LT3376B - N-substituted heterocyclic derivatives, process fof their preparation, intermediates, process for their preparation and pharmaceutical composition - Google Patents

Abstract

The subject of the invention is N-substituted imidazolinone derivatives. These derivatives correspond to the formula: <IMAGE> in which: - R1 and R2, which are alike or different, each independently represent hydrogen, an alkyl, an alkoxy, a carboxyl, an alkoxycarbonyl, a cyano, a tetrazolyl, a methylsulphonylamino or a trifluoromethylsulphonylamino, provided that at least one of the R1 or R2 substituents is other than hydrogen; - R3 represents an alkyl, an alkenyl, a phenyl, a phenylalkyl or a phenylalkenyl, the said phenyl groups being substituted one or more times by a halogen atom, an alkyl, a hydroxyl or an alkoxy; - R4 and R5 each independently represent an alkyl, a phenyl or a phenylalkyl, the said alkyl, phenyl and phenylalkyl groups optionally being substituted; - or R4 and R5, bonded together, represent either a group of the formula (CH2)n or a group of formula (CH2)pY(CH2)q in which n is an integer between 2 and 6, p + q = n and Y is an oxygen or sulphur atom or a group N-R6 in which R6 represents a hydrogen, an alkyl, a phenylalkyl or an N-protective group; and its salts. Application: Angiotensin-II antagonists.

Description

The present invention is directed to - N-substituted heterocyclic derivatives, processes for their preparation and pharmaceutical compositions containing said derivatives.

The compounds of the invention exhibit antagonistic properties with respect to angiotensin II, a peptide hormone having the following formula:

H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH

Angiotensin II is a potent vasopressor, a biologically active product of the reninangiotensin system: the action of renin on the plasma of angiotensinogen results in the formation of angiotensin 1, which is converted to angiotensin II by the enzyme.

The compounds of the present invention are non-peptide compounds, angiotensin II antagonists. By inhibiting the action of angiotensin II through their respective receptors, the compounds of the present invention inhibit the increase in blood pressure produced by the hormone-receptor interaction and also exhibit other physiological activity at the central nervous system level.

Thus, the compounds of the invention are useful in the treatment of cardiovascular disorders such as hypertension, heart failure as well as central nervous system disorders, glaucoma and diabetic reticopathy.

The present invention relates to compounds having the formula:

K,

here:

-R _x and R ₂ are the same or different and independently of one another are hydrogen or a group selected from alkyl C _x -C ₆ , C ₁ -C ₄ -alkoxylamino, aminomethyl, carboxyl, alkoxycarbonyl wherein the alkoxy group is C _x -C ₄ type, cyano, tetrazoline, methyltetrazoline, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N - ((4-carboxy) -1,3-thiazol-2-yl / acetamide, ureido, 2 -cyanoguanidine carbonyl, 2-cyanoguanidine methyl, 1-imidazolylcarbonyl, 3-cyano-2-methylisothioureidmethyl, wherein at least one of R _x or R _{2 is} different from hydrogen;

-R ₃ is hydrogen, alkyl Ο _χ- Ο ₆ , unsubstituted or substituted by one or more halogen atoms, alkenyl C ₂ -C ₆ , cycloalkyl C ₃ -C ₇ , phenyl, phenylalkyl in which the alkyl is C 1 -C 4, phenylalkenyl wherein the alkenyl is of the C ₂ -C ₃ type, wherein the phenyl groups are one or more unsubstituted halogen, alkyl C _x -C ₄ , haloalkyl C _x -C ₄ , polyhaloalkyl C _x -C ₄ , hydroxy or alkoxy C ₁ -C ₄ ;

-R ₄ and R ₅ independently of one another are alkyl C _x -C ₆ , phenyl, phenylalkyl having C _x C ₃ alkyl, and the alkyl, phenyl and phenylalkyl groups mentioned are unsubstituted or substituted by one or more halogen, or one group selected from alkyl C _x -C ₄ , hydroxyl, alkoxy C _x -C ₄ ;

or R ₄ and R ₅ together form a group of formula = CR ₇ R ₈ wherein R ₇ is hydrogen, alkyl C _x -C ₄ or phenyl, and R ₈ is alkyl C _x -C ₄ or phenyl;

- either R ₄ and R ₅ , taken together, form a group of formula (CH ₂ ) _n or (CH ₂ ) _p y (CH ₂ ) _q , where γ is either an oxygen atom, a sulfur atom, or a carbon atom, substituted by alkyl C _x -C ₄ , phenyl or phenylalkyl whose alkyl is C _x -C ₃ , or by a NR ₆ group in which R ₆ is hydrogen, alkyl C _x -C ₄ , phenylalkyl whose alkyl is C _x -C ₃ type, alkylcarbonyl C _x -C ₄ , haloalkylcarbonyl C _x -C ₄ , polyhaloalkylcarbonyl C _x -C ₄ , benzoyl, alpha-aminoacyl or N-protecting group, R ₄ and R ₅ together with the carbon to which they are attached consisting of indan or adamantane:

-p + q = m;

-n is an integer from 2 to 11;

-m is an integer from 2 to 5;

-x is an oxygen atom or a sulfur atom;

-Z and t are zero or one of these indices is zero and the other is one;

or salts thereof.

When the carbon of the compounds of the invention is asymmetric, the optical 2 isomers of these compounds are also included in the invention.

The salts of the compounds of the formula (I) of the present invention include salts containing mineral or organic acids which are capable of isolating or properly crystallizing the compounds of the formula (I), such as picric acid, sour acid, optically active acid such as formic acid or camph forms pharmaceutically acceptable salts such as chlorohydrates, bromohydrates, sulfates, hydrosulfates, dihydrophosphates, methanesulfonates, methyl sulfonates, maleates, fumarates, 2-naphthalenesulfonates.

Also salts of the compounds of formula (1) include organic and mineral bases, e.g. alkali or alkaline earth metal salts such as sodium, potassium, calcium salts, more preferably sodium and potassium salts, or with a tertiary amine such as trimetamol, or salts of arginine, lysine or any physiologically acceptable amine.

In this specification and other references, halogen atoms include bromine, chlorine or fluorine atoms; An N-protecting group (also designated as Pr) is a group commonly used in peptide chemistry to temporarily protect amino groups, such as BOK, Z, FMOK, or benzyl; an esterified carboxy group is an ester which is unstable under appropriate conditions such as, for example, methyl, ethyl, benzyl or tert-butyl ester. Alkyl is the residue of an aliphatic saturated linear or branched hydrocarbon.

More preferred are compounds of formula (I) wherein R _x in the ortho position is carboxy or tetrazolyl and R ₂ is hydrogen.

More preferred are compounds of formula / 1 / wherein R ₄ and R ₅ together with the carbon to which they are attached form cyclopentane or cyclohexane.

Similarly, compounds of formula I are more preferred when R ₃ is a linear alkyl group C 1 -C 8.

Also preferred are compounds of formula / 1 / wherein X is an oxygen atom.

Finally, compounds of the formula / 1 / where Z-t = 0 are more suitable.

The following abbreviations are used in the description and examples:

Et: Ethyl

n-But, t-Bu: n-butyl, tert-butyl DMFA: dimethylfo rmamida s THF: tetrahydrofuran ether: ethyl ether TFR: trifluoroacetic acid Z: benzyloxycarbonyl BOK: tert-butoxycarbonyl FBO: phosphonium benzotriazolyloxitrisdi- methylamine hexafluorophosphate FMOK: fluorenylmethyloxycarbonyl

DChM: Dichloromethane

NBS: N-Bromosuccinimide

DCK: Dicyclohexylcarbodimine

DIPEA: Diisopropylethylamine

The present invention also relates to a process for the preparation of compounds of formula I, moreover, this process is characterized in that:

s / takes the formula:

reaction of a heterocyclic derivative containing

H (2) wherein Z, t, R ₃ , R ₄ and R _{5 have the} meanings given above for compound 1, biphenyl / methyl of formula:

are as with derivative / 415

wherein Hal is, respectively, a precursor to R ₂ ;

a halogen atom, R 1 and R ₂ , or o R ' _l and a group

R ' ₂ is a compound of formula R _x and bl /, where appropriate, of the formula:

treated with Lawesson's reagent: 2,4-bis / 4-methoxyphenyl / 1,3-dithia-2,4-diphosphetane-2,4-disulfide;

cl / compound of steps ai and bl of the formula:

(5) wherein X is an oxygen atom or a sulfur atom, r'i and / or R _'2 groups respectively forced to R _d and / or R ₂ group to obtain the compound (1).

Among the compounds of formula / 2 / compounds / 11 / as noted below, the compounds are novel.

Thus, the present invention also relates to compounds of formula:

here:

-R ₃ is hydrogen, alkyl C _x -C ₈ , unsubstituted or substituted by one or more halogen atoms, alkenyl C ₂ -C ₆ , cycloalkyl C ₃ -C ₇ , phenyl, phenylacyl having alkyl of C _x -C ₃ , phenylakenyl wherein the alkenyl is of the C ₂ -C ₃ type and the phenyl groups mentioned are unsubstituted or substituted one or more times by halogen, alkyl C 1 -C ₄ ,, haloalkyl C _x -C ₄ , polyhaloalkyl hydroxy or alkoxy

C ₇ -C ₄ ;

- R ₄ and R ₅ independently of one another are C₁-C₆ alkyl, phenyl, phenylalkyl wherein alkyl is a C _x -C ₃ type, in addition to the alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or one group selected from perfluoroalkyl C ₁ -C ₄ , hydroxyl, C ₁ -C ₄ alkoxy;

- or R ₄ and R ₅ together form a group of formula = CR ₇ R ₈ wherein R ₇ is hydrogen, alkyl C _x -C ₄ or phenyl and R _A is alkyl C _x -C ₄ or phenyl;

- either R ₄ and R _s , taken together, form either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) _p y (CH ₂ ) _q in which γ is either an oxygen atom or a sulfur an atom, or a carbon atom substituted by alkyl C _x -C ₄ , phenyl or phenylalkyl whose alkyl is Ο _χ- Ο ₃ , or a group NR ₆ where R ₆ is hydrogen, alkyl C _x -C ₄ , phenylalkyl whose alkyl is is of the type, alkylcarbonyl C _x -C ₄ , haloalkylcarbonyl C _x C ₄ , polyhaloalkylcarbonyl C ₁ -C ₄ , benzoyl, or aaminoacyl or N-protecting group, or R ₄ and R ₅ together with the carbon to which they are attached forms indan or adamantane;

-p + q = m;

-n is an integer from 2 to 11;

-m is an integer from 2 to 5;

-x is an oxygen atom or a sulfur atom;

-Z and t are zero or one of these indices is zero and the other is one;

limiting that:

- when Z and t are zero and X is an oxygen atom, R ₄ and R ₅ are different from:

. C ₁ -C ₈ alkyl, phenyl, phenylalkyl having C _x -C ₃ alkyl, and the alkyl, phenyl and phenylalkyl groups listed are unsubstituted or substituted with one or more halogen atoms or with one group selected from perfluoroalkyl C _x -C ₄ , hydroxyl, C 1 -C 4 alkoxy;

io. or R ₄ and R ₅ , taken together, are different from R ₆ , wherein R ₆ is hydrogen, alkyl C ₁ -C ₄ , phenylalkyl whose alkyl is C-C ₃ ;

. n is different from 6;

- and when Z = 1 and R ₃ is phenyl, then R ₄ and R _{5 are} each different from methyl.

Among the derivatives of compound (11), compounds wherein Z = t = 0 and R ₄ and R ₅ together with the carbon to which they are attached form cyclopentane are more suitable. The following compounds have the formula:

wherein X is an oxygen atom or a sulfur atom and R ₃ is hydrogen, alkyl C ₁ -C ₆ , unsubstituted or substituted with one or more halogen atoms, alkenyl C ₂ -C ₆ , cycloalkyl C ₃ -C ₇ , phenyl, phenylalkyl having alkyl is a Ci-03 type phenylalkenyl wherein the alkenyl is C ₂ -C ₃ type, in addition, the phenyl group being unsubstituted or substituted one or more times with a halogen atom, alkyl, C ~ C _Rf haloalkyl C ₁ -C ₄ polyhaloalkyl _y C -CA, hydroxy, or alkoxy C _x C _4.

More preferred are compounds of formula / 11 / where Z = 0 and t = l having the formula:

in which above

Rj1 R41 specified

R ₅ and X mean / 11 / compounds.

are such as

Finally, compounds of formula / 11 / where Z = 1 and t = 0 are more suitable:

where:

R ₃ is hydrogen, C₁-C₆ alkyl unsubstituted or substituted with one or more halogen atoms, alkenyl, _C2-C₆, cycloalkyl C ₃ -C _7, phenyl, phenylalkyl wherein alkyl is a C _t -C ₃ type phenylalkenyl wherein the alkenyl is of the C ₂ -C ₃ type and the phenyl groups mentioned are unsubstituted or substituted one or more times by halogen, alkyl C ₇ -C ₄ , haloalkyl C ₁ -C ₄ , polyhaloalkyl C ₁ -C ₄ , hydroxy or alkoxy Ci ~ C _4;

R ₄ and R ₅ independently of one another are C₁-C₆ alkyl, phenyl, phenylalkyl wherein alkyl is a C _l -C ₃ type, in addition to the alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or one group selected from perfluoroalkyl C ₁ -C ₄ , hydroxyl, C ₁ -C ₄ alkoxy;

- or R ₄ and R ₅ together form a group of the formula = CR ₇ R _b wherein R ₇ is hydrogen, alkyl C _l -C ₄ or phenyl, and R ₈ is alkyl C ₁ -C ₄ or phenyl;

- either R ₄ and R ₅ , taken together, are either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) _p y (CH ₂ ) _q , where γ is either an oxygen atom or a sulfur atom. or a carbon atom substituted by alkyl C ₁ -C _4, a phenyl or a phenylalkyl wherein alkyl is a C _r C ₃ type or a group R ₆ wherein R ₆ is hydrogen, alkyl

C ₁ -C ₄ phenylalkyl wherein alkyl is a type of alkylcarbonyl, haloalkylcarbonyl C ^ -C ^ polihalogenalkilkarbonilas Οχ _Ο-4, benzoyl, alfaaminoacilas or an N-protective group, or R ₄ and R ₅ together with the carbon to which they are bonded atoms to form an indane or adamantane:

-p + q = m;

- n is an integer from 2 to 11;

- m is an integer from 2 to 5;

- X is an oxygen atom or a sulfur atom;

limiting that R ₃ is not phenyl when R ₄ and R _{5 are} each methyl;

Derivatives 2 are obtained by known methods. For example, the method described by Jasquien et al. (Bull. Chem. Soc. France, 1971, 3, 1040-1051) or Brunken et Bach (Chim. Ber. 1956, 89, 1363-1373) can be used to act on the amino acids, or its ester alkylimidate according to the following reaction scheme:

O /?

wherein R is alkyl C \ -C _4, R * is hydrogen or alkyl C _l -C ₄ and R _3, R _4, R _s, Z and t are as previously defined / 1 / combined.

The reaction takes place under heating in an acidic medium in an inert solvent such as xylene or toluene.

Compound 2_ can be prepared by another method, by reaction of an orthoic acid alkyl ester / 10 / aminoalkylamide / 5 * * / in the acidic environment with the following reaction scheme:

Wherein R is alkyl-C 1 -C 4.

Compound 2 can be obtained by another method described by Takenaka et al., (Heterocycles 1989, 29, / 6 /, 1185-89) by treatment with a derivative of 5 '' acid halide anhydride of the formula:

R ₃ C ₂ 0 Hal wherein Hal is halogen is more preferably chlorine.

The reaction takes place in an alkaline medium.

The compound _2, in part according to another object of the present invention, is obtained by a process wherein:

compound of the formula:

and wherein A is OH, NH ₂ or OR ', in addition R' is hydrogen or alkyl C _x -C ₄ , treated with a compound of the formula:

R ₃ -B 14 wherein B is:

-group C / OF / ₃ ;

NH //

- Group C \

OR

- or CoHal;

in addition, R is alkyl C _x -C ₄ and Hal is a halogen atom, more preferably chlorine;

- then, if necessary, treating the resulting compound with Lawesson's reagent: 2,4-bis / 4-methoxyphenyl /

1,3-dithia-2,4-diphosphetane-2,4-disulfide.

