SK141193A3 - 3-(quinoline-6-ylmethyl)-4h-imidazole-4-on derivatives method of their preparation and their therapeutical using - Google Patents

Abstract

3-(Quinol-6-ylmethyl)-4H-imidazol-4-one derivatives corresponding to the formula (I) <IMAGE> in which R1 represents a straight or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of the other, either a hydrogen atom, or a straight or branched (C1-C5)alkyl group, or a group (CH2)n-aryl where n = 0 to 3, or R2 and R3 can form, with the imidazole ring, a spirocyclo(C3-C8)alkyl group, and their addition salts with pharmaceutically acceptable acids and bases. Therapeutic application.

Description

Technical field

The invention relates to 3- (quinol-6-ylmethyl) -4H-imidazo-4-one derivatives, to a process for their preparation and to their therapeutic use.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula I

in which

R 1 represents a straight or branched (C 2 -C) alkyl group,

Ra and Ra independently of one another represent either a hydrogen atom or a straight or branched alkyl group having from 1 to 5 carbon atoms or a (CHa) n -aryl group in which n = 0 to 3, or Ra and R3 may be taken together. to form a spirocycloalkyl group in which the alkyl radical contains 3 to 8 carbon atoms.

Preferred compounds of formula I wherein the 2 to 5 alkyl group of the invention are those wherein R 1 is straight or branched carbon atoms, F 1 and R ₃ independently of one another are straight or branched (C 1 -C 5) alkyl groups or R 8 and R 8 together with the imidazole cycle may form a spirocycloalkyl group in which the alkyl radical contains 3 to 8 carbon atoms.

Of these, compounds of the formula I in which R @ 1 is butyl, Ra and R @ ₃ independently of one another are straight or branched (C1 -C5) alkyl, or R @ 1 and R @ 2 together with the imidazole ring may form sp an irocycloalkyl group in which the alkyl radical contains 3 to 8 carbon atoms.

The compounds of the invention may exist in free form or in the form of pharmaceutically acceptable organic or inorganic salts.

Compounds of formula (I) may be synthesized by the method of the invention, which is illustrated by the following Reaction Scheme 1.

Reaction scheme 1 'Ό, AA (Π) ^K 3 ^C

(Π)

»

m

When the reaction mixture is heated to reflux, 4-methylbenzenamine (paratoluidine) is reacted with a benzaldehyde of formula II wherein X is bromine or iodine in the presence of a catalyst such as 4-methylbenzenesulfonic acid (paratoluenesulfonic acid). phonic acid) in benzene solution. After cooling, propiolic acid is added to the reaction mixture, and the reaction mixture is then heated to reflux to give the compound of formula III. Then, a mixture of the compound of formula III and copper (I) cyanide is heated in a solvent such as pyridine to form 2- (6-methylquinolin-2-yl) benzonitrile of formula IV, which is then reacted with an organometallic azide such as trimethyl or a metal azide, such as sodium azide, to form a compound which is treated with a stream of hydrogen chloride to form a quinoline of formula V. The first reaction is carried out in a solvent such as xylene at reflux temperature. The second reaction is carried out in a solvent, such as a mixture of toluene and tetrahydrofuran, at an ambient temperature of 1 ° C.

Then the protecting CR with R e R t, in formula V, protects the group of the formula, the tetrazole quinoline group R a, wherein R ₄ is wherein R 5, R 6 and R ₇ independently of one another are C 1 -C 2 alkyl or aryl. At this stage, the compound of formula V is reacted with a preservative such as trityl chloride at room temperature and in a solvent such as dichloromethane in the presence of a base such as N-methylmorpholine or triethylamine, to obtain a compound of formula VI, wherein a _5, R and R? are as defined above. The function she izuje 1 methyl group in position 6 of the quinoline of formula VI introducing paragraph iepiteľ best of the L, najjtíkJadatómu bromine, in a position to give a compound of formula VII, wherein R, R _e, and Yu are defined as above. This reaction is carried out at the reflux temperature of n, in the presence of an initiator such as benzoyl peroxide or alpha, alpha-azobisisobutyronitrile. Finally, the compound of formula VII is condensed with an imidazolone of formula VIII in which R 1, R ₂ and R ₃ are as defined above, wherein the methyl forms are at a temperature of 0 to 50 ° C and in the presence of a base such as potassium hydroxide or potassium carbonate. to give a compound of formula IX from which the protecting groups are removed.

