The method of obtaining piperazinylmethyl-3(2h)-pyridazinone or their pharmaceutically acceptable salts

 

(57) Abstract:

The use of the invention: herbal medicines for high blood pressure and heart diseases in medicine. The inventive product piperazinylmethyl - 3(2H) pyridazinone General formula where R1and R2- same or different and denote H or C1-C6- alkyl; B - C1-C6- alkyl, Z is unsubstituted or mono - or disubstituted C1-C4-alkyl, C1-C4- alkoxy, trifluoromethyl, halogen or nitro-group is phenyl, or their pharmaceutically acceptable salts. Reagent 1: the corresponding pyridazin General formula , where the values of the radicals indicated above, and R3- C1-C6- alkyl. Reagent 2: water. Reaction conditions: in an acidic environment.

The invention relates to nitrogen-containing heterocyclic compounds, particularly, to a method of obtaining new piperazinylmethyl-3(2H) pyridazinones General formula I

where R1and R2the same or different and denote H or C1-C6-alkyl;

B - C1-C6-alkylen,

Z is unsubstituted or mono - or disubstituted WITH1-C4-alkyl, C1-C4-alkoxyl, trifluoromethyl, halogen or nitro is m, and that may as herbal medicines used for high blood pressure and heart diseases in medicine.

It is known that alpha blockers1receptors can be used as lowering blood pressure means. So, for example, known arylsubstituted piperazineethanol, which lowers blood pressure and block the effect of an increase in blood pressure, adrenaline and noradrenaline in rats with spinal cord puncture [1].

The aim of the invention is the creation on the basis of the known methods, the method of obtaining the new derivatives piperazinylmethyl-3(2H)-pyridazinone General formula 1 or their pharmaceutically acceptable salts have affinity for alpha1-adrenergic receptors, namely, in models in vitro show inhibition of peripheral alphareceptors (alpha-adrenergic receptors), and also have a effect on the Central NT-1A-receptors.

This objective is achieved in that pyridazin General formula II

where R3-C1-C6-alkyl, and R1-R2, And Z described above, is transferred to the corresponding 3(2H)-pyridazinone splitting of a simple ester of the acid.

Pharmaceutically when the hydrogen acid, sulfuric acid, phosphoric acid or nitric acid, or with organic acids, like citric acid, tartaric acid, maleic acid, fumaric acid, succinic acid, malic acid, methanesulfonate, aminosalicylate, acetic acid, benzoic acid, etc.

Used as starting substances, pyridazine known or can be known methods. So get: 4,5-dichloro-3(2H)-pyridazinone and 4,5-dichloro-2-methyl-3(2H)-pyridazinone condensation mucochloric acid with hydrazine or methylhydrazine, then 4,5-dichloro-2-hydroxy-ethyl-3(2H)-pyridazinone and 4,5-dichloro-2-diethylaminoethyl-3(2H)-pyridazinone as the connection is similar to 4,5-dichloro-2-dimethyl-amino-ethyl-3(2H)-pyridazin - none in similar reactions. Used as starting substances derived piperazinylmethyl known or can be obtained analogously to known methods. Thus, derivatives of 4-aryl - and 4-heteroarylboronic, which in position 1 have tionally balance can be restored by catalytic hydrogenation to the desired derivatives AMINOETHYLPIPERAZINE.

Pyridazine formula II can be obtained as indicated in example 1 method.

Compounds of General formula I can be used in the Ohm blood pressure and heart diseases. These compounds have low toxicity.

The compounds of formula 1 are used for the treatment of humans and can be assigned in the usual way, as for example, orally or parenterally. Preferably be administered orally, and the daily dose is about of 0.015 to 15 mg/kg body weight, preferably 0.15 to 1.5 mg/kg of body weight. When receiving intravenous daily dose is from about 1.5 to 1500 µg/kg body weight, preferably about 15-150 μg/kg body weight. However, the attending physician, depending on the General condition and age of the patient, the substance of the formula I, the type of disease and type of formulation may also prescribe doses above or below.

