NO179905B - Analogous Process for Preparation of 6-alkylpyridazine Derivatives and Intermediates for Preparation of Such - Google Patents

Abstract

Pyridazine derivatives of formula: <IMAGE> in which: - Ar denotes an optionally mono- or disubstituted phenyl group, a pyridyl group or a thienyl group; - R3 denotes a C1-C5 straight or branched alkyl, a -CH2-C6H5 group or a -CH2-CH2-C6H5 group; - R4 denotes the group <IMAGE> in which: - X denotes a C1-C6 straight or branched alkylene - each of R5 and R6 independently denotes hydrogen or a C1-C4 alkyl, or, together with the nitrogen atom to which they are bonded, they form a heterocyclic ring chosen from pyrrolidine, morpholine or piperidine, or else R4 denotes a group chosen from: <IMAGE> in which n is as defined above and R7 denotes H or a C1-C4 alkyl; <IMAGE> in which n is as defined above or <IMAGE> and their salts with inorganic or organic acids. Application: medications useful for the treatment of a cholinergic deficiency.

Description

For many years, pyridazine derivatives have been proposed as drugs, particularly active in the cardiovascular or central nervous system.

In particular, it is disclosed in FR-patent 1 510 998 and EP-patent

72,726 pyridazine derivatives which are substituted in different ways in the pyridazine ring and which all have an amine substituent in the 3-position of the type

where X and Y independently represent hydrogen, an alkyl group or, together with the nitrogen atom to which they are attached, form a heterocyclic compound such as e.g. morpholine.

All these compounds have an activity when it

applies to the central nervous system as an antidepressant.

According to the present invention, it has been found that by modifying the substituents in the pyridazine ring, compounds are obtained which have lost their antidepressant activity and have acquired an interesting activity as ligands of cholinergic receptors of the Mx type.

The present invention relates to an analogue method for the production of new, therapeutically active 6-alkylpyridazine derivatives with the formula:

in which

Ar represents a phenyl group of the formula

a pyridyl group or a thienyl group,

R 1 and R 2 each independently represent hydrogen, a halogen atom, a hydroxyl group, a C 1 -C 4 alkyl group,

a C 1 -C 6 alkoxy group or trifluoromethyl group,

R 3 represents a straight-chain or branched C 1 -C 1 -alkyl, -CH 2 -C 6 H 5 - or -CH 2 -CH 2 -C 6 H 5 ,

R4 represents

in which: X represents a linear or branched Cl- C6- alkylene group and is particularly

<0> -(CH2)n group, in which n is an integer from 1

to 3,

° is one

in which nx is 0 or 1 and Xx represents a (^-O 3 -alkyl group,

R 5 and R 6 each independently represent hydrogen, a straight-chain or branched C-L-C 4 -alkyl, or together with the nitrogen atom to which they are attached constitute a heterocycle selected from pyrrolidine, morpholine or

piperidine,

or R4 also represents a group selected from:

in which n is an integer from 1 to 3, and R, is hydrogen or C 1 -C 2 -alkyl, preferably C -L -C 1 -alkyl, in which n is as defined above or or or

as well as their salts with mineral acids or organic acids, as well as the intermediate product for the preparation of the compounds of formula (I).

The salts of the compounds of formula (I) include both the compounds with mineral acids or organic acids which enable a suitable separation or a crystallization of the compounds of formula (I), such as picric acid or oxalic acid, as well as those which form pharmaceutically acceptable salts, such as the hydrochloride , the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methanesulfonate, the methyl sulfate, the maleate, the fumarate and the naphthalene-2-sulfonate.

According to the present invention, the compounds of formula (I) are prepared by reacting a 3-chloropyridazine with the formula in which Ar and R3 are as defined previously with an amine of the formula:

in which R4 is as defined before, and optionally a salt is formed of the compound thus obtained with a mineral acid or organic acid.