Compounds of Formula IX

wherein R 1, R c, R a and R 6 are as defined above, are novel compounds and thus form part of the invention.

The starting compounds are either commercially available or described in the literature or can be prepared by methods known in the literature or known to those skilled in the art.

The imidazolones of formula VIII may thus be synthesized by the method described by Jacquier et al. (Bull.Soc.Ch.France, 1971,3,1040-1051) based on the condensation of an alkylamidate with an amino acid ester such as 1-amino-1-cyclopropylcarboxylate.

Methyl methyl 1-amino-1-cyclopropylcarboxylate was prepared by the method described by Valdyanathan (J. Org. Chem., 1939, 54, 188101315).

Compounds of formula VII are prepared by the method described in European patent application 0540500.

In the following, the invention will be explained in more detail by means of specific examples thereof, which are illustrative only and do not limit the scope of the invention, which is clearly defined by the wording of the claims.

DETAILED DESCRIPTION OF THE INVENTION

The chemical structures of the compounds obtained in these examples were verified by elemental microscopy and infrared and nuclear magnetic resonance spectroscopy.

Example 1

5-Butyl-6- [2 - [(1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl] 4,6-diazaspiro [2.4] hept-4-en-7-one

Stage 1. 1

6- Bromomethyl-2- / 2- / 1 (or 2) - (triphenylmethyl) -1 (or 1) 2-H-tetrazol-5-yl / phenyl / quinoline

Stage 1.1.1

2- (2-Bromophenyl) -6-methylquinoline

In a flask to which a Dean-Stark apparatus is attached, 50 g (270 mmol) of 2-bromobenzaldehyde with 29.5 g (27.6 mmol) of paratoluidine and 0.5 g of paratoluenesulfonic acid are heated to reflux. in solution in one liter of benzene. When the precipitation of water (about 5 ml) is complete, 8.3 ml (15 mmol) of propiolic acid are added to the reaction mixture, which has been previously cooled to about 50 ° C. The carbon dioxide evolved significantly and the reaction mixture was heated to reflux for 3 hours. The reaction was monitored by thin layer chromatography, eluting with a dichloromethane / hexane (70:30; v / v) mixture. Under these experimental conditions, it was necessary to add a 20% excess of propiolic acid and reflux the mixture for one hour to complete the reaction. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using a 70:30 mixture of dichloromethane and hexane as the eluent. 22 g of the desired derivative are thus obtained in the form of a crystalline compound.

Yield: 22 g, ¹ H-NMR resonance spectrum:

(200 MHz, CDCl 3) 2.55 (S, 3H),

7.25-7.70 (m, 7H);

8.02-8.1 (m, 2H).

2- (2-Iodophenyl) -6-methyl-quinoline was prepared in the same manner from 2-iodobenzaldehyde.

Melting point: 77-77.5 ° C.

Stage 1.1.2.2

2- (6-Methylquinolin-2-yl) benzonitrile g (50 mmol) of the compound obtained in the previous reaction step 1.1.1 and 5 g (56 mmol) of copper (I) cyanide in 60 ml of pyridine are heated at 160 ° C for 12 hours under argon atmosphere. The progress of the reaction was monitored by thin layer chromatography, eluting with dichloromethane. The pyridine is then evaporated under reduced pressure and the residue is taken up in dichloromethane. The organic phase is washed several times with aqueous ammonia solution until the aqueous phase remains colorless. After the last water wash, the organic phase is dried over magnesium sulphate, then the solvent is evaporated. The residue was taken up in petroleum ether.

Yield: 9.6 g (78%), m.p. 157 ° C.

Stage 1. 1. 3

6-methyl-2- / 2- (1H-tetrazol-5-yl) phenyl / quinoline hydrochloride

9.6 g (39.3 mmol) of the nitrile obtained in the previous reaction step 1.1.2 and 14.96 g (72.7 mmol) of trimethyltin azide are introduced into 110 ml of xylene. The resulting reaction mixture was then heated to reflux for 15 hours. After cooling, the solid was filtered off and suspended in 115 ml of toluene and 7 ml of tetrahydrofuran. Hydrogen chloride gas was then introduced into the ice-cooled reaction mixture for 2 hours. The insoluble material is collected by filtration, then washed with toluene and then with water.

