CA2057913C - N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present - Google Patents

N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present

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Publication number
CA2057913C
CA2057913C CA002057913A CA2057913A CA2057913C CA 2057913 C CA2057913 C CA 2057913C CA 002057913 A CA002057913 A CA 002057913A CA 2057913 A CA2057913 A CA 2057913A CA 2057913 C CA2057913 C CA 2057913C
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alkyl
group
phenyl
formula
ppm
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CA2057913A1 (en
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Claude Bernhart
Jean-Claude Breliere
Jacques Clement
Dino Nisato
Pierre Perreaut
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Sanofi Aventis France
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Sanofi SA
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Priority claimed from FR9003563A external-priority patent/FR2659967B1/en
Priority claimed from FR9010144A external-priority patent/FR2665702B1/en
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to N-substituted hetero-cyclic derivatives.
These derivatives have the formula (see fig.I) in which:

R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C6 alkyl, a C1-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyano-acetamide, an N-hydroxyacetamide, an N-4-carboxy-1,3-thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyanoguanidinomethyl, an imidazol-1-ylcarbonyl and a 3-cyano-2-methylisothio-ureidomethyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen;
R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;
R4 and R5 are each independently a C1-C6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C1-C4 perfluoro-alkyl, a hydroxyl and a C1-C4 alkoxy;
or R4 and R5 together form a group of the formula =CR7R8, in which R7 is hydrogen, a C1-C4 alkyl or a phenyl and R8 is a C1-C4 alkyl or a phenyl;
or else R4 and R5 together are either a group of the formula (CH2)n or a group of the formula (CH2)pY-(CH2)q, in which Y is either an oxygen-atom, or a sulfur atom, or a carbon atom substituted by a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or a group N-R6, in which R6 is a hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C3, a C1-C4 alkylcarbonyl, a C1-C4 halo-genoalkylcarbonyl, a C1-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adamantane;
- p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
and its salts (sic).

Description

, The present invention relates to N-substituted heterocyclic derivatives, to their preparation and to the pharmaceutical compositions in which they are present.
05 The compounds according to the invention anta-gonize the action of angiotensin II, which is a peptide hormone of the formula H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH
Angiotensin II is a potent vasopressor and the biologically active product of the renin-angiotensin system: renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angio-tensin II by the action of the angiotensin I converting enzyme.
The compounds of the present invention are non-peptide compounds which antagonize angiotensin II. By inhibiting the action of angiotensin II on its recep-tors, the compounds according to the invention prevent especially the increase in blood pressure produced by the hormone-receptor interaction; they also have other physiological actions on the central nervous system.
Thus the compounds according to the invention are useful in the treatment of cardiovascular com-plaints such as hypertension and heart failure, as well as in the treatment of complaints of the central ner-vous system and in the treatment of glaucoma and dia-betic retinopathy.
The present invention relates to compounds of the formula R57L( C~H ~ ) t z(C~12) .~' CHz ~ ~ (I) in which:
- R1 and R, are similar or different and are each inde-pendently hydrogen or a group selected from a C~-C~
alkyl, a C~-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C~-C,, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyano-carbamoyl, an N-hydroxycarbamoyl, an N-(4-carboxy-1~3-thiazol-2-yl)carbamoyl~ a ureido, a 2-cyano-quanidinocarbonyl, a 2-cyanoguanidinomethyl, an imi-dazol-1-ylcarbonyl and a 3-cyano-2-methylisothio-ureidomethyl, with the proviso that at least one of the substituents R~ or R~ is other than hydrogen;
- R3 is a hydrogen, a C~-C~ alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, a C2-C~ alkenyl, a C3-C, cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C~-C3, or a phenyl-alkenyl in which the alkenyl is C,-c3 ~ said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cl-C~ alkyl, a cl-c, halogenoalkyl, a C~-C, polyhalogenoalkyl, a hydroxyl or a Cl-C, alkoxy;
- R~ and R, are each independently a C~-C~ alkyl, a phenyl or a phenylalkyl in which the alkyl is CL_C3, said al~yl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen -atoms or by a group selected from a Cl-C4 perfluoro-alkyl, a hydroxyl and a C1-C4 alkoxy;
- or R4 and Rs together form a group of the formula =CR,R8, in which R7 is hydrogen, a Cl-C4 alkyl or a 05 phenyl and R8 is a Cl-C4 alkyl or a phenyl;
- or else R4 and R5 together are either a group of the formula (CH2)~ or a group of the formula (CH2)~Y-(CH2)q~ in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cl-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cl-C3, or a group N-R~, in which R~ is a hydrogen, a Cl-C4 alkyl, a phenylalkyl in which the alkyl is Cl-C3, a Cl-C4 alkylcarbonyl, a Cl-C4 halo-genoalkylcarbonyl, a C1-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adaman-tane;
_ p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
and their salts.
If a compound according to the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound.
The salts of the compounds of formula (I) according to the present invention include those with mineral or organic acids which permit separation or suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a campho-sulfonic acid, and acids which form pharmaceutically acceptable salts such as the hydrochloride, the hydro-bromide, the sulfate, the hydrogensulfate, the dihydro-genphosphate, the methanesulfonate, the methylsulfate, the maleate, the fumarate and the naphthalene-2-sulfo-nate.
05 The salts of the compounds of formula (I) also include the salts with organic or mineral bases, for example the salts of alkali or alkaline earth metals, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, or else the salts of arginine, lysine or any physiologically acceptable amine.
According to the present description and in the claims which follow, halogen atom is understood as meaning a bromine, chlorine or fluorine atom; N-pro-tecting group (also designated by Pr) is understood as meaning a group conventionally used in peptide chemis-try for affording temporary protection of the amine group, for example a Boc, Z or Fmoc group or a benzyl group; esterified carboxyl group is understood as meaning an ester which is labile under appropriate conditions, such as, for example, a methyl, ethyl, benzyl or tert-butyl ester. "Alkyl" denotes linear or branched saturated aliphatic hydrocarbon radicals.
The compounds of formula (I) in which R1 is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen are preferred compounds.
The compounds of formula (I) in which R~ and R5 together form, with the carbon to which they are bonded, a cyclopentane or a cyclohexane are preferred compounds.
Likewise, the compounds of formula (I) in which R3 is a linear Cl-C~ alkyl group are preferred com-pounds.
The compounds of formula (I) in which X is an -oxygen atom are also preferred compounds.
Finally, the compounds of formula (I) in which z = t = O are preferred compounds.
The following abbreviations are used in the 05 description and in the Examples:
Et : ethyl nBu, tBu : n-butyl, tert-butyl DMF : dimethylformamide THF : tetrahydrofuran 10 DCM : dichloromethane NBS : N-bromosuccinimide DCC : dicyclohexylcarbodiimide DIPEA : diisopropylethylamine ether : ethyl ether 15 TFA : trifluoroacetic acid Z : benzyloxycarbonyl Boc : tert-butoxycarbonyl BOP : benzotriazolyloxytrisdimethylaminophospho-nium hexafluorophosphate 20 Fmoc : fluorenylmethoxycarbonyl The present invention further relates to the method of preparing the compounds (I). In said method:
al) a heterocyclic derivative of the formula Rs 1 (CH2)t z(CH2) N 2 O ~ N
H

in which z, t, R3, R4 and ~5 are as defined above for (I), is reacted with a (biphenyl-4-yl)methyl derivative of the formula _ - 6 -R'2 R' H~l-C~2 in which Hal is a halogen atom and R' and R'z are res-pectively either Rl and R2 or a precursor group of R
and R2;
bl) if appropriate, the resulting compound of the formula R~
R~L( CH2 ) t z(CH ~
o ~ R 1 4 C n ~

is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide];
and cl) the compound obtained in al) or bl), of the formula Rs ~ (CH2) t z(CH2) ~

X ~ N R'l ~

in which X is an oxygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the - _ 2057913 groups R'l and/or R' 2 to the groups Rl and/or Rz respectively.
Among the compounds 2, the compounds (II) as defined below are novel.
05 Thus the present invention further relates to the compounds (II) of the formula R5 ~ (CH2)t 10 z(CH2) N (II) H

in which:
- R3 is a hydrogen, a Cl-C~ alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, a CZ_CG alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cl-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a Cl-C4 halogenoalkyl, a Cl-C4 polyhalogenoalkyl, a hydroxyl or a Cl-C4 alkoxy;
- R4 and R5 are each independently a C1_CG alkyl, a phenyl or a phenylalkyl in which the alkyl is Cl-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a cl-c~ perfluoro-alkyl, a hydroxyl and a Cl-C4 alkoxy;
- or R4 and R5 together form a group of the formula =CR7RB, in which R7 is hydrogen, a Cl-C4 alkyl or a phenyl and R8 is a Cl-C4 alkyl or a phenyl;
- or else R4 and R5 together are either a group of the formula (CHz)~ or a group of the formula (CH2)pY--~ 2057913 (CH2)q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cl-C~
alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or a group N-R~, in which R~ is a 05 hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C3, a Cl-C4 alkylcarbonyl, a Cl-C~ halo-genoalkylcarbonyl, a Cl-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adaman-tane;
_ p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
with the limitation that - if z and t are zero and X is an oxygen atom, R4 and Rs are other than a Cl-C~ alkyl, a phenyl or a phenylalkyl in which the alkyl is Cl-C3, said alkyl, phenyl and phenyl-alkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a Cl-C4 perfluoroalkyl, a hydroxyl and a Cl-C4 alkoxy;
or R4 and Rs together are other than a group of formula -(CH2)p-Y-(CH2)q- in which Y represents a group N-R6 in which R6 is a hydrogen, a Cl-C4 alkyl or a phenylalkyl in which the alkyl is C1-C3; and n is other than 6;
and - if z = 1 and R3 is a phenyl, R4 and R5 are each other than a methyl.
Among the derivatives (II), the compounds in which z = t = 0 and R4 and R5, together with the carbon to which they are bonded, form a cyclopentane are pre-g ferred compounds. These compounds have the formula N (II') X~\ N i H

in which X is an oxygen atom or a sulfur atom and R3 is a hydrogen, a C1_CG alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2_CG
alkenyl, a C3-C~ cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cl-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsub-stituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy.
The compounds (II) in which z = O and t = 1, of the formula R ~ N
X ~ ~ (II") in which R3, R4, R5 and X are as defined above for (II), are preferred compounds.
Finally, the compounds (II) in which z = 1 and t = O, of the formula -~ N
05 X~N ( II"') H
in which:
- R3 is a hydrogen, a Cl-C~ alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, aC2-C~ alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cl-C4 alkyl, a Cl-C~ halogenoalkyl, a Cl-C4 polyhalogenoalkyl, a hydroxyl or a Cl-C4 alkoxy;
- R4 and R5 are each independently a Cl-C~ alkyl, a phenyl or a phenylalkyl in which the alkyl is Cl-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a Cl-C~ perfluoro-alkyl, a hydroxyl and a Cl-C~ alkoxy;
- or R~ and Rs together form a group of the formula =CR7R8, in which R7 is hydrogen, a Cl-C4 alkyl or a phenyl and R8 is a Cl-C~ alkyl or a phenyl;
- or R4 and R5 together are either a group of the formula (CH2)~ or a group of the formula (CH2)pY-(CH2)q~ in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cl-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cl-C3, or a group N-RG, in which R~ is a hydrogen, a Cl-C4 alkyl, a phenylalkyl in which the alkyl is Cl-C4, a Cl-C~ alkylcarbonyl, a Cl-C4 halo-genoalkylcarbonyl, a Cl-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adaman-tane;
05 - p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5; and - X is an oxygen atom or a sulfur atom;
with the limitation that R3 is other than a phenyl if R4 and R5 are each a methyl, are preferred compounds.
The derivatives 2 are prepared by known meth-ods. For example, it is possible to use the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, 3, 1040-1051) and by Brunken and Bach (Chem.
Ber., 1956, 89, 1363-1373) and to react an alkyl imidate with an amino acid or its ester in accordance with the following reaction scheme:

R4 (CH2)z~c02R~ hH
C + R3 - C
R5 (CH2)t-NH2 OR

R~
R; 1(CH2)t z(CH2) N
~ ~ R3 O ~ 2 H

in which R is a Cl-C4 alkyl, R' is hydrogen or a Cl-C4 alkyl and R3, R4, R5, z and t are as defined above for (I)-_ 2057913 This reaction is carried out in an acid medium by heating in an inert solvent such as xylene or toluene.
According to another procedure, the compound 2 05 can be prepared by reacting an aminoalkylamide (5") with an alkyl ortho-ester (10) in an acid medium in accordance with the following reaction scheme:

R4 (CH2)z~cOl~H2 ~C \ + R3-C(OR)3 ~ 2 R5 (CH2)t-~H2 5'' 1o in which R is a Cl-C4 alkyl.
Using a procedure described by H. Takenaka et al. (Heterocycles, 1989, 29(6), 1185-89), it is also possible to prepare the compound 2 by reacting an acid halide of the formula R3-CO-Hal 12 in which Hal is a halogen, preferably chlorine, with the derivative 5''.
The reaction is carried out in a basic medium.
More particularly, according to another object of the present invention, the compound 2 is prepared by a method which comprises reacting a compound of the formula in which B is - a group C(OR)3 ~NH
- a group C or ~ OR
- a group COHal 05 R being a Cl-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula R4 (CHz)zCOA
~ 13 R5 (C~2)t~HZ

in which A is an OH group, an NH2 group or a group OR', R' being hydrogen or a C1-C4 alkyl, and then, if appropriate, treating the resulting compound with 15Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-di-thia-2,4-diphosphetane disulfide).
The (biphenyl-4-yl)methyl derivative (3) is prepared by a method described in European patent application 324 377.
20The conversion of a group R'1 and/or R'2 to a group R1 and/or R2 is effected by methods well known to those skilled in the art. ThUs, if the compound (I) to be prepared possesses a group R1 and/or R2 = carboxyl, R'l and/or R'2 are an esterified carboxyl group. If the compound (I) to be prepared possesses a group R1 and/or R2 = tetrazolyl, R'1 and/or R'2 can be either a tetrazolyl protected for example by a trityl group, or a cyano group which will subsequently be replaced with a tetrazolyl group protected if necessary by a trityl.
The conversion of the cyano group to a tetrazolyl can be effected with an azide, for example tributyltin azide or sodium azide.
It is also possible to use groups R'l and/or R' 2 such as nitro, carboxyl, cyano or acid chloride groups and then to convert them by reactions well known - 20~7913 to those skilled in the art to give groups Rl and/or R2 as defined for the compound (I).
Thus, if R'l and/or R'2 are a carboxyl, they can be converted to Rl and/or R2 in the form of an 05 imidazol-l-ylcarbonyl or else an N-(4-carboxy-1,3-thiazol-2-yl)carbamoyl.
The group R'l and/or R'2 in the form of an acid chloride can be converted to Rl and/or R2 in the form of N-hydroxycarbamoyl, N-cyanocarbamOyl, ureido or 2 cyanoguanidinocarbonyl.
The group R'l and/or R'2 in the form of a nitro can be converted to amino, from which Rl and/or R2 is prepared in the form of methylsulfonylamino, trifluoro-methylsulfonylamino or trifluoromethylsulfonylamino-methyl.
The group R'l and/or R'2 in the form of a cyano can be converted to aminomethyl, from which a 3-cyano-2-methylisothioureidomethyl is prepared (according to C. Gordon et al., J. Org. Chem., 1970, 35(6), 2067-202069) or a 2-cyanoguanidinomethyl is prepared (accor-ding to R.W. Turner, Synthesis, 1975, 332).
Step al) is carried out in an inert solvent such as DMF, DMSO or THF, in a basic medium, for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate or tri-ethylamine.
Step bl) is carried out by heating under nitrogen in a solvent such as toluene, according to the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 2Z, 5061.
In the description below, the method comprising steps al, bl and cl is referred to as method 1.
Alternatively, the compounds (I) can be pre-pared by another method, which is also a subject of the 3S present invention. In this method:

-a2) an amino acid of the formula R4 (CH2)t-NHPr \ C 7 05 Rs (CIH2)z COO~{

in which z, t, R4 and R5 are as defined above for (I), and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methylamine derivative of the formula H2~'-C~2 ~ ~ ) 8 in which R'1 and R'2 are respectively either Rl and R2 or a precursor group of R1 and R2;
b2) after deprotection of the amine, the resul-ting compound of the formula R'2 R'l \C- (CH2)z-C~h'H~CH2 ~ g Rs (cH2)t-hH2 is then treated with an alkyl ortho-ester of the formula R3C(OR)3 (10), in which R3 is as defined above for (I) and R is a C1-C4 alkyl;
c2) if appropriate, the resulting compound of the formula -R5~ L (CH2)t z(CH2) N

05 0 N ~ ~ 4 is treated with Lawesson's reagent [2,4-bis(4-methoxy-10phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide];
and d2) the compound thus obtained in b2 or c2, of the formula R5 ~ CH2) t z(CH2) N

~ ~ ~3 ~'~ R ' I 5 is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'l to the groups R2 and/or Rl respectively.
The compounds 7 are known or are prepared by known methods (Chemistry of the Amino Acids, Greenstein and Winitz, published by John Wiley, 1961, vol. I, p.
697).
30The compounds 8 are prepared according to Euro-pean patent application 324 377. Step a2) is carried out under the usual conditions for the coupling of an acid with an amine, for example in the presence of BOP
and DIPEA.
35Step b2), which is the cyclization of the com-~ _ - 17 - 20S7913 pound 9 in the presence of 10, is carried out according to Jacquier et al. (Bull. Soc. Chim. France, 1971, (3), 1040-1051) and according to Brunken and Bach (Chem.
Ber., 1956, 89, 1363-1373).
05 In the description below, the method comprising steps a2 to d2 is referred to as method 2.
In one variant of method 2, in step b2, it is possible, if appropriate, to isolate an intermediate 9 of the formula R'l R'2 R5-C-(CH2)z-CO-NH-CH
(CH2) t-~H-co-R3 and then to prepare the compound 4 by cyclization in an acid medium.
In another variant of method 2, in order to prepare a compound (I) in which R~R5 is a group =CR7R8, an amino acid of the formula CH2-(CH2)t-~HC0~3 7 (CH2)z-cooH

can be reacted in an acid medium with an aldehyde or a ketone of the formula in which R7 and R8 are as defined above for (I), and the product is then reacted with the compound 8 to give a compound of the formula `_ R'l R'2 R7R8C=C-(CH2)2-C-NH-CH7 ~ 9 (CH~)t-~HCOR3 The cyclization of this compound in an acid medium leads to the compound 4.
In this method, to prepare a compound (I) in which R1 and/or R2 are a carboxyl group, the substi-tuents R'1 and/or R'2 are preferably a tert-butoxycar-bonyl group.
Finally, another alternative for the prepara-tion of the compounds (I) according to the invention in which z and t are equal to zero is the photooxidation method, which is also a subject of the present inven-tion.
In this last method:
a3) a (biphenyl-4-yl)methyl derivative of the formula R'2 R~ 1 Hal-CH2 in which Hal is a halogen atom and R'l and R'2 are res-pectively either R1 and R2 or a precursor group of Rl and R2, is reacted with an imidazole derivative of the formula \ N

R5 ~HNI ~R3 11 - ~_ 2057913 in which R3, R~ and R5 are as defined above for (I), in the presence of oxygen and W irradiation and in a basic medium;
b3) if appropriate, the resulting compound of 05 the formula R5\ u 1 ~ R3 R 2 R~
~ H 2 =

is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide];
and c3) the compound thus obtained in b3 or c3, of the formula R,~ ~I

X~

is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'1 and/or R'2 to the groups Rl and/or R2 respectively.
The imidazole derivative 11 is either commer-cially available, or known, or is prepared by known methods indicated above for the preparation of the com-pounds 2.
Step a3) is carried out in an inert solvent such as, for example, DMF; to facilitate the reaction, 205731~

a photosensitizing product such as methylene blue can be added.
In the description below, the method comprising steps a3) to c3) is referred to as method 3.
05The compounds (I) according to the invention in which R4 and R5 together are a group of the formula (CH2)pY(CH2)~ in which Y is an NH group can be prepared by catalytic hydrogenolysis of a corresponding compound (I) in which Y is a group N-RG, R~ being a benzyl.
10The affinity of the products according to the invention for angiotensin II receptors was studied in a test for the binding of angiotensin II, labeled with iodine 125, to rat liver membrane receptors. The method used is the one described by S. KEPPENS et al.
15in Biochem. J., 1982, 208, 809-817.
The IC50, namely the concentration which gives a 50~ displacement of the labeled angiotensin II bound specifically to the receptor, is measured. The IC50 of the compounds according to the invention is less than 10-~ M.
Also, the effect of the products according to the invention as angiotensin II antagonists was obser-ved on different animal species in which the renin-angiotensin system had been activated beforehand (C.
25LACOUR et al., J. Hypertension, 1989, 7 (suppl. 2), S33-S35).
The compounds according to the invention are active after administration by different routes, espe-cially after oral administration.
30No signs of toxicity are observed with these compounds at the pharmacologically active doses.
Thus the compounds according to the invention can be used in the treatment of various cardiovascular complaints, especially hypertension, heart failure and venous insufficiency, as well as in the treatment of - _ 20S7913 glaucoma, diabetic retinopathy and various complaints of the central nervous system, for example anxiety, depression, memory deficiencies or Alzheimer's disease.
The present invention further relates to phar-05 maceutical compositions containing an effective dose of a compound according to the invention, or of a pharma-ceutically acceptable salt, and suitable excipients.
Said excipients are chosen according to the pharma-ceutical form and the desired mode of administration.
In the pharmaceutical compositions of the pre-sent invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula I above, or their salts if appropriate, can be administered to animals and humans in unit forms of administration, mixed with conven-tional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin cap-sules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administra-tion and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
To achieve the desired prophylactic or thera-peutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg of body weight per day.
Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably - `_ 20~7913 1 to 2500 mg.
When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lac-05 tose, magnesium stearate, talc, gum arabic or the like.The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient in conjunction with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring and an appropriate color.
The water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents, or suspending agents such as poly-vinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using sup-positories prepared with binders which melt at the rectal temperature, for example cacao butter or poly-ethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain phar-macologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.

- _ 2057913 The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In addition to the products of formula I above 05 or one of the pharmaceutically acceptable salts, the compositions of the present invention can contain other active principles such as, for example, tranquilizers or other drugs which can be useful in the treatment of the disorders or diseases indicated above.
Thus the present invention relates to pharma-ceutical compositions containing several active prin-ciples in association, one being a compound according to the invention and it being possible for the other or others to be a beta-blocking compound, a calcium anta-gonist, a diuretic, a non-steroidal antiinflammatory or a tranquilizer.
The following Examples illustrate the invention without however implying a limitation. The following abbreviations are used in these Examples: d denotes density, RT denotes room temperature, KHSO4-K2SO4 denotes an aqueous solution containing 16.6 g of potassium bisulfate and 33.3 g of potassium sulfate per liter.
The melting points (m.p.) are given in degrees Celsius; unless indicated otherwise, they were measured without recrystallization of the product.
The purity of the products is checked by thin layer chromatography (TLC) or HPLC. The products are characterized by their NMR spectra run at 200 MHz in deuterated DMSO with tetramethylsilane as the internal reference.
The following abbreviations are used in the interpretation of the NMR spectra:
s : singlet sb : broad singlet 20~7913 d : doublet t : triplet q : quadruplet quint : quintuplet 05 sext : sextuplet m : unresolved signals or multiplet In addition, im denotes imidazole.
Conventionally, the hydrogen atoms are numbered on the biphenylyl as shown in the following formula:

Rs~(CH2)t z(CH2) N

X ~ ~ ~ R2 Rl (I) 6 6' 5' In the following compounds, z and t are zero except where the compound prepared is a pyrimidinone.

2S 2-n-Butyl-4-spirocyclopentane-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one and 2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate -Method 2 A) l-N-Fmoc-aminocyclopentanecarboxylic acid is pre-pared according to the method described by CHI-DEU
CHANG et al. (Int. J. Peptide Protein Res., 1980, 1~, 59-66). M.p. = 89-91 C.

~1 - _ 2057913 B) N-(2'-Tert-butoxycarbonylbiphenyl-4-ylmethyl)-1-(N-Fmoc-amino)cyclopentane-l-carboxamide 700 mg of the product prepared in the previous step are dissolved in 8 ml of DMF, and 576 mg of 4-05 aminomethyl-2'-tert-butoxycarbonylbiphenyl, 970 mg of BOP and a sufficient amount of DIPEA to bring the pH to 6 are added successively.
After stirring for 1 hour, the reaction medium is diluted with 100 ml of ethyl acetate and 20 ml of water; the organic phase is washed successively with a saturated solution of sodium bicarbonate, then with a KHSO~-K2SO~ solution and finally with a saturated solution of sodium chloride. After drying over sodium sulfate, the solution is evaporated to dryness to give an oil. m = 1.2 g.
C) N-(2'-Tert-butoxycarbonylbiphenyl-4-ylmethyl)-1-aminocyclopentane-l-carboxamide The product obtained in the previous step is dissolved in 10 ml of DMF, 1 ml of diethylamine is then added and the mixture is stirred for 1 hour 15 minutes at RT. The reaction medium is taken up in 100 ml of ethyl acetate and 20 ml of water and the organic phase is then washed once with water and once with a satura-ted solution of sodium chloride and then dried over sodium sulfate and evaporated to dryness.
The residue is chromatographed on silica gel using an ethyl acetate/methanol/30% aqueous ammonia mixture (99/1/0.5; v/v/v) as the eluent to give 600 mg of the expected product.
- IR (CHCl 3) 3350 cm-l : H (amide and amine) 1700 cm-l : C=O (CO2tBu) 1650 cm~l : C=O (CONH) - NMR spectrum: --1.25 ppm : s : 9 H : tBu 2~57913 2.15-1.40 ppm : m : 10 H : C5H8, NH2 4.40 ppm : d : 2 H : C_2-NH
7.15-7.75 ppm~: m : 8 H : biphenyl 8.60 ppm : t : 1 H : NH-CH2 05 D) 2-n-Butyl-4-spirocyclopentane-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 394 mg of the product prepared in the previous step and 250 mg of ethyl orthovalerate are mixed in 2 ml of DCM. 1 drop of acetic acid is added and the mix-ture is then heated at 90 C with the DCM being allowedto evaporate off. After 1 hour 15 minutes, the reac-tion medium is taken up in 50 ml of ethyl acetate, 10 ml of water and 1 ml of a saturated solution of sodium bicarbonate. The organic phase is then washed with a saturated solution of sodium chloride and subsequently dried over sodium sulfate and evaporated to dryness.
The residue is chromatographed on silica gel using an ethyl acetate/toluene mixture (1/2; v/v) as the eluent to give 390 mg of the expected product, which crystal-lizes. M.p. = 63-65 C.
- IR (CHCl3):
1710-1720 cm-1 : C=O, C=0 (ester and imidazoline) 1625 cm-l : C=N
- NMR spectrum:
0.88 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : s : 9 H : tBu 1.35 ppm : sext : 2 H : CH3-CH2-1.58 ppm : quint : 2 H : CH3-CH2-C_2-1.95-1.65 ppm : m : 8 H : cyclopentane 2.42 ppm : t : 2 H : CH3-CH2-CH2-CH2-4.78 ppm : s : 2 H : CH2-C~H4-7.20-7.80 ppm : m : 8 H : aromatic protons - Mass spectrum:
MH' : 461 E) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate 180 mg of the product prepared in the previous step are treated with 3 ml of DCM and 4 ml of TFA for 05 45 minutes. After evaporation under vacuum, the resi-due is taken up in ether to give a white solid, which is filtered off, washed with ether and then dried under vacuum. m = 155 mg. M.p. = 176-178 C.
- NMR spectrum:
0.78 ppm : t : 3 H : CH3 (nBu) 1.25 ppm : sext : 2 H : CH3-CH2 1.50 ppm : quint : 2 H : CH3-CH2-CH2 1.75-2.00 : m : 8 H : cyclopentane 2.65 ppm : t : 2 H : CH3-CH2-CH2-CH2-4.83 ppm : s : 2 H : CH2-C~H4-7.20-7.75 ppm : m : 8 H : aromatic protons - Mass spectrum:
MH+ : 405 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate - Method 1 A) 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one The ethyl ester of l-aminocyclopentanecarboxy-lic acid is prepared according to ADKINS and BILLICA
(J. Amer. Chem. Soc., 1948, 70, 3121).
Ethyl valerimidate is prepared according to Mac ELVAIN (J. Amer. Chem. Soc., 1942, 64, 1825-1827) and then freed from its hydrochloride by reaction with potassium carbonate and extraction with DCM.
The ethyl ester of l-aminocyclopentanecarboxy-lic acid (1.57 g) and ethyl valerimidate (1.56 g) are dissolved in 12 ml of xylene containing-6 drops of acetic acid. After refluxing for 6 and a half hours, -the reaction medium is concentrated under vacuum and the residue is then chromatographed on silica gel using a chloroform/methanol/acetic acid mixture (94/4/2;
v/v/v) as the eluent. The fraction containing the 05 expected product is evaporated several times in the presence of xylene and then benzene in order to remove the acetic acid. l.91 g of product are obtained in the form of a thick oil.
- IR (CHCl3):
1720 cm-l : C=O
1635 cm~l : C=N
Note: The fact that there is no visible band between 1500 and 1600 cm-l indicates that, in chloroform solution, the product is an imidazolin-5-one.
- NMR spectrum:
0.92 ppm : t : 3 H : CH3 (nBu) 1.35 ppm : sext : 2 H : CH3-CH2-1.50-1.93 ppm : m : 10 H : CH3-CH2-C_ 2 and cyclo-pentane 2.33 ppm : t : 2 H : CH3-CH2-CH2-C_ 2-10.7 ppm : m : N_ - Mass spectrum:
MH' : 195 The 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one prepared in step A can also be obtained by another procedure described below, using cyclopentanone as the starting material.
a) l-Aminocyclopentanenitrile This step is carried out according to A.
Strecker (Org. Synth., 1955, 3).
1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a round-bottomed flask and a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% aqueous ammonia is added;
finally, 3 g of cyclopentanone in 3.8 ml of methanol 2057gl3 -are added to the flask. After stirring for 1 and a half hours, the mixture is heated at 60C for 45 minutes, heating is then stopped, stirring is continued for 45 minutes and the mixture is then cooled to 25 C.
05 It is extracted several times with methylene chloride.
The extracts are dried over sodium sulfate, filtered and concentrated under vacuum to give 4 g of the expected product in the form of an oil.
The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone, and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is added, with stirring. The precipitate formed is fil-tered off, washed with acetone and then dried.
m = 4.71 g.
M.p. = 220 C.
This compound i~ 1-aminocyclopentanenitrile hemioxalate.
b) 1-Aminocyclopentanecarboxamide This step i~ carried out according to J.
Zabicky (The Chemistry of Amides, Interscience, New York, 1970, 119).
5.1 g of the oxalate obtained in the previous step are treated with 7.65 ml of concentrated sulfuric acid (d = 1.84) over 45 minutes, with stirring. The evolution of a gas is observed and the temperature rises to 100 C. The mixture is cooled to about 35 C
and poured into a mixture of ice and concentrated aqueous ammonia (10 g/2.8 ml). The suspension formed is extracted 6 times in succession with chloroform con-taining 5% of methanol. 3 ml of aqueous ammonia (d =0.92) are added to the aqueous phase and the mixture is extracted again with chloroform containing methanol (1/0.5; v/v). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The expected product is obtained in the form of a white D

