CA2111302A1

CA2111302A1 - 3-(6-quinolylmethyl)-4h-imidazol-4-one derivatives, their preparation and their application in therapy

Info

Publication number: CA2111302A1
Application number: CA002111302A
Authority: CA
Inventors: Gerard Cremer; Jean-Claude Muller
Original assignee: Individual
Current assignee: Synthelabo SA
Priority date: 1992-12-14
Filing date: 1993-12-13
Publication date: 1994-06-15
Also published as: JP2548511B2; PL301461A1; ZA939333B; SK141193A3; HU9303560D0; NO934566L; MX9307834A; FR2699174B1; IL108011A0; NZ250441A; HUT69701A; CN1095378A; AU5233893A; EP0604259A1; FR2699174A1; NO934566D0; FI935575A0; CZ273293A3; FI935575A; KR940014386A

Abstract

3-(6-QUINOLYLMETHYL)-4H-IMIDAZOL-4-ONE DERIVATIVES, THEIR
PREPARATION AND THEIR APPLICATION IN THERAPY

SYNTHELABO

An invention of: Gérard CREMER, Jean-Claude MULLER

Abstract 3-(6-Quinolylmethyl)-4H-imidazol-4-one deriva-tives corresponding to the formula (I):
(I) in which R1 represents an unbranched or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of one another, either a hydrogen atom, or an unbranched or branched (C1-C5)alkyl qroup, or a (CH2)n-aryl group where n = 0 to 3, or R2 and R3 with the imidazole ring can form a spiro-cyclo(C3-C8)alkyl group, as well as their addition salts with pharmaceutically acceptable acids and bases.
Therapeutic application.

Description

-` 2~ ~ ~3~

The present invention relates to 3-(6-quinolyl-methyl)-41f-imidazol-4-one deri~atives, to th~ir prepara-tion and to their application in therapy.
The compounds of the invention ccr~2spond to the formula (I) N~Z~ 11 ( I ) in which Rl repre~ents an unbranched or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of one another, either a hydrogen atom, or an unbranched or branched (Cl-C5)al~yl group, or a (CM2)n-aryl ~roup where n = O to 3, or R2 and R3 with the imidazole ring can form a spiro-cyclo(c3-ca)alkyl group.
The preferred compounds o~ the invention are compounds having formula (I) wherein, R~ represents an unbranched or branched l~-C5)alkyl group, and R3 represent, each independently of on~ another, an unbranched or branchad (C~-C5~alkyl group, or ~ and R3 with the i~idazole ring can form a 6pirocyclo (C~-C~)alkyl group.

Among the~ the compounds of choice are those having formula (I) ~herein, Rl represents a butyl group, , ... ,. ,," . ... ~ - , .r ~; ~

~ --`` 21113~.~

R2 and R3 represent, each independently of one another, an unbranched or branched (Cl-C5) alkyl group, or R2 and R3 with the imidazol,e ring can form a spirocyclo (C3-C8)alkyl group.
The compound~ of the invention ma~ ~e presented in frea form or in the form of pharmaceut.cally accep-table organic or inorganic salts.
According to the invention, th~ co~.~cunds of formula (I) may be synthesized according to Sc~eme 1.

4-~ethylbenzenamine (para-toluidine) is r acted at the re~luxing temperature with a benzaldehyde of for-mula ~II), in which X represents a bromine or iodine atom, in the pre~ence of a catalyst such as 4-methylben-zenesulfonic acid (para-toluenesulfonic acid), in solu-tion in benzene. After cooling, propiolic acid is aàded and the mixture is heated to the refluxing temperature so as to obtain the compound of formula (III). Next, a mixture of the compound of formula (III) and cuprous cyanide is heated in a solvent cuch as pyridine so as to obta~n 2-(6-methyl-2-quinolyl)benzonitrile (IV), which is reacted with an organometallic a~ide such as trimethyltin azide, or a metal azide such a~ sodium azide, so as to obtain a compound over which a stream of gaseous hydro-chloric acid i~ passed in order to obtain the quinoline of formula (V). The first reaction is performed in a solvent ~uch as xylene at the refluxing temperature; ~he second reaction is perfor~ed in a solvent such as a toluene/tetrahyd,oluran mixture at room temperature.
The tetrazole group of the quinoline of formula (V) i8 then protected with a protective group R4, where R~

. ,.... . . ~ .. ~ . . ~ . . .:: .

