Derivatives tetrazole, the method of production thereof and pharmaceutical composition having the properties of a receptor antagonist of angiotensin p

 

(57) Abstract:

Use as therapeutic agents for the treatment of high blood pressure and cardiovascular disease. The product 5-/4'-/2-butyl-4-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl) -1-imidazolyl-methylbiphenyl-2-yl/-/-triphenylmethyl-1H-tetrazol BF C43H37N8ClO, yield 43%, so pl. 175-177oC. Thin layer chromatography: solvent of toluene: ethyl acetate 10:1 Rf=0,4. 5 C. I. 2 C.p. f-crystals, 3 ill.

The invention relates to new, therapeutically valuable derivative tetrazole, method of their production and their use.

From the literature already know many of the compounds that can be used to treat high blood pressure induced by angiotensin II.

Known receptor antagonist of angiotensin II, DuP 753 /2-n-butyl-4-chloro-5-oxymethyl-1-//2'-/1-H-tetrazol-5-yl/-biphenyl-4-yl-/methyl/-antifungals/ described, for example, gournal of Pharmacology and Experimental Therapeutics, P. C. Wong et 1990 so 255, S. 211-217. DuP 753, however, when in vavo application becomes noncompetitive metabolite EXP 3174, /2-n-butyl-4-chloro-1//2'-/1H-tetrazol-5-yl/-biphenyl-4-yl/methyl/-imidazole-5-carboxylic acid, which is responsible largely for the duration of DuP 753. the porom and cause changes in cellular structure.

The present invention was to find a purely competitive antagonists, which do not form any noncompetitive metabolites. This problem now can be solved in an unexpected way by using the substances according to the invention.

The subject of the invention therefore is a new derivative of tetrazole formula /I/:

< / BR>
in which

R1denotes a saturated or unsaturated, linear or branched /C1-C6/-alkyl residue, and R2denotes methyl or ethyl, as well as their pharmaceutically acceptable salts.

In the formula I R1denotes a saturated or unsaturated, linear or branched /C1-C6/-alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, sec, -butyl, tert.-butyl, hexyl, ethinyl, propinyl, hexenyl. Preferred compounds in which R1represents butyl, and also those in which R2denotes methyl.

The invention further relates to a method for producing compounds of formula (I):

< / BR>
in which

R1denotes a saturated or unsaturated, linear or branched /C1-C6/-alkyl residue, and R2denotes methyl) - Rev. BR> in which R1have the above significance and R3denotes methyl or ethyl, and S denotes a protective group,

in an inert under the reaction conditions an organic solvent and in the atmosphere of inert gas injected into the interaction with the compound of the formula /III/.

< / BR>
in which R2denotes methyl or ethyl and Me represents sodium or potassium, with obtaining the compounds of formula /IV/:

,

where R1and R2have the above meaning, and then remove the protective group.

Proposed according to the invention, the interaction is performed, so that a suspension of the compounds of formula III in an inert under the reaction conditions, anhydrous organic diluent, such as, for example, in a simple ether, such as tetrahydrofuran, diethyl ether or dioxane, in an atmosphere of inert gas, such as argon, helium or nitrogen, is injected into the interaction with the compound of formula II, dissolved in the same solvent. The reaction temperature is about -20 to +40oC, preferably from -10 to +20oC; reaction time, depending on the respective components of the reaction and the reaction conditions, is about 2-40 h, preferably 2-20 hours as protective groups are used, for example, Tr is their protective group "S" from the resulting compounds of the formula IV is carried out depending on the applicable protective groups, for example, by stirring in a mixture of HBr /glacial acetic acid in chloroform or triperoxonane acid in chloroform at room temperature or better by heating in a lower aliphatic alcohol, such as methanol or ethanol.

Compounds of formulas II and III are known in the literature /T. Hirotsu et g. Chem. Soc. Dalton, 1609, 1986; D. g.Carini and others European patent 0324377, 1989/.

