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LV10439B - N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing them - Google Patents

N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing them Download PDF

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Publication number
LV10439B
LV10439B LVP-93-147A LV930147A LV10439B LV 10439 B LV10439 B LV 10439B LV 930147 A LV930147 A LV 930147A LV 10439 B LV10439 B LV 10439B
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alkyl
phenyl
compound
formula
group
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LVP-93-147A
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LV10439A (en
Inventor
Bernhart Claude
Breliere Jean-Claude
Clement Jacques
Nisato Dino
Perreaut Pierre
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Sanofi Elf
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Priority claimed from FR9003563A external-priority patent/FR2659967B1/en
Priority claimed from FR9010144A external-priority patent/FR2665702B1/en
Application filed by Sanofi Elf filed Critical Sanofi Elf
Publication of LV10439A publication Critical patent/LV10439A/en
Publication of LV10439B publication Critical patent/LV10439B/en

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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

Heterocyclic N-substituted derivatives of formula (I) and their salts are new. R1, R2 = H, 1-6C alkyl, 1-4C alkoxy, NH2, NH2CH2-, COOH, (1-4C alkoxy)carbonyl, CN, tetrazolyl, methyltetrazolyl, methylsulphonylamino, trifluoromethyl sulphonylamino(methyl), N-cyanoacetamide, N-hydroxy- acetamide, N-((4-carboxy)-1, 3-thiazol-2-yl) acetamido, ureido, 2-cyanoguanidinocarbonyl, 2-cyano-guanidino-methyl, imidazol-1-yl-carbonyl, 3-cyano-2-methyl isothioureidomethyl, with the proviso that R1 and R2 are not both H. R3 = H, 1-6C alkyl (optionally substituted by one or more halogen, 2-6C alkenyl, 3-7C cycloalkyl, Ph, phenyl-(1-3C alkyl) or (2-3C alkenyl)phenyl; the Ph groups are optionally substituted by at least 1 halogen, 1-4C alkyl, halogen-(1-4C alkyl), polyhalogeno-(1-4C alkyl), OH or 1-4C alkoxy. R4, R5 = 1-6C alkyl, Ph, phenyl-(1-3C alkyl), the alkyl, phenyl and phenylalkyl groups being optionally substituted by one or more halogen, perfluoro-(1-4C alkyl), OH or 1-4C alkoxy. Or R4 and R5 together form =CR7R8, (CH2)n or (CH2)pY(CH2)q. R7 = H, 1-4C alkyl or Ph; R8 = 1-4C alkyl or Ph. Y = O, S, C (substituted by 1-4C alkyl, Ph or phenyl-(1-3C alkyl) or NR6. R6 = H, 1-4C alkyl, phenyl-(1-3C alkyl), 1-4C alkylcarbonyl, halogeno-(1-4C(alkyl)carbonyl, polyhalo-(1-4C alkyl)carbonyl, -COPh, alpha-aminoacyl or an N-protecting group. Or R4 and R5 together form indane or adamantane. p + q = m; n = 2-11; m = 2-5; X = O or S. z and t = 0 or one is 0 and the other is 1. Specifically claimed is 2-n-butyl-4- spirocyclopentane -1-((2'-(5-tetrazolyl) biphenyl-4-yl)methyl) -2-imidazolin-5-one.

Description

- 1 - 05 10 15 20 25 LV 10439
The present invention relates to N-substituted heterocyclic derivatives, to their preparation and to the pharmaceutical compositions in which they are present. The compounds according to the invention anta-gonize the action of angiotensin II, which is a peptide hormone of the formula H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH Angiotensin II is a potent vasopressor and the biologically active product of the renin-angiotensin system: renin acts on the angiotensinogen of the plasma to producē angiotensin I, which is converted to angiotensin II by the action of the angiotensin I converting enzyme. The compounds of the present invention are non-peptide compounds which antagonize angiotensin II. By inhibiting the action of angiotensin II on its recep-tors, the compounds according to the invention prevent especially the increase in blood pressure produced by the hormone-receptor interaction; they also have other physiological actions on the Central nervous system. Thus the compounds according to the invention are useful in the treatment of cardiovascular cora-plaints such as hypertension and heart failure, as well as in the treatment of complaints of the central nervous system and in the treatment of glaucoma and dia-betic retinopathy. The present invention relates to compounds of the formula 30
2 R4 R57UCH2)t zfCH?) N
I ch2
Ri
in which: - Rx and Ra are sirailar or different and are each inde-pendently hydrogen or a group selected from a Οχ-Οβ alkyl, a C^-C* alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is cx”Cd/ a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trif luoromethylsulfonylaminomethyl, an N-cyano-acetamide, an N-hydroxyacetamide, an N-(4-carboxy-l,3-thiazol-2-yl)acetamide, " a ureido, a 2-cyano-guanidinocarbonyl/ a 2-cyanoguanidinoraethyl, an irai-dazol-l-ylcarbonyl and a 3-cyano-2-methylisothio-ureidomethyl, with the proviso that at least one of the substituents Rx or R2 is other than hydrogen; - R3 is a hydrogen, a Cx-Ce alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, a C2-Ce alkenyl, a C3-Ca cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C^Cj, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C^-C* alkyl, a Ci-C4t halogenoalkyl, a C^-C^ polyhalogenoalkyl, a hydroxyl or a CX-CA alkoxy; - R4 and R3 are each independently a C^-C^ alkyl, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen - 3 - LV 10439 atoms or by a group selected from a perfluoro- alkyl, a hydroxyl and a C1-C4 alkoxy; - or R4 and Rs together form a group of the formula =CR7Re, in which R7 is hydrogen, a <2χ-<24 alkyl or a phenyl and Rs is a Cx-C4 alkyl or a phenyl; - or else R4 and Rs together are either a group of the formula (CH2)„ or a group of the formula (CH2)pY-(CH2)q/ in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cx-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, or a group N-R6, in which Rs is a hydrogen, a Cx-C4 alkyl, a phenylalkyl in which the alkyl is Cx-C3, a Cx-C4 alkylcarbonyl, a Cx-C4 halo-genoalkylcarbonyl, a Cx-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R^ and Rs, together with the carbon atom to which they are bonded, form an indane or an adaman-tane; - p + q = m; - n is an integer between 2 and 11; - m is an integer between 2 and 5; - X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one; and their salts.
If a compound according to the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound.
The salts of the compounds of formula (I) according to the present invention include those with mineral or organic acids which permit separation or suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a campho-sulfonic acid, and acids which form pharmaceutically acceptable salts such as the hydrochloride, the bydro- 4 bromide, the sulfate, the hydrogensulfate, the dihydro-genphosphate, the methanesulfonate, the methylsulfate, the maleate, the fumarate and the naphthalene-2-sulfo-nate.
The salts of the compounds of formula (I) also include the salts with organic or mineral bases, for example the salts of alkali or alkaline earth metāls, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, 'or else the salts of arginine, lysine or any physiologically acceptable amine.
According to the present description and in the claims which follow, halogen atom is understood as meaning a bromine, chlorine or fluorine atom; N-pro-tecting group (also designated by Pr) is understood as meaning a group conventionally used in peptide chemis-try for affording temporary protection of the amine group, for example a Boc, Z or Fmoc group or a benzyl group; esterified carboxyl group is understood as meaning an ester which is labile under appropriate conditions, such as, for example, a methyl, ethyl, benzyl or tert-butyl ester. "Alkyl" denotes linear or branched saturated aliphatic hydrocarbon radicals.
The compounds of formula (I) in which Rx is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen are preferred compounds.
The compounds of formula (I) in which R4 and Rs together form, with the carbon to which they are bonded, a cyclopentane or a cyclohexane are preferred compounds.
Likewise, the compounds of formula (I) in which R3 is a linear alkyl .group are preferred compounds.
The compounds of formula (I) in which X is an - 5 - LV 10439 oxygen atom are also preferred compounds.
Finally, the compounds of formula (I) in which z = t = 0 are preferred compounds. 05
The following abbreviations are used in the description and in the Examples:
Et : ethyl nBu, tBu : n-butyl, tert-butyl DMF : diTnethylformamide THF : tetrahydrofuran 10 DCM : dichloromethane NBS : N-bromosuccinimide DCC : dicyclohexylcarbodiimide DIPEA : diisopropylethylamine ether : ethyl ether 15 TFA : trifluoroacetic acid Z : benzyloxycarbonyl
Boc : tert-butoxycarbonyl BOP : benzotriazolyloxytrisdimethylaminophospho- nium hexafluorophosphate 20 Fmoc : fluorenylmethoxycarbonyl
The present invention further relates to the method of preparing the compounds (I). In said method: al) a heterocyclic derivative of the formula 25 K57L(CH2)t z(CH?) N 2
H 30 in which z, t, R3, R4 and Rs are as defined above for (I), is reacted with a (biphenyl-4-yl)methyl derivative of the formula 35 ” 6
in which Hal is a halogen atom and R'x and R'a are res-pectively either Rx and Ra or a precursor group of and Ra; bl) if appropriate, the resulting compound of the formula
4 is treated with Lawesson's reaģent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulf ide]; and cl) the compound obtained in al) or bl), of the formula
in which X is an oxygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the - 7 - LV 10439 groups R'x and/or R'a to the groups Rx and/or Ra respectively.
Among the compounds 2, the compounds (II) as defined below are novel.
Thus the present invention further relates to the compounds (II) of the formula R4
in which: - R3 is a hydrogen, a Cx-C6 alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, a Ca-Ce alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cx-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cx-C4 alkyl, a Cx-C4 halogenoalkyl, a Cx-C4 polyhalogenoalkyl, a hydroxyl or a Cx-C4 alkoxy; - R4 and Rs are each independently a Cx-C6 alkyl, a phenyl or a phenylalkyl in which.the alkyl is Cx-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a Cx-C4 perfluoro-alkyl, a hydroxyl and a Cx-C4 alkoxy; - or R4 and Rs together form a group of the formula =CR^Ra, in which Rv is hydrogen, a Cx-C4 alkyl or a phenyl and Ra is a CX-CA alkyl or a phenyl; - or else R4 and Rs together are either a group of the formula (CHj,),, or a group of the formula (CHa)pY- 8 (°Η3)ς,/ in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cx-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, or a group N-Re, in which R6 is a hydrogen, a cx-C4 alkyl, a phenylalkyl in which the alkyl is Cx-C3, a 0χ-<:4 alkylcarbonyl, a Cx-C4 halo-genoalkylcarbonyl, a Cx-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and Rs, together with the carbon atom to which they are bonded, form an indane or an adaman-tane; - p + q = m; - n is an integer between 2 and 11; - m is an integer between 2 and 5; - X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one; with the limitation that - if z and t are zero and X is an oxygen atom, R4 and Rs are other than » a C1-C(5 alkyl, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, said alkyl, phenyl and phenyl-alkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a Cx-C4 perfluoroalkyl, a hydroxyl and a Cx-C4 alkoxy; • or R4 and Rs together are other than a group N-R* in which R6 is a hydrogen, a Cx-C4 alkyl or a phenylalkyl in which the alkyl is Cx-C3; and • n is other than 6; and - if z = 1 and R3 is a phenyl, R4 and Rs are each other than a methyl.
Araong the derivatives (II), the compounds in which z = t = 0 and R4 and Rs, together with the carbon to which they are bonded, form a cyclopentane are pre- 9 LV 10439 ferred compounds. These compounds have the formula
H in which X is an oxygen atom or a sulfur atom and R3 is a hydrogen, a C^~C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-Ce alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is 0Χ“03, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C^-C* alkyl, a halogenoalkyl, a C^-C* polyhalogenoalkyl, a hydroxyl or a C^-C* alkoxy.
The compounds (II) in which z = 0 and t = 1, of the formula
H in which R3, R4, Rs and X are as defined above for (II), are preferred compounds.
Finally, the compounds (II) in which z = 1 and t = 0, of the formula 10 10 r4 R5
t ;
H in which: - R3 is a hydrogen, a Cx-Ce alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, a C^-C* alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cx-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or r polysubstituted by a halogen atom, a Cx-C4 alkyl, a 0Χ-<2Λ halogenoalkyl, a Cx-C4 polyhalogenoalkyl, a hydroxyl or a Cx-C4 alkoxy; - R4 and Rs are each independently a Cx-Ce alkyl, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a CX-CA perfluoro-alķyl, a hydroxyl and a Cx-C4 alkoxy? - or R4 and Rs together form^ a group of the formula =CR7Re/ in which R2 is hydrogen, a Cx-C4 alkyl or a phenyl and Ra is a Cx-C4 alkyl or a phenyl; - or R4 and Rs together are either a group of the formula (CH;,),, or a group of the formula (CH2)pY-(CH2)q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cx-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, or a group N-Re, in which Re is a hydrogen, a Cx-C4 alkyl, a phenylalkyl in which the alkyl is Cx-C4, a Cx-C4 alkylcarbonyl, a Cx-C4 halo-genoalkylcarbonyl, a Cx-C4 polyhalogenoalkylcarbonyl, - 11 - LV 10439 a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and Rs, together with the carbon atom to which they are bonded, form an indane or an adaman-tane; 05 - p + q = m; - n is an integer between 2 and 11; - ra is an integer between 2 and 5; and - X is an oxygen atom or a sulfur atom; with the limitation that R3 is other than a phenyl if 10 R4 and Rs are each a methyl, are preferred compounds. The derivatives 2 are prepared by known meth-ods. For .example, it is possible to use the method described by Jacquier et al. (Buli. Soc. Chim. France, 15 1971, 3, 1040-1051) and by Brunken and Bach (Chem. Ber., 1956, 89, 1363-1373) and to react an alkyl imidate with an amino acid or its ester in accordance with the following reaction scheme: 20
Ra (CH2)z-C02R’ / N R5 (CH2)t —NH2
NH + R3 - -> 0R 5' 6 25 (CH2)t z(CH2) ŅL J-53 30
I H 2 in which R is a Cx-C^ alkyl, R' is hydrogen or a C^-C^ alkyl and R3, R4, Rs, z and t are as defined above for (I). 35 12
This reaction is carried out in an acid mediuīn by heating in an inert solvent such as xylene or toluene.
According to another procedure, the compound 2 can be prepared by reacting an aminoalkylamide (5") with an alkyl ortho-ester (10) in an acid mediuīn in accordance with the following reaction scheme: R4 (CH2)2-C0NH2 + R3-C(0R)3 -> 2 RS (CH2)t-NH2 £1 10 in which R is a C^-C* alkyl.
Using a procedure described by H. Takenaka et al. (Heterocycles, 1989, 29.(6), 1185-89), it is also possible to prepare the compound 2 by reacting an acid halide of the formula R3-C0-Hal 12 in which Hal is a halogen, preferably chlorine, with the derivative 5".
The reaction is carried out in a basie medium. More particularly, according to another object of the present invention, the compound 2 is prepared by a method which comprises reacting a compound of the formula R3-B 14 in which B is - a group C(OR)3 - 13 - LV 10439
^NH - a group c___ 0r
^OR - a group COHal 05 R being a C^-C^ alkyl and Hal denoting a halogen atora, preferably chlorine, with a compound of the formula 10
(CH2)2C0A X R5 (CH2)tNH2 13 in which A is an OH group, an NH2 group or a group OR', R' being hydrogen or a C^-C^ alkyl, and then, if appropriate, treating the resulting compound with 15 Lawesson's reaģent (2,4-bis(4-methoxyphenyl)-l,3-di-thia-2,4-diphosphetane disulfide).
The (biphenyl-4-yl)methyl derivative (2) is prepared by a method described in European patent application 324 377. 20 The conversion of a group R1 x and/or R'2 to a group Rx and/or R2 is effected by methods well known to those skilled in the art. Thus, if the compound (I) to be prepared possesses a group Rx and/or R2 = carboxyl, R'^ and/or R'2 are an esterified carboxyl group. If 25 the compound (I) to be prepared possesses a group Rx and/or R2 = tetrazolyl, R'x and/or ,.R'2 can be either a tetrazolyl protected for example by a trityl group, or a cyano group which will subsequently be replaced with a tetrazolyl group protected if necessary by a trityl. 30 The conversion of the . cyano group to a tetrazolyl can be effected with an azide, for example tributyltin azide or sodiura azide.
It is also possible to use groups R'^ and/or R'a such as nitro, carboxyl,' cyano or acid chloride groups and then to convert them by reactions well known 35 14 to those skilled in the art to give groups Rx and/or Ra as defined for the compound (I).
Thus, if R\ and/or R'2 are a carboxyl, they can be converted to Rx and/or Ra in the form of an imidazol-l-ylcarbonyl or else an N-(4-carboxy-l,3-thiazol-2-yl)acetamide.
The group R'^ and/or R'., in the form of an acid chloride can be converted to Rx and/or Ra in the form of N-hydroxyacetamide, N-cyanoacetamide, ureido or 2-cyanoguanidinocarbonyl.
The group R'A and/or R'a in the form of a nitro can be converted to amino, from which Rx and/or Ra is prepared in the form of methylsulfonylamino, trifluoro-methylsulfonylamino or trifluoromethylsulfonylamino-methyl.
The group R'x and/or R'a in the form of a cyano can be converted to aminomethyl, from which a 3-cyano-2-methylisothioureidomethyl is prepared (according to C. Gordon et al., J. Org. Chem., 1970, H(6), 2067-2069) or a 2-cyanoguanidinomethyl is prepared (according to R.W. Turner, Synthesis, 1975, 332).
Step al) is carried out in an inert solvent such as DMF, DMSO or THF, in a basie medium, for example in the presence of potassium hydroxide, a mētai alcoholate, a mētai hydride, calcium carbonate or tri-ethylamine.
Step bl) is carried out by heating under nitrogen in a solvent such as toluene, according to the method deseribed by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061.
