SK283197B6 - N-substituted heterocycle derivatives, their preparation, compositions containing them - Google Patents

Abstract

N-substituted heterocycle derivatives of general formula (II), wherein R3 is for example hydrogen atom, alkyl group or alkenyl group, R4 and R5 independently are for example alkyl or phenyl group or R4 and R5 together are -CR7R8 group, wherein R7 is hydrogen atom, alkyl or phenyl group and R8 is alkyl or phenyl group, p + q = m, n is an integral number from 2 to 11, m is an integral number from 2 to 5, X is oxygen atom or sulphur atom, z and t are zero or one of them is zero and other is one; their preparation method. These derivatives are intermediates for preparation of compounds agonising the angiotensine II effect.

Description

Technical field

The invention relates to a nitrogen-containing heterocyclic derivative and to a process for its preparation. These derivatives are intermediates for the preparation of angiotensin antagonistic compounds.

BACKGROUND OF THE INVENTION

N-substituted heterocyclic derivatives of formula (I)

in which

R 1 and R ₂ , which are the same or different, each independently represent a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 4 alkoxy group, an amino group, an aminomethyl group, a carboxy group, an alkoxycarbonyl group in which the alkoxy radical contains from 1 to 4 carbon atoms, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanocarbamoyl, N-hydroxycarbamoyl (3-carboxy), N - thiazol-2-yl) carbamoyl, ureido, 2-cyanoguanidinocarbonyl, 1-imidazolylcarbonyl, 3-cyano-2-methylisothioureidomethyl, wherein at least one of R 1 or R ₂ is different from hydrogen,

R ₃ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms and optionally substituted by one or more halogen atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a phenylalkyl group in which the alkyl group the radical contains 1 to 3 carbon atoms, the phenylalkenyl group in which the alkenyl radical contains 2 or 3 carbon atoms, said phenyl groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, alkyl group containing 1 to 4 carbon atoms, haloalkyl (C 1 -C 4) group, (C 1 -C 4) polyhaloalkyl, (C 1 -C 4) hydroxyl group, and (C 1 -C 4) alkoxy group;

R and R independently _of one another are alkyl having 1 to 6 carbon atoms, a phenyl group, a phenylalkyl in which the alkyl portion contains 1 to 3 carbon atoms, wherein said alkyl, phenyl and phenylalkyl optionally substituted by one or more halogen halogen or a group selected from perfluoroalkyl of 1 to 4 carbon atoms, hydroxyl and alkoxy of 1 to 4 carbon atoms, or

R ₄ and R ₅ together form a group of the formula = CR ₇ R ₅ in which R ₇ represents a hydrogen atom, a C 1 -C 4 alkyl group or a phenyl group and R ₈ represents a C 1 -C 4 alkyl group or a phenyl group, or so

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 in which Y represents either an oxygen or sulfur atom or an alkyl-substituted carbon atom containing up to 4 carbon atoms, phenyl or phenylalkyl, in which the alkyl radical contains 1 to 3 carbon atoms, or the group N1 < ₆ in which R ₆ represents a hydrogen atom, alkyl group containing 1 to 4 carbon atoms, phenylalkyl, in wherein the alkyl moiety contains 1 to 3 carbon atoms, an alkylcarbonyl moiety wherein the alkyl moiety contains 1 to 4 carbon atoms, a haloalkylcarbonyl moiety wherein the alkyl moiety contains 1 to 4 carbon atoms, a polyhaloalkylcarbonyl moiety wherein the alkyl moiety contains 1 to 4 carbon atoms atoms, benzoyl, alpha-aminoacyl or N-protecting group, or

R ₄ and R _{5 taken} together with the carbon atom to which they are attached form an indane or adamantane group, p + q represents m, n represents an integer from 2 to 11, m represents an integer from 2 to 5,

X is oxygen or sulfur, z and t are 0 or one of them is 0 and the other is 1 and their salts agonize the effect of angiotensin II, which is a peptide hormone of the formula

H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH-Plie.

Angiotensin II is a potent vasoconstrictor and is a biologically active product of the renin-angiotensin system: renin acts on plasma angiotensinogen to produce angiotensin I, which is then converted to angiotensin II by the enzyme to convert angiotensin I.

The compounds of formula (I) are non-peptide compounds antagonizing the effect of angiotensin II. By antagonizing the effect of angiotensin II on its receptors, the compounds of the invention mainly prevent the increase in blood pressure caused by the hormone-receptor interaction. The compounds of the invention also have other physiological effects at the level of the central nervous system.

Accordingly, the compounds of formula (I) are useful in the treatment of cardiovascular disorders such as, in particular, high blood pressure and cardiac insufficiency, and in the treatment of central nervous system disorders, as well as in the treatment of glaucoma and diabetic retinopathy.

Recently, suitable intermediates have been found for the preparation of said compounds of formula (I) and these intermediates form the basis of the invention.

SUMMARY OF THE INVENTION

The present invention provides a nitrogen-containing heterocyclic derivative of formula (II) ⁴

Κ, -Χ-ζΗζΗ,), z (CH ₂ ) N

I

H in which

R ₃ is H, unsubstituted alkyl of 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms and substituted by at least one halogen atom, an alkenyl group having 2 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, phenyl, a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms, a phenylalkenyl group wherein the alkenyl moiety contains 2 or 3 carbon atoms, wherein the phenyl groups and the phenyl moieties are unsubstituted or at least once substituted substituents selected from the group consisting of halogen, (C 1 -C 4) alkyl, (C 1 -C 4) haloalkyl, (C 1 -C 4) polyhaloalkyl, (C 1 -C 4) hydroxy or (C 1 -C 4) alkoxy, where z = 1 and t = 0, then

R 4 and R ₅ independently of one another represent an alkyl group having 1 to 6 carbon atoms, a phenyl group, a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms, said alkyl, phenyl and phenylalkyl group being unsubstituted or at least once substituted with substituents selected from the group consisting of halogen atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a hydroxy group and an alkoxy group having 1 to 4 carbon atoms, or

R 4 and R ₅ together form a group of the formula = CR ₇ R ₈ in which

R ₇ represents a hydrogen atom, a (C 1 -C 4) alkyl group or a phenyl group; and

R ₈ represents a C 1 -C 4 alkyl or phenyl group;

R 4 and R ₅ together represent either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) _p Y (CH ₂ ) _<1 in which Y represents either an oxygen or sulfur atom or an alkyl-substituted carbon atom having 1 to 4 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl radical contains 1 to 3 carbon atoms, or a group NR 4 in which R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenylalkyl group in which an alkyl radical of 1 to 4 carbon atoms, an alkylcarbonyl group in which the alkyl radical contains 1 to 4 carbon atoms, a haloalkylcarbonyl group in which the alkyl radical contains 1 to 4 carbon atoms, a benzoyl group, an alpha-aminoacyl group or an N-protecting group, or

R 4 and R ₅ together with the carbon atom to which they are attached form an indane or adamantane group, p + q represents m, n represents an integer from 2 to 11, m represents an integer from 2 to 5, X represents an oxygen atom or a sulfur atom, with the proviso that R _{3 is} not a phenyl group when R 1 and R ₅ each represent a methyl group when = 0 and t = 1, then

X, R 4 and R ₅ have the meanings given, provided that R _{3 is} not a phenyl group, when R 1 and R ₅ each represent a methyl group, and when z = t = 0 and X is as defined above, then R 4 and R ₅ together form - (CH ₂ ) 4 - with the proviso that R _{3 is} not a substituted phenyl group when X is an oxygen atom, and its acid addition salts.

A preferred compound of the invention is the nitrogen heterocyclic derivative according to claim 1, wherein X is oxygen and R ₃ is n-butyl.

A particularly preferred compound of the invention is the nitrogen heterocyclic derivative of formula (II) which is 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride.

The present invention also relates to a process for the preparation of a nitrogen-containing heterocyclic derivative of the general formula (II), which comprises reacting a compound of the general formula (13):

(13) wherein R 4 and R 5 have the meanings set forth in claim 1 for formula (II), A represents a hydroxy group, an amino group or an OR ¹ group in which R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group with of formula (14)

R ₃ -B (14), wherein R ₃ is as defined above, and B is C (OR) ₃ , C (= NH) OR, or COHal, where R is C 1-4 alkyl and Hal is a halogen atom, preferably a chlorine atom, optionally reacting the compound so obtained with Lawesson's reagent, and optionally converting the compound to an acid addition salt.

Said compounds of formula (I) may be prepared from intermediates of the invention by a method comprising: a1) a heterocyclic derivative of formula (II)

R

H in which z, t, R ₃ , R 4 and R ₅ are as defined for formula (I), reacts with a (biphenyl-4-yl) methyl derivative of formula (3) wherein Hal represents a halogen atom and R 3 and R ' ₂ are R _b and C _b, respectively. R ₂ or a precursor group R _b, respectively. R ₂ , whereupon b) optionally the compound of formula (4) thus obtained

reacts with Lawesson's reagent, which is 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethane-2,4-disulfide, and cl) the compound obtained in step a1) or b1). ) and having the general formula (5)

(5)) wherein X is an oxygen or sulfur atom, is converted to a compound of formula (I) by converting the groups Rh and / or R ' ₂ to R 1 and / or R _2, and optionally converting the compound to one of their salts .

The derivatives of the general formula are prepared by known methods. Thus, for example, the procedure described by Jacquier et al. (Bull. Soc. Chim. France, 1971, 3, 1040-1051) and Brunken and Bach (Chem. Ber. 1956, 89, 1363-1373) and react the alkylimidate with the amino acid or ester thereof according to the following reaction scheme:

Λ 7

wherein R is C 1 -C 4 alkyl, R 1 is hydrogen or C 1 -C 4 alkyl, and R ₃ , R 1, R ₃ are as defined for formula (I).

This reaction is carried out in an acidic medium by heating in an inert solvent such as xylene or toluene.

Alternatively, a compound of formula (2) can be prepared by treating an ortho-alkyl ester of formula (10) with an aminoalkylamide of formula (5 ") in an acidic environment according to the following reaction scheme:

\

and-COML.

C / ob / J

(2) in which R represents an alkyl group having 1 to 4 carbon atoms.

The compound of formula (2) may also be prepared using the procedure described by H. Takenaka et al. (Heterocycles, 1989, 29, 6, 1185-1189). The process comprises treating the derivative of formula (5) with an acid halide of formula (12)

R ₃ -CO-Hal (12), wherein Hal represents halogen, preferably chlorine. The reaction is carried out in an alkaline medium.

In particular, the compound of formula (2) is prepared by a process according to the invention which comprises the step of:

(13)) wherein A is OH, NH ₂ or OR ', where R' is hydrogen or (C 1 -C 4) -alkyl, acts with a compound of formula (14)

R3-B wherein B is: -C (OR) ₃

- the group

COHal, wherein R is C 1 -C 4 alkyl and Hal is halogen, preferably chlorine, optionally treated with Lawesson's reagent.

The (biphenyl-4-yl) methyl derivative of general formula (3) is prepared according to the procedure described in European Patent Application EP 324 377.

Conversion of R 1 and / or R ' ₂ into R 1! and / or R ₂ is carried out by procedures known to those skilled in the art. When the compound of formula (I) to be prepared has the group R 1 and / or R ₂ = = carboxyl, then R 1 and / or R ' ₂ represents an esterified carboxyl group. Where the compound of formula (I) to be prepared has an R 1 and / or R ₂ = tetrazolyl group, then R 1 and / or R ₂ may be either a tetrazolyl group protected, for example, with a trityl group, or cyano, which will then be replaced by a tetrazolyl group optionally protected by a trityl group. Conversion of the cyano group to a tetrazophyll group can be accomplished by an azide, for example, tributyltin azide or sodium azide.

It is also possible to use groups R 'and / or R' _2, such as nitro, carboxyl, cyano or acid chloride groups, and then convert these groups by reactions which are well known to the person skilled in the art to R 1 and / or R 1 groups. ₂ as described for the compound of formula (I).

When R 1 and / or R ₁ is a carboxyl group, this group can be converted to R 1 and / or R ₂ meaning an imidazol-1-ylcarbonyl group or else N - [(4-carboxy) -1,3-thiazole-2] -yl] carbamoyl group.

When R 1 and / or R ₂ is an acid chloride group, this group may be converted to R 1 and / or R ₂ representing an N-hydroxycarbamoyl group, an N-cyanocarbamoyl group, an ureide group or a cyano-2-guanidino-carbonyl group.