The compounds of formula I in the usual manner with inorganic and organic bases can be converted to their pharmaceutically acceptable salts. The salt formation can be carried out, for example, that the above compounds of formula I are dissolved in a suitable solvent, for example, water; lower aliphatic alcohol; simple ether, such as tetrahydrofuran, dioxane, diethylether, dimethylformamide or dimethyl sulfoxide; add an equivalent amount of the desired base, provides good mixing and at the end of the salt formation, the solvent is evaporated.

If necessary salt, after selection, you can precrystallization.

Pharmaceutically acceptable salts are, for example, metal salts, particularly salts of alkaline or alkaline earth metals, as salt is liseuses ammonium salt. The latter are derived from ammonia or organic amines, for example mono-, di - or trialkyl, cycloalkyl or oxyalkylene, alkylenediamines or oxyalkyl, arylalkyl or alkylammonium bases, such as methylamine, diethylamine, triethylamine, cyclohexylamine, triethanolamine, Ethylenediamine, Tris/oximeter/-aminomethan, benzyltrimethylammonium and the like.

The new compounds of formula I and their salts are orally effective and inhibit the vasoconstrictor and increases blood pressure action of angiotensin II.

In animal models of compounds show excellent blood pressure-lowering effect.

The invention is illustrated in Fig.1-3.

For example, /Fig.1/ curve dose-effect of angiotensin per dose and competitiveness, shifted to the right. In the case of comparative experiments with DuP 753 /Fig.2/ it appears that the substance in in vitro experiments, there is also competitive, however, in in vivo experiments /Fig.3/ you can see the transformation in active, non-competitive metabolite with a longer compared to the proposed invention substances duration of action. Tests Wong and others 1990, gPET, volume 255, S. 211-217, showed that this active metabolite EP actions.

Proposed in the invention of a substance, on the contrary, bound to the receptor is reversible, so that it is not modified or destroyed. This reversible binding is manifested in a shorter duration of action, allowing also turns out that these substances are effective without the active, non-competitive metabolite.

Based on these pharmacological properties the new compounds, either individually or in a mixture with other active substances in the form of conventional galenical compositions can find use as therapeutic agents for the treatment of high blood pressure and other cardiovascular diseases.

The invention relates, further, to medicines, which are used, for example, in the form of pharmaceutical preparations containing proposed in the invention the compounds of formula I or their salts in a mixture with one or more, suitable for intestinal or parenteral administration, pharmaceutical, organic or inorganic bases, such as, for example, water, gelatin, gum Arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline or the like.

Pharmaceutical prep the street, or in liquid form, e.g. as solutions, injectable solutions, suspensions or emulsions, or in the form of compositions with prolonged secretion of biologically active substances. If necessary, they are sterilized and/or they contain auxiliary substances, such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers.

In particular, the pharmaceutical preparations can contain proposed in the invention compounds in combination with other therapeutically valuable substances. The proposed invention in connection with these valuable substances, as well as with the above-mentioned auxiliary substances and/or bases can be formulated in a combination of drugs.

Suitable dose for accepting new connections is about 4-200 mg/kg / day, the preferred dose per patient is approximately 60-200 mg, however, depending on the state of the radiated patient, taking into account also other dose. New connections can be introduced in the form of multiple doses of oral way.

New connections in the proposed according to the invention pharmaceutical compositions /compositions/ can be in an amount of about 4 the first filler.