In the deseription below, the method comprising steps al, bl and cl is referred to as method 1.
Alternatively, the compounds (I) can be prepared by another method, which is also a subject of the present invention. In this method: - 15 - LV 10439 a2) an amino acid of the formula R4 (CH2)t-NHPr *5 (CH2)z C00H · in which z, t, R4 and Rs are as defined above for (I), and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methylamine derivative of the formula h2n-
8 in which R'x and R'a are respectively either Rx and Ra or a precursor group of Rx and Ra; b2) after deprotection of the amine, the resul-ting compound of the formula R’2 R’i R4 0 -J . Λ-, 9 yC- (ch2)z-c-nh-ch2—^ \
R5CCH2)t-NH2 \=J \=J is then treated with an alkyl ortho-ester of the formula R3C(OR)3 (10), in which R3 is as defined above for (I) and R is a Cx-C4 alkyl; c2) if appropriate, the resulting compound of the formula 16
is treated with Lawesson's reaģent [ 2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide]; and d2) the compound thus obtained in b2 or c2, of the formula R5_J_iC!l2)t
is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'a and/or R'^ to the groups R2 and/or Rj^ respectively.
The compounds 7 are known or are prepared by known methods (Cheraistry of the Amino Acids, Greenstein and Winitz, published by John Wiley, 1961, vol. I, p. 697) .
The compounds £ are prepared according to Euro-pean patent application 324 377. Step a2) is carried out under the usual conditions for the coupling of an acid with an amine, for example in the presence of BOP and DIPEA.
Step b2), which is the cyclization of the com- - 17 - LV 10439 pound £ in the presence of 10, is carried out according to Jacquier et al. (Buli. Soc. Chim. France, 1971, (3), 1040-1051) and according to Brunken and Bach (Chem. Ber., 1956, 89/ 1363-1373).
In the description below, the method comprising steps a2 to d2 is referred to as method 2.
In one variant of method 2, in step b2., it is possible, if appropriate, to isolate an intermediate £! of the formula
R4 R5-C-(CH2)
(CH2)c-N and then to prepare the compound 4 by cyclization in an acid medium.
In another variant of method 2, in order to prepare a compound (I) in which R4RS is a group =CR7Ra, an amino acid of the formula CH2-(CH2)t-NHC0R3 Zi
(CH2)z-C00H can be reacted in an acid medium with an aldehyde or a ketone of the formula R.,CQRa in which R7 and Ra are as defined above for (I), and the product is then reacted with the compound 8 to give a compound of the formula 05 18
0 II
R7RSC=C-(CHO,-C-NH-CH l (CH2)t-NHC0R3
The cyclization of this compound in an acid medium leads to the compound 1. 10
In this method, to prepare a compound (I) in which Rx and/or Ra are a carboxyl group, the substi-tuents R/1 and/or R'a are preferably a tert-butoxycar-bonyl group. 15 R'l R1
Finally, another alternative for the prepara-tion of the compounds (I) according to the invention in which z and t are equal to zero is the photooxidation method, which is also a subject of the present invention.
In this last method: a3) a (biphenyl-4-yl)methyl derivative of the formula 20
2 25 in which Hal is a halogen atom and.R'^ and R'a are res-pectively either Rx and R2 or a precursor group of Rx and R3, is reacted with an imidazole derivative of the formula 30 R4
R5 N R3
H 35 11 - 19 - LV 10439 in which R3, R4 and RB are as defined above for (I), in the presence of oxygen and UV irradiation and in a basie medium; b3) if appropriate, the resulting compound of the formula
is treated with Lawesson's reaģent [2,4-bis(4-raethoxy-phenyl) -1,3-dithia-2,4-diphosphetane 2,4-disulfide]; and c3) the compound thus obtained in b3 or c3, of the formula
Ra
is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'x and/or R'a to the groups R1 and/or Ra respectively.
The imida2ole derivative 11 is either commer-cially available, or known, or is prepared by known methods indicated above for the preparation of the com-pounds 2.
Step a3) is carried out in an inert solvent such as, for example, DMF; to facilitate the reaction, 20 a photosensitizing product such as methylene blue can be added.
In the description below, the method comprising steps a3) to c3) is referred to as method 3.
The compounds (I) according to the invention in which R4 and Rs together are a group of the formula (CH2)pY(CH2)q in which Y is an NH group can be prepared by catalytic hydrogenolysis of a corresponding compound (I) in vhich Y is a group N-R^.·, Re being a benzyl.
The affinity of the products according to the invention for angiotensin II receptors was studied in a tēst for the binding of angiotensin II, labeled with iodine 125, to rat liver membrane receptors. The method used is the one described by S. KEPPENS et al. in Biochem. J., 1982, 208. 809-817.
The IC50, namely the concentration which gives a 50% displacement of the labeled angiotensin II bound specifically to the receptor, is measured. The ICso of the compounds according to the invention is less than 10-« M.
Also, the effect of the products according to the invention as angiotensin II antagonists was obser-ved on different animal species in which the renin-angiotensin system had been activated beforehand (C. LACOUR et al., J. Hypertension, 1989, 2 (suppl. 2), S33-S35).
The compounds according to the invention are active after administration by different routes, espe-cially after oral administration.
No signs of toxicity are observed with these compounds at the pharmacologically active doses.
Thus the compounds according to the invention can be used in the treatment of various cardiovascular complaints, especially hypertension, heart failure and venous insufficiency, as well as in the treatment of - 21 - LV 10439 glaucoma, diabetic retinopathy and various complaints of the Central nervous system, for example anxiety, depression, memory deficiencies or Alzheimer's disease.
The present invention further relates to phar-05 maceutical compositions containing an effective dose of a compound according to the invention, or of a pharraa-ceutically acceptable salt, and suitable excipients. Said excipients are chosen according to the pharma-ceutical form and the desired mode of administration. 10 In the pharmaceutical compositions of the pre sent invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula I above, or their salts if 15 appropriate, can be administered to animals and humāns in unit forms of administration, mixed with conven-tional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms 20 for oral administration, such as tablets, gelatin cap-sules, powders, granules and Solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administra-25 tion and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
To achieve the desired prophylactic or thera-peutic effect, the dose of active principle can vary 30 between 0.01 and 50 mg per kg of body weight per day.
Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered l to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 35 22 1 to 2500 mg.
When a solid composition irr the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lac-tose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously. A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules. A preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient in conjunction with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring and an appropriate color.
The water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting aģents, or suspending aģents such as poly-vinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using sup-positories prepared with binders which melt at the rectal temperature, for example cacao butter or poly-ethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline Solutions or sterile and injectable Solutions which contain phar-macologically compatible dispersants and/or wetting aģents, for example propylene glycol or butylene glycol. - 23 - LV 10439
The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In addition to the products of formula I above or one of the pharmaceutically acceptable salts, the compositions of the present invention can contain other active principles such as, for example, tranquilizers or other drugs which can be useful in the treatment of the disorders or diseases indicated above,
Thus the present invention relates to pharma-ceutical compositions containing several active principles in association, one being a compound according to the invention and it being possible for the other or others to be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal antiinflammatory or a tranquilizer.
The following Examples illustrate the invention without however implying a limitation. The following abbreviations are used in these Examples: d denotes density, RT denotes room temperature, KHS04-K2S04 denotes an aqueous solution containing 16.6 g of potassium bisulfate and 33.3 g of potassium sulfate per liter.
The melting points (m.p.) are given in degrees Celsius; unless indicated otherwise, they were measured without recrystallization of the product.
The purity of the products is checked by thin layer chromatography (TLC) or HPLC. The products are characterized by their NMR spectra run at 200 MHz in deuterated DMSO with tetramethylsilane as the internai reference.
The following abbreviations are used in the interpretation of the NMR spectra: s : singlet sb : broad singlet - 24 - d : doublet t : triplet q : quadruplet quint : quintuplet sext : sextuplet ra : unresolved signāls or multiplet In addition, im denotes imidazole. Conventionally/ the hydrogen atoms are numbered on the biphenylyl as shown in the following formula: R4 R5^-(C^2)t
In the following compounds, z and t are zero except where the compound prepared is a pyrimidinone. EXAMPLE 1 2-n-Butyl-4-spirocyclopentane-l-((2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]:-2-imidazolin-5-one and i2-n-butyl-l- [ (2'-carboxybiphenyl-4-yl )methyl ]-4-spirocyclopentane-2-imidazolini-5-one trifluoroacetate -Method 2 A) l-N-Fmoc-arainocyclopentanecarboxylic acid is prepared according to the method described by CHI-DEU CHANG et al. (Int. J. Peptide Protein Res., 1980, 15, 59-66). M.p. = 89-91*C. - 25 - LV 10439 B) N-( 2'-!Tert-butoxycarbonylbiphenyl-4-ylmethyl )-1-(N-Fraoc-amino)cyclopentane-l-carboxamide 700 mg of the product prepared in the previous step are dissolved in 8 ml of DMF, and 576 mg of 4-05 aminomethyl-2'-tert-butoxycarbonylbiphenyl, 970 mg of BOP and a sufficient amount of DIPEA to bring the pH to 6 are added successively.
After stirring for 1 hour, the reaction medium is diluted with 100 ml of ethyl acetate and 20 ml of 10 water; the organic phase is washed successively with a saturated solution of sodium bicarbonate, then with a KHS04-K2S04 solution and finally with a saturated solution of sodium chloride. After drying over sodium sulfate, the solution is evaporated to dryness to give 15 an oil. m = 1.2 g. c) N— (2'-Tert-butoxycarbonylbiphenyl-4-ylmethy1)-1-aminocyclopentane-l-carboxamide
The product obtained rin the previous step is dissolved in 10 ml of DMF, 1 ml of diethylamine is then 20 added and the mixture is stirred for 1 hour 15 minūtes at RT. The reaction medium is taken up in 100 ml of ethyl acetate and 20 ml of water and the organic phase is then washed once with water and once with a saturated solution of sodium chloride and then dried over 25 sodium sulfate and evaporated to dryrtess.
The residue is chromatographed on silica gel using an ethyl acetate/methanol/30% aqueous ammonia mixture (99/1/0.5; v/v/v) as the eluent to give 600 mg of the expected product. 30 - IR (CHC13); 3350 cm-1 : H (amide and amine) 1700 cm-1 ; C=0 (COatBu) 1650 cm-1 : C=0 (CONH) - NMR spectrum; 1.25 ppra : s ; 9 H : tBu 35 26
2.15- 1.40 ppm : m : 10 Η : CsHa, NHa 4.40 ppm : d : 2 H : CHa-NH 7.15- 7.75 ppm : ra : 8 H : biphenyl 8.60 ppm : t : 1 H : NH-CHa, D) 2-n-Butyl-4-spirocyclopentane-l-[ (2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 394 mg of the product prepared in the previous step and 250 mg of ethyl orthovalerate are mixed in 2 ml of DCM. 1 drop of acetic acid is added and the mix-ture is then heated at 90’c with the DCM being allowed to evaporate off. After 1 hour 15 minūtes, the reac-tion raedium is taken up in 50 ml of ethyl acetate, 10 ml of water and 1 ml of a saturated solution of sodium bicarbonate. The organic phase is then washed with a saturated solution of sodium chloride and subsequently dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using an ethyl acetate/toluene mixtur$.. (1/2; v/v) as the eluent to give 390 mg of the expected product, which crystal-lizes. M.p. = 63-65 ° C. - IR (CHCl3): 1710-1720 cm-1 : C=0, C=0 (ester and imidazoline)
1625 cm-1 : C=N - NMR spectrum: 0.88 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : s : 9 H : tBu 1.35 ppm : sext : 2 H : CH3-CH2- 1.58 ppm : quint : 2 H : CH3-CH2-CEa- 1.95-1.65 ppm : m : 8 H : cyclopentane 2.42 ppm : t : 2 H : CH3-CHa-CHa-CHa- 4.78 ppm : s : 2 H : CH2-CeH4- 7.20-7.80 ppm : m : 8 H : aromatic protons - Mass spectrum: MH* : 461 - 27 - LV 10439 E) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl ]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate 180 mg of the product prepared in the previous step are treated with 3 ml of DCM and 4 ml of TFA for 05 45 minūtes. After evaporation under vacuum, the resi- due is taken up in ether to give a white solid, which is filtered off, washed with ether and then dried under vacuum. m = 155 mg. M.p. = 176-178‘C. - NMR spectrum: 10 0.78 ppm : t : 3 H : CH3 (nBu) 1.25 ppm : sext : 2 H : CH3-CH2 1.50 ppm : quint : 2 H : CH3-CH2-CH2 1.75-2,00 : m : 8 H : cyclopentane 2.65 ppm : t : 2 H : CH3-CH2-CH2-CH2-15 4.83 ppm : s : 2 Η : ΟΗ2-ΟβΗ4- 7.20-7.75 ppm : m : 8 H : aromatic protons - Mass spectrum: MH- : 405 20 EXAMPLE 2 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate - Method 1 A) 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one 25 The ethyl ester of l-aminocyclopentanecarboxy- lic acid is prepared according to ADKINS and BILLICA (J, Amer. Chem. Soc., 1948, 10, 3121).
Ethyl valerimidate is prepared according to Mac ELVAIN (J. Amer. Chem. Soc., 1942, M, 1825-1827) and 30 then freed frora its hydrochloride by reaction with potassium carbonate and extraction with DCM.
The ethyl ester of l-aminocyclopentanecarboxy-lic acid (1.57 g) and ethyl valerimidate (1.56 g) are dissolved in 12 ml of xylene containing 6 drops of 35 acetic acid. After refluxing for 6 and a half hours, 28 the reaction medium is concentrated under vacuum and the residue is then chromatographed on silica gel using a chloroform/methanol/acetic acid mixture (94/4/2; v/v/v) as the eluent. The fraction containing the 05 expected product is evaporated several times in the presence of xylene and then benzene in order to remove the acetic acid. 1.91 g of product are obtained in the form of a thick oil. - IR (CHC13); 10 1720 cm-1 : C=0
1635 cm-1 : C=N
Note: The fact that there is no visible band between 1500 and 1600 cm-1 indicates that, in chloroform solution, the product is an imidazolin-5-one. 15 - NMR spectrum: 0.92 ppm ; t : 3 H : CH3 (nBu) 1.35 ppm : sext ; 2 H : CH3-CH2- 1.50-1.93 ppm : m : 10 H ; CH3-CH2-CH2 and cyclo- pentane 20 2.33 ppm : t : 2 H ; CH3-CH2-CH2-CH2-
10.7 ppm ; m ; NH - Mass spectrum: MH* : 195
The 2-n-butyl-4-spirocyclopentane-2-imidazolin-25 5-one prepared in step A can also be obtained by another procedure described below, -using cyclopentanone as the starting material. a) l-Arainocyclopentanenitrile This step is carried out according to A. 30 Strecker (Org. Synth., 1955, 2). 1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a round-bottomed flask and a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3,5 ml of 20% aqueous ammonia is added; finally, 3 g of cyclopentanone in 3.8 ml of methanol 35 - 29 - LV 10439 are added to the flask. After stirring for 1 and a half hours, the mixture is heated at 60 °C for 45 minūtes, heating is then stopped, stirring is continued for 45 minūtes and the mixture is then cooled to 25*C. It is extracted several times with methylene chloride. The extracts are dried over sodium sulfate, filtered and concentrated under vacuum to give 4 g of the expected product in the form of an oil.
The l~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 filtered off, washed with acetone and then dried. m = 4.71 g. M.p. = 220"C.
This compound is l-aminocyclopentanenitrile hemioxalate. b) l-Aminocyclopentaneacetamide
This step is carried out according to J, Zabicky (The Chemistry of Amides, Interscience, New York, 1970, 119). 5.1 g of the oxalate obtained in the previous step are treated with 7.65 ml of concentrated sulfuric acid (d = 1.84) over 45 minūtes, with stirring. The evolution of a gas is observed and the temperature risēs to 100’c. The mixture is cooled to about 35’C and poured into a mixture of ice and concentrated aqueous ammonia (10 g/2.8 ml). The suspension formed is extracted 6 times in succession with chloroform con-taining 5% of methanol. 3 ml of aqueous ammonia (d = 0.92) are added to the aqueous phase and the mixture is extracted again with chloroform containing methanol (1/0.5; v/v). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The expected product is obtained in the form of a white 30 solid. : m = 3.79 g. M.p. = 95 * C.
The structure can be confirmed by the results of analysis and the IR spectrum. c) 2-n-Butyl-4-spirocyclopentane-2-imidazolin- 5-one
This step is carried out according to H. Takenaka et al., Heterocycles, 1989, 2^(6), 1185-89. 3 g of the compound prepared in the previous step are placed in 70 ml of anhydrous THF and 3.3 ml of triethylamine/ and 3 ml of valeryl chloride in 10 ml of anhydrous THF are added, with stirring. A white sus-pension is formed. The intermediate which is formed, but not isolated, is l-(N-v.aleryl)aminocyclopentane-carboxamide. 6 g of potassium hydroxide pellets, 7 ml of water and 16 ml of methanol are added. The mixture is refluxed for 2 and a half hours and 9 g of ammonium chloride are then added. After stirring for 15 minūtes, the mixture is concentrated under vacuum. The residue obtained is taken up in 40 ml of water and extracted with 10 ml of ethyl acetate and then twice with 5 ml of ethyl acetate. The combined organic phases are dried over sodium šulfate and filtered. The filtrate is concentrated to dryness to give 4.85 g of the expected product. The NMR spectrum is similar to that described previously. The hydrochloride of this compound can be prepared by the addition of concentrated hydrochloric acid. The hydrochloride melts at 240*C with sublimation. B) 2-n-Butyl-4-spirocyclopentane-l-[ (2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 970 mg of the product obtained in step A) are dissolved in 10 ml of DMF. 270 mg of sodium methylate are added and the mixture is stirred for 15 minūtes at - 31 - LV 10439 RT. 2.08 g of 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl are added to the suspension and then, after 30 minūtes, the mixture is heated at 40*C for 3 and a half hours under nitrogen. The reaction medium is taken up 05 in a mixture containing 100 ml of ethyl acetate, 10 ml of water and 1 ml of a saturated solution of sodium bicarbonate. The organic phase is washed with a saturated solution of sodium chloride and then dried over sodium sulfate and evaporated to dryness. The 10 residue is chromatographed on silica gel using an ethyl acetate/toluene mixture (1/2; v/v) as the eluent to give 1.25 g of the expected product, which crystal-lizes. M.p. = 63-66 ° C.