The derivative / 4-biphenylyl / -methyl / 3 / is prepared in a corresponding manner as described in the European patent application EP 324 377.

Conversion of groups R'i and / or R ' _{2 to} R! and / or R ₂ is carried out by methods well known to those skilled in the art. So when / 1 / in the compound to be obtained is a group R! and / or R ₂ = carboxy group, then R 'y and / or R' ₂ is an esterified carboxy group. When R ₁ and / or R ₂ is tetrazolyl in the resulting compound (1), it is R *! and / or R ' ₂ is either tetrazolyl protected, for example, by a trityl group, or cyano, which is subsequently substituted by a tetrazolyl group, optionally protected by trityl. The conversion of the cyano group to tetrazolyl can be effected by the action of an azide such as tributyl azide or sodium azide.

One can use such R'y and / or R _'2 groups as nitro, cyano, or carboxylic acid chloride group and reaction well known specialist help them into the groups y and / or R ₂ of the kind as stated / 1 / compound.

Thus, when R'y and / or R ' ₂ is a carboxy group, it can be converted to a group R _x and / or R ₂ corresponding to

1-imidazolylcarbonyl, or N - [(4-carboxy) -1,3-thiazol-2-yl] acetamide.

The group R _x and / or R _'2, which is an acid chloride, R may become the _R and / or R ₂ corresponding Nhidroksiacetamidą, N-cyanoacetamide, ureido or

2-cyanoguanidicarbonyl.

The groups R ' _x and R' ₂ which are nitro may be converted to the amino group from which R _x and / or R ₂ are derived, such as methylsulfonylamino, trifluoromethylsulfonylamino or trifluoromethylsulfonylaminomethyl.

The groups R ' _x and R' ₂ , which are cyano, can be converted to aminomethyl to give 3.cyano-2-methylisothioureidomethyl / according to C. Ctordon et al. J. Org. Chem., 197, 66, 2667-2669) and 2-cyanoguanidine methyl (by RW Turner, Synthesys, 1975).

The step ai / takes place in an inert solvent such as DMFA, DMSO or THF in an alkaline environment, for example in the presence of potassium hydroxide, metal alcoholate, metal hydride, calcium carbonate or triethylamine.

The step b1 / 2 is carried out by heating under a nitrogen atmosphere in a solvent such as toluene according to the method described by M. P. Cava et al. Tetrahedron, 41, 22, 5061 (1985).

The method described below, comprising steps ai, bl and cl, is called method I.

On the other hand, the compounds of the invention may also be obtained in another manner which is also the object of the present invention. This method differs in that:

a2 / Reaction of an amino acid of the formula:

CCeU wherein Z, t, R ₄ and R ₅ are as defined above for compound (1) and wherein the amino group is protected by P _r with a 4-biphenylyl / -methylamine derivative of the formula:

where R *! and R ' ₂ is either R _x and R ₂ respectively or R is a group; and R ₂ precursor;

b2 / after deprotection of the amino acid, a compound of the following formula is obtained:

ortorūgšties reacted with alkyl ethers of formula R ₃ C / OR / _3/10 /, wherein R ₃ is as defined above / 1 / of the compound, and R is alkyl CL-Cu;

c2 / where necessary, a compound of the formula:

treated with Lawesson's agent 2,4-bis- (4-methoxyphenyl) -1,3,3-thia-2,4-diphosphetane-2,4-disulfide;

d2 / Compound obtained in the following manner in steps b2 or c2 of the formula:

is then subjected to conditions suitable for the preparation of / 1 / compound by converting R *! and / or R ' ₂ groups to the corresponding R ₁ and / or R ₂ groups.

The compounds 7 are known or prepared by known methods / Chemistry of the Amino Acids, Ctreenstein and Winitz, John Wiley et 1961, p.697 _lf t /.

Compounds _8_ are obtained according to European patent application EP 324 377. Step a2 / takes place under conditions customary for the acid to be attached to the amine, for example in the presence of FBO and DIPEA.

Step b2 /, which is the cyclization of compound 9 in the presence of compound 10, occurs according to Jacquie et al. (Bull. Soc. Chem. France, 1971, / 3 /, 1040-1051) and Brunken et Bach (Chem. Be 1956, 89, 1363-1373).

The most recently described method comprising steps a2-d2 is called method 2.

According to one embodiment of method 2, in step b2, intermediates 9 'can be isolated, where appropriate, having the formula:

and then the compound _ £ can be obtained as a result of cyclization in an acidic environment.

According to another embodiment of Method 2, for the preparation of Compound I wherein R ₄ R ₅ is a group = CR ₇ R _f , the reaction must take place in an acidic environment between the amino acids of formula

CH ^ - / CH ^ / _t -NHCOf? ₃ \

/ CH ^ / i-COOH and an aldehyde or ketone of the formula:

R 6 COR 8, and wherein R ₇ and R ₈ have the same meanings as given above for the compound / 1 /, and then the compound of the formula:

This compound undergoes cyclization in acidic environment to form compound 4.

According to the present method in order to obtain / 1 / reacting a compound of _R-R and / or R ₂ is carboxy, R \ and / or R _'2 are preferred tert-butoxycarbonyl.

Finally, another alternative of the present invention to obtain the compound of the invention where Z and t are equal to 0 is a method of photooxidation which is also the subject of the present invention.

The latter method is characterized in that:

a3 / imidazole derivative of formula:

H wherein R ₃ , R ₄ , R _{5 have the same} meaning as above for compound (1), are treated with an (biphenylyl) -methyl derivative having the following formula:

wherein Hal is a halogen atom and R _'X and R' ₂ are respectively either R 5 _R and R ₂ or a group - R ₁ and

A precursor of R ₂ in the presence of oxygen and ultraviolet radiation in an alkaline environment;

b3 / where appropriate a compound of the following formula 10 is obtained:

treated with Lawesson's reagent: 2,4-bis / 4-methoxyphenyl / 1,3-dithia-2,4-diphosphetane-2,4-disulfide;

c3 / Compound obtained in the following manner in steps b3 and c3 of the formula:

is then subjected to conditions suitable for obtaining the compound (1) by converting the groups R ' _L and / or R' ₂ into groups R _x and / or R _{2 respectively} .

The imidazole derivative 11 is either commercially available or known, or is obtained in a known manner as previously described to give compound 2.

Stage a3 / occurs in an inert solvent such as

DMFA, for example: a photosensitizing compound such as methylene blue can be added to improve the reaction.

The method described below comprising the steps a3 / - c3 / is called method 3.

According to the invention, the compounds of R ₄ and R ₅ together form a group of the formula (CH ₂ ) _p y (CH ₂ ) _q , where γ is an NH group, can be obtained by catalytic hydrogenation of the corresponding compound / 1 / compound wherein γ is NR Group ₆ , moreover, R ₆ is benzyl.

The similarity of the products according to the invention with respect to angiotensin II receptors was investigated by the assay of binding of angiotensin II labeled with iodine-125 to rat hepatocellular receptors. This method is described in S. Keppens et al. et al., Biochem. J., 208, 809-817 (1982).

Cl _{50 is} measured as the concentration that 50% replaces the labeled angiotensin II specifically bound to the receptor.

The compounds of the invention have a Cl ₅₀ value of less than 10 ' ⁶ M.

In addition, the angiotensin II antagonistic activity of the products of the invention has been demonstrated in various animal species pre-activated by the renin-angiotensin system (C.Lacour et al., J. Hypertension, 1989, 7 / Suppl. 2 /, .33- 35).

The compounds of the present invention are activated by various routes, including oral administration. No signs of toxicity of the compounds were detected at pharmacologically active doses.

The compounds of the invention can be used in the treatment of a variety of cardiovascular diseases, partial hypertension, heart failure, venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathy and various central nervous system disorders such as anxiety, depression, amnesia or Alzheimer's disease.

It is also an object of the present invention to provide pharmaceutical compositions comprising an effective dose of a compound or a pharmaceutically acceptable salt of the invention and suitable indifferentiating agents. The indifferent substances indicated are selected according to the pharmaceutical form and the desired mode of application.

According to the present invention, the active compounds of the formula I or their salts can be used in animals or in pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, tracheal, intranasal, transdermal or rectal administration. for the prophylaxis of human beings or for the treatment of the above diseases and disorders, either in a topical form or in admixture with classic pharmaceutical carriers. Unit dosage forms can be oral forms such as tablets, gelatin capsules, powders, granules and oral solvents or suspensions, as well as sublingual, self-dissolving, intracranial, intranasal, subcutaneous, intramuscular, intravenous and rectal formulations. forms of use. For topical use, the compounds of the invention may be formulated in creams, ointments or lotions.

The dosage of the active component may range from 0.01 to 50 mg / kg / day to achieve the desired prophylactic or therapeutic effect.

Each unit dose of the active ingredient in combination with pharmaceutical carriers may contain from 0.1 to 1000 mg, more preferably from 1 to 500 mg. This unit dose may be administered 1 to 5 times daily in a dosage range of 0.5 to 5000 mg, more preferably 1 to 2500 mg per day.

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The tablets may be coated with, or treated with, a sucrose, cellulose derivative or other appropriate material to prolong or delay the action and to maintain a sustained release of the active ingredient.

The preparation in gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

The preparation used as a syrup or elixir, or in the form of drops, with the active ingredient, may also contain a sweetener, a lower caloric agent, antiseptics such as methylparaben and propylparaben, a flavoring agent and an appropriate colorant.

In powders and granules having an aqueous dispersion, the active ingredient may be in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, and sweetening or flavoring agents.

For rectal application, candles are used which are made with a binder that melts at a rectal temperature such as cocoa butter or polyethylene glycol.

Aqueous suspensions, isotonic saline solutions or sterile solutions for spraying containing a pharmacologically compatible dispersion and / or wetting agent such as propylene glycol or butylene glycol are used for parenteral administration.

The active ingredient in the formulation may be in the form of a microcapsule and, if necessary, one or more carriers or excipients.

Other active components, such as, for example, tranquilizers or other medicaments used in the treatment of the aforementioned diseases and disorders, may be included in the composition of the present invention with the products of the above formula I or one pharmacologically acceptable salt.

Thus, the present invention relates to pharmaceutical compositions comprising several of the combined active components, one of which is in accordance with the invention and the other or others may be blocking compounds, a calcium antagonist, a diuretic, a non-steroidal anti-inflammatory or a tranquilizer.

The latter examples illustrate the invention without limiting it. The following abbreviations are used in these examples: d is density; kT - room temperature, KHSO ₄ -K ₂ SO ₄ aqueous solution containing 16.6 g potassium bisulphate and 33.3 g potassium sulphate per liter.

Melting point / T _melted / measured in degrees Celsius; except in some particularly noteworthy cases, the temperature was measured without recrystallization.

The purity of the product is checked by thin layer chromatography (PCh) or by high performance liquid chromatography (ESCh). The products are characterized by NMR spectra recorded in 200 MH ₂ deuterated DMSO, in addition to which tetramethylsilane is an internal standard.

The following meanings are used for the interpretation of NMR spectra:

- s - singlet,

- p.s. - broad singlet,

-d - doublet,

-t - triplet,

-k is a quadruplet,

- kv is the quintet,

- sec - sextet,

- m - array or multiplet.

Also, im is imidazole.

Classically, the hydrogen atoms in biphenyl are numbered as shown in the formula:

(I) iv

CH,

In the examples below, Z and t are zero unless the resulting compound is pyrimidinone.

An example

2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one and 2-n-butyl-1 '- (2'-carboxy biphenyl-4-yl) methyl / -4-Spirocyclopentan-2-imidazolin-5-one trifluoroacetate (Method 2).

A / 1N-FMOK- -aminocyclopentanecarboxylic acid is prepared as described by Chi-Deu Chang et al. / Int. J. Peptide Protein Res., 15, 59-66 (1980).

_M.p. = 89-91 ° C.

B / N- (2'-tert-Butoxycarbonyl-biphenyl-4-yl) methyl / -1- (NFMOK-amino / cyclopentane-1-carboxamide).

Dissolve 700 mg of the product obtained in the previous step in 8 ml of DMFA and add 57 6 mg of 4-aminomethyl/2'-tert-butoxycarbonyl-biphenyl, 970 mg of FBO and raise DIPEA to pH = 6.

The reaction medium is stirred for 1 hour, diluted with 100 ml of ethyl acetate and 20 ml of water; the organic phase is gradually washed with saturated sodium bicarbonate solution, then KHSO ₄ -K ₂ SO _4, and finally with saturated sodium chloride solution, and the solution is evaporated to dryness after drying with sodium sulfate. A liquid oil having a mass (m) equal to 1.2 g is obtained.

C / N - [2'-tert-Butoxycarbonyl-biphenyl-4-yl-methyl] -amino] -cyclopentane-1-carboxamide.

The product from the previous step was dissolved in 10 mL of DMFA, followed by the addition of 1 mL of diethylamine and stirring at kT for 1 h. The reaction medium is extracted with 100 mL of ethyl acetate and 20 mL of water, then the organic phase is washed once with water, once with saturated sodium chloride solution, then dried over sodium sulfate and evaporated to dryness.

Chromatography of the residue on silica gel eluting with 30% ethyl acetate / methanol / ammonia (99/1 / 0.5; v / v) yields 600 mg of the expected compound.

- AND / CHC1 ₃ /:

3350 cm ¹ : H / amide and amine /,

1700 ^cm-1: C = 0 / CO ₂ -tBu) /,

1650 cm ^-1 : C = 0 / CONH /,

NMR Spectrum:

- 1.25 m.d. : s: 9H: tBu, - 2, 15 - b 40 years .d. : m: 10H: (C ₅ H ₆ , NH ₂ ), - 4.40 m.d. : d: 2H: ch ₂ -nh, - 7, 15 - 7, 75 years .d. : m: 8H: biphenyl, - 8, 60 m.d. : t: 1H: nh-ch ₂ .

D / 2-n-Butyl-4-spirocyclopentan-1 - ((2'-tert-butoxycarbonyl-biphenyl-biphenyl-4ii) methyl / 2-imidazolin-5-one.

The product from the previous step, 354 mg, is mixed with 250 mg ethyl orthovalerate in 2 mL DChM. Add 1 drop of acetic acid, then heat to 90 ° C to evaporate DChM. After 1 h, the reaction mixture was extracted with 50 mL of ethyl acetate, 10 mL of water and 1 mL of saturated sodium bicarbonate solution. The organic phase is then washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Chromatography of the residue on silica gel eluting with ethyl acetate / toluene (1/2; v / v). 390 mg of the expected product is crystallized.

_Mp = 63-65 ° C.

AND / CHC1 ₃ /:

N 1710-1720 cm ' ¹ : C = 0, C = O / ester and imidazoline /:

- 1625 cm ^-1 : C = N

NMR Spectrum:

- 0.88 m.d. : : t: 3H: CH ₃ / nBu /, - 1.20 m.d. : s: 9H: tBu, - 1.35 m. d. : sec ;: 2H :: ch ₃ -ch ₂ -, - 1.58 m.d. : kV: 2H: ch ₃ —ch ₂ —ch ₂ - - 1.95- -1.65 m. d. : m; 8H: cyclopentane, - 2.42 m.d. : t: 2H: ch ₃ -ch ₂ -ch ₂ -ch ₂ -, - 4.78 m.d. : s: 2H: CH ₂ -CgH ₄ -, - 7.20- -7.80 m. d. : m: 8H: aromatic prot

Mass Spectrum: MH ⁺ : 4 61

E / 2-n-butyl-1 - ((2'-carboxy biphenyl-4-yl) methyl) -4-spirocyclopentan-2-imidazolin-5-one trifluoroacetate.

The product from the previous step was treated with 180 mg of 3 ml of DChM and 4 ml of TFR for 45 minutes. After evaporation in vacuo, the residue is extracted with ether. A white solid is obtained which is filtered, rinsed with ether and then dried under vacuum.

m = 155 mg.

T _mp. = 176-178 ° C.

NMR Spectrum:

- 0.78 ppm: t: 3 H: CH ₃ / nBut /.

- 1.25 md: sec: 2H: CH ₃ -CH ₂ -,

- 1.50 ppm: kV: 2H: CH ₃ -CH ₂ -CH ₂ -,

- 1.75-2.00 ppm: m: 8H: cyclopentane,

- 2.65 md: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

- 4.83 ppm: s: 2H: CH ₂ -CgH ₄ -,

- 7.20-7.75 ppm: m: 8H: aromatic protons

Mass Spectrum: MH +: 405

An example

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one trifluoroacetate (method 1).