When R 1 and / or R 1 is nitro, this may be converted to an amine group from which R 1 and / or R ₂ , such as methylsulfonylamino, trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl, may be prepared.

When R ', and / or R' ₂ is cyano, it can be converted to an aminomethyl group from which a 3-cyano-2-methylisothioureidomethyl group is prepared (according to the method of C. Gordon et al., Described in J. Org. Chem. 1970, 35, 6, 2067-2069) or a 2-cyanoguanidinomethyl group (following the procedure of RW Tumer described in Synthesis, 1975, 332).

Step a1) is carried out in an inert solvent such as DMF, DMSO or THF in an alkaline medium, for example in the presence of potassium hydroxide, metal alcoholate, metal hydride, calcium carbonate or triethylamine.

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

In the classification of compounds of formula (I), the positions of biphenyl are numbered in the classical manner, as can be seen from the following formula (I):

In the following, the invention will be explained in more detail by means of specific examples thereof, these examples being illustrative only and not in any way limiting the scope of the invention, which is clearly defined by the definition of the claims.

In the following compounds of z and t, they are zero except when the compound to be prepared is pyrimidinone.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one and trifluoroacetate-2-n-butyl-1 - [( 2'-Carboxybiphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one (Method 2)

Grade A

N-Fmoc-1-aminocyclopentanecarboxylic acid

This acid is prepared as described by CHIDE Chang et al. in Int. J. Peptide Protein Res., 1980, 15, 59-66.

Melting point: 89-91 ° C.

Step B N- (2'-tert-Butoxycarbonylbiphenyl-4-ylmethyl) -1- (N-Fmoc-amino-1-cyclopentanecarboxamide

700 mg of the product obtained in the preceding step are dissolved in 8 ml of dimethylformamide, followed by the stepwise addition of 576 mg of 4-amino-methyl- (2'-tert-butoxycarbonyl) biphenyl, 970 mg of benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate and sufficient diisopropylethylamine. pH = 6.

After stirring for 1 hour, the reaction mixture is diluted with 100 mL of ethyl acetate and 20 mL of water; the organic phase is washed successively with a saturated aqueous solution of sodium bicarbonate, then with a solution of potassium hydrogen sulphate and potassium sulphate and finally with a saturated aqueous solution of sodium chloride. After drying over sodium sulfate, the solution is evaporated to dryness. An oily product is obtained. Yield: 1.2 g.

Step C N- (2'-tert-butoxycarbonylbiphen-4-ylmethyl) - (1-amino) -1-cyclopentanecarboxamide

The product obtained in the preceding step is dissolved in 10 ml of dimethylformamide, to which 1 ml of diethylamine is added and the mixture is stirred for one hour and 15 minutes at ambient temperature. The reaction mixture is then taken up in 100 ml of ethyl acetate and 20 ml of water and the organic phase obtained is washed once with water, once with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness.

The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate, methanol and ammonia at a concentration of 30% (99: 1: 0.5 by volume).

Yield of product: 600 mg. Infrared spectrum:

(CHCl,)

350 cm ^-1 : H (amide and amine),

700 cm ^-1 : C = O (CO ₂ tBu),

650 cm ^-1 : C = O (CONH). Nuclear Magnetic Resonance Spectrum:

1.25 ppm: 9H: tBu;

2.15 -1.40 ppm: m: 10 H / C ₆ H ₈ NH ₂ /;

4.40 ppm: d: 2H: _CH2 NH;

7.15-7.75 ppm: u: 8 H: biphenyl; 8.60: t: 1 H: NH-CH ₂

Grade D

2-n-Btyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

394 mg of the product obtained in the preceding step and 250 mg of ethyl ortovalerate are mixed with 2 ml of dichloromethane. One drop of acetic acid was then added to the mixture, and the mixture was heated to 90 ° C until the dichloromethane was evaporated. After 1 hour and 15 minutes, the reaction mixture is taken up in 50 ml of ethyl acetate, 10 ml of water and 1 ml of saturated aqueous sodium bicarbonate solution. The organic phase is then washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 1: 2 mixture of ethyl acetate and toluene. The desired product crystallizes from the eluate obtained.

Product yield: 390 mg. Melting point: 63 - 65 ° C. Infrared spectrum (CHCl3)

710-170 cm ¹ : C = O, C = O (ester and imidazoline)

625 cm ´: C = N.

NMR spectrum: 0.83 ppm: t: 3H: _CH3 (nBu);

1.20 ppm: s: 9H: tBu;

1.35 ppm: sext: 2 H: _CH3-CH2 -;

1.58 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -;

1.95-1.65: u.c.: 8H: cyclopentane;

2.42 ppm: t: 2H: CH2-CH2-CH2-CH2-;

4.78 ppm: s: 2H: _{CH2-C 6} H ₄ -;

7.20-7.30 ppm: s: 8H: H-aromatic; Mass spectrum:

MH ⁺ : 461.

Grade E

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

180 mg of the product obtained in the previous step are kept in contact with 3 ml of dichloromethane and 4 ml of tetrahydrofuran for 45 minutes. After evaporation under reduced pressure, the residue is taken up in ether. A white solid is obtained, which is filtered off, washed with ether and dried under reduced pressure.

Yield of product: 155 mg. Melting point: 176-178 ° C.

NMR spectrum: 0.78 ppm: t: 3H: _CH3 (nBu);

1.25 ppm: sext: 2 H: _{CH3 --CH2;}

1.50 ppm: quint: 2 H: _CH3-CH2-CH2;

1.75-2.00: u.c.: 8H: cyclopentane;

2.65 ppm: t: 2H: CH2-CH2-CH2-CH2;

4.83 ppm: s: 2H: _{CH2-C 6} H ₄ -;

7.20-7.75 ppm: 8H: aromatic;

Mass Spectrum: MH ⁺ : 405.

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

Step A 2-n-Butyl-4-spirocyciopentan-2-imidazolin-5-one

1-Aminocyclopentanecarboxylic acid ethyl ester was prepared according to the procedure of Adkins and Billic (J. Amer. Chem. Soc., 1948,70,3121).

Ethyl valerimidate was prepared according to the procedure of Mac Elvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827) and was liberated from its hydrochloride by treatment with potassium carbonate and extraction with dichloromethane.

1-Aminocyclopentanecarboxylic acid ethyl ester (1.57 g) and ethyl valerimidate (1.56 g) were dissolved in 12 ml of xylene containing 6 drops of acetic acid. After heating at reflux for 6.5 hours, the reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with a 94: 4: 2 mixture of chloroform, methanol and acetic acid. The product fraction is evaporated. several times in the presence of xylene and then benzene to remove acetic acid. The desired product is obtained as a thick oil. Product yield: 1.91 g.

IR (CHC1 ₃₎

720 cm- ¹ : C = O,

635 cm ^-1 : C = N.

Note that can not be observed between the strip 1 500 and 1 600 ^cm-1 indicate that, in chloroform solution, the product is 5-imidazolinone.

NMR spectrum: 0.92 ppm: t: 3H: _CH3 (nBu);

1.35 ppm: sext: 2 H: _{CH3 --CH2;}

1.50 to 1.93 ppm: m: 10H: _CH3-CH2-CH2 and cyclopentane; 2.33 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

10.7 ppm: u.c.: NH; Mass Spectrum: MH ⁺ : 195.

The 2-n-Butyl-4-spirocyclopentan-2-imidazolin-5-one prepared in Step A can also be obtained by another procedure described below using cyclopentanone as the starting product.

Step a)

-Aminocyklopentánnitril

This step was performed according to A. Strecker (Org. Synth., 1955.3).

Dissolve 1.97 g of sodium cyanide in 3.9 ml of water in a flask, then add a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% ammonia, to the solution thus obtained. flasks add 3 g of cyclopentanone in 3.8 ml of methanol. After stirring for 1.5 hours, the reaction mixture was heated at 60 ° C for 45 minutes, then the heating was stopped, the reaction mixture was stirred for 45 minutes and then cooled to 25 ° C. It is then extracted several times with methylene chloride. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is obtained as an oil. Product yield: 4 g.

The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is added with stirring. The precipitate formed is centrifuged, washed with acetone and then dried.

Yield: 4.71 g. Melting point: 220 ° C.

This compound is 1-aminocyclopentanenitrile hemioxalate.

Step b)

-Aminocyklopentánkarboxamid

This step is carried out as described by J. Zabloky in The Chemistry of Amides, Intersciences, New York, 1970, 119.

To the 5.1 g of oxalate obtained in the previous step, 7.65 ml of concentrated sulfuric acid (density: 1.84) are added with stirring, and the mixture is stirred for 45 minutes. Gas evolution is observed and the temperature of the reaction mixture rises to 100 ° C. The mixture was then cooled to 35 ° C and poured into a mixture of ice and concentrated ammonia (10 g / 2.8 mL). The resulting suspension was extracted six times with chloroform containing 5% methanol. Then 3 ml of ammonia / density (0.92) are added to the aqueous phase and this phase is extracted again with 1: 0.5 by volume of chloroform containing methanol. The combined organic phases are dried over sodium sulphate, filtered and concentrated. The desired product is obtained as a white solid. Yield: 3.79 g. Melting point: 95 ° C.

Analysis and infrared spectroscopy confirmed the structure of the product.

Step c) 2-n-Butyl-4-spirocyclopentan-2-imidazolin-5-one

This step is performed according to H. Takenak et al., Heterocycles, 1989, 29, 6, 1185-1189.

g of the compound obtained in the preceding step are introduced into 70 ml of anhydrous tetrahydrofuran and 3 ml of triethylamine, and 3 ml of valeryl chloride in 10 ml of anhydrous tetrahydrofuran are added thereto with stirring. A white suspension is formed. The formed but not isolated intermediate is (N-valeryl) -1-aminocyclopentanecarboxamide. 6 g of stone potassium hydroxide, 7 ml of water and 16 ml of methanol are added. The mixture was then heated to reflux for two hours and 30 minutes, then

9 g of ammonium chloride are added thereto. After stirring for 15 minutes, the reaction mixture was concentrated under reduced pressure.

The residue is taken up in 40 ml of water and extracted with 10 ml of ethyl acetate and then twice with 5 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated to dryness to give the desired product.

Yield: 4.85 g.

The nuclear magnetic resonance spectrum is similar to that described in the previous case.

The hydrochloride of this compound can be prepared by adding concentrated hydrochloric acid. The hydrochloride obtained melted at 240 ° C and sublimed.

Grade B

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

970 mg of the product obtained in Step A are dissolved in 10 ml of dimethylformamide. 270 mg of sodium methylate are added and the mixture is stirred for 15 minutes at ambient temperature. 2.08 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) are added to the suspension, and after 30 minutes the mixture is heated at 40 ° C under nitrogen for 3 hours and 30 minutes. The reaction mixture is then taken up with a mixture containing 100 ml of ethyl acetate, 10 ml of water and 1 ml of saturated sodium bicarbonate solution.

The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 1: 2 by volume mixture of ethyl acetate and toluene. The desired product is crystallized from the eluate.

Yield of product: 1.25 g. Melting point: 63 - 66 ° C.

The infrared spectrum, the nuclear magnetic resonance spectrum, the mass spectrum and the Rf value are the same as the corresponding values of the product of Step D of Example 1.

Grade C

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

1.22 g of the product obtained in the previous step are stirred for 40 minutes in a solution containing 6 ml of dichloromethane and 8 ml of trifluoroacetic acid. After concentration under reduced pressure, the residue is taken up in ethyl ether; The white precipitate formed is filtered, washed with ether and then dried under reduced pressure to give the desired product.

Yield of product: 1.15 g. Melting point: 176-178 ° C.

The infrared spectrum, the nuclear magnetic resonance spectrum and the mass spectrum are identical to those of the product obtained in step E of Example 1. The same applies to the Rf value obtained by thin-layer chromatography.

Example 3

2-n-Butyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate (method 3)

Grade A

2-n-butylbenzimidazole

2-n-Butylbenzimidazole was prepared according to the procedure of WO Pool (J. Amer. Chem. Soc., 1937, 59, 178), followed by the preparation of 2-n-butyl-4,5,6,7-tetrahydrobenzimidazole by the procedure of M. Hartmann and L. Panizzona (Hel. Chim. Acta, 1938, 21, 1692-1694).

Melting point: 145 ° C.

NMR spectrum: 0.82 ppm: t: 3 H: CH ₃ - (nBu);

1.23 ppm: sext: 2 H: _CH3-CH2 -;

1.50 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -;

I, 65 ppm: s: 4 H: _{H5, H6} (tetrahydrobenzimidazole);

2.35 ppm: s: 4H: H ₄ , H ₇ (tetrahydrobenzimidazole);

2.45 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

II, 1 ppm: u.c.: NH; Mass Spectrum: M ⁺ : 178.