2 1 1 :~ 3 3 ~
.

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.

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~ ~ .. ..
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p_ " :
~ L

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: :` 2~ .2 represents a group of formula CR,R6R7 in which Rs~ R6 and R7 aro, each independsntly of one another, a (Cl-Cz)alkyl group or an aryl ~roup; in this step, the compound (V) is reacted with a protective agent such a~, for example, trityl chloride at room temperature in a solvent such as dichloromethane, in the presence of a base such as N-methylmorpholina or triethylamine, and a compound of formula (VI) in which R5, R6 and R7 are as defined above is obtained. Next, the methyl group at position 6 of the quinoline of formula (VI~ is functionalized by introduc-ing a leaving group L, for example a bromo radical, into it, and a compound of formula (VII) where R5, R6 and R~
are as defined a~ove is obtained; the reaction is per-form~d at the refluxing temperature in a solvent such as carbon tetrachloride, in 'he presence of an initiator ~uch as benzo~il peroxide or ~ azobisisobuty.onitrile, at the refluxing temperature. Finally, the compound of formula (VII) is condensed, in dLmethylforma~ide at a temperature of 0C to 50C, in the presence of a base such ~s potassium hydroxide or potassium carbonate, with an imidazolone of formula (VIII) in which ~, R2 and R3 -~
are as defined above~ and a compound of formula ~IX) is obtained, which compound is sub~ected to deprotection.
The compounds of formula ~IX) N ~ / ~ R4 (IX) /J~3 ' '"",,. ~", ~,~ ", " " ,~ ", .: i:' ' ' " '''; ' ' ' '' ~ ` ' ~` '~ '' ''` ' ~ ' ~ `` 2 ~

in which R~, R2, R3 and R~ are as defined abo-.-e, are new and form part of the invention.
The 3tar~ing compounds are commerciall~ available or described in the literature, or may be prepared accor~ing to methods which are described therein or which are known to those skilled in the art.
Thus, the imidazolones of formula (VIII) may be synthe~ized according to the method described by Jacquier et al ~Bull. Soc. Chim. France, 1971, 3, 1040-1051~, by condensation o~ an alXyl imi~ate and an amino ac~ d ester such as, ~or example, methyl l-amino-l-cyclopropylcar-boxylate.
Methyl l-amino-l-cyclopropylcarboxylate is prepared according to the method described by Valdyanathan (J. Orq. Chem., 1989, 54, 1810-1815).
- The compounds of formula (VII) are prepared according to the method described in the European Patent Application published under ~oO 0540500 by the Applicant The ~xamples which follow illustrate the : invention.
The microanalyses and the IR and NMR spectra confirm the structure of the compounds obtained.
!
Example 1 : 5-butyl-6-~t2-t2~ tetraæol-5-yl~phenyl~-6-quinolyl3me- ::
thyl~-4,6-diazaspiro~2.4]hept-4-en-7-one .

1.1. 6-bromomethyl-2-[2-t2-((triphenylmethyl)2~-tetrazol-5-yl]phenyl~quinoline 1.1.1. 2-(2-bromophenyl)-6-methylquinoline . .
50 ~ (270 mmol~ of 2-bromcbenzaldehyd~ are heate~

2 ~ 3 ~ ~

to the refluxing temperature, in a round-bottomed flask surmounted by a Dean and Stark apparatus, wi.h 29.5 g (276 mmol) of para-toluidine and 0.5 g of pa-a-toluene-sulfonic acid dissolved in one liter of benzene. When the removal of water is complete (approximately 5 ml), 8.3 ml (135 mmol) of propiolic acid are added to the reaction medium which has been cooled beforehand to about 50~C. A
substantial evolution of C02 iS noted, and the mixture is brought to reflux for 3 hours. The reaction is monitored by thin-layer chromatography in a mixture of dichloro-methane and hexane (70:30). Under these experLmental conditions, it has been necessary to add a 20 % excess of propio}ic acid followed by 1 hour of reflux in order to complete the reaction. The solvent is evaporated off under reduced pressure ànd the residue is purified by chromatography on a silica col~n, elutin~ with a mixture :
of dichloromethane and hexane ~70:30).
~ 22 g of ths expected derivati~e are recovered in ;~ the form of a crys~allized compound.
` M = 22 g ;~ ~H NMR (200 MHz, CDC13): ~ 2.55 (s, 3~), 7.25-7.70 (~, 7H), 8.02-8.15 (m, 2 In the same manner, 2-(2-iodophenyl)-6-methyl-. : quinoline is prepared from 2-iodobenzaldehyde.
M.p. = 77-77.5C