N-2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one.

The ethyl ester of 1-aminocyclopentanecarboxylic acid is obtained from / Adkins et Bllica, / J. Amer. Chem. Soc., 1948, 70, 3121 /.

Ethyl valerimidate is obtained by Mac Elvain / J. Amer. Chem. Soc., 1942, 64. 1825-1827 /. Thereafter, extraction with potassium carbonate and DC1M separates it from its hydrochloride.

Dissolve 1-aminocyclopentanecarboxylic acid ethyl ether (1.57 g) and ethyl valerimidate (1.56 g) in 12 ml of xylene, add six drops of acetic acid, heat the reaction medium for six and a half hours, then concentrate in vacuo, and Chromatography of the residue on silica gel eluting with a mixture of chloroform / methanol / acetic acid (94/4/2 by volume). The fraction containing the desired product is evaporated several times in the presence of xylene followed by benzene to remove the acetic acid. 1.91 g of product are obtained in the form of a liquid oil.

AND / CHC1 ₃ /:

- 1720 cm @ ^-1 : C = 0

- 1635 cm @ ^-1 : C = N

Note: The fact that you don't see the bar between 1500 and

1600 cm ¹ indicates that the product in the chloroform solution is imidazolinone -5-one

NMR Spectrum:

- 0.92 ppm: t: 3 H: CH ₃ / nBut /,

- 1.35 billion; sec: 2H: CH ₃ -CH ₂ -,

- 1.50 to 1.93 md: m: 10H: CH ₃ -CH ₂ -CH ₂ - and cyclopentane,

- 2.33 ppm: t: 2H: CH ₂ = CH ₂ -CH ₂ -CH ₂ -,

- 10.7 ppm: m: NH.

Mass Spectrum: MH ⁺ : 195.

The 2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one obtained in Step A can also be obtained by another method described below using cyclopentanone as the primary reagent.

α / 1-aminocyclopentanenitrile.

This stage takes place according to A. Strecker / Org. Synth., 1955, 3 /.

Dissolve 1.97 g of sodium cyanide in 3.9 ml of water in a flask and add a solution of 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% ammonia, and finally add 3 g of cyclopentanone 3 to the flask. , 8 mL of methanol. Stir for 1.5 hours, then leave for 45 minutes. After stirring at 60 ° C, stir again for 45 minutes, then cool to 25 ° C. Extract several times with methylene chloride. Dry over sodium sulfate, filter, and concentrate in vacuo. 4 g of the expected product are obtained in the form of an oily liquid.

The resulting 1-aminocyclopentanenitrile is dissolved in 300 ml of acetone and added with stirring to a solution of 2.25 g of dihydrated acid in 200 ml of acetone.

The resulting precipitate is centrifuged, washed with acetone and then dried.

m = 4.71 g.

_{Melting point} = 220 ° C.

That compound is I-aminocyclopentanitrile hemioxalate.

b / I-Aminocyclopentanacetamide.

This step is carried out according to the method described by J. Zabicky / The Chemistry of Amides, Intersciences, New York, 1970, 119 ../.

The oxalate obtained in the previous step was 5.1 g. 45 min with stirring treated with 7.65 ml of concentrated sulfuric acid / d = 1.84 /.

The gas evolves and the temperature rises to 100 ° C. Cool to 35 ° C and add ice and concentrated ammonia (10 g /

2.8 ml).

The resulting suspension is extracted 6 times with 5% methanol in chloroform. To the aqueous phase is added 3 ml of ammonia / d = 0, 92 / and again extracted with chloroform containing methanol (1 / 0.5 volumes). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The expected product is obtained in the form of a white solid.

m = 3.79 g

_{Melting point} = 95 ° C.

Analysis results and IR spectrum confirm the structure.

c / 2-n-Butyl-4-spirocyclopentan-2-imidazolin-5-one.

This stage is according to H. Takenaka et al. Heterocycles 1989, 29/6 /, 1185-89.

3 g of the product obtained in the previous step are added to 70 ml of anhydrous THF and 3.3 ml of triethylamine and 3 ml of valeryl chloride are added to 10 ml of anhydrous THF under stirring. A white suspension is obtained. The resulting intermediate, which cannot be isolated in pure form, is l- / N-valeryl / aminocyclopentanecarboxamide. Add 5 g of potassium hydroxide in the form of tablets, 7 ml of water and 16 ml of methanol. Heat for two and a half hours until phlegm is formed, followed by the addition of 9 g of ammonium chloride. Stir for 15 minutes, then concentrate in vacuo. The resulting precipitate is extracted with 40 mL of water and extracted with 10 mL of ethyl acetate followed by 2 x 5 mL of ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. The filtrate is concentrated to dryness. 4.85 g of the expected product are obtained. The NMR spectrum is similar to that described above. Chlorohydrate of this compound can be obtained by addition of concentrated hydrochloric acid. Chlorohydrate melts at 240 ° C while subliming.

b / 2-n-Butyl-4-spirocyclopentane-1- (2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl / -2-imidazolin-5-one.

The product obtained in the previous step A / is dissolved in methylate and suspended in ml of DMFA. Add 270 mg and leave under stirring for 15 min with 2.08 g of butoxycarbonyl / biphenyl, after heating at 40 ° C

970 mg of sodium kT. To

4-Bromomethyl- / 2'-tert is begun for 30 minutes under nitrogen and heated for three and a half hours. The reaction medium is extracted with a mixture of 100 ml of ethyl acetate, 10 ml of water and 1 ml of saturated sodium bicarbonate solution. The organic phase is washed with a saturated sodium chloride solution, then dried over sodium sulfate and evaporated to dryness. Chromatography of the residue on silica gel eluting with ethyl acetate / toluene (1/2; v / v). 125 g of the expected product are obtained, which crystallizes.

_{Melting point} = 63-66 ° C.

IR, NMR and mass spectrum as well as R _f are identical to those obtained in step D / 1.

c- (2-n-Butyl-1- (2'-carboxy-biphenyl-4-yl) methyl) -4-spirocyclopentan-2-imidazolin-5-one trifluoroacetate.

The product obtained in the previous step, 1.22 g, was stirred for 40 min. in a solution containing 6 ml DChM and 8 ml TFR. After concentration in vacuo, the residue is extracted with ethyl ether, the resulting white precipitate is filtered off, washed with ether and then dried under vacuum. 1.15 expected product to be obtained.

Tiy _d. = 176-178 ° C

IR, NMR, and mass spectra are identical to those obtained in Example 1E, analogous to P in TSCh.

Example 3.

2-n-Butyl-1- (2'-carboxy biphenyl-4-yl) methyl-4-spirocyclopentan-2-imidazolin-5-one trifluoroacetate (Method 3).

A / 2-n-Butylbenzimidazole is obtained according to wo. Pool / J. Amer. Chem. Soc. 1937, 59, 178, followed by the preparation of 2-n-butyl-4-5,6,7-tetrahydrobenzimidazole according to M. Hartmann and L. Panizzon, Helv. Chim. Act, 1938, 21, 1692-1694 /.

_Mp = 145 ° C.

NMR Spectrum:

- 0.82 ppm: t: 3 H: CH ₃ / nBu /,

- 1.23 ppm: s: 2H: CH ₃ -CH ₂ -,

- 1.50 md: kV: 2H; CH ₃ -CH ₂ -CH ₂ -,

- 1.65 ppm: s: 4 H H _5, H ₆ (tetrahidrobenziimidazolas)

- 2.35 ppm: s: 4 H: H _4, H ₇ (tetrahidrobenziimidazolas)

- 2.45 md: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

- 11.1 ppm: m: NH.

Mass spectrum: M ^t : 178.

B / 2-n-butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonyl-4-biphenyl) -methyl] -2-imidazolin-5-one.

Dissolve 1 g of the product obtained in the preceding step in 45 ml of DMFA containing 303 mg of sodium methylate and several mg of methylene blue. Oxygen is blown into the reaction medium, which is irradiated with an ultraviolet lamp. After 15 minutes, 2.14 g of 4-bromomethyl- / 2'-tert-butoxycarbonyl / -biphenyl is added and after 1 hour the reaction medium is extracted with 300 ml of ethyl acetate, 50 ml of water and 5 ml of saturated sodium bicarbonate solution are added. The organic phase is then washed with a saturated sodium chloride solution, then dried over sodium sulfate and evaporated to dryness. Chromatograph the residue on silica gel eluting with ethyl acetate / toluene (1/2; v / v). 610 mg of the expected product is obtained, which crystallizes.

_M.p. = 62-65 ° C

IR, NMR spectra, mass spectrum, and R are identical to those obtained previously for the same compound.

C / 2-n-Butyl-1 - ((2'-carboxy biphenyl-4-yl) methyl) -4-spirocyclopentan-2-imidazolin-5-one trifluoroacetate.

This compound is obtained in the acidic medium as described in the final step of Example 1 and Example 2. The physico-chemical data are identical for the same compound prepared according to Methods 1 and 2.

An example

2-n-Butyl-4,4-dimethyl-1 - [(2'-butoxycarbonyl-biphenyl-4-yl) -methyl] -2-imidazolin-5-one and 2-n-butyl-1 - ((2'-carboxy-biphenyl-) 4-yl) methyl (-4,4-dimethyl-2-imidazolin-5-one trifluoroacetate (method 1).

N-2-n-butyl-4,4-dimethyl-2-imidazolin-5-one.

The ethyl ester of alpha-aminoisobutyric acid is prepared according to R. Jacąuier et al. Bull, Soc., Chim. Fran. 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 heated for 7 hours until phlegm is formed. The reaction medium is then concentrated in vacuo and the residue is chromatographed on silica gel eluting with chloroform / methane / acetic acid (95/5/2; v / v). After evaporating several times with xylene, and after

of that benzene to remove vinegar acid, is obtained 560 mg of the expected product which crystallize. Mp = 35-38 ° C. IR (CHCl3): - 1725 cm ^-1 : C = 0, - 1635 cm ^-1 : C = N. Note: According to that between 1500 and 1,600 cm ¹ is not available signal, one can judge that the compound, of chloroform

solution, contains 2-imidazolin-5-one.

NMR Spectrum:

- 0, 92 m.d. : t: 3H: CH ₃ / nBu /, - b 20th m.d. : s: 6H: C / CH _3/2, - b 38 m.d. : sec : 2] H: CH ₃ -CH ₂ -, - 1, 63 m.d. : kV: 2H : CH ₃ -CH ₂ -CH ₂ -, - 2, 38 m.d. : t: 2H: ch ₃ -ch ₂ -ch ₂ -ch ₂ - 10 »7 m.d. : m: 1H: 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.

In the previous step, 520 milligrams of the product were dissolved in 10 mL of DMFA, added 167 mg of sodium methylate and stirred under nitrogen for 15 minutes. 1.25 g of 4-bromomethyl- / 2'-tert-butoxycarbonyl / biphenyl are then added and left under stirring for three and a half hours at 40 ° C. The reaction medium is extracted with 150 ml of ethyl acetate followed by 20 ml of water and 2 ml of saturated sodium bicarbonate solution. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Chromatography of the residue on silica gel eluting with a mixture of ethyl acetate / toluene (1,2 / 2; v / v). 570 mg of the expected product is obtained, which crystallizes.

Mp = 98-100 ° C.

IR (CHCl3):

1710-1720 cm- ¹ : C = 0, C = 0 (imidazolinone, ester),

- 1625 cm ^-1 : C = N.

NMR Spectrum:

- 0.78 m.d. : t: 3H: CH ₃ / nBu /, - 1.08 m.d. : s: 9H: C / CH _3/3 f - 1.15 m. d. : s: c / CH _3/2 ► 8H - 1.20 m. d. : sec : CH ₃ -CH ₂ - - 1.45 m. d. : kV: 2H: CH ₃ -CH ₂ -CH ₂ -, - 2.30 m.d. : t: 2H: CH ₃ CH ₂ -ch ₂ -ch ₂ -, - 4.65 m.d. : s: 2H: CH ₂ -C ₆ H 4- '

-7.15-7.65 ppm: m: 8H: aromatic protons.

The OBE (Overhauzer Nuclear Effect) assays can confirm the position of the substituted 5-one and 4,4-dimethyl imidazoline:

Mass Spectrum: MH ⁺ : 435.

C / 2-n-Butyl-1- (2'-carboxy biphenyl-4-yl) methyl / -4,4-dimethyl-2-imidazolin-5-one trifluoroacetate.

In the previous step, 400 mg of the product was treated with 3 ml of DChM and 4 ml of TFR for 40 minutes. After concentration in vacuo, the residue is extracted with ether and the resulting precipitate is filtered off, washed with ether and then dried under vacuum. 450 mg of the expected product are obtained in the form of a white solid.

T _mp = 168-171 ° C.

NMR Spectrum:

0.82 ppm

- 1.30 ppm

1.35 m.d. 1.55 m.d. 2, 62 m. d. 4, 82 m.d. 7.20- -7.75

t: 3H: CH ₃ / nBu /, sec: CH ₃ -CH ₂ -

8H of C / CH _3/2 kV: 2H: CH ₃ -CH ₂ -CH ₂ -, that is: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -, s: 2H: CH ₂ -C ₆ H ₄ -,

m.d .: m: 8H: aromatic protons

Mass Spectrum: MH ⁺ : 379.

An example

1 - [(2'-Cyano-biphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one and 2-n-butyl-4-spirocyclopentane-1 - [2'- (tetrazol-5-yl) biphenylyl-4-yl) methyl-2-imidazolin-5-one (Method 1).

N - [(2'-Cyano-biphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one.

A mixture of 250 mg of sodium hydride (80% dispersed in mineral oil) and 5 ml of DMFA is added under a nitrogen atmosphere and a solution of 0, 97 g of 2-n-butyl-4-spirocyclopentane-2-imidazoline-5 is added dropwise. ono (obtained in Example 2, Step A) in 10 ml of DMFA. After stirring for 30 minutes at kT, a solution of 1.5 g of 4-bromomethyl-2-cyanobiphenyl in 10 ml of DMFA is added. Stir in 1 or. at kT followed by evaporation of the DMFA under reduced pressure, then the residue was extracted with ethyl acetate, the organic phase was washed with water, then dried over sodium sulfate, filtered and evaporated. Chromatography of the residue on silica gel eluting with a mixture of DCM / ethyl acetate (9/1; v / v). 1.68 g of the expected product are isolated.

_Mp = 92-93 ° C.

B / 2-n-butyl-4-spirocyclopentan-1- (2 '- (triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl) -methyl--2-imidazolin-5-one.

1.56 g of the product obtained in the previous step, 2.6 g of tributylol azide and 30 ml of xylene are heated for 66 hours until phlegm is formed. The xylene is then evaporated and the residue is dissolved in 20 mL of DChM and 5 mL of THF by adding 0.8 mL of 10N sodium hydroxide and after stirring for 30 min, 2.5 g of trimethyl chloride, followed by stirring for 26 h. After evaporation of the solvents, the residue is extracted with ethyl acetate and washed with water followed by 3% potassium hydrosulphate solution and water. Dried and evaporated. Chromatograph the residue on alumina using a mixture of hexane / ethyl acetate (9/1; v / v).

1.97 g of the expected product are obtained.

_{Melting point} = 150-152 ° C.

C2- (n-butyl-4-spirocyclopentan-1- (2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl) -2-imidazolin-5-one.

1.96 g of the product obtained in the previous step are dissolved in 10 ml of methanol and 10 ml of THF. After cooling the reaction solution to 5 ° C, 1.5 ml of 4N hydrochloric acid is added and stirred for 3 hours and 1 hour. At 30 ° C. After evaporation of the solvents, the residue was extracted with water and adjusted to pH = 12 by the addition of 10 N sodium hydroxide. The aqueous phase is extracted with ether, toluene and again with ether. The aqueous phase is acidified to pH = 2 with 1N hydrochloric acid, then extracted with ethyl acetate, dried and evaporated. The resulting white solid was dried at 50 ° C under a pressure of 0.05 mm of mercury. 840 g of the expected product are obtained.

T _mp. = 180-180 ° C.