Grade B

2-n-Buty 1-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one g of the product prepared in the previous step is dissolved in 45 ml of dimethylformamide with 303 mg of sodium methylate and a few milligrams of methylene blue. Oxygen is then bubbled through the mixture and the reaction mixture is illuminated with a UV lamp. After 15 minutes, 2.14 g of 4-bromomethyl- (2'-butoxycarbonyl) biphenyl is added and after one hour the reaction mixture is taken up in 300 ml of ethyl acetate, to which 50 ml of water and 5 ml of saturated aqueous sodium hydrogen carbonate solution are added.

The organic phase is then washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 1: 2 by volume mixture of ethyl acetate and toluene. The desired product is crystallized from the eluate obtained. Yield of product: 610 mg. M.p .: 62-65 ° C.

The infrared spectrum, the nuclear magnetic resonance spectrum, the mass spectrum and the Rf value are the same as those of the same product obtained by the described process.

Step C 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate

This compound is obtained by the acidic reaction described in the last step of Example 1 and Example 2. The physicochemical properties of this compound coincide with similar properties of the same compound prepared by Method 1 or Method 2.

Example 4 2-n-Butyl-4,4-dimethyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one and 2-n-Butyl-1 - [( 2'-carboxybiphenyl-4-yl) methyl] -4,4-dimethyl-2-imidazolin-5-one (method 1)

Step A 2-n-butyl-4,4-dimethyl-2-imidazolin-5-one

Ethyl alpha-amino isobutyrate was prepared according to the procedure of R. Jacquier et al. (Bull. Soc. Chim., Franc., 1971, 3, 1040-1051). 650 mg of this compound and 780 mg of ethyl valerimidate are dissolved in 8 ml of xylene containing 4 drops of acetic acid and the solution thus obtained is refluxed for 7 hours. The reaction mixture is then concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with a 95: 5: 2 mixture of chloroform, methanol and acetic acid. Evaporation of xylene and benzene several times to remove the acid acetic acid yields the desired product which is crystallized.

Yield of product: 560 mg. Melting point: 35 - 38 ° C. Infrared spectrum:

(CHCl₃):

725 cm @ -1: C = O

635 cm ^-1 : C = N

Note: the absence of a signal between 1500 and 1600 cm ^-1 confirms that the compound is present as 2-imidazolin-5-one in the chloroform solution.

NMR spectrum: 0.92 ppm: t: 3H: _CH3 (nBu);

1.20 ppm: s: 6 H: C _{(CH3) 2;}

1:38 ppm: sext: 2 H: _{CH3 --CH2;}

1.63 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -;

2:38 ppm: t: 2 H: _{CH3 CH2 CH2} CH2; 10.7ppm: u.c.: 1H: NH;

Mass spectrum:

MH ⁺ : 169.

Grade B

2-n-Butyl-4,4-dimethyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

520 mg of the product obtained in the previous step are dissolved in 10 ml of dimethylformamide. 167 mg of sodium methylate are then added to the obtained solution, and the mixture is stirred for 15 minutes under a nitrogen atmosphere. 1.25 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl are then added and the mixture is stirred at 40 ° C for three hours and 30 minutes. The reaction mixture is then taken up in 150 ml of ethyl acetate and then with 20 ml of water and 2 ml of saturated aqueous sodium hydrogen carbonate solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene (1.2 / 2 by volume). The product is crystallized.

Yield of product: 570 mg. Melting point: 98-100 ° C. Infrared spectrum:

(CHCl,):

1710-1702 cm ^-1 : C = O, C = O (imidazolinone, ester)

625 cm ^-1 : C = N

NMR spectrum: 0.78 ppm: t: 3 H: CH ₃ - (nBu);

1.08 ppm: s: 9 H: C _{(CH3) 3;}

1.15 ppm: s: C (CH ₃ ) ₂ and 1.20 ppm: sext: CH ₃ -CH ₂ - / 8H;

2.30 ppm: t: 2 H: _{CH3 CH2 CH2} CH2;

4.65 ppm: s: 2H: _{CH2-C 6} H ₄ -;

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

The study of the nuclear Overhauser effect confirms the substitution of 5-one and 4,4-dimethyl on imidazolinone. Mass spectrum:

MH ⁺ : 435.

Step C 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4,4-dimethyl-2-imidazolin-5-one

460 mg of the product obtained in the previous step are treated for 45 minutes with 3 ml of dichloromethane and 4 ml of trifluoroacetic acid. After concentration under reduced pressure, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and dried under reduced pressure. The desired product is obtained as a white solid.

Yield of product: 450 mg. Melting point: 168-171 ° C.

NMR spectrum: 0.82 ppm: t: 3H: _CH3 (nBu);

1.30 ppm: sext: CH ₃ -CH _{2 and} 8H;

1.35ppm: s: C (CH3) ₂ ;

1.55 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -;

2.62 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

4.82 ppm: s: 2H: _{CH2-C 6} H ₄ -

7.20-7.75: u.c.: 8H aromatic; Mass spectrum:

MH ⁺ : 379.

Example 5 1 - [(2'-Cyanobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one a

2-n-butyl-4-spirocyclopentan-1 - [((2 '- (5-tetrazolyl) biphenyl-4-yl) methyl] -2-imidazolin-5-one (method 1)

Grade A

1- [2'-Cyanobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one

A mixture containing 250 mg of sodium hydride (in the form of an 80% dispersion in mineral oil) and 5 ml of dimethylformamide is prepared under a nitrogen atmosphere and a solution containing 0.97 g of 2-n-butyl-4-spirocyciopentane- is added dropwise. Of 2-imidazolin-5-one (prepared in Step A of Example 2) in 10 ml of dimethylformamide. After stirring at room temperature for 30 minutes, a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of dimethylformamide is added. After stirring at ambient temperature for 1 hour, the dimethylformamide was evaporated under reduced pressure and the resulting residue was taken up in ethyl acetate; the organic phase is washed with water, dried over sodium sulphate, filtered and evaporated.

The residue is chromatographed on silica gel, eluting with a 9: 1 by volume mixture of dichloromethane and stannous acetate. The desired product is obtained from the eluate.

Yield of the product: 1.68 g. Melting point: 92-93 ° C.

Grade B

2-n-Butyl-4-spirocyclopentan-1- [2 '- (5-triphenylmethyl-tetrazolyl) biphenyl-4-ylmethyl] -2-imidazolin-5-one

1.56 g of the preceding product, 2.6 g of tributyltin azide and 30 ml of xylene are heated to reflux for 66 hours. The xylene is then evaporated and the residue is dissolved in 20 ml of dichloromethane and 5 ml of tetrahydrofuran, with 0.8 ml of 10N sodium hydroxide solution added; after stirring for 30 minutes, 2.5 g of trityl chloride are added and the mixture is stirred for 26 hours. After evaporation of the solvents, the residue is taken up in ethyl acetate and washed with water, 3% potassium hydrogen sulphate solution and then with water. After drying and evaporation, the residue is chromatographed on alumina eluting with hexane / ethyl acetate 9: 1. The desired product is obtained from the eluate obtained. Yield of the product: 1.97 g.

Melting point: 150-152 ° C.

Grade C

2-n-Butyl-4-spirocyclopentan-1 - [(2 '- (5-tetrazolyl) biphenyl-4-ylmethyl) -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 tetrahydrofuran. After cooling the reaction mixture to 5 ° C, it is added

1.5 ml of 4N hydrochloric acid are added and the mixture is stirred for 3 hours at ambient temperature and then for one hour and 30 minutes at 30 ° C. After evaporation of the solvents, the residue is taken up in water and basified to pH 12 by the addition of 10 N sodium hydroxide solution.

The aqueous phase is extracted with ether, toluene and again with ether. The aqueous phase is then acidified to pH 2 by the addition of 1N hydrochloric acid, extracted with ethyl acetate, dried and evaporated. The white solid obtained is dried at 50 DEG C. under a pressure of 0.05 mm of mercury to give the desired product. Yield: 840 mg.

Melting point: 180-181 ° C. NMR spectrum: 0.75 ppm: t: 3H: _CH3 (nBu);

1.10 ppm: sext: 2 H: _CH3-CH2 -;

1.20 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -;

1.5-2 ppm: m: 8 H: C ₅ H _8;

2.2 ppm: t: 2 H: _CH3-CH, -CH ₂ -CH ₂ -;

4.6 ppm: s: 2H: _{CH2-C 6} H ₄ -;

ppm: s: 4H: _{CH2-C 6} H ₄ -;

7.35-7.7 ppm: u.c.: 4H: H ₃ , ₄ , ₅ , ₆ -aromatic.

The study of the nuclear Overhauser effect confirms the position of the 5-one substitution to imidazole.

Grade D

Potassium salt of 2-n-butyl-4-spirocyclopentan-1 - [(- 2 '- (5-tetrazolyl) biphenyl-4-yl) methyl] -2-imidazolin-5-one

970 mg of the compound obtained in the preceding step are dissolved in 40 ml of a 1: 1 v / v mixture of isopropanol and methanol and the pH of the solution is adjusted to 12 by addition of 85% aqueous and methanolic (1: 1 v / v) potassium hydroxide solution. After evaporation, the residue is taken up with isopropanol and the solvent is evaporated again. The residue was then dissolved in 20 ml of isopropanol with gentle heating, and the solution was allowed to cool to ambient temperature. After decanting and evaporating the filtrate, the residue is taken up in heptane. After trituration the product solidifies; filtered, washed again with heptane and dried under reduced pressure to give the desired product. Product yield: 945 mg.

M.p .: 142-144 ° C. Elemental analysis: C ₂₅ H ₂₇ KN ₆ O, H ₂ O: Calculated (%): C 61.95 H 6.03 N 17.34 Found (%): C 62.02 H 6.13 N 17, 14

Example 6

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (4-spirotetrahydropyran) -2-imidazolin-5-one and

2-n-butyl-4- (4-spirotetrahydropyran) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one (method 2)

Grade A

4-Amino-4-tetrahydropyranecarboxylic acid

4-Amino-4-tetrahydropyranecarboxylic acid is prepared from 4-tetrahydropyranone by the method described in German patent DE 2 215 721.

Step B 4- (N-Benzyloxycarbonylamino) -4-carboxytetrahydropyran

1.015 g of the compound of Step A are introduced into 12 ml of water, and 1.22 ml of diisopropylethylamine are added thereto at 10 ° C, followed by 3.33 g of N- (benzyloxycarbonyloxy) succinimide dissolved in 12 ml of acetonitrile. minutes, the reaction mixture was diluted with 70 mL of ethyl acetate and 10 mL of water and the pH of the mixture was adjusted to 2 with a saturated aqueous solution of potassium hydrogen sulfate.

After decantation, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and then evaporated under reduced pressure. The residue is dissolved in 60 ml of ether and 7 millimoles of dicyclohexylamine are added. The precipitate formed is filtered off and washed with ether. The washed precipitate is then dissolved in a mixture of ethyl acetate and water, and the pH of the solution is adjusted to 1.5 with a saturated solution of potassium hydrogen sulfate. The organic phase is decanted, washed with saturated sodium chloride solution and evaporated under reduced pressure to give a white solid.

Product yield: 1.9 g. Melting point: 110-115 ° C.

Step C N- (2'-tert-Butoxycarbonylbiphenyl-4-ylmethyl) -4- (N-benzyloxycarbonylamino) -4-tetrahydropyranecarboxamide

850 mg of the compound prepared in Step B are dissolved in 15 ml of dimethylformamide and treated with equimolar amounts of 4-aminomethyl- (2'-tert-butoxycarbonyl) biphenyl and diisopropylethylamine, followed by benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate (10% fluorophosphate). After 40 minutes, the reaction mixture is taken up in 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted and then washed twice with saturated aqueous sodium hydrogen carbonate solution, twice with 5% sodium hydrogen sulphate solution and once with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic phase is evaporated under reduced pressure to give the desired product. Yield of product: 1.8 g.

Step D N- (2'-tert-Butoxycarbonylbiphenyl-4-ylmethyl) -4-amino-4-tetrahydropyranecarboxamide

The product obtained in Step C is dissolved in 30 ml of methanol. To this solution is then added 400 mg of 10% palladium on charcoal and the product is hydrogenated at atmospheric pressure. After one hour, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate, methanol and 33% ammonia (99: 1: 0.5 by volume). The desired product is then obtained from the eluate as a white solid. Yield of product: 0.93 g.