Yield: 13 g.

Stage 1 .1. 4

6-Methyl-2- (2- / 1 (or 2) - / 3-phenylmethyl) -1 (and 1 or 2) H-tetrazol-15-yl) phenyl / quinoline

To one liter of dichloromethane at room temperature were added 80.5 g (219 mmol) of the compound obtained in the previous reaction step 1.1.3, 60 ml (547 mmol) of N-methylmorpholine and 73.1 g (262 mmol) of three weeks. or idu. The solution is stirred overnight, then taken up in water, then the organic phase is washed twice with water and then dried. The solvent is evaporated and the residue is crystallized, preferably from the smallest amount of ether. Yield: 119 g (87%), m.p. 176-177 ° C.

6-Bromomethyl-2- / 2- / 1 (and 1 or 2) - (triphenylmethyl) -1 (and 1 or 2) H-tetrazol-5-yl) phenyl / quinoline

To 300 ml of carbon tetrachloride is added 10 g (189 mmol) of the compound obtained in the previous reaction step 1.1.4 and the mixture is heated to 60 ° C until all the solids have dissolved. At the same temperature, 3.7 g (20.8 mmol) of N-bromosuccinimide and 60 mg (0.37 mmol) of alpha, alpha'-azobisisobutyronitrile are added in one portion. The reaction mixture is then heated to boiling for 2 to 3 hours until the N-bromosuccinimide disappears. To the cooled mixture was added 100 ml of water and 300 ml of dichloromethane. The organic phase is washed several times with water, then dried. The solvent was evaporated and the residue was triturated in diisopropyl ether. 90% pure product is obtained, which product is used as is in the following stage. Yield: 10.3 g.

Stage 1.2

5-butyl-4,6-diazaspiro / 2.4 / hept-4-en-7-one hydrochloride

A mixture of 15.6 g (121 mmol) of ethyl pentanediate and 13.5 g (117.4 mmol) of methyl 1-amino-1-cyclopropylcarboxylate in 150 ml of xylene to which 20 drops were added of acetic acid, was heated at reflux for 8 hours. The solvent was evaporated, the residue was taken up in ether and acidified with 12N hydrochloric acid. A precipitate formed which was filtered off. Nukle-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl ₃ , delta values) 0.95 (t, 3H), 4.5 (m, 2H),

6-2.0 (broad m, 4H), 20 (m, 2H),

-3.0 (t, 2H).

Stage 1.3

5-Butyl-6- (diphenylmethyl) -1 (or 2) H-1-methyl-phenyl] -quinolin-6-yl (methyl) -4,6-di azaspiro [2.4] hept-4-en-7-one

To 0.35 g (1.73 mmol) of the hydrochloride obtained in reaction step 1.2 are added 1 g (7.24 mmol) of potassium carbonate and 1.42 g (1.87 mmol) of the compound obtained in the above reaction step 1.1, s purity of 80% and 6 ml of dimethylformamide. The mixture was stirred overnight at room temperature. The reaction mixture was taken up in water and extracted with dichloromethane. The organic phase was separated, the solvent was evaporated and dried over magnesium sulphate. The residue is purified by chromatography on a column of silica gel, eluting with a toluene / ethyl acetate mixture (80/20; v / v).

Stage 1 .4

5-butyl-6 - // 2- / 2- (1H-tetrazol-5-yl) phenyl / quinolin-6-yl / methyl /

-4,6-diazaspiro / 2.4 / hept-4-en-7-one

0.5 g of the compound obtained in the preceding step in solution in 20 ml of a 90:10 mixture of acetic acid and methanol is heated at reflux for 5 hours. Evaporation of the solvents afforded a gum which was purified by silica gel column chromatography using a 100: 5: 0.5 mixture of ethyl acetate, methanol and acetic acid as the eluent. The product obtained is crystallized from water.

Nukle-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3) 0.77 (t, 3H),

1.17-1.4 (m, 2H).

1.42-1.75 (m, 6H);

2.5 (t, 2H).

4.98 (s, 2H).

7.5-8 (m. 8H);

8.3 (d, 1 H),

16.2-16.6 (mass f, 1H).

