NO881899L - NEW 2-AMINOALKYL-4-BENZYL-1- (2H) -PHTHALAZINO DERIVATIVES. - Google Patents

Description

DE specification 1 046 625 relates to a process for the production of basic substituted phthalazones with the general formula

in which R^ denotes an aryl or aralkyl residue which is optionally substituted in the core, R 2 is divalent, linear or

branched, aliphatic chain with at least 2 and at most 5 carbon atoms and R3 and R4 low molecular weight alkyl groups, which together with the nitrogen can be linked in a heterocyclic ring, resp. their salts or quaternary ammonium compounds.

For these compounds, a histamineolytic (antihistamine effect), spasmolytic and local anesthetic effect is indicated.

According to the invention with formula I, however, wood excels

the following, surprising effect: they act as antiasthmatic, antiallergic, Paf-antagonistic (Paf = platelet activating factor, "Mediator, which, among other things, triggers asthma) as well as leukotriene-inhibiting.

The residue R is preferably in the 4-position of the phenyl ring. Occurring C₁-C₂-alkyl groups, C₁-C₂-alkoxy groups, alkenyl groups or alkynyl groups can be linear or branched, in particular these residues consist of 1-4 or, if they are unsaturated, of 3-4 C atoms.

If R3 is an alkenyl or alkynyl group, there is at least one saturated C atom between the unsaturated bond and the nitrogen. Preferably, the unsaturated bond is in the 2,3-position or 3,4-position.

When it comes to the C 3 -C 8 cycloalkyl residue, it is in particular the cyclopentyl residue or the cyclohexyl residue.

If R 3 is a phenyl-C 1 -C 3 -alkyl radical, this can be substituted once, twice or three times with the stated radicals. The alkyl part in this phenylalkyl residue preferably consists of 1, 2 or 3 C atoms and may optionally also be branched.

The alkylene bridge Alk can be linear or branched and preferably consists of 2, 3 or 4 C atoms. If this alkylene bridge Alk contains a double bond, this is isolated to the group NR2R3, if Rg means hydrogen (ie not conjugated to this group). Preferably, there is at least one saturated carbon atom between such a double bond and the two nitrogen bonds.

Particularly favorable effects have e.g. such compounds, where the radicals R^ to R3, Alk have the following meanings: R], = fluorine, chlorine or bromine, especially in the 4-position, preferably fluorine in the 4-position, R2 = C^-C^-alkyl, preferably methyl , R 3 phenyl-C 1 -C 4 -alkyl, optionally substituted as indicated.

When it comes to the substituents in the phenyl-C^-C^-alkyl residue, these are preferably C^-C^j-alkyl groups (especially methyl) or a halogen (e.g. Cl, F) or C1-C4-alkoxy groups (especially methoxy groups). The substituents in the phenyl part of this phenylalkyl residue are preferably in the 2-position, 3-position, 4-position or 2,4-position. Occurring alkyl, alkoxy, alkanoyloxy, alkanoylamino or alkoxy alkyl groups may be linear or branched. Alkyl- or Alkockic acid residues preferably consist of 1 to 4 C atoms, the alkanoyl residues preferably of 2 to 4 C atoms.

For procedure a)

The method can be carried out without a solvent or in a suitable solvent or dispersant. As solvents or dispersants, e.g. in consideration: aromatic hydrocarbons such as benzene, mesitylene, toluene, xylene; pyridine; lower aliphatic ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, methylene chloride; ethers such as tetrahydrofuran, dioxane, diisopropyl ether; sulfoxides such as dimethyl sulfoxide; tertiary acid amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, tetramethylurea, n-methylpyrrolidone; lower alcohols such as methanol, ethanol, isopropanol, amyl alcohol, butanol, tert.-butanol as well as mixtures of the aforementioned agents, optionally also with water. If the group -Alk-NHR2 or -Alk-NHR3 occurs in the starting substance II, dipolar, aprotic solvents such as dimethylsulfoxide or tertiary acid amides are preferably used.

The reaction is carried out, for example, at temperatures between 20 and 200°C, preferably 40 to 160°C or also 50 to 120°C.

If a solution or dispersant, it is often worked at the reflux temperature for this agent. The reaction often proceeds even at room temperature, or at a temperature between 40 and 120°C.

