N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT

DERIVES HETEROCYCLIQUES A SUBSTITUANT EN N, LEUR OBTENTION ET COMPOSITIONS PHARMACEUTIQUES OU IL S'EN TROUVE

English 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).

French Abstract

Dérivés de substitution en N d'hétérocycles. Ces dérivés ont la formule de la fig. I, où R1 et R2 sont semblables ou différents et sont chacun indépendamment de l'hydrogène ou un groupe sélectionné parmi un alkyle C1-C6, un alcoxy C1-C4, un amino, un aminométhyle, un carboxyle, un alcoxycarbonyle dont l'alcoxy est C1-C4, un cyano, un tétrazolyle, un méthyltétrazolyle, un méthylsulfonylamino, un trifluorométhylsulfonylamino, un trifluorométhylsulfonylamino-méthyle, un N-cyanoacétamide, un N-hydroxyacétamide, un N-4-carboxy-1,3-thiazol-2-yl)acétamide, un uréido, un 2-cyanoguanidinocarbonyle, un 2-cyanoguanidinométhyle, un imidazol-1-ylcarbonyle et un 3-cyano-2-méthylisothio-uréidométhyle, à condition qu'au moins un des substituants R1 ou R2 soit autre que l'hydrogène; R3 est de l'hydrogène, un alkyle C1-C6 après substitution ou non par un ou plusieurs atomes d'halogènes, un alcényle C2-C6, un cycloalkyle C3-C7, un phényle, un phénylalkyle dont l'alkyle est C1-C3, ou un phénylalcényle dont l'alcényle est C2-C3, lesdits phényles étant sans substitution ou avec mono- ou polysubstitution par un ou plusieurs atomes d'halogène, un alkyle C1-C4, un halogénoalkyle C1-C4, un polyhalogénoalkyle C1-C4, un hydroxyle ou un alcoxy C1-C4; R4 et R5 sont chacun indépendamment un alkyle C1-C6, un phényle ou un phénylalkyle dont l'alkyle est C1-C3, lesdits groupes alkyle, phényle et phénylalkyle étant sans substitution ou avec substitution par un ou plusieurs atomes d'halogène ou par un groupe choisi parmi un perfluoroalkyle C1-C4, un hydroxyle et un alcoxy C1-C4; ou R4 et R5 forment ensemble un groupe de formule =CR7R8, où R7 est de l'hydrogène, un alkyle C1-C4 ou un phényle, et R8 est un alkyle C1-C4 ou un phényle; ou encore R4 et R5 sont ensemble soit un groupe de formule (CH2)n, soit un groupe de formule (CH2)pY- (CH2)q, où Y est soit un atome d'oxygène, soit un atome de soufre, soit un atome de carbone avec substitution par un alkyle C1-C4, un phényle ou un phénylalkyle dont l'alkyle est C1-C3, ou un groupe N-R6, dont R6 est un hydrogène, un alkyle C1-C4, un phénylalkyle, dont l'alkyle est C1-C3, un alkylcarbonyle C1-C4, un halogénoalkylcarbonyle C1-C4, un polyhalogénoalkylcarbonyle C1-C4, un benzoyle, un alphaaminoacyle ou un groupe N-protecteur, ou enfin R4 et R5, de concert avec le carbone auquel ils sont liés, forment un indane ou un adamantane; - p + q = m; - n est un entier compris entre 2 et 11; - m est un entier compris entre 2 et 5; - X est un atome d'oxygène ou de soufre; et - z et t sont égaux à zéro, ou alors l'un est égal à zéro et l'autre à un; et leurs sels (sic).

Claims

- 79 -
The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A compound of the formula
<IMG>
(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;

- 80 -
- 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

-81-
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
<IMG> 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
<IMG>
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

-82-
<IMG> 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
<IMG> 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
<IMG> 7

-83-
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
<IMG>
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
<IMG> 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
<IMG> 4
is treated with lawesson's reagent [2,4-bis(4-methoxy-

-84-
[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
<IMG> 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
<IMG>
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
<IMG>
11

-85-
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
<IMG> 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
<IMG> 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

- 86 -
<IMG>
(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,

- 87 -
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
<IMG> (II')
in which X is an oxygen atom or a sulfur atom and R3 is

-88-
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
<IMG> (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
<IMG>
(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

- 89 -
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
R3-B 14

- 90 -
in which R3 has the definition indicated in claims 13 to 18
and B is
- a group C(OR)3
-a group <IMG> or
- a group COHal
R being a C1-C4 alkyl and Hal denoting a halogen atom,
preferably chlorine, with a compound of the formula
<IMG> 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.

- 91 -
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.