2os~9l3 solid.
m = 3.79 g.
M.p. = 95 C.
The structure can be confirmed by the results 05 of analysis and the IR spectrum.
c) 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one This step is carried out according to H.
Takenaka et al., Heterocycles, 1989, 29(6), 1185-89.
3 g of the compound prepared in the previous step are placed in 70 ml of anhydrous THF and 3.3 ml of triethylamine, and 3 ml of valeryl chloride in 10 ml of anhydrous THF are added, with stirring. A white sus-pension is formed. The intermediate which is formed, but not isolated, is l-(N-valeryl)aminocyclopentane-carboxamide. 6 g of potassium hydroxide pellets, 7 ml of water and 16 ml of methanol are added. The mixture is refluxed for 2 and a half hours and 9 g of ammonium chloride are then added. After stirring for 15 min-utes, the mixture is concentrated under vacuum. Theresidue obtained is taken up in 40 ml of water and extracted with 10 ml of ethyl acetate and then twice with 5 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated to dryness to give 4.85 g of the expected product. The NMR spectrum is similar to that described previously. The hydrochloride of this compound can be prepared by the addition of concentra-ted hydrochloric acid. The hydrochloride melts at 240 C with sublimation.
B) 2-n-Butyl-4-spirocyclopentane-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 970 mg of the product obtained in step A) are dissolved in lO ml of DMF. 270 mg of sodium methylate are added and the mixture is stirred for 15 minutes at ~ _ - 31 - 20~7913 RT. 2.08 g of 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl are added to the suspension and then, after 30 minutes, the mixture is heated at 40 C for 3 and a half hours under nitrogen. The reaction medium is taken up 05 in a mixture containing 100 ml of ethyl acetate, 10 ml of water and 1 ml of a saturated solution of sodium bicarbonate. The organic phase is washed with a saturated solution of sodium chloride and then dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using an ethyl acetate/toluene mixture (1/2; v/v) as the eluent to give 1.25 g of the expected product, which crystal-lizes. M.p. = 63-66 C.
The IR and NMR spectra and the mass spectrum, as well as the Rf, are identical to those obtained in step D) of Example 1.
C) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate 1.22 g of the product obtained in the previous step are stirred for 40 minutes in a solution con-taining 6 ml of DCM and 8 ml of TFA. After concen-tration under vacuum, the residue is taken up in ethyl ether; the white precipitate formed is filtered off, washed with ether and then dried under vacuum to give 25 1.15 g of the expected product. M.p. = 176-178 C.
The IR and NMR spectra and the mass spectrum are identical to those obtained in Example lE; like-wise, the Rf observed in TLC is identical.

2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate - Method 3 A) 2-n-Butylbenzimidazole is prepared according to W.O.
35 POOL (J. Amer. Chem. Soc., 1937, 59, 178) and 2-n-butyl-4,5,6,7-tetrahydrobenzimidazole is then prepared according to M. HARTMANN and L. PANIZZON (Helv. Chim.
Acta, 1938, 21, 1692-1694). M.p. = 145 C.
- NMR spectrum:
05 0.82 ppm : t : 3 H : CH3 (nBu) 1.23 ppm : sext : 2 H : CH3-CH2-1.50 ppm : quint : 2 H : CH3-CH2-CH2-1.65 ppm : s : 4 H : H5, H~ (tetrahydrobenzimidazole) 2.35 ppm : s : 4 H : H~, H7 (tetrahydrobenzimidazole) 2.45 ppm : t : 2 H : CH3-CH2-CH2-C_2-11.1 ppm : m : NH
- Mass spectrum:
M+ : 178 B) 2-n-Butyl-4-spirocyclopentane-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 1 g of the product prepared in the previous step is dissolved in 45 ml of DMF with 303 mg of sodium methylate and a few mg of methylene blue. Oxygen is bubbled into the reaction medium, which is illuminated with a W lamp. After 15 minutes, 2.14 g of 4-bromo-methyl-2'-tert-butoxycarbonylbiphenyl are added and then, after 1 hour, the reaction medium is taken up in 300 ml of ethyl acetate to which 50 ml of water and 5 ml of a saturated solution of sodium bicarbonate have been added. The organic phase is then washed with a saturated solution of sodium chloride and subsequently dried over sodium sulfate and evaporated to dryness.
The residue is chromatographed on silica gel using an ethyl acetate/toluene mixture (1/2; v/v) as the eluent to give 610 mg of the expected product, which crystal-lizes. M.p. = 62-65 C.
The IR and NMR spectra and the mass spectrum, as well as the Rf, are identical to those obtained previously for the same compound. --20~791~
-C) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate This compound is obtained by treatment in an acid medium as described in the last step of Example 1 05 and Example 2. The physicochemical data are identical to those obtained for the same compound prepared by method 1 or 2.

2-n-Butyl-4,4-dimethyl-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one and 2-n-butyl-l-[(2'-carboxybiphenyl-4-yl)methyl]-4,4-di-methyl-2-imidazolin-5-one trifluoroacetate - Method 1 A) 2-n-Butyl-4,4-dimethyl-2-imidazolin-5-one The ethyl ester of alpha-aminoisobutyric acid is prepared according to R. Jacquier et al. (Bull. Soc.
Chim. France, 1971, (3), 1040-1051). 650 mg of this compound and 780 mg of ethyl valerimidate are dissolved in 8 ml of xylene containing 4 drops of acetic acid and the solution is refluxed for 7 hours. The reaction medium is then concentrated under vacuum and the resi-due is chromatographed on silica gel using a chloro-form/methanol/acetic acid mixture (95/5/2; v/v/v) as the eluent. After several evaporations with xylene and then benzene to remove the acetic acid, 560 mg of the expected product are obtained, which crystallizes.
M.p. = 35-38 C.
- IR (CHCl3):
1725 cm-l : C=o 1635 cm-1 : C=N
Note: The absence of a signal between 1500 and 1600 cm-l confirms that the compound present in chloroform solution is a 2-imidazolin-5-one.
- NMR spectrum: --0.92 ppm : t : 3 H : CH3 (nBu) `_ 20~7~13 1.20 ppm : s : 6 H : C(C_3)2 1.38 ppm : sext : 2 H : CH3-C_2 1.63 ppm : quint : 2 H : CH3-CH2-CH2 2.38 ppm : t : 2 H : CH3-CH2-CH2-CHz 05 10.7 ppm : m : 1 H : N-H
- Mass spectrum:
MH+ : 169 B) 2-n-Butyl-4,4-dimethyl-1-[(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-imidazolin-5-one 520 mg of the product prepared in the previous step are dissolved in 10 ml of DMF. 167 mg of sodium methylate are added and the mixture is stirred under nitrogen for 15 minutes. 1.25 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl are then added and the mix-ture is stirred at 40 C for 3 and a half hours. The reaction medium is taken up in 150 ml of ethyl acetate and then 20 ml of water and 2 ml of a saturated solu-tion of sodium bicarbonate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to dryness.
The residue is chromatographed on silica gel using an ethyl acetate/toluene mixture (1.2/2; v/v) as the eluent to give 570 mg of the expected product, which crystallizes. M.p. = 98-100 C.
- IR (CHCl3):
1710-1720 cm-l : C=O, C=O (imidazolinone, ester) 1625 cm-l : C=N
- NMR spectrum:
0.78 ppm : t : 3 H : CH 3 ( nBu) 1.08 ppm : s : 9 H : C(CH3)3 1.15 ppm : s : C(CH3)2 1.20 ppm : sext : CH3-C_2- ~ 8 H
1.45 ppm : quint : 2 H : CH3-CH2-CH2-2.30 ppm : t : 2 H : CH3-CH2-CH2-c_ 2-4.65 ppm : s : 2 H : C_z-C~H~-- _ 2057913 7.15-7.65 ppm : m : 8 H : aromatic protons An NOE (Nuclear Overhauser Effect) study confirms the position of the 5-one and 4,4-dimethyl substituents on the imidazolinone.
05 - Mass spectrum:
MH+ : 435 C) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4,4-dimethyl-2-imidazolin-5-one trifluoroacetate 460 mg of the product prepared in the previous step are treated with 3 ml of DCM and 4 ml of TFA for 45 minutes. After concentration under vacuum, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and then dried under vacuum to give 450 mg of the expected product in the form of a white solid. M.p. = 168-171 C.
- NMR spectrum:
0.82 ppm : t : 3 H : CH3 (nBu) 1.30 ppm : sext : CH3-C~2- ~
1.35 ppm : s : C(C_3)2- ~ 8 H
1.55 ppm : quint : 2 H : CH3-CH2-CH2-2.62 ppm : t : 2 H : CH3-CH2-CH2-CH2-4.82 ppm : s : 2 H : C_2-CGH4-7.20-7.75 : m : 8 aromatic H
- Mass spectrum:
MH+ : 379 1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-s-one and 2-n-butyl-4-spirocyclopentane-1-t(2'-(tetrazol-5-yl)biphenyl-4-yl)-methyl]-2-imidazolin-5-one - Method 1 A) 1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spiro-cyclopentane-2-imidazolin-5-one A mixture containing 250 mg of sodium hydride (as an 80% dispersion in mineral oil) and 5 ml of DMF

is prepared under a nitrogen atmosphere and a solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (prepared in Example 2, step A) in 10 ml of DMF is added dropwise. The mixture is stirred for 30 minutes at RT and a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of DMF is then added. After stirring for 1 hour at RT, the DMF is evaporated off under reduced pressure, the residue is then taken up with ethyl acetate and the organic phase is washed with water and then dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using a DCM/ethyl acetate mixture (9/1;
v/v) as the eluent. 1.68 g of the expected product are recovered. M.p. = 92-93C.
B) 2-n-Butyl-4-spirocyclopentane-1-[(2'-(triphenyl-methyltetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 1.56 g of the previous product, 2.6 g of tributyltin azide and 30 ml of xylene are refluxed for 66 hours. The xylene is then evaporated off and the residue is dissolved in 20 ml of DCM and 5 ml of THF with the addition of 0.8 ml of 10 N sodium hydroxide solution and, after stirring for 30 minutes, 2.5 g of trityl chloride, and the mixture is stirred for 26 hours. After evaporation of the solvents, the residue is taken up in ethyl acetate and washed with water and with a 3%
solution of potassium bisulfate and water. It is dried and evaporated. The residue is chromatographed on alumina using a hexane/ethyl acetate mixture (9/1; v/v) as the eluent to give 1.97 g of the expected product.
M.p. = 150-152C.
C) 2-n-Butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 1.96 g of the product prepared in the previous step are dissolved in 10 ml of methanol and 10 ml of 1~
~' .