The reaction is advantageously carried out in the presence of acid-binding agents such as alkali carbonates, pot ash, soda ash, alkali acetates, alkali hydroxides or tertiary bases (triethylamine, pyridine).

If the residue X in the starting substance with formula II is hydrogen, this is preferably used in the form of its metal salt. In particular, the alkali salts (Na, K, Li) come into play here. The preparation of the alkali salts takes place, for example, with the help of the corresponding alkali amides, alkali alcoholates or also the alkali metals in a solvent (lower alcohol, aromatic hydrocarbon) or with aqueous alkali (e.g. NaOH).

If Y means an esterified hydroxy group, this means reactive esters. A reactive ester is thereby e.g. the ester of a strong organic or inorganic acid, such as above all of a hydrohalic acid, e.g. the chloro, bromo or hydroiodo acid, or a sulphonic acid, such as an aryl or C 1 -C 4 -alkylsulphonic acid, e.g.

of lower alkylbenzenesulfonic acids (p-toluenesulfonic acid).

Unknown starting substances with formula III can, for example, be obtained analogously to Houben-Weyl, Methoden der Organischen Chemie, volume 5/3 (1962), page 503 and the following, volume 6/2 (1963), page 475

and the following or volume 9 (1955), page 426. Starting substances III with the formula ZR3, where Z e.g. is a hydroxy group, which

is esterified with an aryl sulfonic acid residue, can e.g. is obtained from the corresponding alcohols (R3OH) by reaction with the corresponding aryl sulfonic acid chlorides in a known manner. In an analogous way, e.g. the corresponding compounds with Z - Cl or Br from the alcohols and thionyl chloride or thionyl bromide.

In an analogous way, the starting materials Z-Alk-NR2R3 can be obtained from the alcohols HO-Alk-NRgRs by esterification.

Preparation of the starting substances of formula II:

Unknown starting substances II, where X means the group -Alk-NHRg

respectively -Alk-NHR3, can e.g. is produced analogously to the method described in DE explanatory note 1 046

625, whereby the basic nitrogen atom in the halides Hal-Alk-NHR2 respectively. Hal-Alk-NHR3, which is used for this purpose, is suitably protected with a benzyl group. This benzyl group is then split off in the usual way (e.g. dehydrated). The starting material II, where X is the group Alk-Y, can e.g. is obtained by reacting the corresponding phthalazone with an alcohol Hal-

Alk-OH according to DE specification 1 046 625 and subsequent esterification of the hydroxy group (e.g. as stated above).

Production of starting substances II, where X is hydrogen, can for example take place as described in DE-explanatory document 1 046 625, as well as analogously to what is indicated in the examples; also analogous to the working method according to DE Off.skrift 36 34 942.9.

To procedure b)

As reactive derivatives of the carboxylic acid with the general formula IV come in particular the acid halides (-chlorides, -bromides, -iodides), -esters (especially with C^-C^-alkanols; or also internal esters with the enolized keto group (for example p-chloro -benzylidene-phthalide) and the anhydrides in question. The compounds of formula IV as well as the corresponding acid halides and esters with C₁-C₂-alkanols can also exist in the tautomeric, cyclic form. This cyclic form is expressed by means of the following formula:

Herein, T means the hydroxy group, halogen or C 1 -C 4 -alkyloxy.

The reaction is carried out in the presence or absence of the usual solvents and auxiliaries at temperatures between 40 and 200°C and in a wide pH range from acidic to alkaline.

Suitable solvents are e.g. water, aromatic hydrocarbons such as benzene, mesitylene, toluene, xylene; halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, methylene chloride; ethers such as tetrahydrofuran, dioxane, diisopropyl ether; sulfoxides such as dimethyl sulfoxide; tertiary acid amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric acid tri-

amide, tetramethylurea, N-methylpyrrolidone; lower alcohols such as methanol, ethanol, isopropanol, amyl alcohol, butanol, tert.-butanol and mixtures of the aforementioned agents,

as well as tertiary amines, e.g. pyridine. As auxiliaries, bases, acids and common condensing agents for these reactions can be used.

The compound V can also be used in the form of an N-acyl derivative,

which is then first hydrolysed and, without further purification or isolation, immediately reacted further with compound IV in the same reaction medium.