The IR and NMR spectra and themass spectrum, 15 as well as the Rf, are identical to those obtained in step D) of Example 1. C) 2-n-Butyl-l-[ (2'-carboxybiphenyl,-4-yl)methyl J-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate 1.22 g of the product obtained in the previous 20 step are stirred for 40 minūtes in a solution containing 6 ml of DCM and 8 ml of TFA. After concen-tration under vacuum, the residue is taken up in ethyl ether; the white precipitate formed is filtered off, washed with ether and then dried under vacuum to give 25 1.15 g of the expected product. M.p. = 176-178'C.
The IR and NMR spectra and the mass spectrum are identical to those obtained in Example 1E; like-wise, the Rf observed in TLC is identical. 30 EXAMPLE 3 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate - Method 3 A) 2-n-Butylbenzimidazole is prepared according to W.O. 35 POOL, (J. Amer. Chem. Soc., 1937, j>£, 178) and 2-n- 32 butyl-4,5,6,7-tetrahydrobenzimidazole is then prepared according to M. HARTMANN and L. PANIZZON (Helv. Chim. Acta, 1938, 21, 1692-1694). M.p. = 145*C. - NMR spectrum: 0.82 ppm : t : 3 H : CH3 (nBu) 1.23 ppm : sext : 2 H : CH3-CHa-1.50 ppm : quint : 2 H : CH3-CH2-Cii2- I. 65 ppm : s : 4 H : Hb, H6 (tetrahydrobenzimidazole) 2.35 ppm : s : 4 H : H4, H7 i(tetrahydrobenzimidazole) 2.45 ppm : t : 2 H : CH3-CH2-CH2-CH2-
II. 1 ppm : m : NH - Mass spectrum: M-" : 178 B) 2-n-Butyl-4-spirocyclopentane-l-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 1 g of the product prepared in the previous step is dissolved in 45 ml of DMF with 303 mg of sodium methylate and a few mg of methylene blue. Oxygen is bubbled into the reaction medium, which is illuminated with a UV lamp. After 15 minūtes, 2.14 g of 4-bromo-methyl-2'-tert-butoxycarbonylbiphenyl are added and then, after 1 hour, the reaction medium is taken up in 300 ml of ethyl acetate to which 50 ml of water and 5 ml of a saturated solution of sodium bicarbonate have been added. The organic phase is then washed with a saturated solution of sodium chloride and subsequently dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on 'silica gel using an ethyl acetate/toluene mixture (1/2; v/v) as the eluent to give 610 mg of the expected product, which crystal-lizes. M.p. = 62-65°C.
The IR and NMR spectra and the mass spectrum, as well as the Rf, are identical to those obtained previously for the same compound. - 33 - LV 10439 C) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate
This compound is obtained by treatment in an acid medium as described in the last step of Example 1 05 and Example 2. The physicochemical data are identical to those obtained for the same compound prepared by method 1 or 2. EXAMPLE 4 10 2-n-Butyl-4,4-dimethyl-l-[(2'-tert-butoxy- carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one and 2-n-butyl-l-[ (2'-carboxybiphenyi-4-yl)methyl ]-4,4-di-methyl-2-imidazolin-5-one trifluoroacetate - Method 1 A) 2-n-Butyl-4,4-dimethyl-2-imidazolin-5-one 15 The ethyl ester of alpha-aminoisobutyric acid is prepared according to R. Jacquier et al. (Buli. Soc. Chim. France, 1971, (3), 1040-1051). 650 mg of this compound and 780 mg of ethyl valerimidate are dissolved in 8 ml of xylene containing 4 drops of acetic acid and 20 the solution is refluxed for 7 hours. The reaction medium is then concentrated under vacuum and the resi-due is chromatographed on silica gel using a chloro-form/methanol/acetic acid mixture (95/5/2; v/v/v) as the eluent. After several evāporations with xylene and 25 then benzene to remove the acetic acid, 560 mg of the expected product are obtained, which crystallizes. M.p. = 35-38 °C. - IR (CHC13); 1725 cm-1 : C=0
30 1635 cm-1 : C=N
Note: The absence of a signal between 1500 and 1600 cm-1 confirms that the compound present in chloroform solution is a 2-imidazolin-5-one. - NMR spectrum: 0.92 ppm ; t ; 3 H : CM3 (nBu) 35 34 1.20 ppm : s : 6 H : C(CH3)a 1.38 ppm : sext : 2 H : CH3-CH2 1.63 ppm : quint : 2 Η : CH3-CH2-Cli2- 2.38 ppm : t : 2 H : CH3-CH2-CH2-CH2-
10.7 ppm : m : 1 H : N-H - Mass spectrum: MH·*" : 169 B) 2-n-Butyl-4,4-dimethyl-l-[ (2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-imidazolin-5-one 520 mg of the product prepared in the previous step are dissolved in 10 ml of DMF. 167 mg of sodium methylate are added and the mixture is stirred under nitrogen for 15 minūtes. 1.25 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl are then added and the mix-ture is stirred at 40°C for 3 and a half hours. The reaction medium is taken up in 150 ml of ethyl acetate and then 20 ml of water and 2 ml of a saturated solu-tion of sodium bicarbonate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using an ethyl acetate/toluene mixture (1.2/2; v/v) as the eluent to give 570 mg of the expected product, which crystallizes. M.p. = 98-100eC. - IR (CHC13); 1710-1720 cm-1 ; C=0, C=0 (imidazplinone, ester)
1625 cm-1 : C=N - NMR spectrum: 0.78 ppm : t : 3 H : CH3 (nBu) 1.08 ppm : s : 9 H : C(Cū3)3 1.15 ppm : s : C(CH3)2 )
1.20 ppm : sext : CH3-Cii2- ) 8 H 1.45 ppm : quint : 2 H : CH3-CH2-CH2-2.30 ppm : t : 2 H : CH3-CH2-CH2-CH2- 4.65 ppm : s : 2 H : CH2-CeH4- - 35 LV 10439 7.15-7.65 ppm : m : 8 H : aromatic protons An NOE (Nuclear Overhauser Effect) study confirms the position of the 5-one and 4,4-dimethyl substituents on the imidazolinone. 05 - Mass spectrum: MH- : 435 C) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl ]-4,4-dimethyl-2-imidazolin-5-one trifluoroacetate 460 mg of the product prepared in the previous 10 step are treated with 3 ml of DCM and 4 ml of TFA for 45 minūtes. After concentration under vacuum, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and then dried under vacuum to give 450 mg of the expected product in the 15 form of a white solid. M.p. = 168-171*C. - NMR spectrum: 0.82 ppm : t : 3 H : CH3 (nBu) 1.30 ppm : sext : CH3-Cil2- ) 1.35 ppm : s : C(CH3)2- ) 8 H, 20 1.55 ppm : quint : 2 H : CH3-CH2-CH2-
2.62 ppm : t : 2 Η : 0Η3-^-0Η2-01ί2-4.82 ppm : s : 2 H : CH2-C6H4-7.20-7.75 : m : 8 aromatic H - Mass spectrum: 25 MH- : 379 EXAMPLE 5 l-[ (2'-Cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one and 2-n-butyl-4-30 spirocyclopentane-l-[ (2'-(tetrazol-5-yl)biphenyl-4-yl)-methyl]-2-imidazolin-5-one - Method 1 A) l-[ (2i-Cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spiro-cyclopentane-2-imidazolin-5-one
A mixture containing 250 mg of sodium hydride (as an 80% dispersion in mineral oil) and 5 ml of DMF 35 36 is prepared under a nitrogen atmosphere and a solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (prepared in Example 2, step A) in 10 ml of DMF is added dropwise. The mixture is stirred for 30 minūtes at RT and a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of DMF is then added. After stirring for 1 hour at RT, the DMF is evaporated off under reduced pressure, the residue is then taken up with ethyl acetate and the organic phase is washed with water and then dried over sodiura sul-fate, filtered and evaporated. The residue is chroma-tographed on silica gel using a DCM/ethyl acetate mix-ture (9/1; v/v) as the eluent. 1.68 g of the expected product are recovered. M.p. = 92-93*C. B) 2-n-Butyl~4-spirocyclopentane-l-[ (2'-(triphenyl-methyltetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 1.56 g of the previous product, 2.6 g of tri-butyltin azide and 30 ml of xylene are refluxed for 66 hours. The xylene is then evaporated off and the residue is dissolved in 20 ml of DCM and 5 ml of THF with the addition of 0.8 ml of 10 N sodium hydroxide solution and, after stirring for 30 minūtes, 2.5 g of tri-tyl chloride, and the mixture is stirred for 26 hours. After evaporation of the solvents, the residue is taken up in ethyl acetate and washed with' water and with a 3% solution of potassium bisulfate and water. It is dried and evaporated. The residue is chromatographed on alumina using a hexane/ethyl acetate mixture (9/1; v/v) as the eluent to give 1.97' g of the expected product. M.p. = 150-152'C. C) 2-n-Butyl-4-spirocyclopentane-l-[ (2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 1.96 g of the product prepared in the previous step are dissolved in 10 ml of methanol and 10 ml of - 37 - LV 10439 ι THF. After the reaction medium has been cooled to 5°C, 1.5 ml of 4 N hydrochloric acid are added and the mix-ture is stirred for 3 hours at RT and 1 hour at 30eC. After evaporation of the solvents, the residue is taken 05 up in water and the pH is brought'to 12 by the addition of 10 N sodium hydroxide solution. The aqueous phase is extracted with ether, toluene and ether again. The aqueous phase is acidified to pH 2 by the addition of 1 N hydrochloric acid and then extracted with ethyl 10 acetate and the extract is dried and evaporated. The white solid obtained is dried at 50’c under 0.05 mm of mercury to give 840 mg of the expected product. M.p. = 180-181eC. - NMR spectrum: 15 0.75 ppm : t : 3 H : CHa (nBu) 1.10 ppm : sext : 2 H : CH3-CH2-1.20 ppm : quint : 2 H : CH3-CHa-CIia-1.5-2 ppm : m : 8 H : -CsHe 2.2 ppm : t : 2 H : CH3-CHa-CHa-CHa-20 4.6 ppm : s : 2 H : ,CHa-CeH*- 7 ppm : s : 4 H : CH2-C^H4-7.35-7.7 ppm : m : 4 H : aromatic H3,
An NOE study confirms the position of the 5-one sub-stituent on the imidazole. 25 D) Potassiura salt of 2-n-butyl-4-spirocyclopentane-l-[ (2'~(tetrazol-5-yl)biphenyl-4-yl)raethyl]-2-imidazolin-5-one 970 mg of the compound obtained in the previous step are dissolved in 40 ml of an isopropanol/methanol 30 mixture (1/1? v/v) and the pH is adjusted to 12 by the addition of an 85% solution of potassium hydroxide in a methanol/water raixture (20/1; v/v). The reaction medium is evaporated, the residue is taken up in iso-propanol and the medium is evaporated again. The resi-35 due is dissolved in 20 ml of isopropanol, with gentle 38 - heating, and then left to return to room temperature. The mixture is left to decant, the filtrate is evapora-ted and the residue is then taken up in heptane. After trituration, the product solidifies; it is filtered off and then washed again with .heptane and dried under vacuum to give 94 5 mg of the expected potassium salt. M.p. = 142-144 *C. - Elemental analysis: C2SH27KN60.Ha0 calc. % C : 61.95 H : 6.03 N : 17.34 found % 62.02 6.13 17.14 EXAMPLE 6 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl ]-4-(4-spirotetrahydropyran)-2-imidazolin-5-one tri-fluoroacetate and 2-n-butyl-4-(4-spirotetrahydropyran)-1-[ (2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one - Method 2 A) 4-Aminotetrahydropyran-4-carboxylic acid is prepared from tetrahydropyran-4-one by the method described in German patent 2 215 721. B) 4-(N-Benzyloxycarbonylaraino)-4-carboxytetrahydro-pyran 1.015 g of the compound of step A are placed in 12 ml of water and treated at 10eC with 1.22 ml of di-isopropylethylamine and then 3.33 g of N-(benzyloxy-carbonyloxy)succinimide dissolved in 12 ml of aceto-nitrile. After 1 hour 15 minūtes, the reaction mediura is diluted with 70 ml of ethyl acetate and 10 ml of water and the pH is brought to 2 with a saturated solution of potassium bisulfate.
After decantation, the organic phase is washed with a saturated solution of sodium chloride, dried over sodiura sulfate and then evaporated under vacuum. The residue is diluted with 60· ml of ether, after which 7 mmol of dicyclohexylamine are added. The precipitate - 39 - LV 10439 formed is filtered off and washed with ether; it is then dissolved in an ethyl acetate/water mixture and the pH is brought to 1.5 with a saturated solution of potassium bisulfate. The organic phase is decanted, washed with a saturated solution of sodium chloride and evaporated under vacuuiti to give 1.9 g of a white solid. M.p. = 110-115*0. C) N-(2'-rert-butoxycarbonylbiphenyl-4-ylmethyl)-4-(N-benzyloxycarbonylamino)tetrahydropyran-4-carboxamide 850 mg of the compound prepared in step B are dissolved in 15 ml of DMF, and equimolar amounts of 4-aminomethyl-2'-tert-butoxycarbonylbiphenyl, DIPEA and then BOP (10% excess) are added. After 40 minūtes, the medium is taken up in 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted and then washed twice with a saturated solution of sodium bi-carbonate, twice with a 5% solution of sodium bisulfate and then once with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase is evaporated under vacuum to give 1.8 g of the expected product. D) N-(2'-!Tert-butoxycarbonylbiphenyl-4-ylmethyl)-4-aminotetrahydropyran-4-carboxamide
The product obtained in step C is dissolved in 30 ml of methanol. 400 mg of 10% palladium-on-charcoal are added and the raixture is hydrogenated at atmos-pheric pressure. After 1 hour, the catalyst is filtered off and the filtrate is then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/methanol/33% aqueous ammonia mixture (99/1/0.5; v/v/v) as the eluent to give 0.93 g of the expected product in the form of a white solid. M.p. = 125-127’C. - NMR spectrum;
8.50 ppm : t ; 1 H ; araide H 40 7.60-7.05 ppm : m : 8 Η : aromatic protons 4.25 ppm : d : 2 Η : CHa-C6H4- 3.70-3.50 ppm : m : 4 H : CHa in the 2 and 6 posi- tions of the tetrahydro-pyran 2.00-1.80 ppm : m : 4 H : CHa in the 3 and 5 posi- tions of the tetrahydro-pyran 1.05 ppm : s : 9 H : tBu E) 2-n-Buty1-4-(4-spirotetrahydropyran)-l-[(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 is heated for 3 hours at 110"C. The reaction medium is taken up in 100 ml of ethyl acetate, then washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and then dried over sodium sulfate and the ethyl acetate is evaporated off. The residue obtained is chromatographed on silica using an ethyl acetate/ toluene mixture (2/1; v/v) as the eluent to give 550 mg of the expected product in the form of a wax, - NMR spectrum: 7.05- 7.60 ppm : m ; 8 H : aromatic protons 4.63 ppm ; s : 2 H : CH2-C6H4- 3.85-3.55 ppm : m ; 4 H : CHa in .the 2 and 6 posi- tions of the tetrahydro-pyran 2.30 ppm : t : 2 H : CHa-C3H7 1.05- 1.80 ppm : m : 8 H : CHa-CHa-CH2-CH3 and CHa in the 3 and 5 positions of the tetrahydropyran 1.03 ppm ; s : 9 H : tBu 0.75 ppm : t : 3 H ; (CHa)3-CH3 - 41 - LV 10439 - IR (CHCla):
1710-1720 cm-3· : C=0, C=0 1625 cm-3· : C=N F) 2-n-Butyl-4-(4-spirotetrahydropyran)-l-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoroacetate...(sic) 530 mg of the product obtained in the previous step are treated with 4 ml of dichloromethane and 5 ml of TFA for 45 minūtes. After evaporation under vacuum, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and then dried under vacuum to give 510 mg of the expected pro-duct. M.p. ,·« 159-162*0. NMR spectrum: 7.80-7.10 ppm : m : 8 H : aromatic protons 4.80 ppm : s : 2 H : CE2-C6H4- 4.00-3.75 ppm : m : 4 H : CH2 in the 2 and 6 posi- tions of the tetrahydro-pyran 2.60 ppm : t : 2 H : CH2-C3H7 1.45-2.00 ppm : m : 6 H : CH2-CH2-CH2-CH3 and CH2 in the 3 and 5 positions of the tetrahydropyran 1.30 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 EXAMPLE 7 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl ]-4-[spiro(l-benzyl-4-piperidine)]-2-imidazolin-5-one trifluoroacetate and 2-n-butyl-4-[spiro(l-benzyl-4-pipepidine)]-1-[(2tert-butoxycarbonylbiphenyl-4-yl)-methyl]-2-imidazolin-5-one - Method 1 A) 4-Amino-l-benzylpiperidine-4-carboxylic acid is pre-pared from N-benzylpiperidin-4-one by the method described in German patent 2 215 721. 42 B) Ethyl 4-amino-l-benzylpiperidine-4-carboxylate 3.80 g of the compound prepared in step A are added to a solution of 13 g of hydrochloric acid in 50 ml of ethanol at o’c and the mixture is then refluxed for 5 hours. After concentration under vacuum, the residue is washed with ether and then dissolved in an ether/water mixture, to which a saturated solution of potassium carbonate is added to bring the pH to 9. The ether phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness to give 3.50 g of the expected product in the form of an oil. - NMR spectrum: 7.20- 7.40 ppm : m : 5 H : aromatic protons 4.10 ppm : q : 2 H : CH2-CH3 3.45 ppm : s : 2 H : CHa of the benzyl 2.25-2.60 ppm : m : 4 H : CH2 in the 2 and 6 posi- tions of the piperidine 1.80-2.05 ppm : m : 2 H ļ CH2 in the 3 and 5 posi- 1.20- 1.40 ppm : m : 2 H ) tions of the piperidine ; 1.12 ppm : t : 3 H : CH3-CH2- C) 2-n-Butyl-4-[spiro(l-benzyl-4-piperidine)]-2-imi-dazolin-5-one
Ethyl valerimidate is prepared as in Example 2, step A. 2.06 g of ethyl valerimidate, 3.40 g of the compound prepared in step B and 8 drops of acetic acid are mixed in 15 ml of xylene and the mixture is re-fluxed for 6 hours. After concentration under vacuum, the residue is chromatographed on silica gel using a chloroform/methanol/acetic acid mixture (82/15/3; v/v/v) as the eluent. 2.80 g of the expected product are obtained after extraction with chloroform at pH 9 to remove the acetic acid. M.p. = 170-172°C. - IR (chloroform): 1725 cm”1 : C=0 - 43 - LV 10439
1640 cm-1 : C=N - NMR spectrum:
7.10- 7.30 ppm : m : 5 H : aromatic protons 3.45 ppm : s : 2 H : -CH2-C6HS 1.10- 2.75 ppm : 5 m : 14 H : CHa in the 2, 3, 5 and 6 positions of the piperidine and (CHa)3-CH3 0.80 ppm : t : 3 H : (CHa)3-Cii3 D) 2-n-Butyl-4-[spiro(l-benzyl-4-piperidine)]-l-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 513 mg of sodiura methylate and, after 15 minūtes, 4.16 g of 4-bromomethyl-2'-tert-butoxycar-bonylbiphenyl are added to a solution of 2.78 g of the compound obtained in step C in 25 ml of DMF. The reac-tion medium is heated at 40eC for 5 hours and then taken up in 300 ml of ethyl acetate, 50 ml of water and 5 ml of a saturated solution of sodium bicarbonate. The organic phase is decanted, washed once more with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under vacuum. The resi-due is chromatographed on silica using an ethyl ace-tate/methanol mixture (95/5? v/v) as the eluent to give 0.98 g of the expected product. M.p. = 103-106eC. - IR (CHC13): 1710-1725 cm-a· : C=0, c=0 (imidazoline, ester)
1630 cm-1 : C=N - NMR spectrum: 7.70-7.10 ppm : ra : 13 H : aromatic protons 4.70 ppm : s : 2 H : CH2-CeH4-3.55 ppm : s : 2 H : C£a-CeHs 1.20-2.75 ppm : 5 m : 14 H :CH2 in the 2, 3, 5 and 6 positions of the piperidine and (CH2)3-CH3 - 44 - 1.15 ppm : s : 9 Η : tBu 0.85 ppm : t : 3 H : (CH2)3-CH3 E) 2-n-Butyl-l- [ (2'-carboxybiphenyl-4-yl )methyl ]-4-[spiro(l-benzyl-4-piperidine)]-2-imidazolin-5-one trifluoroacetate 350 mg of the compound obtained in step D are dissolved in 4 ml of dichloromethane and 5 ml of TFA.