THF. After the reaction medium has been cooled to 5 C, 1.5 ml of 4 N hydrochloric acid are added and the mix-ture is stirred for 3 hours at RT and 1 hour at 30 C.
After evaporation of the solvents, the residue is taken 05 up in water and the pH is brought to 12 by the addition of 10 N sodium hydroxide solution. The aqueous phase is extracted with ether, toluene and ether again. The aqueous phase is acidified to pH 2 by the addition of 1 N hydrochloric acid and then extracted with ethyl acetate and the extract is dried and evaporated. The white solid obtained is dried at 50 C under 0.05 mm of mercury to give 840 mg of the expected product. M.p. =
180-181 C.
- NMR spectrum:
0.75 ppm : t : 3 H : CH3 (nBu) 1.10 ppm : sext : 2 H : CH3-CH2-1.20 ppm : quint : 2 H : CH3-CH2-CH2-1.5-2 ppm : m : 8 H : -C5H8 2.2 ppm : t : 2 H : CH3-CH2-CH2-C_2-4.6 ppm : s : 2 H : C_2-C~H4-7 ppm : s : 4 H : CH2-C~H~-7.35-7.7 ppm : m : 4 H : aromatic H3, ~, 5, ~, An NOE study confirms the position of the 5-one sub-stituent on the imidazole.
D) Potassium salt of 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 970 mg of the compound obtained in the previous step are dissolved in 40 ml of an isopropanol/methanol mixture (1/1; v/v) and the pH is adjusted to 12 by the addition of an 85% solution of potassium hydroxide in a methanol/water mixture (20/1; v/v). The reaction medium is evaporated, the residue is taken up in iso-propanol and the medium is evaporated again. The resi-due is dissolved in 20 ml of isopropanol, with gentle 2~7913 -heating, and then left to return to room temperature.
The mixture is left to decant, the filtrate is evapora-ted and the residue is then taken up in heptane. After trituration, the product solidifies; it is filtered off 05 and then washed again with heptane and dried under vacuum to give 945 mg of the expected potassium salt.
M.p. = 142-144 C.
- Elemental analysis: C25H27KN~O.H20 calc. % C : 61.95 H : 6.03 N : 17.34 found % 62.02 6.13 17.14 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(4-spirotetrahydropyran)-2-imidazolin-5-one tri-fluoroacetate and 2-n-butyl-4-(4-spirotetrahydropyran)-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one - Method 2 A) 4-Aminotetrahydropyran-4-carboxylic acid is prepared from tetrahydropyran-4-one by the method described in German patent 2 215 721.
B) 4-(N-Benzyloxycarbonylamino)-4-carboxytetrahydro-pyran 1.015 g of the compound of step A are placed in 12 ml of water and treated at 10 C with 1.22 ml of di-isopropylethylamine and then 3.33 g of N-(benzyloxy-carbonyloxy)succinimide dissolved in 12 ml of aceto-nitrile. After 1 hour 15 minutes, the reaction medium is diluted with 70 ml of ethyl acetate and 10 ml of water and the pH is brought to 2 with a saturated solution of potassium bisulfate.
After decantation, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated under vacuum.
The residue is diluted with 60 ml of ether, after which 7 mmol of dicyclohexylamine are added. The precipitate -formed is filtered off and washed with ether; it is then dissolved in an ethyl acetate/water mixture and the pH is brought to 1.5 with a saturated solution of potassium bisulfate. The organic phase is decanted, 05 washed with a saturated solution of sodium chloride and evaporated under vacuum to give 1.9 g of a white solid.
M.p. = 110-115 C.
C) N-(2'-Tert-butoxycarbonylbiphenyl-4-ylmethyl)-4-(N-benzyloxycarbonylamino)tetrahydropyran-4-carboxamide 850 mg of the compound prepared in step B are dissolved in 15 ml of DMF, and equimolar amounts of 4-aminomethyl-2'-tert-butoxycarbonylbiphenyl, DIPEA and then BOP (10% excess) are added. After 40 minutes, the medium is taken up in 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted and then washed twice with a saturated solution of sodium bi-carbonate, twice with a 5% solution of sodium bisulfate and then once with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase is evaporated under vacuum to give 1.8 g of the expected product.
D) N-(2'-Tert-butoxycarbonylbiphenyl-4-ylmethyl)-4-aminotetrahydropyran-4-carboxamide The product obtained in step C is dissolved in 30 ml of methanol. 400 mg of 10% palladium-on-charcoal are added and the mixture is hydrogenated at atmos-pheric pressure. After 1 hour, the catalyst is fil-tered off and the filtrate is then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/methanol/33% aqueous ammonia mixture (99/1/0.5: v/v/v) as the eluent to give 0.93 g of the expected product in the form of a white solid. M.p. =
125-127 C.
- NMR spectrum: -8.50 ppm : t : 1 H : amide H

7.60-7.05 ppm : m : 8 H : aromatic protons 4.25 ppm : d : 2 H : CHz-CGH4-3.70-3.50 ppm : m : 4 H : CHz in the 2 and 6 posi-tions of the tetrahydro-05 pyran 2.00-1.80 ppm : m : 4 H : CH2 in the 3 and 5 posi-tions of the tetrahydro-pyran 1.05 ppm : s : 9 H : tBu E) 2-n-Butyl-4-(4-spirotetrahydropyran)-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one A mixture containing o.s g of the compound obtained in step D, 327 mg of methyl orthovalerate and 2 drops of acetic acid is heated for 3 hours at llo C.
The reaction medium is taken up in 100 ml of ethyl acetate, then washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and then dried over sodium sulfate and the ethyl acetate is evaporated off. The residue obtained is chromatographed on silica using an ethyl acetate/
toluene mixture (2/1; v/v) as the eluent to give 550 mg of the expected product in the form of a wax.
- NMR spectrum:
7.05-7.60 ppm : m : 8 H : aromatic protons 4.63 ppm : s : 2 H : CH2-C~H~-3.85-3.55 ppm : m : 4 H : CH2 in the 2 and 6 posi-tions of the tetrahydro-pyran 2.30 ppm : t : 2 H : C_2-C3H, 1.05-1.80 ppm : m : 8 H : CH2-CH2-CH2-CH3 and CH2 in the 3 and 5 positions of the tetrahydropyran 1.03 ppm : s : 9 H : tBu 0.75 ppm : t : 3 H : (CH2)3-CH3 - IR (CHCl3):
1710-1720 cm~l : C=o, C=0 1625 cm~l : C=N
F) 2-n-Butyl-4-(4-spirotetrahydropyran)-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoroacetate (sic) 530 mg of the product obtained in the previous step are treated with 4 ml of dichloromethane and 5 ml of TFA
for 45 minutes. After evaporation under vacuum, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and then dried under vacuum to give 510 mg of the expected product. M.p. =
159-162C.
- NMR spectrum:
7.80-7.10 ppm : m : 8 H : aromatic protons 4.80 ppm : s : 2 H : CH2-C6H4-4.00-3.75 ppm : m : 4 H : CH2 in the 2 and 6 positions of the tetrahydropyran 2.60 ppm : t : 2 H : CH2-C3H7 1.45-2.00 ppm : m : 6 H : CH2-CH2-CH2-CH3 and CH2 in the 3 and 5 positions of the tetrahydropyran 1.30 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-[spiro(l-benzyl-4-piperidine)]-2-imidazolin-5-one trifluoroacetate and 2-n-butyl-4-[spiro(l-benzyl-4-piperidine)]-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)-methyl]-2-imidazolin-5-one - Method 1 A) 4-Amino-1-benzylpiperidine-4-carboxylic acid is prepared from N-benzylpiperidin-4-one by the method described in German patent 2 215 721.

~3~

-B) Ethyl 4-amino-1-benzylpiperidine-4-carboxylate 3.80 g of the compound prepared in step A are added to a solution of 13 g of hydrochloric acid in 50 ml of ethanol at 0 C and the mixture is then refluxed 05 for 5 hou~s. After concentration under vacuum, the residue is washed with ether and then dissolved in an ether/water mixture, to which a saturated solution of potassium carbonate is added to bring the pH to 9. The ether phase is decanted, washed with a saturated solu-tion of sodium chloride, dried over sodium sulfate and then evaporated to dryness to give 3.50 g of the expected product in the form of an oil.
- NMR spectrum:
7.20-7.40 ppm : m : 5 H : aromatic protons 4.10 ppm : q : 2 H : CH2-CH3 3.45 ppm : s : 2 H : CH2 of the benzyl 2.25-2.60 ppm : m : 4 H : CH2 in the 2 and 6 posi-tions of the piperidine 1.80-2.05 ppm : m : 2 H ~ CH2 in the 3 and 5 posi-1.20-1.40 ppm : m : 2 H ~ tions of the piperidine 1.12 ppm : t : 3 H : C_3-CH2-C) 2-n-Butyl-4-[spiro(l-benzyl-4-piperidine)]-2-imi-dazolin-5-one Ethyl valerimidate is prepared as in Example 2, 25 step A. 2.06 g of ethyl valerimidate, 3.40 g of the compound prepared in step B and 8 drops of acetic acid are mixed in 15 ml of xylene and the mixture is re-fluxed for 6 hours. After concentration under vacuum, the residue is chromatographed on silica gel using a 30 chloroform/methanol/acetic acid mixture (82/15/3;
v/v/v) as the eluent. ~.80 g of the expected product are obtained after extraction with chloroform at pH 9 to remove the acetic acid. M.p. = 170-172 C.
- IR (chloroform):
1725 cm~l : C=O