Melting point: 125-127 ° C.

Nuclear Magnetic Resonance Spectrum:

8.50 ppm: t: 1H: H amide,

7.60 - 7.05 ppm: m: 8H: H aromatic,

4.25 ppm d 2 H CH ₂ -C ₆ H ₄ -,

3.70 to 3.50 ppm: m: 4H: _CH2 at position 2 and 6 tetrahydropyran,

2.00 to 1.80 ppm: m: 4 H: _CH2 in the 3 and 5 tetrahydropyran,

1.05 ppm: s: 9H: tBu.

Step E 2-n-Butyl-4- (4-spirotetrahydropyran) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

A mixture containing 0.9 g of the compound obtained in Step D, 327 mg of methyl orthovalerate and 2 drops of acetic acid was heated at 110 ° C for 3 hours. The reaction mixture is then taken up in 100 ml of ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated with ethyl acetate.

The residue is chromatographed on silica gel, eluting with a 2: 1 by volume mixture of ethyl acetate and toluene. The desired product is obtained from the eluate as a wax.

Yield of product: 550 mg. Nuclear Magnetic Resonance Spectrum: 7.05 - 7.60 ppm: m: 8H: H aromatic,

4.63 ppm: s: 2H: _{CH2-C 6} H ₄ -,

3.85-3.55 ppm: m: 4 H: _CH2 in the 2 and 6 tetrahydropyran,

2.30 ppm: t: 2 H: _CH2 - C ₃ H _7,

1.05-1.80 ppm: m: 8 H: _{CH2 CH2 CH2 CH3} and _CH2 in the 3 and 5 tetrahydropyran,

1.03 ppm: s: 9H: tBu,

0.75 ppm: t: 3H: (CH ₂ ) ₃ -CH ₃

Infrared spectrum:

(Chčije)

710-1 720 cm ^-1 : C = O, C = O,

625 cm- ¹ : C = N.

Step F 2-n-Butyl-4- (4-spirotetrahydropyran) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

530 mg of the product obtained in the preceding step are treated with 4 ml of dichloromethane and 5 ml of trifluoroacetic acid for 45 minutes. After evaporation under reduced pressure, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and dried under reduced pressure to give the desired product. Yield of product: 510 mg.

M.p .: 159-162 ° C.

Nuclear Magnetic Resonance Spectrum:

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

4.80 ppm: s: 2H: _{CH2-C 6} H ₄ -,

4.00-3.75 ppm: m: 4H, CH ₂ in position 2 and 6 of tetrahydropyran,

2.60 ppm: t: 2 H: _{CH2-C 3} H _7,

1.45 to 2.00 ppm: m: 6 H: _{CH2 CH2 CH2 CH3} and _CH2 in the 3 and 5 of the tetrahydropyran

1.30 ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH _3, 0.80 ppm: t: 3 H: _{(CH2) 3} CH _third

Example 7

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)

Grade A

4-Amino-1-benzyl-4-piperidinecarboxylic acid

4-Amino-1-benzyl-4-piperidinecarboxylic acid is prepared from N-benzyl-4-piperidone according to the procedure described in German patent DE 2 215 721.

Grade B

Ethyl 4-amino-1-benzyl-4-piperidinecarboxylate

3.80 g of the compound prepared in Step A are introduced into a solution of 13 g of hydrochloric acid in 50 ml of ethanol at 0 ° C, and the reaction mixture is heated to reflux for 5 hours. After concentration under reduced pressure, the residue is washed with ether and then dissolved in a mixture of ether and water. To which a saturated aqueous solution of potassium carbonate was added to obtain a pH of 9. The ether phase was decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The desired product is obtained as an oil. Product yield: 3.50 g.

Nuclear Magnetic Resonance Spectrum:

7.20 - 7.40 ppm: m: 5H: aromatic H,

4.10 ppm: q: 2H, CH ₂ CH _3,

3.45 ppm: s: 2H: _CH2 of benzyl,

2.25 to 2.60 ppm: m: 4 H: _CH2 in the 2 and 6 of the piperidine,

1.80 - 2.05 ppm: m: 2H:

and

1.20 - 1.40 ppm: m: 2H: _CH2 at position 3 and 5, piperidine, l, 12ppm: t: 3 H: CH ₃ CH ₂ -,

Step C 2-n-Butyl-4- [spiro- (1-benzyl-4-piperidine)] - 2-imidazolin-5-one

Ethyl valerimidate was prepared according to the procedure of Step A of Example 2. A mixture of 2.06 g of ethyl valerimidate, 3.40 g of the compound prepared in step B and 8 drops of acetic acid in 15 ml of xylene was heated to reflux for 6 hours. After concentration under reduced pressure, the residue is chromatographed on silica gel, eluting with a 82: 15: 3 mixture of chloroform, methanol and acetic acid. Extraction with chloroform at pH 9 to remove acetic acid gives the desired product.

Yield of product: 2.80 g. Melting point: 170-172 ° C. Infrared spectrum: (chloroform)

725 cm ^-1 C = O,

640 cm ^-1 C = N.

Nuclear Magnetic Resonance Spectrum:

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

3.45 ppm: s: 2H: _{CH2-C 6} H ₅ -,

1.10 - 2.75 ppm: 5 m: 14 H, _CH2 of the 2, 3, 5 and 6 of the piperidine and _{(CH2) 3} CH _3,

0.80 ppm: t: 3H: (CH ₃ ) ₃ CH ₃ .

Step D 2-n-Butyl-4- [spiro- (1-benzyl-4-piperidin)] -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazoline 5-one

To 2.78 g of the compound obtained in Step C dissolved in 25 ml of dimethylformamide was added 513 mg of sodium methylate and after 15 minutes 4.16 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl was heated. After 5 hours, the reaction mixture is taken up in 300 ml of ethyl acetate, 50 ml of water and 5 ml of saturated sodium bicarbonate solution, the organic phase is decanted, washed once with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to dryness. on silica gel, eluting with a 95: 5 mixture of ethyl acetate and methanol. The desired product is then obtained from the eluate.

Product yield: 0.98 g. Melting point 103-106 ° C. Infrared spectrum (CHCl3)

710 - 1725 cm ^-1 C = O, C = O (imidazoline, ester)

630 cm ^-1 C = N.

Nuclear Magnetic Resonance Spectrum:

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

4.70 ppm: s: 2H: _{CH2-C 6} H ₄ -,

3.55 ppm: s: 2H: _CH2-C <, H ₅

1.20 - 2.75 ppm: 5m: 14H, CH ₂ in position 2, 3, 5, 6 of piperidine and (CH ₂ ) ₃ -CH ₃

1.15 ppm: s: 9H: tBu,

0.85 ppm: t: 3H: (CH ₂ ) ₃ -CH ₃

Grade E

2-n-butyl-l - [(2 ' karboxybifcnyl-4-yl) methyl] -4- [spiro (l-benzyl-4-piperidine)] - 2-imidazolin-5-one

350 mg of the compound obtained in Step D are dissolved in 4 ml of dichloromethane and 5 ml of trifluoroacetic acid. After 45 minutes, the reaction mixture is concentrated under reduced pressure and the residue is taken up in a mixture of ether and hexane, the precipitate formed is filtered off, washed with ether and dried under reduced pressure to give the desired product.

Product yield: 350 mg.

Melting point: 198-200 ° C.

Nuclear Magnetic Resonance Spectrum:

7.05-7.15 ppm: u.c.: 13H: H aromatic;

4.75 ppm: s: 2H: _{CH2-C 6} H _4;

4:40 ppm: s: 2H: _{CH2-C 6} H _5;

3.20 - 3.60 ppm: m: 4 H: _CH2 in the 2 and 6 of the piperidine;

2.35: t: 2H: CfL-CH2-CfL-CH2;

2.20 - 1.40 ppm: 3 multiplets: _CH2 in the 3 and 5 of the piperidine and CH ₂ CH ₂ CH ₂ CH _3;

1.25 ppm: sext: 2H: _CH2-CH-CH2, CH _3;

0.80 ppm: t: 3H (CH ₂ ) ₃ -CH ₃ .

Example 8

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- [4-spiropiperidine]] - 2-imidazolin-5-one difluoroacetate and

2-n-butyl 4- [4-spiropipcridín)] - l - [(2'-t-butoxykarbonylbifenyl-4-yl) methyl] -2-imidazolin-5-one

Step A 2-n-Butyl-4- (4-spiropiperidine)] - 1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

300 mg of the compound of Example 7, Step D are dissolved in 10 ml of methanol. To this solution was added 180 mg of 10% palladium on charcoal, and the mixture was hydrogenated with hydrogen for 3 hours. The catalyst is then filtered off and the filtrate is concentrated to dryness to give the desired product.

Product yield: 200 mg.

Nuclear Magnetic Resonance Spectrum:

7.20-7.75 ppm: u.c.: 8H: H aromatic;

4.75 ppm: s: 2H: _{CH2-C 6} H ₄ -;

3.00 - 1.70 ppm: 3 multiplets for 4 CH ₂ piperidine;

2:40 ppm: t: 2 H CH ₂ CH ₂ CH ₂ CH _3;

1.60 ppm: quint: 2H: CH ₂ CH ₂ CH ₂ CH _3;

1:35 ^ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH _3;

1.20 ppm: s: 9H: tBu;

0.90 ppm: t: 3H: (CH ₂ ) ₃ -CH ₃ .

Step B 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- [4-spiropiperidine] -2-imidazolin-5-one

160 mg of the product obtained in Step A are stirred in 3 ml of dichloromethane and 4 ml of trifluoroacetic acid for 45 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was taken up in ether. After drying under reduced pressure, a gummy product is obtained and then a foamed product.

Product yield: 150 mg. Melting point: 80 - 85 ° C.

Nuclear Magnetic Resonance Spectrum:

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

4.75 ppm: s: 2H: CH ₂ C ₆ H ₄ -;

3.20 - 1.60 ppm: multiplets, 3: 4 _CH2 of piperidine;

2:40 ppm: t: 2 H CH ₂ CH ₂ CH ₂ CH _3;

1:50 ppm: quint: 2H: CH ₂ CH ₂ CH ₂ CH _3;

1.30 ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH _3;

0.80 ppm: t: 3H: (CH ₂ ) ₃ -CH ₃ .

Example 9

2-n-Butyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4,4-diphenyl-2-imidazolin-5-one trifluoroacetate; and

2-n-Butyl-4,4-diphenyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one (Method 1)

Grade A

Valeramidine hydrochloride g of ethylvalerimidate hydrochloride is added to the solution

6.75 ammonia in 80 ml methanol at 0 ° C. After 18 hours, the reaction mixture is concentrated under reduced pressure to give the desired product as a white solid.

Step B 2-n-Butyl-4,4-diphenyl-2-imidazolin-5-one

This compound is prepared according to the procedure of J. Nyitrale and K. Lempert, described in Tetrahedron, 1969, 25, 4265 - 4275, from benzyl and valeramidine hydrochloride. Melting point: 135 ° C.

Infrared spectrum:

(CHCl₃):

725 cm '' C = O

640 cm ^-1 C = N.

Nuclear Magnetic Resonance Spectrum:

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

2:50 ppm: t: 2 H CH ₂ CH ₂ CH ₂ CH _3;

1.65 ppm: quint: 2H: CH ₂ CH ₂ CH ₂ CH _3;

1.35 ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH _3; 0.90 ppm: t: 3H: CH ₂ CH ₂ CH ₂ CH _3;

ppm: p. e .: NH.

Grade 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 treatment of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl in Step B in the presence of sodium methylate in dimethylformamide.

Infrared spectrum:

(CHCl,):

715 - 1725 cm ^-1 C = O, C = O (ester, imidazolinone)

635 cm ^-1 C = N.

Nuclear Magnetic Resonance Spectrum:

7.25-7.80 ppm: m: 18H: H aromatic;

4.85 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -;

2.60 ppm: t: 2 H CH ₂ CH ₂ CH ₂ CH _3;

1.75 ppm: quint: 2H: CH ₂ CH ₂ CH ₂ CH _3;

1:40 ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH _3;

1.15 ppm: s: 9H: tBu;

0.90 ppm: t: 3H: _CH3 of n-butyl.

Grade D

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-, 4-diphenyl-2-imidazolin-5-one trifluoroacetate

500 mg of the product of Step C was treated with 2.5 mL of dichloromethane and 2.5 mL of trifluoroacetic acid at 20 ° C for 40 minutes. After concentration under reduced pressure, the resulting residue is taken up in ether / hexane, the precipitate formed is filtered off, washed with hexane and dried to give the desired product.