The substitution reaction between the 3-chloro-pyridazine (II) and the amine R4NH2 is carried out at a temperature between 100 and 150°C without solvent or in the presence of an inert solvent such as e.g. n-butanol.

The thus obtained product of formula (I) is isolated, in the form of a free base or a salt, according to conventional techniques.

When the compound of formula I has been obtained in the form of the free base, the salt formation is carried out by treatment with the selected acid in an organic solvent. When treating the free base, e.g. dissolved in an alcohol such as isopropanol, with a solution of the chosen acid in the same solvent, the corresponding salt is obtained which is isolated according to conventional techniques.

In this way, e.g. the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, oxalate, maleate, fumarate and 2-naphthalene sulfonate.

At the end of the reaction, the compound of formula (I) can be isolated in the form of one of these salts, e.g. the hydrochloride, oxalate or fumarate. If necessary, the free base can in this case be produced by neutralization of said salt with a mineral or organic phase such as e.g. sodium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate, such as e.g. the sodium or potassium carbonate or bicarbonate.

When Rx and/or R2 represent a hydroxyl group, the compound is obtained by starting from compound (I) in which Rx and/or R2 represents an alkoxy group, all other substituents having the above-mentioned definitions, by dealkylation using known methods.

The 3-chloro-pyridazines (II) which are used as starting products in the required synthesis step according to the invention, and in which R3 and Ar are as defined in formula (I), except that when r1 = r2 = h, R3 is different from methyl, is prepared from 3-2H-pyridazinones (III) with the formula:

by reaction with an excess of phosphorus oxychloride in heat, without solvent or in the presence of an inert solvent such as e.g. acetonitrile.

The above-mentioned 3-2H-pyridazinones (III) are obtained by dehydrogenation of compounds of formula (IV):

e.g. by the action of bromine in acetic acid. The 3-tetrahydro-2,3,4,5-pyridazinones with formula:

and the 3-dihydro-2,3-pyridazinones of formula (III), wherein R3 and Ar are as defined in formula (I), except that when R-1 = R2 = H, R3 is different from methyl, likewise form part of

the invention and is produced according to the methods described by Sutter et al., J. Am. Chem. Soc., 1942, 64, 533-536, D. Mukhirji, Science and Culture, 1948, 13, 426 and G. Pinna et al., Il Farmaco, Ed. Sci., 1988, 43, 539-549.

The intermediate products used for the production of (I) with the formula:

as defined above, are new and form part of the invention. As examples, the compounds of formula (IV) and (III) are described in tables 1 and 2 below. The chlorine compounds of formula (II)

wherein R 3 or Ar is as defined in formula (I), except that when R]_ = R 2 = H, R 3 is different from methyl, are new and form part of the invention and are prepared according to usual methods as indicated above. As an example, the compounds of formula (II) are described in Table 3 below.

The substitution of these chlorine compounds (II) with an amine makes it possible to obtain the compounds (I), and the reaction scheme below illustrates the preparation.

Starting from a nitrile 1, the S-ketonitrile 2 is obtained by heating in the presence of a base and a carboxylic acid ester derivative R3C02Et, which is converted in an acidic environment to a corresponding ketone derivative 3.

The cyclization to 2-tetrahydro-2,3,4,5-pyridazinone is accomplished by reaction with ethyl bromoacetate in an alcoholic solvent at ambient temperature, followed by action of hydrazine hydrate in heat.

The dehydrogenation of compound (IV) by the action of bromine in acetic acid enables the preparation of the 3-dihydro-2,3-pyridazinone (III).

In the case where nx = 0, the amines are produced

for which X represents a group in which Xx is as defined previously, starting from a cyano derivative of the formula: which is reacted with an amine of the formula HNR5R6, optionally in the presence of a salt of a strong acid such as e.g. sodium or magnesium sulfate, at a temperature between 40 and 80°C to obtain the aminonitrile of the formula: which is hydrated according to usual conditions in an acidic environment to provide the corresponding amide of the formula: which is then reduced by the action of a metal hydride such as . lithium aluminum hydride or borohydride to provide the expected amine

,JThe following examples illustrate the invention.