In particular, tertiary acid amides (e.g. dimethylformamide), aromatic hydrocarbons (e.g. toluene, lower alcohols) or also water are used as solvents, whereby work is often done in the presence of basic substances (e.g. alkali hydroxides or alkali alcoholates ). Preferably work at temperatures between 50 and 200°C, especially 80 and 150°C.

Preparation of starting compounds of formula V:

Such starting materials can, for example, be obtained as follows:

Reaction of corresponding oxo compounds with the formula 0 Alk'-NR2R3 with acetylhydrazine (e.g. in an aromatic hydrocarbon (toluene) between 50 and 150°C) or benzoyl-hydrazine (e.g. in an aliphatic alcohol between 20 and 100°C ) to the corresponding hydrazones, subsequent reduction of these by catalytic hydrogenation (e.g. in glacial acetic acid in the presence of PtC>2 at 5-6 bar) or reduction with a complex metal hydride (NaBH4) in an inert agent (lower alcohols such as methanol or dioxane) and subsequent cleavage of the acyl group by hydrolysis with dilute hydrochloric acid (20-3756-ig). In the case of the oxo compounds with the formula 0 = Alk'-NR2R3, the Alk' residue means Alk, whereby the carbon atom that connects Alk with the phthalazinone residue, instead of a hydrogen bond, has a second bond with the oxo-oxygen.

Another possibility for the preparation of the starting substances V is, for example, the reaction of an amine with the formula R2R3N-Alk-NH2 with a ketone (e.g. cyclohexanone) and hydroxylamine-O-sulfonic acid analogously to Weygand-Hilgetag, Organisch-Chemische Experimehtierkunst, 1970, page 602, publisher Johann Ambrosius Barth, Leipzig.

Starting substances with formula IV can, for example, be obtained in a known manner by the usual Perkin synthesis from phthalic anhydride and the phenylacetic acid which is substituted with the radical R₁.

The cleavage of a benzyl group (if R 2 and R 3 are, for example, benzyl, or if R 2 is benzyl and R 3 has the indicated meanings) takes place in a known manner in a solution, respectively. suspending agent such as aromatic hydrocarbons (benzene, toluene, xylene), aliphatic alcohols (ethanol, propanol, butanol), lower aliphatic acid amides (dimethylformamide), tetramethylurea, dimethyl sulfoxide, alicyclic and cyclic, saturated ethers (diethyl ether, dioxane) at temperatures between 20 and 200°C, especially 50 and 140°C.

The spin-off takes place e.g. using hydrogen in the presence of common hydrogenation catalysts. Metallic hydrogenation catalysts such as Raney nickel, platinum or palladium catalysts, especially palladium catalysts, are preferably used.

Depending on the process conditions and the starting substances, the end substances of formula I are obtained in free form or in the form of their salts. The salts of the final substance can be transferred back to the bases in a manner known per se, for example with alkali or ion exchangers. From the latter, the salts can be obtained by reaction with organic or inorganic acids, especially those which are suitable for the production of therapeutically applicable salts.

The compounds of formula I according to the invention may contain asymmetric hydrocarbons and are then usually obtained as racemates. Such racemates can be resolved in a manner known per se into the optically active isomers, for example by fractional crystallization of the salts of racemic compounds I with optically active acids or also by chromatographic racemate separation (see for example Angewandte Chemie 92/1

(1980), page 14). However, it is also possible to use an optically active starting substance in advance, whereby a corresponding optically active form is then obtained as the final product. With more asymmetric C atoms, diastereomeric mixtures are obtained. Separation can take place using the methods that are known for this.

The present invention also includes the racemates and the diastereomeric forms as well as the corresponding optically active, dextrorotatory and levorotatory forms.

The alkanoyl residues in the compounds of formula I can be split off solvolytically, whereby the corresponding compounds of formula I are obtained, which have five hydroxy groups or amino groups. This solvolytic separation takes place, for example, by saponification with dilute acids or with the help of basic substances (pot ash, soda ash, aqueous alkali solutions, NH3) at temperatures between 10 and 150°C, especially 20 and 100°C.

The compounds according to the invention are suitable for the production of pharmaceutical compositions or preparations. The pharmaceutical compositions or the medicines contain as active substance one or more of the compounds according to the invention, possibly in a mixture with other pharmacological or pharmaceutically active substances. The preparation of the medicines can take place using known and common pharmaceutical carriers and excipients.

