Derivatives of 3-aminopyridazine or their acid-additive, pharmaceutical acceptable salt, intermediate compounds, the method of obtaining derivatives of 3-aminopyridazine or their acid-additive pharmaceutically acceptable salts and pharmaceutical composition

 

(57) Abstract:

Usage: in the pharmaceutical industry. The essence of the invention: derivatives of 3-aminopyridazine formula (I), where Rv(C1-C4) alkyl, R6Is H or OH, Z is the group (CH2)nT, where, when n=0, T group of the formula IV, where P = 2-3, R-(C1-C3) alkyl when n=1, T is a group of formula V, where p' and p"= 3-4, when n=2, T is a group of formula VI, where p = 2-3, or their acid-additive pharmaceutically acceptable salt, intermediate compounds of formula (I') where R' (C1-C3) alkoxygroup, Rvand Z have the above meanings, and pharmaceutical composition based on compounds of the formula I, having the binding activity of cholinergic receptors. The compounds of formula (I) are obtained by the interaction of the amine of formula (II) with compounds of the formula (III). When you get compound of formula (I), where R6- OH, the intermediate compound of formula I reacts with galogenovodorodov acid. 4 C. and 3 h.p. f-crystals, 3 PL.

The structure of the compounds and groups

The invention relates to derivatives of 3-aminopyridazine actively influencing the Central nervous system.

Numerous derived pyridazines has already been proposed in the quality of the Central nervous system.

In particular, in French patent A-2510998 and in the patent EP-A-72726 described pyridazine with various substitutions and containing at position 3 aminirovanie Deputy type:

< / BR>
in which X and Y denote independently hydrogen, alkyl group or form together with the nitrogen atom to which they are bound, a heterocycle such as morpholine. These compounds have an active effect on the Central nervous system as protivodiversionnaya drugs.

Currently, the applicant has developed a new derivatives of 3-aminopyridazine not having protivodiversionnaya action, but active as binders cholinergic receptors, in particular the binder muscarinergic receptor type M1.

The subject of this invention are pyridazine formula:

< / BR>
where Rvmeans alkyl group with straight or branched chain C1C4;

R6hydrogen, alkoxygroup C1C3or a hydroxyl group;

The Z group of formula:

< / BR>
in which: n1and n2means independently 0 or 1;

Y1and Y2independently hydrogen or an alkyl group of C1-C3;

T dialkylamino, in which the alkyl radical is as the following groups:

< / BR>
if n1=n2=1;

Y1=CH3and Y2=H or

Y1=H and Y2=CH3< / BR>
and W denotes an oxygen atom or sulfur;

< / BR>
if n1=n2=1

Y1=Y2=H

and p is then 2 or 3;

< / BR>
if n1=n2=0

and p is then 2 or 3, R is an alkyl group of C1-C3< / BR>
< / BR>
if n1=1, n2=0

Y1=H

and p' and p" means 3 or 4, and their salts with organic or inorganic acids.

In accordance with this invention, the preferred such compounds, in which:

or n1and n2equal to 1; Y1and Y2indicate each a methyl group or hydrogen and T dialkylamino, with alkyl group, a C1-C3;

or n1and n2equal to 1; Y1means a methyl group and Y2hydrogen, or Y1means hydrogen and Y2methyl group, and T means the above-mentioned group a);

or n1and n21; Y1and U2mean hydrogen and T-heterocycle type B);

or n1and n20 and T means a heterocycle c);

or n11 and n20; Y1means hydrogen and T-heterocycle type g), and their salts of inorganic T. salt of inorganic or organic acids, which allow you to make the necessary crystallization or separation of compounds of formula (I), such as picric or oxalic acid, as well as those which form suitable for pharmaceutical respect salts, such as hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, maleate, fumarate, naphthalenesulfonate-2.

In accordance with one aspect of the present invention, its object is also a method of obtaining compounds of formula (I).

This method differs in that interact amine of the formula:

H2N Z II

in which Z has the above value for (I), with 3-chloropyridazine formula:

< / BR>
in which Ryand R6have the above values for (I) thus obtained compound converts the salt of inorganic or organic acids.