1640 cm~l : C=N
- NMR spectrum:
7.10-7.30 ppm : m : 5 H : aromatic protons 3.45 ppm : s : 2 H : -CH2-CGH5 05 1.10-2.75 ppm : 5 m : 14 H : CH2 in the 2, 3, 5 and 6 positions of the piperidine and (CH2)3-CH3 0.80 ppm : t : 3 H : (CH2)3-C_3 D) 2-n-Butyl-4-[spiro(1-benzyl-4-piperidine)]-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 513 mg of sodium methylate and, after 15 minutes, 4.16 g of 4-bromomethyl-2'-tert-butoxycar-bonylbiphenyl are added to a solution of 2.78 g of the compound obtained in step C in 25 ml of DMF. The reac-tion medium is heated at 40C for 5 hours and then taken up in 300 ml of ethyl acetate, 50 ml of water and 5 ml of a saturated solution of sodium bicarbonate.
The organic phase is decanted, washed once more with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under vacuum. The resi-due is chromatographed on silica using an ethyl ace-tate/methanol mixture (95/5; v/v) as the eluent to give 25 0.98 g of the expected product. M.p. = 103-106 C.
- IR (CHCl3):
1710-1725 cm~1 : C=o, C=O (imidazoline, ester) 1630 cm-l : C=N
- NMR spectrum:
7.70-7.10 ppm : m : 13 H : aromatic protons 4.70 ppm : s : 2 H : C_2-C~H~-3.55 ppm : s : 2 H : C_2-C~H5 1.20-2.75 ppm : 5 m : 14 H : CH2 in the 2, 3, 5 and 6 positions of the piperi-dine and (CH2)3-CH3 _ ~ _ 44 _ 2 0 5 7 9 1 3 1.15 ppm : s : 9 H : tBu 0.85 ppm : t : 3 H : (CH2)3-C_3 E) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-[spiro(1-benzyl-4-piperidine)]-2-imidazolin-5-one trifluoroacetate 350 mg of the compound obtained in step D are dissolved in 4 ml of dichloromethane and 5 ml of TFA.
After 45 minutes, the medium is concentrated under vacuum, the residue is then taken up in an ether/hexane mixture and the precipitate formed is filtered off, washed with ether and dried under vacuum to give 350 mg of the expected product. M.p. = 198-200C.
- NMR spectrum:
7.05-7.75 ppm : m : 13 H : aromatic protons 4.75 ppm : s : 2 H : C_2-C6H4-4.40 ppm : s : 2 H : CH2-C6Hs 3.20-3.60 ppm : m : 4 H : CH2 in the 2 and 6 positions of the piperidine 2.35 ppm : t : 2 H : CH2-CH2-CH2-CH3 2.20-1.40 ppm : 3 unresolved signals : CH2 in the 3 and 5 positions of the piperidine and CH2-C_2-CH2-CH3 1.25 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(4-spiropiperidine)-2-imidazolin-5-one ditrifluoro-acetate and 2-n-butyl-4-(4-spiropiperidine)-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one a3 _~ 2057913 A) 2-n-Butyl-4-(4-spiropiperidine)-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 300 mg of the compound of Example 7, step D, are dissolved in 10 ml of methanol. 180 mg of 10%
05 palladium-on-charcoal are added and the mixture is hydrogenated for 3 hours at atmospheric pressure. The catalyst is filtered off and the filtrate is concentra-ted under vacuum to give 200 mg of the expected pro-duct.
- NMR spectrum:
7.20-7.75 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : C_z-CGH4-3.00-1.70 ppm : 3 unresolved signals for the 4 CH2 of the piperidine 2.40 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.60 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.35 ppm : sext : 2 H : CH2-cH2-c-2-cH3 1.20 ppm : s : 9 H : tBu 0.90 ppm : t : 3 H : (CH2)3-CH3 B) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(4-spiropiperidine)-2-imidazolin-5-one ditrifluoroacetate 160 mg of the product obtained in step A are stirred for 45 minutes in 3 ml of dichloromethane and 4 ml of trifluoroacetic acid. The mixture is concentra-ted under vacuum and the residue is taken up in ether to give a gum and then a foam after drying under vacuum (150 mg). M.p. = 80-85 C.
- NMR spectrum:
7.15-7.80 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : C_2-CGH4-3.20-1.60 ppm : 3 unresolved signals : 4 CH2 of the piperidine 2.40 ppm : t : 2 H : CH2-CH2-CHz-CH3 1.50 ppm : quint : 2 H : CH2-CHz-CH2-CH3 1.30 ppm : sext : 2 H : CH2-CH2-C_2-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-05 4,4-diphenyl-2-imidazolin-5-one trifluoroacetate and 2-n-butyl-4,4-diphenyl-1-[(2'-tert-butoxycarbonylbi-phenyl-4-yl)methyl]-2-imidazolin-5-one - Method 1 A) Valeramidine hydrochloride 6 g of ethyl valerimidate hydrochloride are added to a solution of 6.75 g of ammonia in 80 ml of methanol at 0 C. After 18 h, the reaction medium is concentrated under vacuum to give the expected product in the form of a white solid.
B) 2-n-Butyl-4,4-diphenyl-2-imidazolin-5-one This compound is prepared according to the pro-cedure described by J. NYITRAI and K. LEMPERT in Tetra-hedron, 1969, 25, 4265-4275, from benzil and valerami-dine hydrochloride. M.p. = 135 C.
- IR (CHCl3):
1725 cm-l : C=0 1640 cm-l : C=N
- NMR spectrum:
7.20-7.50 ppm : m : 10 H : aromatic protons 2.50 ppm : t : 2 H : C_2-CH2-CH2-CH3 1.65 ppm : quint : 2 H : CH2-C_2.CH2-CH3 1.35 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.90 ppm : t : 3 H : CH2-CH2-CH2-C_3 11 ppm : sb : NH
C) 2-n-Butyl-4,4-diphenyl-l-[(2~-tert-butoxycarbonylbi-phenyl-4-yl)methyl]-2-imidazolin-5-one This compound is prepared according to the usual method by reacting 4-bromomethyl-2'-tert-butoxy-carbonylbiphenyl with the compound prepared in step B, in the presence of sodium methylate in DMF.-- IR (CHCl3):
1715-1725 cm-l : C=O, C=O (ester, imidazolinone) 1635 cm-l : C=N
- NMR spectrum:
05 7.25-7.80 ppm : m : 18 H : aromatic protons 4.85 ppm : s : 2 H : N-CH2-C~H4-2.60 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.75 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 1.15 ppm : s : 9 H : tBu 0.90 ppm : t : 3 H : CH3 of the n-butyl D) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4,4-diphenyl-2-imidazolin-5-one trifluoroacetate 500 mg of the product prepared in step C are treated with 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid at 20 C for 40 minutes. After concentration under vacuum, the residue is taken up in an ether/hexane mixture and the precipitate formed is filtered off, washed with hexane and dried to give 440 mg of the expected product. M.p. = 55-60 C.
- NMR spectrum:
7.15-7.80 ppm : m : 18 H : aromatic protons 4.85 ppm : s : 2 H : N-C_2-C~H~-2.60 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.70 ppm : quint : 2 H : CH2-C_2-CH2-CH3 1.40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.90 ppm : t : 3 H : CH3 of the butyl 2-n-Butyl-3-[(2'-carboxybiphenyl-4-yl)methyl]-6-spirocyclopentane-5,6-dihydro-lH-pyrimidin-4-one trifluoroacetate A) (1-Aminocyclopentyl)acetic acid Cyclopentylideneacetic acid is prepared accor-ding to G.A.R. KON and R.P. LINSTEAD, J. Chem. Soc., 1925, 127, 616. 740 mg of this acid and 5 ml of 20%
aqueous ammonia are placed in an autoclave and the mix-ture is heated at 150 C for 24 hours. After evapora-tion of the solvents, the residue is chromatographed on os a silica column using a DCM/methanol/20% aqueous ammonia solution mixture (70/30/1; v/v/v) as the eluent to give 330 mg of the expected acid.
B) Ethyl (l-aminocyclopentyl)acetate 330 mg of the acid are dissolved in 10 ml of ethanol. The solution is cooled in an ice bath and saturated with gaseous hydrochloric acid. After 24 hours under reflux, the reaction medium is evaporated, the residue is taken up in a solution of sodium car-bonate and extracted with ethyl acetate and the extract is then dried over sodium sulfate, filtered and eva-porated to give 312 mg of the expected ester.
C) 2-n-Butyl-6-spirocyclopentane-5,6-dihydro-lH-pyri-midin-4-one A mixture containing 310 mg of the compound obtained in step B, 348 mg of ethyl valerimidate, 10 ml of xylene and 6 drops of acetic acid is brought to the reflux point. After 2 hours and 18 hours, a further 348 mg of ethyl valerimidate are added and, after a total reflux time of 24 hours, the reaction medium is evaporated and then chromatographed on silica using a DCM/methanol mixture (97/3; v/v) as the eluent to give 153 mg of the expected product.
D) 2-n-Butyl-3-[(2'-tert-butoxycarbonylbiphenyl-4-yl)-methyl]-5,6-dihydro-lH-pyrimidin-4-one A mixture of 10 ml of DMF and 40 mg of sodium hydride as an 80~ dispersion in oil is prepared under a nitrogen atmosphere. 144 mg of the compound prepared in step C, dissolved in 5 ml of DMF, are added dropwise at room temperature. After stirring for 30 minutes, a solution of 288 mg of 4-bromomethyl-2'-tert-butoxy-carbonylbiphenyl in 5 ml of DMF is added. The mixture is stirred for 2 hours and then evaporated and the residue is taken up in water and extracted with ethyl acetate. The extract is dried over sodium sulfate, 05 filtered, evaporated and then purified by column chro-matography using a hexane/ethyl acetate mixture (85/5;
v/v) as the eluent to give 174 mg of the expected pro-duct.
E) 10 ml of trifluoroacetic acid are cooled in a bath of iced water and 161 mg of the compound prepared in step D are added. The mixture is stirred for 30 minutes and then evaporated. The residue is taken up in ethyl ether and the mixture is then evaporated again. This operation is repeated and the residue is then dried under vacuum to give 140 mg of the expected compound in the form of an amorphous powder. M.p. =
108-115 C.
- NMR spectrum:
0.9 ppm : t : 3 H : (CH2)3-CH3 1.1 to 2.1 ppm : m : 12 H : cyclopentane and CH2-CH2-2.7 ppm : t : 2 H : CH2-CH2-CH2-CH3 3.1 ppm : s : 2 H : -C_2-CO
5.1 ppm : s : 2 H : N-CH2-C~H5 7.2 to 7.8 ppm : m : 8 H : aromatic protons 2-n-Butyl-4-spirocyclopentane-l-[(2~-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thione and 2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-spirocyclopentane-2-imidazolin-5-thione tri-fluoroacetate A) 2-n-Butyl-4-spirocyclopentane-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thione 5.63 g of the compound prepared in Example 1, step D, are dissolved in 40 ml of anhydrous toluene and treated with 3 g of Lawesson's reagent at 80C under nitrogen. After 6 hours, the reaction mixture (sic) is filtered and concentrated. The concentrate is chromatographed on silica using a DCM/ethyl acetate mixture (95/5; v/v) as the eluent to give the expected product in the form of an oil, which crystallizes in the cold.
m = 4.5 g. M.p. = 77-79C.
- NMR spectrum:
0.90 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : s : 9 H : tBu 1.35 ppm : sext : 2 H : CH3-C_ 2-1.60 ppm : quint : 2 H : CH3-CH2-CH2-1.80-2.10 ppm : m : 8 H : cyclopentane 2.60 ppm : t : 2 H : CH3-CH2-CH2-C_ 2 5.35 ppm : s : 2 H : CH2-C6H4-7.25-7.80 ppm : m : 8 H : aromatic protons B) 2-n-Butyl-1-~(2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-thione trifluoroacetate 225 mg of the compound obtained in step A are treated with 5 ml of DCM and 5 ml of TFA for 30 minutes.
After concentration, the residue is taken up in ether.
The expected compound is obtained in the form of a yellow powder, which is filtered off and then rinsed with hexane. m = 160 mg. M.p. = 185-190C.
- Mass spectrum:
MHt 421 - NMR spectrum:
0.78 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : sext : 2 H : CH3-CH2 1.50 ppm : quint : 2 H : CH3-CH2-C_ 2-nl ~1 - _ 2057913 - Sl -1.75-2.00 ppm : m : 8 H : cyclopentane 2.40 ppm : t : 2 H : CH3-CH2-CH2-C_2 5.20 ppm : s : 2 H : C_2-CGH~-7.00-7.65 ppm : m : 8 H : aromatic protons 2-n-Butyl-4-(2-spiroindane)-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)me~hyl]-2-imidazolin-5-one and 2-n-butyl-l-[(2'-carboxybiphenyl-4-yl)methyl]-4-(2-spiro-indane)-2-imidazolin-5-one - Method 1 A) 2-Aminoindane-2-carboxylic acid is prepared accor-ding to R.M. Pinder, J. Med. Chem., 1971, 14, 9, 892, and the corresponding ethyl ester is then prepared according to Adkins (ref. cited in Example 2A).
B) 2-n-Butyl-4-(2-spiroindane)-2-imidazolin-5-one 2.78 g of the ethyl ester prepared in step A
and 2.5 g of ethyl valerimidate are dissolved in 20 ml of xylene in the presence of 60 ~1 of acetic acid and refluxed for 3 hours. A further 500 mg of ethyl valer-imidate are added and reflux is maintained for afurther 3 hours. The reaction medium is concentrated and then chromatographed on silica using a hexane/
ethyl acetate/acetic acid mixture (3/8/0.3; v/v/v) as the eluent. The pure fractions are combined and eva-porated with toluene to give 3.07 g of the expected product in the form of a white solid. M.p. = 148-150 C.
- NMR spectrum:
o.9o ppm : t : 3 H : CH 3 ( nBu) 1.2-1.7 ppm : m : 4 H : CH2-CH2-CH3 2.4 ppm : t : 2 H : C_2-(CH2)2-CH3 2.8-3.2 ppm : q : 4 H : 2C_2 (indane) 4.90 ppm : s : 2 H : C_2-C~H~-7.2 ppm : m : 4 H : aromatic protons C) 2-n-Butyl-4-(2-spiroindane)-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one The compound obtained in the previous step is dissolved in 20 ml of anhydrous DMF and treated with 450 mg of sodium methylate under nitrogen. After 20 minutes at room temperature, 3.6 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl are added and the mixture is stirred at 40C for 6 hours. The reaction medium is concentrated, the usual washes are then carried out and the product is chromatographed on silica using di-chloromethane/ethyl acetate (95/5; v/v) as the eluent to give (sic) the expected compound in the form of a foam (m = 1.84 g).
- NMR spectrum:
0.80 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : s : 9 H : tBu 1.20-1.60 ppm : m : 4 H : CH2-CH2-CH3 2.40 ppm : t : 2 H : CH2-(CH2)2-CH3 2.9-3.3 ppm : q : 4 H : 2CH2 (indane) 4.80 ppm : s : 2 H : N-CH2-C6H4-7.20-7.80 ppm : m : 12 H : aromatic protons D) 2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(2-spiroindane)-2-imidazolin-5-one 1.71 g ... (sic) of the compound obtained in the previous step are dissolved in 15 ml of DCM and treated with 20 ml of TFA. After 30 minutes, the reaction medium is concentrated and then taken up in ether. After trituration, the solid obtained is filtered off, rinsed with ether and dried to give 1.42 g of the expected product. M.p. = 217-218C.
- NMR spectrum:
0.70 ppm : t : 3 H : CH3 (nBu) 1.10-1.50 ppm : m : 4 H : C_2-CH2-CH3 2.30 ppm : t : 2 H : CH2-(CH2)2-CH3 2.8-3.3 ppm : q : 4 H : 2CH2 (indane) ~3~

4.70 ppm : s : 2 H : N-CH2-C~H~-7.1-7.7 ppm : m : 12 H : aromatic protons Other compounds according to the invention were prepared by one of the methods described above. They 05 are collated in Table 1. The structure of each of these compounds is consistent with the analysis of their NMR spectra.

2-n-Butyl-1-[(2'-(imidazol-1-ylcarbonyl)bi-phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (I: R1 = -C-N I , R2 = H, R3 = n-C4Hg, o ~ ~

CR4R5 = cyclopentane, X = O) A mixture containing 404 mg of the compound prepared in Example 1, step E, 15 ml of THF and 260 mg of carbonyldiimidazole is stirred at room temperature for 72 hours. The reaction medium is evaporated, the residue is taken up in ethyl acetate and the mixture is washed with water and then with a solution of sodium chloride to give 420 mg of product, which are purified ~y chromatography on silica using a DCM/ethyl acetate mixture (70/30; v/v) as the eluent to give the expected compound.
m = 230 mg.
M.p. = 120 C.

_ 54 _ 2057913 2-n-Butyl-1-[(2'-(3-cyano-2-methylisothio-ureidomethyl)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (I: Rl = -CH2-NH-C=N-CN, R2 = H, R3 = n-C4Hg, CR4R5 = cyclopentane, X = O) A) 1-[(2'-Aminomethylbiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one This compound is obtained by hydrogenation of the compound prepared in Example 5.
1 g of the compound prepared in Example 5, step A, is placed in 15 ml of absolute methanol and 2.3 ml of ethanol in the presence of 0.5 g of 5% palladium-on-charcoal and the mixture is hydrogenated at room tem-perature for 24 hours. After treatment, 730 mg of the expected product are obtained in the form of an oil.
B) A mixture containing 300 mg of the compound prepared in the previous step and 113 mg of N-cyan-imido-S,S-dimethyldithiocarbonate in 3 ml of ethanol is refluxed for 24 hours. After the usual treatment, the reaction medium is purified by chromatography on silica using a DCM/ethyl acetate mixture (50/50; v/v) as the eluent. The expected product is isolated in the form of a white solid.
m = 307 mg.
M.p. = 83 C.

2-n-Butyl-1-[(2'-(2-cyanoguanidinomethyl)bi-phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (I: R1 = CHz-NH-C=N-CN, R2 = H, R3 = n-C4Hg, CR4R5 = cyclopentane, X = O) 05 This compound is obtained from the compound prepared in the previous Example. 200 mg of the com-pound are placed in 10 ml of absolute ethanol and the mixture is saturated with ammonia at about 10 C and then heated at 80 C in an autoclave ovérnight. After concentration of the reaction medium to dryness, the residue is chromatographed on silica using a DCM/
methanol mixture (95/5; v/v) as the eluent to give 130 mg of the expected product.
M.p. = 100 C.