EXAMPLE 1

2-Diethylamino-2-methyl-1-propyl)-3-amino-5-(4-fluorophenyl)-6-propy1-pyridazine-dihydrochloride

A) ot-butyryl-4-fluorophenyl acetonitrile

10.9 g of sodium are introduced into 150 ml of absolute ethanol. Under reflux, 49.5 g of 4-fluorophenylacetonitrile dissolved in 65.2 g of ethyl butyrate are added. The reaction mixture is heated under reflux for 4 hours and then allowed to stand overnight at ambient temperature. The solvents are concentrated in vacuo, the residue is taken up in water and washed with ether. The aqueous phase is cooled in an ice bath and acidified to pH 5-6 by adding concentrated acetic acid. Crystals are then obtained which are separated by filtration, washed with water and dissolved in dichloromethane.

The organic phase is decanted, dried over MgSO 4 , filtered and concentrated in vacuo.

m = 50 g

m.p. = 53-54°C

B) 1-(4-fluorophenyl)-2-pentanone

50 g of the product obtained above is treated with 36 ml of water and 148 ml of concentrated sulfuric acid which is added dropwise while stirring at 4°C. The mixture is then heated to 80°C for half an hour, cooled, then 534 ml of water are added and heated under reflux overnight: The mixture is extracted with dichloromethane, the organic phase is decanted, dried over Na 2 SO 4 , filtered and concentrated in vacuo.

The residue is chromatographed on silica gel, eluent: cyclohexane/methylene chloride: 50/50.

m = 39.2 g C) 5-(4-fluorophenyl)-6-propyl-2,3,4,5-tetrahydro-3-pyridazinone.

2.76 g of sodium are dissolved in 115 ml of isopropanol. During cooling in an ice bath, 21.56 g of the product obtained above dissolved in 30 ml of isopropanol are added. The mixture is stirred for one hour at ambient temperature and then 15 ml of ethyl bromoacetate dissolved in 20 ml of isopropanol is added dropwise and the mixture is allowed to stand at ambient temperature for 24 hours.

The residue is taken up in acidic water (HCl-pH=2) and extracted with dichloromethane. The organic phase is decanted and dried over MgSO 4 . It is filtered and concentrated in vacuo. The residue is taken up in 75 ml of butanol, 11.25 ml of hydrazine hydrate is added, and the reaction mixture is heated under reflux for 4 hours.

The mixture is concentrated in vacuo, the residue is taken up in water and extracted with dichloromethane. The organic phase is decanted, dried over MgSO 4 , filtered and concentrated in vacuo.

m = 13.7 h

m.p. = 78-79°C

D) 2,3-dihydro-5-(4-fluorophenyl)-6-propyl-3-pyridazinone.

9.37 g of the product obtained above are dissolved in 40 ml of acetic acid and heated to 80°C. 7.6 g of bromine in solution in 70 ml of acetic acid are then added dropwise and the reaction mixture is heated under reflux for 4 hours. It cools down

to 15°C and a precipitate is separated by filtration,

m = 6.6 g

m.p. = 193-194°C

E) 3-chloro-5-(4-fluorophenyl)-6-propylpyridazine.

4.64 g of the product obtained above are dissolved in 28 ml of acetonitrile and 8.6 ml of phosphorus oxychloride, the reaction mixture is heated to reflux for 4 hours and then concentrated in vacuo. The residue is taken up in ice water, ammonia is added and then extracted with dichloromethane. The organic phases are decanted, dried over MgSO 4 , filtered and concentrated in vacuo. The residue is chromatographed on silica gel, eluent: dichloromethane/ethyl acetate 95/5.

m = 4.35 g

m.p. = 64°C

F) Compound 1

1 g of the product obtained above and 3 g of 1-amino-2-diethylamino-2-methylpropane are heated to 120°C under nitrogen in

48 hours.