Yield of product: 449 mg. Melting point: 55-60 ° C.

Nuclear Magnetic Resonance Spectrum:

7.15-7.8 ppm: m: 18H: H aromatic;

4.85 ppm: s: 2H: N-CH 2 -C ₆ H ₄ -;

2.60 ppm: t: 2 H CH ₂ CH ₂ CH ₂ CH _3;

1.70 ppm: quint: 2 H: _{CH2-CH2-CH2-CH2;}

1.40 ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH ₃ -; 0.90 ppm: t: 3H: _CH3 of the butyl.

Example 10 2-n-Butyl-3 - [(2'-carboxybiphenyl-4-yl) methyl] -6-spirocyclopentane-5,6-dihydro-4H-pyrimidinone trifluoroacetate

Grade A

(1-Aminocyclopentyl) acetic acid

Cyclopentylideneacetic acid was prepared as described by G. A. R. Horse and R. P. Linstead in J. Chem. Soc., 1925, 127, 616. 740 mg of this acid and 5 ml of 20% ammonia are introduced into the autoclave and the mixture is heated at 150 ° C for 24 hours. After evaporation of the solvents, the resulting residue is chromatographed on a column of silica gel, eluting with a dichloromethane / methanol / 20% ammonia solution (70/30/1, v / v) mixture.

Step B (1-Aminocyclopentyl) ethyl acetate

330 mg of the acid is dissolved in 10 ml of ethanol. The solution was then cooled in an ice bath and saturated with hydrogen chloride gas. After refluxing for 24 hours, the reaction mixture is evaporated, the residue is taken up with sodium carbonate solution and extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give the desired ester.

Product yield: 312 mg.

Step C 2-n-Butyl-6-spirocyclopentane-5,6-dihydro-4-1H-pyrimidinone

A mixture containing 310 mg of the compound obtained in Step B, 348 mg of ethyl valerimidate, 10 ml of xylene and 6 drops of acetic acid was heated to reflux. After 2 hours and 18 hours, 348 mg of ethyl valerimidate are again added and after 24 hours of total reflux, the reaction mixture is evaporated and the residue is chromatographed on a column of silica gel, eluting with a dichloromethane / methanol (97: v / v) mixture. 3. The desired product is then obtained from the eluate.

Product yield: 153 mg.

Step D 2-n-Butyl-6-spirocyclopentan-3 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -5,6-dihydro-4-1H-pyrimidinone

A mixture of 10 ml of dimethylformamide and 40 mg of 80% (in oil) sodium hydride is prepared under a nitrogen atmosphere. 144 mg of the compound prepared in Step C, dissolved in 5 ml of dimethylformamide, are then added dropwise at ambient temperature. After stirring for 30 minutes, 288 mg of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl dissolved in 5 ml of dimethylformamide is added. After stirring for two hours, the reaction mixture is evaporated, the resulting residue is taken up in water and extracted with ethyl acetate. After drying over sodium sulfate, filtration and evaporation, the residue is chromatographed on a column of silica gel, eluting with a hexane / ethyl acetate mixture (85/5; v / v).

Grade E

To 10 ml of trifluoroacetic acid cooled in an ice-water bath was added 161 mg of the compound prepared in Step D. The mixture was stirred for 30 minutes and then evaporated. The residue was taken up in ethyl ether and then evaporated again. This operation is repeated once more and the residue is dried under reduced pressure. The desired compound is thus obtained in the form of an amorphous powder.

Yield: 140 mg. Melting point 108-115 ° C.

Nuclear Magnetic Resonance Spectrum:

0.9 ppm: t: 3H: (CH ₂ ) ₃ -CH ₃ ;

1.1 to 2.1 ppm: m: 12 H: cyclopentane and _{CH2 CH2 CH2 CH3;}

2.7 ppm: t: 2 H CH ₂ CH ₂ CH ₂ CH _3;

3.1 ppm: s: 2H: _CH2-CO;

5.1 ppm: s: 2 H: N-CH ₂ -C ₆ H _5;

7.2 to 7.8 ppm: m: 8H: H aromatic.

Example 11

2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazoline-5-thione and 2-n-butyl-1 - [(2'-carboxybiphenyl) 4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-thione

Step A 2-n-Butyl-4-spirocyclopentane-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazoline-5-thione

5.63 g of the compound prepared in Step D of Example 1 are dissolved in 40 ml of anhydrous toluene and 3 g of Lawesson's reagent are added to this solution at 80 ° C. After 6 hours, the reaction mixture is filtered and the filtrate is concentrated. The residue is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate. The desired product is obtained as an oil which crystallizes on cooling. Product yield: 4.5 g.

Melting point: 77-79 ° C.

Nuclear Magnetic Resonance Spectrum:

0.90 ppm: t: 3H: _CH3 (nBu);

1.20 ppm: s: 9H: tBu;

1:35 ppm: sext: 2 H: _CH3-CH2 -;

1.60 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -; 1.80-2.10 ppm: u.c.: 8H: cyclopentane;

2.60 ppm: t: 2 H: _{CH3-CH2-CH2-CH2;}

5:35 ppm: s: 2H: _{CH2-C 6} H ₄ -;

7.25 - 7.80 ppm: m: 8H: H aromatic.

Step 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 was treated with 5 ml of dichloromethane and 5 ml of trifluoroacetic acid for 30 minutes. After concentration, the resulting residue is taken up in ether. The title compound is obtained as a yellow powder, which is centrifuged and washed with hexane. Yield of product: 160 mg.

Melting point: 185-190 ° C. Mass Spectrum: MH ⁺ : 421.

0.78 ppm: t: 3H: _CH3 (nBu);

1.20 ppm: sext: 2 H: _CH3-CH2 -;

1.50 ppm: quint: 2H: CH ₃ CH ₂ CH ₂ -;

1.75-2.00 ppm: u.c.: 8H: cyclopentane;

2.40 ppm: t: 2 H: _{CH3 CH2 CH2} CH2;

5.20 ppm: s: 2H: _{CH2-C 6} H ₄ -;

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

Example 12

2-n-Butyl-4- (2-spiroindan) -1 - [(2'-tert-carbonylbiphenyl-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)

Step A 2-Amino-2-indanecarboxylic acid was prepared as described by R. M. Pinder in J. Med. Chem., 1971, 14, 9, 892 and the corresponding ethyl ester is then prepared according to the procedure of Adkins (see Example A Step A).

Step B 2-n-Butyl-4- (2-spiroindan) -2-imidazolin-5-one

2.78 g of the ethyl ester prepared in step A and 2.5 g of ethyl valerimidate are dissolved in 20 ml of xylene in the presence of 60 μΐ of acetic acid and the solution is then heated to reflux for three hours. 500 mg of ethyl valerimidate are then added and refluxing is continued for a further 3 hours. The reaction mixture is then concentrated and the residue is chromatographed on silica gel, eluting with a 3: 8: 0.3 hexane / ethyl acetate / acetic acid mixture. The pure fractions were combined and evaporated with toluene. The desired product is obtained as a white solid. Product yield: 3.07 g.

M.p .: 148-150 ° C.

NMR spectrum: 0.90 ppm: t: 3H: _CH3 (nBu);

1.2 to 1.7 ppm: m: 4 H: _{CH2-CH2 -CH3;}

2.4 ppm: t: 2 H: CH2 _{(CH2) 2} CH ₃ -;

2.8 to 3.2 ppm: q: 4 H: CH2 ₂ (indan);

4.90 ppm: s: 2H: _{CH2-C 6} H ₄ -;

7.20 ppm: u.c.: 4H: H aromatic.

Grade C

2-n-Butyl-4- (2-spiroindan) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

The compound obtained in the preceding step is dissolved in 20 ml of anhydrous dimethylformamide and 450 mg of sodium methylate are added to this solution under a nitrogen atmosphere. After 20 minutes at ambient temperature, 3.6 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl is added and the mixture is allowed to stir at 40 ° C for 6 hours. The reaction mixture is concentrated, followed by conventional washing, and the residue is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate. The desired product is obtained as a foamed product.

Yield of product: 1.84 g.

Nuclear Magnetic Resonance Spectrum:

0.80 ppm: t: 3H: CH ₃₁ nBu;

1.20 ppm: s: 9H: tBu;

1.20 - 1.60 ppm: m: 4 H: _{CH2-CH2 -CH3;}

2.40 ppm: t: 2 H: CH2 _{(CH2) 2} -CH _3;

2.9 - 3.3 ppm: q: 4 H: CH2 ₂ (indan);

4.80 ppm: s: 2H: N-CH 2 Cl 6;

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

Step 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 preceding step are dissolved in 15 ml of dichloromethane, and 20 ml of trifluoroacetic acid are added thereto. After 30 minutes, the reaction mixture is concentrated and the residue is taken up in ether. After trituration, the solid obtained is centrifuged, washed with ether and dried to give the desired product. Yield of product: 1.42 g. Melting point: 217-218 ° C.

Nuclear Magnetic Resonance Spectrum:

0.70 ppm: t: 3H: _CH3 (nBu);

1.10 -1.50 ppm: m: 4 H: _CH2-CH2-CH3;

2.30 ppm: t: 2 H: _CH2 - _{(CH2) 2} -CH _3;

2.8-3.3 ppm: q: 4H: 1H: (indane);

4.70 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -;

7.1-7.7 ppm: m: 12H: H aromatic.

Other compounds of the invention were prepared according to any of the procedures described. These compounds are shown in Table 1. The structure of each of these compounds was confirmed by analysis of their nuclear magnetic resonance spectra.

Example 13

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

General formula (I):

R ₂ = H,

R ₃ = n-C ₄ H _9,

CR4R5 = cyclopentane,

X = 0.

A mixture of 404 mg of the compound prepared in Step E of Example 1.15 ml of tetrahydrofuran and 260 mg of carbonyldiimidazole is stirred at ambient temperature for 72 hours. The reaction mixture is then evaporated, taken up in ethyl acetate, washed with water and then brine, to give 420 mg of product which is purified by chromatography on silica gel, eluting with a dichloromethane / ethyl acetate mixture (70/30; v / v). The desired product is then isolated.

Yield: 230 mg. Melting point: 120 ° C.

Example 14 2-n-Butyl-1 - [(2 '- (3-cyano-2-methylisothioureidomethyl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one General Formula (I) :

sch ₃

I r ₁ = -ch ₂ -nh-c = n-cn r ₂ = h

R ₃ nC ₄ H ₉ ,

CR4R5 = cyclopentane,

X = 0.

Grade A

1 - [(2'-Aminomethylbiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one.

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

g of the compound prepared in Step A of Example 5 is introduced into 15 ml of absolute methanol and 2.3 ml of ethanol containing 0.5 g of 5% palladium on charcoal and the compound is hydrogenated at ambient temperature for 24 hours. After the usual treatment of the hydrogenation mixture, the desired product is obtained in the form of an oily product. Yield of product: 730 mg.

Grade B

A mixture containing 300 mg of the compound obtained in the preceding step and 113 mg of N-cyanimido-S, S-dimethyldithiocarbonate in 3 ml of ethanol was heated to reflux for 24 hours. After usual work-up, the reaction mixture is purified by chromatography on silica gel, eluting with a 50:50 mixture of dichloromethane and ethyl acetate. The desired product is isolated as a white solid. Yield of product: 307 mg. Melting point: 83 ° C.

Example 15

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

General formula (I):

NH ₂

R 1 = -CH ₂ -NH-C = N-CN r ₂ = h,

R ₃ ⁼ n-C ₄ H _9,

CR ₄ R ₅ = cyclopentane,

X = 0.

This compound is obtained from the compound prepared in the previous example. 200 mg of this compound are introduced into 10 ml of absolute alcohol, the alcohol is saturated with ammonia at 10 ° C and heated to 80 ° C in an autoclave for one hour. After concentrating the reaction mixture to dryness, the residue is chromatographed on silica gel, eluting with a dichloromethane / methanol (95/5; v / v) mixture. The desired product is then isolated from the eluate. Product yield: 130 mg. Melting point: 100 ° C.

Example 16 2-n-Butyl 4-spirocyclopentane-1 - [(2'-trifluoromethylsulfonylaminobiphenyl-4-yl) methyl] -2-imidazolin-5-one trifluoromethylsulfonate

General formula (I):

R 1 = -NHSO ₂ CF ₃ , r ₂ = h,

R ₃ ~ nC ₄ H ₉ ,

CR ₄ R _s = cyclopentane,

X = 0.