The compounds of formula 1 can be assigned individually or in combination with other pharmaceutically active substances, and the content of compounds of the formula 1 is approximately between 0.1 and 99%. In General pharmaceutically active compounds are mixed with suitable inert excipients and/or carriers or diluents, as for example, should not cause concern in the pharmaceutical industry solvents, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, pills, suppositories, capsules, etc., in semi-solid form, for example, as an ointment or liquid form, e.g. as solutions, suspensions or emulsions. If necessary, sterilize them and they contain auxiliary substances, such as preservatives, stabilizers or emulsifiers, salts for modifying the osmotic pressure, etc.

In particular, the pharmaceutical preparations can contain the compounds according to the invention in combination with other therapeutically valuable substances.

P R I m e R 1. 6-Chloro-4-[(4-{4-(2-methoxyphenyl)piperazinil-1}butyl)amino]-3(2H)-pyridazinone .

of 4.00 g (0,00985 mol) 6-chloro-3-methoxy-4-{[4-(4-(2-methoxyphenyl)piperazinil-1)butyl] amino} pyridazine dissolved in 40 ml of glacial acetic acid and mixed with 40 ml of 63% Nug. Boil for 2 h with the phlegm, mixed with 200 ml of water, neutralized with 30% KOH to pH and sucked off the precipitated substance and well washed with water. Gain of 3.85 g (99.7% of theory) of 6-chloro-4-{ [4-(4-(2-methoxyphenyl)piperazinil-1)butyl] amino} -3(2H)-pyridazinone, purified by recrystallization from ethanol with the addition of coal, immediately added to a solution of hydrochloric acid in ethanol and receive 3,26 g (68.7% of theory) of pure dihydrochloride, so pl. 247-252aboutWith; To 47.2%, N 6,0%, Cl (all) of 21.9%, Cl - 14.6% And 14.4 per cent, 10.0 per cent.

Not the 6-Chloro-3-methoxy-4-{[4-(4-(2-methoxide - nil) piperazinil-1)butyl]amino} pyridazin.

3.28 g (0,008 mol) of 3,6-dichloro-4-{[4-(4-(2-methoxyphenyl)-1-piperazinil)butyl]amino}pyridazine and 0.32 g (0,008 mol) of sodium methylate is stirred in 150 ml of methanol 144 h at 50aboutC. Then concentrated in vacuo, dissolve the residue in chloroform and extracted by shaking with water. The solvent is evaporated, dissolved in a simple ether, filtered to a transparent state and precipitated using ethereal HCl solution of the hydrochloride of 6-chloro-3-methoxy-4-{[4-(4-(2-methoxyphenyl)piperazinil-1)buta - yl]amino}pyridazine, 3,14 equivalent HCl) with so pl. 139-150aboutS; output: for 91.1% of theory.

3,6-Dichloro-4-{ [4-(4-(2-methoxyphenyl)PI pyrazinyl-1)butyl] amino} pyridazin.

a 9.25 g (0,050 mol) 3,4,6-trichloropyridine mix from 6.90 g (0,050 mol), anhydrous powdered potassium carbonate and 13,15 g (0,050 mol) of 1-(4-aminobutyl)-4-(2-methoxyphenyl)piperazin-in 1350 ml of dry acetonitrile 96 h at room temperature. Then sucked off and concentrated the filtrate under vacuum. The remainder absorb ethanol and precipitated using ether solution of HCl trihydrochloride 3,6-dichlo-4-{ [4-(4-(2-methoxyphenyl)piperazin-Neil-1)butyl] amino} pyridazine with melting point: 155-170aboutS; output: 54,2% of theory.

Similarly receive the following compounds: 6-chloro-4-{[2-(-247aboutC;

yield: 86.8% of theory

Calculated, %: C 44,26; N 5,77; Cl 23,82; CL 16,14; N 15,18; O 10,96.

Found, %: From 44.6; H 5,3; Cl 23,7; CL 16,1; H 15,1; O 10,9.

2-Methyl-6-chloro-4-{ [2-(4-(2-methoxide - nil)piperazinil-1)ethyl]amino}-3(2H)- pyridazinone.

Sol: 2,0 HCl; MES: 0,05 N2ABOUT

So pl. 233-237aboutWITH

Output: 63,0% of theory.

Calculated, %: 47,79; N. Of 5.82; Cl 23,67; CL 15,83; N 15,48; O 7,24.

Found, %: C Of 47.8; H 5,8; 23,5 Cl; CL 15,8; N 15,4; O To 7.2. 6-Chloro-4-{ [2-(4-(2-ISO-propoxyphenyl)piperazinil-1)ethyl]amino}-3(2H)-peridis and - non.