After 45 minūtes, the medium is concentrated under vacuum, the residue is then taken up in an ether/ hexane mixture and the precipitate formed is filtered off, washed with ether and dried under vacuum to give 350 mg of the expected product. M.p. = 198-200*C. - NMR spectrum: 7.05-7.75 ppm : m : 13 H : aromatic protons 4.75 ppm : s : 2 H : CH2-C6H4- 4.40 ppm : s : 2 H : CH2-C6H5 3.20- 3.60 ppm : m : 4 H : CHa in the 2 and 6 posi- tions of the piperidine 2.35 ppm : t : 2 H : CH2-CH2-CH2-CH3 2.20- 1.40 ppm : 3 unresolved signāls : CH2 in the 3 and 5 posi-tions of the piperidine and CH2-CH2-CH2- ch3 1.25 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 EXAMPLE 8 2-n-Butyl-l-[(2f-carboxybiphenyl-4-yl)raethyl]-4-(4-spiropiperidine)-2-imidazolin-5-one ditrifluoroacetate and2-n-butyl-4-(4-spiropiperidine)-l-[ (2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one - 45 - LV 10439 A) 2-n-Butyl-4-(4-spiropiperidine)-l-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 300 mg of the compound of Example 7, step D, are dissolved in 10 ml of methanol. 180 mg of 10% 05 palladium-on-charcoal are added and the mixture is hydrogenated for 3 hours at atmospheric pressure. The catalyst is filtered off and the filtrate is concentra-ted under vacuum to give 200 ,mg of the expected pro-duct. 10 - NMR spectrum: 7.20- 7.75 ppm : m : 8 H : aromatic protons .4.75 ppm : s : 2 H : CH^C^H*- 3.00-1.70 ppm : 3 unresolved signāls for the 4 CH2 of the piperidine 15 2.40 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.60 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.35 ppm : sext : 2 H : CH2-CH2-CH2-CH3 1.20 ppm : s : 9 H : tBu 0.90 ppm : t : 3 H : (CH2)3-CH3 20 B) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-(4-spiropiperidine)-2-imidazolin-5-one ditrifluoroacetate 160 mg of the product obtained in step A are stirred for 45 minūtes in 3 ml of dichloromethane and 4 ml of trifluoroacetic acid. The mixture is concentra-25 ted under vacuum and the residue is taken up in ether to give a gum and then a foam after drying under vacuum (150 mg). M.p. = 80-85°C. - NMR spectrum: 7.15-7.80 ppm : ra : 8 H : aromatic protons 30 4.75 ppm : s : 2 H : CH2-CeH4- 3.20- 1.60 ppm : 3 unresolved signāls : 4 CH2 of the piperidine 2.40 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.50 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.30 ppm : sext : 2 H : CH2-CH2-CH2-CH3 35 46 0.80 ppm : t : 3 Η : (CH2)3-CH3 EXAMPLE 9 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4,4-diphenyl-2-imidazolin-5-one trifluoroacetate and 2-n-butyl-4,4-diphenyl-l-[ (2'-terfc-butoxycarbonylbi-phenyl-4-yl)methyl]-2-imidazolin-5-one - Method 1 A) Valeramidine hydrochloride 6 g of ethyl valerimidate hydrochloride are added to a solution of 6.75 g of ammonia in 80 ml of methanol at 0eC. After 18 h, the reaction medium is concentrated under vacuum to give the expected product in the form of a white solid. B) 2-n-Butyl-4,4-diphenyl-2-imidazolin-5-one
This compound is prepared according to the pro-cedure described by J. NYITRAI and K. LEMPERT in Tetra-hedron, 1969, 25, 4265-4275, from benzil and valerami-dine hydrochloride. M.p. = 135*C. - IR (CHC1J:
1725 cm-1 : C=0 1640 cm-1 : C=N - NMR spectrum:
7.20-7.50 ppm : m : 10 H : aromatic protons 2.50 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.65 ppm : quint : 2 Η : ΟΗ2-ΟΗ2-ΟΗ2-ΟΗ3 1.35 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.90 ppm : t : 3 H : CH2-CH2-CH2-CH3 11 ppm : sb : NH C) 2-n-Butyl-4,4-diphenyl-l-[(2'-tert-butoxycarbonylbi-phenyl-4-yl)methyl]-2-imidazolin-5-one
This compound is prepared according to the usual method by reacting 4-bromomethyl-2'-tert-butoxy-carbonylbiphenyl with the compound prepared in step B, in the presence of sodium methylate in DMF. - 47 - LV 10439 - IR (CHC13): 1715-1725 cm-1 : C=0, C=0 (ester, imidazolinone)
1635 cm-1 : C=N - NMR spectrum: ' 7.25-7.80 ppm : m : 18 H : aromatic protons 4.85 ppm : s : 2 H,: N-CH2-CeH4- 2.60 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.75 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 1.15 ppm : s : 9 H : tBu 0.90 ppm : t : 3 H : CH3 of the n-butyl D) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4,4-diphenyl-2-imidazolin-5-one trifluoroacetate 500 mg of the product prepared in step C are treated with 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid at 20"c for 40 minūtes. After concentration under vacuum, the residue is taken up in an ether/hexane mixture and the precipitate formed is filtered off, washed with hexane and dried to give 440 mg of the expected product. M.p. = 55-60*C. - NMR spectrum: 7.15-7.80 ppm : m : 18 H : aromatic protons 4.85 ppm : s : 2 H : N-CH2-C6H4- 2.60 ppm : t : 2 H : Cīi2-CH2-CH2-CH3 1.70 ppm : quint : 2 H : CH2;-CH2-CH2-CH3 1.40 ppm : sext : 2 H : CH2-CH2-CE2-CH3 0.90 ppm : t : 3 H : CH3 of the butyl EXAMPLE 10 2-n-Butyl-3-[ (2'-carboxybiphenyl-4-yl)methyl]-6-spirocyclopentane-5,6-dihydro-lH-pyrimidin-4-one trifluoroacetate A) (l-Aminocyclopentyl)acetic acid
Cyclopentylideneacetic acid is prepared accor-ding to G.A.R. KON and R.P. LINSTEAD, J. Chem. Soc.; 48 1925, 127, 616. 740 mg of this acid and 5 ml of 20% aqueous ammonia are placed in an autoclave and the mix-ture is heated at 150’C for 24 hours. After evapora-tion of the solvents, the residue is chromatographed on a silica column using a DCM/methanol/20% aqueous ammonia solution mixture (70/30/1; v/v/v) as the eluent to give 330 mg of the expected acid. B) Ethyl (l-aminocyclopentyl)acetate 330 mg of the acid are dissolved in 10 ml of ethanol. The solution is cooled in an ice bath and saturated with gaseous hydrochloric acid. After 24 hours under reflux, the reaction medium is evaporated, the residue is taken up in a solution of sodium car-bonate and extracted with ethyl acetate and the extract is then dried over sodium sulfate, filtered and evaporated to give 312 mg of the expected ester. C) 2-n-Butyl-6-spirocyclopentane-5,6-dihydro-lH-pyri-midin-4-one A mixture containing' 310 mg of the compound obtained in step B, 348 mg of ethyl valerimidate, 10 ml of xylene and 6 drops of acetic acid is brought to the reflux point. After 2 hours and 18 hours, a further 348 mg of ethyl valerimidate are added and, after a total reflux time of 24 hours, the reaction medium is evaporated and then chromatographed on silica using a DCM/methanol mixture (97/3; v/v) as. the eluent to give 153 mg of the expected product. D) 2-n-Butyl-3-[ (2'-tert-butoxycarbonylbiphenyl-4-yl)-methyl]-5,6-dihydro-lH-pyrimidin-4-one A mixture of 10 ml of DMF and 40 mg of sodium hydride as an 80% dispersion in oil is prepared under a nitrogen atmosphere. 144 mg of the compound prepared in step C, dissolved in 5 ml of DMF, are added dropwise at room temperature. After stirring for 30 minūtes, a solution of 288 mg of 4-bromomethyl-2'-tert-butoxy- - 49 - LV 10439 carbonylbiphenyl in 5 ml of DMF is added. The mixture is stirred for 2 hours and then evaporated and the residue is taken up in water and extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered, evaporated and then purified by column chro-matography using a hexane/ethyl acetate mixture (85/5; v/v) as the eluent to give 174 mg of the expected pro-duct. E) 10 ml of trifluoroacetic acid are cooled in a bath of iced water and 161 mg of the compound prepared in step D are added. The mikture is stirred for 30 minūtes and then evaporated. The residue is taken up in ethyl ether and the mixture is then evaporated again. This operation is repeated and the residue is then dried under vacuum to give 140 mg of the expected compound in the form of an amorphous powder. M.p. = 108-115’C. - NMR spectrum: 0.9 ppra : t : 3 H : (CH2)3-CH3 1.1 to 2.1 ppm : m : 12 H : cyclopentane and CH2-CH2- CH2-CH3 2.7 ppm : t : 2 H : CH2-CH2-CH2-CH3
3.1 ppm : s : 2 H : -CH2-CO 5.1 ppm : s : 2 H : N-CH2-CeHs 7.2 to 7.8 ppm : m : 8 H : aromatic protons EXAMPLE 11 2-n-Butyl-4-spirocyclopentane-l-[(2 '-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thione and 2-n-butyl-l-[ (2'-carboxybiphenyl-4-yl)-methyl]-4-spirocyclopentane-2-imidazolin-5-thione tri-fluoroacetate 50 A) 2-n-Butyl-4-spirocyclopentane-l-[ (2'-tert-butoxy-carbonylbiphenyl-4-yl )methyl ]-2-imidazolin-5-thione 5.63 g of the compound prepared in Example 1, step D; are dissolved in 40 ml of anhydrous toluene and treated with 3 g of Lawesson's reaģent at 80’C under nitrogen. After 6 hours, the reaction mixture (sic) is fil-tered and concentrated. The concentrate is chromato-graphed on silica using a DCM/ethyl acetate mixture (95/5; v/v) as the eluent to give the expected product in the form of an oil, which crystallizes in the cold. m = 4.5 g. M.p. = 77-79‘C. - NMR spectrum; 0.90 ppm ; t ; 3 H : CH3 (nBu) 1.20 ppm ; s : 9 H : tBu 1.35 ppm ; sext ; 2 H ; CH3-CH2- 1.60 ppm : quint : 2 H : CH3-CH2-CH2-1.80-2.10 ppm : m : 8 H ; cyčlopentane 2.60 ppm : t ; 2 H : CH3-CH2-CH2-CH2 5.35 ppm : s : 2 H : CH2-C6H4- 7.25-7.80 ppm : m : 8 H : aromatic protons B) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-thione trifluoro-acetate 225 mg of the compound obtained in step A are treated with 5 ml of DCM and 5 ml of TFA for 30 minūtes. After concentration, the residue is taken up in ether. The expected compound is obtained in the form of a yellow powder, which is filtered off and then rinsed with hexane. m = 160 mģ. M.p. = 185-190eC. - Mass spectrum; MH"- ; 421 - NMR spectrum; 0.78 ppm ; t ; 3 H ; CH3 (nBu) 1.20 ppm : sext : 2 H ; CH3-CH2 1.50 ppm ; guint ; 2 H : CH3-CH2-CH2- - 51 - LV 10439 1.75-2.00 ρρτη : m : 8 Η : cyclopentane 2.40 ppm : t : 2 Η : CH3-CH2-CH2-CH2 5.20 ppm : s : 2 H : CH2-C6HA-7.00-7.65 ppm : m : 8 H : aromatic protons 05 EXAMPLE 12 2-n-Butyl-4-(2-spiroindane)-l-[ (2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imida2olin-5-one and 2-n-butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-(2-spiro-10 indane)-2-imidazolin-5-one - Method 1 A) 2-Aminoindane-2-carboxylic acid is prepared accor-ding to R.M. Pinder, J. Med. aChem., 1971, 14, 9, 892, and the corresponding ethyl ester is then prepared according to Adkins (ref. cited in Example 2A). 15 B) 2-n-Butyl-4-(2-spiroindane)-2-imidazolin-5-one 2.78 g of the ethyl ester prepared in step A and 2.5 g of ethyl valerimidate are dissolved in 20 ml of xylene in the presence of 60 μΐ of acetic acid and refluxed for 3 hours. A further 500 mg of ethyl valer- 20 imidate are added and reflux is maintained . for a further 3 hours. The reaction mediunt is concentrated and then chromatographed on silica using a hexane/ ethyl acetate/acetic acid mixture (3/8/0.3; v/v/v) as the eluent. The pure fractions are combined and eva-25 porated with toluene to give 3.07 g of the expected product in the form of a white solid. M.p. = 148- 150*C. - NMR spectrum: 0.90 ppm : t : 3 H : CH3 (nBu) 30 1.2-1.7 ppm : m : 4 Η : CH2-Cīia-CH3 2.4 ppm : t : 2 H : CH2-(CH2)2-CH3 2.8-3.2 ppm : q : 4 H : 2CH2 (indane) 4.90 ppm : s : 2 H : CH2-CeHA-7.2 ppm : m : 4 H : aromatic protons 35 52 C) 2-n-Butyl-4-(2-spiroindane)-l-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one
The compound obtained in the previous step is dissolved in 20 ml of anhydrous DMF and treated with 450 mg of sodium methylate under nitrogen. After 20 minūtes at room temperature, 3.6 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl are added and the mixture is stirred at 40*C for 6 hours. The reaction medium is concentrated, the usual washes are then carried out and the product is chromatographed on silica using di-chloromethane/ethyl acetate (95/5? v/v) as the eluent to give the expected compound in the form of a foam (m = 1.84 g). - NMR spectrum: 0.80 ppm : t : 3 H : CHa (nBu) 1.20 ppm : s : 9 H : tBu 1.20- 1.60 ppm : m : 4 H : CH2-CH2-CH3 2.40 ppm : t : 2 H : CH2-(CH2)2-CH3 2.9- 3.3 ppm : q : 4 H : 2CH2 (indane) 4.80 ppm : s ī 2 H : N-CH2-C6H4- 7.20- 7.80 ppm : m : 12 H ; aromatic protons D) 2-n-Butyl-l-[ (2'-carboxybiphenyl-4-yl)roethyl]-4-(2-spiroindane)-2-imidazolin-5-one 1.71g... (sic) of the .compound obtained in the previous step are dissolved in 15 ml of DCM and treated with 20 ml of TFA. After 30 minūtes, the reaction medium is concentrated and then taken up in ether. After trituration, the solid obtained is filtered off, rinsed with ether and dried to give 1.42 g of the expeqted product. M.p. = 217-218*C. - NM3R. spectrum: 0.70 ppm : t : 3 H : CH3 (nBu) 1.10- 1.50 ppm : m : 4 Η : CH2-Cii2-CH3 2.30 ppm : t : 2 H : CH2-(CH2)2-CH3 2.Ģ-3.3 ppm : q : 4 H : 2CH2 (indane) 53 LV 10439 4.70 ppm : s : 2 H : N-CH2-C6H4-7.1-7.7 ppm : m : 12 H : aromatic protons
Other compounds according to the invention were prepared by one of the methods described above. They 05 are collated in Table 1. The štructure of each of these compounds is consistent with the analysis of their NMR spectra. EXAMPLE 13 10 2-n-Butyl-l-[ (2'— (imidazol-l-ylcarbonyl)bi- phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one 15
/ ~ h, R3 n-C4H9/ CR4Rs = cyclopentane, X = O) 20 A mixture containing 404 mg of the compound prepared in Example 1, step E, 15 ml of THF and 260 mg of carbonyldiiraidazole is stirred at room temperature for 72 hours. The reaction medium is evaporated, the residue is taken up in ethyl acetate and the mixture is 25 washed with water and then with a solution of sodium chloride to give 420 mg of product, which are purified by chromatography on silica using a DCM/ethyl acetate mixture (70/30; v/v) as the eluent to give the expected compound. 30 m = 230 mg. M.p. = 120*C. 35 54 EXAMPLE 14 2-n-Butyl-l-[ (2'-(3-cyano-2-methylisothio*-ureidomethyl)biphenyl-4-yl)methyl]-4-spirocyclopentanie-2-imidazolin-5-one SCH,