1.1.2. 2-(6-methyi-2-quinolyl)benzonitrile A mixture containing 15 g (50 m~.ol~ of the 2~ fl ?

.
compound obtained above in 1.1.1 and 5 g (56 mmol) of cuprous cyanide is heated to 160C for 12 hours, under argon, in 60 ml of pyr.idine. The reaction is monitored by thin-layer chromatography in dichloromethane. The pyridine is evaporated off under reduced pressure and the residue is taken up with dichloromethane. The organic phase is washed several tLmes with aqueous ammonia solution un~il the aqueous phase is colorless. After a final wash wi~h water, the oryanic phase is dried over magnesium sulfate and the solvent is evaporated off. The residue is taken up with petroleum e~her.
M = 9.6 g ~.p. 5 157 C Yld - 78 %

1.1.3. 6-methyl-2-~2-(lH-tetrazol-5-yl)phenyl]quinoline hydrochloride :~
9.6 g (3~.3 mmol) of nitrile obtained above in ~`
1.1.2 and 14.96 g (72.7 mmol) of trLmethyltin azide are introduced into 110 ml of xylene. This mixture is brought to reflux for 15 hour~. After cooling, the solid is filtered off and sus~ended in 115 ml of toluene and 7 ml of tetrahydrofuran. The mixture is cooled in an ice bath and subjected to a stream of hydrogen chloride gas bubbled through for 2 hours. The insoluble fraction is recovered by filtration and then washed with toluene and with water.
M = 13 g 2 ~ 3 ~ ~f 1'' i ' .
1.1.4. 6-m~thyl-2-[2-[l(or 2)-~triphenylmethyl)-l(or 2)~-tetrazol-5-yl]phenyl~quinoline 80.5 g (219 mmol) of the compound obta n~d above in 1.1. 3, 60 ml ~54~ mmol) of N-methyLmorpholin2 and 73.1 g ~262 m~ol) of trityl chloride are added at room~-temperature to one liter of dichloromethane. The solution is stirred overnight and taken up with water, and the organic phase i washed twice with water and then dried.
The solvent is evaporated off and the residue is crystal-lized in a minimum amount of ether.
M = 119 g ~.p. = 176-177C Yld = 87 % ~ - :

1.1.5. 6-bromomethyl-2-[2-~l(or 2~-(triphenylmethyl) ol (or 2)~-tetrazol-5-yl]phenyl]quinoline 10 g (189 mmol) of the compound obtained above in 1.1.4 are added to 300 ml of carbon tetrachloride, and the mixture ls brought to about 60C until dissolution is complete. At this temperature, 3.7 g (20.8 mmol) of N-bromosuccinLmide and 60 mg ~0.37 mmol) of ~ azobisiso-butyro~itrile are added in a single portion. The mixture is brousht to the refluxing temperature for 2 to 3 hours until the N-bromosuccinimide has disappeared. 100 ml of water and 300 ~il of dichloromethane are added to the cooled mixture. The organic phase is washed several ti~es ~ith water and then dried. The solvent i~ evaporated off and the residue is ground in diisopropyl ether. A 90 %
pure product is obtained, which product will be used as ~ :
it is.