The reaction of substitution of 6-chloropyridazine (III) with the amine (II) is conducted at a temperature of 100 150oC without solvent or in the presence of an inert solvent, such as alkanol, and optionally in the presence of ammonium chloride. Then, the compound (I) is isolated and purified by conventional means. Thus obtained product is isolated in the form of Svobodova the base of the salt formation is effected by treatment with acid in an organic solvent. By treating the free base, dissolved, for example in an alcohol, such as isopropanol, a solution of the acid in the same solvent to obtain the corresponding salt, allocated in the usual way. For example, in such a way we obtain a hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methyl sulfate, oxalate, maleate, fumarate, 2-naphthalenesulfonate.

At the end of the reaction the compound of formula (I) can be isolated in the form of any of its salts, e.g. the hydrochloride. In this case, if necessary, the free base can be obtained by neutralizing the named salts of any organic or inorganic base, for example sodium hydroxide or triethylamine, or an alkali carbonate or bicarbonate, for example, carbonate or bicarbonate of sodium or potassium.

When the compounds of formula (I) contain a chiral core and obtained in the form of a racemic mixture of optical isomers, the corresponding enantiomers, which can be distinguished by conventional means, are also subject of this invention.

6-chloropyridazine formula (III) used as starting product is obtained by processing 2H-pyridazin-3-ones of the formula (IV):

example acetonitrile.

2H-pyridazin-3-ones of the formula (IV) are known compounds or are obtained by known methods according to the following reaction scheme:

< / BR>
The reaction of aldol condensation between the derivative 1 of acetophenone and ethyl glyoxylate, being allows to obtain the ester of oxycodone 2; it is then subjected to cyclization by means of hydrazine hydrate to obtain compound 3, which is not allocated.

The transition hydroxyacetamido 2 pyridazine 4 is carried out in one stage, comprising cyclization and dehydration.

Amines H2N-Z of the formula (2) in themselves known and are obtained by known methods.

The following scheme of reactions illustrate the method of obtaining amines H2N-Z of the formula (2).

When n1n21, Y1Y2H and T is a heterocycle of b), in which p is 2 or 3, the corresponding amine of formula (2) are obtained according to the following reaction scheme:

< / BR>
When n1n20 and T means a heterocycle c), the appropriate amine of formula (2) is produced by a method described in the publication: Doster et al. Eur. Med. Chem. Chim. Ther. 1984, 19 (2), 105-110 C., the following reaction scheme 3, to obtain compounds of formula (2), in which the group NH2has either Equatorial co and Z is 1-azabicyclo-[3,3,0]-octane, a heterocycle (d), the corresponding amine 1-azabicyclo-[3,3,0]-octyl-2-methylamine is obtained by a method described in the publications: 1) Miyano et al. J. Heterocyclic Chim. 1982, 19, 1465; 2) Miyano et al. Synthesis, 1878, 701; 3) Miyano et al. J. Heterocyclic Chem. 1987, 47, according to the following reaction scheme:

< / BR>
The heterocycle of the form (g) may be obtained by the method described in the publication: J. Med. Chem. 1987, 30, 1987, or in accordance with patent EP-287356.

When n1n21, Y1CH3, Y2H and T-N(C2H5)2N, N-1 diethylamino-2-propanamine obtained by adaptation of the method described in the publication: Philips et al. J. Med. Chem. 1990, 33, 627-633, according to the following reaction scheme:

< / BR>
When replacing diethylamine any other dialkylamino, symmetric or asymmetric, the following formula:

< / BR>
get amines of the following formula:

< / BR>
in which AlK and AlK' means alkyl groups of C1C3.

Following technological scheme 5, but using as initial products of compounds of the formula AlK COOH2and AlK NH-AlK', in which AlK and Alk' have the above meanings, get amines of the formula (II), where n1n21, Y1AlK, Y2H and T - dialkylamino.