2-n-Butyl-4-spirocyclopentane-1-[(2'-trifluoro-methylsulfonylaminobiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoromethylsulfonate (I: Rl = -NHS02CF3, R2 = H, R3 = n-C4Hg, CR4R5 = cyclopentane, X = O) A) 4-Methyl-2'-nitrobiphenyl 11.2 g of 2-nitrobromobenzene are mixed with 15 g of 4-iodotoluene and the mixture is heated to 195 C and stirred at this temperature for 3 and a half hours. After returning to room temperature, it is taken up in DCM and heated to the reflux point, the hot solution is filtered on Celite~ and the DCM is then evaporated off.
m = 6.5 g.
B.p. = 80-120 C under 0.2 mm Hg, nD24 = 1.6042.
B) 4-Bromomethyl-2'-nitrobiphenyl A mixture containing 6.5 g of 4-methyl-2'-nitrobiphenyl, 5.42 g of NBS, 118 mg of azo-bis-iso-butyronitrile and 500 ml of carbon tetrachloride is refluxed for 5 hours. It is cooled to 0C and filtered and the filtrate is concentrated to give 9 g of an oily 05 product, which is used as such in the next step.
C) 2-n-Butyl-1-[(2'-nitrobiphenyl-4-yl)methyl~-4-spiro-cyclopentane-2-imidazolin-5-one A mixture containing 260 mg of 80% sodium hydride in 5 ml of DMF is prepared and 500 mg of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one, prepared in Example 2, step A, are added at room temperature under nitrogen. After stirring for 15 minutes, 901 mg of 4-bromomethyl-2'-nitrobiphenyl in 5 ml of DMF are added and stirring is continued for 24 hours. The reaction medium is concentrated to dryness and the residue is taken up in a water/ethyl acetate mixture.
The organic phase is decanted, dried over sodium sul-fate and filtered and the ethyl acetate is then eva-porated off. The product obtained is chromatographed on silica using a DCM/ethyl acetate mixture (9/1: v/v) as the eluent to give 500 mg of the expected product.
D) 1-[(2'-Aminobiphenyl-4-yl)methyl]-2-n-butyl-4-spiro-cyclopentane-2-imidazolin-5-one 450 mg of the product obtained in the previous step are placed in 10 ml of methanol in the presence of 5% palladium-on-charcoal, at room temperature, for hydrogenation. After filtration of the catalyst and evaporation, 240 mg of the expected product are ob-tained.
E) In 4 ml of DCM, 225 mg of the product obtained in the previous step are mixed with 0.1 ml of tri-ethylamine, 0.2 ml of trifluoromethylsulfonic anhydride is added under argon at -78 C and the mixture is then left to return to room temperature. The reaction -medium is washed with water and a solution of sodium bicarbonate and then dried and concentrated to give 150 mg of an amorphous white solid.
- NMR spectrum:
05 0.4-1.3 ppm : m : 7 H : CH3-CH2-CH2-1.4-2.3 ppm : m : 10 H : CH3-CH2-CH2-CH2 and cyclo-pentane 4-4.8 ppm : AB system : 2 H : N-CH2-CGH4-7-7.6 ppm : m : 8 H : aromatic protons 8.3 ppm : s : 1 H : -NH
10 ppm : sb : 1 H : CF3S03H

2-n-Butyl-4-spirocyclopentane-1-[(2'-trifluoro-methylsulfonylaminomethylbiphenyl-4-yl)methyl]-2-imi-dazolin-5-one trifluoromethylsulfonate (I: Rl = CH2NHS02CF3, R2 = H, R3 = n-C4Hg, CR~R~ = cyclopentane, X = 0) The preparation is effected starting from the 1-[(2'-aminomethylbiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one prepared in Exam-ple 14, step A. 322 mg of this compound and 0.122 ml of triethylamine are placed in 3.4 ml of DCM at -70 C
and 0.294 ml of trifluoromethylsulfonic anhydride is added. The mixture is left to return to room tempera-ture, poured into dilute acetic acid and extracted with DCM, the extract is dried over sodium sulfate and filtered and the DCM is evaporated off. The residue is chromatographed twice on silica using DCM/ethyl acetate (95/5; v/v, then 99.5/0.5; v/v) as the eluent.
This gives m = 90 mg.
M.p. = 90 C.

- NMR spectrum:
0.4-1.2 ppm : m : 7 H : -CH2-CH2-CH3 1.3-2.45 ppm : m : 10 H : CH~-CH2-CH2-CH3 and cyclo-pentane 05 4.1-5 ppm : m : 4 H : N-C~,-C~H~- and NH-CH,-C~H~-7.1-7.7 ppm : m : 8 H : aromatic protons 8.4 ppm : s : 1 H : NH

2-n-Butyl-1-[(2~-N-hydroxycarbamoyl)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one tI: R = -CO-NHOH, R~ = H, R, = n-C4H9, CR~R5 = cyclopentane, X = O) The compound prepared in Example 2 is freed from its trifluoroacetic acid salt by taking up this compound in an ethyl acetate/water mixture and bringing the solution to pH 6 by the addition of a saturated solution of sodium bicarbonate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to give the free base in the form of a white solid.
450 mg of this compound are dissolved in chloroform, 860 ml of thionyl chloride are added at 0 C
and the mixture is stirred at room temperature for 2 hours. The solution is concentrated and the traces of thionyl-chloride are removed by azeotropic distillation with toluene. The acid chloride thus obtained is added dropwise in DMF solution to a solution containing 200 mg of hydroxylamine hydrochloride and 700 ~1 of DIPEA
in 10 ml of DMF. After 2 hours at O-C, the reaction medium is concentrated and the concentrate is taken up in 100 ml of DCM and 50 ml of water. The mixture is brought to pH 7 and the organic phase is extracted and E

20~7913 then dried over sodium sulfate. After filtration, the solution is concentrated. The product obtained is recrystallized from an ethyl acetate/ethyl ether/hexane mixture.
05 m = 360 mg.
M.p. - 85 C.

2-n-Butyl-4-spirocyclopentane-1-~(2'-ureido-biphenyl-4-yl)methyl]-2-imidazolin-5-one (I: R1 = NHCONH2, R2 = H, R3 = n-C4Hg, CR4R5 = cyclopentane, X = O) This compound is prepared using the method des-cribed by B.B. Kobu et al. in Org. Synth., 1957, 37, 52, starting from the l-[(2'-aminobiphenyl-4-yl)-methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one prepared in Example 14, step A.
1 g of the latter is dissolved in 50 ml of 6 N
hydrochloric acid and treated with potassium isocyanate for 1 hour at 5 C. The reaction medium is concentra-ted, the concentrate is taken up in ethyl acetate and the mixture is washed with sodium bicarbonate and then with a saturated solution of sodium chloride. After drying over sodium sulfate and filtration, the solution is concentrated and the oil obtained is purified by chromatography on silica using a DCM/methanol mixture (9/1; v/v) as the eluent.
m = 600 mg.
- NMR spectrum:
0.85 ppm : t : 3 H : CH2-CH3 1.35 ppm : sext : 2 H : CH2-CH3 1.6 ppm : quint : 2 H : CH2-CH2-CH3 --1.7-2 ppm : m : 8 H : cyclopentane 2.45 ppm : t : 2 H : CH2-CH2-CH2-CH3 4.8 ppm : s : 2 H : -CH2-C~H4-6.05 ppm : s : 2 H : NH2 7-8 ppm : m : 9 H : 8 aromatic H + NHCO

1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one and 1-[(2'-N-cyanocarboxamidebiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (I: Rl = C0-NH-CN, R2 = H, R3 = n-C3H7, CR4R5 = cyclohexane, X = O) A) Ethyl butyrimidate hydrochloride /NH
CH3 - CH2 - CH2 - C . HCl This compound is prepared according to Mc Elvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827).
23 ml of butyronitrile are added at 0 C to a solution of 10.6 g of gaseous hydrochloric acid in 20 ml of anhydrous ethanol and then, after the reaction medium has been left to stand for 4 days at 0 C, it is poured into 200 ml of anhydrous ether at 0C, with stirring; the precipitate formed is filtered off, washed with ether and then dried under vacuum to give 25.8 g of the expected product.
B) Ethyl butyrimidate 16 g of the imidate obtained in step A are dissolved in 100 ml of dichloromethane and 50 ml of water, and 15 g of potassium carbonate-are added.
After decantation, the dichloromethane is dried over -potassium carbonate and then evaporated off to dryness without heating.
C) Ethyl ester of 1-aminocyclohexane (sic) carboxylic acid 1-Aminocyclohexanecarboxylic acid is commercially available. 15 g of this amino acid are added at 0C to a solution of 23 g of gaseous hydrochloric acid in 150 ml of anhydrous ethanol. The reaction medium is refluxed for 5 hours and then concentrated to dryness and the residue is taken up in ether. The white solid obtained is filtered off, washed with ether and then dissolved in a mixture of 300 ml of ether and 100 ml of water. The pH is brought to 9 by the addition of a solution of potassium carbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness to give 14 g of the expected product in the form of an oil.
D) 2-n-Propyl-4-spirocyclohexane-2-imidazolin-5-one 14 g of the product obtained in step C are dissolved in 200 ml of xylene containing 0.6 ml of acetic acid. Half the imidate obtained in step B is added and the mixture is heated to the reflux point. After 1 and a half hours, half the remaining imidate is added and the last quarter is then added after 4 hours. After a total reflux time of 7 hours, the medium is evaporated to dryness. The solid obtained is taken up in hexane, filtered off, washed with ether and then dried.
This gives 10.3 g of the expected imidazolinone.
M.p. = 124-125C.
- IR (CHCl3):
1715 cm~l : C=o 1635 cm~l : C=N
Note: The compound present in solution is indeed an ~31 imidazolin-5-one according to the values of the IR
bands.
E) 2-n-Propyl-4-spirocyclohexane-1-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 05 970 mg of the imidazolinone obtained in step D
are added to 0.24 g of sodium hydride as an 80% disper-sion in oil, suspended in 10 ml of dimethylformamide.
After stirring for 20 minutes under nitrogen, 1.91 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl, prepared according to European patent application 324 377, are added over 5 minutes. After stirring for 1 hour, the medium is concentrated to half its volume under vacuum and taken up in 100 ml of ethyl acetate and then in 20 ml of water. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum.
The residue is chromatographed on silica using an ethyl acetate/toluene mixture as the eluent to give 2.10 g of the expected product in the form of a wax.
- IR (CHCl3):
1705-1715 cm-1 : C=O, C=O (ester, imidazolinone) 1635 cm-1 : C=N
Analysis of the NMR spectrum confirms the structure.
F) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 20) 1.25 g of the tert-butyl ester obtained in step E are stirred for 45 minutes in a mixture of 11 ml of dichloromethane and 15 ml of trifluoroacetic acid.
After concentration under vacuum, the residue is taken up in ether. The solid formed is filtered off, washed with ether and then dried to give 1.04 g of a white solid.
M.p. = 170-172 C.
- NMR spectrum:
7.10-7.80 ppm : m : 8 H : aromatic protons ~057913 4.90 ppm : s : 2 H : N-CH2-C6H4-2.45 ppm : t : 2 H : CH3-CH2-C_ 2-1.40-1.80 ppm : m : 12 H : spirocyclohexane + CH3-c_2-CH2-0.90 ppm : t : 3 H : C_3-CH2-CH2-1.60 g of the trifluoroacetate obtained previously are dissolved in 150 ml of ethyl acetate and 20 ml of water. 1 N sodium hydroxide solution is added to bring the pH to 5Ø The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness.
The solid residue is taken up in ethyl ether, filtered off and dried.
m = 1.14 g.
M.p. = 208-210C.
G) 1-[(2'-N-Cyanocarboxamidebiphenyl-4-yl)methyl]-2-propyl-4-spirocyclohexane-2-imidazolin-5-one (sic) (Example 21) 0.54 ml of thionyl chloride is added to 300 mg of the compound prepared in the previous step, suspended in 5 ml of DCM. After 1 and a half hours, the reaction medium is concentrated under vacuum and then evaporated twice with benzene. The acid chloride thus obtained is dissolved in 2 ml of dioxane and added to a solution of 42 mg of cyanamide in 1 ml of dioxane containing 0.2 ml of 10 N sodium hydroxide solution. After 1 and a half hours, the reaction medium is diluted with 150 ml of ethyl acetate and 20 ml of water, the pH is brought to 5 with acetic acid and the organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness.
The residue is chromatographed on silica using a chloroform/methanol/acetic acid mixture (90/8/2; v/v) as the eluent to give 160 mg of the expected product in the form of a solid.

ID

- 64 - 20~7913 - IR (KBr):
2150 cm-l : C3N
- Mass spectrum:
MH~ : 429 - NMR spectrum:
7.20-7.70 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : N-CH2-C~H~-2.40 ppm : t : 2 H : CH3-CH2-CH~-1.30-1.80 ppm : m : 12 H : CH3-C~2-CH2- and spiro-cyclohexane 0.85 ppm : t : 3 H : CH3-CH2-CH2 l-[(2~-(N-4-carboxy-l~3-thiazol-2-ylcarbamoyl) biphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one N COOH
(I: Rl = -Co.~H- ~ ~ ,R2 = H, R3 = n-C3H,~

CR~R = cyclohexane, X = O) This compound is prepared from the compound obtained in Example 20.
2-Amino-4-ethoxycarbonyl-1,3-thiazole is pre-pared according to B. Plouvier et al., J. Heterocycl.
Chem., 1989, 26(6), 1646.
A) l-[(N-4-carbethoxy-l~3-thiazol-2-ylcarbamoyl)-methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (sic) 500 mg of BOP and 0.14 ml of triethylamine are added to a solution of 404 mq of the compound prepared in Example 20 and 190 mg of thiazole derivative in 4 ml of DCM and 1 ml of DMF. The mixture is stirred for 40 20~7913 hours at room temperature and then 7 hours at 50 C.
The reaction medium is taken up in 50 ml of ethyl acetate and washed twice with a KHS04-K2S04 solution, then twice with a saturated solution of sodium bicar-05 bonate and then once with a saturated solution ofsodium chloride. After drying over sodium sulfate, the organic phase is concentrated under vacuum and the residue is chromatographed on silica using an ethyl acetate/toluene mixture as the eluent to give 120 mg of the expected product.
M.p. = 96-98 C.
B) 0.5 ml of 2 N sodium hydroxide solution is added to 110 mg of the product obtained in the previous step, dissolved in 1 ml of methanol and 1 ml of diox-ane. After stirring for 35 minutes, the reaction medium is diluted with 10 ml of water and 60 ml of ethyl acetate and the pH is brought to 5 by the addi-tion of 1 N hydrochloric acid. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concen-trated. The residue is taken up in ether, filtered off and dried.
m = 100 mg.
M.p. = 145-148 C.
- NMR spectrum:
8.0 ppm : s : 1 H : H in the 5 position of the thiazole 7.1-7.7 ppm : m : 8 H : aromatic protons 4.7 ppm : s : 2 H : N-C_2-C~H4-2.25 ppm : t : 2 H : CH2-CH2-CH3 1.2-1.8 ppm : m : 12 H : cyclohexane and CH2-C_2-CH3 0.85 ppm : t : 3 H : CH2-CH2-C_3 -2-n-Butyl-1-[(2'-(2-cyanoguanidinocarbonyl)-biphenyl-4-yl)methyll-4-spirocyclopentane-2-imidazolin-5-one NHz (I: Rl = CONH-C=N-CN, R2 = H, R3 = n-C4Hg, CR4R5 = cyclopentane, X = O) The acid chloride of the compound obtained in Example 2 is prepared. 1 g of this compound is placed in 20 ml of DCM, in the presence of 1.8 ml of thionyl chloride, and the mixture is stirred at room tempera-ture for 2 hours. After concentration of the medium, the residue is taken up in benzene and the mixture is then concentrated again. The crude product isolated is then used. It is mixed with 417 mg of dicyanodiamide, 0.5 ml of 10 N sodium hydroxide solution, 0.5 ml of water and 10 ml of dioxane and the mixture is then stirred for 5 hours. The reaction medium is taken up in water and ethyl acetate, potassium carbonate is added and the mixture is then concentrated. The resi-due obtained is chromatographed on silica using a DCM/
methanol mixture (95/5; v/v) as the eluent. 100 mg of the expected product are isolated.
M.p. = 105 C.