Stage 1.5

5-Butyl-6- [2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl] -4,6-diazaspiro [2.4] hept-4-en-7- O-hydrochloride i

1

The compounds obtained in step 1.3 above are dissolved in a minimum volume of ether, 2 equivalents of 4N hydrochloric acid are added to the obtained solution, and the reaction mixture is stirred overnight at room temperature. The hydrochloride crystallizes from the reaction medium. This product was collected by filtration and washed with ether.

Melting point: 128 ° C (dec.).

Example 2

2-Butyl-3- [2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl] -1,3-diazaspiro [4.4] n-1-en-4- one

Stage 2.1

2-Butyl-3- [2- / 2- / 1 (and 1 or 2) - (triphenylmethyl) -1 (and 1 or 2) H-tetrazol-5-yl) phenyl (quinolin-4-yl) methyl 1 / -1,3-diazaspiro [4.4] n-1-en-4-one

Stage 2. 1. 1

2-Butyl-1,3-diazaspiro / 4.4 / non-1-en-4-one hydrochloride

2-Butyl-1,3-diazaspiro [4.4] non-1-en-4-one hydrochloride was prepared as described in step 1.2 from ethyl 1-1-amino-1-cyclopentyl carboxylate.

Stage 2.1.2

2-Butyl-3- [2- [2- (1-a-2-yl) - (3-phenylmethyl) -1 (a-1-2) H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl] -1,3-diazaspiro [4.4] n-1-en-4-one

To 0.35 g (1.52 mmol) of the hydrochloride obtained in the preceding step, in solution in 6 ml of dimethylformamide, was added 1 g (7.24 mmol) of potassium carbonate and 1.25 g (1.64 mmol) of the compound obtained in degree 1.1, with a purity of 80%. The mixture was stirred overnight at room temperature. The reaction mixture is then taken up in water and extracted with toluene. The organic phase is separated, the solvent is removed and dried over magnesium sulphate. The residue is purified by chromatography on a column of silica gel, eluting with a toluene / ethyl acetate (85/15 by volume) mixture. 0.8 g of the expected product is obtained.

Stage 2.2

2-8utyl-1-3- [2- (2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl) methyl / 1,3-diazaspiro / 4.4 / non-1-en-4- One ml of a 90:10 mixture of methanol and acetic acid containing 0.8 g of the compound obtained in the previous step 2.1 is heated to reflux. The solvents were removed under reduced pressure and the residue was crystallized in ether. 0.3 g of the expected product is obtained. ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3, delta) 0.8 (t, 3H),

1.17 to 1.37 (m, 2H);

1.38-1.62 (m, 2H);

1.62-2 (m, 8H);

2.4 (t, 2H);

4.95 (s, 2H).

7.55 (d, 2 H),

7.76 (m, 6H);

3.5 (d, 1 H),

16.2-16.6 (mass f, 1H).

Example 3

2-Butyl-3 - // 2- / 2- (1H-tetrazol-5-yl) phenyl / quinolin-6-yl / methyl / -1,3-diazaspiro / 4,5 / dec-1-en-4 one

Stage 3.1

3

2-Butyl-3- [2- / 2- / 1 (or 2) - (triphenylmethyl) -1 (or 2-H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl] -1,3-diazaspiro [4,5] dec-1-en-4-one

Stage 3.1.1

2-butyl-1,3-diazaspiro / 4,5 / dec-1-en-4-one

A mixture of 11.3 g (8.8 mmol) of ethylpentaimidate and 11.56 g (6.7 mmol) of ethyl 1-amino-1-cyclohexanecarboxylate in 100 ml of xylene containing 0.6 ml of acetic acid The mixture was heated at reflux for 8 hours. The reaction mixture was then allowed to cool, the solid was removed and the solvent was evaporated under reduced pressure. The product is recrystallized from ether.

Melting point 124-125 ° C.

Stage 3.1.2

2-Butyl-3- [2- / 2- / 1 (or 2) - (3-phenylmethyl) -1 (and 1 or 2) H-tetrazol-5-yl) phenyl] quinolin-6-yl / methyl / -1,3-diazaspiro / 4,5 / dEC1-en-4-one

To 25 ml of N, N-dimethylformamide is added 1.64 g (7.88 mmol) of the compound obtained in the previous step, 3 g, (21.7 mmol) of potassium carbonate and 5 g (7.47 mmol) of the compound obtained in degree 1.1, with a purity of 90%. The reaction mixture was stirred overnight at room temperature, then poured into 100. ml of water. The mixture is filtered and the residue is purified by chromatography on a column of silica gel, eluting with a toluene / ethyl acetate mixture (80/20; v / v). 2.3 g of product are obtained in the form of a gum.

