LT3469B - Novel acylales of imidazol-5-carboxylic acid derivatives, process for their preparation and use thereof - Google Patents

Abstract

New imidazole -5-carboxy acids acylales, which coincide with the general formula:<IMAGE>where: R1 - in a specific case, unsaturated rectilinear alkyl with 1-6 carbonic atoms, R2 - hydrogen, chlorine, bromine, iodine or CF3 and R3 C1-C10 - alkyl, C3-C7 - cycloalkyl or benzyl and its pharmacologically acceptable saline.

Description

The present invention relates to novel acylals of imidazole-5-carboxylic acid derivatives and their salts, processes for their synthesis and their use in antihypertensive medicaments.

Many compounds that can be used to treat high blood pressure caused by angiotensin II are already known.

The known angiotensin II receptor-antipode DUP 753 (2n-butyl-4-chloro-5-hydroxymethyl-1 - ((2'-1-H-tetrazol-5-yl) diphenyl-4-yl) -methyl) imidazole is described, for example: Journal of Pharmacology and Experimental

Therapeutics, P.C. Wong et al. 1990, vol. 225, S. 211217. However, when Dup 753 is used in vivo as a non-competitive metabolite of ΕΧΡ 3174, chloro-1- (1H-tetrazol-5-yl) diphenyl-4-ii) methyl) imidazole-5-carboxylic acid, the latter . The disadvantage of non-competitive antipodes is that they irreversibly bind to the receptor and induce cellular structural changes there.

it is converted into (2-n-butyl-4EP, Application No. 0253310, inter alia, angiotensin II receptor blocking imidazolecarboxylic acids of particular activity and of formula

(! '),

Which may contain: R _x - unsaturated, unbranched allyl with 1-6 carbon atoms in the chain; R ₂ is hydrogen, chlorine, bromine, iodine and CF ₃ . These compounds are particularly effective in lowering blood pressure when administered intravenously. They have the disadvantage that they are only slightly absorbed when administered internally and that less efficacy is achieved or their dose needs to be increased.

The net of the present invention was thus to find purely competitive antipodes which, when administered intravenously, would exhibit a much better resorption and also greater efficiency than the carbonic acids of the general formula (I ') and would pass in the blood in the form of free carboxylic acids.

The present invention thus relates to novel compounds of the general formula:

wherein: R _x is optionally unsaturated straight-chain alkyl of 1-6 carbon atoms, R ₂ is hydrogen, chlorine, bromine, iodine or CF ₃ and R ₃ is C ₁ -C ₀ -alkyl, C ₃ -C ₇ -cycloalkyl or benzyl and their pharmacologically acceptable salts. A more preferred class of compounds is that wherein R _x is butyl, R ₂ is chloro, R 1 is ethyl.

Another object of the present invention is a process for the synthesis of novel compounds of formula (I) wherein R 1, R ₂ and R _{3 are as} defined above, wherein in step a) the compound of formula

(II) wherein _R: R ₂ and R ₃ has the above specified, is reacted with a compound of the formula

wherein: X is chlorine, bromine or iodine, a triphenylmethyl protecting group, to form a compound of the formula

wherein R _1f R ₂ , R ₃ and jS are as defined above, which in step b) is heated with a lower aliphatic alcohol and the compound of formula (I) thus obtained is converted into a generally non-crystalline amorphous compound, if necessary, converted into a pharmacologically acceptable crystalline salt. organic bases.

The interaction of the present invention in step a) is best achieved by heating a mixture of the compounds of formulas II and III in a chemically inert, anhydrous organic solvent, such as ether, dioxane, tetrahydrofuran, acetone, dimethylformamide or dimethylsulfoxide, with equivalent dry potassium carbonate. Thus, a suitable reaction temperature is 20100 ° C, depending on the reaction time, 0.5-20 seconds. The separation of the triphenylmethyl group S in Step b) from the resulting compounds of formula IV is carried out by boiling in a lower aliphatic alcohol such as methanol or ethanol for a reaction time of from minutes to 10 hours. In interaction, the compounds of formula (I) obtained in step b) may be converted in conventional manner into inorganic and organic bases into pharmacologically acceptable salts. For example, salts can be obtained by reaction of the named compounds of formula (I) with appropriate equivalents in suitable solvents such as water, lower aliphatic alcohols, tetrahydrofuran, dioxane, benzene, CH ₂ Cl ₂ , CH ₂ Cl ₃ , diethyl ether, dimethylformamide or dimethyl sulfoxide. amount of the desired base, ensuring good mixing and evaporation of the solvent in vacuo at the end of the salt formation. If necessary, the separated salts may be recrystallized.