4-Benzylidene-2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoroacetate (I: Rl = CO2H, R2 = H, R3 = n-C4Hg, R4R5 =
=CH-C~j,Hs, X = O) A) Tert-butyl 4-(1-benzylidene-1-valerylaminomethyl-amidomethyl)biphenyl-2-carboxylate (sic) C02tBu n-c4llg-co-~H-c-co-~lH-cH2-c6H~ ~\<3 Starting from N-Boc-~-dehydro-(L)-phenylala-nine, the N-carboxyanhydride of ~-dehydro-(L)-phenyl-alanine is prepared according to R. Jacquier et al., Tetrahedron Lett., 1984, 25(26), 2775. p. (sic). 644 mg of tert-butyl 4-aminomethylbiphenyl-2'-carboxylate are added to a solution of 430 mg of this compound in 5 ml of THF, the mixture is stirred for 2 hours at room temperature, 1 ml of methyl orthovalerate is then added and the mixture is evaporated to dryness under vacuum without heating. The residue is heated for 3 hours at 100 C, concentrated under vacuum and then chromato-graphed on silica using a hexane/ethyl acetate mixture(4/1; v/v) as the eluent to give 580 mg of a white solid.
M.p. = 154 C.
- NMR spectrum:
1.3 ppm : s : 9 H : tBu 0.65 ppm : t : 3 H : CH3 (nBu) 2 ppm : t : 2 H : CH3-CH2-CH2-CH2-CO
4.4 ppm : d : 1 H : CH2-NH
6.8 ppm : s : 1 H : CH (=C_-C H5) B) 4-Benzylidene-2-n-butyl-1-~(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-imidazolin-5-one 440 mg of the compound obtained in step A are dissolved in 1 ml of acetic acid and heated for 30 minutes at 100C.
The solution is evaporated to dryness under 20~7913 ,.~

vacuum and the residue is chromatographed on silica using a hexane/ethyl acetate mixture (4/1; v/v) as the eluent to give 130 mg of the expected product in the form of an oil.
05 - NMR spectrum:
4.9 ppm : s : 2 H : CH2 (N-CH2-C~H4-) C) 100 mg of the compound obtained in the previous step are dissolved in 1 ml of DCM, 1 ml of trifluoro-acetic acid is added and the mixture is then stirred for 40 minutes at room temperature and evaporated under vacuum. The residue is taken up several times in DCM
and then evaporated. A white solid precipitates on the addition of ethyl ether.
m = 101 mg.
M.p. = 85 C.
- Mass spectrum:
MH' : 439 - NMR spectrum:
0.82 ppm : t : 3 H : CH3 (nBu) 1.3 ppm : sext : 2 H : CH3-C_ 2-1.6 ppm : m : 2 H : CH3-CH2-C_2-2.6 ppm : t : 2 H : CH3-CH2-CH2-C_2-4.82 ppm : s : 2 H : C_2-C~H4-7.05 ppm : s : 1 H : =CH-C~H5 7.2-8.2 ppm : m : 13 H : aromatic protons 4-Benzylidene-1-[(2'-carboxybiphenyl-4-yl)-methyl]-2-phenyl-2-imidazolin-5-one (I: Rl = CO2H, R2 = H, R3 = C~Hs, R4R5 =
=CH-C~H5, X = O) -A) 4-Benzylidene-2-phenyloxazol-5-one 1.8 g of hippuric acid and 0.4 g of potassium bicarbonate are dissolved in 4 ml of acetic anhydride, the solution is heated for a few minutes at 50 C and 05 then cooled to room temperature and 1.49 g of benz-aldehyde are added. After 1 hour at room temperature, 20 ml of distilled water are added at 80C. The solid which precipitates is filtered off, washed with water and ethanol and then dried to give 1.24 g of the expected product in the form of a yellow solid.
M.p. = 215 C.
- NMR spectrum:
7.4 ppm : s : 1 H : =CH-C~HS
8.1-8.4 ppm : m : 10 H : aromatic protons B) Tert-butyl 4-(1-benzoylamino-1-benzylidenemethyl-amidomethyl)biphenyl-2'-carboxylate A mixture containing 500 mg of the compound obtained in the previous step, 570 mg of tert-butyl 4-aminomethylbiphenyl-2'-carboxylate and 10 ml of pyri-dine is heated at 110C for 3 hours. It is evaporatedunder vacuum, the residue is taken up in chloroform and the mixture is then evaporated again. The residue is chromatographed on silica using a hexane/ethyl acetate mixture (3/1 then 2/1; v/v) as the eluent to give 106 mg of the expected product in the form of a yellow solid.
- NMR spectrum:
1.1 ppm : s : 9 H : tBu 4.35 ppm : t : 2 H : -CHz-NH
7.05-7.06 ppm : m : 19 H : aromatic protons +
C~H5-CH=
8.65 ppm : t : 1 H : NH-CH2 9.9 ppm : s : 1 H : N_-CH=

C) A mixture of 1.2 g of the compound obtained in -the previous step and 1.1 g of freshly melted sodium acetate is refluxed for 6 hours in 5 ml of acetic acid.
It is left to cool and an insoluble material is then precipitated by the addition of chloroform. The fil-05 trate is evaporated and the residue is chromatographedon silica using a chloroform/methanol mixture (98/2;
v/v) as the eluent. The solid obtained is recrystal-lized from ethyl ether.
m = 692 mg.
M.p. = 120 C.
- NMR spectrum:
4.95 ppm : s : 2 H : CH2-CGH4-7.1-8.3 ppm : m : 19 H : aromatic protons + =CH-C~H5 Z-n-Butyl-1-[(2'-(2-methyltetrazol-5-yl)bi-phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (Example 26) and 2-n-butyl-1-[(2'-(1-methyltetra-zol-5-yl)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (Example 27) In 10 ml of DMF, 500 mg of the compound pre-pared in Example 5 are mixed with 58 mg of sodium hydride, the mixture is stirred for 30 minutes, 179 mg of methyl iodide and 2 ml of DMF are then added and the mixture is stirred at room temperature for 4 hours.
The reaction medium is concentrated and the concentrate is taken up in water and then extracted with ethyl acetate. The extract is dried over sodium sulfate and filtered and the solvent is evaporated off. The resi-due is chromatographed on silica using a hexane/ethylacetate mixture (6/4: v/v) as the eluent. 2 fractions are isolated:
90 mg of the compound of Example 26 and 184 mg of the compound of Example 27 - NMR spectra:
Example 26 0.7 ppm : t : 3 H : CH3- (nBu) 1.2 ppm : sext : 2 H : CH3-CH2-05 1.4 ppm : quint: 2 H : CH3-CH2-C_2-1.5-1.9 ppm : m : 8 H ; cyclopentane 2.25 ppm : t : 2 H : CH3-CH2-CH2-CH2-4.15 ppm : s : 3 H : N-CH3 4.6 ppm : s : 2 H : -N-CH2-CGH4-7 ppm : AA', BB' system : 4 H : CH2-C~H~-7.3-7.75 ppm : m : 4 H : CH2-C~H~-C~H4-Example 27 0.7 ppm : t : 3 H : CH 3 ( nBu) 1.15 ppm : sext : 2 H : CH3-CH2-1.38 ppm : quint : 2 H : CH3-CH2-CH2-1.5-l.9 ppm : m : 8 H : cyclopentane 2.2 ppm : t : 2 H : CH3-CH2-CH2-CH2-3.35 ppm : s : 3 H : N-cL3 4.6 ppm : s : 2 H : N-C_2-CGH~
7 ppm : AA', BB' system : 4 H : N-CH2-CGH~-7.4-7.8 ppm : m : 4 H : CH2-CGH~-C~H4-2-n-Butyl-6-spirocyclopentane-3-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-4(lH)-5,6-dihydropyrimidin-4-one A) Ethyl cyclopentylideneacetate 6 g of 80% sodium hydride are placed in 40 ml of benzene, and 57.1 ml of ethyl triethylphosphono-acetate are added dropwise at a temperature below 35 C.
After 1 hour at room temperature, 24.3 ml of cyclo-pentanone are added dropwise. The mixture is heated at 65 C for 15 minutes and then cooled to room temperature and the supernatant liquor is decanted. 25 ml of benzene are added, the mixture is heated at 65C for 15 2057~1~

minutes, cooled and decanted and the supernatant liquor is then recovered. The operation is repeated once.
Evaporation of the liquors gives 42 g of the expected product, which is distilled.
B.p. = 102C under 11 mm of mercury.
m = 22.8 g.
B) (1-Aminocyclopentyl)acetamide 150 ml of gaseous ammonia are added to 20 g of the ethyl cyclopentylideneacetate prepared previously and the mixture is heated at 150C for 72 hours. The product obtained after evaporation is purified by chromatography on silica using a DCM/methanol/20% aqueous ammonia mixture (so/lo/1; v/v/v) as the eluent. The product obtained is dissolved in DCM and the solution is dried over sodium sulfate. It is filtered and the DCM is evaporated off to give 7.2 g of the expected product.
C) 2-n-Butyl-6-spirocyclopentane-4(lH)-5,6-dihydropyri-midin-4-one A mixture containing 4.57 g of the (1-amino-cyclopentyl)acetamide prepared previously, 25 ml of methyl orthovalerate and a few drops of acetic acid is heated at 100C for 18 hours. After evaporation of the excess orthovalerate, the residue is taken up in an ethyl acetatetsodium bicarbonate mixture, then washed with an aqueous solution of sodium chloride, dried over (sic) sodium sulfate and then purified by chromatography on silica using a DCM/methanol mixture (98/2; v/v) as the eluent.
m = 5 g.
- NMR spectrum:
0.75 ppm : t : 3 H : CH3 (nBu) 1.2 ppm : sext : 2 H : CH3-CH2-1.3-1.8 ppm : m : 10 H : CH3-CH2-CH2 and cyclopentane 2 ppm : t : 2 H : CH3-CH2-CH2-CH2-~3' ;

2.15 ppm : s : 2 H : CH2-C0 9.95 ppm : sb : 1 H : NH
This compound is the one obtained in Example 10, step C.
05 D) 2-n-Butyl-4-spirocyclopentane-1-[(2'-(triphenyl-methyltetrazol-5-yl)biphenyl-4-yl)methyl]pyrimidin-6-one 327 mg of 80% sodium hydride in 30 ml of DMF
are mixed for 30 minutes under nitrogen with 1.5 g of the pyrimidinone prepared previously, and 5.27 g of 4-bromomethyl-2'-(triphenylmethyltetrazol-5-yl)biphenyl are added. After stirring for 4 hours at room tempera-ture, the solvents are evaporated off and the residue is taken up in ethyl acetate and water, dried over sodium sulfate and concentrated. The product obtained is purified by chromatography on silica using an ethyl acetate/hexane mixture (3/7; v/v) as the eluent.
m = 3.2 g.
E) 3 g of the compound obtained in the previous step are placed in 15 ml of methanol, the mixture is cooled in a water/ice bath, 2.2 ml of 4 N HCl are added and the mixture is stirred for 5 hours at room tempera-ture. After evaporation, the residue is taken up in ethyl acetate and water, and sodium hydroxide solution is then added to give a basic pH (pH 11). The mixture is left to decant and the aqueous phase is washed with ethyl ether and toluene and then ether again. This aqueous phase is brought to pH 5 by the addition of dilute hydrochloric acid and is then extracted with ethyl acetate and the extract is dried and concentra-ted. The product obtained is purified on silica using a DCM/methanol mixture (95/5; v/v) as the eluent to give 800 mg of the expected product.