The mixture is concentrated in vacuo, the residue is taken up in a 5% sodium carbonate solution and extracted with dichloromethane. The organic phase is decanted, dried over MgSO 4 , filtered and concentrated in vacuo. The residue is chromatographed on silica gel H Merck, eluent: dichloromethane/methanol 96/4.

The pure product fractions are concentrated in vacuo, the residue is taken up in ether and the addition of hydrochloride ether allows the preparation of the hydrochloride which is separated by filtration.

m = 1.4 g

m.p. = 100-115°C

EXAMPLES 2 TO 19

A) By working as described in example 1, steps A, B and C, but by optionally replacing the starting nitrile with another nitrile derivative and varying the carboxylic acid ester, the 2,3,4,5-tetrahydro-3-pyridazinones listed are obtained in table 1 below. B) By starting from the compounds in table 1, the 2,3-dihydro-3-pyridazinones listed in table 2 below are obtained as described in example 1, step D, by the action of bromine followed by a dehydrohalogenation. These compounds are all recrystallized from a mixture of dichloromethane and hexane. C) Starting from the compounds in table 2, the chlorine derivatives are prepared by the action of phosphorus oxychloride as described in example 1, step E. These chlorine derivatives, which are listed in table 3 below, are all recrystallized from dichloromethane. D) The substitution of the chlorine derivatives with an amine, according to example 1, step F, enables the preparation of the compounds (I) prepared according to the invention, which are listed in tables 4, 5 and 6 below.

The pharmacological properties of the compounds produced according to the invention have been investigated and in particular as regards their affinity towards cholinergic, muscarinic receptors of the type Mx and M2.

In vitro, the compounds (I) have been examined according to the technique described by L. Potter et al., J. Pharmacol. Exp. Ther., 1989, 284, 974-978 in terms of their affinity for receptors of the Mx type and according to the technique described by R. Hammer et al., Life Science, 1986, 38, 1653-1662, when concerns their affinity for receptors of the M2 type.

The compounds produced according to the invention show a good affinity for receptors of the type Mx and a marked specificity for central receptors of the type Mx vis a vis receptors of the type M2.

As an example, compound 6 has shown an inhibitory concentration of 50 in micromoles of 0.16 and 1.5 respectively for the receptors Mx and M2.

Likewise, compound 25 has shown inhibitory concentrations 50 of 0.04 and 0.9 respectively on the receptors Mx and M2.

In vivo, the compounds prepared according to the invention were examined by means of the rotation test induced by pirenzepine intrastrially described by P. Worms et al., Psychopharmacology, 1987, 93, 489-493.

At the dose of 3 mg per kg body weight per os, the products according to the invention strongly inhibit the number of rotations induced by pirenzepine. As an example, compound 6 inhibits 71% of the rotations induced by pirenzepine.

The compounds produced according to the invention have also been shown to be active against the memory impairment induced by scopolamine and pentetrazole in the passive avoidance test in rats described by P. Worms et al., Psychopharmacol., 1989, 98, 286-288.

Thus, according to the results of this test, compound 6 according to the invention counteracts the memory impairment induced by pirenzepine administered intraperitoneally in an amount of 75 mg/kg with a DES0 of 0.47 mg/kg po.

Finally, the compounds produced according to the invention have not shown any signs of toxicity in the doses in which they are active.

As a result, the compounds (I) can be used as drugs.

The aforementioned results show that the compounds produced according to the invention exhibit a good affinity for muscarinic receptors and a good activity in the tests on amnesia induced with scopolamine or pirenzepine. They make it possible to recommend the use of the products manufactured according to the invention in all cases where a colonic deficiency is found and in particular for the treatment of memory problems, cognitive problems, degenerative syndromes associated with age-related impairment and senile dementia.

According to another of these aspects or the present application pharmaceutical preparations containing at least one of the compounds of formula (I) or one of their salts as active substance.