Additional pharmacological and pharmaceutical indications.

The compounds according to the invention show a good antiasthmatic and antiallergic effect in asthma tests on awake guinea pigs. For example, with the above-mentioned test method, an asthma-protective effect against allergic asthma is achieved at a dose of 3 mg/kg body weight in guinea pigs.

The lowest dose that is already effective in the above-mentioned animal experiment is an example

0.3 mg/kg orally

0.1 mg/kg intravenously

As a general dose range for the effect (animal experiments as above) the following can be mentioned, for example:

0.1-30 mg/kg orally, especially 1.0-10.0 mg/kg

0.1-10 mg/kg intravenously, especially 0.3-5.0 mg/kg

The direction of action of the compounds according to the invention can be compared to the action of the known pharmaceutical active substance disodium cromoglycinic acid, however, there are particularly the following differences: oral action, stronger action, longer duration of action.

Indications for the compounds according to the invention which may come into consideration: allergic Rhinitis, Asthma bronchiale. The pharmaceutical preparations generally contain between 0.1 and 30, preferably 0.3 and 10 mg of the active component according to the invention.

The supply can, for example, take place in the form of tablets, capsules, pills, dragees, Zapfchen, ointments, gels, creams, powders, dust powders, aerosols or liquid form. As liquid forms of application, e.g. in question: oil-based or alcoholic, respectively. aqueous solutions as well as suspensions and emulsions. Preferred application forms are tablets, which contain between 1 and 10 mg or solutions, which contain between 1 and 10 wt-56 of active substance.

The single dose of the active ingredients according to the invention can, for example, a) in the case of oral medicinal forms lie between 0.1 and 30 mg, preferably 1 and 10 mg, b) in the case of parenteral medicinal forms (e.g. intravenously, intramuscularly) lie between 0.1 and 10 mg, preferably

0.3 and 5.0 mg,

c) in the case of pharmaceutical forms for inhalation (solutions or aerosols) be between 1 and 10 mg, preferably 3. and'5

mg.

(The doses are calculated on the free base)

d) in pharmaceutical forms for rectal or vaginal application be between 0.5 and 50 mg, preferably 1 and 30 mg and e) in pharmaceutical forms for local application to the skin and mucous membranes (e.g. in the form of solutions, washing liquid,

emulsions, ointments, etc.) between 1 and 10 mg, preferably 3 and 5 mg.

For example, it can be recommended 3 times a day 1 to 2

tablets with a content of 1.0 to 10 mg of active substance or e.g. by intravenous injection 1 to 2 times a day an ampoule of 1 to 10 ml content with 0.3 to 5.0 mg of substance. For oral administration, the minimum daily dose is, for example, 1 mg. The maximum daily dose with oral administration should not exceed 30 mg.

For the treatment of dogs and cats, the single oral dose is generally between approximately 0.5 and 30 mg/kg body weight. The parenteral dose is approximately between 0.1 and 10 mg/kg body weight.

For the treatment of horses and cattle, the single oral dose is generally between approximately 0.5 and 30 mg/kg. The single parenteral dose is approximately between 0.1 and 10 mg/kg body weight.

(The doses are calculated on the free base).

The acute toxicity of the compounds according to the invention on mice (expressed at LD 50 mg/kg: Method according to Miller and Tainter: Proe. Soc. Exper. Biol. a. Med. 57 (1944 ) 261 ) lies, for example, with oral application between 250 and 1000 mg/kg.

The drugs can be used in human medicine, veterinary medicine as well as in agriculture alone or in a mixture with other pharmacologically active substances.