- NMR spectrum:
0.85 ppm : t : 3 H : CH3 (nBu) 1.30 ppm : sext : 2 H : CH3-CH2 1.40-1.95 ppm : m : 10 H : cyclopentane and 05 CH2-cH2-cH2-cH3 2.30 ppm : t : 2 H : CH2-CH2-CH2-CH3 2.55 ppm : s : 2 H : CH2-CO
4.95 ppm : s : 2 H : N-CH2-C~H4-7.05 ppm : m : 4 H : CH2-CGH4-7.55-7.82 ppm : m : 4 H : CH2-C~H4-C~H4-2-n-Butyl-3-[(2'-carboxybiphenyl-4-yl)methyl]-5-spirocyclopentane-5(1H)-s,6-dihydropyrimidin-4-one trifluoroacetate A) Ethyl l-cyanocyclopentanecarboxylate This compound is prepared according to Helv.
Chim. Acta, 1952, 35(7), 2561.
9.2 g of sodium are dissolved in 200 cm3 of absolute ethanol. Half the solution of sodium ethylate formed is poured into a funnel. 24.88 g of ethyl cyanoacetate are added to the remaining half and the mixture is brought to the reflux point.
43.19 g of 1,4-dibromobutane are poured into another funnel and the solution of sodium ethylate and the 1,4-dibromobutane are simultaneously added dropwise to the reaction medium. When the addition is complete, reflux is maintained for 2 hours. The mixture is eva-porated and the residue is taken up in an ethyl ether/
water mixture, washed with a saturated solution of sodium chloride and then dried. The product obtained distils at 115-120 C under 11 mm of mercury.
m = 24 g.
B) Ethyl l-aminomethylcyclopentanecarboxylate This compound is prepared by the catalytic hydrogenation of ethyl l-cyanocyclopentanecarboxylate.
20 g of ethyl 1-cyanocyclopentanecarboxylate are placed in 200 ml of a 10% solution of ammonia in ethanol and hydrogenated at 60C under a pressure of 05 100 bar in the presence of rhodium-on-alumina for 72 hours. After filtration on cellite~ (sic) and evapora-tion, the residue is chromatographed on silica using a DCM/methanol/20~ aqueous ammonia mixture (98/2/0.5;
v/v/v) as the eluent.
m = 12.8 g.
C) 2-n-Butyl-5-spirocyclopentane-4(lH)-5,6-dihydropyri-midin-4-one A mixture containing 13.12 g of the compound obtained in the previous step and 13.5 g of ethyl valerimidate in 100 ml of xylene containing a few drops of acetic acid is refluxed for 13 hours. The reaction medium is evaporated and the residue is taken up in ethyl acetate and a 10% solution of sodium carbonate and then dried and concentrated.
m = 14 g.
M.p. = 89-91 C.
- NMR spectrum:
0.80 ppm : t : 3 H : CH3 (nBu) 1.10-1.80 ppm : m : 12 H : CH3-C~2-CH2- and cyclo-pentane 2.05 ppm : t : 2 H : CH3-CH2-CH2-C_ 2-3.20 ppm : s : 2 H : CH2 (pyrimidinone) 10 ppm : 1 H : s : N_-CO
D) 2-n-Butyl-5-spirocyclopentane-3-[(2~-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-4(lH)-5,6-dihydropyrimi-din-4-one 500 mg of the product obtained in the previous step are placed in 40 ml of DMF in the presence of 115 mg of an 80% dispersion of sodium hydride in oil, under argon, and stirred at room temperature for half an hour. 1.08 g of 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl are added and the mixture is stirred for 2 hours. After evaporation, the residue is taken up in an ethyl acetate/water mixture, washed with a saturated 05 solution of sodium chloride and then dried, concentra-ted and chromatographed on silica using an ethyl acetate/hexane mixture (3/7; v/v) as the eluent.
m = 280 mg.
E) 250 ml of the tert-butyl ester prepared in the previous step are dissolved in 10 ml of DCM. The solu-tion is cooled in a bath of iced water, 5 ml of cold trifluoroacetic acid are then added and the mixture is stirred for one hour in the cold and then 1 hour at room temperature. It is evaporated under reduced pres-sure. The residue is taken up in ethyl ether and then evaporated. The operation is repeated 3 times, the evaporation residue is then taken up in hexane and tri-turated and the hexane is then decanted. The product is taken up in ethyl ether and the precipitate is fil-tered off.
m = 190 mg.
M.p. = 153-155 C.
- NMR spectrum:
0.85 ppm : t : 3 H : CH3 (nBu) 1.35 ppm : sext : 2 H : CH3-CH2-1.45-2.20 ppm : m : lO H : CH3-CH2-CH2- and cyclo-pentane 2.80 ppm : t : 2 H : CH3-CHz-CH2-C_z-3.80 ppm : s : 2 H : CH2 (pyrimidinone) 5.15 ppm : s : 2 H : N-CH2-7.25 ppm : m : 8 H : aromatic protons Table 1 R~ N
~ ~ R3 H (or R2) Rl 05 0 N ~ ( I (I) (Ex.)Rl R3 CR4R5 Salt M.p. C
(30)C0zH n~C4Hs cyclohexane TFA 172-174 (31)COzCH3 n~C4Hs cyclopentane - 86-87 (32)*C0zH n~C4Hs C(CH3)C6Hs TFA 55-60 (33)C0zH n~C4Hs C(CzHs)z TFA 82-84 (34)C0zH n-C3H7 cyclopentane TFA 164 (35)(**) n-C~Hg cyclopentane - 163-164 (36)C0zH C6H5 cyclopentane TFA 178 (37)C0zH n~C4Hs cycloheptane TFA 160-162 (38)C0zH CH3 cyclopentane TFA 140 (39)C0zH n~C4Hs cyclopropane - 204-205 (40)tetrazol- -CH2-CH2- cyclopentane - 110 5-yl CH=CHz (41) tetrazol- n-C4Hg cyclohexane - 130 5-yl (42)tetrazol- n-C3H7 cyclohexane - 141 5-yl (43)C0zH cyclo- cyclopentane TFA 82-88 pentyl (44)CO2H n~C5Hll cyclopentane TFA 151 (45)C02H CH2-C6H5 cyclopentane TFA 88 (46)C0zH H cyclopentane - 230 (47)COzH n-C4H9 cyclobutane TFA 178 _.

(48) C02H n~C4Hs cyclododecane TFA 130-135 (49) C0zH n~C4Hs 2-adamantaneTFA 164-166 (50) C02H n~C4Hs 4-phenyl- TFA 155-157 cyclohexane (51) C02H n-C4Hg 4-methyl- TFA 198-200 cyclohexane (52) CO2H n-C4Hg N-acetyl-4- TFA 90-95 piperidine (53) C02H C3F7 cyclopentane - 141-143 (54)* C02H n~C4Hs C ~ CF3 207-209 C ~/ \~ Cl (55)* C02H n~C4Hs CH3\ ~ TFA 105 (56) C02H n~C4Hs / N-C0 TFA 95-105 _/--\N-CO-CH-~YH2 (57) C02H n-C4Hg \ ~ CH-C2Hs 125-135 (58) C02H n~C4Hs ~ N-C0 TFA 85-90 ~ C6H5 ** Rl = H and R2 = C02H
* These compounds have an asymmetric carbon and are isolated in the form of a mixture of optical isomers.

Claims (26)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A compound of the formula (I) in which:
- R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C6 alkyl, a C2-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazo1yl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyano-carbamoyl, an N-hydroxycarbamoyl, an N-(4-carboxy-1,3-thiazol-2-yl)carbamoyl, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyanoguanidinomethyl, an imidazol-l-ylcarbonyl and a 3-cyano-2-methylisothio-ureidomethyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen:
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;

- R4 and R5 are each independently a C1-C6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C1-C4 perfluoro-alkyl, a hydroxyl and a C1-C4 alkoxy;
- or R4 and R5 together form a group of the formula =CR7R8, in which R7 is hydrogen, a C1-C4 alkyl or a phenyl and R8 is a C1-C4 alkyl or a phenyl;
- or else R4 and R5 together are either a group of the formula (CH2)n or a group of the formula (CH2)pY-(CH2)q, in which Y is either an oxyqen atom, or a sulfur atom, or a carbon atom substituted by a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or a group N-R6, in which R6 is a hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C3, a C1-C4 alkylcarbonyl, a C1-C4 halo-genoalkylcarbonyl, a C1-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adaman-tane;
- p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
and its salts.
2. A compound according to claim 1 wherein R1 is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen.
3. A compound accordinq to claim 1 or claim 2 wherein R4 and R5 form a cyclopentane or a cyclohexane with the carbon to which they are bonded.
4. A compound according to claim 1 or 2 wherein R3 is a linear C1-C6 alkyl group.
5. A compound according to claim 1 or 2 wherein X is oxygen.
6. A compound according to claim 1 or 2 wherein z =
t = 0.
7. A compound according to claim 1 or 2, wherein R3 is a linear C1-C6 alkyl group and X is oxygen.
8. A compound according to claim 1 or 2, wherein R3 is a linear C1-C6 alkyl group, X is oxygen and z = t= 0.
9. A compound according to claim 1 which is 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one or one of its salts with acids or bases.
10. A method of preparing a compound (I) according to claim 1 or 2, wherein:
a1) a heterocyclic derivative of the formula 2 in which z, t, R3, R4 and R5 are as defined for (I) in claim 1, is reacted with a (biphenyl-4-yl)methyl derivative of the formula in which Hal is a halogen atom and R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2 ;
b1) if appropriate, the resulting compound of the formula 4 is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide] ;
and c1) the compound obtained in a1) or b1), of the formula 5 in which X is an oxygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the groups R'1 and/or R'2 to the groups R1 and/or R2 respectively.
11. A method of preparing a compound (I) according to claim 1 or 2, wherein;
a2) an amino acid of the formula 7 in which z, t, R4 and R5 are as defined for (I) in claim 1, and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methyl-amine derivative of the formula in which R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2 ;
b2) after deprotection of the amine, the resulting compound of the formula 9 is then treated with an alkyl ortho-ester of the formula R3C(OR)3 (10), in which R3 is a defined for (I) in claim 1 and R is a C1-C4 alkyl;
c2) if appropriate, the resulting compound of the formula 4 is treated with lawesson's reagent [2,4-bis(4-methoxy-[2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide] ;
and d2) the compound thus obtained in b2 or c2, of the formula 5 is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'1 to the groups R2 and/or R1 respectively.
12. A method of preparing a compound (I) according to claim 6, wherein:
a3) a (biphenyl-4-yl)methyl derivative of the formula in which Hal is a halogen atom and R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2, is reacted with an imidazole derivative of the formula in which R3, R4 and R5 are as defined for (I) in claim 1, in the presence of oxygen and UV irradiation and in a basic medium :
b3) if appropriate, the resulting compound of the formula 4' is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide];
and c3) the compound thus obtained in b3 or c3, of the formula 5' is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'1 and/or R'2 to the groups R1 and/or R2 respectively.
13. A compound of the formula (II) in which:
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl qroups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalaqenoalkyl, a hydroxyl or a C1-C4 alkoxy;
- R4 and R5 are each independently a C1-C6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C3.
said alkyl, phenyl and phenylalkyl groups beinq unsubstituted or substituted by one or more halogen atoms or by a group selected from a C1-C4 perfluoroalkyl, a hydroxyl and a C1-C4 alkoxy;
- or R4 and R5 together form a group of the formula =CR7R8, in which R7 is hydroqen, a C1-C4 alkyl or a phenyl and R8. is a C1-C4 alkyl or a phenyl;
or else R4 and R5 together are either a group of the formula (CH2)n or a group of the formula (CH2)pY-(CH2)q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3 or a group N-R6, in which R6 is a hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C3 a C1-C4, alkylcarbonyl, a C1-C4 halo-genoalkylcarbonyl, a C1-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, toqether with the carbon atom to which they are bonded, form an indane or an adamantane;
- p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
with the limitation that - if z and t are zero and X is an oxygen atom, R4 and R5 are other than a C1-C6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C2-C4 perfluoroalkyl, a hydroxyl and a C1-C4 alkoxy;
or R4 and R5 together are other than a group of the formula -(CH2)p-Y-(CH2)q- in which Y represents a group N-R6 in which R6 is a hydrogen, a C1-C4 alkyl or a phenylalkyl in which the alkyl is C1-C3; and n is other than 6 ; or when R3 represents a substituted phenyl group, R4 and R5 together are other than a (CH2)n group in which n is between 3 and 5 ;
and - if z = 1 and R3 is a phenyl, R4 and R5 are each other than a methyl.
14. A compound according to claim 13 of the formula (II') in which X is an oxygen atom or a sulfur atom and R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsbstituted or monsubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy with the proviso that R3 is other than a substituted phenyl group when X is oxygen.
15. A compound according to claim 14 in which X is 0 and R3 is the n-butyl radical.
16. A compound according to claim 15 which is the hydrochloride of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one.
17. A compound according to claim 13 of the formula (II") in which R3, R4, R5 and X are as defined above for (II) in claim 13.
18. A compound according to claim 13 of the formula (II'") in which - R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;
- R4 and R5 are each independently a C1-C6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C1-C4 perfluoroalkyl, a hydroxyl and a C1-C4 alkoxy;
- or R4 and R5 together form a group of the formula =CR7R8, in which R7 is hydroqen, a C1-C4 alkyl or a phenyl and R8 is a C1-C4 alkyl or a phenyl:
or R4 and R5 together are either a group of the formula (CH2)n or a group of the formula (CH2)pY-(CH2)q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C2-C3 or a group N-R6, in which R6 is a hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C4, a C1-C4 alkylcarbonyl, a C1-C4 halogenoalkylcarbonyl, a C1-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adamantane;
- p + q = m;
- n is an integer between 2 and 11;
- m is an integer between 2 and 5; and - X is an oxygen atom or a sulfur atom;
with the limitation that R3 is other than a phenyl if R4 and R5 are each a methyl.
19. A method of preparing a compound according to any one of claims 13, 14, 15, 16, 17 or 18, which comprises reacting a compound of the formula in which R3 has the definition indicated in claims 13 to 18 and B is - a group C(OR)3 -a group or - a group COHal R being a C1-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula 13 in which R4, R5, t and z are as defined above for (II) in claim 13 and A is an OH group, an NH2 group or a group OR', R' being hydrogen or a C1-C4 alkyl, and then, if appropriate, treating the resulting compound with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-di-thia-2,4-diphosphetane disulfide).
20. A pharmaceutical composition in which a compound according to claim 1 is present as the active principle.
21. A pharmaceutical composition according to claim 20 in which the compound of claim 9 is present as the active principle.
22. A pharmaceutical composition in which a compound according to claim 1 is present in association with beta-blocking compound.
23. A pharmaceutical composition in which a compound according to claim 1 is present in association with a diuretic.
24. A pharmaceutical composition in which a compound according to claim 1 is present in association with a non-steroidal antiinflammatory.
25. A pharmaceutical composition in which a compound according to claim 1 is present in association with a calcium antagonist.
26. A pharmaceutical composition in which a compound according to claim 1 is present in association with a tranquilizer.
CA002057913A 1990-03-20 1991-03-20 N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present Expired - Lifetime CA2057913C (en)

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FR9003563A FR2659967B1 (en) 1990-03-20 1990-03-20 N-SUBSTITUTED IMIDAZOLINONE DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAME.
FR9003563 1990-03-20
FR9010144A FR2665702B1 (en) 1990-08-08 1990-08-08 N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
FR9010144 1990-09-01

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