- -~ 2 ~

M = 10.3 g 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 pen-tanimidate and 13.5 g (117.4 mmol) of methyl l-amino-l-cyclopropylcarboxylate is heated to the refluxing temper-ature for 8 hours in lS0 ml of xylene to which 20 drops of acetic acid are added. The solv~nt is evaporated off, the residue is taken ~p with ether and the mixture is acidified with 12 N hydrochloric acid. A precipitate is ~`
obtained and is filtered off.
H NMR, 200 M~z(CDCl3) d [sic] 0.95 tt, 3H), 1.4S (m, 2H) 1.6-2.0 (unresolved complex, 4H~, 2.20 (m, 2H), 3.0 (t, 2H). `

1.3. 5 butyl-6-tt2-~2-tl(or 2~-(triphenylmethyl)-l(or 2)~- :
tetrazol-5-yl~phenyl];6-quinolyl]methyl~-4,6-diaza spiro[2.4]
hept-4-~n-7-on~

1 g (7.24 ~mol) of potassium carbonate and 1.42 g (1.87 mmol) of the 80 % pure compound obtained above in step 1.1 and 6 ml of dimethylformamide are added to 0.35 g (1.73 mmol~ of the hydrochlori~e obtained in ~ :
step 1.2. The mixture is left stirring at room temper-ature overnight. The reaction medium is taken up with water and extracted with dichloromethane. The organic phase is recovered, the sclven~ is evaporated off and the residue is dried over magnesium sulfate. The residue is -purified ~y chromatography on a column of silica sel, "
eluting with a toluene/ethyl acetate (80;20) mixture.

1.4. S-butyl-6-~[2-t2-(lH-tetra201-S-yl)phenyl]-6-quinol-yl]methyl]-4,6-diazaspiro[2.4~hept-4-en-7-one .500 mg of the compound obtained in step 1.3, dissolved in 20 ml of an acetic acid/methanol ~gO:10) mixture, are heated for 5 hours to the refluxing tempera-ture. ~he solvents are evaporated off and a gum is obtained, which gwm is purlfied by chromatography on a column of ~ilica gel, eluting with an ethyl acetate~meth-anol/acetic acid (100:5:0.5) mi~ture. The product is crystallized in water.
NMR d tsic] 0.77 (t, 3H), 1.17-1.4 (m, 2~), 1.~2-1.75 (m, 6~), 2.5 (t, 2H), 4.~8 (s, 2~), 7.5-8 (m, 8~), 8.3 (d, 1~), 16.2-16.6 (~nresolved complex, 1~

1.5. 5-butyl-6-tt2-~2~ tetrazol-5~yl)phenyl}6-quinolyl]
methyl`]-4,6-diazaspiro[2.4]hept-4-an-7-one, dihydrochloride Compound obtained in ~tep 1.3 is dissolved in a ~ini~al volumo of ether and 2 eguivalents of an aqueou~ ~ N ~olution of hydrochloric a~d are added. The reaction m~xture i8 lef~
6tirring at room temperature overnight. The chlorhydride cri~tallized in th~ reaction mixture, is filtered and washed with ether.
Melting point = 12~ ~C (daco~po6ition) 2~ J
' 11 E~cample 2 2-butyl-3-[[2~[2-(l~f-teLrasol-5-yl)phenyl]-6-quinolylJme-thyl]-1,3-diazaspiro[4.4]non-1-en-4-one 2.10 2-butyl-3-~[2-t2-~l(or 2)-(triphenylmethyl)-l(or 2)~-tetrazol-5-yl]phenyl]-6-~uinolyl]methyl]-1,3-diaza~pi ro~4.4~non-1-en-4-one 2.1.1. 2-butyl-1,3-diazaspirot4.4]no~-1-en-4-~one chlorhydride Title compound is prepared as described in step 1.2 from ethyl l-amino-l-cyclopentylcarboxylate.

2.1.2. 2-butyl-3-[[2-~2-Cl(or 2)-(triphenylmethyl)-l(or 2)~
tetrazol-5-yl]phenyl]-6-quinolyl~ethyl]-1,3-d~azaspirot4.4 non-l-en 4-one 1 g (7.24 mmol) of potassiu~ carbonate and 1.25 9 (1.64 ~ol) of the 80 ~ pure [~ic] compound Gbtained in step 1.1 are added to 0.35 g (1.52 mmol)of compound obtained in ~tep 2.1.2 dissolved in 6 ml of -dimethylformamide. The reaction mixture is left stirring at room temperature overnight. It is taXen.up with water and extracted with toluene. The organic phase is recovered, the solvent is evaporated off and ~he ~ :
organic phase [sic] is dried over magnesium sulfate. The residue is purified by chromatography on a column of silica gel, eluting with a toluenefethyl acetate (85:15) mix~ure. :~
0.8 g of the expected product is oDtained.