Example 1 5-/4-/2-Butyl-4-chloro-5-/3-methyl-1,2,4-oxadiazol-5-yl/-1-imidazolyl-methyl-biphenyl-2-yl/-1-triphenylmethyl-1H-tetrazol

To a solution of 0.28 g /0,0038 mol/ N-hydroxy-ethane-imidated in 20 ml of absolute THF add 0,09 7 /0,0038 mol of sodium hydride and this suspension is heated for one hour over a molecular sieve in a nitrogen atmosphere at 60oC. the Mixture is cooled to 0oC and rapidly added dropwise a solution of 2.20 g /0,0032 mol/ methyl ester 1-//2-/N-triphenylmethyl-tetrazol-5-yl/ - biphenyl-4-yl/methyl/-2-butyl-4-chloro-1H-imidazole-carboxylic acid in 45 ml of absolute THF. The suspension is warmed to room temperature and stirred for 18 hours, the Reaction mixture is filtered and the filtrate is evaporated in vacuum. The residue is partitioned between 10 ml of water and 10 ml of ethyl acetate, the phases are separated and the aqueous phase is extracted 3 times with 20 ml ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed. Purification of the product is carried out by column chromatography /KG60; 30g; solvent: toluene: ethyl acetate 10:1/. Product by infusion in the air is brought to crystallization.

Output: 1,00 g of colorless crystals /43% of theory/.

So pl. 175-177oC /acetone/

Thin layer chromatography: RASO mol.weight=717,28

calculated C 72,01 H 5,20 N 15.62 WIDE

found, 71,80 lower than the 5.37 15,68

1H-NMR /CDCl3/: /ppm/: 7,93-7,87 /multiplet, 1H, Bz-H3/; 7,63-7,47 /multiplet, 2H, Bz-H'5, -H'6/; 7,41-7,26 /multiplet, 1H; Bz-H'4/; 7,39-7,28 /multiplet, 10H; Bz-H/; 7,11; 7,07; 6,78; 6,72 /A2B2; 4H; Bz-H2, -H6and Bz-H3, -H5/; 6,99-6,89 /multiplet, 6N, Bz-H/; 5,67 /singlet, 2H, 1m-CH2-Bz/; 2,53 /triplet, 2H, Bu1-CH2/; 2,35 /singlet, 3H, -CH3/; 1,63 /multiplet, 2H, Bu2-CH2/; 1,22 /multiplet, 2H, Bu3-CH2/; 0,84 /triplet, 3H, Bu-CH3/.

13C-NMR /CDCl3/; d/ppm/: 166,68; 163,92; 153,06; 141,21, 140,94; 134,16; 130,72; 130,21; 129,98; 129,83; 128,26; 127,61; 126,22; 125,53; 113,83; 82,87; 48,49; 29,29; 26,94; 22,31; 13,70; 11,51.

5-/4'-/2-Butyl-4-chloro-5-/3-methyl-1,2,4-oxadiazol-5-yl/-1-imidazolyl-methyl/ - biphenyl-2-yl/-1H-tetrazol 0.40 g/0,0006 mol/ 5-/4'-/-2 Butyl-4-chloro-5-/3-methyl-1,2,4-oxadiazol-5-yl/-1-imidazolyl-methyl-biphenyl- -2-yl/ -1-triphenyl-methyl-1H-tetrazol suspended in 12 ml of methanol and boiled for two hours. The solvent is distilled off, the residue insist when heated with 3 ml of boiling diethyl ether and the resulting crystals filtered off. The crude product precrystallizer of ethyl acetate with active charcoal.

Yield: 0.10 g of colorless crystals (35 from theory).

So pl. 178 180oC (UB> 0,6.

Microelementary analysis: C24H23N8ClO mol. weight. 474,96

Calculated C 60,69; H 4,88; N 23,59

Found, 60,51; H 4,94; N 23,29

1H-NMR /CDCl3/: d/ppm/: 7,93 7,87 /multiplet, 1H, Bz-H3/; 7,63 7,47 /multiplet, 2H, Bz-H5; -H6; 7,41 - 7,26 /multiplet 1H, Bz-H4,/; 7,11; 7,07; 6,92; 6,87/A2B2; 4H, Bz-H2, -H6and Bz-H3, -H5,/; 5,67 /singlet, 2H, Im-CH2-Bz/; 2,53 /triplet, 2H, Bu11-CH2/; 2,35 /singlet, 3H, -CH3/; 1,63 /multiplet, 2H, Bu2-CH2/; 1,22 /multiplet, 2H, Bu3-CH2/; 0,84/triplet, 3H, Bu-CH3/