Pharmaceutically acceptable salts are, for example, metal salts, in particular alkaline or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts. Other pharmacologically acceptable salts are, for example, readily crystallized ammonium salts. The latter are formed by reaction with ammonia or organic amines such as mono-, di- or tri-alkyl (alkylcycloalkyl or hydroxyalkyl) amines, lower alkylenediamines or (hydroxy-lower alkyl or aryl-lower alkylammonium bases such as methylamine, diethylamine, triethylamine, ethylenediamine, tris (hydroxymethyl) -aminomethane, benzyltrimethylammonium hydroxide and analogues.

Compounds of general formula (II) may be prepared by conventional and art-known chemical synthesis from compounds of formula (V) wherein R _L and R _{2 are as} defined above, according to the following reaction scheme:

Compounds corresponding to (III) and described in the literature (D.J. No. 0324377, 1989).

(V) The general formulas of Carini et. et al., EP

The novel compounds of the general formula (I) and their salts are effective when administered intravenously and inhibit the vasoconstrictive effect of angiotensin II.

Based on these pharmacological properties, the novel compounds, alone or in combination with other active ingredients in the form of conventional medications, can be used as drugs for the treatment of high blood pressure and other cardiovascular diseases.

Therefore, it is contemplated that the present invention is a medicament comprising, as an active hypotensive component, compounds of formula (I) or salts thereof according to the present invention alone or in combination with other active ingredients in the form of conventional medicaments for internal use. The compounds of the present invention may be used in the form of tablets or capsules in which the dosage compound is dispersed with corn starch, chalk, calcium hydrogen phosphate, alginic acid, lactose, magnesium stearate, primogel or talc. Conventionally, the contents are granulated and compressed to form tablets or filled into hard gelatin capsules of appropriate size.

For internal human administration, the compounds of the present invention are dosed in an amount of 0.1 to 30 mg / kg for an average adult patient of 70 kg. Therefore, tablets or capsules may contain from 0.1 to 50 mg of the active compound three times daily for internal use.

It goes without saying that in each case the exact dosage will be optimized for the individual patient by the physician, especially since the dosage may vary according to the age, weight and need of the patient.

example:

2-Butyl-4-chloro-1 - ((2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylic acid 1-ethoxycarbonyloxyethyl ester.

8.0 g (10.06 mmol) of 2-butyl-4-chloro-1 - ((2 '- (N-triphenylH-tetrazol-5-yl) -biphenyl-4-yl) -methyl) -1H-imidazolecarboxylic acid The 1-ethoxycarbonyloxyethyl ester is heated to boiling in 175 ml of methanol for 3 hours, the solvent is evaporated and the crude product thus obtained is purified on a chromatographic column (Et ₂ O; 400 g KG 60).

Yield: 5.0 colorless amorphous materials.

Trace element analysis:

C ₂₇ H ₂₉ ClN ₆ O ₅ - Molecular Weight 553.02 Calculated Found

C

58, 64 58.3

H

5.29

5.4

N

15.29 15, 3

-H-NMR:

(CDC1 ₃₎

7, 91 δ (dd)

7.91 (dd, 1H, Biph-H3 '); 7.64-7.43 (m, 2H,

Biph-H4 ', H5'); 7.41 (dd, 1H, Biph-H6 '); 7.10 (AA ', 2H, Biph-H3, H5); 6.89 (BB ', 2H, Biph-H2, H6); 6.82 (q, 1H, CH-CH _3); 5.48 (s, 2H, BiphCH ₂ ); 4.15 (q, 2H, -CH ₂ -CH _3); 2.66 (t, 2H, H-); 1.63 (m, 2H, Bu ₂ -CH ₂ -); 1.54 (d, 3H, CHCH ₃ ); 1.32 (m, 2H, Bu 3 -CH ₂ -); 1.21 (t, 3H, -CH ₂ CH _3); 0.86 (t, 3Hm, Bu 4 -CH ₃ )

C-NMR (CDC1 ₃₎ δ (ppm): 156.71; 156.59; 153.20; 152.37; 140.63; 139.21;

136.54; 135.23; 130.51; 130.37; 129.94; 129.18; 127.45; 125.94; 125.72; 115.74, 91.37; 64.16;

47.80; 28.58; 25.83; 21.53; 19.22; 13.85; Example 13.50:

2-Butyl-4-chloro-1 - ((2 '- (1H-tetrazol-5-yl) -biphenyl-4yl) -methyl) -1H-imidazole-5-carboxylic acid 1-ethoxycarbonyloxyethyl ester, sodium salt

To 2.0 g (3.62 mmol) of 2-butyl-4-chloro-1 - ((2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) methyl)-)-imidazole- 5-Carboxylic acid 1-ethoxycarbonyloxyethyl ester is added dropwise to a solution of 0.41 g (3.62 mmol) of sodium trimethylsilanolate in 3 ml of dichloromethane, the solvent is evaporated and the residue is crystallized from diisopropyl ether, filtered and washed three times with cold diisopropyl ester.