NMR Spectrum:

- 0.75 ppm: t: 3 H: CH ₃ / nBu /,

- 1.10 md: sec: 2H; CH ₃ -CH ₂ -,

1.20 ppm: kV: 2H: CH ₃ -CH ₂ -CH ₂ -,

- 1.5-2 md: m: 8H: - C ₅ H ₈ ,

- 2.2 md: t: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

- 4.6 ppm: s: 2H: CH ₂ -C ₆ H ₄ -,

- 7 md: m; s: 4H: CH ₂ -C ₆ H ₄ -,

7.35-7.7 md: m; 4H: H ₃ , 4, 5, 6 aromatic protons

Examination of the OBE confirms the position of the imidazole substituted 5-one.

D / 2-n-Butyl-4-spirocylopentan-1 - ((2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl) -2-imidazolin-5-one potassium salt.

970 mg of the compound obtained in the preceding step is dissolved in 40 ml of isopropanol-methanol (1/1; v / v), adjusted to pH 12 with 85% potassium hydroxide solution in methanol-water (20/1; v / v). Evaporate, extract the residue with isopropanol and evaporate again.

Dissolve the residue in 20 ml of isopropanol with gentle heating, then reduce it again to room temperature. Decant, evaporate the filtrate, then extract the residue with heptane. The product is then concentrated, filtered, rinsed with heptane and dried in vacuo. 945 mg of the expected potassium salt is obtained.

_{Melting point} = 142-144 ° C.

Elemental Analysis: C ₂₅ H ₂₇ KN ,, OxH ₂ O

Found: C, 61.95 H: 6.03 N: 17.34

Found,% 62.02 6.13 17.34

An example

2-n-Butyl-1- (2'-carboxy-biphenyl-4-yl) methyl-4- (spiro-tetrahydropyran) -2-imidazolin-5-one trifluoroacetate and 2-n-butyl-4- (4-spirotetrahydro-pyran) (-1- (2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl) -2-imidazolin-5-one (Method 2).

N-4-aminotetrahydropyran-4-carboxylic acid is obtained from tetrahydropyran-4-one according to the process described in German patent no. 2215 721.

B / 4- / N-benzyloxycarbonylamino / -4-carboxytetrahydropyran.

From Step A, 1.015 g of the product is added to 12 ml of water and treated with 1.22 ml of diisopropylethylamine at 10 ° C, followed by 3.33 g of N- / benzyloxycarbonyloxy / succinimide dissolved in 12 ml of acetonitrile. After 1 or. 15 mins the reaction medium is diluted with 70 mL of ethyl acetate and 10 mL of water, then adjusted to pH = 2 by addition of a saturated potassium bisulfate solution.

After decantation, the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulphate and then dried under vacuum. The residue is diluted with 60 ml of ether, followed by the addition of 7 moles of dicyclohexylamine. The precipitate formed is filtered off and washed with ether; they are then dissolved in ethyl acetate-water and adjusted to pH = 1.5 by the addition of a saturated solution of potassium bisulphate. Decant the organic phase, wash with saturated sodium chloride solution, evaporate in vacuo to give 1.9 g of a white solid.

_{Melting point} = 110-115 ° C.

C- N - (2'-tert-Butoxycarbonyl-biphenyl-4-yl-methyl) -4- (N-benzyloxycarbonylamino) -tetrahydropyran-4-carboxamide.

850 mg of the product obtained in Step B are dissolved in 15 ml of DMFA and an equimolar amount of 4-aminomethyl / 2'-tert-butoxycarbonylbiphenyl, DIPEA, followed by FBO / with 10% excess / is added. After 40 minutes the reaction medium is extracted with 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted, then washed twice with saturated sodium bicarbonate solution, twice with 5% sodium bisulphate solution and then once with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase is evaporated to dryness. 1.8 g of the expected product are obtained.

D / N- (2'-tert-Butoxycarbonyl-biphenyl-4-yl-methyl / -4-amino-tetrahydropyran-4-carboxamide.

The product obtained in Step C is dissolved in 30 ml of methanol. Add 400 mg palladium, 10% carbon and hydrogenate at atmospheric pressure. After 1 or. the catalyst is filtered off and the filtrate is concentrated in vacuo. Chromatography of the residue on silica eluting with a mixture of ethyl acetate-methanolic ammonia at 33% (99/1 / 0.5; v / v). 0.93 g of the expected product is obtained in the form of a white solid.

T _melt = 125-127 ^ū C.

NMR Spectrum:

- 8.50 ppm: t: 1H: amide H,

- 7.60-7.05 ppm: m; 8H: Aromatic Protons

- 4.25 ppm: d: 2H: CH ₂ -C ₆ H ₄ -,

- 3.70-3.50 md: m; 4H: CH _{2 at the} 2 and 6 positions of the tetrahydropyran,

- 2.00-1.80 md: m; 4H: CH _{2 at} positions 3 and 5 of tetrahydropyran.

- 1.05 ppm: s: 9H, tBu.

E- (2-n-butyl-4- (4-spirotetrahydropyran [-1,2'-tetrabutoxycarbonyl-biphenyl-4-yl) methyl-2-imidazolin-5-one].

A mixture of 0.9 g of the compound obtained in Step D, 327 mg of methylorthovalerate and 2 drops of acetic acid is heated for 3 hours. At 110 ° C. The reaction medium is extracted with 100 ml of ethyl acetate solution, washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, then dried over sodium sulfate, and evaporated with ethyl acetate. Chromatography of the residue obtained on silica eluting with ethyl acetate / toluene (2.1; v / v).

550 mg of the expected product are obtained in the form of a wax.

NMR Spectrum:

- 7.65-7.60 ppm: m: .8.H: aromatic protons

- 4.63 ppm: s: 2H: CH ₂ -C ₆ H ₄ -,

- 3.85-3.55. ppm: m: 4H: CH ₂ tetrahydropyran 2 and 6 position.

- 2.30 md: 2H: CH ₂ -C ₃ H ₇ ,

- from 1.05 to 1.80 ppm: m: 8H: CH ₂ -CH ₂ -CH ₂ -CH ₃ and CH ₂ tetrahydropyran 3 and 5 position.

- 1.03 ppm: s: 9H: tBu; - 0.75 da: t: 3H: / CH _2/3 -CH ₃ AND / CHC1 ₃ /: - 1710-1720 -1 cm : C = 0, C = 0, - 1625 cm ' ¹ : C = N

F / 2-n-Butyl-4- (4-spirotetrahydropyran) -1- (2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl / -2-imidazolin-5-one trifluoroacetate.

The product from the previous step was treated with 530 mg of 4 ml of dichloromethane and 5 ml of TFR for 45 minutes. After evaporation in vacuo, the residue is extracted with ether, the resulting precipitate is filtered off, washed with ether and then dried under vacuum. 510 mg of the expected product are obtained.

_{Melting point} = 159-162 ° C.

NMR Spectrum:

- 7.80-7.10 ppm: m; 8H: Aromatic Protons

- 4.80 md: s: 2H: CH ₂ -C _f .H ₄ -,

- from 4.00 to 3.75 ppm: m: 4H: CH ₂ tetrahydropyran 2 and 6 position;

- 2.60 md: 2H: CH ₂ -C ₃ H ₇ ,

- from 1.45 to 2, 00 ppm: m: 6H: CH ₂ -CH ₂ -CH ₂ -CH ₃ and CH ₂ tetrahydropyran 3 and 5 position,

- 1.30 md: sec: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

- 0.80 ppm: t: 3H: / CH _2/3 -CH _third

An example

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (spiro (1-benzyl-4-piperidin)) -2-imidazolin-5-one trifluoroacetate and 2-n- butyl-4- (spiro- (1-benzyl-4-piperidin) / 1- (2'-tert-butoxycarbonylbiphenyl-4-yl) methyl) -2-imidazolin-5-one (method 1).

N-4-amino-1-benzylpiperidine-4-carboxylic acid is obtained from N-benzylpiperidin-4-one according to German patent no. 2215 721.

B / 4-amino-1-benzyl ethyl piperidine-4-carboxylate.

To a solution of 13 g of hydrochloric acid in 50 ml of ethanol is added 3.8 g of the compound obtained in Step A at 0 [deg.] C. and then maintained for 5 hours at the temperature of phlegm formation. After concentration in vacuo, the residue is rinsed with ether and then dissolved in ether-water, to which a saturated solution of potassium carbonate is added until pH = 9. The ethereal phase is decanted off, washed with saturated sodium chloride solution, dried over sodium sulphate and then evaporated to dryness. 3.50 g of the expected product are obtained in the form of an oil.

NMR Spectrum:

- 7.20-7.40 m.d .: m: 5H: Aromatic Protons - 4.10 da.s. : k: 2H: ch ₂ -ch ₃ , - 3.45 ppm. : s: 2H: CH ₂ benzyl, - 2.25-2.60 6 positions, m.d .: m: 4H: CH ₂ piperidine 2 and

1, 80-2, 05 md: m: 2H: 2H _{2 at} piperidine 3 and positions.

- 1.20-1.40 md: m: 2H: 2H _{2 at the} 3 and 5 positions of piperidine.

- 1.12 ppm: t: 3 H: CH ₃ -CH ₂ -.

C 2-n-butyl-4- spiro (1-benzyl-4-piperidinyl) -2-imidazolin-5-one.

Ethyl valerimidate is obtained in the same manner as in Example 2, Step A. 2.06 g of ethyl valerimidate, 3.40 g of the compound obtained in Step B and 8 drops of acetic acid are added with 15 ml of xylene and the mixture is heated for 6 hours until phlegm is formed. After concentration in vacuo, the residue is chromatographed on silica gel eluting with a mixture of chloroform / methanol / acetic acid (82/15/5; v / v). The acetic acid is removed by extraction with chloroform at pH = 9 to give 2.80 g of the expected product.

_{Melting point} = 170-172 ° C.

IR / chloroform /:

- 1725 cm ^-1 : C = 0,

- 1640 cm ^-1 : C = N.

NMR Spectrum:

- 7.10-7.30 ppm: m: 5H: aromatic protons

- 3.45 ppm: s: 2H: -CH ₂ -C ₆ H ₅ -,

- 1.10-2.75 md: 5m: 14H: CH ₂ piperidino 2, 3,

5, and 6 positions / CH _2/3 -CH _third

- 0.80 ppm: t: 3H: / CH _2/3 -CH _3,

D / 2-n-Butyl-4- / spiro- (1-benzyl-4-piperidin) -1- (2'-tert-butoxycarbonylbiphenyl-4-yl) methyl / -2-imidazolin-5-one.

2.78 g of the compound obtained in Step C are dissolved in 25 ml of DMFA, 513 mg of sodium methylate are added, and 4.16 g of 4-bromomethyl- (2'-tert-butoxycarbonylbiphenyl) are added after 15 min. After heating at 40 ° C for 5 hours, the reaction mixture is extracted with 300 ml of ethyl acetate, 50 ml of water and 5 ml of saturated sodium bicarbonate solution. The organic phase is decanted off, washed once with saturated sodium chloride solution, dried over sodium sulphate and chromatographed on a mixture of ethyl acetate / methanol (95/5; 0.98 g of the expected product).

to dryness. Fractions of silicon oxide (by volume).

_{Melting point} = 103-106 ° C,

IK / CHC1 ₃ /:

1710-1725 cm ¹ : C = 0, C = 0 / imidazoline, ester /;

- 1630 cm ^-1 : C = N.

NMR Spectrum:

- 7.70-7.10 ppm: m: 13H: aromatic protons

- 4.70 ppm: s: 2H: CH ₂ -C ₆ H -,

- 3.55 ppm: s: 2H: CH ₂ -C ₆ H _5,

- from 1.20 to 2.75 ppm: 5 m: 14H: CH ₂ piperidine 2, 3, 5, and 6 positions / CH _2/3 -CH _3,

- 1.15 ppm: s: 9H: tBut

- 0.85 ppm: t: 3H: / CH _2/3 -CH _third

E / 2-n-butyl-1- (2'-carboxybiphenyl-4-yl) methyl / -4-spiro- (1-benzyl-4-piperidin) -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 TFR. After 45 min, the reaction medium is concentrated in vacuo, then the residue is extracted with ether-hexane, the resulting precipitate is filtered off, washed with ether and dried in vacuo. 350 mg of the expected product are obtained.

_Mp = 198-200 ° C.

NMR Spectrum:

- 7.05-7.75 ppm: m: 13H: aromatic protons

4.75 ppm: s: 2H: CH ₂ -C H ₄ -,

- 4.40 ppm: s: 2H: CH ₂ -C ₅ H _ę,

- from 3.20 to 3, 60 ppm: m: 4H: CH ₂ piperidino 2 and 6 positions.

- 2.35 ppm: t: 2H: CH ₂ -CH ₂ -CH ₂ -CH _3,

- 2,20-1,40 md: 3 signals: CH _{2 at} piperidine 3 and positions and CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

- 1.25 md: sec: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

- 0.80 ppm: t: 3H: / CH _2/3 -CH _third

An example

2-n-Butyl-1- (2-carboxybiphenyl-4-yl) methyl-4- (4-spiropiperidino) -2-imidazolin-5-one ditrifluoroacetate and n-2-butyl-4- (4-spiropiperidine) - 1- (2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one.

A / 2-n-Butyl-4- / 4-spiropiperidin / l- / 2 -tretbutoksikarbonilbifenil ^one-4-yl) methyl / -2-imidazolin-5-one.

300 mg of the compound obtained in Example 7, Step D, are dissolved in 10 ml of methanol. 180 mg of palladium on 10% carbon are added and hydrogenated at atmospheric pressure for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. 200 mg of the expected product are obtained.

NMR Spectrum:

- 7.20-7.75 ppm: m: 8H: aromatic protons

4.75 ppm: s: 2H: CH ₂ -C ₆ H ₄ -,

3.00-1.70 md: 3 signals for 4CH ₂ -groups

piperidino, - 2.40 m.d .: m: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ , - 1.60 m.d .: kV: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ , - 1.35 m.d. : sec: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ , - 1.20 m.d. : s: 9H: tBu, - 0.90 m.d. : t: 3H: / CH _2/3 -CH _third

B / 2-n-Butyl-1- (2'-carboxybiphenyl-4-yl) methyl / -4- (4-spiropiperidin) -2-imidazolin-5-one ditrifluoroacetate.

160 mg of the product of Step A are stirred in 3 ml of dichloromethane and 4 ml of trifluoroacetic acid for 45 minutes. Concentrate in vacuo and extract the residue with ether. Rubber-like material is obtained, and after vacuum drying, a foam-like material is obtained.

m = 150 mg

Mp = 80-85 ° C.

NMR Spectrum:

- 7.15-7.80 ppm: m: 8H: aromatic protons

- 4.75 ppm: s: 2H: CH ₂ -C H ₄ -,

3.20-1.60 md: 3 signals for 4CH ₂ groups,

- 2.40 md: t: 2H: CH ₂ -CH ₂ -CH ₇ -CH ₃ , piperidino

- 1.50 m.d. : kV: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ , - 1.30 m.d. : sec; 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ , - 0.80 m.d. : t: 3H: / CH _2/3 -CH _third

An example

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4,4-diphenyl-2-imidazolin-5-one trifluoroacetate and 2-butyl-4,4-diphenyl-1 '- 2' tert -butoxycarbonyl biphenyl-4-yl) methyl) 2-imidazolin-5-one (method 1).

A / Valerimidine Chlorhydrate.

of ethyl valerimidate chlorohydrate is added to a solution of 6.75 g of ammonia in 80 ml of methanol at 0 ° C. After 18 hours, the reaction medium is concentrated in vacuo to give a white solid.

B / 2-n-butyl-4,4-diphenyl-2-imidazolin-5-one.

This compound is prepared from dibenzoyl and valerimidine chlorohydrate in the manner described by J. Nyitrai, K. Lempert, Tetrahedron, 1969, 25, 4265-75.

_{Melting point} = 135 ° C.

AND / CHC1 ₃ /:

- 1725 cm ^-1 : C = 0,

- 1640 cm ^-1 : C = N.

NMR Spectrum:

- 7.20-7.50 ppm: m: 10H: aromatic protons

- 2.50 ppm: t: 2H: CH ₂ -CH ₂ -CH ₂ -CH _3,

- 1.65 ppm: kV: 2H: CH ₂ -CH ₂ -CH ₂ -CH _3,

- 1.35 md: sec: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

- 0.90 ppm: t: 3H: CH ₂ -CH ₂ -CH ₂ -CH _3,

- 11 ppm: p.s: NH.