Stage 3.2

2-Butyl-3 - // 2- / 2- (1H-tetrazol-5-yl) phenyl / quinolin-6-yl / methyl / -1,3-diazaspiro / 4,5 / dec-4-ene one

4

0.59 g (0.8 mmol) of the compound obtained in the preceding step in 20 ml of a 90:10 mixture of methanol and acetic acid was heated to reflux for 5 hours. The solvents were evaporated in vacuo and the residue was recrystallized from ether. 0.2 g of the expected product is obtained.

Melting point: 122-123 ° C,

Nukle-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3, delta) 0.8 (t, 3H),

1.17-1.37 (m, 2H),

1.37-1.88 (mass, 12H), 2.4 (t, 2H),

4.9 (s, 2H);

7.5 (d, 2H).

7.6 to 8 (m, 6H);

8.35 (d, IH).

The chemical structures and physical properties of several compounds of the invention are shown in the following table.

table

The

RMN XH Cn w »S σ \ r> O ^W * · *% * MI 7 -.-. 'H Λ X x cn H ™ g J · e' e ~ _ '-'--' in co oo _ - i SS 'V - CN P' - f - * C? i-4? <N = -e T ° C-T 3 H *> % 1 - CN X CN - CN hx cn ľ K - φ ŕ - B 'TX''''N' - m Ό C, 4J Tl X ~. ^M • ^ | χ in m cn ® ° 0 N ¹ - - - P 'y4 CO S'x'cN * ™ CO * »*, * Í · ** - CN CN T? On · - - - σ OH '- f Ό M3 rC Á ' T x H ™ t? CD x - S σ 'H x β ”3 ' y, r s® s Τ'-x Woo, in co - " "in n ™ e h 1 C? - CN S —CO T X 1 M3 Ό in H cG m o T U about 4J • rh 0 cn 1 1 1 n C n X about 1 cn about • M G 1 1 CM _r IM O 1 M Pi cn m about 1 cn G (M G 1 Ά cn G n M •in G 1 n G n E4 G 1 cn G cn M kh> ABOUT 1 > U H <N n

Table (continued)

RMN __ = -X x Τ3 CM - - Γ ** 1 * * n <n 'h -' tn ^- ^ ^{1 H} x 'S X pl O £ £ Ť x -cm eo ⁰¹ rj: · u? ** “* T * ^ 4 ^{ω H} S '''' - r o CO n ', CM * xx ^ CM Ό Sii a * 0 0 C, ' ¹ T * x -x' (MH r4 K i — 1 T, * 04 TJ U U_i * * - * • hd tn cn '-'cn ie tn »é ® ~ CO ^{03 x} ™ ° ffl -or ' ^u n σι H t? about about 4-1 * E-i 128 (dec) 122-123 x-! 0 cn rh about x cm 1 1 m (X 1 «Μ ~ M * T ABOUT 1 1 in w x at 1 l W) M X about 1 r * (X and n X at n r « X at 1 n X about I * L - * x C 1 n ref Λ IM X about 1 > CJ T tn Ό

ε

P ú

4J λ:

(For cu <n 'Φ

C> o c

(0 c

about

N

Φ

L o

λ:

υ • H

OJ

0)

C t7>

(0 ε

<0 Φ C 2 G Φ '03 D Φ - 03 γ-Η D R ~ H Λί • H λ: Ρ S-l Ν C 0 ο R-T g 'Φ X > about • Η 0 0 L C L Οι 0 D ς +4 > 1 0 X '03 G • H G ch D Φ ε 'Φ • '03 03 C φ C G Φ D Φ Ν ε • Η ε 03 X IX) = G Ο C Ο Ν 44 N 'φ ι-1 D : Ρ from Σ X 03 i-1 2 r4 U Ν X > 1 x 03 Σ 4> Μ Φ CM "> 1 Ν ε ; > 03 Ή Μ D N with "> 1 03 - > > L Ο "> 1 Ο • Η Ν Φ > - υ X Λί <Χ with rh = • \ -ι and rh 4J 4> ο Λ 0 • 03 ο T) 03 Ε-ι CM 4> from ζ ε ο • Η Λί G G Ή -Η D ch (0 υ Ο φ D 04 Λ I-1 'Φ C Ή V-1 0} C Φ 4> 4> 0 03 tP ω 03 ch G Φ Φ J > > ► ε

7

The compounds of the invention have been subjected to pharmacological tests which demonstrate their angiotensin II antagonistic properties.