Yield: 1.3 g of colorless crystals.

Melting point: decomposes at 138 ° C.

Trace element analysis:

C ₂₇ H ₂₈ ClN,; O ₅ Na * H ₂ O - Molecular Weight 593.02 av

calculated found

C

54, 69 54.47

H

5, 10 5.08

-H-NMR: (dimethylsulfoxide)

Δ (m.d.): 7.56 (dd, 1H, Biph-H3 '); 7.41 ·

Biph-H4 ', H5, H6'); 7.10 (AA ',

H5); 6.86 (BB ', 2H, Biph-H2, H6); CH-CH ₃ ); 5.52 (AB, 2H, Biph-CH ₂ );

-CH ₂ -CH ₃ ); 2, 65 (t, 2H, Bul-CH ₂ -); Bu ₂ -CH ₂ -); 1.48 (d, 3H, CH-CH ₃ ); Bu ₃ -CH ₃ -); 1, 19 (t, 3H, -CH ₂ -CH ₃ );

Bu4-CH ₃ )

14, 17th 14, 28th 7.23 (m, 3H, 2H, Biph- H3, 6, 78 (sq, 1H, 4.13 (sq, 2H, 1.56 (m, 2H, 1.29 (m, 2H, 0, 82 (t, 3H,

NMR δ (md) (CDCl ₃ )

160.66; 156.72; 153, 19; 152.36; 141.20; 139.74; 136.52; 134.10; 132, 54; 130.46; 130.00; 129.40; 127.21; 126.67; 125 , 14; 115.68, 91.38; 64.16;

47.84; 28.62; 25.87; 21.56; 19.27; 13.88; 13.58

The starting materials are prepared as follows:

2-Butyl-4-chloro-1H-imidazole-5-carboxylic acid 1-ethoxycarbonyloxyethyl ester.

To a solution of 7.66 g (37.80 mmol) of 2-butyl-4-chloro-1H-imidazole-5-carboxylic acid is added dropwise 4.88 g (43.47 mmol) of sodium silanolate dissolved in 20 ml of tetradihrofuran in 155 ml of hexamethylphosphoric acid triamide. minutes.

6.34 g (41.58 mmol) of chloroethyl carbonate in 25 ml of hexamethylphosphoric triamide are added dropwise and the solution is kept at 80 ° C for one hour. The reaction mixture is then poured into 760 mL of water, extracted with 8 x 75 mL of diethyl ether, the combined organic phases are combined and washed with 3 x 65 mL of aqueous sodium bicarbonate and 3 x 100 mL of water. The organic phase is dried over sodium sulfate / activated carbon, filtered and the solvent is distilled off. The product obtained is purified by chromatography on a column.

(EE: CH ₂ Cl ₂ = 1:25; 300 g silica gel KG 60)

Yield: 7.4 g of colorless crystals

Melting point: 108-110 ° C

Trace element analysis:

C ₁₃ H ₁₉ Molecular weight of C1N ₂ O ₅

318.76 a.v.

calculated found

C H N

48, 99 6, 01 8.79

48.84 5, 86 8, 65

-H- (NMR): (CDCl ₃ )

5 (ppm): 6.92 (q, 1H, CH-CH _3); 4.18 (q, 2H, -CH ₂ -CH _3); 2.71 (t, 2H, Bul-CH ₂ -); 1.69 (m, 2H, Bu ₂ -CH ₂ -); 1.57 (d, 3H, CH-CH _3); 1.43 (m, 2H, Bu 3 -CH ₂ ); 1.28 (t,

3H, CH ₂ -CH ₃ ), 0.86 (t, 3H, Bu 4 -CH ₃ ) - C-NMR: (CDCl ₃ ) δ (ρριη): 157, 48; 152.95; 141.91; 136.71; 115.73; 91.47;

