Pyrimido (6,1-a) isoquinolin-4-ones, process for their preparation and their application in medicaments; intermediates and their preparation.

0001The present invention relates to pyrimido- (6,1-a) -isoquinolin-4-one derivatives, new intermediates used in their preparation and a new process for the preparation of pyrimido- (6,1-a) -isoquinolin-4-ones.

0002The present invention relates to pyrimido (6,1-a) isoquinolin-4-ones of the formula I.<chemistry id="chem0001" num="0001"><img file="EP0010759A2_D0001.tif" /></chemistry>where R¹, R² and R³ may be the same or different and are hydrogen, hydroxy, C_1-6-Alkoxy or halogen, where two adjacent radicals R¹, R or R together can form a methylenedioxy or ethylenedioxy group, R⁴ Hydrogen, C_1-6-Alkyl, C_3-6-Cycloalkyl, optionally by C_1-3-Alkoxy, di- (C_1-4-alkyl) -amino or di- (C_1-4 alkyl) phosphine (C_1-4) -alkyl substituted alkyl with up to 6 carbon atoms, aralkyl with up to 8 carbon atoms, the aryl radical being substituted by halogen, nitro, C_1-3-Alkoxy and / or C._1-3-Alkyl can be mono- or poly-substituted, heterocyclic alkyl or by halogen, C_1-3-Alkyl, C_1-3-Alkoxy, halo-C_1-3-alkyl, amino, hydroxy or the group -OMet, in which Met represents an alkali metal atom, represents mono- or polysubstituted aryl, or denotes a pair of electrons if R⁵ represents one of the radicals mentioned below, and R⁵ and R⁶ may be the same or different and are hydrogen, hydroxy, C_1-6-Alkoxy, amino, C_1-3Alkylamino, di-C_1-3-alkylamino, arylamino, amino or C substituted by a 5- or 6-membered carbon ring with up to 3 heteroatoms from the series N, O or S._1-6-Alkyl, C_3-7-Cycloalkyl, hydroxy-C_1-6-alkyl, alkoxy-C_1-6-alkyl, dialkoxy-C_1-6-alkyl, halo-C_1-6-alkyl, di-C_1-4- alkylamino-C_1-6-alkyl, C_6-8Aralkyl, C_1-6Acyl and optionally substituted aryl, where aryl is an aromatic hydrocarbon radical having up to 10 carbon atoms or R⁵ a pair of electrons if R⁴ represents one of the above radicals, and R⁵and R⁶ together with the nitrogen atom to which they are attached represent an optionally substituted nitrogen heterocycle which may contain another nitrogen or oxygen atom.

0003The present invention furthermore relates to pyrimido- (6,1-a) -isoquinolin-4-ones of the formula II<chemistry id="chem0002" num="0002"><img file="EP0010759A2_D0002.tif" /></chemistry>where R¹, R², R³ have the meaning given for formula I, R⁴ has the meaning given for the formula I, in which case X denotes oxygen or sulfur, or represents a pair of electrons, in which case X denotes a halogen atom.

0004The compounds of the formula II are used as intermediates in the preparation of the compounds of the formula I.

0005If at least one of the two residues _R⁵ and _R⁶ represents a hydrogen atom, the above definition of the pyrimido- (6,1-a) -isoquinolin-4-one derivatives of the formula I also includes those corresponding to the following formula, either obtained by complete isomerization of the compounds of the formula Ia or with the Compounds of formula Ia in equilibrium isomers Ib.<chemistry id="chem0003" num="0003"><img file="EP0010759A2_D0003.tif" /></chemistry>

0006The definition of the pyrimido- (6,1-a) -isoquinolin-4-one derivatives also includes the Ic isomer of the following formula, in which _R¹, _R², _R³, _R⁴ and _R⁵ have the above meaning.<chemistry id="chem0004" num="0004"><img file="EP0010759A2_D0004.tif" /></chemistry>

0007Preferred C1-6 alkoxy groups for R¹, R²and R³are those with up to 3 carbon atoms.

0008If R¹, R²or R³ Halogen is chlorine is preferred. Suitable alkyl radicals for R⁴ are, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

0009As aralkyl radicals for R⁴ are particularly suitable those with at most 8 carbon atoms, in which the aryl radical by halogen, nitro, C_1-3-Alkoxy and / or C._1-3-Alkyl can be substituted once, twice or three times.

0010Suitable heterocyclic alkyl radicals are, for example, furfuryl and tetrahydrofuryl.

0011Suitable aryl residues for R⁴ are, for example, optionally one or more times, preferably one, two or three times, by halogen, for example fluorine, chlorine and bromine, C._1-3-Alkyl and C_1-3Alkoxy, for example methyl, ethyl, methoxy and ethoxy, haloalkyl, for example trifluoromethyl, amino or Ilydroxy substituted phenyl radicals, where the hydrogen atoms in the hydroxyl radical can optionally be replaced by an alkali metal, for example sodium.