Sol: 1,0 HBr; MES: 0,3 N2O.

So pl. 230-295aboutC. recrystallization: ethanol.

Yield: 12.7% of theory.

Calculated, %: C 47,72; N. Of 5.82; Cl 7,41; N 14,64; O 7,70; Br 16,71.

Found, %: From 48.1; H 6,0; Cl 6,6; N 14,6; 8,0, Br 16,7.

Ultraviolet: solvent 1 and HCl, 210 (4,48), 234 (S, 4,08), 246 (S, 3,94), 288 (4,13), 309 (S, 3, 82). 6-Chloro-4-{[3-(4-(2-methoxyphenyl)Pipa-retinyl-1)propyl]amino}-3(2H)pyridazin - non.

Sol: 2,0 HCl; MES: 0,35 H2ABOUT

So pl. 267-275aboutC;

Output: 88.1% of theory.

Calculated, %: C 47,3; N. Of 5.89; Cl 23,27; Cl 15,51; N 15,32; 8,23.

Found, %: C 47,2; N 5,8; Cl 23,1; Cl 15,5; N 15,3; O 8,2.

6-Chloro-4-{ [3-(4-(2-methoxy-4-were) piperazinil-1)propyl]amino}- 3(2H)-pyridazinone.

With theory.

Calculated, %: C 37,08; N 5,72; Cl Of 5.75; N 11,35; O 14,27; Br 25,91.

Found, %: From 37.3; H 5,2; Cl 5,5; N 11,4; O 14,7; Br 25,9.

Ultraviolet: solvent: 0.1 and HCl, 206 (4,6), 226 (S, 4,19), 288 (4,28), 09 (S, a 4.03).

2-Methyl-6-chloro-{ 3-[4-(4-(2-ethoxyphenyl) piperazinil-1)propyl] amino}- 3(2H)-pyridazinone.

Sol: 2,0 HCl.

So pl. 211 to 215aboutS; output: 7.9% of theory.

Calculated, %: C 50,17; N 6,32; CL: 22,21; Cl 14,81; N 14,63; O 6,68;

Found, %: From 50.3; H 6,4; CL 21,9; Cl 14,6; N 14,5; About 7.1.

6-Chloro-2-methyl-4-{ [3-(4-(2-metaquote - nil)piperazinil-1)propyl]amino}- 3(2H)-pyridazinone.

Sol: 2,0 HCl.

So pl. 218-229aboutC.

Output: 14.5% of theory.

Calculated, %: C 47,62; N 6,23; Cl 22,19; Cl 14,80; N 14,61; 9,35.

Found, %: From 47.1; H 6,0; CL 22,7; 15,0 Cl; N 14,7; 9,5.

6-Chloro-2-ethyl-4-{ [3-(4-(2-methoxyphenyl) piperazinil-1)propyl] amino}- 3(2H)-pyridazinone.

Sol: 2,0 HCl; MES: 0,35 H2ABOUT

So pl. 202-207aboutC.

Output: 30.6% of theory.

Calculated, %: 49,51; N 6,38; CL 21,92; Cl 14,62; N 14,44; 7,75.

Found, %: C 49,4; N. Of 6.4; Cl 21,8; Cl 14,6; N 14,3; O 7,7.

6-Chloro-2-oxyethyl-4-{ [3-(4-(2-methoxide - nil)piperazinil-1)propyl] amino} - 3(2H)-pyridazinone.

Sol: 2,0 HCl; MES: 1,0 N2ABOUT

So pl. 168-175aboutC.

Output: 5.

P R I m e R to the Determination of the affinity of the compounds of formulas 1 to alpha1-adrenoceptors.

The affinity of compounds of General formula I to the alpha1-adrenoceptors was determined by the method described by R. S. Williams, D. F. Dukes and R. F. Lefkowitz in J. Cardiovasc. Pharmacol. 3, 522-531 (1981). In this method measure specific wipe saturated with tritium prazosin (2-(4-(2-furoyl)-1-piperazinil)-4-amino-6,7-dimethoxyquinazoline) on cardiac membranes test substances and is defined as the IC50(inhibition concentration 50%) is the concentration that causes 50% inhibition of specific communications saturated with tritium prazosin at alpha1-adrenoceptors in cardiac membranes of rats.