Step A 4-Methyl-2'-nitrobiphenyl

A mixture of 2-nitrobromobenzene (11.2 g) and 4-iodotoluene (15 g) was heated to 195 ° C and stirred at this temperature for three hours and 30 minutes. After cooling to ambient temperature, the reaction mixture was taken up in dichloromethane, heated to reflux, and the warm solution was filtered through celite, whereupon dichloromethane was evaporated from the filtrate. Yield: 6.5 g.

Boiling point: 80-120 ° C at 26.6 Pa. n _D ²⁴ = 1.6042.

Grade B

4-bromomethyl-2'-nitrobiphenyl

A mixture containing 6.5 g of 4-methyl-2'-nitrobiphenyl, 5.42 g of N-bromosuccinimide, 118 mg of azo-bisisobutyronitrile and 500 ml of carbon tetrachloride was heated to reflux for 5 hours. The reaction mixture was then cooled to 0 ° C and centrifuged. The liquid fraction obtained is concentrated to give an oily product which is used in the next step.

Step C 2-n-Butyl-1 - [(2'-nitrobiphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one

A mixture containing 260 mg of sodium hydride (80%) in 5 ml of dimethylformamide is prepared, and 500 mg of 2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one, prepared under nitrogen atmosphere, is added to this mixture under nitrogen. in Example 2, Step A. After stirring for 15 minutes, 901 mg of 4-bromomethyl-2'-nitrobiphenyl in 5 ml of dimethylformamide was added thereto, followed by stirring for 24 hours. The reaction mixture is then concentrated to dryness, the residue is taken up in a mixture of water and ethyl acetate. The organic phase is decanted, dried over sodium sulphate and filtered. Ethyl acetate was then evaporated from the filtrate. The product is chromatographed on silica gel, eluting with a 9/1 mixture of dichloromethane and ethyl acetate. The desired product is then isolated from the eluate.

Yield of product: 500 mg

Step D 1 - [(2'-Aminobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one

450 mg of the product obtained in the preceding step are introduced into 10 ml of methanol and the resulting mixture is hydrogenated in the presence of 5% palladium on charcoal at ambient temperature. Filtration of the catalyst and evaporation of the solvent gave the desired product.

Yield: 240 mg

Grade E

225 ml of the product obtained in the preceding step and 0.1 ml of triethylamine are mixed in 4 ml of dichloromethane, 0.2 ml of trifluoromethylsulphonic anhydride are added to the mixture under argon at -78 ° C and the mixture is allowed to cool to room temperature. ambient temperature. The reaction mixture was washed with water and then with sodium bicarbonate solution, then dried and concentrated to give a white solid amorphous product.

Product yield: 150 mg.

NMR: 0.4 -1.3 ppm: m: 7 H: _CH3-CH2-CH2 -;

1.4 to 2.3 ppm: m: 10H: _{CH3-CH2-CH2-CH2} and cyclopentane; 4 - 4.8 ppm: system AB, 211: N-CH ₂ -C ₆ H ₄ -;

7.6 ppm: m, 8H: aromatic;

8.3 ppm: s: 1H: -NH;

ppm: a, H: CF ₃ SO ₃ H.

Example 17

2-n-Butyl 4-spirocyclopentane-1 - [(2'-trifluoromethylsulfonylaminomethylbiphenyl-4-yl) methyl] -2-imidazolin-5-one trifluoromethylsulfonate

General formula (I):

R 1 = CH ₂ NHSO ₂ CF ₃ , r ₂ = h,

R ₃ = n-C ₄ H _9,

CR4R5 = cyclopentane,

X = 0.

Starting from 1 - [(2'-aminomethylbiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one prepared in Step A of Example 14. 322 mg of this compound and 0.122 ml The triethylamine is introduced into 3.4 ml of dichloromethane at -70 ° C and 0.294 ml of trifluoromethylsulfonic anhydride is added. The mixture is then allowed to warm to ambient temperature, poured into dilute acetic acid, extracted with dichloromethane, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed twice on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate and then 99.5: 0.5.

Product yield: 90 mg Melting point: 90 ° C.

NMR: 0.4 -1.2 ppm: m: 7 H: _{-CH2-CH2 -CH3;}

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

4.1 - 5 ppm: 4 H: N-CH ₂ -C ₆ H ₄ - and -CH ₂ NH-C ₆ H ₄ -;

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

8.4ppm: s: 1H: NH.

Example 18

2-n-Butyl-1 - [(2 '- (N-hydroxycarbamoyl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one General Formula (I):

R 1 = -CO-NHOH, r ₂ = h,

R ₃ = n-C ₄ H _9,

CR4R5 = cyclopentane,

X = 0.

The compound prepared in Example 2 is released from its salt (trifluoroacetic acid salt) by removing this compound with a mixture of ethyl acetate and water and adjusting the pH of the solution to 6 by adding a saturated aqueous solution of sodium bicarbonate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give the free base as a white solid.

450 mg of this compound is then dissolved in chloroform, 860 ml of thionyl chloride are added thereto at 0 ° C, and the mixture is then stirred for two hours at ambient temperature. The solution is then concentrated and traces of thionyl chloride are removed by azeotropic distillation with toluene. The acid chloride thus obtained is then added dropwise as a solution in dimethylformamide to a solution containing 200 mg of hydroxylamine hydrochloride. After 2 hours at 0 ° C, the reaction mixture is concentrated, taken up in 100 ml of dichloromethane and 50 ml of water. The pH of the mixture is then adjusted to 7, the organic phase is extracted and dried over sodium sulfate. After filtration, the filtrate is concentrated. The product obtained is crystallized from a mixture of ethyl acetate, ethyl ether and hexane.

Product yield: 360 mg, mp 85 ° C.

Example 19 2-n-Butyl-4-spirocyclopentan-1 - [(2'-ureidobiphenyl-4-yl) methyl] -2-imidazolin-5-one

General formula (I):

R 1 = NHCONH ₂ , r ₂ = h,

R ₃ - nC ₄ H ₉ ,

CR4R5 = cyclopentane,

X = 0.

This compound was prepared using the method described by B. B. Kobu et al. in Org. Synth., 1957, 37, 52, from 1 - [(2'-aminobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one, prepared in Step A of Example 14 .

g of the latter product is dissolved in 50 ml of 6N hydrochloric acid, potassium isocyanate is added and the mixture is left at 5 DEG C. for 1 hour. The reaction mixture is then concentrated, taken up in ethyl acetate, washed with sodium bicarbonate solution and then with saturated sodium chloride solution. After drying over sodium sulfate, the solution is concentrated and the oil obtained is purified by chromatography on silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. Yield: 600 mg NMR: 0.85 ppm: t: 3H: CH ₂ CH _3;

1.35 ppm: sext, 2H: CH-CH _3;

1.6 ppm: quint, 2H, CH ₂ CH ₂ CH _3; 1.7-2 ppm: m, 8H: cyclopentane;

2.45 ppm: t: 2 H: _{CH2-CH2-CH2 -CH3;}

4.8 ppm: s, 2H, CH ₂ -C ₆ H ₄ -; 6.05 ppm: s, 2H, NH _2;

- 8 ppm: m, 9H: 8H aromatic + NHCO.

Examples 20 and 21 1 - [(2'-Carboxybiphenyl-4-yl) methyl] -2-n-propyl-4-spirocyclopentan-2-imidazolin-5-one and 1 - [(2'-N-cyanocarbamoylbiphenyl-4) yl) methyl] -2-n-propyl-4-spirocyclopentane-2-imidazolin-5-one

General formula (I):

R = CO-NH-CN,

R ₂ = H,

R ₃ ⁼ nC ₃ H ₇ ,

CR1R5 = cyclohexane,

X = 0.

Step A Ethyl butyrimidate hydrochloride, NH

X

CH ₃ - CH ₂ - CH ₂ - C, HCl

OC ₂ Hs

This compound was prepared as described by McElvain in J. Amer. Chem. Soc., 1942, 64, 1825-1827.

To a solution of hydrogen chloride gas (10.6 g) in ethanol (20 ml) was added butyronitrile (23 ml) at 0 ° C and after stirring at 0 ° C for 4 days, the reaction mixture was poured into 200 ml of anhydrous ether at 0 ° C with stirring. ; the precipitate formed is filtered off, washed with ether and dried under reduced pressure to give the desired product.

Yield of product: 25.8 g.

Step B The ethylbutyrimidate g of the imidate obtained in Step A was dissolved in 100 ml of dichloromethane and 50 ml of water, followed by the addition of 15 g of potassium carbonate. After decantation, the dichloromethane phase is dried over potassium carbonate and evaporated without heating.

Grade C

1-Aminocyclohexanecarboxylic acid ethyl ester

1-Aminocyclohexanecarboxylic acid is commercially available. 15 g of this amino acid is added at 0 ° C to a solution of 23 g of hydrogen chloride gas in 150 ml of anhydrous ethanol. The mixture was then heated to reflux for 5 hours, then concentrated to dryness and taken up in ether. The white solid obtained is filtered off, washed with ether and dissolved in a mixture of 300 ml of ether and 100 ml of water. The pH is adjusted to 9 by addition of potassium carbonate solution. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulphate and then evaporated to dryness. The desired product is thus obtained in the form of an oil.

Product yield: 14 g.

Step D 2-n-Propyl-4-spirocyclohexane-2-imidazolin-5-one 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 imidate obtained in step B is then added and the mixture is heated to reflux. After one hour and 30 minutes, the remaining imidate is added, with the last quarter of the imidate added after 4 hours. After heating to reflux for 7 hours, the reaction mixture is evaporated to dryness. The solid residue is taken up in hexane, filtered, washed with ether and dried to give the desired imidazolinone.

Yield: 10.3 g. Melting point: 124-125 ° C. IR (CCH1 _3):

715 cm ^1: C = O,

635 cm ^-1 : C = N.

Note: according to the infrared band values, the compound present in the solution is indeed 5-imidazolinone.

Grade E

2-n-Propyl-4-spirocyclohexane-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

To 0.24 g of sodium hydride (80% in oil) suspended in 10 ml of dimethylformamide was added 970 mg of the imidazolinone obtained in step D. After stirring for 20 minutes, under a nitrogen atmosphere, 1.91 g of 4-bromomethyl- was added over five minutes. 2'-tert-butoxycarbonylbiphenyl prepared according to European patent application 324 377. After stirring for one hour, the reaction mixture is concentrated to half its original volume under reduced pressure, and then 100 ml of ethyl acetate and then 20 ml of water are taken out. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulphate and then concentrated to dryness.

The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene. The desired product is obtained as a waxy solid. Yield: 2.10 g.

Infrared spectrum:

(CHCl,):

705 - 1715 cm ^-1 : C = O, C = O (ester, imidazolinone),

635 cr ¹ : C = N.

Analysis of the nuclear magnetic resonance spectrum confirms this structure.

Step F 1 - [(2'-Carboxybiphenyl-yl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 20)

1.25 g of the tert-butyl ester obtained in step E is stirred for 45 minutes in a mixture of 11 ml of dichloromethane and 15 ml of trifluoroacetic acid. After concentration under reduced pressure, the residue is taken up in ether. The solid residue is filtered off, washed with ether and then dried. The desired product is obtained as a white solid. Product yield: 1.04 g.

Melting point: 170-172 ° C.

Nuclear Magnetic Resonance Spectrum:

7.10 - 7.80 ppm; m, 8H: aromatic;

4.90 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -;

2.45 ppm: t: 2H: CH2-CH2-CH2-;

1.40 to 1.80 ppm m 12 H: spirocyclohexane + CH ₃ CH ₂ CH ₂ -;

0.90 ppm: t: 3 H: CH ₃ CH ₂ CH ₂ -;

1.60 g of the trifluoroacetate obtained above are dissolved in 150 ml of ethyl acetate and then 1N sodium hydroxide solution is added to adjust the pH to 5.0. The organic phase is then decanted, washed with saturated sodium chloride solution and then evaporated to dryness. The solid residue was taken up in ethyl ether, filtered and dried. Yield of product: 1.14 g.

Mp .: 208-210 ° C.