C 2 -N-butyl-4,4-diphenyl-1- (2'-tert-butoxycarbonylbiphenyl-4-yl) methyl-2-imidazolin-5-one.

This compound is prepared in a conventional manner by reacting the compound obtained in Step B with 4-bromomethyl- / 2'-tert-butoxycarbonyl-biphenyl in the presence of sodium methylate in DMFA.

AND / CHC1 ₃ /:

- 1715-1725 cm- ¹ : C = 0, C = 0 / ester, imidazolinone /,

- 1635 cm @ ^-1 : C = N.

NMR Spectrum:

- 7.25 to 7.80 ppm: m: 18H: aromatic H,

- 4.85 m.d. : s: 2H: n-ch ₂ -c ₆ h ₄ -, - 2.60 m. d. : t: 2H: ch ₂ -ch ₂ -ch ₂ -ch ₃ , - 1.75 m. d. : kV: : 2H- -: CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

1.40 md: sec: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

- 1.15 ppm: s: 9H: tBu,

- 0.90 ppm: t: 3 H: CH ₃ 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 obtained in step C are treated with 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid for 40 minutes at 20 ° C. After concentration in vacuo, the residue is extracted with ether-hexane, the resulting precipitate is filtered off, washed with hexane and dried. 440 mg of the expected product is obtained.

_{Melting point} = 55-60 ° C.

NMR Spectrum:

- 7.15-7.80 ppm: m: 18H: aromatic protons

- 4.85 md: N-CH ₂ -C ₆ H ₄ -,

- 2.60 ppm: t: 2H: CH ₂ -CH ₂ -CH ₂ -CH _3,

- 1.70 ppm: kV: 2H: CH ₂ -CH ₂ -CH ₂ -CH _3,

- 1.40 md: sec: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₃ ,

- 0.90 md: t: 3H: CH ₃ butyl.

An example

2-n-Butyl-3 - [(2'-carboxybiphenyl-4-yl) methyl-6-spirocyclopentane-5,6-dihydro-1H-4-pyrimidinone trifluoroacetate.

N-l-aminocyclopentyl / -acetic acid.

Cyclopentylideneacetic acid is obtained from G. A. R. Kon, R. P. Linstead, J. Chem. Soc. 1925, 127, 616 in the manner indicated. Heat 740 mg of this acid and 5 ml of 20% ammonia in an autoclave at 150 ° C for 24 hours. After evaporation of the solvents, the residue is chromatographed on a column of silica eluting with DCM / methanol-20% ammonia solution (70/30/1; v / v). 330 mg of the expected acid are obtained.

B / l-aminocyclopentyl / ethyl acetate.

Dissolve 330 mg of acid in 10 ml of methanol. Cool in an ice bath and add gaseous hydrochloric acid. After 24 hours at the temperature where the phlegm is formed, the reaction medium is evaporated, the residue is extracted with sodium acetate, ethyl acetate, sulfate, filtered and carbonate solution and then dried over sodium vapor. 312 mg of the expected ester is obtained.

C 2 -N-Butyl-6-spirocyclopentane-5,6-dihydro-1H-pyrimidin-4-one

A mixture of 310 mg of product obtained in Step B, 348 mg of ethyl valerimidate, 10 ml of xylene and 6 drops of acetic acid is achieved in a phlegm state. Then, after 2 h and 18 h, 348 mg of ethyl valerimidate were added again and the whole was maintained at reflux for 24 h, then the reaction medium was evaporated, followed by chromatography on silica eluting with DCM / methanol (97/3; v / v). 153 mg of the expected product are obtained.

D / 2-n-Butyl-3 / (2'-tert-butoxycarbonylbiphenyl-4-yl) methyl / -5,6-dihydro-1H-pyrimidin-4-one

A mixture of 10 ml of DMFA and 40 mg of sodium hydride in 80% liquid oil is prepared under a nitrogen atmosphere. At room temperature, 144 mg of the compound obtained in Step C and dissolved DMFA are added dropwise. After stirring for 30 min, 288 mg of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl dissolved in 5 ml of DMFA are added. The mixture is left under stirring for 2 hours, then evaporated and the residue is extracted with water and extracted with ethyl acetate. Dry over sodium sulfate, filter and evaporate, then purify by column chromatography eluting with hexane-ethyl acetate (85/5: V / K). 174 mg of the expected product is obtained.

E / Water-ice bath was cooled with 10 mL of trifluoroacetic acid and 161 mg of compound obtained in Step D was added. Leave for 30 min with stirring, then evaporate. This operation is repeated, then the residue is dried under vacuum. 140 mg of the expected compound are obtained in the form of an amorphous powder.

_Mp = 108-115 ° C.

NMR Spectrum:

- 0.9 ppm: t: 3H: / CH _2/3 -CH _3,

- 1.1 to 2.1 md: m: 12H: cyclopentane and CH ₂ -CH ₂ CH ₂ -CH ₃ ,

2.7 m.d. : t; 2H: ch ₂ -ch ₂ -ch ₂ -ch 3.1 m.d. : s: 2H: -CH-CO, 5.1 m.d. : s: 2H: -CH ₂ -C _f , H ₅ ,

- 7.2 to 7.8 ppm: m: 8H: aromatic protons

An example

2-n-butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-thione and 2-n-butyl-1 - [(2 ') -carboxy biphenyl-4-yl) methyl-4-spirocyclopentane-2-imidazolin-5-thione trifluoroacetate

N-2-n-butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-thione.

5.63 g of the compound obtained in Example 1, Step D is dissolved in 40 ml of anhydrous toluene and 3 g of Lawesson's reagent at 80 ° C. After 6 hours, the reaction medium is filtered and concentrated. Chromatography on silica eluting with a mixture of: DChM: ethyl acetate (95/5; v / v). The product is obtained in the form of an oil, which crystallizes in the cold.

m = 4.5 g

_M.p. = 77-79 ° C.

NMR Spectrum: - 0, 90 m.d. : t: 3H: CH ₃ (nBu), - 1.20 m. d. : s: 9H: tBu, - 1.35 m. d. : sec : 2H : CH ₃ -CH ₂ -, - 1.60 m. d. : kV: 2H: ch ₃ -ch ₂ -ch ₂ -, - 1.80- 2, 10 m.d. : m: 8H: Cyclopentane - 2.60 m. d. : t: 2H: ch ₂ -ch ₂ -ch ₂ -ch ₂ ,

- 5.35 ppm: s: 2H: CH ₂ -C ₆ H ₄ -,

- 7.25-7.80 ppm: 8H: aromatic protons

B / 2-n-Butyl-1 - ((2'-carboxybiphenyl-4-yl) methyl) -4-spirocyclopentane-2-imidazoline-5-thione trifluoroacetate.

225 mg of the compound obtained in Step A are treated with 5 ml of DChM and 5 ml of TFR for 30 minutes. After concentration, the residue is extracted with ether.

The product is obtained as a yellow powder which is washed with hexane.

m = 160 mg

T _mp. = 185-190 ° C.

Mass spectrum: MH ⁺ : 421

NMR Spectrum:

0.78 m.d. : t: 3H: CH ₃ / nBu /, 1.20 m.d. : sec :: 2H: CH ₃ -CH ₂ -, 1.50 m.d. : kV: 2H: CH ₂ -CH ₂ -CH ₂ -, 1.75- -2, 00 m.d. : m: 8H: cyclopentane 2.40 m.d. : t: 2H: CH ₂ -CH ₂ -CH ₂ -CH ₂ -, 5.20 m.d. : s: 2H: CH ₃ -CgH -,

- 7.00-7.65 ppm: m: 8H: aromatic protons

An example

2-n-Butyl-1 - [(2'-spiroindan / -1- (2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one and

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (2-spiroindan) -2-imidazolin-5-one (method 1).

The 2-aminoindan Z-carboxylic acid is obtained from R.M.Pinder, J.Med. Chem., 14, 9, 892, 1971, and the corresponding ester is obtained according to Adkins (Reference Example 2A).

B / 2-n-butyl-4- / 2-spiroindan / -2-imidazolin-5-one.

Dissolve 2.78 g of ethyl ester obtained in Step A and 2.5 g of ethyl valerimidate in 20 ml of xylene, using 60 μΐ acetic acid, and keep at reflux for 3 hours. Again, 500 mg of ethyl valerimidate are added and the mixture is maintained at the phlegm for an additional 3 hours. The reaction medium is concentrated and then purified by chromatography on silica eluting with hexane: ethyl acetate-acetic acid (3/8/03; v / v). The purified fractions were combined and evaporated with toluene. 3.07 g of the expected product are obtained in the form of a white solid.

T _melt = 148-150 ° C.

NMR Spectrum:

- 0.90 ppm: t: 3 H: CH ₃ .nBu /,

- 1.2 to 1.7 ppm: m: 4H: CH ₂ -CH ₇ CH _3,

2.4 md: t: 2H: CH _? - / CH _2/2 -CH ₃

- 2.8 to 3.2 ppm k: 4H: 2CH ₂ / indan /,

- 4.90 ppm: s: 2H: CH ₂ -C ₆ H ₄ -,

- 7.2 ppm: m: 4H: aromatic protons

C-2-n-butyl-4- / 2-spiroindan-1 - [(2'-tert-butoxycarbonyl-biphenylmethyl) -2-imidazolin-5-one.

In the previous step, 20 ml of anhydrous DMFA in 450 mg of sodium methylate.

The resulting product was dissolved and exposed to a nitrogen atmosphere. After 20 min kT, 3.6 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl was added and left under stirring at 40 ° C for 6 hours. The reaction medium is concentrated, then usually washed and purified by chromatography on silica eluting with dichloromethane-ethyl acetate (95.5; v / v) to give the expected compound as a foam.

/ m = 1.84 g / m.

NMR Spectrum:

- 0.80 m.d. : t: 3H: CH ₃ : nBu, - 1.20 m.d: s: 9H: tBu, - 1.20 -1.60 m.d . : m: 4H: CH ₂ -CH ₂ -CH ₃ , - 2.40 m.d. : t: 2H: CH ₂ - / CH _2/2 -CH _3, - 2, 9- 3, 3 yrs .d. : k: 4H: 2-CH2 ₍ indane), - 4.80 m.d. : s: 2H: N-CH -, - CgH ₄ ,

7.20 - 7.80 ppm: m: 12H: aromatic protons

D / 2-n-Butyl-1- (2'-carboxybiphenyl-4-yl) methyl-4- (2-spiroindan) -2-imidazolin-5-one.

1.71 g of the compound obtained in the previous step is dissolved in 15 ml of DChM and treated with 20 ml of TFR. After 30 min, the reaction medium is concentrated, then extracted with ether. After the formation of a powder, the resulting solid is decanted off, washed with ether and dried. 1.42 g of the expected product are obtained.

_{Melting point} = 217-218 ° C.

NMR Spectrum:

- 0.70 ppm: t: 3 H: CH ₃ / nBu /,

- from 1.10 to 1.50 ppm: m: 4H: CH ₂ -CH ₂ -CH _3,

- 2.30 ppm: t: 2H: CH ₂ - / CH _2/2 -CH _3,

- 2.8 to 3.3 ppm k: 4H: 2CH ₂ / indan /,

- 4.70 ppm: s: 2 H: N-CH ₂ -C _fi H ₄ -,

- 7.1 to 7.7 ppm: m: 12H: aromatic protons

Other compounds of the invention were obtained by one of the methods described above. Examples are collected in Table 1. The structure of each compound was confirmed by NMR spectral analysis.

An example

2-n-Butyl-1 - [[2 '- (1-imidazol-1-ylcarbonyl) biphenyl-4-yl] methyl] -4-spirocyclopentan-2-imidazolin-5-one f / ··

If o

R ₂ -H, R ₃ -nC ₄ H ₉ ,

CR ₄ R ₅ = cyclopentane, X = 0

A mixture of 404 mg of the compound obtained in Example 1, Step E, 15 ml of TMF and 260 mg of carbonylimidazole was stirred at RT for 72 h. The reaction medium is evaporated, extracted with ethyl acetate, washed with water followed by brine, and 420 mg of product is purified by chromatography on silica eluting with DCM / ethyl acetate (70/30; v / v) to give the title compound.

m = 230 mg,

_{Melting point} = 120 ° C.

An example

2-n-Butyl-1- [2 '- (3-cyano-2-methylisothioureidomethyl-biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one

S CH ₃ I / 1: R ₁ = -CH ₂ -NH-C = N - CN, R = H, R ₃ = nC ₄ H ₉ ,

CR ₄ R ₅ - Cyclopentane, X = 0 /

N- (2'-Aminomethyl-biphenyl-4-yl) -methyl- -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one.

This compound is obtained by hydrogenation of the compound obtained in Example 5.

of the compound obtained in Example 5, Step A, is added to 15 ml of absolute methanol and 2.3 ml of ethanol using 0.5 g of palladium on 5% carbon and hydrogenated for 24 hours. After treatment, 730 mg of the expected product is obtained in the form of an oil.

B / A mixture of 300 mg of the compound obtained in the preceding step and 113 mg of N-cyanimide-S, dimethyldithiocarbonate in 3 ml of ethanol is heated at reflux for 24 hours. After usual work-up, the reaction medium is purified by chromatography on silica eluting with a mixture of DCM / ethyl acetate (50/50; v / v).

The expected product is isolated as a white solid.

m = 307 mg.

_Mp = 83 ° C.

An example

2-n-Butyl-1- [2 '(-cyanoguanidinomethyl) biphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one.

NH ₂

I / 1: R ₁ = CH ₂ -NH-C = N-CN, R ₂ = H, R = nC ₄ H ₉ ,

CR ₄ R ₅ -cyclopentane, X = 0 /.

This compound is obtained from the compound obtained in the previous example. 200 mg of the compound is added to 10 ml of absolute ethanol, saturated with ammonia at about 10 ° C, then heated to 80 ° C in an autoclave overnight. After concentration of the rake medium to dryness, the residue is purified by chromatography on silica eluting with a mixture of DCM / methanol (95/5; v / v). 130 mg of the expected product are obtained.

_{Melting point} = 100 ° C.

An example

2-n-Butyl-4-spirocyclopentan-1 - [(2'-trifluoromethylsulfonylaminobiphenyl-4-yl) methyl] -2-imidazolin-5-one trifluoromethylsulfonate / 1: R ₁ = -NHSO ₂ CF ₃ , R ₂ = H, R ₃ = nC ₄ H ₉ ,

CR ₄ R ₅ = cyclopentane, X = 0 /

N-4-methyl-2'-nitrobiphenyl.

11.2 g of 2-nitrobromobenzene and 15 g of 4-iodotoluene are mixed, heated to 195 ° C and left at that temperature for three and a half hours. After falling to kT, DChM is extracted, brought to phlegm formation, and the hot solution is filtered through celite®, then evaporated with DChM.

m = 6.5 g

Boiling point T _vir = 80-120 ° C at a pressure of 0.22 mm of mercury column.

n _D 24 = 1.6042.

B / 4-Bromomethyl-2'-nitrobiphenyl.

A mixture of 6.5 g of 4-methyl-2-'nitrophenyl, 5.42 g of NBC, 118 mg of azobisisobutyronitrile and 500 ml of carbon tetrachloride is heated by heating with phlegm. Cool to 0 ° C, centrifuge and concentrate the filtrate to give 9 g of product as an oil, which is used as such in the next step.

C / 2-n-butyl / (2'-nitrobiphenyl-4-yl) methyl / -4-spirocyclopentan-2-imidazolin-5-one.

A mixture of 260 mg of sodium hydride at 80% concentration in 5 mL of DMFA is prepared by adding 500 mg of 2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one obtained in Example 2, Step A under kT nitrogen. Stir for 15 min, then add 901 mg of 4-bromomethyl-2 'nitrobiphenyl in 5 mL of DMFA and keep stirring for 24 h. The reaction medium is concentrated to dryness; extracted with water / ethyl acetate. The organic phase is decanted off, dried over sodium sulfate and filtered, after which the ethyl acetate is evaporated. The resulting product is purified by chromatography on silica eluting with DCM / ethyl acetate (9/1; v / v). 500 mg of the expected product are obtained.

D / 1- (2'-Aminobiphenyl-4-yl) methyl / -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one.