When n1n21, Y1H, Y2AlK and T - dialkylamino, IMHO product using amine of the formula

< / BR>
When n1n21, Y1H, Y2-CH3and T means morpholino or thiomorpholine, D, L-morpholino-2-Propylamine or D, L-thiomorpholine-2-Propylamine receive according to the following reaction scheme:

< / BR>
The same scheme can be obtained amines of the formula (II), where n1n21, Y1H, Y2Alk where Alk alkyl, C1- C3and T means morpholino or thiomorpholine group, at the same time as the original product use amine of the formula:

< / BR>
The invention is illustrated by the following examples, which, however, do not limit its scope. When the melting point (F) was measured on the heating installation Koffler.

Example 1: N-3-(8-Aza-[3,2,1] -bicycloalkyl)ethylamino-6-(2-hydroxyphenyl)-5-methylpyridazin

R62-OH; Ry-CH3; Y1Y2H; n1n2"1;

< / BR>
A) N-3-(8-Aza-[3,2,1] -bicycloalkyl)ethylamino-6-(2-methoxyphenyl)-5-methylpyridazin.

1.04 g of N-(8-Aza-[3,2,1] -bicycloalkyl)ethylamine, 1,58 g 3-chloro-5-methyl-6-(2-methoxyphenyl)pyridazine and 0.38 g of ammonium chloride dissolved in 2.5 ml of butanol and heated at the reflux in an argon atmosphere in 48 hours, the Reaction mixture was concentrated under Aquaticum, separate the organic phase by desantirovaniya and then add 30 ml of an aqueous solution of citric acid (10). Then separated from the aqueous phase, washed with ethyl acetate and alkalinized 30 ml of an aqueous solution of sodium hydroxide (33). The resulting oily fraction is extracted with ethyl acetate, the organic phase is separated, dried on sodium sulfate, filtered and concentrated under vacuum.

The residue is purified by chromatography on aluminium hydroxide eluant: ethyl acetate, then ethyl acetate-methanol 9-1 (volume), with the addition of 2% of triethylamine.

Concentration of the fractions of pure product is 1.2 g of the target product.

B) N-3-(8-Aza-[3,2,1] -bicycloalkyl)ethylamino-6-(2-hydroxyphenyl)-5-methyl-pyridazin.

1.2 g of the product obtained at stage A, dissolved in 60 ml of Hydrobromic acid (48), the solution is heated at the reflux for 48 hours the Reaction mixture is concentrated under vacuum, the residue is placed in water, saturated with potassium carbonate. The obtained oily composition extracted in dichloromethane, the organic phase is separated, washed with saturated sodium chloride solution, dried with magnesium sulfate and is infilled under vacuum. The residue is ground to powder in EFL 8-2 (volume) + 2% triethylamine. Concentration of the fractions of pure product was 0.8 g of the target product. Melting point 208oC.

Described in example 1 by the method, and variations of the original 3-chloropyridazine, synthesized compounds are given in table. 1:

Example 4: difumarat[3 - 3-(N-8-utiliza-[3,2,1]-bicyclo)amino]-6-phenyl-5-propylpyridine

R6H; Ry-CH2CH2CH3; n1n20;

< / BR>
1 g of 3-chloro-6-phenyl-5-propylpyridine and 1 g of diamine (II a) is heated to 160oC in the autoclave during the night. Then the reaction mixture is placed in dichloromethane and washed with saturated aqueous sodium carbonate. Then decanted organic phase, dried on magnesium sulfate, filtered and concentrated under vacuum. The remainder chromatographic on silica gel, eluant: dichloromethane 97-3 (volume). The concentration of the pure fractions gives a precipitate, crystallising two equivalents of fumaric acid. The mass of 0.44, So pl. 82oC.

Example 5: difumarat 3-[3 -(N-8-utiliza-[3,2,1]-bicycloalkyl)amino]-6-phenyl-5-propyl-pyridazine.

R6H; Ry-CH2CH2CH3; n1n20;

< / BR>
Operate according to example 4, by replacing the diamine (II-a) to the diamine (II-e). The result is about-5-methyl-6-phenyl-pyridazine.