0012Suitable nitrogen-containing heterocyclic radicals for _R⁴ are, for example, pyrrolidine, piperidine, morpholine and piperazine, which may be replaced by C_1-3-Alkyl, C_2-4Alkoxycarbonyl, may be substituted by optionally substituted phenyl or another nitrogen heterocycle.

0013As alkylamino or dialkylamino radicals for R or _R⁶ those with alkyl groups with at most 3 carbon atoms, for example methylamino or dimethylamino groups, are particularly suitable.

0014As arylamino residues for R⁵ or R⁶ are suitable phenylamino radicals with phenyl radical optionally substituted one or more times by halogens, for example chlorine, alkyl groups with at most 3 carbon atoms, for example methyl or the nitro group. A suitable amino group substituted for a nitrogen-containing heterocycle for R⁵ or R⁶ is, for example, the N-morpholinoamino residue.

0015As alkyl residues for R⁵ or R⁶ Suitable are those with a maximum of 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

0016As suitable cycloalkyl radicals for R⁵ or R⁶ Let those with at most 6 carbon atoms be mentioned, such as cyclohexyl.

0017As a substituted alkyl group for R⁵ or R⁶ a radical with up to 6 carbon atoms can be used, which can be substituted with one or two hydroxyl or alkoxy groups, the alkoxy groups each having a maximum of 3 carbon atoms, furthermore halogen, for example chlorine, amino or dialkylamino, the alkyl groups having a maximum of 4 carbon atoms , as well as dialkylphosphinylalkyl, for example dimethylphosphinylmethyl.

0018Examples of aralkyl radicals for R⁵ or R⁶ are those with a maximum of 8 carbon atoms in which the aryl radical can be substituted one or more times, in particular one, two or three times, with the substituents given for R above.

0019Suitable heterocyclic alkyl radicals for R⁵ or R⁶ are, for example, furfuryl or tetrahydrofurfuryl groups.

0020Suitable aryl residues for R⁵ or R⁶ are, for example, optionally one or more, in particular one, two or three times, by halogen atoms, for example fluorine, chlorine or bromine atoms, alkyl or alkoxy groups having at most 3 carbon atoms, for example methyl, ethyl, methoxy and ethoxy groups, haloalkyl groups, for example Phenyl radicals substituted by trifluoromethyl groups, amino or hydroxyl groups, it being possible for the hydrogen atoms in the hydroxyl groups to be replaced by an alkali, for example sodium.

0021Suitable residues of nitrogen-containing heterocycles are, for example, the pyrrolidino, piperidino, morpholino or piperazino radical, which can be substituted by alkyl, alkoxycarbonyl, aryl or a nitrogen heterocycle, alkyl, alkoxy, aryl or nitrogen heterocycle having the above meaning.

0022Examples of suitable acyl radicals for R⁵ or R⁶ are straight-chain or branched alkanoyl radicals having 1 to 6 carbon atoms, such as acetyl, or aroyl, such as benzoyl, the phenyl radical having one or more than the above for R⁵ and R⁶ if these represent an aryl radical, the substituents listed can be substituted.

0023Examples of salts of the pyrimido (6,1-a) -isoquinolin-4-one derivatives of the formula I which may be mentioned are those of inorganic or organic acids, for example hydrochlorides, hydrobromides, sulfates, phosphates, acetates, oxalates, tartrates, citrates, Maleate or fumarate.

0024Suitable quaternary ammonium salts of the pyrimido- (6,1-a) -isoquinolin-4-one derivatives of the formula I are, for example, the salts derived from alkyl halides, such as methiodides.

0025The following are preferred substituents:<ul id="ul0001" list-style="none"><li>for R¹and R² C._1-3-Alkoxy, for R³ Hydrogen, for R⁵ C._1-6Alkyl or phenyl which is mono- or trisubstituted by substituents of the type indicated above, for R⁶ Hydrogen, for _R⁴ Hydrogen when X is oxygen and a pair of electrons when X is chlorine.</li></ul>

0026Particularly preferred compounds of the formula I are:<ul id="ul0002" list-style="none"><li>9,10-dimethoxy-2-tert-butylamino-6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one hydrochloride,</li><li>9,10-dimethoxy-2-sec-butylamino-6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one hydrochloride,</li><li>9,10-dimethoxy-2- (2,6-dimethylanilino) -6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one,</li><li>9,10-dimethoxy-2- (2,4-dimethylanilino) -6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one,</li><li>9,10-dimethoxy-2- (2-chloroanilino) -6,7-dihydro-4H-pyrimido (6,1-a) isoquinolin-4-one hydrochloride monohydrate and</li><li>9,10-dimethoxy-2- (2,4,6-trimethylanilino) -6,7-dihydro-4H-pyrimido (6,1-a) isoquinolin-4-one hydrochloride dihydrate.</li></ul>