Test demonstrating the effect of [ ³ H] -angiotensin II binding on rabbit adrenal cortex

Fauves de Bourgogne male rabbits weighing 2-3 kg are used in this test. After the animals are sacrificed by cervical dislocation, the adrenals are removed. On ice cooling, the adrenal cortex is dissected and then introduced into 10 ml of ice-cold 10 mM three sec (hydroxymethyl) am inomethane buffer containing 0.33 M sucrose and 1 mM ethylenediaminetetraacetic acid. The pH of the buffer was adjusted to 7.4 with hydrochloric acid. The tissue is homogenized by a Potter electric apparatus 13 by moving the piston back and forth at a speed of 1200 rpm. The volume of the preparation is adjusted to 25 ml with Tris-sucrose buffer, then the mixture is centrifuged for 15 minutes at 1075 x g. The supernatant is stored. After re-suspension in 10 ml of Trissaccharose buffer, the sedimentation pellet is re-homogenized by passing through a Potter apparatus, then centrifuged under the conditions described above. The supernatant obtained is combined with the first supernatant obtained previously and the combined supernatant is centrifuged for 30 minutes at 47,800 x g. The obtained pellet is finally withdrawn with 150 ml (ie 100 mg of tissue in 15 ml of buffer) with 50 mM Tris-HCl 1 buffer containing 150 mM sodium chloride, 5 mM lithium ethylenediamine acetic acid, 25 pg / ml bacitracin, 100 μΜ of phenylmethylsulphonyl fluoride and 0.2% bovine serum albumin (pH = 7.4 at 25 ° C).

This suspension contains adrenal cortex microsomes and will be used in the following test. A 100 μl aliquot of said suspension is incubated in the presence of [ ³ H] -angiotensin II (New England Nuclear, specific activity 61 Ci / mol) in a final volume of 1 ml of Tris-HCl buffer as described above. After incubation for 30 minutes at 25 ° C, the microsomes are isolated by filtration through nitrates with a 1 µl M 1lipore HAWP 0.45 µm filter, which was pre-prepared by immersion in a 1% bovine serum albumin solution. The filter was washed three times with 5 ml of ice-cold Tris-HCl buffer. The amount of tissue bound radioactivity retained on the filter is measured by scintillation spectrometry.

Non-specific binding of [ ³ H] -angiotensin II is measured by incubation in the presence of 1 μΜ of non-active angiotensin II. This non-specific binding represents 5 to 10% of the total amount of radioactivity bound to the filter. Specific binding corresponds to the difference between total radioactivity trapped on the filter and non-specific radioactivity. The [ ³ H] -angiotensin binding is measured in the presence of various concentrations of test compounds, then the IC 50 value, which is the concentration of the test compound that inhibits 50% of the specific binding of [ ³ H] angiotensin II, is graphically determined. The C 50 values of the compounds of the invention are less than 50 nm.

Inhibition of the effect of angiotensin II on arterial pressure in rats

Male rats (SpragueDawley, Charles River, France) weighing 250 to 280 g, anesthetized with sodium natriumpet (55 mg / kg, intraperitoneally) and kept under artificial respiration (Harvard respirator, respiratory rate 70) are used in this test. m 1 / min, air volume 1 ml / 100 g body weight). The test animals are spinalized with a metal stem inserted through the right orbit further along the spine. The right and left wander nerves (bivagotomy) are separated, the right carotid is ligated, while the left carotid is truncated to measure arterial pressure using a pressure cell (Statham P23Db type). The femoral vein is catheterized to administer the individual compounds.

Angiotensin-induced changes in mean arterial pressure administered before administration of the compounds of the invention at 0.5 ph / kg as well as angiotensin-induced changes in arterial pressure induced by the angiotensin administered under the same conditions 5 minutes after intravenous administration of the compounds of the invention or 30 minutes after their oral administration. The compounds of the invention are administered in doses from 0.01 to 100 mg / kg. The percentage inhibition of the control response of angiotensin II is taken as a basis for determining the ability of the compounds of the invention to antagonize the effects of alpha-gensin II.

