HRP980297A2 - Process for the preparation of a 3(2h)-pyridazinone-4-substituted amino-5-chloro derivative - Google Patents

Description

The field of technology

The invention is from the field of pharmacology and organic chemistry.

The invention relates to the preparation process of 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino}-propylamino}-3(2H)-pyridazinone of the following formula (AND).

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State of the art

British patent specification no. 2,262,526 describes new 3(2H)-pyridazinone-4-substituted amine-5-halo derivatives which have valued antiarrhythmic properties and prevent ventricular and atrial fibrillation. 5-chloro-4-{3-{N-[2-3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinone of formula (I) is described in the above British patent specification.

According to British patent specification no. 2 262 526 the compound of formula (I) was prepared by the reaction of 4,5-di-chloro-3(2H)-pyridazinone of formula (XI)

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with an amine of formula (X).

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The disadvantage of the procedure lies in the fact that a mixture of the compound of formula (I) and its regioisomer of formula (IA) is obtained:

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whereby the basic component is the unwanted isomer of formula (IA), while the desired compound of formula (I) occurs as a side product, in a smaller percentage. The compound of formula (I) can be separated and isolated in a pure state from the thus obtained mixture only by expensive and complex column chromatography. Another disadvantage of the method is that an acceptable (2.5-3-fold) molar excess of the expensive amino component of formula (X) is obtained if the reaction is applied in several steps, which makes the method less economical.

Technical problem solution with implementation examples

The aim of this invention is the realization of a regio-selective method for the preparation of 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propyl-amino}-3(2H )-pyridazinone of formula (I), which is devoid of the disadvantages of currently known processes.

It was found that the above objective can be achieved by obtaining 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propylamino}-3(2H)-pyridazinone of formula (I) and its pharmaceutically acceptable acid addition salts according to the method of the invention, which includes

a1) reaction of the compound of general formula (II),

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where X denotes a leaving group, with N-methyl-homoveratryl amine of formula (VI),

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or

a2) reaction of the compound of general formula (III),

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where R denotes lower alkanoyl, aroyl or aryl-lower alkanoyl), with a substance containing the leaving group of formula X and the reaction of the thus obtained compound of general formula (II) with compound of formula (VI);

or

a3) by the reaction of 4-(3-hydroxypropylamino)-3,5-dichloro-pyridazine of formula (IV)

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with a suitable compound for introducing a group of formula R, by reacting the thus obtained compound of general formula (III) with a compound containing the leaving group of formula X and by reacting the thus obtained compound of general formula (II) with a compound of formula (VI);

or

a4) by the reaction of 3,4,5-trichloropyradosine of formula (V)

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with 3-amino-1-propanol, the reaction of the thus obtained compound of formula (IV) with a substance suitable for the introduction of a group of formula R, the reaction of the thus obtained compound of general formula (III) with a substance containing the leaving group of formula X and the reaction of the thus obtained compound of general formula (II) with a compound of formula (VI);

or

b1) by removing a group of formula R (where R is as defined above) from a compound of general formula (IX);

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or

b2) by reaction of the compound of formula (VIII)

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with a substance that is suitable for introducing a group of formula R and removing a group of formula R from the thus obtained compound of general formula (IX);

or

b3) by reaction of the compound of general formula (VII),

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where X is as stated above, with the compound of formula (VI), the reaction of the thus obtained compound of formula (VIII) with a substance suitable for the introduction of the group of formula R, and the removal of the group of formula R from the thus obtained compound of general formula (IX);

or

b4) by the reaction of the compound of formula (IV) with a compound containing the leaving group of formula X, by the reaction of the thus obtained compound of the general formula (VII) with the compound of the formula (VI), by the reaction of the thus obtained compound of the general formula (VIII) with a substance that is suitable for the introduction of the group of the formula R and removing the group of the formula R from the thus obtained compound of the general formula (IX);

and, if desired, by converting the thus obtained compound of formula (I) into its acid addition salt.

The invention is based on the discovery that the regio-selectivity of the reaction can be significantly increased by using 3,4,5-trichloropyridazine of formula (V) as a starting material. By reacting the compound of formula (V) with 3-amino-1-propanol, an approximately 1:1 mixture of the desired compound of formula (IV) and its regio-isomer of formula (IVA) is obtained.