Example 1

4-(p-Fluorobenzyl)-2- r2-(N-benzyl-N-methylamino)-ethyl-1-(2H)-phthalazinone

116.94 g (0.4 mol) of the callum salt of 4-(p-fluorobenzyl)-1-(2H)-phthalazinone are suspended in 1,350 ml of dimethylacetamold and dissolved by stirring. To this solution is added 55.10 g (0.3 mol) of N-benzyl-N-methyl-2-chloro-ethylamine (the free base is obtained from the corresponding hydrochloride by liberation with NH3 and shaking out the amine with CH2CI2, as well as subsequent evaporation . The solution is heated for 5 hours to 100°C, whereby the original yellow solution above orange is colored deep red. The dimethylacetamide is filtered off with suction and the residue is taken up in CH2CI2/H2O. The organic phase is dried over MgSO4, filtered off and then evaporated. The residue is taken up in 500 ml of acetone and 28.35 g (0.32 mol) of anhydrous oxalic acid in 150 ml of acetone are added. The crystals that form overnight are filtered off with suction and dried. The salt is slurried in 300 ml of H2O and 12.30 g (0.31 mol) of NaOH in 150 ml H20, whereby a milky solution is formed. In a separatory funnel, the solution is shaken with 200 ml ether and the organic phase is separated. The ether solution is dried over MgSO4, filtered off and evaporated. The residue is dissolved in 150 ml acetone and 40 ml 7.2 n isopropanolic HC1 ( 0.28 mol).Ether is then added t il faint obscurity. The white crystals that fall out during the night are sucked off and dried in a vacuum at 50°C.

Yield: 105.22 g (60$ of theory)

Melting point for hydrochloride: 183-184°C

Production of the starting materials

Potassium salt of 4-(p-fluorobenzyl-1-(2H)-phthalazinone

37.83 g (0.573 mol) of KOH are dissolved in 450 ml of methanol and 143.17 g (0.56 mol) of 4-(p-fluoro-benzyl)-1-(2H)-phthalazinone are added in the heat while stirring. The clear solution is evaporated on a vacuum rotary evaporator, whereby white crystals remain (melting point above 250°C).

N-benzyl-N-methyl-(2-chloro)-ethylamine

Dissolve 219.35 g (1.09 mol) N-benzyl-N-methyl-(2-hydroxy)-ethylamine x HC1 in 400 ml chloroform and add 54.6 ml (0.75 mol) thionyl chloride dropwise to dissolve (if not the reaction starts, "a few drops of dimethylformamide are added to start, the reaction can be recognized by a strong evolution of gas). After the violent reaction has subsided, the solution is refluxed for 2 hours. After adding another 40 ml (0.55 mol) of SOCI2, the solution is heated for another 2 hours.

During the night, white crystals fall out, which are filtered off, stirred with ether and then filtered off. The substance is recrystallized in 400 ml of isopropanol. The white hydrochloride crystals are dried in vacuum at 50°C.

Yield: 236.27 g ($98 of theory)

Melting point: 139-140°C.

N-benzyl-N-methyl-(2-hydroxy)-ethylamine x HC1 is obtained, e.g. as follows: To a solution of lb9-, 76 g (1.38 mol) of N-benzylmethylamine in 280 ml of methanol which has been cooled to 0°C, 82 ml (1.65 mol) of ethylene oxide are added at once. The solution is stirred for 1.5 hours at 5°C. The ice bath is then removed (no exothermic reaction can be observed anymore) and stirred for a further 2 hours at room temperature. The solution is evaporated on a vacuum rotary evaporator, leaving behind a yellowish oil residue. This is distilled in a vacuum, whereby a clear liquid is obtained:

Boiling point 85-90°C at 0.27-0.33 mbar.

Yield: 193.75 g ($84 of theory).

The substance purified by distillation is dissolved in 1 liter of diethyl ether and added while cooling 260 ml (1.3 mol) 7.2

n Isopropanolic HC1. The solvent is evaporated and the residue taken up in methanol. The solution is evaporated again, leaving a yellowish, oily liquid.

Examples 2-11 are listed in Table 1.

The examples have the following structural formula A:

In table 1, column 2 (R3) shows the benzene ring in the following form:

Joint work regulations for examples 2-11

For reaction, the base is released from the hydrochloride of 4-(p-fluoro-benzyl)-2-[2-(N-methylamino)-ethyl]-1-(2H )-phthalazinone (formula A, whereby R 3 is hydrogen). To achieve this, the hydrochloride is dissolved in water and the corresponding amount of concentrated NH3 is added, resulting in a milky solution. The aqueous solution is shaken with CH2C12 and the organic phase is dried over MgSC>4, then evaporated and evaporated, whereby the free base remains. 4-(p-Fluorobenzyl)-2-[2-(N-methylmino)-ethyl]-1-(2H)-phthalazinon (= the starting phthalazinon) is dissolved in p-dioxane or dimethylacetamide and a 3 to 4 times greater amount of triethylamine or K2CO3 as a proton trap. A 2 to 5 times greater amount of the alkylating agent, i.e. the substance R3-Z, is added to this solution. The slower-reacting chlorine compounds require more extreme conditions with K2CO3i dimethylacetamide, while the more reactive bromides and p-toluenesulfonic acid ester are easily converted into p-dioxane and with triethylamine as a proton trap. The solution is heated for the indicated reaction time up to the boiling point 101°C (p-dioxane) or 110°C (dimethylacetamide). Formed triethylammonium hydrochloride or potassium chloride is filtered off and the solution is evaporated on a vacuum rotary evaporator. The remaining deep red to brown residue is partitioned between CH2C12/H20. The CH2Cl2 phase is dried over MgSO4, filtered off and evaporated. The oil thus obtained is purified using column chromatography and/or salt formation with subsequent recrystallization.

Salt formation:

a) Hydrochloride

The purified oil is taken up in a little isopropanol and acidified with it

the corresponding amount of 7.2 N isopropanolic HCl (the solution must react acidic). Diethyl ether is then added until a slight, permanent cloud appears and crystallization is continued overnight in a refrigerator. When grafting off

the solution with seed crystals that have previously been formed in a test tube, the crystallization process can be supported.

b) Maleate or oxalates

The oil is taken up in a little acetone and added accordingly

quantity of anhydrous malein- or oxalic acid dissolved in acetone. Diethyl ethers are then added to slight haze. The crystallization is carried out overnight in the refrigerator

and possibly by adding seed crystals.

Details appear in the following table:

Example 2

Example 3

Example 4

Example 5

Example 6 Example 7

Example 8

Example 9

The free base precipitates out crystalline after the work-up and is purified by expulsion with ether and subsequent filtration. A thin layer chromatogram still gives 5-6$ impurities. For purification, the hydrochloride is formed from the free base and recrystallized.

Example 10

Example 11

Example 12 Example 13

Example 14

8.15 g (26.2 mmol) of starting phthalazinone are dissolved in 50 ml of dimethylacetamide and 3.79 g (27.4 mmol) of K 2 CO 3 are added. 7.5 ml (82.3 mmol) of 1-chloro-2-methoxyethane are pipetted into the solution and this is boiled for 18 hours at 110°C under reflux. The cooled mixture is evaporated (rotary evaporator), distributed between CH2CI2/H2O and the phases are separated. The organic phase is dried over MgSO4, filtered and the filtrate is evaporated. The resulting oil is chromatographed over a silica gel column (eluent: CH2Cl2/niethanol/25% NH3= 90/9/1). The corresponding fractions are evaporated and the salt is formed as indicated for the others the examples.

Yield: 1.2 g (10$ of theory)

The starting phthalazinone is prepared, for example, as follows: 4-fp-fluorobenzyl)-2-f 2- (N-methyl-aminoethyl) 1-1-(2H)-phthalazinone - hydrochloride

105.22 g (0.24 mol) 4-(p-fluorobenzyl)-2-[2-(N-benzyl-N-methyl-amino)-ethyl]-1-(2H)-phthalazinone x HCl (Example 1 ) dissolve 1,500 ml of methanol and add 7.26 g of T0$ Pd on activated carbon,

suspended in 40 ral ethanol. This solution is hydrated for 1 hour at atmospheric pressure, whereby 6,300 liters of H2 are consumed (theoretical consumption: 5,856 liters of H2). The activated carbon is removed and the solution is evaporated. The residue is added to ether until slightly cloudy. Crystals form overnight, which are suctioned off. The white crystals are dissolved in 100 ml of boiling ethanol and ether is added to the cooled solution until slightly cloudy. The obtained white crystals of p-(p-fluorobenzyl)-2-[2-(N-methyl-amino)-ethyl]-1-(2H)-phthalazinone hydrochloride are suctioned off and dried in a vacuum at 50°C. Yield: 78.71 g ($95.8 of theory). Melting point of the hydrochloride: 139-141.5<0>C.