# I (I: Rx = -CH2-NH-C=N-CN, R2 = H, R3 = n-C4H9, CR4RS = cyclopentane, X = 0) A) l-[ (2'-Aminomethylbiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one
This compound is obtained by hydrogenation of the compound prepared in Example 5. 1 g of the compound prepared in Example 5, step A, is placed in 15 ml of absolute raethanol and 2.3 ml of ethanol in the presence of 0.5 g of 5% palladium-on-charcoal and the mixture is hydrogenated at room tem-perature for 24 hours. After treatment, 730 mg of the expected product are obtained in the form of an oil. B) A mixture containing 300 mg of the compound prepared in the previous step and 113 mg of N-cyan-imido-S/S-dimethyldithiocarbonate in 3 ml of ethanol is refluxed for 24 hours. After the usual treatment, the reaction medium is purified by chromatography on silica using a DCM/ethyl acetate mixture (50/50; v/v) as the eluent. The expected product is isolated in the form of a white solid. m = 307 mg. M.p. = 83 *C. EXAMPLE 15 2-n-Butyl-l-( (2'-( 2-cyanoguanidinomethyl )bi-phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one - 55 - LV 10439
NH , l 3 (I: R^ = CH2-NH-C=N-CN, R2 = H, R3 = n-C4H9, CR4Rb = cyclopentane, X = O)
This compound is obtained from the compound prepared in the previous Example. 200 ing of the com-pound are placed in 10 ml of absolute ethanol and the mixture is saturated with ammonia at about 10 eC and then heated at 80 °C in an autoclave overnight. After concentration of the reaction medium to dryness, the residue is chromatographed on silica using a DCM/ methanol mixture (95/5; v/v) as the eluent to give 130 mg of the expected product. M.p. = 100°C. EXAMPLE 16 2-n-Butyl-4-spirocyclopentane-l-[ (2'-trifluoro-methylsulfonylaminobiphenyl-4-yl)methyl]-2-iraidazolin-5-one trifluoromethylsulfonate (I: R^ = -NHS02CF3, R2 = H, Ra = n-C4H9, CR4RS = cyclopentane, X - 0) A) 4-Methyl-2'-nitrobiphenyl 11.2 g of 2-nitrobromobenzene are mixed with 15 g of 4-iodotoluene and the mixture is heated to 195‘ģ and stirred at this temperature for 3 and a half hours. After returning to room temperature, it is taken up in DCM and heated to the reflux point, the hot solution is filtered on Celite® and the DCM is then evaporated off. ra = 6.5 g. B.p. = 80-120°C under 0.2 mm Hg, nD24 = 1.6042. B) 4-Bromomethyl-2'-nitrobiphenyl A mixture containing 6.5 g of 4-methyl-2'- 56 nitrobiphenyl, 5.42 g of NBS, 118 mg of azo-bis-iso-butyronitrile and 500 ml of carbon tetrachloride is refluxed for 5 hours. It is cooled to 0°C and filtered and the filtrate is concentrated to give 9 g of an oily product, which is used as such in the next step. C) 2-n-Butyl-l-[ (2'-nitrobiphenyl-4-yl)methyl]-4-spiro-cyclopentane-2-imidazolin-5-one A mixture containing 260 mg of 80% sodium hydride in 5 ml of DMF is prepared and 500 mg of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one, prepared in Example 2, step A, are added at room temperature under nitrogen. After stirring for 15 minūtes, 901 mg of 4-bromomethyl-2'-nitrobiphenyl in 5 ml of DMF are added and stirring is conti.nued for 24 hours. The reaction medium is concentrated to dryness and the residue is taken up in a water/ethyl acetate mixture. The organic phase is decanted, dried over sodium sul-fate and filtered and the ethyl acetate is then eva-porated off. The product obtained is chromatographed on silica using a DCM/ethyl acetate mixture (9/1; v/v) as the eluent to give 500 mg of the expected product. D) l-[ (2'-Arainobiphenyl-4-yl)methyl]-2-n-butyl-4-spiro-cyclopentane-2-imidazolin-5-one 450 mg of the product obtained in the previous step are placed in 10 ml of methanol in the presence of 5% palladium-on-charcoal, at room temperature, for hydrogenation. After filtration of the catalyst and evaporation, 240 mg of the expected product are obtained. E)
In 4 ml of DCM, 225 mg of the product obtained in the previous step are mixed with 0.1 ml of tri-ethylamine, 0.2 ml of trifluoromethylsulfonic anhydride is added under argon at -78*C and the mixture is then left to return to room temperature. The reaction - 57 - LV 10439 medium is washed with water and a solution of . sodium bicarbonate and then dried and concentrated to give 150 mg of an amorphous white solid. - NMR spectrum: 0.4-1.3 ppm : m : 7 Η : CH3-CH2-Cii2- 1.4-2.3 ppm : m : 10 H : CH3-CH2-CH2-CH2 and cyclo- pentane 4-4.8 ppm : AB system : 2 H : N-CH2-C6H4-7-7.6 ppm : m : 8 H : aromatic protons
8.3 ppm : s : 1 Η : -NH
10 ppm : sb : 1 H : CF3S03H EXAMPLE 17 2-n-Butyl-4-spirocyclopentane-l-[ (2'-trif luoro-methylsulfonylaminomethylbiphenyl-4-yl)methyl]-2-imi-dazolin-5-one trifluoromethylsulfonate (I: Rx = CH2NHS02CF3/ R2 = H, R3 = n-C4H9, CR4Rs « cyclopentane, X = 0)
The preparation is effected starting from the 1-[ (2,-aminomethylbiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one prepared in Exara-ple 14, step A. 322 mg of this compound and 0.122 ml of triethylamine are placed in 3.4 ml of DCM at -70eC and 0.294 ml of trifluoromethylsuļfonic anhydride is added. The mixture is left to return to roora tempera-ture, poured into dilute acetic acid and extracted with DCM, the extract is dried over sodium sulfate and filtered and the DCM is evaporated off. The residue is chromatographed twice on silica using DCM/ethyl acetate (95/5; v/v, then 99.5/0.5; v/v) as the eluent.
This gives m = 90 mg. M.p. = 90*C. 58 - NMR spectrum: 0.4-1.2 ppm : m : 7 H : -CH2-CH2-CH3 1.3-2.45 ppm : m : 10 H : CH2-CH2-CH2-CH3 and cyclo- pentane 4.1- 5 ppm : m : 4 H : N-CH2-C6H4- and NH-CH2-CeH4- 7.1- 7.7 ppm : m : 8 H : aromatic protons
8.4 ppm : ε : 1 Η : NH EXAMPLE 18 2-n-Butyl-l-[ (2'-(N-hydroxyacetamide)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (I: Rx = -CO-NHOH, R2 = H, R3 = n-C*H9, CRaRs = cyclopentane, X = O)
The compound prepared in Example 2 is freed from its trifluoroacetic acid salt by taking up this compound in an ethyl acetate/water mixture and bringing the solution to pH 6 by the addition of a saturated solution of sodium bicarbonate. The organic phase is washed with a saturated solution Of sodium chloride, dried over sodium sulfate, filtered and concentrated to give the free base in the form of a white solid. 450 mg of this compound are dissolved in chloroform, 860 ml of thionyl chloride are added at 0*C and the mixture is stirred at room temperature for 2 hours. The solution is concentrated and the traces of thionyl chloride are removed by azeotropic distillation with toluene. The acid chloride thus obtained is added dropwise in DMF solution to a solution containing 200 mg of hydroxylamine hydrochloride and 700 μΐ of DIPEA in 10 ml of DMF. After 2 hours at 0eC, the reaction medium is concentrated and the concentrate is taken up in 100 ml of DCM and 50 ml of water. The mixture is brought to pH 7 and the organic phase is extracted and - 59 - LV 10439 then dried over sodium sulfate. After filtration, the solution is concentrated. The product obtained is recrystallized from an ethyl acetate/ethyl ether/hexane mixture. 05 m = 360 mg. M.p. = 85*C. EXAMPLE 19 2-n-Butyl-4-spirocyclopentane-l- [ (2'-ureido- 10 biphenyl-4-yl)methyl]-2-imidazolin-5-one (I: = NHCONH2, R2 = H, R3 = n-CAH9, CR4Rb = cyclopentane, X = O) 15 This compound is prepared using the method des- cribed by B.B. Kobu et al. in Org. Synth., 1957, 37. 52, starting from the l-[ (2,-aminobiphenyl-4-yl)-methyl ] -2-n-butyl-4-spirocyclopentane-*2-*imidazolin-5-one prepared in Example 14, step A.
20 1 g of the latter is dissolved in 50 ml of 6 N hydrochloric acid and treated with potassium isocyanate for 1 hour at 5ec. The reaction medium is concentrated, the concentrate is taken up in ethyl acetate and the mixture is washed with sodium bicarbonate and then 25 with a saturated solution of sodium chloride. After drying over sodium sulfate and filtration, the solution is concentrated and the oil obtained is purified by chromatography on silica using a DCM/methanol mixture (9/1; v/v) as the eluent. 30 m = 600 mg. - NMR spectrum: 0.85 ppm ; t : 3 H : CHa-CH3 1.35 ppm : sext : 2 H : CH2-CH3 1.6 ppm : quint : 2 H : CH2-CH2-CH3 1.7-2 ppm ; m : 8 H : cyclopentane 35 60 2.45 ppm : t : 2 Η : CH2-CH2-CH2-CH3 4.8 ppm : s : 2 H : -CH2-C6H4- 6.05 ppm : s : 2 H : NH2
7-8 ppm : m : 9 H : 8 aromatic H + NHCO * EXAMPLES 20 AND 21 l-[ (2'-Carboxybiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imida2olin-5-one and l-[(2'-N-cyanocarboxamidebiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (I: Rx = CO-NH-CN, R2 = H, R3 = n-C3H7, CR4Rs = cyclohexane, X = 0) A) Ethyl butyrimidate hydrochloride
/H CH3 - CH2 - CH2 - C . HC1 OC2H5
This compound is prepared according to Mc Elvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827). 23 ml of butyronitrile are added at 0eC to a solution of 10.6 g of gaseous hydrochloric acid in 20 ml of anhydrous ethanol and then, after the reaction medium has been left to stand for 4 days at 0*C, it is poured into 200 ml of anhydrous ether at 0°c, with stirring; the precipitate formed is filtered off, washed with ether and then dried under vacuum to give 25.8 g of the expected product. B) Ethyl butyrimidate 16 g of the imidate obtained in step A are dissolved in 100 ml of dichloromethane and 50 ml of water, and 15 g of potassiura carbonate are added. After decantation, the dichloromethane is dried over - 61 LV 10439 potassium carbonate and then evaporated off to dryness without heating. C) Ethyl ester of l-arainocyclohexane (sic) carboxylic acid l-Aminocyclohexanecarboxylic acid is commer-cially available. 15 g of this amino acid are added at 0*C to a solution of 23 g of gaseous hydrochloric acid in 150 ml of anhydrous ethanol. The reaction medium is refluxed for 5 hours and then concentrated to dryness and the residue is taken up in ether. The white solid obtained is filtered off, washed with ether and then dissolved in a mixture of 300 ml of ether and 100 ml of water. The pH is brought to 9 by the addition of a solution of potassium carbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness to give 14 g of the expected product in the form of an oil. D) 2-n-Propyl-4-spirocyclohexane-2-imidazolin-5-one 14 g of the product obtained in step C are dissolved in 200 ml of xylene containing 0.6 ml ot acetic acid. Half the imidate obtained in step B is added and the mixture is heated to the reflux point. After 1 and a half hours, half the remaining imidate is added and the last quarter is then added after 4 hours. After a total reflux time of 7 hours, the medium is evaporated to dryness. The solid obtained is taken up in hexane, filtered off, washed with ether and then dried.
This gives 10.3 g of the expected imidazoli- none, M.p. = 124-125’C. - IR (CHC13):
1715 cm-1 : C=0 1635 cm-1 : C=N
Not;e: The compound present in solution is indeed an 62 imidazolin-5-one according to the values of the IR bands. E) 2-n-Propyl-4-spirocyclohexane-l-[ (2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 970 mg of the imidazolinone obtained in step D are added to 0.24 g of sodium hydride as an 80% disper-sion in oil, suspended in 10 ml of dimethylformamide. After stirring for 20 minūtes under nitrogen, 1.91 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl, prepared according to European patent application 324 377, are added over 5 minūtes. After stirring for 1 hour, the medium is concentrated to half its volume under vacuum and taken up in 100 ml of ethyl acetate and then in 20 ml of water. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/toluene mixture as the eluent to give 2.10 g of the expected product in the form of a wax. - IR (CHC13): 1705-1715 cm-1 : C=0, C=0 (ester, imidazolinone)
1635 cm-1 : C=N
Analysis of the NMR spectrum confirms the structure. F) l-[ (2'-Carboxybiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 20) 1.25 g of the tert-butyl ester obtained in step E are stirred for 45 minūtes in a mixture of 11 ml of dichloromethane and 15 ml of trifluoroacetic acid. After concentration under vacuum, the residue is taken up in ether. The solid formed is filtered off, washed with ether and then dried to give 1.04 g of a white solid. M.p. = 170-172*C. - NMR spectrum: 7.10-7.80 ppm : m : 8 H : aromatic protons - 63 - LV 10439 4.90 ρρτη : s : 2 Η : N-Ciļ2-C6H4- 2.45 ppm : t : 2 H : CH3-CH2-CH2- 1.40-1.80 ppm : m : 12 H : spirocyclohexane + CH3- CH3-CHa- 0.90 ppm : t : 3 H : CH3-CH2-CH2- 1.60 g of the trifluoroacetate obtained pre-viously are dissolved in 150 ml of ethyl acetate and 20 ml of water. 1 N sodium hydroxide solution is added to bring the pH to 5.0. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dry-ness. The solid residue is taken up in ethyl ether, filtered off and dried. m = 1.14 g. M.p. = 208-210‘C. G) 1-[ (2'-N-Cyanocarboxamidebiphenyl-4-yl)methyl]-2-propyl-4-spirocyclohexane -2-imidazolin-5-one (sic) (Example 21) 0.54 ml of thionyl chloride is added to 300 mg of the compound prepared in the previous step, suspen-ded in 5 ml of DCM. After 1 and a half hours, the reaction medium is concentrated under vacuum and then evaporated twice with benzene. The acid chloride thus obtained is dissolved in 2 ml of dioxane and added to a solution of 42 mg of cyanamide in 1 ml of dioxane con-taining 0.2 ml of 10 N sodium hydroxide solution. After 1 and a half hours, the reaction medium is dilu-ted with 150 ml of ethyl acetate and 20 ml of water, the pH is brought to 5 with acetic acid and the organic phase is decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. The residue is chromatographed on silica using a chloroform/methanol/acetic acid mix-ture (90/8/2; v/v) as the eluent to give 160 mg of the expected product in the form of a solid. 64 - IR (KBr):
2150 cm-1 ; C^N - Mass spectrum: MH- : 429 - NMR spectrum: 7.20-7.70 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 Η : Ν-0Η2-06Η4- 2.40 ppm : t : 2 H : CH3-CH2-CH2- 1.30-1.80 ppm : m : 12 H : CH3-CH2-CH2- and spiro- cyclohexane 0.85 ppm : t : 3 H : CH3-CH2-CH2 EXAMPLE 22 l-[ (2'-(N-4-carboxy-l,3-thiazol-2-ylacetamide)-biphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one
C00H (I: Ra = -CONH-, y t R2 — H, R3 n-C3H7, CR4Rs = cyclohexane, X = O)
This compound is prepared from the compound obtained in Example 20. 2-Amino-4-ethoxycarbonyl-l,3-thiazole is prepared according to B. Plouvier et al., J. Heterocycl.