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A further advantage of using the compound of formula (V) as a starting material lies in the fact that the isomers of formulas (IV) and (IVA) can be easily separated by crystallization, thus eliminating the need for expensive column chromatography, which is clumsy on an industrial scale. A further advantage of the process of the present invention is that the regio-isomers can be separated at the beginning of the synthesis, when the first intermediate is formed, so that further reaction steps and the final step are carried out to result in only one regio-isomer. Therefore, the desired product can be separated from the reaction mixture with reduced losses and with higher purity compared to known procedures. Until now, it has not been possible to see that the regio-isomers of formulas (IV) and (IVA) can be separated so easily, by crystallization, and converted into compounds of the general formulas (II) and (III), with such a high yield.

In the first stage of version a) according to this invention, 3,4,5-trichloropyridazine of formula (V) reacts with 3-amino-1-propanol. the reaction is carried out in an organic solvent. Lower alkanols (such as methanol, ethanol, n-propanol, preferably ethanol) or dipolar aprotic solvents (such as acetonitrile or dimethylformamide) are preferably used as the reaction medium. The reaction is carried out in the presence of an acid-binding agent. For this purpose, inorganic acid-binding agents (e.g. alkali carbonates, such as sodium carbonate or potassium carbonate, alkaline hydrocarbons, such as sodium or potassium bicarbonate), or organic acid-binding agents (e.g. amines, such as are triethylamine or diethyl isopropyl amine). According to a preferred embodiment of the process according to this invention, an excess of 3-amino-1-propanol, which is used as a reactant, can be used as a solvent. The reaction can be carried out at a temperature between 50°C and 100°C, preferably at the temperature of the boiling point of the reaction mixture.

When the reaction ends, the reaction mixture is refined by removing the solvent and treating the residue with distilled water or with a 5 to 15% sodium chloride solution. Thus, the two isomers can be easily separated, because the precipitate which is rich in the unwanted isomer of the formula (IVA) can be easily separated by filtration from the aqueous solution which is rich in the desired isomer of the formula (IV). If desired, both isomers can be further purified. The isomer of formula (IVA) can be purified by recrystallization from alcohol, while the compound of formula (IV) can be purified by extraction with an organic solvent (e.g. ethyl acetate or halogenated hydrocarbons, such as dichloroethane or chloroform), followed by drying and evaporation of the extract and by recrystallizing the residue from diethyl ether.

In the second reaction step of version a) the thus obtained compound of formula (IV) reacts with a substance which is suitable for the introduction of a group of formula R, where R is lower alkanoyl (e.g. acetyl, propionyl or butyryl), aroyl (e.g. benzoyl carrying an arbitrary substituent which is selected from the group consisting of halogen, alkoxy and trifluoromethyl) or aryl-(lower alkanoyl) (eg phenylacetyl). Compounds of the general formula (III) containing an acetyl group instead of R are prepared and preferentially used in the synthesis.

The starting compound of formula (IV) used in the second step of the synthesis can be purified or unpurified. Surprisingly, it was found that if the compound of the formula (IV) is used, which is unpurified, the compound of the general formula (III) is obtained with at least such purity and good yield as when the purified compound of the formula (IV) is used as the starting material. If the compound of the formula ( III) containing acetyl instead of R, the compound of formula (IV) reacts with acetic acid, in the presence of excess sodium acetate. The reaction medium is preferably anhydrous acetic acid and sodium acetate is preferably used in a 2.5 to 3-fold molar excess. The reaction can be carried out at a temperature between 80°C and 120°C, preferably at a temperature of around 100°C. The reaction mixture can be refined by extraction with an organic solvent (preferably dichloromethane), followed by drying and evaporation of the organic phase. The product was purified by recrystallization from alkanol (preferably methanol).

The compound of formula (III) obtained in the third reaction stage of version a) reacts with a substance containing the leaving group of formula X, where X preferably denotes a halogen atom (e.g. chlorine or bromine) or alkylsulfonyloxy (such as benzenesulfonyloxy, p-tolylsulfonyloxy or p-bromophenylsulfonyloxy) group.