Description

2057913
,
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

- 2 - 2057913
R4
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

2057313
-
-- 3
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-

2057913
- 4 -
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

2057913
-
-- 5 --
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
R4
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

- 2057913
_ - 6 -
R'2 R'
H~l-C~2
05
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
R4
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
-- 7 --
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
R4
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-

2057913
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

- 2057913
-
-- 10 --
R4 R5
~ 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,

2057913
-- 11 --
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
- 12 -
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
R3-B 14
in which B is
- a group C(OR)3

2057913
- 13 -
~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
- 14 -
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:

2057913
-
- 15 -
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

2057913
-
- 16 -
R4
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
15R4
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
R7COR8
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

2057913
`_
- 18 -
R'l R'2
R7R8C=C-(CH2)2-C-NH-CH7 ~ 9
(CH~)t-~HCOR3
05
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
2S
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
R4
\ N
R5 ~HNI ~R3 11

- ~_ 2057913
-- 19 --
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
R4
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
R4
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~
- 20 -
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
- 21 -
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
- 22 -
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
- 23 -
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
- 24 -
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:
R4
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.
EXAMPLE 1
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
- 25 -
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
- 26 -
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

20S7913
- 27 -
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
EXAMPLE 2
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,

2057913
-
- 28 -
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
-
- 29 -
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
- 30 -
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.
EXAMPLE 3
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-

- 32 - 20S7913
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~
-
- 33 -
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.
EXAMPLE 4
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
- 34 -
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
EXAMPLE 5
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

20S7913
- 36 -
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~
~'

2057313
.
- 37 -
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
-
- 38 -
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
EXAMPLE 6
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

2057913
-
- 39 -
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

2057913
- 40 -
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

2057913
- 41 -
- 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
EXAMPLE 7
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~

- 2057913
-
- 42 -
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

- -- 2057913
- 43 -
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
EXAMPLE 8
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
- 45 -
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

2057913
- 46 -
0.80 ppm : t : 3 H : (CH2)3-CH3
EXAMPLE 9
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.-

2057913
- 47 -
- 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
EXAMPLE 10
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.,

2057913
- 48 -
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-

2057913
- 49 -
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-
CH2-CH3
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
EXAMPLE 11
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

2057913
- 50 -
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
05
EXAMPLE 12
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

2057913
- 52 -
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~

2057913
- 53 -
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.
EXAMPLE 13
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
EXAMPLE 14
2-n-Butyl-1-[(2'-(3-cyano-2-methylisothio-
ureidomethyl)biphenyl-4-yl)methyl]-4-spirocyclopentane-
2-imidazolin-5-one
05
SCH 3
(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.
EXAMPLE 15
2-n-Butyl-1-[(2'-(2-cyanoguanidinomethyl)bi-
phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-
one

- 2057913
- 55 -
NIH2
(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.
EXAMPLE 16
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'-

2057913
- 56 -
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

-
-- 2057913
- 57 -
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
EXAMPLE 17
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.

- 58 - 2057913
- 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
EXAMPLE 18
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
- 59 -
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.
EXAMPLE 19
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

2057913
- 60 -
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
05
EXAMPLES 20 AND 21
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
OC2H5
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

-
- 61 - 2057913
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

20S7913
- 62 -
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
- 63 -
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
EXAMPLE 22
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
- 65 -
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

20S7913
-
- 66 -
EXAMPLE 23
2-n-Butyl-1-[(2'-(2-cyanoguanidinocarbonyl)-
biphenyl-4-yl)methyll-4-spirocyclopentane-2-imidazolin-
5-one
05
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.
EXAMPLE 24
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)

2057913
- 67 -
A) Tert-butyl 4-(1-benzylidene-1-valerylaminomethyl-
amidomethyl)biphenyl-2-carboxylate (sic)
C02tBu
n-c4llg-co-~H-c-co-~lH-cH2-c6H~ ~\<3
CH-C6H5
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
,.~
- 68 -
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
EXAMPLE 25
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)

2057913
-
- 69 -
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

2057913
-
- 70 -
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
EXAMPLES 26 AND 27
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

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- 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-
EXAMPLE 28
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~
- 72 -
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'

2057913
;
- 73 -
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.

20S7913
- 74 -
- 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-
EXAMPLE 29
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

2057913
- 75 -
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

- 2057913
- 76 -
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

2057913
- 77 -
Table 1
R4
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

- 2057913
_.
- 78 -
(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
05
(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
CH3
C ~/ \~ Cl
(55)* C02H n~C4Hs CH3\ ~ TFA 105
(56) C02H n~C4Hs / N-C0 TFA 95-105
CF3
_/--\N-CO-CH-~YH2
(57) C02H n-C4Hg \ ~ CH-C2Hs 125-135
CH3
(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.

Representative Drawing