~"` 2~3~

2.2. 2-bu;yl-3-~[2-[2~ -t~tra~ol-5-yl)p~.enyl]-6-quinolyl]methyl]-1,3-diazaspiro[4.~]non-1-en-4-one 20 ml of a m2thanol/acetic acid (~0:10) ~ x~ure containing 0.8 g of tha co~pcund obtained above in s~ep 1.3 are heated to the refluxing temperature for 6 hours.
The solven~s are removed under reduced pressure and the residue is crystallized in ether.
0.3 g of product is obtained.
NMR d Isic] 0.8 (t, 3H), 1.17-1.37 (m, 2H), 1.38-1.62 (m, 2H~, 1.62-2 (m, ~H), 2.4 (t, 2H), 4.95 (s, 2H), 7.55 ~d, 2H), 7.6-8 (m, 6H), 3.5(d, lH), 16.2-16.6(unresolved co~plex, lH).

amPle ~
2-butyl-3-~2-t2-(1~-tetrazol-5-yl)phenyl~-6-quinolyl]
methyl]-1,3-diaPaspirot4,5]dec-1-en-4-on~

3.~. 2-butyl-3-lt2-[2-[l(ou ~)-(triphenyl~athyl)-l(ou 2)H-t~-trazol-5-yl)phenyl~6-quinolyl]methyl]-1,3-diazaspirot4,5~ :~
dec-1-en-4-one ~ -3.1.1. 2-~utyl-1,3-diaz~spirot4,5]d~c-1-sn-4-one A ~ixture of 11,3 g (8,8 mmol) of ethyl pe~tanimidate and of 11,56 g (6,7 mmol) of ethyl 1-amino-1-cyclopentyl~arboxylat~
in 100 ml o~ xylen containing 0,6 ~l o~ ac~tic acid i8 heat~d to refluxing temperature. Then reaction mixture i~ allowed to ool, residue is eliminated by filtrat~on and ~olvent ~:
evaporated under reduced pressure.Titl~ compound cri6t~11ized in ether.
Melting point = 124-125 C.

3.1.2. 2-butyl-3-[[2-t2-[1(or 2)-~triphenylmethyl)-l~or 2)~
tetrazol-5-yl)phenyl]-6-quinolyl~methyl~-1,3-diazaspiro [4,5]dec-1-en-4-one 1,64 g (7,88 mmol) of compound obtained in step 3.1.1, 3 g (21,7 mol) of potassium carbonate and 5 g (7,47 mmol) of the -2~3~

90 % pure compound obtained in ~tep 1.1 are added to 25 ml of dimethylformamide. The reaction mixture is le~t stirring at room temperature overnight and is poured into 100 ml o~
water. A~ter filtration, t~e residue is purified by chromato-graphy on a column of silica gel eluting with a toluen/ethyl acetate (80:20) mixture.
2,3 g of the expected product is obtained in th~ form of a 302. 2-butyl-3-~2-~2-(1~-tetrazol-5-yl)pheny~]-6-quinolyl]
methyl]-1,3-diazaspiro~4,5]dec-1-en-4-one 20 ml of methanol/acetic acid (90:10) mixture conta~ning 0,59 g (0,8 mmol) of the compound obtained above in step 3.1 are heating to the refluxing temperature for 5 hour3. The solvents are removed under vacuum and the residue i8 cris-tallized in ether.
0,2 g of product are obtained.
Melting point = 122-123 C

N~R : d 0,8(t,3H), 1,17-1,37(~2H), 1,37-1,88 (unresolved complex, 12H), 2,4(t,2H), 4,9(~,2H), 7,5~d,2H), 7,6-B(m,6~), 8,35(d,lH) The ta~le which follo~s illustrates the struct~res and physical properties of a faw compounds according to the invention.
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The compound~ of the invention were subjected to pharmacological studies which demonstrated their angiotensin II-antagonist properties.