It is preferable to carry out the reaction via an intermediate of the general formula (II), where X denotes bromine. In this case, the compound of general formula (III) reacts with an aqueous solution of hydrogen bromide. It is preferable to use a 48% aqueous solution of hydrogen bromide. Thus, the group of formula R can be removed from the amino and hydroxy groups with excellent yield in one reaction step, and 4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone of formula (II) is obtained. The reaction is carried out at a temperature between 80°C and 110°C, preferably at a temperature of around 98°C. The reaction mixture can easily be worked up. The secreted product is separated by filtration and centrifugation, and arbitrarily crystallized from alcohol. The compound of the general formula (II) containing a bromine atom instead of X is a particularly desirable intermediate, because the bromine atom can be easily cleaved as a leaving group.

In the next reaction stage of version a), the compound of general formula (II) reacts with N-methyl-N-[2-(3,4-dimethylphenyl)-ethyl]-amine (N-methyl-homoveratrilamine). The reaction is carried out in a solvent, in the presence of an acid-binding agent. Dipolar aprotic solvents (such as acetone, acetonitrile or dimethylformamide) can be used as a reaction medium. As an acid-binding agent, inorganic compounds (eg alkaline carbonates, such as sodium carbonate or potassium carbonate, or alkaline hydrocarbons, such as sodium bicarbonate or potassium bicarbonate) or organic compounds (eg triethylamine or dipropylethylamine) can be used. The reaction is carried out at a temperature between 40°C and the boiling point of the reaction mixture. The reaction can also be carried out using an excess of amine of formula (VI) which serves as an acid binding agent.

The reaction mixture can be worked up by known methods, eg the mixture is evaporated and the residue is taken up in water, extracted with an organic solvent (such as dichloromethane or ethyl acetate), the organic extract is filtered, dried and purified by crystallization.

In the first step of version b) of the process according to this invention, the compound of formula (IV) reacts with a substance containing the leaving group of formula X.

When preparing compounds of general formula (VII) containing bromine or chlorine instead of X, the compound of formula (IV) reacts with thionyl bromide or phosphorus oxybromide, or thionyl chloride or phosphorus oxychloride. The reaction is carried out at a temperature between -10°C and 100°C, in an inert organic solvent. Halogenated hydrocarbons (such as dichloromethane, dichloroethane, chloroform, trichlorethylene, chlorobenzene or carbon tetrachloride), dipolar aprotic solvents (such as acetonitrile) or aromatic solvents (such as benzene or toluene) can be used as solvents. The compound of general formula (VII), where X denotes bromine, can be prepared from the compound of formula (IV) with an aqueous solution of hydrogen bromide in organic acids (eg acetic or formic acid), at a temperature between 20°C and 150°C.

Compounds of general formula (VII), where X is alkylsulfonyloxy or arylsulfonyloxy, can be prepared by reacting the compound of formula (IV) with the appropriate sulfonic chloride in an inert solvent, in the presence of an acid-binding agent, at a temperature between -20°C and 60°C. Halogenated hydrocarbons (such as dichloromethane, dichloroethane, chloroform, trichlorethylene, chlorobenzene or carbon tetrachloride) or aromatic hydrocarbons (such as benzene or toluene) can be used as reaction medium. Organic bases (eg triethylamine or pyridine) can be used as acid binding agents.

In the next reaction stage of version b), the thus obtained compound of the general formula (VII) reacts with the amine of the formula (VI). The reaction is preferably carried out in a dipolar aprotic solvent (eg acetone, acetonitrile, dimethylformamide) in the presence of an acid binding agent. Inorganic compounds (such as potassium carbonate or potassium bicarbonate) or organic compounds (such as triethylamine) can be used as an acid binding agent. An excess of the amine of formula (VI) can also serve as an acid binding agent. The reaction is carried out at a temperature between 10°C and the boiling point of the reaction mixture. The reaction mixture is worked up by known methods, eg the solvent is removed, the residues are placed in water, extracted with an organic solvent (such as dichloromethane or diethyl acetate) and the extract is filtered and dried.

The thus obtained compound of the general formula (VIII) is then reacted with a substance suitable for the introduction of the group of the formula R. The reaction is carried out as stated above in connection with the conversion of the compound of the formula (IV) into the compound of the formula (III). Compounds of the general formula (IX) containing an acetyl group instead of R are preferably prepared. For this purpose, it is preferable to carry out the reaction of the compound of the formula (VIII) with anhydrous acetic acid, in the presence of anhydrous sodium acetate in a 1 to 5-fold molar excess, at a temperature between 40°C and 140°C, preferably between 80°C and 120°C.