0027Particularly preferred compounds of the formula II are:<ul id="ul0003" list-style="none"><li>9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido- (6,1-a) -isoquinoline-2,4-dione,</li><li>2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one,</li><li>2-chloro-9,10-methylenedioxy-6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one.</li></ul>

0028Some pyrimido- (6,1-a) -isoquinolin-4-one derivatives of the formula II<chemistry id="chem0005" num="0005"><img file="EP0010759A2_D0005.tif" /></chemistry>are listed in Table I below.<tables id="tabl0001" num="0001"><img file="EP0010759A2_D0006.tif" /></tables> The present invention further relates to new barbituric acid derivatives of the formula III for the preparation of the pyrimido- (6,1-a) -isoquinolin-4-ones of the formula II.

0029In particular, two new barbituric acid derivatives, namely 1- (3,4-dimethoxyphenethyl) -barbituric acid and 1- (3,4-methylenedioxyphenethyl) -barbituric acid, are listed below with the corresponding melting points:<chemistry id="chem0006" num="0006"><img file="EP0010759A2_D0007.tif" /></chemistry><tables id="tabl0002" num="0002"><img file="EP0010759A2_D0008.tif" /></tables>

0030The present invention furthermore relates to a process for the preparation of the compounds of the formula I, which is characterized in that a<ul id="ul0004" list-style="none"><li>a) barbituric acid derivative of the formula III<chemistry id="chem0007" num="0007"><img file="EP0010759A2_D0009.tif" /></chemistry>where R¹, R2, R³and R⁴have the meanings given for the formula I and X is oxygen or sulfur, is cyclized in the presence of a water-releasing agent, for example in the presence of an acid such as polyphosphoric acid, phosphorus pentoxide or sulfuric acid, to give a compound of the formula II in which _R¹, _R², _R³, _R⁴ and _X have the meanings given above, or in the presence of an acid halide such as, for example, phosphorus oxychloride, thionyl chloride or a corresponding inorganic halide, such as, for example, phosphorus pentachloride₅ of formula I._I., in which _R¹, R², R³and R⁴the formula _I. have the meanings mentioned and X represents a halogen atom, in particular chlorine, and</li><li>b) the compound of formula II obtained with a compound of formula<chemistry id="chem0008" num="0008"><img file="EP0010759A2_D0010.tif" /></chemistry>where R⁵ and R⁶ have the meanings given for formula I, is reacted in the presence of a base, after which the product in the form of the free base can be reacted with an acid to form a salt.</li></ul>

0031If an acid such as polyphosphoric acid is used for the process step, the reaction can be accelerated or completed by heating the reactants to 80-150 ° C. If an acid halide or an inorganic halide is used, the reactions can be carried out in the presence of a solvent such as ether such as dioxane or tetrahydrofuran, aliphatic halogenated hydrocarbons such as chloroform or aromatic hydrocarbons such as Benzene or toluene can be carried out, acceleration being achieved by heating to the boiling point of the solvent.

0032In process step b), the base in the presence of which the reaction takes place can be the compound of the formula<chemistry id="chem0009" num="0009"><img file="EP0010759A2_D0011.tif" /></chemistry>act themselves, which can be added in excess of the amount required for the reaction, or an alkali metal hydride, for example sodium hydride, or a tertiary amine, for example triethylamine, or an acid scavenger, for example diazabicyclonones. The reaction can be carried out in the presence of polar solvents, for example dimethylformamide, dimethyl sulfoxide, aliphatic halogenated hydrocarbons, for example chloroform, or alkanols, for example butanol, or in the presence of aprotic solvents, for example high-boiling ether, such as diethylene glycol dimethyl ether. The reaction can be accelerated by application of heat, for example by heating to the boiling point of the solvent.

0033Compounds of the formula I in which R 2 or R³ can mean an acyl radical from compounds of the formula I in which at least one of the radicals R 2 or R³ Hydrogen means can be prepared by treatment with an acyl halide or acyl anhydride, the acyl group being an alkanoyl group having at most 6 hydrocarbon atoms, for example the acetyl group, or an aroyl group, for example that being benzoyl group, in which the phenyl nucleus can be substituted as described above and where the halide eg the chloride can be. The reaction can be carried out in the presence of a base such as an alkali carbonate, e.g. Potassium carbonate, or a tertiary amine, for example triethylamine, can be carried out. The reaction can be accelerated by heating to the boiling point of the acylating agent.