450 mg of the product obtained in the preceding step are added for hydrogenation in 10 ml of methanol with the addition of palladium in a concentration of 5% in carbon. After filtration of the catalyst and evaporation, 240 mg of the expected product remain.

E / 225 mg of the product obtained in the previous step are mixed with 0.1 ml of triethylamine in 4 ml of DChM and 0.2 ml of trifluoromethylsulphuric anhydride are added under argon at -78 ° C, then allowed to fall to kT. The reaction medium is washed with water, sodium bicarbonate solution, then dried and concentrated. 150 ml of a white amorphous solid are obtained.

NMR Spectrum:

- 0.4 to 1.3 ppm: m: 7H: CH ₃ -CH ₂ -CH ₂ -,

- 1.4 to 2.3 md: m: 10H: CH ₃ -CH ₂ -CH ₂ -CH ₂ and cyclopentane,

- 4 to 4.8 md: AB system: 2H: N-CH ₂ -C ₆ H ₄ -,

- 7-7.6 ppm: m: 8H: aromatic protons

- 8.3 dd: s: 1H: -NH,

- 10 md: ps: 1H: CF ₃ -SO ₃ H.

An example

2-n-Butyl-4-spirocyclopentan-1 - [(2'-trifluoromethylsulfonylaminomethyl-biphenyl-4-yl) -methyl] -2-imidazolin-5-one trifluoromethylsulfonate.

/ 1: R ₁ = CH _? NHCO ₂ CF ₃ , R ₂ = H, R ₃ = nC ₄ H ₇ ,

CR ₄ R ₅ = cyclopentane, X = 0 /

Synthesis is carried out from 1 / (2'aminomethylbiphenyl-4-yl) -methyl / 2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one obtained in Example 14, Step A. Add 322 mg of this compound and at 0.122 mL, the sulfuric acid will fall to extract DChM and evaporate to DChM.

triethylamine to 3.4 mL DChM -70 C and 0.294 mL trifluoromethyl anhydride was added. Wait until the temperature kT is added to the dilute acetic acid, dried over sodium sulfate and the residue is purified twice by chromatography eluting with a mixture of: DChM:

ethyl acetate (95/5; v / v) followed by (99.5 / 0.5; v / v).

M = 90 mg is obtained.

_{Melting point} = 90 ° C.

NMR Spectrum:

- 0.4 to 1.2 ppm: m: 7H: -CH ₂ -CH ₂ -CH _3,

- from 1.3 to 2.45 ppm: m: 10 H: CH ₂ -CH ₂ -CH ₂ -CH _3, and cyclopentane,

- from 4.1 to 5 ppm: m: 4 H: N-CH ₂ -C ₆ H ₄ - and -CH ₂ NH -CgH ₄ -,

- 7.1 to 7.7 ppm: m: 8H: aromatic protons,

- 8.4 ppm: s: 1H: NH.

An example

2-n-Butyl-1 - [[2 '- (N-hydroxyacetamide) -biphenyl-4-yl] methyl] -4-spirocyclopentan-2-imidazolin-5-one.

/ 1: R 1 -CO-NHOH, R ₂ = H, R -, = nC ₂ H ₉ ,

CR ₄ R ₅ = cyclopentane, X = 0 /

The compound obtained in Example 2 is liberated from the trifluoroacetic acid salt by extraction with ethyl acetate-water and adjusted to pH = 6 with saturated sodium bicarbonate. The organic phase is washed with sodium sulfate, filtered and concentrated to give the free base as a white solid.

450 mg of this compound are dissolved in chloroform, 860 mg of thionyl chloride is added at 0 [deg.] C. and left under stirring for 2 hours. The solution is concentrated and traces of thionyl chloride are removed by distillation with toluene. The acid chloro anhydride thus obtained is added dropwise as a solution of DMFA to a solution of 200 mg of hydroxylamine chlorohydrate and 700 µL of DIPEA in 10 ml of DMFA. After 2 h at 0 ° C, the reaction medium is concentrated and extracted with 100 mL of DCM and 50 mL of water. Adjust to pH = 7, extract the organic phase and dry over sodium sulfate. After filtration, the solution is concentrated. The resulting product was recrystallized from ethyl acetate-ethyl ether-hexane.

m = 360 mg.

_{Melting point} = 85 ° C.

An example

2-n-Butyl-4-spirocyclopentan-1 - [(2'-ureidobiphenyl-4-yl) methyl] -2-imidazolin-5-one / 1: R ₁ = NHCONH ₂ , R ₂ = H, R ₃ = nC ₄ H ₉ , CR ₄ R ₅ = cyclopentane,

X = 0 /

This compound is obtained by B.B. Kobu et. al., Otg. Synth., 1957, 37, 52 from 1 - [(2'-aminobiphenyl-4-yl) -methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one obtained in Example 14, Step A.

of the title compound is dissolved in 50 ml of 6N hydrochloric acid at a temperature. extracted with bicarbonate treated with potassium reaction ethyl acetate, isocyanate for 1 hour. The 5 C medium is concentrated and washed with sodium followed by a saturated sodium chloride solution. After drying over sodium sulfate, it is filtered off and the solution is concentrated, and the resulting liquid oil is purified by chromatography on silica eluting with DCM / MeOH (9/1; v / v).

m = 600 mg

NMR Spectrum:

- 0.85 ppm: t: 3H: CH ₂ -CH _3,

- 1.35 ppm: s: 2H: CH ₂ -CH _3,

- 1.6 da: kV: 2H: ch ₂ -ch ₂ -ch ₃ , - 1.7-2 m.d. . : m : 8H : cyclopentane, - 2.45 da.s. : t: 2H: ch ₂ -ch ₂ -ch ₂ -ch ₃ , - 4.8 da: s: 2H: -ch ₂ -c ₆ h ₄ -, - 6.05 ppm. : s: 2H: nh ₂ , - 7.8 ppm: m: 9H: 8H aromatic + NHCO 20 and 21 Examples

1 - [(2'-Carboxybiphenyl-4-yl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one and 1 - [(2'-N-cyanocarboxamide biphenyl-4-yl) methyl] - 2-n-propyl-4spirocikloheksan-2-imidazolin-5-one / one R ^ -CO-NH-CH, R _z = H, R ₃ = nC ₃ H _7,

CR ₄ R ₅ = cyclopentane, X = 0 /

A / Ethyl butyrimidate chlorohydrate:

NH //

CH ₃ -CH ₂ -CH ₂ -C, HCl

OC ₂ H ₅

This compound is obtained in Mc. Elvain / J. Amer. Chem. Soc., 1942, 64, 1825-1827 /.

To a solution of 10.6 g of hydrogen chloride gas in 20 ml of anhydrous ethanol at 0 ° C is added 23 ml of butyronitrile, and the reaction medium is maintained at 0 ° C for 4 days and then stirred under ether at room temperature with stirring under vacuum. product.

200 ml of anhydrous ether;

filtered, rinsed dried. 25.8 g are obtained

B / Ethylbutyrimidate Dissolve g of imidate obtained in Step A in 100 ml of dichloromethane and 50 ml of water and add 15 g of potassium carbonate. After decantation, the dichloromethane is dried over potassium carbonate and then evaporated to dryness without heating.

C / 1-aminocyclohexane carboxylic acid ethyl ether

1-Aminocyclohexane carboxylic acid is a commercial product. Add 15 g of this acid at 0 ° C to a solution of 23 g of hydrogen chloride gas and 150 ml of anhydrous ethanol. The mixture is heated for 5 hours under a drip of phlegm, after which the reaction medium is concentrated to dryness and extracted with ether. The resulting white solid was filtered, rinsed with ether, then dissolved in a mixture of 300 mL of ether and 100 mL of water. Adjust the pH to 9 with potassium carbonate solution. The organic phase is decanted off, washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to dryness. 14 g of the expected product are obtained in the form of a liquid 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 of the amount of imidate obtained in step B is added and heated until a phlegm is formed. After an hour and a half, half of the rest of the imidate is added, and another 4 or 15 after the last quarter. The whole mixture is maintained at the phlegm formation temperature for 7 hours, then the reaction medium is evaporated to dryness. The resulting solid was extracted with hexane, filtered, rinsed with ether and then dried.

10.3 g of the expected imidazolinone are obtained.

T _mp. = 124-125 ° C.

· AND / CHC1 ₃ /:

- 1715 cm ^-1 : C = 0,

- 1635 cm ^-1 : C = N.

Note: The value of the IR spectral bands indicates that the compound in solution is 5-imidazolinone.

E / 2-n-Propyl-4-spirocyclohexane-1 - [(2'-tert-butoxy] carbonyl-biphenyl-4-yl) -methyl] -2-imidazolin-5-one.

L T 3376 B

To a suspension of 80% in a liquid oil, 0.24 g of sodium hydride in 10 ml of dimethylformamide is added 970 mg of imidazolinone obtained in Step D. After stirring for 20 min under nitrogen, 1.91 g of 4-bromomethyl-2'-tert-butoxycarbonylphenyl obtained according to European patent application no. 324 377. The reaction medium is stirred for 1 hour. Concentrate to half volume in vacuo and extract with 100 mL ethyl acetate followed by 20 mL water. The organic phase is decanted off, washed with saturated sodium chloride solution, dried over sodium sulphate and then concentrated in vacuo. The residue is purified by chromatography, eluting with ethyl acetate-toluene. Incoming

2.10 g of the expected product in the form of a waxy substance.

AND / CHC1 ₃ /:

- 1705-1715 cm- ¹ : C = 0, C = 0 / ester, imidazolinone /,

- 1635 cm @ ^-1 : C = N.

NMR spectrum analysis confirms the structure.

F / 1- (2'-Carboxybiphenyl-4-yl) methyl / -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 20).

A mixture of 11 ml of dichloromethane and 15 ml of trifluoroacetic acid was added with 1.25 g of tert-butyl ester obtained in Step E and stirred for 45 min. After concentration in vacuo, the residue is extracted with ether. The resulting solid is filtered, rinsed with ether and then dried. 1.04 g of a white solid are obtained.

_Mp = 170-172 ° C.

NMR Spectrum:

- 7.10-7.80 ppm: m: 8H: aromatic protons

- 4.90 md: s: 2H: N-CH ₂ -C ₆ H ₄ -,

- 2.45 md: 2H: CH ₃ -CH ₂ -CH ₂ -,

- from 1.40 to 1.80 ppm: m: 12 H: CH ₃ -CH ₂ -CH ₂ - and spirocyclohexane,

- 0.90 ppm:: 3 H: CH ₃ -CH ₂ -CH ₂ -.

Dissolve 1.60 g of the previously obtained trifluoroacetate in 150 ml of ethyl acetate and 20 ml of water. 1N sodium hydroxide is added to adjust the pH to 5.0. The organic phase is decanted off, washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to dryness. The solid residue is extracted with ethyl ether, filtered and dried.

m = 1.14 g

T _mp = 208-210 ° C.

G / 1 - / (2'-N-Cyanocarboxamidobiphenyl-4-yl) methyl / -2-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 21).

To a suspension of 300 mg of the compound obtained in the preceding step in 5 ml of DChM is added 0.54 ml of thionyl chloride. After one and a half hours, the reaction medium was concentrated in vacuo, then evaporated twice with benzene. The acid chloride thus obtained is dissolved in 2 ml of dioxane and added to 42 mg of cyanamide dissolved in 1 ml of dioxane containing 0.2 ml of 10N sodium hydroxide. After one and a half hours, the reaction medium is diluted with 150 ml of ethyl acetate, 20 ml of water and acetic acid are adjusted to pH = 5, the organic medium is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica eluting with a mixture of chloroform / methanol / acetic acid (90/8/2; v / v). 160 mg of the expected product are obtained in the form of a solid.

IR / kVg /:

-2150 cm ^-1 : C = N.

Mass Spectrum: MH

NMR Spectrum:

- 7.20-7.70 ppm: m: 8H: aromatic protons - 4.75 md: s: 2H: N-CH ₂ -C ₆ H ₄ -, - 2.40 md: 2H: CH ₃ -CH ₂ -CH ₂ -, - 1.30-1, 80 md: m: 12H: CH ₃ -CH ₂ -CH ₂ · - and

spirocyclohexane.

- 0.85 ppm: t: 3H: CH -CH ₂ -CH ₂ -.

An example

1 - (2'-N- (4'-carboxy-1,3-thiazol-2-ylacetamide) biphenyl4-yl) methyl) -2-n-ipropyl-4-spirocyclohexan-2imidazolin-5-one.

/ 1: R _X = CONH j - j COOH \ /

R? -H _r R ₃ -nC ₃ H ₇ ,

CR ₄ R ₅ = cyclohexane, X = 0 /

This compound is obtained from the compound obtained in Example 20.

2-Amino-4-ethoxycarbonyl-1,3-thiazole is obtained in B.

Plouvier. et. et al., J. Heterocycl. Chem. 1989, 26/6 /, 1646.

N - {N - (4-Carboethoxy) -1,3-thiazol-2-yl-acetamido-2'-biphenyl-yl-methyl} -2-n-propyl-4-spirocyclohexan-2imidazolin-5-one .

To a solution of 404 mg of the compound obtained in Example 20, 190 mg of 4 ml of DChM and 1 ml of DMFA thiazole derivative are added 500 mg of FBO and 0.14 ml of triethylamine. Stir at 40 or kT, then at 7 or 50 ° C. The reaction medium is extracted with 50 ml of ethyl acetate, washed twice with KHSO ₄ -K ₂ SO ₄ solution, then twice with saturated sodium bicarbonate solution and then once with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase is concentrated in vacuo and the residue is purified by chromatography on silica eluting with ethyl acetate - toluene. 120 mg of the expected product are obtained.

_Yield = 96-98 ° C.

B / To 110 mg of the product obtained in the previous step, dissolved in 1 ml of methanol and 1 ml of dioxane, add 0.5 ml of 2N sodium hydroxide. The reaction medium is stirred for 35 minutes, then diluted with 2 ml of water and 60 ml of ethyl acetate and adjusted to pH = 5 with hydrochloric acid. The organic layer was washed with saturated sodium dried sodium sulfate, and then the residue was extracted with ether dried.

by adding 1 N chlorine, decant the solution with chloride and concentrate.

, filtered and m = 100 mg.

_Mp = 145-148 ° C.

NMR Spectrum:

- 8.0 ppm: s: 1H: H of the thiazole at position 5,

- 7.1 to 7.7 ppm: m: 8H: aromatic H,

- 4.7 md: s: 2H: N-CH ₂ -C ₆ H ₄ -,

- 2.25 ppm: t: 2H: CH ₂ -CH ₂ -CH _3,

- 1.2 to 1.8 ppm: m: 12 H: CH ₂ -CH ₂ -CH _3, and cyclohexane,

- 0.85 ppm: t: 3H: CH ₂ -CH ₂ -CH _third

An example

2-n-Butyl-1- {2 '- (2-cyanoguanidine-carbonyl) -biphenyl-4'-yl) methyl} -4-spirocyclopentan-2-imidazolin-5-one.

NH ₂ i

/ 1: R ₁ = CONH-C = N-CN, R ₂ = H, R ₃ = nC ₄ H ₉ ,

CR ₄ R ₅ = cyclopentane, X = 0 /

The chloro anhydride of the compound synthesized in Example 2 is prepared as follows: 1 g of the compound is added to 20 ml of DChM by the addition of 1.8 ml of thionyl chloride and stirred for 2 h. After concentration, the reaction medium is extracted with benzene and then concentrated again. The isolated crude product shall continue to be used,

It is mixed with 417 mg of dicyandiamide, 0.5 ml of 10 N sodium hydroxide, 0.5 ml of water and 10 ml of dioxane for 5 hours. The reaction medium is concentrated by addition with ethyl acetate. The resulting mixture is then stirred under stirring, extracted with water and potassium carbonate, and the residue is purified by chromatography on silica eluting with a mixture of DCM / MeOH (95/5; v / v). 100 mg of the expected product are isolated.

T _melt = 105 C.

An example

4-Benzylidene-2-n-butyl-1- (2'-carboxy) biphenyl-4-yl) methyl / -2-imidazolin-5-one trifluoroacetate.