64.57; 29.90; 28.28; 22.13; 19.56; 14.00; 13.53

2-Bey-4-chloro-1 - ((2 '- (N-triphenyl-1H-tetrazol-5-yl) biphen-4-yl) methyl) -1H-imidazolecarboxylic acid 1-ethoxycarbonyloxyethyl ester

7.1 g (22.27 mmol) of 2-butyl-4-chloro-1H-imidazole-5-carboxylic acid 1-ethoxycarbonyloxyethyl ester, 15.52 g (27.84 mmol) of n-triphenylmethyl-5- (4'-bromomethyl) -biphenyl-2-yl) -α-tetrazole and 3.85 g (27.84 mmol) of calcium carbonate are stirred at 70 ° C for 230 hours in 230 ml of dimethylformamide. After distilling off the solvent, the residue is extracted with 250 ml of a semi-concentrated ammonium chloride solution and 100 ml of diethyl ether, the phases are separated and the aqueous solution is extracted with 4 * 50 ml of diethyl ether. The organic phases are washed together with 5 x 50 ml of water. The resulting product was purified by chromatography on a column (Bz: Et ₂ O = 6: 1; 400 g silica gel KG 60).

Yield: 9.65 colorless crystals

Melting point: 150-153 ° C

Trace element analysis:

C ₄₆ H43C1N ₆ O ₅ - molecular weight

C calculated 69.47 found 69.39

795, 34 a.v.

H

5.45 5.65

N

10.57 10.74

-H- (NMR): (dimethylsulfoxide)

7, 92 (dd, 1H, Biph-H3 '); 7.54-7.39 (m, 2H, Biph-H5 ', H6'); 7.39-7.23 (m, 9H, Trit-H2, H4, H6); 7.21 (t, 1H, Biph-4H '); 7.10 (AA ', 2H, Biph -H3, H5); 6, 98-6, 90 (m, 6H, Trit-H3, H5); 6.88 (sq, 1H, CH-CH ₃ ); 6.81 (BB *, 2H, Biph-H2, H6); 5, 45 (AB, 2H, Biph-CH ₂ ); 4.19 (q, 2H, -CH ₂ -CH _3); 2.50 (t, 2H, Bul-CH ₂ -); 1.64 (m, 2H, Bu ₂ -CH ₂ -); 1.53 (d, 3H, CH-CH _3); 1.28 (m, 2H, Bu 3 -CH ₂ -); 1.27 (t, 3H, -CH ₂ -CH ₃ ); 0.86 (t, 3H, Bu 4 -CH ₃ )

- C-NMR: (dimethylsulfoxide) δ (m.d.): 163.84; 147.40; 153.03; 152.92; 141.29; 141.13;

140.15; 140.64; 138.05; 134.39; 130.67; 130.19; 130.09; 129.87; 129.66; 128.17; 127.73; 127.54; 126.13; 125.53; 116.12; 91.28; 82.78; 64.34; 48.20; 29.15; 26, 72; 22.17; 19.47; 14.02; Example 13.60

Substance affinity for the angiotensic subtype II-1 receptor was determined using rat adrenal cortex microsomes (H-DuP 753 system).

When IC ₅₀ = 79, the affinity of the 4 nmol / L compound of Example 1 is less than DuP 753 (7.24 nmol / L) and ΕΧΡ 3174 (7.87 nmol / L).

Studies in isolated rat aorta have shown that the compound of Example 1 and ΕΧΡ 3174 are selective non-competitive angiotensin II receptor antipodes (Fig.1). Both substances dose-dependently (IO ⁹ - 10 ⁷ mol / l) reduce maximal angiotensin II-induced contraction, although ΕΧΡ 3174 has a greater relative effect:

Isolated rat aorta: maximal percent inhibition of angiotensin II (3x10 ⁷ mol / l) contraction:

mol / l compound according to Example 1 ΕΧΡ 3174 10 ' ⁹ 63 76 10 ' ⁸ 72 95 io ~ ⁷ 98 100 So too in despinalized rats compound according to 1 example and ΕΧΡ 3174 non-compete blocked an-

hypertonic activity of giotensin II. In contrast, the effect of DuP 753 is competitive, that is, it shifts the angiotensin II dose-response curve to the right without decreasing at maximum efficacy (Fig.2).

Following intravenous administration of the compound of Example 1 (0.3-10 mg / kg)

i.v.) is slightly less potent than DuP 753 (ΙΙΟ mg / kg i.v.) and about as effective as ΕΧΡ 3174. When administered intraduodenally, the compound of Example 1 proved to be most effective. The sequence of efficacy obtained by intraduodenal administration:

compound according to Example 1> DuP 753> ΕΧΡ 3174 (Fig.4).