Chem., 1989, 2£(6), 1646. A) l-[(2-(N-4-carbetoxy-l»3-thiazol-2-ylacetamido)-biphenyl-4-yl)methyl3-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (sic) 500 mg of BOP and 0.14 ml of triethylamine are added to a solution of 404 mg of the compound prepared in Example 20 and 190 mg of thiazole derivative in 4 ml of DCM and 1 ml of DMF. The mixture is stirred for 40 - 65 - LV 10439 hours at room temperature and then 7 hours at 50eC. The reaction raedium is taken up in 50 ml of ethyl acetate and washed twice with a KHS04-K2S04 solution, then twice with a saturated solution of sodium bicar-05 bonate and then once with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase is concentrated under vacuum and the residue is chromatographed on silica using an ethyl acetate/toluene raixture as the eluent to give 120 mg of 10 the expected product. M.p. = 96-98*C. B) 0.5 ml of 2 N sodium hydroxide solution is added to 110 mg of the product obtained in the previous 15 step, dissolved in 1 ml of methanoi and 1 ml of diox-ane. After stirring for 35 minūtes, the reaction medium is diluted with 10 ml of water and 60 ml of ethyl acetate and the pH is brought to 5 by the addi-tion of 1 N hydrochloric acid. The organic phase is 20 decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated. The residue is taken up in ether, filtered off and dried. m = 100 mg. 25 M.p. = 145-148°C. - NMR spectrum: 8.Q ppm : s : 1 Η : H in the 5 position of the thiazole 7.1- 7.7 ppm : ra : 8 H : aroraatic protons 30 4.7 ppm : s : 2 H ; N-CH2-CeH4- 2.25 ppm : t : 2 H : Cli2-CH2-CH3 1.2- 1.8 ppm : m : 12 H : cyclohexane and CH2-Cū2-CH3 0.85 ppm : t : 3 Η ί CH2-CH2-CH3 35 66 EXAMPLE 23 2-n-Butyl-l-[ (2'-(2-cyanoguanidinocarbonyl) -biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one ŅH2 (I: R^ = CONH-C=N-CN, R2 = H, R3 = n-C4H9, CR4Rs = cyclopentane, X = 0)
The acid chloride of the compound obtained in Example 2 is prepared. 1 g of this compound is placed in 20 ml of DCM, in the presence of 1.8 ml of thionyl chloride, and the mixture is stirred at roora tempera-ture for 2 hours. After concentration of the medium, the residue is taken up in benzene and the mixture is then concentrated again. The crude product isolated is then used. It is mixed with 417 mg of dicyanodiamide, 0.5 ml of 10 N sodium hydroxide solution, 0.5 ml of water and 10 ml of dioxane and the mixture is then stirred for 5 hours. The reaction medium is taken up in water and ethyl acetate, potassium carbonate is added and the mixture is then concentrated. The residue obtained is chromatographed on silica using a DCM/ methanol mixture (95/5; v/v) as the eluent. 100 mg of the expected product are isolated. M.p. = 105*C. EXAMPLE 24 4-Benzylidene-2-n-butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoroacetate (I: Rx = COaH, R2 = H, R3 = n-C4He, R^RS = =CH-CeHs, X = 0) A) Tert-butyl 4-(l-benzylidene-l-valerylaminomethyl-amidomethyl)biphenyl-2-carboxylate (sic) C02tBu
n-CiHq-C0-NH-C-C0-NH-CH2"C6Hi il CH-C6H5
Starting from N-Boc-a-dehydro-(L)-phenylala-nine, the N-carboxyanhydride of a-dehydro-(L)-phenyl-alanine is prepared according to R. Jacquier et al., Tetrahedron Lett., 1984, 23.(26), 2775. p. (sic). 644 mg of tert-butyl 4-aminomethylbiphenyl-2'-carboxylate are added to a solution of 430 mg of this compound in 5 ml of THF, the mixture is stirred for 2 hours at room temperature, 1 ml of methyl orthovalerate is then added and the mixture is evaporated to dryness under vacuum without heating. The residue is heated for 3 hours at 100°C, concentrated under vacuum and then chromato-graphed on silica using a hexane/ethyl acetate mixture (4/1; v/v) as the eluent to give 580 mg of a white solid. M.p. = 154*C. - NMR spectrura; 1.3 ppm : s : 9 H ; tBu 0.65 ppm : t : 3 H : CH3 (nBu)
2 ppm : t : 2 H : CH3-CH2-CH2-Cži2-CO
4.4 ppm : d : 1 H ; CH2-NH 6.8 ppm ; s : 1 H ; CH (=CH-CeHs) B) 4-Benzylidene-2-n-butyl-l-[(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-imidazolin-5-one 440 mg of the compound obtained in step A are dissolved in 1 ml of acetic acid and heated for 30 minūtes at 100*0.
The solution is evaporated to dryness under 68 vacuum and the residue is chromatographed on silica using a hexane/ethyl acetate mixture (4/1; v/v) as the eluent to give 130 mg of the expected product in the form of an oil. - NMR spectrum: 4.9 ppm : s : 2 H : CH2 (N-CH2-C6H4-) C) 100 mg of the compound obtained in the previous step are dissolved in 1 ml of DCM, 1 ml of trifluoro-acetic acid is added and the mixture is then stirred for 40 minūtes at room temperature and evaporated under vacuum. The residue is taken up several times in DCM and then evaporated. A white solid precipitates on the addition of ethyl ether. m = 101 mg. M.p. = 85°C. - Mass spectrum: MH- : 439 - NMR spectrum: 0.82 ppm : t : 3 H : CH3 (nBu) 1.3 ppm : sext : 2 H : CH3-CH2- 1.6 ppm : m : 2 H : CH3-CH2-CH2- 2.6 ppm : t : 2 H : CH3-CH2-CH2-CHa-4.82 ppm : s : 2 H : CH2-C6H4- 7.05 ppm : s : 1 H : =Cū~C6Hs 7.2-8.2 ppm : m : 13 H : aromatic protons EXAMPLE 25 4-Benzylidene-l-[(2'-carboxybiphenyl-4-yl)-methyl]-2-phenyl-2-imidazolin-5-one (I: Rx = COaH, Ra = H, R3 = CeHs/ R4Rs = =CH-CeH5, X = 0) - 69 - LV 10439 A) 4-Benzylidene-2-phenyloxazol-5-one 1.8 g of hippuric acid and 0.4 g of potassium bicarbonate are dissolved in 4 ml of acetic anhydride, the solution is heated for a few minūtes at 50 *C and then cooled to room temperature and 1.49 g of benz-aldehyde are added. After 1 hour at room temperature, 20 ml of distilled water are added at 80eC. The solid which precipitates is filtered off, washed with water and ethanol and then dried to give 1.24 g of the expected product in the form of a yellow solid. M.p. = 215*C. - NKR spectrum: 7.4 ppm : s : 1 H : =CH-CeHs 8.1-8.4 ppm : m : 10 H : aromatic protons B) Tert-butyl 4-(l-benzoylamino-l-benzylidenemethyl-amidomethyl)biphenyl-2'-carboxylate A mixture cčntaining 500 mg of the compound obtained in the previous step‘; 570, mg of tert-butyl 4-aminomethylbiphenyl-2,-carboxylate and 10 ml of pyri-dine is heated at 110°C for 3 hours. It is evaporated under vacuum, the residue is taken up in chloroform and the mixture is then evaporated again. The residue is chromatographed on silica using a hexane/ethyl acetate mixture (3/1 then 2/1; v/v) as the eluent to give 106 mg of the expected product in the form of a yellow solid. - NHR spectrum:
1.1 ppm : s : 9 H : tBu 4.35 ppm : t : 2 H : -CHa-NH 7.05-7.06 ppm : m : 19 H : aromatic protons + . CeH5-CS= 8.65 ppm : t : 1 H : Niļ-CH2 9.9 ppm : s : 1 H : NH-CH= C) A mixture of 1.2 g of the compound obtained in 70 the previous step and l.l g of freshly melted sodium acetate is refluxed for 6 hours in 5 ml of acetic acid. It is left to cool and an insoluble material is then precipitated by the addition of chloroform. The fil-trate is evaporated and the residue is chromatographed on silica using a chloroform/methanol mixture (98/2; v/v) as the eluent. The solid obtained is recrystal-lized from ethyl ether. m = 692 mg. M.p. = 120*C. - NMR spectrum; 4.95 ppm : s : 2 H : CH_,-C6H4- 7.1-8.3 ppm : m : 19 H : argmatic protons + =CH-C6H5 EXAMPLES 26 AND 27 2-n-Butyl-l-[(2'-(2-methyltetrazol-5-yl)bi-phenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (Example 26) and 2-n-butyl-l-[ (2'-(l-methyltetra-zol-5-yl)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one (Example 27)
In 10 ml of DMF, 500 mg of the compound pre-pared in Example 5 are mixed with 58 mg of sodium hydride, the mixture is stirred for 30 minūtes, 179 mg of methyl iodide and 2 ml of DMF are then added and the mixture is stirred at room temperature for 4 hours. The reaction medium is concentrated.and the concentrate is taken up in water and then extracted with ethyl acetate. The extract is dried over sodium sulfate and filtered and the solvent is evaporated off. The residue is chromatographed on silica using a hexane/ethyl acetate mixture (6/4; v/v) as the eluent. 2 fractions are isolated; 90 mg of the compound of Example 26 and 184 mg of the compound of Example 27 - 71 - LV 10439 - NMR spectra:
Example 26 0.7 ppm : t : 3 H : CH3- (nBu) 1.2 ppm : sext : 2 H : CH3-CH2- 05 1.4 ppm : quint: 2 H : CH3-CH2-CH2- 1.5- 1.9 ppm : m : 8 Η ; cyclopentane 2.25 ppm : t : 2 H : CH3-CH2-CH2-CH2- 4.15 ppm : s : 3 H : N-CH3 4.6 ppm : s : 2 H : -N-CK2-C6H4- 10 7 ppm : AA', BB' system : 4 H : CH2-CeH4- 7.3- 7.75 ppm : m : 4 H : CH2-CeH4-C6H4-Example 27 0.7 ppm : t : 3 H : CH3 (nBu) 1.15 ppm : sext : 2 H : CH3-CE2- 15 1.38 ppm : quint : 2 H : CH3-CH2-CH2- 1.5- 1.9 ppm : m : 8 H : cyclopentane 2.2 ppm : t : 2 H : CH3-CH2-CH2-Ca2-3.35 ppm : s : 3 H : N-CHa 4.6 ppm : s : 2 H : N-CH2-CeH4 20 7 ppm : AA', BB' system : 4 H : N-CH2-C6H4- 7.4- 7.8 ppm : m : 4 H : CH2-CeH4-C6H4- EXAMPLE 28 2-n-Butyl-6-spirocyclopentane-3- [ (2'-(tetrazol-25 5-y1)biphenyl-4-yl)methyl]-4(1H)-5,6-dihydropyrimidin- 4-one A) Ethyl cyclopentylideneacetate 6 g of 80% sodium hydride are placed in 40 ml of benzene, and 57.1 ml of ethyl triethylphosphono-30 acetate are added dropwise at ā temperature below 35*C. After 1 hour at room temperature, 24.3 ml of cyclo-pentanone are added dropwise. The mixture is heated at 65*C for 15 minūtes and then cooled to room temperature and the supernatant liquor is decanted. 25 ml of benzene are added, the mixture is heated at 65°C for 15 35 72 minūtes, cooled and decanted and the supernatant liquor is then recovered. The opefation is repeated once. Evaporation of the liquors gives 42 g of the expected product, which is distilled. B.p. = 102"c under 11 mm of mercury. m = 22.8 g. B) (l-Aminocyclopentyl)acetamide 150 ml of gaseous ammonia are added to 20 g of the ethyl cyclopentylideneacetate prepared previously and the mixture is heated at 150*C for 72 hours. The product obtained after evaporation is purified by chromatography on silica using a DCM/methanol/20% aqueous ammonia mixture (90/10/1; v/v/v) as the eluent. The product obtained is dissolved in DCM and the solution is dried over sodium sulfate. It is filtered and the DCM is evaporated off to give 7.2 g of the expected product. C) 2-n-Butyl-6-spirocyclopentane-4(1H)~5,6-dihydropyri-midin-4-one A mixture containing 4.57 g of the (1-amino-cyclopentyl)acetamide prepared previously, 25 ml of methyl orthovalerate and a few drops of acetic acid is heated at 100’c for 18 hours. After evaporation of the excess orthovalerate, the residue is taken up in an ethyl acetate/sodium bicarbonate mixture, then washed with an aqueous solution of sodium chloride, dried over (sic) sodium sulfate and then purified by chromato-graphy on silica using a DCM/methanol mixture (98/2; v/v) as the eluent. m = 5 g. - NMR spectrum: 0.75 ppra : t : 3 H ; CH3 (nBu) 1.2 ppm ; sext ; 2 H : CH3-CK2- 1.3-1.8 ppm : m : 10 H ; CH3-CH2-CH2 and cyclopentane 2 ppm : t : 2 H ; CH3-CH2-CH2-CE2- - 72 - LV 10439
2.15 ppm : s : 2 H : CH2-CO 9.95 ppm : sb : 1 Η : NH
This compound is the one obtained in Example 10, step C. D) 2-n-Butyl-4-spirocyclopentane-l-[(2'-(triphenyl-methyltetrazol-5-yl)biphenyl-4-yl)methyl]pyrimidin-6-one 327 mg of 80% sodium hydride in 30 ml of DMF are mixed for 30 minūtes under nitrogen with 1.5 g of the pyrimidinone prepared previously, and 5.27 g of 4-bromomethyl-2'-(triphenylmethyltetrazol-5-yl)biphenyl are added. After stirring for 4 hours at room tempera-ture, the solvents are evaporated off and the residue is taken up in ethyl acetate and water, dried over sodium sulfate and concentrated. The product obtained is purified by chromatography on silica using an ethyl acetate/hexane mixture (3/7; v/v) as the eluent. m = 3.2 g. E) 3 g of the compound obtained in the previous step are placed in 15 ml of methanol, the mixture is cooled in a water/ice bath, 2.2 ml of 4 N HCl are added and the mixture is stirred for 5 hours at room tempera-tūre, After evaporation, the residue is taken up in ethyl acetate and water, and sodium hydroxide solution is then added to give a basie pH (pH 11). The mixture is left to decant and the aqueous phase is washed with ethyl ether and toluene and then ether again. This aqueous phase is brought to pH 5 by the addition of dilute hydrochloric acid and is then extracted with ethyl acetate and the extract is dried and concentrated. The product obtained is purified on silica using a DGM/methanol mixture (95/5? v/v) as the eluent to give 800 mg of the expected product. 74 - NMR spectrum: 0.85 ppm : t : 3 H : CH3 (nBu) 1.30 ppm : sext : 2 H : CH3-CH2 1.40-1.95 ppm : m : 10 H : cyclopentane and CH2-CH2-CH2-CH3 2.30 ppm : t : 2 H : CH2-CH2-CH2-CH3
2.55 ppm : s : 2 H : CH2-CO 4.95 ppm : s : 2 H : N-CH2-CeH4>- 7.05 ppm : m : 4 H : CH2-C6H4- 7.55-7.82 ppm : m : 4 H : CH2-C6H4-CeH4- EXAMPLE 29 2-n-Butyl-3-[ (2'-carboxybiphenyl-4-yl)methyl ]-5-spirocyclopentane-5(1H)-5,6-dihydropyrimidin-4-one trifluoroacetate A) Ethyl l-cyanocyclopentanecarboxylate
This compound is prepared according to Helv. Chim. Acta, 1952, 21(7), 2561. 9.2 g of sodium are dissolved in 200 cm3 of absolute ethanol. Half the solution of sodium ethylate formed is poured into a funnel. 24.88 g of ethyl cyanoacetate are added to the remaining half and the mixture is brought to the reflux point. 43.19 g of 1,4-dibromobutane are poured into another funnel and the solution of sodium ethylate and the 1,4-dibromobutane are simultaneously added dropwise to the reaction medium. When the addition is complete, reflux is maintained for 2 hours. The mixture is eva-porated and the residue is taken up in an ethyl ether/ water mixture, washed with a saturated. solution of sodium chloride and then dried. The product obtained distils at 115-120*C under 11 mm of mercury. m = 24 g. B) Ethyl l-aminomethylcyclopentanecarboxylate
This compound is prepared by the catalytic - 75 - LV 10439 hydrogenation of ethyl l-cyanocyclopentanecarboxylate. 20 g of ethyl l-cyanocyclopentanecarboxylate are placed in 200 ml of a 10% solution of ammonia in ethanol and hydrogenated at 6.0 °C under a pressure of 100 bar in the presence of rhodium-on-alumina for 72 hours. After filtration on cellite® (sic) and evapora-tion, the residue is chromatographed on silica using a DCM/methanol/20% aqueous ammonia mixture (98/2/0.5; v/v/v) as the eluent. m = 12.8 g. C) 2-n-Butyl'-5-spirocyclopentane-4(lH)-5, 6-dihydropyri-midin-4-one A mixture containing.. 13.12 g of the compound obtained in the previous step and 13.5 g of ethyl valerimidate in 100 ml of xylene containing a few drops of acpetic acid is refluxed for 13 hours. The reaction medium is evaporated and the residue is taken up in ethyl acetate and a 10% solution of sodium carbonate and then dried and concentrated. m = 14 g. M.p. = 89-91’c. - NMR spectrum: 0.80 ppm : t : 3 H : CH3 (nBu) 1.10-1.80 ppm : m : 12 H : CH3-Cti2-CH2- and cyclo- pentane 2.05 ppm ; t : 2 H ; CH3-CH2-CH2-CH2- 3.20 ppm ; s : 2 H : CH2 (pyrimidinone)