The compounds of the invention or suitable salts thereof can be used to treat various forms of hypertensive pathologies and cardiac insufficiency, renal. deficiencies and lung deficiencies, as well as for the treatment of glaucoma.

The compounds of the invention or their respective salts may also be used in combination with other cardiovascular activity agents such as diuretics and 1-phiocators, beta-blockers, calcium antagonists or inhibitors of the enzyme responsible for angiotensin conversion. I.

The compounds of the invention or their respective salts can be formulated in any pharmaceutical form suitable for oral, parenteral, intramuscular or rectal administration. These are in particular tablets, capsules, gelatin capsules, sterile solutions or suspensions, and lace.

For the treatment of glaucoma, the compounds of the invention may take the form of tablets, gelatin capsules, other solutions or topical ophthalmic formulations.

The compounds of the invention may be administered to patients in an amount of from 1 to 1000 mg / day / patient in single or multiple doses.

Claims (10)

PATENT Claims pv -? 3 3- (Choline-6-ylmethyl) -4H-imidazol-4-one derivatives of the general formula I (I) in which: R 1 represents a straight or branched alkyl group s 2 to 5 carbon atoms, R 5 and R 5 are, independently of one another, either a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms or (CH 3 Jn-aryl in which n is 0 to 3), or R 7 and R 8 may form a spirocycloalkyl wherein the alkyl moiety contains 3 to 8 carbon atoms, and addition salts thereof with pharmaceutically acceptable acids and bases. 5. A compound according to claim 1, in which it represents a straight or branched alkyl group containing 2 to 5 carbon atoms, R and R independently of one another represent straight-chain or branched alkyl having 1 to 5 carbon atoms or R a and R ₃ can form the imidazole ring sleep rocyk 1oa1kýlovú radicals in which the alkyl portion contains 3-8 carbon atoms. 3. A compound according to claim 2 wherein: R 1 represents a butyl group and R a and R ₃ independently represent a straight or branched (C 1 -C 5) alkyl group or R a and R a may form a spirocycloalkyl group with an imidazole ring in which the alkyl moiety contains 3 to 8 carbon atoms. 4. 5-Butyl-6- [2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl] -4,6-diazaspiro [2.4] hept-4-ene- 7-one. 5. 2-Butyl-3- [2- (2- (1H-tetrazol-5-yl) phenyl] -quinolin-6-yl] -methyl] -1,3-diazaspiro (4.4) non-1-en-4-one. 6. 2-Butyl-3- [2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} -1,3-diazaspiro [4,5] dec-1- en-4-one. A process for the preparation of derivatives according to claim 1, characterized in that the compound of formula VII (VII) in which L is a leaving group and R 11 is a group of the formula CR 5 R e R v, in which R 5, R 6 and R 6 is R 6. each independently of one another represents an alkyl group having 1 or 2 carbon atoms or an aryl group, reacted with an imidazolone of formula VIII R, (VIII) branched alkyl, independently of one another are branched alkyl N-aryl group, wherein the forming of the imidazole Kruve which the alkyl radical to form a compound všeobecnév wherein R is a straight or a 2 to 5 carbon atoms, R ₂ and R a hydrogen or (CH 3) n represents 0 to 3, or R 5 and R 5 can each be a homo spirocycloalkyl group containing from 3 to 8 carbon atoms, in which case IX (IX) is deprotected. Medicament, characterized in that it comprises a compound according to any one of claims 1 to 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 in combination with any suitable excipient. 10. A compound of formula (IX) wherein: R. represents a straight or branched alkyl group having 2 to 5 carbon atoms 5 atoms and carbon, Ra and Ra independently of one another represent either a hydrogen atom or a straight or branched alkyl group having 1 to 5 atoms or (CHa) n -aryl in which n is 0 to 3 or Ra and Ra can form with the imidazole ring sp a cycloalkyl group in which the alkyl radical contains 3 to 8 carbon atoms, R a represents a group of the formula CR 5 R e R 6, wherein R 8 R 5 and R 7 each independently of one another represent an alkyl group having 1 or 2 carbon atoms or an aryl group, useful as intermediate products for the synthesis of derivatives according to claim