In the last reaction step of variant b), the group of formula R is removed from the compound of general formula (IX). The reaction is preferably carried out with hydrogen bromide, especially a 48% aqueous solution of hydrogen bromide.

The thus obtained compound of general formula (I) is preferably translated into its pharmaceutically acceptable addition salt. Obtaining the salt is carried out by methods that are known per se, with acids that are generally used in the pharmaceutical industry. Inorganic acids (eg hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (such as maleic, fumaric, citric, malic, lactic, succinic acid, etc.) can be used. It is preferable to prepare the acid addition salt of the compound of formula (I) using hydrogen chloride or fumaric acid.

The compound of formula (V) can be prepared by the reaction of 4,5-dichloro-3(2H)-pyridazinone with phosphorus oxychloride [T. Kuraishi: Pharm. Bull. (Tokyo) 4, 497 (1956)].

The advantages of the process according to this invention, compared to known processes, are as follows:

- the reaction is significantly more stereoselective than known procedures,

- the desired isomer can be separated from the obtained stereoisomer by simple crystallization, so that complex column chromatography, which is clumsy on an industrial level, can be removed,

- stereoisomers are separated in the early stages of the synthesis, and accordingly only one stereoisomer is used in further stages of the process,

- reaction stages can be carried out with high yield (e.g. preparation of compounds of formulas (II) and (III)),

the final product of formula (I) is obtained with high yield and high purity.

The invention is illustrated below by the following non-limiting examples.

Example 1

4-(3-hydroxypropylamino)-3,5-dichloropyridazine (IV) and 5-(3-hydroxypropylamino-3,4-dichloropyridazine (IVA)

47.93 g (0.261 mol) of 3,4,5-trichloropyridazine was dissolved in ethanol and 49.7 ml (r = 0.982 g/cm 3 , 0.65 mol) of 3-amino-1-propanol was added with stirring. The solution was heated to boiling, it was boiling for 30 minutes and a sample was taken for TLC (eluent 10:10:0.5 mixture of ethyl acetate:acetone:triethylamine, Rf values: (XI)=0.90, (IV)=0, 48, (IVA)=0.32, pollution of unknown composition=0.75). The reaction is generally complete within 30 minutes to 1 hour, with all of the starting material being consumed. The reaction mixture is then evaporated, 13 g of sodium chloride is dissolved in distilled water and the resulting solution is added to the evaporated mixture, with stirring. The reaction mixture was then left in the refrigerator overnight at 5°C. The precipitated crystals were washed with 10 to 12 ml of distilled water and the precipitate was dried. Thus, 27.7 g (47.7%) of the crude product (IVA) was obtained. T.p.: 150-153°C. After recrystallization from methanol, the melting point increased to 157-158°C. Physical properties will be listed below.

The aqueous motherwort was extracted 5 times, each time with 200 cm3 of ethyl acetate, dried over magnesium sulfate, filtered on activated carbon and evaporated to dryness. The predominant part of the remaining crude product is the compound of formula (IV).

Yield of raw product: 28.02 g (48.32%), according to HPLC analysis it contains 7 to 8% (IVA) and 1 to 2% impurities of unknown composition. The crude product was purified by recrystallization from cold diethyl ether as follows:

300 ml of diethyl ether was added in 5 portions and the oily product was stirred at room temperature. The ether solution was decanted each time and fresh ether was used. The ether solutions were combined, evaporated to a volume of 100 ml and the separated crystals were filtered. Thus, 15.6 g (26%) of the compound of formula (IV) was obtained. T.p.: 65-66°C. According to HPLC analysis performed after purification (IVA) <3.0% and (IV)>97%. To calibrate the HPLC method, small amounts of standards were prepared using column chromatography.

HPLC method:

Column: Ultrasphere SI 3 mm, 75 cm×4.6 mm.

Eluent: cyclohexane:ethyl acetate (1:1).

Flow rate: 1.0 ml/min.

Detection: UV 254 nm.

Injected volume: 20 ml (0.8% dilution).