From the IC50-values were determined independent of the concentration constants of inhibitors TO1-alpha in accordance with the data Y. Cheng and H. Prusoff W. in Biochem. Pharmacol., 22, 3099-2108 (1973).

The results of these studies are presented below.

Constant braking on alpha-1-adrenoceptor (TO):

6-chloro-2-methyl-4-{ [3-(4-(2-methoxyphenyl) piperazinil-1)propyl]amino}- 3(2H)pyridazinone.

Ki=11,0

6-chloro-2-ethyl-4-{ [3-(4-(2-methoxyphenyl) piperazinil-1)propyl]amino}-3(2H)- pyridazinone

Ki=18,0;

6-chloro-4-{ [4-(4-(2-methoxyphenyl)Pipera - sinil-1)butyl] amino} -3(2=12,8;

2-methyl-6-chloro-4-{ [2-(4-(2-methoxyphenyl) piperazinil-1)ethyl]amino}-3(2H) - pyridazinone

Ki=5.63; 6-chloro-4-{[2-(4-(2-ISO-propoxyphenyl)piperazinil-1-ethyl]amino} -3(2H)- pyridazinone

Ki=10,0;

6-chloro-4-{ [3-(4-(2-methoxyphenyl)Pipera - sinil-1)propyl] amino}-3(2H)- pyridazinone

Ki= 11,0; 6-chloro-4-{ [3-(2-methoxy-4-were)piperazinil-1)propyl] amino}-3(2H)- pyridazinone

Ki=7,49;

2-methyl-6-chloro-3-{ [3-(4-(2-ethoxyphenyl) piperazinil-1)propyl]amino}-3(2H)- pyridazinone

Ki= 6,5; 6-chloro-2-oxyethyl-4-{ [3-(4-(2-methoxy-phenyl)piperazinil-1)propyl]amino}-3(2H )- pyridazinone

Ki=9,6;

Comparative material:

6-{2-[4-(2-methoxyphenyl)piperazinil-1) propyl]amino}-1,3-di-methyluracil (Urapidil)

Ki=110,0;

P R I m e R C. Determination of the affinity of the compounds of formulas 1 to 5-HT-1A receptors.

The affinity of the compounds of General formulas 1 to 5-HT-1A receptors was determined according to the method described by H. Gozlan., S. Elmestikawy, L. Pichat, J. Glowinski and M. Hamon in Nature, 306, 140-142 (1983). In this method measure specific wipe saturated with tritium 8-HE-D (8-hydroxy-(di-p-propylamino)tetralin) on cardiac membranes of rats test substance and is defined as the IC50(inhibition concentration 50%) is the concentration that causes 50% inhibition of specific communication busy travisia concentration constants of inhibitors TO1-alpha1and K1-NT-1A in accordance with the data Y. Cheng and H. Prusoff W. in Biochem. Pharmacol, 22, 3099-3108 (1973).

The results of these studies are listed below:

Constants of inhibition on 5-HT-1A-receptor (Ki):

6-chloro-2-methyl-4-{ [3-(4-(2-methoxide - nil) piperazinil-1)propyl]amino}- 3(2H)-pyridazinone.

Ki=46,6;

2-methyl-6-chloro-4-{ [2-(4-(2-methoxyphenyl) piperazinil-1)ethyl]amino}-3(2H)- pyridazinone.

Ki=28,4;

Comparative material:

6-{ 3-[4-(2-methoxyphenyl)piperazinil-1) propyl]amino}-1.3-dimethyluracil (Urapidil).

Ki=br93.1.

Thus, the method for obtaining compounds of General formula 1, having useful pharmacological properties.

The method of obtaining piperazinylmethyl-3(2H)-pyridazinone General formula

< / BR>
where R1and R2- same or different, hydrogen or C1-C6-alkyl;

B-C1-C6-alkylen;

Z is unsubstituted or mono-or disubstituted C1-C4-alkyl, C1-C4-alkoxyl, trifluoromethyl, halogen or nitro-group is phenyl,

or their pharmaceutically acceptable salts, characterized in that pyridazin General formula

< / BR>
where R3-C1-C6-alkyl;

R1, adequate 3(2H)-pyridazinone.

 

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EFFECT: valuable medicinal properties of compounds.

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FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

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