Table 5 Hydrochloride salts of the compounds of the gen.formula I

= dihydrochloride

- 14 -

Continuation of Table 5