Retention time: 5.13 for compound (IV) and 13.46 minutes for compound (IVA).

Physico-chemical properties of 4-(3-hydroxypropyl-amino)-3,5-dichloropyridazine (IV):

T.p.: 65-66°C.

TLC: ethyl acetate:triethylamine = 20:0.5 Rf=0.36.

Analysis of the compound C7H9Cl2NO3 (222.08):

C H Cl N

Calculated: 37.86% 4.09% 31.93% 18.92%

Found: 37.62% 4.12% 31.71% 1 8.67%

IR (KBr) ν cm-1: 3249, 2947, 1591, 1454, 1390, 1353, 1212, 1177, 1124, 1075, 1037, 908, 683, 522, 460.

1H-NMR (DMSO): δ 8.70 [s, (1H) pyridazine C-6], 6.8 [t, (1H) 4-NH], 4.7 [t, (1H) OH], 3 .74 [qa, (2H), N-CH2], 3.5 [qa, (2H) CH2-O-], 2.73 [m, (2H), C-CH2-C].

13CNMR (DMSO) δ ppm: 150.8; 116.0; 140.1; 114.7 (pyridazine carbon atoms), (60 C-OH), (43.6 NH-C), (31.9 C-CH2-C).

Physico-chemical properties of 5-(3-hydroxypropyl-amino)-3,4-dichloropyridazine (IVA):

T.p.: 157-158°C.

TLC: ethyl acetate:triethylamine = 20:0.5 Rf=0.16

Analysis for the formula C7H9Cl2N3O (22.08):

C H Cl N

Calculated: 37.86% 4.09% 31.93% 18.92%

Found: 37.68 4.11% 31.77% 18.73%

IR (KBr) ν cm-1: 3269, 2935, 1568, 1334, 1283, 1224, 1139, 1070, 1043, 861, 830, 795, 661, 540, 514.

1H-NMR (DMSO): δ ppm: 8.73 [s, (1H)pyridazine C-6], 7.59 [t, (1H)5-NH], 4.66 [t, (1H)OH] , 3.4-3.6 [m, (4H) CH2-X X=heteroatom], 1.73 [m, (2H) C-CH2-C].

The stereoscopic proximity of the NH proton at position 5 and the pyridazine proton at position 6 was proven by the DNOE experiment.

13CNMR (DMSO) δ ppm: 152.1; 143.7; 137.2; 114.4 (pyridazine carbon atoms), (58.4 C-OH), (39.9 C-NH), (31.4 C-CH2-C).

Example 2

Preparation of 4-N-acetyl-4-N-(3-acetoxy-propyl)-5-chloro-3(2H)-pyridazinone (III)

Method A

A mixture of 3 g (13.5 mmol) of 4-(3-hydroxypropylamino)-3,5-dichloropyridazine (IV) and 3 g (35.6 mmol) of anhydrous sodium acetate was suspended in 30 cm3 of anhydrous acetic acid, and the mixture was heated 3 hours (TLC ethyl acetate:acetone:triethylamine = 10:10:0.5). The starting substance (Rf=0.48) has been used. The reaction mixture was then cooled, 100 cm3 of distilled water was added and the mixture was extracted 3 times, each time with 50 cm3 of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered with activated carbon and evaporated. The crude oily residues were dissolved in 5 cm3 of hot methanol. After cooling, 4-N-acetyl-4-N-(3-acetoxypropyl)-5-chloro-3(2H)-pyridazinone (III) begins to separate. The separated crystals were filtered and washed successively with cold methanol and ether. Yield: 2.0 g (51.6%).

Method B

A mixture of 28 g (0.12 mol) of the crude product of formula (IV) and 28 g (0.34 mol) of anhydrous sodium acetate was suspended in 280 cm 3 of anhydrous acetic acid. The mixture was heated to boiling and the reaction was carried out as described above. The mixture was then cooled, sodium acetate was filtered off and washed with anhydrous acetic acid. The queen is steamed in a vacuum. To completely remove acetic acid, 2×50 cm3 of toluene was added and the mixture was evaporated again. The residues were then dissolved in 100 cm3 of distilled water, the aqueous mother liquor was extracted 3 times, each time with 100 cm3 of dichloromethane, dried over magnesium sulfate, filtered over activated carbon and evaporated. The last crude product (29-30 g) was dissolved in 15-20 cm3 of hot methanol, purified with activated carbon and filtered while still hot. The product is separated after cooling. The product was filtered and washed successively with cold methanol and cold ether. Yield: 16-20 g (45-50%).