0034The barbituric acid derivatives of the formula III used as intermediates can be prepared by methods known from the literature. If, for example, R⁴ Hydrogen and X are oxygen, can be according to the following reaction scheme<chemistry id="chem0010" num="0010"><img file="EP0010759A2_D0012.tif" /></chemistry>according to that of CF Kurzer in Organic Synthesis, Coll. Vol. 4 (1963) described methods for urea formation and that of JB Dickey and AR Gray in Organic Synthesis, Coll. Vol. 2 (1943) described method for the production of barbituric acid.

0035The pyrimido- (6,1-a) -isoquinolin-4-one derivatives according to formula I have valuable pharmacodynamic properties, for example hypotensive, bronchodilating and anti-allergic activity.

0036Due to the hypotensive effect, the new active substances are suitable for the treatment and prophylaxis of cardiovascular diseases such as essential and malignant hypertension, heart failure, angina pectoris and disorders of the peripheral cervical course. The active ingredients can also be used in conjunction with other pharmacologically active substances, for example diuretics, antiarrhythmics, β-blockers, sedatives, cardiovascular agents, hypolipidemics, etc.

0037Due to the bronchodilating and anti-allergic effect, the new active ingredients are suitable for the treatment and prophylaxis of respiratory diseases such as bronchial asthma, chronic bronchitis and emphysema and allergies such as allergic asthma, hay fever, allergic rhinitis, conjunctivitis, urticaria etc. The active ingredients can also be used in conjunction with other pharmacologically active substances, such as, for example Corticosteroids, sympathomimetics, xanthine derivatives, antihistamines, sedatives, heart medications, etc.

0038The active compounds according to the invention can be administered orally, parenterally (intramuscularly, intravenously, subcutaneously), rectally, as an aerosol or applied topically.

Example 1:

9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido- (6,1-a) -isoquinoline-2,4-dione (formula II)

003910th g of polyphosphoric acid are heated to 105 ° C. and 1.0 g of 1- (3,4-dimethoxyphenylethyl) barbituric acid is added with stirring. The reaction mixture is heated for 4 hours and then poured onto crushed ice to form a white solid which is filtered off, washed with water, dried and recrystallized from dimethylamide. Yield: 500 mg, melting point: 323-325 ° C.

Example 2:

2

-Chlor-9,10-dimethoxy-6,7-dihydro-2H-pyrimido- (6,1-a) -isoquinolin-4-one (formula II)

0040A mixture of 20.2 g of 1- (3,4-dimethoxyphenylethyl) barbituric acid and 100 ml of phosphorus oxychloride is heated under reflux at a temperature of 100 to 110 ° C for 2.5 hours. Excess phosphorus oxychloride is distilled off. The residue is poured onto crushed ice and made basic with a cold aqueous 30% sodium hydroxide solution. The yellow, gummy precipitate formed is separated off and extracted with chloroform. The extract is washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is purified on a silica gel column using chloroform as the eluent to give the desired compound. Yield: 20.2 g (approx. 100%), melting point: 235-236 ° C.

Example 3:

2-chloro-8,10-methylenedioxy-6,7-dihydr

p-

2H-pyrimido- (6,1-a) -isoquinolin-4-one (Formula II)

0041The procedure is analogous to Example 2, with 1- (3,4-methylenedioxyphenylethyl) barbituric acid being used instead of 1- (3,4-dimethoxyphenylethyl) barbituric acid. Yield: 80%, melting point: 245-247 ° C.

Example 4:

9.10 dimethoxy-3-methylene-3,4,5,7-tetrahydro-2H-pyrimido (6,1-a) -isoquinoline-2,4-dione (formula I)

0042A mixture of 9.10 dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido- (6,1-a) -isoquinoline-2,4-dione (4.11 g), oil-free sodium hydride (0.75 g) and dimethylformamide (100 ml) is heated to 100 ° C. for 15 minutes and then cooled to room temperature. Methyl iodide (10 ml) is added. The reaction mixture is heated to 100 ° C for 12 hours. The solvent is removed in vacuo and the residue is treated with cold water. The solid is filtered off and recrystallized from ethyl acetate-methylene chloride. Yield: 4.0 g, melting point: 260-262 ° C.

Example 5:

9,10-dimethoxy-2-tert-butylamino-6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one hydrochloride (formula I)

0043A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido- (6,1-a) -isoquinolin-4-one (3.0 g) and tert-butylamine (10, 0 ml) in chloroform (75.0 ml) is heated under reflux for 16 hours. The solvent is evaporated under reduced pressure and the residue is triturated with a dilute sodium hydroxide solution to a white precipitate. The precipitate is filtered off, dried, dissolved in ethanol and converted into its hydrochloride by treatment with hydrochloric acid. The hydrochloride is crystallized from an ethanol / ether mixture. Yield: 3.0 g, melting point: 265-270 ° C.