Step G 1 - [(2'-N-Cyanocarbamoylbiphenyl-4-yl) methyl] -2-propyl-4-spirocyclopentan-2-imidazolin-5-one (Example 21)

To a suspension of 300 mg of the compound obtained in the preceding step in 5 ml of dichloromethane was added 0.54 ml of thionyl chloride. After one hour and 30 minutes, the reaction mixture was concentrated under reduced pressure, then evaporated twice with benzene. The acid chloride thus obtained is dissolved in 2 ml of dioxane and 42 mg of cyanamide dissolved in 1 ml of dioxane containing 0.2 ml of 10N sodium hydroxide solution are added to the solution thus obtained. After one hour and 30 minutes, the reaction mixture is diluted with 150 ml of ethyl acetate, 20 ml of water, and the pH of the solution is adjusted to 5 by addition of acetic acid, the organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated.

The residue is chromatographed on silica gel, eluting with a 90: 8: 2 mixture of chloroform, methanol and acetic acid. The desired product is then isolated from the eluate.

Yield of product: 160 mg. Infrared spectrum:

(KBr):

150 cm ^-1 : C 25 N, Mass spectrum: MH ⁺ : 429. Nuclear Magnetic Resonance Spectrum:

7.20-7.70 ppm: m, 8H: aromatic;

4.75 ppm: s: 2 H: N-CH ₂ -C ₆ H _4;

2.40 ppm: t: 2 H: _CH3-CH2-CH, -;

1.30 to 1.80 ppm m 12 H CH ₃ CH ₂ CH ₂ - and spirocyclohexane;

0.85 ppm: t: 3H: _{CH3 -CH2 second}

Example 22

- [N-2 '- (4-Carboxy-1,3-thiazol-2-ylcarbamoylbiphenyl-4yl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one

General formula (I):

R ₂ = H,

R ₃ = nC ₃ H ₇₎

CK1R5 = cyclohexane,

X = O.

This compound was obtained from the compound obtained in Example 20. 2-Amino-4-ethoxycarbonyl-1,3-thiazole was prepared as described by B. Plouvier et al. in J. Heterocycl. Chem., 1989, 26, 6.1646.

Grade A

- [(N- (4-Carbethoxy) -1,3-thiazol-2-ylcarbamoyl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one

To a solution of 404 mg of the compound prepared in Example 20 and 190 mg of the thiazole derivative in 4 ml of dichloromethane and 1 ml of dimethylformamide were added 500 mg of benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate and 0.14 ml of triethylamine. The mixture was then stirred for 40 hours at ambient temperature and then for 7 hours at 50 ° C. The reaction mixture is then taken up in 50 ml of ethyl acetate and washed twice with potassium hydrogen sulphate solution and potassium sulphate solution, washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene. The desired product is then obtained from the eluate.

Yield of product: 120 mg. Melting point: 96-98 ° C.

Grade B

To 110 mg of the product obtained in the previous step, dissolved in 1 ml of methanol and 1 ml of dioxane, was added 0.5 ml of 2N sodium hydroxide solution. After stirring for 35 minutes, the reaction mixture was diluted with 10 mL of water and 60 mL of ethyl acetate, and then the pH of the reaction mixture was adjusted to 5 by the addition of 1N hydrochloric acid. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulphate and then concentrated. The residue was taken up in ether, filtered and dried. Yield of product: 100 mg.

Melting point: 145-148 ° C.

Nuclear Magnetic Resonance Spectrum: 8.0 ppm: s, 1H: H at position 5 of the thiazole

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

4.7 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -,

2.25 ppm: t: 2 H CH ₂ CH ₂ CH _3,

1.2 - 1.8 ppm: m: 12 H: cyclohexane and _{CH2 CH2 CH3;} 0.85 ppm: t: 3H: _{CH2 -CH2 third}

Example 23

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

General formula (I):

NH ₂

R 1 = CONH-C = N-CN r ₂ = h,

R ₃ nC ₄ H ₉ ,

CR ₄ R ₅ = cyclopentane,

X = O.

The acid chloride of the product obtained in Example 2 is prepared. 1 g of this compound is introduced into 20 ml of dichloromethane and the mixture is stirred in the presence of 1.8 ml of thionyl chloride at ambient temperature for 2 hours. After concentrating the reaction mixture, the residue is taken up with benzene and then concentrated again. The isolated crude product is then used further. 417 mg of dicyanodiamide, 0.5 ml of 10N sodium hydroxide solution, 0.5 ml of water and 10 ml of dioxane are added and the mixture is stirred for 5 hours. The reaction mixture was taken up in water and ethyl acetate, potassium carbonate was added and the mixture was concentrated. The residue is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. The desired product is then isolated from the eluate.

Yield of product: 100 mg. Melting point: 105 ° C.

Example 24

4-Benzylenen-2-n-butyl-1 - [(2'-carboxy) biphenyl-4-ylmethyl] -2-imidazolin-5-one

General formula (I):

R! = CO ₂ H,

R ₂ = H,

R ₃ ⁼ n-C ₄ H _9,

R 4 R ₅ = CH-C ₆ H _5,

X = O.

Step A 4- (1-Benzylidene-1-valerylaminomethylfamidomethyl) -2-biphenyl tert-butyl carboxylate

From N-Boc-alpha-dehydro- (L) -phenylalanine, alpha-dehydro- (L) -phenylalanine-N-carboxyanhydride was prepared as described by R. Jacquier et al. Tetrahedron Lett., 1984, 25, 26, 2775. To 430 mg of this compound dissolved in 5 ml of tetrahydrofuran is added 644 mg of 4-aminomethyl-2'-biphenyl tert-butyl carboxylate, and the mixture is stirred for two hours at ambient temperature. 1 ml of methyl orthovalerate is added and the mixture is evaporated to dryness under reduced pressure without heating. The residue is heated at 100 ° C for 3 hours, concentrated under reduced pressure and chromatographed on silica gel, eluting with hexane / ethyl acetate (4: 1). The white solid is then isolated from the eluate.

Yield: 580 mg.

Mp .: 154 ° C.

Nuclear Magnetic Resonance Spectrum:

1.3 ppm: s, 9H: t-Bu

0.85 ppm: t: 3 H: CH ₃ - (nBu);

1.35 ppm: sext, 2H: CH ₃ CH ₂ -;

1.45-2.20 ppm: m, 10H: CH 2 Cl 2 -CH 2 - and cyclopentane;

2.80 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

3.80 ppm: s: 2H: _CH2 - (pyrimidinone);

5.15 ppm: s: 2 H: _N-CH2 -;

7.25 ppm: m, 8H: aromatic.

Step B 4-Benzylidene-2-n-butyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-ylmethyl) -2-imidazolin-5-one

440 mg of the compound obtained in Step A are dissolved in 1 ml of acetic acid and the solution thus obtained is heated at 100 ° C for 30 minutes. The reaction mixture is then evaporated to dryness and the residue is chromatographed on silica gel, eluting with a 4: 1 by volume mixture of hexane and ethyl acetate. The desired product is then obtained as an oil. Product yield: 130 mg.

Nuclear Magnetic Resonance Spectrum:

4.9 ppm: s: 2 H: _CH2 (N-CH ₂ -C ₆ H ₄ -). Grade C

100 mg of the compound obtained in the preceding step are dissolved in 1000 μΐ of dichloromethane, and then 1 ml of trifluoroacetic acid is added, the mixture is stirred for 40 minutes at ambient temperature and then evaporated under reduced pressure. The residue was taken up several times with dichloromethane and then evaporated. Addition of ethyl ether precipitates a white precipitate.

Yield of product: 101 mg. 85 °.

Mass Spectrum: MH ⁺ : 439.

Nuclear Magnetic Resonance Spectrum. 0.82 ppm: t: 3H: _CH3 (nBu);

1.3 ppm: sext, 2H: CH ₃ CH ₂ -;

1.6 ppm: m, 2H, CH ₃ CH ₂ CH ₂ -;

2.6 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

4.82 ppm: s, 2H, CH ₂ -C ₆ H ₄ -; 7.05 ppm: s, IH, = CH-C ₆ H _3;

7.2-8.2 ppm: m, 13H: aromatic.

Example 25 4-Benzylidene-1 - [(2'-carboxy) biphenyl-4-ylmethyl] -2-phenyl-2-imidazolin-5-one

General formula (I):

R = CO ₂ H,

R ₂ = H,

R ₃ = c ₆ h ₅ , r ₄ r ₃ = ch-c ₆ h ₅ , x = o.

Step A 4-Benzylene-2-phenyl-5-oxazolone

1.8 g of hippuric acid and 0.4 g of potassium bicarbonate were dissolved in 4 ml of acetic anhydride and the solution thus obtained was heated at 50 ° C for a few minutes, after which the solution was cooled to ambient temperature. Then 1.49 g of benzaldehyde is added. After one hour at ambient temperature, 20 ml of distilled water at 80 ° C are added. The precipitated solid is centrifuged, washed with water and ethanol and then dried. The desired product is obtained as a yellow solid. Melting point: 215 ° C.

Nuclear Magnetic Resonance Spectrum:

7.4 ppm: s, IH, = CH-C ₆ H _5,

8.1-8.4 ppm: m, 10H: aromatic

Grade B

4- (1-Benzoylamino-1-benzylidenemethylamidomethyl) -2'-biphenyl tert-butyl carboxylate

A mixture containing 500 mg of the compound obtained in the preceding step, 570 mg of 4-aminomethyl-2'-biphenyl tert-butyl carboxylate and 10 ml of pyridine was heated at 110 ° C for 3 hours. The mixture was then evaporated under reduced pressure, the residue taken up in chloroform and then evaporated again. The residue is chromatographed on silica gel, eluting with hexane / ethyl acetate 3: 1 (v / v) and then 2: 1 (v / v). The desired product is obtained as a yellow solid.

Yield of product: 106 mg.

Nuclear Magnetic Resonance Spectrum:

1.1 ppm: s, 9H: t-Bu;

4.35 ppm: t: 2 H: _CH2 NH;

7.05 to 7.06 ppm m 19 H aromatic H-C ₆ H ₅ CH =;

8.65 ppm: t: 1 H: _NH-CH2;

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

Grade C

A mixture of 1.2 g of the compound obtained in the preceding step a

1.1 g of freshly melted sodium acetate in 5 ml of acetic acid is heated to reflux for 6 hours. The reaction mixture was then allowed to cool, whereupon an insoluble portion precipitated by the addition of chloroform. The filtrate was evaporated and the residue was chromatographed on silica gel, eluting with a 98/2 mixture of chloroform and methanol. The solid obtained was recrystallized from ethyl ether.

Yield of product: 692 mg. Melting point: 120 ° C.

Nuclear Magnetic Resonance Spectrum:

4.95 ppm: s, 2H, CH ₂ -C ₆ H ₄ -,

7.1 - 8.3 ppm: m, 19H, aromatic H + CH-C ₆ H _3rd

Examples 26 and 27 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 prepared in Example 5 and 58 mg of sodium hydride are introduced into 10 ml of dimethylformamide and the mixture is stirred for 30 minutes, 179 mg of methyl iodide and 2 ml of dimethylformamide are added and the mixture is stirred at ambient temperature for 4 hours. hours. The reaction mixture is then concentrated, the residue is taken up in water and extracted with ethyl acetate; The extract was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue is chromatographed on silica gel, eluting with hexane / ethyl acetate (6: 4). Two fractions are collected:

mg of the compound of Example 26 and 184 mg of the compound of Example 27.

Example 26

0.7 ppm: t: 3 H: CH ₃ - (n-Bu);

1.2 ppm: sext, 2H: CH ₃ CH ₂ -:

1.4 ppm: quint, 2H: CH ₃ CH ₂ CH ₂ -;

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

2.25 ppm: t: 2 H: _{CH3 CH2 CH2} CH2;

SK 283197 Β6

4.15 ppm: s: 3H: _NCH3;

4.6 ppm: s, 2H: -N-CH3-C1-;

ppm: System AA ', BB', 4H, CH ₂ -C ₆ H ₄ -;

7.3 - 7.75 ppm: m: 4 H: _{CH2-C 6} H ₄ -C ₆ H ₄ -.

Example 27

0.7 ppm: t: 3H: _CH3 (nBu);

1.15 ppm: sext, 2H: CH ₃ CH ₂ -;

1.38 ppm: quint, 2H: CH ₃ CH ₂ CH ₂ -;

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

2.2 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

3.35 ppm: s: 3H: _NCH3;

4.6 ppm: s: 2 H: N-CH ₂ -C ₆ H _4;

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

7.4 - 7.8 ppm: m: 4 H: _{CH2-C 6} H ₄ -C ₆ H ₄ -

Example 28 2-n-Butyl-6-spirocyclopentan-3 - [(2 '- (5-tetrazoyl) biphenyl-4-yl) methyl] -5,6-4 (1H) -dihydro-4-pyrimidinone

Step A Ethyl cyclopentylideneacetate

6 g of sodium hydride (80%) are introduced into 40 ml of benzene, and 57.1 ml of ethyl triethylphosphonoacetate are added dropwise thereto at a temperature below 35 ° C. After one hour at ambient temperature, 24.3 ml of cyclopentanone are added dropwise. The mixture is heated at 65 ° C for 15 minutes, then cooled to ambient temperature and the supernatant is decanted. 25 ml of benzene are added and after 15 minutes of heating to 65 ° C, the mixture is cooled and the supernatant is decanted again. This procedure is repeated once more. Evaporation of the supernatants gave 42 g of the desired product, which was distilled.