13C-NMR /CDCl3: d/ppm/: 166,94; 166,36; 153,01; 140,58; 139,30; 135,51; 135,16; 131,38; 130,79; 130,66; 129,60; 128,42; 126,25; 122,89; 133,54; 48,59; 28,56; 26,74; 22,27; 13,66; 11,54;

Example 2. Angiotensin-II-receptor-antagonistic action of the substance of example 1 (substance 1) compared with standard substance DuP 753

and/ Isolated rat aorta

Cumulative curves dose-effect of angiotensin II /10-10- 10-7mol/l/ shall isometrically with or without pre-treatment substance from example 1/ or DuP 753 /10-8, 10-7, 10-6mol/l/. and are in the form of a percentage reduction due to noradrenaline /10-5mol/l/. ED50Values and pA2-the value of the substance I

angiotensin II; n 8; ED507,910-10mol/L.

+10-8mol/l of the substance 1, n 8, ED507,910-9mol/l=== === ===

+10-7mol/l of the substance 1, n 8, ED501,910-8mol/l - - -

+10-6mol/l of the substance 1, n 8, ED501,710-7mol/l=======< / BR>
Fig. 2: Isolated rat aorta

Curve dose-effect DuP 753

angiotensin II; n 8; ED507,910-10mol/l-------< / BR>
+10-8mol/l DuP 753, n 8, ED501,610-8mol/l=== === ===

+10-7mol/l DuP 753, n 8, ED501,410-7mol/l - - -

+10-6mol/l DuP 753, n 8, ED501,010-6mol/l========< / BR>
b/ Anesthetized, normotensive rat:

Angiotensin II /1 mg/kg intravenous/ injection before and at 15-minute intervals after intraduodenal injection of the substance.

Fig. 3: Effect of substance I and DuP 753 on angiotensin II-induced increase in mean arterial blood pressure to anesthetized, normotensive rats /n 4/:

control Methocel 0.5% of intraduodenal /I. D./

DuP 753 10 MK/kg I. D.

Y the substance 1 to 30 mg/kg I. D.

1. Derivatives tetrazole General formula I

< / BR>
where R1saturated or unsaturated, linear or branched C1WITH6-alkiliruyuscimi properties of the receptor of angiotensin II.

2. Derivatives tetrazole General formula I on p. 1, where R1butyl.

3. Derived tetrazole General formula I on p. 1, representing 5-[4'(2-butyl-4-chloro-5)-3-methyl-1,2,4-oxadiazol-5-yl- (1-imidazolidinyl)-biphenyl-2'-yl]-1H-tetrazole.

4. The method of obtaining derivatives of tetrazole General formula I on p. 1, characterized in that the compound of formula II

< / BR>
where R1has a specified value;

R3methyl or ethyl;

's protective group,

enter into interaction with the compound of the formula III

< / BR>
where R2methyl or ethyl;

IU sodium or potassium,

in an inert under the reaction conditions an organic diluent and inert gas with the formation of compounds of formula IV

< / BR>
where R1and R2have a specified value,

and then remove the protective group.

5. The method according to p. 4, characterized in that the protective group is removed by treatment with a strong acid or by heating with a lower aliphatic alcohol.

6. The method according to p. 4, characterized in that the protective group used triphenylmethyl group.

7. Pharmaceutical composition having the properties of a receptor antagonist of angiotensin II, containing as it contains derivatives of tetrazole General formula I

< / BR>
where R1saturated or unsaturated, linear or branched C1C6is an alkyl residue;

R2methyl or ethyl,

or their pharmaceutical acceptable salt 4 200 mg.

 

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