Example 15

4-(p-Fluorobenzyl)-2-r2-dlbenzylamino-et,yl-1-2H-phthalazinone Dissolve 25.4 g (0.10 mol) of 4-(p-fluorobenzyl)-1-2H-phthalazinone in 100 ml of ethanol and 42.6 ml (0.11 mol) of 20 µg Na ethanolate are added dropwise. The ethanol is evaporated, dioxane is added to the residue and heated to 70°C. At this temperature, N-(2-chloroethyl)-dibenzylamine, dissolved in dioxane, is added, whereby coke salt is separated. The reaction mixture is suctioned off from NaCl after a further 3 hours of heating at this temperature, the filtrate is evaporated on a rotary evaporator and taken up in methylene chloride. This solution is shaken 3 times with 10% EC1 and 1 time with bicarbonate solution, and again after evaporation to release the base with CH2Cl2/NaOH. The product crystallizes after the addition of diethyl ether. Yield: 31.0 g ($65). Melting point: 92-94°C.

Example 16

4-(p-fluorobenzyl)-2- r2-(N-ethyl-N-phenethylamino)-ethyl-1-(2H)-phthalazinon

General labor regulations.

From the hydrochloride of N-ethyl-N-phenethyl-2-chloroethylamine, the base is liberated and dissolved in dimethylacetamide. For dissolution, the potassium salt of 4-(p-fluorobenzyl)-1-(2H)-phthalazinon is added in excess. The solution is heated for the indicated reaction time to 110°C and stirred. After the reaction time, the solution is evaporated on a vacuum rotary evaporator and the remaining residue is distributed between CH2CI2/H2O. The organic phase is dried over MgSO4, filtered off and evaporated. The remaining residue is dissolved in acetone and the precipitated 4-(p-fluorobenzyl)-l-(2H)-phthalazinone is filtered off or the solution is purified on a silica gel column in a basic eluent (90 vol.-$ CH2Cl2, 10 vol.-$ methanol, 1 vol. -$ concentrated ammonia). The thus pre-purified substance is converted to the hydrochloride or oxalate, recrystallized and dried.

Addition:

Example 17 4-(p-fluorobenzyl)-2-r2-(N-cyclopentyl-N-methyl-amino)-ethyl-1-(2H)-phthalazinone

The production takes place analogously to example 16.

Example 18 4-(p-fluorobenzvl)-2-r2-(N-cyclohexvl-N-p-phenethvl-aiTilno-etvl)~\-l-(2E)-phthalazinone

The production takes place analogously to example 16.

Addition:

The oxalate is sintered at 89-90°C.

Example 19 (Removal of a benzyl group)

4-(p-fluorobenzyl)-2-(2-benzylamino-ethyl)-1-2H-phthalazinone To 15.4 g (0.032 mol) 4-(p-fluorobenzyl)-2-[2-dibenzylamino-ethyl] -1-2H-phthalazinone dissolved in 100 ml of ethanol is added to 1.5 g of 10$-ig Pd on activated carbon, as well as 5 ml of 10$-ig HC1. After flushing the apparatus with hydrogen, it is hydrated for 20 minutes at 40° C, whereby 810 ml of Hg are absorbed (calculated volume: 774 ml). While the mixture is still hot, the catalyst is sucked off, and the filtrate is evaporated on a rotary evaporator. The evaporation residue is recrystallized after acidification with isopropanolic HCl from toluene/methyl ethyl ketone. The aspirated product is slurried in 10 µg HCl and shaken in CHgClg. After drying over NaCl, the evaporated residue is recrystallized from isopropanol, filtered off with suction and dried in a vacuum at 50°C.

Yield: 11.2 g ($81.4)

Melting point for the hydrochloride: 151-154°C.

Examples of pharmaceutical preparations.

Capsules containing 5 mg of compound according to example 1. 5 g of active substance according to example 1 are passed together with 111.7 g of calcium hydrogen phosphate through a sieve (0.8 mm mesh size) and moistened with a solution of 2.3 g of gelatin and 0.1 g polysorbate 80 1 22.6 g water, granulated through a sieve with a mesh size of 2 mm and dried at 40°C. The dry granulate and 20.9 g of cornstarch are passed through a 0.8 mm sieve and homogenized. This mass is filled in a suitable capsule machine to 140 mg in hair-gelatin capsules of size 3. One capsule contains 5 mg of active substance according to example 1.