R6H; RyCH3; Y1H; n11; n20;

1.52 g of 1-Aza-[3,3,0] -bicyclo-2-octylacrylamide, of 2.21 g of 3-chloro-5-methyl-6-phenylpyridazin and of 0.58 g of ammonium chloride dissolved in 10 ml of pentanol and heated at the reflux in an argon atmosphere for 24 hours and Then the reaction mixture is concentrated under vacuum by its azeotropically water. The residue is alkalinized with an aqueous solution of potassium carbonate (10) and extracted with ethyl acetate. Separate the organic phase, add 30 ml of 10% citric acid solution. Separate the aqueous phase, washed twice its ethyl acetate and alkalinized 33% aqueous sodium hydroxide solution to pH 13. This oily composition extracted with ethyl acetate, the organic phase is separated by desantirovaniya and dried on sodium sulfate, then filtered and chromatographic on aluminum, eluant: ethyl acetate, then ethyl acetate-methanol 9-1 (volume) supplemented with 2% triethylamine. The concentration of the product fractions amounted to 1 g of the final product.

0.6 g of the obtained base product is diluted in a minimum quantity of acetone, add 0.45 g of fumaric acid dissolved in acetone. After filtration of the crystals receive 0.1 g fumarata. So pl. 153,3oC.

< Example 8. Difumarate (R, S) N-3-[(1-diethylamino-2-propyl)amino]-5-methyl-6-phenyl-pyridazine.

R6H; Ry-CH3; n1n21; Y1-CH3; Y2H; T-N(C2H5)2< / BR>
of 1.59 g of N,N-1 diethylamino-2-propanamine, 2,49 g 3-chloro-5-methyl-6-phenylpyridazin and 0.65 g of ammonium chloride dissolved in 20 ml of butanol. This reaction mixture is heated at the reflux in 48 hours Then separated from the butanol under vacuum, the residue is again placed in the water and then extracted with ethyl acetate. The organic phase is separated, dried on magnesium sulfate and concentrated under vacuum. The remainder chromatographic on aluminium hydroxide, eluant: ethyl acetate-hexane 5/5 (on/about), then ethyl acetate: methanol 9/1 (V/V) with addition of 2% of triethylamine.

The fraction of pure product is condensed under vacuum and get 1 g of the oily composition which crystallizes.

To obtain fumarata dissolve of 0.54 g of fumaric acid in 5 ml of acetone, add to 0.47 g of the previously prepared base composition in acetone solution. After filtration of the crystals obtain 0.4 g of the target fumarata. So pl. 148,2oC.

In the same way as in the above examples, get a connection, mentioned at nigelle the STI were studied for their affinity to cholinergic receptors muscarinic type M1and M2.

In vitro compound (I) was tested by the method described in the publication: L. Potter et al. J. Pharmacol. Exp. Ther. 1989, 284, 974 978 regarding their affinity for the receptor type M1and by the way discussed in the publication: R. Hammer et al. Life Science, 1986, 38, 1653-1662, from the point of view of their affinity with the receptor type, M2.

The compounds of this invention have a good affinity for the receptor type M1and specificity pronounced for Central receptors of type M1in relation to the receptor type M2.

For example, compound (I) according to this invention possess inhibitory concentration 50, expressed in nanomoles on l, about 3.2 and 110 respectively on the receptors M1and M2.

In vivo, the compounds of this invention were tested for test spins induced by pirenzepine described in the publication: Morms P. et al. Psychopharmacology, 1987, 93, 489 -493.

At a dose of 0.3 mg per kg of body weight when administered compounds according to this invention significantly inhibited the number of rotations induced by pirenzepine. Thus, compounds (I) according to this invention inhibit 62% spins induced by pirentsepina.

Therefore, compound (I) of MOhm affinity to muscarinic receptors and good affinity in the test on the amnesia induced by scopolamine or pirentsepina. They allow you to provide for the use of the preparations according to this invention in all cases, when it is in cholinergic deficits and especially in the treatment of mnesticheskih, cognitive disorders, and degenerative syndromes associated with aging and, in particular with senile dementia.

Finally, the compounds according to this invention gave no signs of toxicity at the doses at which they are active.