/ 1: R ₁ = CO ₂ H, R ₂ = H, R ₃ = n C ₄ H ₉ , R ₄ R ₅ = = CH-C ₆ H ₅ , X = 0 /

N- [4- / 1-Benzylidene-1-valerylaminomethylamidomethyl] -2'-biphenyl-tert-butylcarboxylate n = C ₄ H ₉ -CO-NH-C-CO-NH-CH ₂ -C ₆ H ₄ II ch-c ₆ h ₅

CO ^ tBu

Alpha-dehydro- (L) -phenylalanine N-carboxylic anhydride is obtained by R. Jacquier et al. Tetrahedron Lett 1984, 25/26, P.2775 from N-BOK-alpha-dehydro- / L / -phenylalanine. To 430 mg of this compound in 5 ml of THF was added 644 mg of 4-aminomethyl-2'-biphenyl-tert-butyl carboxylate, 2 ml of 1 ml of methylorthovalerate and evaporated in vacuo to dryness. The residue is heated for 3 hours, followed by stirring

Concentrate in vacuo at 100 ° C then purify by chromatography on silica eluting with hexane-ethyl acetate (4/1; v / v).

580 mg of a white solid are obtained.

_Mp = 154 ° C.

NMR Spectrum:

- 1.3 m.d: s: 9H: tBu. - 0.65 'M.d .: t: 3H: CH ₃ - / nBu /, - 2 m. d: t: 2H : CH ₃ -CH ₂ -CH ₂ -CH ₂ - 4.4 dd: d: 1H: CH ₂ -NH, - 8.8 m.d: s: 1H: CH (= CH-C ₆ H ₅ ).

B-4-Benzylidene-2-n-butyl-1- (2'-tert-butoxycarbonylbiphenyl-4-yl) methyl--2-imidazolin-5-one.

Dissolve 440 mg of the compound obtained in Step A in 1 ml of acetic acid and heat for 30 min at 100 ° C.

Evaporate to dryness in vacuo and purify the residue by chromatography on silica eluting with hexane-ethyl acetate (4/1; v / v). 130 mg of the expected product is obtained in the form of a liquid oil.

NMR Spectrum:

- 4.9 md: s: 2H: CH ₂ (N-CH ₂ -C ₆ H ₄ -).

C / 100 mg of the compound obtained in the previous step was dissolved in 1 ml of DChM and 1 ml of trifluoroacetic acid was added, followed by stirring for 40 min at kT and evaporated in vacuo. Extract several times with DChM, then evaporate. Addition of ether gives a white solid which precipitates.

m = 101 mg

_Mp = 85 ° C.

Mass Spectrum: M ⁺ : 439.

NMR Spectrum:

0.82 m.d. : t: 3H: CH ₃ / nBu /, 1.3 m.d. : sec: 2H : CH ₃ / CH ₂ -, 1.6 m.d. : m: 2H: ch ₃ -ch ₂ -ch ₂ -, 2.6 m.d. : t: 2H: ch ₃ -ch ₂ -ch ₂ -ch ₂ -,

- 4.82 ppm: s: 2H: CH ₂ -C ₆ H ₄ -,

- 7.05 md: s: 1H: = CH-C ₆ H ₅ ,

- 7.20-8.2 ppm: m: 13H: aromatic protons

An example

4-Benzylidene-1- (2'-carboxy) biphenyl-4-yl) methyl-2-phenyl-2-imidazolin-5-one.

/ 1: R ₁ = CO ₂ H, R ₂ = H, R ₃ = C _(S H ₅ , R ₄ R ₅ = = CH-C ₆ H ₅ ,

X = 0 /

N, 4-Benzylidene-2-phenyl-5-oxazolone.

Dissolve 1.8 g of hypuric acid and 0.4 g of potassium bicarbonate in 4 ml of acetic anhydride, heat at 50 ° C for several minutes, then cool to kT and add 1.49 g of benzaldehyde. Maintain for 1 hour kT, then add 20 ml of distilled water at 80 ° C. The solid which settles on the precipitate is squeezed, washed with water, ethanol and then dried. 1.24 g of the expected product are obtained in the form of a yellow solid.

_Mp = 215 ° C.

NMR Spectrum:

- 7.4 md: s: 1H: CH-C ₆ H ₅ ,

- 8.1 to 8.4 ppm: m: 10H: aromatic protons

B / tert-Butyl 4- / 1-benzylamino-1-benzylidenemethylamidomethyl / biphenyl-2'-carboxylate

A mixture of 500 mg of the compound obtained in the preceding step, 570 mg of tert-butyl 4-aminomethylbiphenyl-2 'carboxylate and 10 ml of pyridine is heated at 110 ° C for 3 hours. Evaporate in vacuo, extract with chloroform, then evaporate again. The residue is purified by chromatography on silica eluting with hexane-ethyl acetate (3/1 then 2/1; v / v). 106 mg of the expected product are obtained in the form of a yellow solid.

NMR Spectrum:

- 1.1 ppm: s: 9H: tBu,

4.35 ppm: t: 2H: -CH ₂ -NH-,

- 7.05-7.06 md: m: 19H; aromatic protons + C ₆ H ₅ -CH =,

- 8.65 ppm: t: 1 H: NH-CH _2,

- 9.9 ppm: s: 1H: NH-CH =.

A mixture of 1.2 g of the 5 ml acetic acid compound obtained in the previous step and 1.1 g of freshly dissolved sodium acetate is heated for 6 hours with dripping of phlegm. After cooling, insoluble matter is precipitated by the addition of chloroform. The filtrate is evaporated and the residue is purified by chromatography on silica eluting with a mixture of chloroform-methanol (98/2; v / v). The resulting solid was recrystallized from ethyl ether.

m = 692 mg

_{Melting point} = 120 ° C.

NMR Spectrum:

- 4.95 ppm: s: 2H: CH ₂ -C ₆ H ₄ ~

7.1-8.3 md: m; 19H: aromatic protons = CH-C ₆ H ₅ .

and 27 examples

2-n-Butyl-1 - [(2 '- (2-methyltetrazol-5-yl) -biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one (Example 26) and 2-n- butyl 1 - [(2 '- (1-methyltetrazol-5-yl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one (Example 27).

500 mg of the compound obtained in Example 5 and 58 mg of sodium hydride are stirred in 10 ml of DMFA for 30 minutes, then 179 mg of methyl iodide and 2 ml of DMFA are added and left under stirring for 4 h. The reaction medium is concentrated, extracted with water, then extracted with ethyl acetate. Dry over sodium sulfate, filter, and evaporate the solvent. The residue is purified by chromatography on silica eluting with a mixture of hexane / ethyl acetate (6/4; v / v). 2 fractions are distinguished:

- 90 mg of the compound of Example 26,

184 mg of the compound of Example 27.

NMR Spectrum: 26 Example: - 0.7 ppm: t: 3H: CH ₃ - / nBu /, - 1.2 ppm: sec : 2H: CH ₃ -CH ₂ -, - 1.4 da.wm: sq: 2H: CH ₃ -CH ₂ -CH ₂ -, - 1.5-1.9 ppm: m; 8H: cyclopentane, - 2.25 da: t: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -, - 4.15 ppm: s: 3H N-CH _3, - 4.6 ppm; s: 2H: - N-CH ₂ -C ₆ H ₄ -, - 7pm: AA ', BB 'system: 4H: CH ₂ -C - 7.3-7.75 da.s. : m: 4H: CH ₂ -C ₆ H ₄ -C ₆ H ₄ -.

Example:

0.7 ppm: t: 3H: CH- / nBu /,

- 1.15 md: sec: 2H: CH ₃ -CH ₂ -,

- 1.38 md: kv: 2H: CH ₃ -CH ₂ -CH ₂ -,

- 1.5 to 1.9 ppm: m: 8H: cyclopentane,

- 2.2 md: t: 2H; CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

- 3.35 billion; s: 3 H: N-CH _3,

- 4.6 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -, »

- 7 md: AA ', BB' system: 4H: N-CH ₂ -C ₆ H ₄ -,

- 7.4 to 7.8 ppm: m: 4H: CH ₂ -C ₆ H ₄ -C ₆ H ₄ -.

An example

2-n-Butyl-6-spirocyclopentan-3 - [(2 '- / tetrazol-5-yl) biphenyl-4-yl) methyl] -4- (1H) -5,6-dihydro-4-pyrimidinone.

A / Ethylcyclopentylideneacetate.

Add 80 g of 80% sodium hydride to 40 ml of benzene and add dropwise 57.1 ml of triethyl phosphonoacetate at a temperature below 35 ° C. KT is maintained for 1 hour, then 24.3 ml of cyclopentanone are added dropwise. Heat at 65 ° C for 15 min, then cool to kT and decant the surface liquid. Add 25 ml of benzene, heat at 65 ° C for 15 minutes, cool, decant and then separate the supernatant liquid. The operation is repeated again. Evaporation of the resulting liquid gives 42 g of the expected product which is distilled.

T _vlr = 102 ^J C / ll mm of mercury column.

m = 22.8 mg.

B / 1-aminocyclopentyl / -acetamide.

To 20 g of ethylcyclopentylideneacetate obtained in the preceding step is added 150 ml of gaseous ammonia and heated at 72 or 150 ° C. After evaporation the product is purified by chromatography on silica eluting with a mixture of DCM / methanol20% ammonia (90/10/1; v / v). The resulting product was dissolved in DCM, dried over sodium sulfate. Filtration, evaporation in DCHM gave 7.2 g of the expected product.

C / 2-n-Butyl-6-spirocyclopentan-4- (1H) -5,6 / dihydropyrimidin-4-one

A mixture of 4.57 g / 1-aminocyclopentyl / acetamide from the previous step, 25 ml of methylorthovalerate and a few drops of acetic acid is heated for 18 hours. At 100 ° C. After evaporation of the excess orthovalerate, the residue was extracted with ethyl acetate-sodium bicarbonate mixture, washed with aqueous sodium chloride solution, dried over sodium sulfate, and then purified by chromatography on silica eluting with a mixture of DCM: methanol (98/2; v / v).

m = 5 g

- 0.75 ppm: t: 3 H: CH ₃ - / nBu /,

- 1.2 ppm: s: 2H: CH ₃ -CH ₂ -,

- 1.3 to 1.8 md: m: 10H: CH ₃ -CH ₂ -CH ₂ - and cyclopentane,

- 2 md: t: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

- 2.15 ppm: s: 2H: CH ₂ -CO,

- 9.95 ppm: p: 1H: NH.

This compound is the one obtained in Example 10, Step C.

D / 2-n-Butyl-4-spirocyclopentan-1- (2 '- (triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl / pyrimidin-6-one

327 g of 80% sodium hydroxide in 30 ml of DMFA and 1.5 g of pyrimidinone obtained in the previous step are stirred for 30 min under nitrogen and 5.27 g of 4-bromomethyl-2 '- (triphenylmethyl-tetrazol-5-yl) -biphenyl are added. After stirring for 4 h, the solvents were evaporated, then extracted with ethyl acetate and water, dried over sodium sulfate and concentrated. The resulting product is purified by chromatography on silica eluting with ethyl acetate / hexane (3/7; v / v).

m = 3.2 g

E / 3 g of the compound obtained in the previous step is added to 15 ml of methanol and cooled in a water-ice bath, 2.2 ml of 4 N HCl are added and the kT is left under stirring for 5 hours. After evaporation, extraction is carried out with ethyl acetate and water, followed by addition of sodium hydroxide to form an alkaline medium / pH = 11 · /. After decantation, the aqueous phase is washed with ethyl ether and toluene, then again with ether. The phase is then adjusted to pH = 5 with dilute hydrochloric acid, then extracted with ethyl acetate, dried and concentrated. The resulting product is purified on silica eluting with DCM / methanol (93/5; v / v). 800 mg of the expected product are obtained.

NMR Spectrum:

- 0.85 ppm: t: 3 H: CH ₃ - / nBu /.

- 1.30 ppm: s: 2H: CH ₃ -CH ₂ ~

- 1.40-1, 95 md: m: 10H: CH ₂ -CH ₂ -CH ₂ -CH ₃ and cyclopentane,

2.30 m.d. : t: 2H: CH ₂ -CH ₂ -CH ₂ -CH. 2.55 m.d. : s: 2H: CH ₂ -CO, 4, 95 m.d. : s: 2HN-CH ₂ -C ₆ H ₄ -, 7.05 m.d. : m: 4H: CH ₂ -C ₆ H ₄ -, 7.55- -7, 82 m.d. . : m: 4H: CH ₂ -C ₆ H ₄

An example

2-n-Butyl-3 - [(2'-carboxybiphenyl-4-yl) methyl] -5-spirocyclopentan-5-1H / -5,6-dihydropyrimidin-4-one trifluoroacetate.

A / Ethyl 1-cyanocyclopentanecarboxylate

This compound is obtained by Helv. Chem. Act, 1952, 35/7

2561, in the manner stated.

9.2 Sodium is dissolved in 200 ml of absolute ethanol. Transfer half of the sodium ethylate solution formed into the flask. 24.88 g of ethyl cyanoacetate are added to the remaining half and heated until a phlegm is formed.

To the other flask was added 43.19 g of 1,4-dibromobutane, and sodium ethylate and 1,4-dibromobutane were added dropwise to the reaction medium. After adding everything to the reaction medium, heat for 2 hours with a drip of phlegm. Evaporate by extraction with ethyl ether-water, wash with saturated sodium chloride solution, and then dry. The product obtained is distilled at 115-120 ° C under a pressure of 11 mm of mercury.

m = 24 g.

B / 1-ethyl-1-aminomethylcyclopentanecarboxylate.

This compound is formed during the catalytic hydrogenation of ethyl 1-cyanocyclopentanecarboxylate.

Add 1 g of ethyl 1-cyanocyclopentanecarboxylate to 200 ml of ethanol and 10% ammonia and hydrogenate at 80 ° C under a pressure of 72 or 100 bars using rhodium in alumina. After filtration through celite P and evaporation, the residue is purified by chromatography on silica eluting with DCM / methanol-20% ammonia (98/2 / 0.5; v / v).

m = 12.8 g.

C / 2-n-butyl-5-spirocyclopentane-4- (1H) -5,6-dihydropyrimidin-4-one.

A mixture of 13.12 g of the compound obtained in the preceding step and 13.5 ethyl valerimidate in 100 ml xylene containing several drops of acetic acid is maintained for 13 hours. dripping phlegm. The reaction medium is evaporated, extracted with ethyl acetate and 10% sodium carbonate solution, then dried and concentrated.

m = 14 g.

T, _yd . = 89-91 ° C

NMR Spectrum:

- 0.80 ppm: t: 3 H: CH ₃ / nBu /,

- 1.10 to 1.80 md: m: 12H: CH ₃ -CH ₂ -CH ₂ - and cyclopentane,

- 2.05 md: 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

- 3.20 ppm: s: 2H: CH ₂ / pirimidinonas /,

- 10 ppm: s: 1H: NH-CO.

D / 2-n-Butyl-5-spirocyclopentan-3 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -4 H, -5,6-dihydropyrimidin-4-one

500 mg of the product in 40 ml of DMFA obtained in the previous step under argon is stirred at 80% 115 g of sodium hydride in liquid oil for half an hour. 1.08 g of 4-bromomethyl-2 'tert-butoxycarbonylbiphenyl are added and the mixture is stirred for 2 hours. After evaporation, the residue is extracted with ethyl acetate-water, washed with saturated sodium chloride solution, then dried, concentrated and the residue is purified by chromatography on silica eluting with ethyl acetate-hexane (3/7; v / v).

m = 280 mg.

E / Dissolve 250 mg of tert-butyl ester obtained in the previous step in 10 ml of DChM. Cool in a water bath, then add 5 ml of cold trifluoroacetic acid and leave for 1 hour under cold stirring, then for 1 hour at kT. Evaporate under reduced pressure. The residue is extracted with ethyl ether and then evaporated.