Injection solution (intravenous), containing 2.5 mg/ml compound according to example 8.

Dissolve 2.5 g of active substance according to example 8 and 9 g of sodium chloride while stirring in 800 g of water for injection purposes and make up to 1 litre. Under aseptic conditions, this injection solution is sterilized by filtration through a germ-proof filter (0.2 µm pore size). Finally, 1.1 ml (indicated volume 1 ml) is filled under aseptic conditions and under nitrogen supply in sterile 2 ml ampoules. 1 ampoule contains 2.5 mg of active substance according to example 8.

Claims (6)

1. 2-Aminoalkyl-4-benzyl-1-(2H)-phthalazinone derivatives of the formula where Ri means hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C± -C^ -alkyl or C^ -C^ -alkoxy, R2 means hydrogen, phenyl, benzyl, C-L-C^ -alkyl or C3 -C8 -c <y> chloroalkyl, R 3 means a C 1 -C 4 - alkoxy-C 3 -C 4 -alkyl radical, a C 3 -C 8 -cycloalkyl radical, a C 3 -C 3 -alkenyl radical, a C 3 -C 3 -alkynyl radical, a phenyl radical or a phenyl- C 2 -C 3 -alkyl radical, which in the phenyl part is optionally substituted with halogen, NO 2 , NH 2 , CN, OH, C 3 -C 3 -alkyl, C 3 -C 4 - alkoxy, C 3 -C 4 -alkanoyloxy or C 2 - C 6 -alkanoylamino and Alk is a C 8 -C 4 -alkylene bridge, which may also contain a double bond and their physiologically acceptable acid addition salts. 2. Process for the preparation of 2-aminoalkyl-4-benzyl-1-(2H)-phthalazinone derivatives of the formula where Ri means hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C± -Cf -alkyl or C₁ -C₁ - alkoxy, R 2 means hydrogen, phenyl, benzyl, C₁ -C₂ -alkyl or Cs -C₃ -cycloalkyl, R 3 means a C 3 -C 4 - alkoxy-C 3 -C 4 -alkyl radical, a C 3 -C 8 -cycloalkyl radical, a C 3 -C 3 -alkenyl radical, a C 3 -C 3 -alkynyl radical, a phenyl radical or a phenyl-C ^ -C^ -alkyl radical, which in the phenyl part is optionally substituted with halogen, NO 2 , NH 2 , CN, OH, C 2 -C 5 -alkyl, C 1 -C 4 -alkyl, C 2 -C 4 -alkanoyloxy or C 2 -C 6 -alkanoylamino and Alk is a C 2 -C 6 -alkylene bridge, which may also contain a double bond and their physiologically acceptable acid addition salts, characterized by ata) a compound of the general formula where Ri has the indicated meanings and X is hydrogen, the group -Alk-NHR2 , the group -Alk-NHR3 or the group -Alk-Y, whereby R2 and R3 have the indicated meanings and Y is a halogen atom or a hydroxy group which is esterified with a strong inorganic or organic acid, and the compound II can also be used in the form of a metal salt, if X is hydrogen, reacted with a compound of the formula where Z is different from X and Y and is hydrogen or a hydroxy group esterified with a strong organic or inorganic acid, and W in the residue R2 or the residue R3 is the group -Alk-NR2 R3 or the group -NR2 R3 and Alk has the indicated meaning, benzyl groups and/or alkanoyl residues which may be present in the obtained compounds are split off and the obtained compounds are optionally transferred to their acid addition salts, or b) a compound with the formula or a reactive derivative thereof, where R^ has de given meanings, is reacted with a hydrazine derivative with the general formula where Alk, R2 and R3 have the given meanings, optionally present alkanoyl residues and/or present benzyl groups are cleaved off, and the compounds obtained are optionally transferred to their acid addition salts. 3. Compound of formula I for use as therapeutic active substances. 4. Medicinal product containing a compound of the general formula I in addition to the usual carrier and/or diluent or excipients. 5. Process for the production of a medicinal product, characterized in that a compound of the general formula I is processed with common pharmaceutical carriers and/or diluents or other excipients for pharmaceutical preparations or brought into a therapeutically usable form. 6. Use of compounds of the general formula I for the production of pharmaceuticals.