10 ppm : 1 H : s : NH-CO D) 2-n-Butyl-5-spirocyclopentane-3-[ (2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-4(lH)-5,6-dihydropyrimi-din-4-one 500 mg of the product obtained in the previous step are placed in 40 ml of DMF in the presence of 115 mg of an 80% dispersion of sodium hydride in oil, under argon, and stirred at room temperature for half an 76 hour. 1.08 g of 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl are added and the mixture is stirred for 2 hours. After evaporation, the residue is taken up in an ethyl acetate/water mixture, washed with a saturated 05 solution of sodium chloride and then dried, concentra-ted and chromatographed on silica using an ethyl acetate/hexane mixture (3/7; v/v) as the eluent. m = 280 mg. E) 10 250 ml of the tert-butyl ester prepared in the previous step are dissolved in 10 ml of DCM. The solution is cooled in a bath of iced water, 5 ml of cold trifluoroacetic acid are then added and the mixture is stirred for one hour in the cold and then 1 hour at 15 room temperature. It is evaporated-under reduced pres-sure. The residue is taken up in ethyl ether and then evaporated. The operation is repeated 3 times, the evaporation residue is then taken up in hexane and tri-turated and the hexane is then decanted. The product 20 is taken up in ethyl ether and the precipitate is fi'l-tered off. m = 190 mg. M.p. = 153-155*C. - NMR spectrum; 25 0.85 ppra ; t : 3 H : CH3 (nBu) 1.35 ppm ; sext ; 2 H ; CH3-CH2“ 1.45-2.20 ppm : m : 10 H ; CH3-CH2-CH2- and cyclo- pentane 2.80 ppm : t : 2 H : CH3-CH2-CH2-CH2-30 3.80 ppm : s : 2 H : CH2 (pyrimidinone) 5.15 ppm ; s : 2 H ; N-CH2- 7.25 ppm : m ; 8 H : aromatic protons 35 - 77 -LV 10439
Table 1 R4
(I) (Ex.) R1 R3 cr4r5 Salt M.p. 9C (30) co2h n-C4Hg cyclohexane TFA 172-174 (31) co2ch3 n-C4H9 cyclopentane - 86-87 (32)* co2h n-C4H9 C(CH3)C6H5 TFA 55-60 (33) co2h n-C4Hg C(C2Hs)2 TFA 82-84 (34) co2h n-C3H7 cyclopentane TFA 164 (35) (**) n-C4H9 cyclopentane - 163-164 (36) co2h c6h5 cyclopentane TFA 178 (37) co2h n-C4H3 cycloheptane TFA 160-162 (38) co2h ch3 cyclopentane TFA 140 (39) co2h n-C4H9 cyclopropane - 204-205 (40) tetra2ol- 5-yi -ch2-ch2- ch-ch2 cyclopentane - 110 (41) tetrazol- 5-yl n-C4H9 cyclohexane - 130 (42) tetrazol-5-yl n-C3H7 cyclohexane - 141 (43) co2h cyclo- pentyl cyclopentane TFA 82-88 (44) co2h n'C5H„ cyclopentane TFA 151 (45) co2h ch2-c6h5 cydopentane TFA 88 (46) co2h H cyclopentane - 230 (47) co2h n-C4Hg cyclobutane TFA 178 78 (48) C0zH n-C4H9 cyclododecane TFA 130-135 (49) co2h n-C4H9 2-a’daraantane TFA 164-166 05 (50) co2h n-C4H9 4-phenyl-cyclohexane TFA 155-157 (51) co2h n*C4Hg 4-raethyl- cyclohexane TFA 198-200 (52) co2h n-C4H9 N-acetyl-4- piperidine TFA 90-95 10 (53) co2h c3f7 cyclopentane - 141-143 (54)* co2h n-C4H9 C-./ ^CF3 - 207-209 15 (55)* co2h n-C4H9 C-/ Vci TFA 105 (56) co2h n-C4H9 N-C0 TFA 95-105 20 (57) co2h n-C4H9 y n-co-ch-nh2 vy CH-C2H; CH3 TFA ) 125-135 (58) co2h n-C4H9 / N-C0 c6h5 TFA 85-90
25 ** R, - H and R2 - C02H * These cornpounds have an asymroetric carbon and are isolated in the form of a mixture of optical isomers. 30 35 - 79 - LV 10439 WHAT IS CLAIMED IS: 1. A compound of the formula R4 R57L(CH2)t
2(CH2) N Λ/'· jL i1 CH2 !ļ \— ('! \=J V=y in which: - Rx and R2 are sirailar or different and are each inde-pendently hydrogen or a group selected from a Cx-Ce alkyl, a Cx-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is Cx-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a raethylsulfonylaraino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyano-acetaraide, an N-hydroxyacetamide, an N-(4-carboxy-1,3-thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyanoguanidinomethyl, an imi-dazol-l-ylcarbonyl and a 3-cyano-2-methylisothio-ureidoraethyl, with the proviso that at least one of the substituents Rx or R2 is other than hydrogen; - R3 is a hydrogen, a Cx-C6 alkyl which is unsubsti-tuted or substituted by one or more halogen atoms, a C2-Ce alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a CX-CA alkyl, a halogenoalkyl, a Cx-C+ polyhalogenoalkyl, a hydroxyl or a Cx-C4 alkoxy; 80 - R4 and Rs are each independently a Cx-Ce alkyl, a phenyl or a phenylalkyl in which the alkyl is said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a perfluoro- alkyl, a hydroxyl and a Cx-C4 alkoxy; - or R4 and Rs together form a group of the formula =CR7Ra, in which R7 is hydrogen, a Cx-C4 alkyl or a phenyl and Re is a Cx-C4 alkyl or a phenyl; - or else R4 and Rs together are either a group of the formula (0Η2)„ or a group of the formula (CH2)pY-(CHa)eī» in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a 0χ-04 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C^C;,, or a group N-R6, in which Re is a hydrogen, a Cx-C4 alkyl, a phenylalkyl in which the alkyl is Cx-C3, a Cx-C4 alkylcarbonyl, a Cx-C4 halo-genoalkylcarbonyl, a Cx-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and Rs, together with the carbon atom to which they are bonded, form an indane or an adaman-tane; - p + q = m; - n is an integer between 2 and 11; - m is an integer between 2 and 5; - X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one; and its salts. 2. A compound according to claim 1 wherein Rx is in the ortho position and is a carboxyl or tetrazolyl group and Ra is hydrogen. 3. A compound according to claim 1 or claim .2 wherein R4 and Rs form a cyclopentane or a cyclohexane with the carbon to which they are bonded. 4. A compound according to any one of claims 1 to 3 - 81 LV 10439 wherein Ra is a linear C1-Ce alkyl group. 5. A compound according to any one of claims 1 to 4 wherein X is oxygen. 6. A compound according to any one of claims 1 to 5 wherein z = t = 0, 7. A compound according to claim 1 which is 2-n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-5-yl)biphenyl-4-yl)raethyl]-2-imidazolin-5-one or one of its salts with acids or bases. 8. A method of preparing a compound (I) according to any one of claims 1 to 7, wherein: al) a heterocyclic derivative of the formula
R4 R5_L(CiI2)t z(C:(2) N λ I I I V* 0 \n'
I II in which z, t, R3, R4 and Rs are as defined for (I) in claim 1, is reacted with a (biphenyl-4-yl)methyl derivative of the formula R'z I Hal-CH2—/ \_/ ΡΛ 3 in which Hal is a halogen atom and R'x and R'a are res-pectively either Rx and Ra or a precursor group of Rj^ and Ra; bl) if appropriate, the resulting compound of the formula 82 R4 R5_L(CH2)t
z(CH2) N
λ 0 nN/ R’z I R1 i 1 Cll2 /īh w W is treated with Lawesson's reaģent [2,4-bis(4-methoxy-phenyl)-l,3-dithia-2,4-diphosphetane 2,4-disulfide ]; and cl) the compound obtained in al) or bl), of the formula R4 R5i-(CH2)t 2(CH2) n Λ/" ·'· R’i 1 5 - - // 1 W r\ " \_/ in which X is an oxygen atora or a sulfur atom, is treated to give the compound (I) by conversion of the' groups R' x and/or R'2 to the groups Rx and/or R2 respectively. 9. A method of preparing a compound (I) according to any one of clains 1 to 7, wherein: a2) an amino acid of the formula 7 1
4\ /(CH2)fSHPr C S5^(CH2)z CGCH' 83 LV 10439 in which z, t, R4 and Rs are as defined for (I) in claim 1, and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methyl~ amine derivative of the formula
8 in which R^ and R'a are respectively either Rx and Ra or a precursor group of Rt and R2; b2) after deprotection of the amine, the resul-ting compound of the formula C- (C!b)2-C-NH-CIb
9 \ 0
II R5 (Cih)t-N"H2 is then treated with an alkyl ortho-ester of the formula R3C(OR)3 (10), in which R3 is as defined for (I) in claim 1 and R is a C^-C* alkyl? c2) if appropriate, the resulting compound of the formula R4 R5/l_iCH2)t V \ 2(CH2) Ν’
1 is treated with Lawesson's reaģent [2,4-bis(4-methoxy- 84 phenyl)-1,3-dithia-2,4-diphosphetane 2, 4-disulfide]; and d2) the compound thus obtained in b2 or c2, of the formula
2(C;l2) S
5 is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'a and/or R\ to the groups R2 and/or Rx respectively. 10. A method of preparing a compound (I) according to claim 6, wherein: a3) a (biphenyl-4-yl)methyl derivative of the formula
3 in which Hal is a halogen atora and R'^ and R'a are res-pectively either Rx and R2 or a precursor group of Rx and R2, is reacted with an iraidazole derivative of the formula
K 11 85 LV 10439 in which R3, R* and Rs are as defined for (I) in claim 1, in the presence of oxygen and UV irradiation and in a basie medium; b3) if appropriate, the resulting compound of the formula
R' R5^-S
is treated with Lawesson's reaģent [2,4-bis(4-methoxy-phenyl)-l,3-dithia-2,4-diphosphetane 2,4-disulfide]; and c3) the compound thus obtained in b3 or c3, of the formula
is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R^ and/or R'a to the groups Rt and/or Ra respectively. 11. Λ compound of the formula (II) 86
z(Cih) N
X
N H in which: - R3 is a hydrogen, a C1-C6 alkyl which is unsubsti- tuted or substituted by one or more halogen atoms, a Ca-Ce alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cx-C3, or a phenyl-alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a alkyl, a
Cx-C4 halogenoalkyl, a 0χ-04 polyhalogenoalkyl, a hydroxyl or a Cx-C4 alkoxy; - R4 and Rs are each independently a C^-Cg alkyl, a phenyl or a phenylalkyl in which the alkyl is said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a Cx-C4 perfluoro-alkyl, a hydroxyl and a CX-CA alkoxy; - or R4 and Rs together form a group of the formula =CR7Ra, in which R7 is hydrogen, a Cx-C4 alkyl or a phenyl and Ra is a C1-C4 alkyl or a phenyl; - or else R4 and R5 together are either a group of the formula (0Η2)Λ or a group of the formula (CHa)pY-(CHa)eļ, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cx-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, or a group N-R6, in which R6 is a hydrogen, a Cx-C4 alkyl, a phenylalkyl in which the alkyl is CJL-C3, a Cx-C4 alkylcarbonyl, a Cx-C4 halo-genoalkylcarbonyl, a Cx-C4 polyhalogenoalkylcarbonyl, - 87 -
LV 1043D a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and Rs, together with the carbon atom to which they are bonded, form an indane or an adaman-tane; - p + q = m; - n is an integer between 2 and 11; - m is an integer between 2 and 5; - X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one; with the liraitation that - if z and t are zero and X is an oxygen atom, • R^ and Rg are other than a C^-Cg alkyl, a phenyl or a phenyl-alkyl in which the alkyl is C^C^, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C^-C* perfluoroalkyl, a hydroxyl and a C^-C* alkoxy; • or R4 and Rs together are other than a group N-R* in which R^ is a hydrogen, a Cl-cji alkyl or a phenylalkyl in which the alkyl is C1~Ca; and . n is other than 6 ; or when Rg represents a substituted phenyl group, R^ and Rg together are other than a group in which n is between 3 and 5 ; and - if z = 1 and Ra is a phenyl, R4 and Rs are each other than a methyl. 12. A corapound according to claim 11 of the formula
(II') in which X is an oxygen atom or a sulfur atom and R3 is 88 a hydrogen, a C^-C^ alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C^-C^, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a CX-CA alkyl, a CX-CA halogenoalkyl, a Cl-C4 polyhalogenoalkyl, a hydroxyl or a Οχ-0Λ alkoxy/ with the proviso that is other than a substituted phenyl group when X is oxygen. 13. A compound according to claim 11 of the formula
i H in which R3, R4, Rs and X are as defined above for (II) in claim 10. 14. A compound according to claim 11 of the formula
(II"7) in which: - R3 is a hydrogen, a alkyl. which is unsubsti tuted or substituted by one or more halogen atoms, a Ca-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is or a phenyl- alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C^-C^ alkyl, a 89
Cx-C4 halogenoalkyl, a Cx-C4 polyhalogenoalkyl, a hydroxyl or a Cx-C4 alkoxy; - R4 and R5 are each independently a 0χ-06 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C=ļ, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C^-C^ perfluoro-alkyl, a hydroxyl and a Cx-C4 alkoxy; - or R4 and Rs together form a group of the formula =CR7Rn, in which R7 is hydrogen, a Cx-C4 alkyl or a phenyl and Ra is a Cx-C4 alkyl or a phenyl; - or R4 and Rs together are either a group of the formula (CH3)n or a group of the formula (CH2)pY-(CHa)q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a Cx-c4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is Cx-C3, or a group N-R6, in which R6 is a hydrogen, a Cx-C4 alkyl, a phenylalkyl in which the alkyl is 0Α-04, a C1-C4 alkylcarbonyl, a Cx-C4 halo-genoalkylcarbonyl, a Cx-C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and Ra, together with the carbon atom to which they are bonded, form an indane or an adaman-tane; - p + q = m; - n is an integer between 2 and 11; - m is an integer between 2 and 5; and - X is an oxygen atom or a sulfur atom; with the limitation that R3 is other than a phenyl if r4 and Rs are each a methyl. 15. A raethod of preparing a compound according to any one of claims 11 to 14, which comprises reacting a compound of the formula 14
Ra-B 90 90 11 to 14 in which R3 has the definition indicated in claims and B is - a group C(OR)3
NH or a group
OR - a group COHal R being a C1-CA alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula
R4 (CH2)3C0A
in which and R5 are as defined above for (II) in claim 10 and A is an OH group, an NH2 group or a group OR', R' being hydrogen or a Cx--C4 alkyl, and then, if appropriate, treating the resulting compound with Lawesson's reaģent (2,4-bis(4-methoxyphenyl)-l,3-di-thia-2,4-diphosphetane disulfide). 16. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present as the active principle. 17. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a beta-blocking compound. 18. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a diuretic. 19. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a non-steroidal antiinflammatory. 20. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a calcium antagonist. LV 10439 - 91 - 21. A pharmaceutical composition in which a conpound according to any one of claims 1 to 7 is present in association with a tranguilizer.