In the pharmaceutical preparations prepared according to the present invention for oral, sublingual, transdermal or rectal administration, the active substances of formula (I) above can provide a unit administration form, in admixture with common pharmaceutical carriers, for humans, in particular for the treatment of cognitive memory problems or degenerative syndromes. Suitable unit administration forms include oral administration forms such as tablets, capsules (gelatinous pills), powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous, intramuscular or intravenous administration forms and rectal administration forms.

To achieve the desired effect, the dose of the active substance can vary between 5 and 1000 mg per day.

Each unit dose may contain from 5 to 200 mg of active substance in combination with a pharmaceutical carrier. This unit dose can be administered 1-5 times per day.

When a solid preparation in the form of tablets is prepared, the important active substance is mixed with a pharmaceutical carrier such as e.g. gelatin, starch, lactose, magnesium stearate, talc, gum arabic or similar. The tablets can be coated with sucrose or other suitable materials, or they can also be treated in such a way that they have a prolonged or retarded activity and so that they continuously release a predetermined amount of active substance.

A preparation in the form of capsules is obtained by mixing the active substance with a diluent and pouring the resulting mixture into soft or hard capsules.

The powders or granules which are dispersible in water may contain the active substance in mixture with

dispersing agents or softening agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweetening agents or flavor correcting agents.

For rectal administration, suppositories are used which are made with binders that melt on wood

the rectal temperature, e.g. cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersants and/or pharmacologically compatible emollients, e.g. propylene glycol and butylene glycol.

The active substance can likewise be formulated in the form of microcapsules, possibly with one or more carriers or additives. As an example of a galenic preparation, capsules containing:

magnesium stearate 0.005 g

and mix the above ingredients well and pour the mixture into stiff gelatin capsules.

Claims (5)

1. Analogous method for the preparation of therapeutically active 6-alkylpyridazine derivatives with formula: in which <*> Ar is a phenyl group of the formula pvridvl or thienvl; <*> R x and R 2 are each independently hydrogen, a halogen, hydroxyl, (C 1 -d )alkyl, {C 1 -C 4 ) alkoxy or trifluoromethyl; <*> R3 is a straight-chain or branched (Cx-Cs) alkyl, -CH2-C6H5 or -CH2-CH2-C6H5; <*>R 4 is wherein -X is a straight or branched (C 3 -C 8 ) alkylene, -R 5 and R 6 are each independently hydrogen, branched or straight chain (C 3 -C 4 ) alkyl, or together with the nitrogen atom to which they are attached form to, a heterocycle selected from morpholine, pyrrolidine and piperidine, otherwise R4 is wherein n is an integer from 1 to 3, and R7 is hydrogen or (C-1-C1), preferably (C-1-C4) alkyl; where n is as defined above;; as well as its salts with mineral acids or organic acids, characterized in that an amine with the formula H2N-R4 in which R 4 is as defined above, is reacted with a 3-chloro-pyridazine of the formula in which Ar and R3 are as defined above, and optionally a salt is formed of the thus obtained compound with a mineral acid or organic acid. 2. Method according to claim 1, characterized in that an amine with the formula H2N-R4 is used, in which R4 represents -X represents <*> either a - (CH2)n group, in which n is an integer from 1 to 3, <*> or one in which nx is 0 or 1, and Xt represents a Cx - C3 alkyl group, - R5 and R6 are as defined in claim 1. 3. Intermediate product for the production of compounds of formula (I) as defined in claim 1, characterized by the formula: wherein R3 and Ar are as defined for (I), except that when R1=R2=H, R3 is different from methyl. 4. Intermediate product for the production of compounds (I) as defined in claim 1, characterized by the formula wherein R3 or Ar is as defined for (I), except that when R1=R2=H, R3 is different from methyl. 5. Intermediate product for the production of compounds (I) as defined in claim 1, characterized by the formula wherein R3 and Ar are as defined for (I), except that when R1=R2=H, R3 is different from methyl.