It was found that the chemical and physical properties of the compound of formula (III), which was prepared according to method A and B, are identical.

Physical and chemical properties of 4-N-acetyl-4N-(3-acetopropyl)-5-chloro-3(2H)-pyridazinone (III)

T.p.: 108-110°C.

TLC: acetonitrile:methanol = 9:1 Rf=0.75

Analysis for the formula C11H14ClN3O4:

C H Cl N

Calculated: 45.92% 4.91% 12.32% 14.61%

Found: 45.63% 5.01% 12.36% 14.40%

IR (KBr) ν cm-1: 3400-2800 [pyridazinone ring (NH-CO)], 1729, 1676 (amides), 1593, 1445, 1406, 1362, 1321, 1256, 1205, 1172, 1128, 1099, 1083 , 1032, 971, 945, 888, 845, 831, 777, 741, 637, 610, 569, 448, 427.

1H-NMR (400 Mhz, CDCl3) δ ppm: 12.8 [s, (1H) pyridazinone-NH], 7.97 [s, (1H) pyridazinone C-6H], 4.12 [t, (2H) J=6.5 Hz, -CH2O], {3.8 [m, (1H) and 3.7 [m, (1H), -N-CH2}, 2.03 [s, (3H), CH3] , 1.97 [s, (3H)CH3], 1.89 [m, (2H), C-CH2-C].

13CNMR (400 MHz CDCl3) δ ppm: 171.07; 169.68; (acetyl-carbonyl carbon atoms), 159.87 (CO-pyridazinone), 138.2; 138.4; 139.9 (pyridazinone ring carbon atoms), 62.0 CH2-O), 44.2 (CH2-N), 27.4 (CH2), 21.7 and 20.9 (CH3 carbon atoms).

The advantage of method B is that the loss of substance during recrystallization from diethyl ether is prevented.

Example 3

4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone (II)

30.5 g (0.106 mol) of 4-N-acetyl-4-N-(3-acetoxypropyl)-5-chloro-3(2H)-pyridazinone (III) was suspended in 136 cm3 of 48% aqueous hydrogen bromide solution in a flask which can be closed with a DuPont screw cap. The reaction mixture is kept at a temperature between 96°C and 98°C for 24 hours with stirring [TLC ethyl acetate:acetone:triethylamine = 10:10:0.5 (III) Rf=0.73]. During this time, the starting material was consumed. The reaction mixture was then cooled, the separated crystals were then filtered and washed with cold dichloromethane. Yield: 27.3 g (95%). The crude product was recrystallized from 100 to 110 cm3 of isopropanol. Yield: 20.2 g (73%).

Physical and chemical properties of 4-(3-bromo-propylamine)-5-chloro-3(2H)-pyridazinone

T.p.: 116-118°C.

TLC: ethyl acetate-acetone-triethylamine = 10:10:0.5 Rf=0.73

Analysis for the formula C7H9BrClN3O4 (266.53):

C H Cl N

Calculated: 31.55% 3.40% 13.30% 15.77%

Found: 31.74% 3.45% 13.15% 15.70%

IR (KBr) ν cm-1: 3183, 2800, 2400, 1545, 1423, 1374, 1324, 1269, 1239, 1214, 1163, 1107, 1037, 936, 819, 750, 572.

1H-NMR (DMSO) δ ppm: 12.45 [s, (1H)NH-pyridazine], 7.65 [s, (1H)-pyridazine], 6.4 [s, (1H)4NH], 3, 78 [t, (2H), N-CH2], 3.58 [t, (2H), Br-CH2], 2.13 [qa, (2H), CH2].

13CNMR (DMSO) δ ppm: 156.93 (Co-pyridazinone), 139.8; 105.9 (carbon atoms of pyridazine ring), 34.16 (C-NH), 41.88 (C-Br), 31.95 (CH2).

