CS250688B2 - Method of pyridazine's derivatives production substituted in position 3 by substituted aminogroup - Google Patents

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of carboxamidoalkylamino group-substituted pyridazine derivatives as well as their acid addition salts.

These compounds have central nervous system effects and can therefore be used as active ingredients in pharmaceutical compositions.

The compounds of the present invention can be represented by Formula I

R 1 -y "NH-Atk V-IV in which halogenated, naphthyl, cyclohexyl, thien-2-yl or thien-2-yl,

R 2 is hydrogen, C 1 -C 4 alkyl or phenyl,

R3 is hydrogen, (C1-C4) alkyl, phenyl or cyano,

R4 represents a group —CONH2, and

Alk is (CH 2) _n wherein n is an integer of 2, 3 or 4.

The compounds of formula I provide addition salts with mineral or organic acids. It is also within the scope of the invention to prepare addition salts of compounds of formula I with pharmaceutically acceptable acids.

The process according to the invention for the preparation of the compounds of the general formula I is characterized in that the correspondingly substituted 3-chloropyridazine of the general formula II

R 1 is hydrogen, C 1 -C 4 alkyl, phenyl, phenyl monosubstituted with halogen or nitro or C 1 -C 4 alkyl or C 1 -C 4 alkoxy or hydroxyl, disubstituted R 1 -NN phenyl lil)

230688 in which

R1, R2 and R3 are as defined above, reacted with an excess of hydrazine hydrate NH2-NH2, and the resulting hydrazino derivative of formula (III) is left _; with a ω-halogenated compound of Formula V

X — Alk — R4 ‘(V) in which

X is halogen, preferably bromine, R &^lt; 4 > is C1-C4 alkyl in the alkyl moiety, and Alk is as defined above, and the resulting ester of formula (I) in which:

R1, R2 and R3 are as defined above, the resulting amino derivative of formula IV is catalytically hydrogenated

Nl i ^

N-N (IVI in which

R 1, R 2 and R 3 are as defined above ^;

N ~ Ň (/ '} in which

R 1, R 2, R 3, R a 'and Alk are as defined above, converted by ammonia treatment to a compound of formula I wherein R 1, R 2, R 3, R 4 and Alk are as defined under formula I, then the compound of formula I obtained If desired, it is converted into its acid addition salt.

The process of the invention can be illustrated by the following reaction scheme:

(II 1

, r

Al-phi, h (VI-NH-Al-h-R, '- N - n ((') (R 4 - COO alkyl of 1 to 4 carbon atoms in the alkyl moiety)

R, R _3, nh ₃

-> · ^R r \\ ^NH- MK ~ CONH?

N-N (II

The starting material used is a pyridazine of the formula II, chlorinated in the 3-position, which is converted to the corresponding 3-amino derivative of the formula IV. Since in practice the direct route to obtain the amino derivative is difficult, the hydrazinated intermediate of formula III is obtained, which is obtained in good yield by refluxing the chlorinated pyridazine of formula II with an excess of hydrazine hydrate. From the hydrazinated derivative of formula (III), an amino derivative of formula (IV) is prepared by hydrogenation in the presence of a catalyst such as Raney nickel,

Treatment of the amino derivative of formula IV with a ω-halogenated ester of formula V yields a compound of formula Γ. The reaction is carried out by heating the reactants in a solvent medium such as dimethylformamide at a temperature of 50 to 100 ° C.

Compounds of formula (I) in which R 4 is -CONH 2 are obtained from compounds of formula (Γ) in which R ⁴ is -COO-alkyl of 1 to 4 carbon atoms in the alkyl moiety by treatment with ammonia dissolved in an aliphatic alcohol such as methanol.

The 3-chloropyridazines used as starting materials are known compounds or can be prepared by known methods, in particular by treating excess 2H-pyridaz-3-ones with an excess of phosphorus oxychloride.

The invention is illustrated by the following examples.

Example 1.

3- (3-Carboxyamidopropylamino) -6- (4-chlorophenyl) -pyridazine of formula I, wherein:

R 2 = R 3 = H, Alk = (CH 2) 3, R 4 = CONH 2

1.3 g of 3- (3-ethoxycarbonylpropylamino) -6- (4-chlorophenyl) pyridazine are dissolved in 100 ml of methanol. 13 grams of ammonia are dissolved in the resulting solution, which is cooled in an ice bath. The reaction mixture was stirred at room temperature for 6 days and then evaporated to dryness under reduced pressure. After recrystallization of the residue from acetonitrile, 0.7 g of the title compound of melting point 180 DEG C. is obtained.

Claims (4)

A process for the preparation of pyridazine substituted at the 3-position by a carboxamidoalkylamino group of the formula I R, R -Alk- R, V-IV (f) wherein R 1 is hydrogen, C 1 -C 4 alkyl, phenyl, phenyl 6 Example 2 Hydrochloride 3- (3-carboxamidopropylamino) -4-methyl-6-phenylpyridazine of formula I wherein: R2 = H, R3 = CH3, Aik = (CH2) 3, R4 = == CONH2 However, following the procedure of Example 1, but starting from 3- (3-ethoxycarbonylpropylamino) -4-methyl-6-phenylpyridazine hydrochloride, the title compound of melting point 130 DEG-132 DEG C. (recrystallized from isopropanol) is obtained. The compounds produced by the method of the invention were tested for their central nervous system activity. The results of these tests show that the compounds of the invention have an effect on the neuron by occupying a β-aminobutyric acid reception site. They have pharmacological properties in animal experiments, so that they can be used in human medicine for the treatment of psychic neurotic or neuroinuscular diseases. In particular, the compounds of the invention may be used for the treatment of mental or behavioral disorders such as depression, asthenia, Parkinson's disease, digestive disorders or insomnia. The compounds of the invention may be administered orally or by injection. The pharmaceutical compositions containing them as active ingredient may be solid or liquid and take the form of, for example, tablets, pills, granules, suppositories, or injections. The dosage may vary within wide limits, in particular depending on the type and severity of the disease and the mode of administration. In an adult, when administered orally, the daily dose is most often 0.05 to 0.5000 and may be divided into several sub-doses. BACKGROUND OF THE INVENTION halo or nitro or C 1 -C 4 alkyl or monosubstituted or C 1 -C 4 alkoxy or hydroxy, halogen-disubstituted phenyl, naphthyl, cyclohexyl, thien-2-yl or thien-3 -yl residue, R 2 is hydrogen, C 1 -C 4 alkyl or phenyl, R3 is hydrogen, (C1-C4) alkyl, phenyl or cyano, R4 represents a group —CONH2, and Alk group (CH2j _n , where n is an integer of 2, 3 or 4, as well as their acid addition salts, characterized in that the correspondingly substituted 3-chloropyridazine of the formula II 6> ~ ^Ct ' N ~ N tm in which R1, R2 and R5, as defined above, are reacted with an excess of hydrazine hydrate NH2-NH2, the resulting hydrazino derivative of formula III in which: R1, R2 and R3 as defined above are reacted with a ω-halogenated compound of formula V X — Alk — R4 * (V) wherein X is halogen, preferably bromine, R4 is --COO-alkyl of 1 to 5 carbon atoms; And Alk is as defined above, and the resulting ester of formula Γ I /// 1 in which R 1, R 2 and R 3 are as defined above, catalytically hydrogenated to form the amino derivative of formula (IV): R 1, R 2, R 3, R d 'and Alk are as defined above, converted by ammonia treatment to a compound of formula I wherein R 1, R 2, R 3, R 4 and Alk are as defined under formula I, then the compound of formula I obtained If desired, it is converted into its acid addition salt.