Test of bindinq of r3Hlangiotensin II to ra~bit adrenal cortex.
Male Fauve de Bourgogne rabbits weighing 2 to 3 kg are used. After sacrifice by cervical dislocation, the adrenal ~lands are excised and the cortex is dissec~ed on a culture dish cooled in ice. It i~ placed in 10 ml of an ic~-cold 10 mN tris(hydroxymethyl)amino-methane buffer solution containing 0.33 ~ sucrose and 1 mM ethylsnediami~etetraacetic acid and whose pH has ~een adjusted to 7.4 with hydrochloric acid. The tissue is homogenized using an electrical Potte_ apparatus with 13 to-and-fro movements of the plunger at a speed of 1200 rpm. The volume o. the preparation is adjusted to 25 ml with Tris-sucrose ~uffer before centrifuging for 15 min at 1075 x g. Th~ su2ernatant is ret~ined. The pellet is homogenized again, after resuspension in 10 ml ~ .
of Tris-sucrose buffer, ~y transfer to the electrical Potter, and then centrifuged under the conditions described above. The supernatant obtained is added to the : . first, and they are centrifuqed for 30 min at 47,800 x ~.
: The pellets are finally taken up with 150 volum9s (equivalent to 100 mg of tissue in 15 ml of buffer) of a 50 m~ Tris-HCl buffer solution containing 150 mM NACl, 5 mM ethylenediaminetetraacetic acid, 1.25 ~y/ml of 3 ~

bacitracin, 100 ~M phenylmethylsulfonyl fluoride and 0.2 ~ of ~ovine serum albumin (pH = 7.4 at 25C).
This suspension contains the microsomes of the adrenal cortex, and will be used as it is in the studies described below.
lO0 ~l aliquot fractions of suspension are incubated in the presence of l3H]angio~ensin II (New England Nuclear, specific actiYity 61 Ci/mmol~ in a final volume of 1 ml of Tris-HCl buffer whose composition has been descri~ed above. A~ter incubation for 30 minutes at 25C, the microsomes are recovered by filtration on 0.45 ~m Millipore HANP~ cellulose nitrate filters condi-tioned be~orehand by immersion in a 1 % solution of bovine serum albumin. The fil~ers are washed three t~mes with 5 ml of ice-cold ~ris-~Cl buffer. The q~antity of radioactivity bound to the tissues and retained on the filters is measured by scintillation spect~ometry.
: Non-speci~ic binding of ~3H]angiotensin II is measured ~y incubation in ~he presence of 1 ~m non-radioacti~e angiotensin II. This non-specific bindins represent~ 5 to lO ~ of the total .quantity of radio-activity bound to the filter. The non-specific binding is the difference between the total radioactivity collected on the filter and the non-specific binding. The binding of t3HI2ngiotensin is measured in the presence of dif-ferent concentrations of ~est compounds, and the IC50, the concentration of the test compound which inhibits 50 % of the specific binding of ~3H~angiotensin II, is determined "~

graphically.
The IC50 concen~rations of the compounds of the invention are les~ than 50 nM.