Example 4

5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinone (I)

A mixture of 10.66 g (0.04 mol) 4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone (II), 10.0 g (0.05 mol) N-methyl-homoveratryl amine ( VI) and 8 g of potassium bicarbonate were suspended in 80 cm3 of acetone. The reaction mixture was refluxed for 8 to 12 hours. The reaction was monitored by TLC (eluent: ethyl acetate:acetone:triethylamine = 10:10:0.5 (II Rf=0.76), (VI Rf=0.14), (I Rf=0.47)). The mixture was filtered while still hot, washed with acetone and the mother liquor was evaporated under vacuum. 50 cm3 of ethyl acetate was added to the residues. Any separated inorganic matter was filtered and the filtrate was re-evaporated. The remaining viscous, oily product (14 to 15 g) was triturated twice with 50 cm 3 of hot water to remove the unreacted starting material of formula (VI). The warm aqueous solution was decanted. The oily residues were dissolved in methanol and dried over magnesium sulfate. After adding a small amount of diisopropyl ether and cooling the mixture, a white porous substance was separated. Thus, 9 g (59.0%) of the crude product was obtained. T.p.: 89-90°C. After recrystallization from diisopropyl ether, 7.0 g (46.0%) of the title compound was obtained.

Physical and chemical properties of 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propyl-amino}-3(2H)

- pyridazinone

T.p.: 90-92°C.

TLC: ethyl acetate-acetone-triethylamine = 10:10:0.5 Rf=0.45

Analysis for the formula C18H25ClN4O3 (380.88):

C H Cl N

Calculated: 56.76% 6.62% 9.31% 14.71%

Found: 56.46% 6.68% 9.26% 14.85%

IR (KBr) ν cm-1: 3290, 3111, 2940, 2860, 2830, 2780, 2700, 1640, 1610, 1570, 1520, 1445, 1350, 1260, 1240, 1140, 1100, 950, 900, 60800 .

1H-NMR (200 MHz, CDCl3) δ ppm: 1.7 [s, (1H) pyridazinone-NH], 7.52 [s, (1H) pyridazinone-CH], 6.75 [m, (3H) Ar -H], 6.62 [t, (1H), NH], 3.84 and 3.86 [s, (6H), CH3O], 3.85 [m, (2H), propyl-CH2], 2 .72 and 2.65 [m, (4H) ethyl-CH2], 2.56 [m, (2H), propyl-CH2], 2.33 [s, (3H), N-CH3], 1.80 [m, (2H), propyl-CH2].

13 CNMR (200 MHz CDCl 3 ) δ ppm: 157.69 (pyridazinone C 3 ), 148.46; 146.94; 132.64; 120.20; 111.73; 110.93 (CH3O-phenyl-aromatic carbon atoms), 140.41 (pyridazinone C6), 139.85 (pyridazinone C5), 106.8 (pyridazinone C4), 59.43 (C1-propyl), 55.54 and 55.49 (O-CH3), 54.83 (C2-ethyl), 42.82 (N-CH3), 41.67 (C3-propyl), 32.87 (CH2-Ar), 27.66 (C2 -propyl).

Example 5

Preparation of starting materials

200 g of commercially available 4,5-dichloro-3(2H)-pyridazinone was refluxed in 1500 cm3 of phosphorus oxychloride for 5 hours. Then the excess phosphorus oxychloride was predistilled in vacuum. The residues were placed in ice-cold water, the crystalline product was filtered and dried. Yield: 200 g (89%) of 3,4,5-trichloro-pyridazine. T.p.: 58-60°C.

Claims (18)