One of his other aspects of this application the invention relates to pharmaceutical compositions containing at least one of the compounds of formula (I) or one of their salts as active principle.

In the pharmaceutical compositions according to this invention, intended for oral administration, sublingual, subcutaneous or rectal, above the active principle of formula (I) can be written in the form of a unitary recipes in a mixture with conventional pharmaceutical basics-carriers, for the treatment of patients with mnesticescimi, cognitive disorders or degenerative syndromes. These unitary form of recipes include n the mA forms for sublingual and oral, intramuscular, intravenous, subcutaneous and rectal forms.

To achieve the desired effect, the dose of active principle in the preparation may vary from 0.5 to 500 mg doctor

Each unitary dose may contain from 0.1 to 100 mg of the active substance in combination with a pharmaceutical carrier. This unitary dose may be prescribed to a patient to receive from 1 to 5 times D.

In the manufacture of compositions in solid form as tablets, the active principle is mixed with a pharmaceutical carrier, for example, gelatin, lactose, starch, talc, magnesium stearate, gum Arabic, or their equivalents. Can be coated tablets with sucrose or other appropriate substances, or you can process them so that the drugs had accelerated or delayed activity and continuously release a predetermined amount of the active agent.

One of the forms of preparations are prepared by mixing the active agent with thinners and conclusions resulting mixture into soft or hard capsules.

Powders or water-soluble granules can contain the active substance in a mixture with dispersio the sweetening or corrective taste additives.

For rectal medication use candles, made on the basis of binders melting at rectal temperature, for example, based on the oil of the cocoa beans or glycols.

For parenteral reception using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersant and/or wetting, pharmacological compatible agents, for example propylene glycol and butyleneglycol.

The active substance can be implemented also in the form of microcapsules in combination with one or more agents, carriers or additives.

As herbal example, you can produce capsules containing, in g:

Connection example 1 0,010

Lactose 0,050

Magnesium stearate 0.005 g

1. Derivatives of 3-aminopyridazine formula I

< / BR>
where Rvunbranched or branched C1- C4-alkyl;

R6hydrogen or hydroxyl group;

Z group (CH2) T, where n 0 T a heterocycle of the formula

< / BR>
where p is 2 or 3, R1WITH3-alkyl, n-1 T - a heterocycle of the formula

< / BR>
where R' and R" 3, or 4, or n 2 T a heterocycle of the formula

< / BR>
where p is 2 or 3,

3. Connection on p. 1, in which ZNH is a group of 8-ethyl-8-azabicyclo (3.2.1) Oct-3-ylamino or one of its acid-additive pharmaceutically acceptable salts.

4. Connection on p. 1, in which ZNH is a group 1-azabicyclo (3.3.0) Oct-5-yl-methylamino or one of its acid-additive pharmaceutically acceptable salts.

5. Intermediate compounds for preparing compounds of formula I on p. 1, where R6hydroxyl group of formula I'

< / BR>
where C1WITH3-alkoxygroup;

Rvand Z have the meanings indicated for the formula I in p. 1.

6. The method of obtaining 3-aminopyridazine formula I under item 1 or acid-additive pharmaceutically acceptable salts, characterized in that the amine of formula II

H2NZ,

where Z has the values specified in paragraph 1 of the claims,

subjected to interaction with 3-chloropyridazine formula III

< / BR>
where Rvmatter specified in paragraph 1 of the claims;

hydrogen or C1WITH3-alkoxygroup,

followed in the case of preparing compounds of formula I, where R6is a hydroxyl group, the interaction obtained intermediate compound of the formula I' in p. 5 FD is in the form of a pharmaceutically acceptable acid additive salt.

7. Pharmaceutical composition having activity of binding of cholinergic receptors containing the derived 3-aminopyridazine as the active agent in a mixture with pharmaceutically inert carrier, characterized in that the quality of the derived 3-aminopyridazine it contains at least one of the compounds of General formula I on p. 1 or its acid-additive pharmaceutically acceptable salt in an amount of 0.1 to 100 mg per unit dose.

 

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< / BR>
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