Inhibition of the resPOnse to anqi~tensin II on rat arterial blood pressure Male rats (Sprague-Dawley, Charles Ri~er France) weighing 250 to 280 g are used, the rats ~eing anes-thetized with pentobarbital sodium (55 mg/kg i.p.) and maintained under artificial respiration (Harvard~ Respir-ator: respiration rate.70 ml per minute, air volume 12 ml per 100 g o~ body weigh~ he animals are ~pithed- using a metal rod introduced via the orbit of the right eye and inserted over the length of the Yertebral column. The left and right vagus ne~v~s are sectior,ed (~ilateral vagotomy); the right carotid artery is ligated, the left carotid artery ~eing catheterized in order to measure the arterial blood pressure using a pressure cell (Stath~m~
type P23Db). A femoral vein is catheterized for the purpose of administration of various compounds.
The changes in mean arterial blood pressure induced by angictensin a~inistered intravenously at a dose of 0.5 ~g~kg before the administration of the compound~ of the in~ention, and those induced by angio-tensin administered under the same condi.ions S minutes after the intravenous administration of the co~pounds of the invention or 30 minutes after the oral a~ministration thereof, are measured. The compounds of the invention are administered at doses ranging from O.01 to 100 mg/kg.
The ?ercentage inhibition of the control response to angiotensin II is used in order to assess the angiotensin II-anta~onist potential of the compounds of the invention.
The compounds of the invention or their suitable sal~s may be used for the treatment of various forms of hypertensive pathologies and of cardiac, renal or pul-monary insufficiencies, 25 well as for the treatment of glaucoma.
The compounds of the invention or their suitable salts ~ay also be u~ed in combination with other substan- :
ces having cardiovascular activity, such a3 diuretics, ~:
~-blockers, ~-~lockers, calcium antagonists or ~ ~:
angiotonsin I-converting enzyme inhibitors.
The compounds of the invention or their suitable salts may be presented in all pharmaceutical forms suited to the treatment, for oral, parenteral, intramuscular or rectal administration: tablets, capsules including hard gelatin capsules, sterile solutions or suspensions, suppositories, and the liXe.
For the treatment of slaucoma, the compounds of the invention may b~ present2d in the for~ of tahlets, hard: gelatin capsules, injections or topical ocular formulations.
The compounds of the invention may be adm~nis-tered to patients in a quantity which can range from 1 to 1000 mg per day per patient, in one or more doses.

,; - , ,: :

Claims

1. 3-(6-Quinolylmethyl)-4H-imidazol-4-one deriva-tives corresponding to the formula (I):
(I) in which R1 represents an unbranched or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of one another, either a hydrogen atom, or an unbranched or branched (C1-C5)alkyl group, or a (CH2)n-aryl group where n = 0 to 3, or R2 and R3 with the imidazole ring can form a spiro-cyclo(C3-C8)alkyl group, as well as their addition salts with pharmaceutically acceptable acids and bases.

2. Derivatives according to claim 1, characterized in that R1 represents an unbranched or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of one another, an unbranched or branched (C1-C5)alkyl group, or R2 and R3 with the imidazole ring can fonm a spiro-cyclo(C3-C8)alkyl group.

3. Derivatives according to claim 2, characterized in that R1 represents a butyl group, R2 and R3 represent, each independently of one another, an unbranched or branched (C1-C5) alkyl group, or R2 and R3 with the imidazole ring can form a spirocyclo (C3-C8)alkyl group.

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

5. 2-butyl-3-[[2-[2-(1H-tetrazol-5yl)phenyl]-6-quinolyl]
methyl]-1,3-diazaspiro[4.4]non-1-en-4-one. ]

6. 2-butyl-3-[[2-(1H-tetrazol-5-yl)phenyl]-6-quinolyl]
methyl]-1,3-diazaspiro[4,5]dec-1-en-4-one.

7. Process for preparing the derivatives according to claim 1, which process is characterized in that a compound of formula (VII) (VII) in which L represents a leaving group and R4 represents a qroup of formula CR5R6R, where R5, R6 and R7 are, each independently of one another, a (C1-C2)alkyl group or an aryl group, is reacted with an imidazoline of formula VIII) (VIII) in which R1 represents an unbranched or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of one another, either a hydrogen atom, or an unbranched or branched (C1-C5)alkyl group, or a (CH2)n-aryl group where n = 0 to 3, or R2 and R3 with the imidazole ring can form a spirocyclo(C3-C8)alkyl group, and a compound of formula (IX) (IX) is obtained, which compound is deprotected.

8. Medicinal product, characterized in that it contains a compound according to either of claims 1 to 6

9. Pharmaceutical composition, characterized in that it contains a compound according to either of claims 1 to 6, in combination with any suitable excipient.

10. Derivatives corresponding to the formula (IX) (IX) in which R1 represents an unbranched or branched (C2-C5)alkyl group, R2 and R3 represent, each independently of one another, either a hydrogen atom, or an unbranched or branched (C1-C5)alkyl group, or a (CH2)n-aryl group where n = 0 to 3, or R2 and R3 with the imidazole ring can form a spiro-cyclo(C3-C8)alkyl group, and R4 represents a group of formula CR5R6R7 where R5, R6 and R7 are, each independently of one another, a (C1-C2)alkyl group or an aryl group, which derivatives are useful as intermediates for the synthesis of the derivatives according to claim 1.