1. Process for preparing 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propylamino}-3(2H)-pyridazinone of formula (I) [image] and its pharmaceutically acceptable acid addition salts, characterized by comprising a1) reaction of the compound of general formula (II), [image] where X denotes a leaving group, with N-methyl-homoveratryl amine of formula (VI), [image] or a2) reaction of the compound of general formula (III), [image] where R denotes lower alkanoyl, aroyl or aryl-lower alkanoyl), with a substance containing the leaving group of formula X and the reaction of the thus obtained compound of general formula (II) with compound of formula (VI); or a3) by the reaction of 4-(3-hydroxypropylamino)-3,5-dichloro-pyridazine of formula (IV) [image] with a suitable substance for introducing a group of formula R, by reacting the thus obtained compound of the general formula (III) with a compound containing the leaving group of the formula X and by reacting the thus obtained compound of the general formula (II) with a compound of the formula (VI); or a4) by the reaction of 3,4,5-trichloropyridazine of formula (V) [image] with 3-amino-1-propanol, the reaction of the thus obtained compound of formula (IV) with a compound suitable for the introduction of the group of formula R, the reaction of the thus obtained compound of the general formula (III) with a substance containing the leaving group of formula X and the reaction of the thus obtained compound of general formula (II) with a compound of formula (VI); or b1) by removing a group of formula R (where R is as defined above) from a compound of general formula (IX); [image] or b2) by reaction of the compound of formula (VIII) [image] with a substance that is suitable for introducing a group of formula R and removing a group of formula R from the thus obtained compound of general formula (IX); or b3) by reaction of the compound of general formula (VII), [image] where X is as stated above, with the compound of formula (VI), the reaction of the thus obtained compound of formula (VIII) with a substance suitable for the introduction of the group of formula R, and the removal of the group of formula R from the thus obtained compound of general formula (IX); or b4) by the reaction of the compound of formula (IV) with a substance containing the leaving group of formula X, by the reaction of the thus obtained compound of the general formula (VII) with the compound of the formula (VI), by the reaction of the thus obtained compound of the general formula (VIII) with a substance that is suitable for the introduction of the group of the formula R and removing the group of the formula R from the thus obtained compound of the general formula (IX); and, if desired, by converting the thus obtained compound of formula (I) into its acid addition salt. 2. The process according to version a3) or a4) of claim 1, characterized in that it includes the reaction of the compound of formula (IV) with a substance suitable for the introduction of an acetyl group. 3. The method as specified in claim 2, characterized in that it includes carrying out the reaction with a mixture of acetic acid and sodium acetate. 4. The process as stated in claim 3, characterized in that it includes carrying out the reaction at a temperature between 80°C and 110°C. 5. The process according to any version a2) to a4) of claim 1, characterized in that it includes the reaction of the compound of the general formula (III) with a substance containing a halogen atom, alkylsulfonyloxy or arylsulfonyloxy group, preferably a chlorine or bromine atom or methanesulfonyloxy, benzylsulfonyloxy, p- toluenesulfonyloxy or p-bromosulfonyloxy group. 6. The process as stated in claim 5, characterized in that it includes the reaction of the compound of the general formula (III) with hydrogen bromide. 7. The process as stated in claim 6, characterized in that it includes carrying out the reaction at a temperature between 80°C and 110°C. 8. The process according to versions a3) or a4) of claim 1, characterized in that it comprises the reaction of the compound of formula (IV) without purification with a substance suitable for the introduction of the group of formula R. 9. The process according to any version a1) to a4) of claim 1, characterized in that it includes carrying out the reaction of the compounds of formulas (II) and (VI) in a dipolar aprotic solvent, in the presence of an acid-binding agent. 10. The process as stated in claim 9, characterized in that it includes the use, as solvent, of acetone, acetonitrile or dimethylformamide and an acid-binding agent such as an alkaline carbonate, an alkaline hydrocarbonate or an amine, preferably triethylamine or an excess of the reagent of formula (VI). 11. The process according to version a4) of claim 1, characterized in that it includes carrying out the reaction of the compound of formula (V) with 3-amino-1-propanol in a lower alcohol or a dipolar aprotic solvent, in the presence of an acid-binding agent. 12. The method as stated in claim 11, characterized in that it uses ethanol, acetonitrile or dimethylformamide as a solvent and as an acid-binding agent alkaline carbonate, alkaline hydrocarbonate, organic amine, preferably triethylamine or an excess of 3-amino-1-propanol. 13. The process as stated in claim 12, characterized in that it includes carrying out the reaction at a temperature between 50°C and 100°C. 14. A compound characterized in that its general formula is (IV). 15. Compounds of the general formula (III), characterized in that R denotes lower alkanoyl, aroyl or aryl-(lower alkanoyl). 16. A compound of the general formula (III) according to claim 15, characterized in that R denotes acetyl. 17. Compounds of the general formula (II), indicated by this, where X denotes a leaving group. 18. A compound of the general formula (II) according to claim 17, characterized in that X denotes bromine.