The duration of exposure was investigated in drug-depleted rats with normal blood pressure. Angiotensin II (1 microgram / kg) is administered intravenously before and every 15 minutes by intraduodenal administration. Again, the efficacy sequence produced the compound of Example 1> DuP 753. 3 mg / kg of the compound of Example 1 was about twice as effective as 10 mg / kg of DuP 753 (Fig. 5). The compound of Example 1 exhibits a particularly abrupt dose-dependent effect. The maximal angiotensin-blocking effect of the compound of Example 1 is attained 15 minutes after intraduodenal administration (3 mg / kg), in contrast to DuP 753 at 30-60 minutes (Fig.6). The effects of the substances remained constant during the 5-hour tests.

Claims (10)

DEFINITION OF INVENTION 1. Novel imidazole-5-carboxylic acid acyls of general formula: where: R! - in each case unsaturated linear alkyl having from 1 to 6 carbon atoms, R ₂ - hydrogen, chlorine, bromine, iodine or CF ₃ and R ₃ C ₁ -C ₄ -alkyl, C ₃ -C ₇ -cycloalkyl or benzyl and their pharmacologically 10 acceptable salts. 2. Compounds according to claim 1 having the general formula (I) as defined in claim 1, wherein R ₃ is butyl. Compounds according to claim 2, characterized in that R ₂ is chlorine. 4. Sodium salt of 2-butyl-4-chloro-1 - ((2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylic acid-1-ethoxycarbonylethyl ester. 5. Sodium salt of 2-butyl-4-chloro-1 - ((2 '- (1H-tetrazol-5-yl) -biphenyl-4yl) -methyl) -1H-imidazole-5-carboxylic acid-1-ethoxycarbonylethyloxyester. 6. A process for the synthesis of compounds according to claim 1, wherein in step a) the compound of formula (II) _Wherein R _1z R ₂ and R _{3 are as} defined above, reacting with a compound of formula (III) wherein: X is chlorine, bromine or iodine, (-protected triphenylmethyl group to form a compound of formula wherein R _x , R ₂ , R ₃ and - (j _{3 -} ) are as defined above, which in step b) is heated with a lower aliphatic alcohol and the compound of formula (I) thus obtained is converted into a pharmacologically acceptable crystalline salt which is usually non-crystalline. 7. A pharmaceutical composition for internal use comprising a compound of formula (I) as defined in claim 1, or a pharmacologically acceptable salt thereof, together with other pharmacologically acceptable excipients or solutions. 8. The pharmaceutical composition of claim 7, further comprising other therapeutically valuable active ingredients. Use of the compounds according to claim 1 and their salts as an active ingredient in medicaments for the treatment of diseases which may be alleviated or during the angiotensin II treatment. Compounds according to claim 1 for use as a therapeutic agent for pressure. cured bloir salts, lowering blood5 FIG. 1. Aortic contraction of isolated rat. Koncentrac and FIG. 1 Concentration however mm Hg FIG. 2 Effects of Compounds on Intravenous Administration of Angiotensin II-Induced Diastolic Despinalized Rat Blood Pressure FIG. 2 C) Compound corresponding to Example 1 Compound corresponding to: Example 1 however mm Hg is dt mm Hg FIG. 3 Effects of Compounds on Increased Angiotensin II-Induced Diastolic Despinalized Blood Pressure in Intraduodenal Dose FIG. 4 c) A compound according to Example 1, oiiap 100 0.01 0.10 1.00 10.00 100.00 1000.00 jug / kg ANGIOTENSIN II Fig. 4DuP 753, ΕΧΡ 3174 and Compound of Example 1 Effect of Angiotensin II on Diastolic Despinalized Rat Blood Pressure Increased Intraduodenally. Ί2Ο rpm mm Hg jug / kg ΛΝ0101Ι NSlN II delta mmHg Fig. 5 poveikis 3174 and effect of compound of Example 1 on angiotensin II-mediated increase in blood pressure in anesthetized normal blood pressure rats _; dosing intraduodenally. ^Fig . ⁶ Effect of Compounds of Example 1 on Angiotensin II-mediated Elevation of Blood Pressure in Anesthetized Normal Blood Pressure Rat by Intraduodenal Administration 120 ioo • Control Methocel 0.5% i d. oConnect according to Example 1 3mg / kg id ▼ Compound according to Example 1 _{Λ mg} / kg id