The operation is repeated 3 times, then evaporated, the residue is extracted with hexane to give a powder and then decanted with hexane. Extract with ethyl ether and filter the precipitate.

m = 190 mg

_Mp = 153-155 ° C

NMR Spectrum:

- 0.85 ppm: t: 3 H: CH ₃ / nBu /,

- 1.35 md: sec: 2H: CH ₃ -CH ₂ -,

- 1.45-2.20 md: m: 10H: CH ₃ -CH ₂ -CH ₂ - and cyclopentane, and

P ° and

- 2.80 m.d. : t: 2H: ch ₃ -ch ₂ -ch ₂ -ch ₂ -, - 3.80 m.d. : s: 2H: CH ₂ - / pyrimidinone /, - 5, 15 m.d. : s: 2H: n-ch ₂ -,

7.25 ppm: m: 8H: Table of aromatic protons

For example, No. Ri r ₃ CFUR5 Drus- ka _ o_ Tlyd. t C 30th CO ₂ H nC ₄ H ₉ cyclohexane TFK 172-174 31st co ₂ ch ₃ nC ₄ H ₉ cyclopentane - 86-87 32 * co ₂ h nC ₄ H ₉ C / CH ₃ / C ₆ H ₅ TFK 58-60 33 co ₂ h nC ₄ H ₉ c / c ₂ h _5/2 TFK 82-84 34 co ₂ h ₄ nC ₃ H ₇ cyclopentane TFK 164 35 / ** / nC ₄ H ₉ cyclopentane - 163-164 36 co ₂ h c ₆ h ₅ cyclopentane TFK 178 37 co ₂ h nC ₄ H ₉ cyclopentane TFK 160-162 38 co ₂ h ch ₃ cyclopentane TFK 140 39 co ₂ h nC ₄ H ₉ cyclopropane - 204-205 40 tetrazol-5-yl -O <H ₂ -CH = CH ₂ cyclopentane - 110 41 -tetrazol-5-yl nC ₄ H ₉ cyclohexane - 130 42 -tetrazol-5-yl nC ₃ H ₇ cyclohexane - 141 43 O ₂ H cyclopentyl hey clopentan TFK 82-88 44 co ₂ h n-C4H11 cyclopentane TFK 151 45 co ₂ h ch ₂ -c ₆ h ₆ cyclopentane TFK 88 46th co ₂ h H cyclopentane - 230 47 co ₂ h nC ₄ H ₉ cyclobutane TFK 178 48 oo ₂ h nC ₄ H ₉ cyclododecane TFK 130-135 49 oo ₂ h nC ₄ H ₉ 2-adaman t ama s TFK 164-166 50 co ₂ h nC ₄ H ₉ (4-phenyl) - cyclohexane TFK 155-157

For example, Ri r ₃ CR ^ Rys Drus- Tlyd./C No. ka 51 CO ₂ H nC ₄ H ₉ / 4-methyl / - TFK 198-200 cyclohexane 52 oo ₂ h nC ₄ H ₉ / N-Acetyl / -4- TFK 90-95 piperidine 53 co ₂ h C ₃ H ₇ cyclopentane - 141-143

54 * 00 ₂ H n C ₄ H ₉

55 * 00, H nC ₄ H ₉

CF «CF ₃ - 'Cl

TFK

207-209

105

OO, H nC ₄ H ₉

C0 ₂ H

CO ₂ H

CH _S

yCO

CF.,

TFK 95-105

TFK 125-135

The IFC 85-90 carbon of these compounds is asymmetric and is isolated in the form of a mixture of optical isomers.

R ^ H and R ₂ = CO ₂ H.

Claims (21)

DEFINITION OF INVENTION wherein: -R _x and R ₂ are the same or different and independently of one another are either hydrogen or a group selected from alkyl C _x -C ₆ , C _x -C ₄ -alkoxyl, amino, aminomethyl, carboxyl, alkoxycarbonyl, having an alkoxy group of the type C _x -C ₄ , cyano, tetrazoline, methyltetrazoline, methylsulfanylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N - [(4-carboxy) -1,3-thiazol-2-yl] acetamide, , 2-cyanoguanidine-carbonyl, 2-cyanoguanidine-methyl, imidazol-1-ylcarbonyl, 3-cyano-2-methylisothiothioureidmethyl, provided that at least one of the substituents R _x and R _{2 is} different from hydrogen; R ₃ is hydrogen, alkyl C _x -C ₆ , unsubstituted or substituted with one or more halogen atoms, alkenyl C ₂ -C ₆ , cycloalkyl C ₃ -C ₇ , phenyl, phenylalkyl of which C _x -C ₃ alkyl, phenylalkenyl of which C ₂ -C ₃ alkenyl is furthermore substituted or unsubstituted or substituted on said phenyl groups by halogen, alkyl C _x -C ₆ , haloalkyl C _x -C ₄ , polyhaloalkyl C _x -C ₄ , hydroxy or alkoxy C _x -C ₄ ; R ₄ and R _{5 are} each independently C 1 -C 8 alkyl, phenyl, phenylalkyl wherein the alkyl is C 1 -C 6, and the alkyl, phenyl and phenylalkyl groups listed are unsubstituted or substituted with one or more several halogen atoms or one group selected from perfluoroalkyl C ₁ -C ₄ , hydroxyl, C ₁ -C ₆ alkoxy; or R ₄ and R ₅ together form a group of formula = CR ₇ R ₈ and R ₇ is hydrogen, alkyl C ₃ -C ₄ or phenyl, R _e is alkyl 0 ₇ -C ₄ or phenyl; or R ₄ and R ₅ , taken together, are either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) _p γ (CH ₂ ) _q , wherein the gamma is either an oxygen atom or a sulfur atom. or a carbon atom substituted by alkyl C ₇ -C _4, phenyl or phenylalkyl substituted with alkyl C ₁ -C ₃ type or a group NR _E, in which R ₆ is hydrogen, alkyl, C ₃ -C ₄ type, phenylalkyl wherein the alkyl is C ₇ C ₃ type ₃ alkylcarbonyl haloalkylcarbonyl Ci ^- C _4, C ₁ -C polihalogenalkilkarbonilas _4, benzoyl, an alpha-aminoacyl or an N-protective group, or R ₄ and R ₅ together with the carbon to which they are attached atom form indan or adamantane; -p + q = m; -n is whole number from 2 up to 11; -m is whole number from 2 up to 5; -X is oxygen atom or a sulfur atom; -Z and t equals zero or one of these indices equals zero while the other is a unit; or a salt thereof. 2. A compound according to claim 1 wherein R _x is in the ortho position and is a carboxy or tetrazole group and R ₂ is hydrogen. Compound according to one of Claims 1 and 2, characterized in that R ₄ and R _{5 together} with the carbon to which they are attached form cyclopentane or cyclohexane. Compound according to one of Claims 1 to 3, characterized in that R ₃ is a linear alkyl group C 1 -C ₆ . 5. A compound according to any one of claims 1-4, wherein X is oxygen. 6. A compound according to any one of claims 1-5, wherein Z = t = 0. 7. A compound according to claim 1, which is 2-n-butyl-4-spirocyclopentan-1 - [{2 '(tetrazol-5-yl) biphenyl-4-yl} methyl] -2-imidazolin-5 -one or one of its salts with an acid or a base. 8. A process for the preparation of a compound of the formula I as claimed in one of claims 1 to 7, characterized in that: (ai) carries a heterocyclic derivative having the formula: H wherein Z, t, R ₃ , R ₄ and R ₅ have the same values as the reaction of the compound (I) according to claim 1 with a (biphenyl-4-yl) methyl derivative of the formula: wherein Hal is a halogen atom and R'y and R ' ₂ are 5 respectively R _x and R ₂ or R _x and R ₂ precursor; (bl) where appropriate, a compound of the formula thus obtained: 10 acts with Lawesson's reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide; cl) the compound of steps ai) and bl) having the formula: wherein X is an oxygen atom or a sulfur atom, the groups R'y and R ' _{2 are} replaced by the groups Ry and / or R respectively to give compound (I). 9. A process for the preparation of a compound of formula (I) according to one of claims 1 to 7, characterized in that a2) an amino acid of the formula: e / (pJ * COCH wherein Z, t, R ₄ and R ₅ have the same meanings as given for compound (I) according to claim 1, and wherein The 10 amino group is protected by a Pr group, reacting with a (biphenyl-4-yl) methylamine derivative of the formula: wherein R'y and R ' ₂ are either Ry and R ₂ , respectively, or a precursor of R and R ₂ ; 100 b2) deprotecting the amino group to give a compound of the formula having the formula: followed by treatment with an orthoic acid alkyl ester of the formula R ₃ C (OR) 3 (10) wherein R ₃ is as defined 5 are as defined for compound (I) according to claim 1, and R is alkyl C ₁ -C ₄ ; c2) if necessary, a compound of the formula thus obtained: 10 acts with Lawesson's reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide; d2) the compound thus obtained in steps b2 or c2 of the formula: 101 then operates under conditions suitable for the preparation of compound (I) by converting R ' ₂ and / or R' _x groups to R ₂ and / or R _x groups, respectively. 10. Compound of formula (I) according to The method of claim 6, wherein: a3) an imidazole derivative having the formula wherein R _3, R _4, R _s have the same meanings as those defined in (i) a compound according to claim 1 with a (biphenyl-4-yl) methyl derivative of the formula and Hal is a halogen atom or, respectively The precursor of R _x and R ₂ or R ₂ in the presence of oxygen while R 1 and R ' ₂ is a group -R _x and also exposed to ultraviolet light in an alkaline environment. (b3) where appropriate, a compound of formula: 102 is treated with Lawesson's reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphenate-2,4-disulfide; c3) The compound 5 thus obtained in steps b3) and c3) having the formula: then operating under conditions suitable for the preparation of compound (I) by converting R ₁ and / or R ₂ groups into R ₁ and / or R ₂ groups respectively. 10th 11. Intermediates of Formula: where: 103 - R ₃ is hydrogen, alkyl C ₁ -C ₆ , unsubstituted or substituted by one or more halogen atoms, alkenyl C ₂ -C ₆ , cycloalkyl C ₃ -C ₇ , phenyl, phenylalkyl of which C _x -C ₃ alkyl, phenylalkenyl having an alkenyl type C ₂ -C ₃ , wherein said phenyl groups are unsubstituted or substituted one or more times with halogen, C 1-4 alkyl, hydroxy or C ₁ -C ₄ alkoxy; - R ₄ and R _{5 are} each independently C 1 -C 8 alkyl, phenyl, phenylalkyl having C 1 -C 4 alkyl, and the alkyl, phenyl and phenylalkyl groups mentioned are not substituted or mono- several halogen atoms or one group selected from perfluoroalkyl C ₁ -C ₄ , hydroxyl, C ₁ -C ₄ alkoxy; - or R ₄ and R ₅ together form a group of the formula = CR ₇ R ₈ wherein R ₇ is hydrogen, alkyl C ₇ -C ₄ or phenyl, and R ₈ is alkyl C ₁ -C ₄ or phenyl; - either R ₄ and R _s , taken together, are either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) _p γ (CH ₂ ) _q where γ is either an oxygen atom or a sulfur atom or a carbon atom substituted by alkyl C _x -C _4, phenyl or phenylalkyl wherein alkyl is a C ₁ -C ₃ type or a group NR _Ä, Kurija R ₆ is hydrogen, C ₁ alkilasC _4, phenylalkyl wherein the alkyl is C _x C ₃ , alkylcarbonyl C ₇ -C ₄ , haloalkylcarbonyl C _x -C ₄ , polyhaloalkylcarbonyl C ₄ -C ₆ , benzoyl, alpha-aminoacyl or N-protecting group, or R ₄ and R ₅ together with the carbon to which they are attached, forms an indane or adamantane in an atom; - p + q = m; - n is a number from 2 to 4; 104 - m is an integer from 2 to 5; - X is an oxygen atom or a sulfur atom; - Z and t are zero or one of these indices is zero and the other is one, provided that: - if Z and t are zero and X is an oxygen atom then R ₄ and R ₅ are not: - alkyl C ₁ -C ₈ , phenyl, phenylalkyl wherein the alkyl is C _x -C ₃ , and the alkyl, phenyl and phenylalkyl groups mentioned are unsubstituted or substituted with one or more halogen atoms or with one group selected from perfluoroalkyl C ₁ -C ₄ , hydroxyl, C 1 -C ₄ alkoxy; or R ₄ and R ₅ taken together are not a group NR ₆ where R ₆ is hydrogen, alkyl C ₁ -C ₄ , phenylalkyl having alkyl type; - n is not 6; or when R ₃ is substituted phenyl and R ₄ and R ₅ together are not a (CH ₂ ) _n group wherein n is between 3 and 5; - and when Z = 1 and R ₃ is phenyl, then R ₄ and R ₅ are each not methyl. 12. A compound of claim 1 having the formula: π (II ') Wherein X is oxygen or sulfur and R ₃ is hydrogen, alkyl C _x -C ₆ , unsubstituted or substituted with one or more halogen atoms; alkenyl, C ₂ -C _6, cycloalkyl C ₃ -C _7, phenyl, phenylalkyl wherein alkyl is a C _l -C ₃ type phenylalkenyl wherein the alkyl is C₁-C₄-type, in addition, the phenyl group being unsubstituted or substituted one or more times halogen, alkyl C ₇ -C ₄ , haloalkyl C ₁ -C ₄ , polyhaloalkyl C ₁ -C ₄ , hydroxy or C ₁ -C ₄ alkoxy. 13. The compound of claim 11 having the formula: (II) wherein R ₃ , R ₄ , R ₅ and X are as defined above for compound (11) according to claim 10. 14. The compound of claim 11 having the formula: (II ') in which R ₃ is hydrogen, C ₁ -C ₈ alkyl, unsubstituted or substituted with one or more halogen atoms, C ₂ -C ₆ alkenyl, C ₃ -C ₇ cycloalkyl, phenyl, phenylalkyl wherein alkyl is Ο ₇ -C ₃ , phenylalkenyl, having alkenyl of the C ₂ -C ₃ type and the phenyl groups listed above being unsubstituted or substituted one or more times 106 halogen atoms, alkyl C 1 -C 6, haloalkyl C 1 -C 4, polyhaloalkyl C 1 -C 4, hydroxy or alkoxy Οχ-C,; - R ₄ and R 5 _are each independently C 1-4 -C ₈ alkyl, phenyl, phenylalkyl in which the alkyl is C ₁ -C ₃ , and the alkyl, phenyl and phenylalkyl groups mentioned are unsubstituted or substituted by one or more several halogen atoms or one group selected from perfluoroalkyl C _x -C ₄ , hydroxyl, alkoxy Ο ₄ -Ο ₄ ; or R ₄ and R ₅ together form a group of the formula = CR ₇ R ₈ wherein R ₇ is hydrogen, alkyl C ₁ -C ₄ or phenyl, and R ₈ is alkyl C ₁ -C ₄ or phenyl; - either R ₄ and R ₅ , taken together, form either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) _p γ (CH ₂ ) _q in which γ is either an oxygen atom or a sulfur atom , or a carbon atom substituted with alkyl of C 1 -C 8, phenyl or phenylalkyl having alkyl of C _x -C ₃ , or a group NR ₆ where R ₆ is hydrogen, alkyl of C ₁ -C ₄ , phenylalkyl of alkyl of C _x C ₃ , alkylcarbonyl C ₁ -C ₄ , haloalkylcarbonyl C ₁ -C ₄ , polyhaloalkylcarbonyl C ₄ -C ₄ , benzoyl, alpha-aminoacyl or N-protecting group, or R ₄ and R ₅ together with the carbon to which they are attached attached, to form an indane or adamantane in an atom; - p + q = m; - n is an integer from 1 to 11; - m is an integer from 2 to 5; 107 - X is an oxygen atom or a sulfur atom, provided that R ₃ is not phenyl when R ₄ and R _{5 are} each methyl. Process for the preparation of a compound according to one of claims 11 to 14, characterized in that - a compound of the formula: r ₄ - ^^ ^ • (CH ₂ ) zcoa r ₅ - ^^ ^ (CH ₂ ) _t NH ₂ 13th and wherein R ₄ and The values of R ₅ are such what was mentioned above (11) for the compound according to 10 point, o A is OH, NH ₂ or OR 'plus R' is hydrogen or alkyl C 1 -C 2, acts on a compound of the formula: R ₃ -B wherein R ₃ is as defined above for (11) in the compound of claim 10 and B is: - group C (OR) ₃ ; - Group C Z ^H \ OR - or a group COHal; in addition, R is alkyl C 1 -C 6 and Hal is a halogen atom, more preferably chlorine; - then, if necessary, treating the compound thus obtained with Lawesson's reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphatane-2,4-disulfide. 108 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 as an active ingredient. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in combination with a beta-blocking compound. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in combination with a diuretic. 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in combination with a non-steroidal anti-inflammatory compound. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in combination with a calcium antagonist. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in combination with a tranquilizer.