Boiling point: 102 DEG C. at a pressure of 1.243 kPa. Product yield: 22.8 g.

Step B (1-Aminocyclopentyl) acetamide

To 20 g of ethyl cyclopentylideneacetate prepared in the previous step is added 150 ml of ammonia gas and the mixture is then heated at 150 ° C for 72 hours. The product obtained after evaporation is purified by chromatography on silica gel, eluting with a dichloromethane / methanol / 20% ammonia (90/10/1) mixture. The product obtained is dissolved in dichloromethane and dried over sodium sulfate. Filtration and evaporation of the dichloromethane from the filtrate gave the desired product.

Yield: 7.2 g.

Step C 2-n-Butyl-6-spirocyclopentane-5,6-4 (1H) -dihydro-4-pyrimidinone

The mixture containing 4.57 g of (1-aminocyclopentyl) acetamide prepared in the previous step, 25 ml of methyl orthovalerate and a few drops of acetic acid was heated to 100 ° C for 18 hours. After evaporating the excess orthovalerate, the residue is taken up in a mixture of ethyl acetate and sodium bicarbonate, washed with brine, dried over sodium sulfate and purified by chromatography on silica gel, eluting with a dichloromethane / methanol (98/2; v / v) mixture.

Product yield: 5 g. NMR spectrum: 0.75 ppm: t: 3H: _CH3 (nBu);

1.2 ppm: sext, 2H: CH ₃ CH ₂ -;

1,3 - 1,8 ppm: m: 10 H: CH ₃ CH ₂ CH ₂ -, and cyclopentane;

ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -;

2.15 ppm: s: 2H: _CH2-CO;

9.95 ppm: p. e., 1H: NH.

This compound is the compound obtained in Step C of Example 10.

Grade D

2-n-Butyl-4-spirocyclopentane-1- [2 '- (triphenylmethyl-5-tetrazolyl) biphenyl-4-ylmethyl] -6-pyrimidinone

327 mg of sodium hydride (80%) in 30 ml of dimethylformamide and 1.5 g of the pyrimidinone prepared in the previous step are mixed under nitrogen atmosphere for 30 minutes, and 5.27 g of 4-bromomethyl-2 '- (triphenylmethyltetrazolyl) are added to the mixture. -5) biphenyl. After stirring at ambient temperature for 4 hours, the solvent is evaporated, the residue is taken up in ethyl acetate and water, dried over sodium sulphate and concentrated. The product obtained is purified by chromatography on silica gel, eluting with a 3: 7 mixture of ethyl acetate and hexane. Yield: 3.2 g.

Step E g of the compound obtained in the preceding step is introduced into 15 ml of methanol and the mixture is cooled in an ice-water bath, 4N hydrochloric acid (2.2 ml) is added and the mixture is stirred for 5 hours at ambient temperature. After evaporation, the residue is taken up in ethyl acetate and water, then sodium hydroxide is added to reach a pH of 11. Decontamination is carried out, the aqueous phase is washed with ethyl ether and toluene and then again with ether. The aqueous phase is adjusted to pH 5 by addition of dilute hydrochloric acid, the aqueous phase is then extracted with ethyl acetate, dried and concentrated. The product obtained is purified on silica gel, eluting with a 95: 5 mixture of dichloromethane and methanol. The desired product is then isolated from the eluate. Yield of product: 800 mg.

NMR spectrum: 0.85 ppm: t: 3H: _CH3 (nBu);

1.30 ppm: sext, 2H: CH ₃ CH _2;

1.40-1.95 ppm: m, 10Η: cyclopentane and CH ₂ -CH ₂ -CH ₂ -CH ₃ ;

2.30 ppm: t: 2 H: _CH2-CH-CH2, CH ₃ -:

2:55 ppm: s: 2H: _CH2-CO;

4.95 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -; 7.05 ppm: m: 4 H: _{CH2-C 6} H ₄ -;

7:55 - 7.82 ppm: m: 4 H: _{CH2-C 6} H ₄ · ^ -.

Example 29 2-n-Butyl 3 - [(2'-carboxybiphenyl-4-yl) methyl] -5-spirocyclopentane-5,6-5 (1H) -dihydro-4-pyrimidinone trifluoroacetate

Grade A

Ethyl-1-anocyclopentanecarboxylate

This compound was prepared as described in Helv. Chim. Acta, 1952, 35, 7, 2561. 9.2 g of sodium are dissolved in 200 ml of absolute ethanol. Half of the sodium ethylate solution thus obtained is poured into a flask. To the remaining half was added 24.88 g of ethyl cyanoacetate and the mixture was brought to reflux.

43.19 g of 1,4-dibromobutane was poured into another flask, and then sodium ethylate and 1,4-dibromobutane were added dropwise to the flask. After completion of the addition, the contents were maintained at reflux for 2 hours. After evaporation, the residue is taken up in a mixture of ethyl ether and water, washed with saturated sodium chloride solution and then dried. The product obtained is distilled at a temperature in the range of 115-120 ° C at a pressure of 1 mm Hg.

Product yield: 24 g.

Grade B

Ethyl 1-aminomethylcyclopentanecarboxylate

This compound is prepared by catalytic hydrogenation of ethyl 1-cyanocyclopentanecarboxylate.

g of ethyl 1-kaynocyclopentanecarboxylate was introduced into 200 ml of ethanol containing 10% ammonia, and the resulting mixture was hydrogenated at 60 ° C under 10 MPa in the presence of alumina for 72 hours. After filtration through celite and evaporation of the filtrate, the residue is chromatographed on silica gel, eluting with a dichloromethane / 20% ammonia (98: 2: 0.5 by volume) mixture. Yield: 12.8 g.

Step C 2-n-Butyl-5-spirocyclopentane-5,6-4 (1H) -dihydro-4-pyrimidinone

A mixture of 13.12 g of the compound obtained in the preceding step and 13.5 g of ethylvalerimidate in 100 ml of xylene containing a few drops of acetic acid is heated to reflux for 13 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and 10% sodium carbonate solution, dried and concentrated. Product yield: 14 g.

M.p .: 89-91 ° C.

NMR spectrum: 0.80 ppm: t: 3H: _CH3 (nBu);

1,10 1,80 ppm: m: 12H: _CH3-CH2-CH2 and cyclopentane; 2.05 ppm: t, 2H: CH ₃ -CH ₂ -CH ₂ -CH ₂ -;

3.20 ppm: s: 2 H: _CH2 (pyrimidinone);

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

Step D 2-n-Butyl-5-spirocyclopentan-3 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -5,6-4 (1H) -dihydro-4-pyrimidinone

500 mg of the product obtained in the preceding step are introduced into 40 ml of dimethylformamide under a nitrogen atmosphere and in the presence of 115 mg of sodium hydride (80% in oil), and the mixture is stirred at ambient temperature for 30 minutes. 1.08 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl are then added and the resulting mixture is stirred for 2 hours. After evaporation, the residue is taken up in ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated, and the residue is chromatographed on silica gel, eluting with a 3: 7 mixture of ethyl acetate and hexane. Yield: 280 mg .

Grade E

250 ml of the tert-butyl ester prepared in the previous step are dissolved in 10 ml of dichloromethane. The solution is cooled in an ice-water bath, 5 ml of cold trifluoroacetic acid are added and the mixture is stirred in the cold for one hour and then at ambient temperature for one hour. The reaction mixture was then evaporated under reduced pressure. The residue was taken up in ethyl ether and then evaporated. This operation is repeated three times, after which the evaporation residue is taken up in hexane, stirred and the hexane is decanted. After addition of ether, the precipitate formed is filtered off. Product yield: 190 mg.

Mp: 153-155 ° C.

Nuclear Magnetic Resonance Spectrum:

0.85 ppm: t: 3H: _CH3 (nBu);

1.35 ppm: sext, 2H: CH ₃ CH ₂ -;

1.45-2.20 ppm: m, 1 OH: CH ₃ -CH ₂ -CH ₂ - and cyclopentane;

2.80 ppm: t: 2 H: _{CH3 -CH2 -CH2 -CH2} -; '

3.80 ppm: s: 2 H: _CH2 (pyrimidinone);

5.15 ppm: s: 2 H: _N-CH2 -;

7.25 ppm: m, 8H: aromatic.

Claims (4)

PATENT CLAIMS A nitrogen-containing heterocyclic derivative of the general formula (Π) 1 (CH 2) N AA H in which R ₃ is H, unsubstituted alkyl of 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms and substituted by at least one halogen atom, an alkenyl group having 2 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, phenyl, a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms, a phenylalkenyl group wherein the alkenyl moiety contains 2 or 3 carbon atoms, wherein the phenyl groups and the phenyl moieties are unsubstituted or at least once substituted with substituents selected from the group consisting of halogen, (C 1 -C 4) alkyl, (C 1 -C 4) haloalkyl, (C 1 -C 4) polyhaloalkyl, (C 1 -C 4) hydroxy or (C 1 -C 4) alkoxy, where z = 1 and t = 0, then R ₄ and R ₅ independently of one another represent an alkyl group having 1 to 6 carbon atoms, a phenyl group, a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms, said alkyl, phenyl and phenylalkyl groups is unsubstituted or at least once substituted with substituents selected from the group consisting of halogen atoms, (C 1 -C 4) fluoroalkyl, hydroxy and (C 1 -C 4) alkoxy or R 4 and R ₅ together form a group of the formula = CR ₇ R ₈ in which R ₇ is H, alkyl of 1 to 4 carbon atoms or phenyl, and _R is alkyl of 1 to 4 carbon atoms or phenyl, or R 4 and R ₅ together are either a group of formula _{(CH2) n,} or a group of formula (CH ₂ ) _p Y (CH ₂ ) q in which Y represents either an oxygen atom, but or a sulfur atom or a carbon atom substituted by a C1-C4 alkyl group, a phenyl or a phenylalkyl group in which the alkyl moiety contains 1 to 3 carbon atoms, or a N-Rfo group in which R6 represents a hydrogen atom, an alkyl group containing 1 up to 4 carbon atoms, phenylalkyl in which the alkyl radical contains 1 to 4 carbon atoms, alkylcarbonyl in which the alkyl radical contains 1 to 4 carbon atoms, a haloalkylcarbonyl radical in which the alkyl radical contains 1 to 4 carbon atoms, benzoyl, an alpha-aminoacyl or N-protecting group, or R ₄ and R ₅ together with the carbon atom to which they are attached form an indane or adamantane group, p + q represents m, n represents an integer from 2 to 11, m represents an integer from 2 to 5, X is an oxygen or sulfur atom, with the proviso that R _{3 is} not a phenyl group, when R 4 and R ₅ each represent methyl; when z = 0 and t = 1, then X, IL, and R ₅ have the meanings given, provided that R _{3 is} not a phenyl group, when R 4 and R _{5 are} each a methyl group, and when z = t = 0 and X has said then R 4 and R ₅ together form - (CH ₂ ) ₄ - with the proviso that R ₃ does not represent a substituted phenyl group when X is an oxygen atom and its acid addition salts. A nitrogen-containing heterocyclic derivative according to claim 1, in which X represents an oxygen atom and R ₃ represents an n-butyl group. 3. A compound according to claim 1, which is 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride. A process for the preparation of a nitrogen heterocyclic derivative according to any one of claims 1 to 3, characterized in that a compound of formula (13) is reacted in which R 4 and R ₅ have the meanings given in claim 1 for formula (II), A represents a hydroxy, amino or OR 'group in which R' represents a hydrogen atom or a (1-4C) alkyl group with a compound of formula (14) R 3 -B (14), wherein R ₃ is as defined in claim 1 and B is C (OR) ₃ , C (= NH) OR, or COHal, wherein R is C 1 -C 4 alkyl and Hal represents a halogen atom, preferably a chlorine atom, the compound so obtained is optionally further reacted with Lawesson's reagent, and optionally the compound thus obtained is converted into an acid addition salt.