Claims (14)

LV 10439 Izgudrojuma formula. I. N-Aizvietoti heterocikliskie savienojumi ar formulu:EN 10439 Invention Formula. I. N-Substituted heterocyclic compounds of the formula: I kurā: - Rj un R2 ir vienādi vai atšķirīgi un katrs, neatkarīgi viens no otra, ir ūdeņradis vai grupa, izvēlēta no alkil- Cj-Cg, alkoksi- C1-C4, amino-, aminometil-, karboksi-, alkoksikarbonil-, kurā alkoksigrupa ir ar C1-C4, ciāno-, tetrazolil-, metiltetrazolil-, metilsulfonilamino-, trifluormetilsulfonilamino-, trifluormetilsulfonilaminometil-, N-ciānoacetamīdo-, N-hidroksiacetamīdo-, N-/(4-karboksi)-I,3-tiazol-2-il/-acetamīdo-, ureīdo-, 2-ciānoguanidīnkarbonil-, 2-ciānoguanidīnmetil-, I-imidazolilkarbonil-, 3-ciāno-2-metilizotioureīdometil- grupām, pie nosacījuma, ka vismaz viens no aizvietotājiem Rj vai R2 ir atšķirīgs no ūdeņraža; - R3 ir ūdeņradis, alkil- Cj-Cg, neaizvietots vai aizvietots ar vienu vai vairākiem halogēna atomiem, alkenil- C2-Cg, cikloalkil-C3-C7, fenilalkil-, kurā alkil-ir ar C1-C3, fenilalkenil-, kurā alkenil- ir ar C2-C3, fenil-, uzrādītās fenilgrupas ir 2 neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēna atomiem, alkil- C1-C4, halogēnalkil- Cj-C^ polihalogēn- C1-C4, hidroksil- vai alkoksi- C1-C4; - R4 un R5 ir katrs, neatkarīgi viens no otra, alkil- Cj-Cg fenil-, fenilalkil-, kurā alkil- ir ar C1-C3, uzrādītās alkil-, fenil- un fenilalkilgrupas ir neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēna atomiem vai vienu grupu, kura izvēlēta no perfluoralkil- C1-C4, hidroksil-, alkoksi- CJ-C4 grupām; - vai R4 un R5 kopā veido grupu ar formulu =CR7Rg, kurā R7 ir ūdeņradis, alkil- CJ-C4 vai fenil-, bet Rg ir alkil- C1-C4 vai fenil-; -vai arī R4 un R5 kopā veido grupu ar formulu (CH2)n. vai grupu ar formulu (CH2)pY(CH2)q, kurā Y ir skābekļa atoms, vai sera atoms, vai oglekļa atoms, aizvietots ar alkil- C1-C4, fenil- vai fenilalkil-, kurā alkil- ir ar C1-C3, vai grupu N-Rg, kurā Rg ir ūdeņradis, alkil- CJ-C4, fenilalkil-, kurā alkil- ir ar C1-C3, alkilkarbonil- C1-C4, halogenalkilkarbonil- C1-C4, polihalogenalkilkarbonil- CJ-C4, benzoil-, α -aminoacil- vai N-aizsarggrupa, vai R4 un R5 kopā ar oglekļa atomu, pie kura tie pievienoti, veido indiān- vai adamantān-; - p + q = m ; - n ir vesels skaitlis ar vērtībām no 2 līdz II; - m ir vesels skaitlis ar vērtībām no 2 līdz 5 ; - X ir skābekļa atoms vai sēra atoms ; - z un t ir nulle vai viens no indeksiem ir nulle, bet otrs - ir I; un tā sāļi.Wherein: R 1 and R 2 are the same or different and each independently of one another is hydrogen or a group selected from alkyl-C 1 -C 8, alkoxy-C 1 -C 4, amino, aminomethyl, carboxy, alkoxycarbonyl, wherein alkoxy and C1-C4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N- (4-carboxy) -1,3-thiazole - 2-yl / -acetamide, urea, 2-cyanoguanidinecarbonyl, 2-cyanoguanidine methyl, I-imidazolylcarbonyl, 3-cyano-2-methylisothioureamethyl, with the proviso that at least one of R 1 or R 2 is different hydrogen; - R 3 is hydrogen, alkyl-C 1 -C 8, unsubstituted or substituted with one or more halogen atoms, alkenyl-C 2 -C 8, cycloalkyl-C 3 -C 7, phenylalkyl, wherein alkyl is C 1 -C 3, phenylalkenyl, wherein alkenyl - is with C2-C3, phenyl, the phenyl groups shown are 2 unsubstituted or substituted with one or more halogen atoms, alkyl-C 1 -C 4, haloalkyl-C 1 -C 4 polyhalogen-C 1 -C 4, hydroxy or alkoxy-C 1 -C 4 ; - R4 and R5 are each independently of each other, alkyl-C 1 -C 8 phenyl, phenylalkyl- in which alkyl is C 1 -C 3, alkyl, phenyl and phenylalkyl groups are unsubstituted or substituted with one or more halogen atoms or one group selected from perfluoroalkyl-C1-C4, hydroxy, alkoxy-CJ-C4; - whether R4 and R5 together form a group of the formula = CR7Rg, wherein R7 is hydrogen, alkyl-CJ-C4 or phenyl, and R8 is alkyl-C1-C4 or phenyl; - or R4 and R5 together form a group of formula (CH2) n. or a group of formula (CH2) pY (CH2) q wherein Y is oxygen or sera or carbon substituted with alkyl-C1-C4, phenyl or phenylalkyl, in which alkyl is C1-C3, or a group N-Rg, wherein Rg is hydrogen, alkyl-CJ-C4, phenylalkyl, wherein alkyl is C1-C3, alkylcarbonyl-C1-C4, haloalkylcarbonyl-C1-C4, polyhaloalkylcarbonyl-CJ-C4, benzoyl, α-aminoacyl or N-protecting group, or R 4 and R 5 together with the carbon atom to which they are attached form an Indian or adamantane; - p + q = m; - n is an integer with values from 2 to II; - m is an integer with values from 2 to 5; - X is an oxygen atom or a sulfur atom; - z and t are zero or one of the indices is zero, the other one is I; and its salts. 2. Savienojums, atbilstoši izg.f.I.punktam, kas a t š ķ i r a s ar to, ka Ri ir orto-stāvoklī un ir kārboksigrupa vai tetrazolilgrupa, bet R2 ir ūdeņradis.2. A compound according to claim 1 wherein R 1 is ortho and is a box or tetrazolyl group, and R 2 is hydrogen. 3. Savienojums, atbilstoši kādam vienam no izg.f.I-2 punktiem, kas atšķiras ar to, ka R4 un R5 veido ar oglekli, pie kura tie pievienoti, ciklopentān- vai cikloheksān- ciklus.A compound according to any one of claims 1 to 2, wherein R 4 and R 5 are formed with the carbon to which they are attached, cyclopentane or cyclohexane. 4. Savienojums, atbilstoši kādam vienam no izg.f.I-3 punktiem, kas a t š ķ i r a s ar to, ka R3 ir alkil- Cj-Cg grupa ar taisnu virkni.A compound according to any one of claims 1-3, characterized in that R 3 is an alkyl-C 1 -C 8 straight chain. 5. Savienojums, atbilstoši kādam vienam no izg.f.I-4 punktiem, kas a t š ķ i r a s ar to, ka X ir skābeklis.A compound according to any one of claims 1 to 4, characterized in that X is oxygen. 6. Savienojums, atbilstoši kādam vienam no izg.f.I-5 punktiem, kas atšķiras ar to, ka z = t = 0.6. A compound according to any one of claims 1-5, wherein z = t = 0. 7. Savienojums, atbilstoši izg.f.I.punktam, kas a t š ķ i r a s ar to, ka tas ir 2-n-butil^-spirociklopentān-I-ļVT -(5-tetrazolil)-4-difenilil/-metil]-2-imidazolīn-5-ons vai viens no tā sāļiem ar skābēm vai bāzēm.7. A compound according to claim 1, which is 2-n-butyl-4-spirocyclopentane-1 H-NMR (5-tetrazolyl) -4-diphenyl] methyl] -2- imidazolin-5-one or one of its salts with acids or bases. 8. Paņēmiens savienojuma (I) , atbilstošs kādam vienam no izg.f.I-7 punktiem, iegūšanai, kas atšķirasar to,ka: ai) heterociklisko savienojumu ar formulu: J4 ZT2 0 = K5/_(CxK2>t (CH0) itf H 2 3 LV 10439 kurā z, t, R3, R4 un R5 ir tādas nozīmes, kā uzrādīts savienojumam (I) izg.f.I.punktā, pakļauj iedarbībai ar (4-difenilil)-metil- atvasinājumu, kura formula ir:A process for the preparation of compound (I) according to any one of claims 1-7, characterized in that: ai) a heterocyclic compound of the formula: J4 ZT2 0 = K5 / _ (CxK2 > t (CH0) itf H 2 3 EN 10439 wherein z, t, R 3, R 4 and R 5 have the meanings indicated for compound (I) at the point (a), are exposed to a (4-diphenyl) -methyl derivative of the formula: 2 kurā Hal ir halogēna atoms, bet R’j un R’2 ir attiecīgi Rj un R2, vai Rj un R2 grupas priekšteces; bl) ja vajadzīgs, iepriekšs iegūto savienojumu ar formulu:2 wherein Hal is a halogen atom, and R'j and R'2 are the predecessors of Rj and R2 or Rj and R2, respectively; (bl) if applicable, the previous connection with the formula: apstrādā ar Lewesson reaktīvu : 2,4-bis-(4-metoksifenil)-l,3-ditia-2,4-difofetān-2,4-disulfīdu; cl) savienojumu, kas iegūts ai) vai bl) stadijās, ar formulu :treated with Lewesson reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-difofetane-2,4-disulfide; cl) the compound obtained in steps ai) or b1) of the formula: kurā X ir skābekļa atoms vai sēra atoms, apstrādā lai iegūtu savienojumu (I), ko realizē pārvēršot grupas R’j un/vai R'2 attiecīgi par grupām Rj un/vai R2.wherein X is an oxygen atom or a sulfur atom treated to form a compound (I) which is realized by converting R'j and / or R'2 to Rj and / or R2, respectively. 9. Paņēmiens savienojuma (I) iegūšanai, atbilstoši kādam vienam no izg.f.I-7 punktiem, kas a t š ķ i r a s ar to, ka: a2) aminoskābi ar formulu: 7 *4 4 RA process for the preparation of compound (I) according to one of claims 1 to 7, characterized in that: a2) an amino acid of the formula: 7 * 4 4 R NHPr 5 <k>* COOLi kurā z, t, R4 un R5 ir tādas nozīmes, kā uzrādīts savienojumam (I) izg.f.I. punktā; un kurā aminogrupa ir aizsargāta ar grupu Pr, pakļauj iedarbībai ar (4-difenilil)-metilamīna atvasinājumu, kura formula ir: I R 2 R- S «2» - CH2 "Λ // kurā R'i un R'2 ir attiecīgi Rj un R2, vai grupa-priekštece grupām Rj un R2 ; b2) pēc aizsarggrupas noņemšanas aminogrupai, iegūto savienojumu ar formulu: Rr IIc - riti- ch.NHPr 5 < k > * COOLi wherein z, t, R4 and R5 have the meanings indicated for compound (I). ; and wherein the amino group is protected by Pr, is exposed to a (4-diphenyl) -methylamine derivative having the formula: IR 2 R-S 2 - CH 2 " Λ // wherein R 'and R'2 are respectively Rj and R2, or a group precursor for Rj and R2; b2) after removal of the protecting group to the amino group, the resultant compound of the formula: Rr IIc - r-ch. pakļauj iedarbībai ar ortoskābes alkil- esteriem ar formulu R3C(OR)3 (10), kur R3 ir nozīmes, kuras uzrādītas savienojumam (I) izg.f.I. punktā, bet R ir alkil- CJ-C4: c2) ja vajadzīgs, iegūto savienojumu ar formulu : R R 5/ (caj rr R. ‘N 4 5 LV 10439 apstrādā ar Lavvesson'a reaktīvu: 2,4-bis-(4-metoksifenil)-I,3-ditia-2,4-difosfetān-2,4-disulfidu; d2) savienojumu, kas iegūts b2) vai c2) stadijās, ar formulu :exposing to ortho-alkyl alkyl esters of formula R3C (OR) 3 (10), wherein R3 has the meaning indicated for compound (I). and R is alkyl-CJ-C4: c2) if necessary with the compound of formula: RR 5 / (caj rr R 'N 4 5 LV 10439 treated with Lavvesson reagent: 2,4-bis (4)) -methoxyphenyl) -I, 3-dithia-2,4-diphosphetane-2,4-disulfide, d2) compounds obtained in b2) or c2), with the formula: apstrādā pēc tam apstākļos, kas piemēroti savienojuma (I) iegūšanai, pārvēršot grupas R'2 un/vai R'j attiecīgi par grupām R2 un/vai Rj.is then treated under conditions suitable for the preparation of compound (I) by converting R'2 and / or R'j to R2 and / or R1 respectively. 10. Paņēmiens savienojuma (I) iegūšanai, atbilstoši izg.f.6. punktam, kas a t š ķ i r a s ar to, ka: a3) uz imidazola atvasinājumu ar formulu : R R10. Method for obtaining compound (I) according to the invention. that is: a3) on an imidazole derivative of the formula: R R N II ti kurā R3, R4, R5 ir nozīmes, kas uzrādītas savienojumam (I) izg.f.I. punkta, iedarbojas ar (4-difenilil)-metil- atvasinājumu ar formulu : RN II ie wherein R 3, R 4, R 5 have the meanings indicated for compound (I). , with (4-diphenyl) -methyl-derivative of the formula: R /T\/ T \ t \ / Hal - CH2 kurā Hal ir halogēna atoms, bet R'j un R'2 ir attiecīgi Rj un R2, vai grupu Rj un R2 grupas-priekšteces, skābekļa klātienē un bāziskā vidē, apstarojot ar UV-starojumu. b3) ja vajadzīgs, iepriekš iegūto savienojumu ar formulu: 4 6 aHal - CH2 wherein Hal is a halogen atom, and R'j and R'2 are Rj and R2, respectively, or a group Rj and R2 group precursor, in the presence of oxygen and in an alkaline medium by irradiation with UV radiation. b3) where applicable, the previously obtained compound of formula: 4a 4' apstrādā ar Lawesson’a reaktīvu: 2,4-bis-(4-metoksifenil)-l,3-ditia-2,4-difosfenāt-2,4-disulfīdu; c3) savienoiumu. kas iegūts b3) vai c3) stadijās, ar formulu : r44 'is treated with Lawesson reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphate-2,4-disulfide; c3) bonding. obtained in steps b3) or c3) of the formula: r4 a2c-Q-Ck, 5 a-j i apstrada pec tam apstaicļos, Kas piemerou savienojuma (I) iegūšanai, pārvēršot grupas R'2 un/vai R'j attiecīgi par grupām R2 un/vai Rj. II. Starpsavienojumi ar formulu R, Rr II —R. kurā: - R3 ir ūdeņradis, alkil- Cj-Cg, neaizvietots vai aizvietots ar vienu vai vairākiem halogēna atomiem, alkenil- C2-Cg, cikloalkil- C3-C7, fenil-, fenilalkil-, kurā alkil- ir ar CJ-C3, fenilalkenil-, kurā alkenil- ir ar C2-C3, uzrādītās fenilgrupas ir neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēna atomiem, alkil- CJ-C4, halogēnalkil- C1-C4, polihalogēnalkil- C1-C4, hidroksil- vai alkoksi- C1-C4; - R4 un R5 katrs, neatkarīgi viens no otra, ir alkil- Cj-Cg, fenil-, fenilalkil-, kurā alkil- ir ar C1-C3, uzrādītās alkil-, fenil- un fenilalkilgrupas ir neaizvietotas vai 7 LV 10439 aizvietotas ar vienu vai vairākiem halogēna atomiem vai vienu grupu, kura izvēlēta no perfluoralkil- C1-C4, hidroksil-, alkoksi- C1-C4 grupām ; - vai R4 un R5 kopā veido grupu ar formulu =CR7Rg, kurā R7 ir ūdeņradis, alkil- C1-C4 vai fenil-, bet Rg ir alkil- C1-C4 vai fenil-; - vaiar R4 un R5 kopā veido grupu ar formulu (CH2)n. vai grupu ar formulu (CH2)nY(CH2)q, kurā Y ir skābekļa atoms, vai sēra atoms, vai oglekļa atoms, aizvietots ar alku- C1.C4, fenil- vai fenilalkil-, kurā alkil- ir ar C1-C3, vai grupu N-R5, kurā Rg ir ūdeņradis, alkil- C1-C4, fenilalkil-, kurā alkil- ir ar C1-C3, alkilkarbonil- C1-C4, halogēnalkilkarbonil- C1-C4, polihalogēnalkilkarbonil- C1-C4, benzoil-, α-aminoacil- vai N-aizsarggrupa, vai R4 un R5 kopā ar oglekļa atomu, pie kura tie pievienoti veido indān- vai adamantān-; - P + q = m - n ir vesels skaitlis ar vērtībām no 2 līdz 11; - m ir vesels skaitlis ar vērtībām no 2 līdz 5; - X ir skābekļa atoms vai sēra atoms; - z un t ir nulle vai viens no indeksiem ir nulle, bet otrs ir viens; ar sekojošiem ierobežojumiem: - ja z un t ir nulle, bet X ir skābekļa atoms, tad R4 un R5 ir atšķirīgi no: . alkil-Cļ-Cg, fenil-, fenilalkil-, kurā alkil- ir ar C1-C3, uzrādītās alkil-, fenil-un fenilalkil- grupas ir neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēna atomiem vai ar grupu, kas izvēlēta no perfluoralkil- C1-C4, hidroksil- vai alkoksi-C1-C4 grupām; . vai R4 un R5, savienoti kopā, atšķiras no grupas N-Rg, kurā Rg ir ūdeņradis, alkil- C1-C4, fenilalkil-, kurā alkil- ir ar C1-C3; . n atšķiras no 6; - ja z = 1 un R3 ir fenil-, tad R4 un R5 katrs atšķiras no metil-.a2c-Q-Ck, 5a-ji are then processed in appendixes, For example, to obtain compound (I) by converting groups R'2 and / or R'j to R2 and / or R1 respectively. II. Intermediates having the formula R, Rr II -R. wherein: - R 3 is hydrogen, alkyl-C 1 -C 8, unsubstituted or substituted with one or more halogen atoms, alkenyl-C 2 -C 8, cycloalkyl-C 3 -C 7, phenyl, phenylalkyl, wherein alkyl is C 1 -C 3, phenylalkenyl-, where alkenyl is C2-C3, the phenyl groups shown are unsubstituted or substituted with one or more halogen atoms, alkyl-CJ-C4, haloalkyl-C1-C4, polyhaloalkyl-C1-C4, hydroxy or alkoxy-C1- C4; - R 4 and R 5 each independently of one another are alkyl-C 1 -C 8, phenyl, phenylalkyl- wherein alkyl is C 1 -C 3, alkyl, phenyl and phenylalkyl are unsubstituted or 7 LV 10439 substituted with one or several halogen atoms or one group selected from perfluoroalkyl-C 1 -C 4, hydroxy, alkoxy-C 1 -C 4; - whether R4 and R5 together form a group of the formula = CR7Rg, wherein R7 is hydrogen, alkyl-C1-C4 or phenyl, and R8 is alkyl-C1-C4 or phenyl; - R4 and R5 together form a group of formula (CH2) n. or a group of formula (CH2) nY (CH2) q wherein Y is an oxygen atom, or a sulfur atom, or a carbon atom substituted with a C 1 -C 4 alkyl, phenyl or phenylalkyl, wherein alkyl is C 1 -C 3, or a group N-R5, wherein Rg is hydrogen, alkyl-C1-C4, phenylalkyl, wherein alkyl is C1-C3, alkylcarbonyl-C1-C4, haloalkylcarbonyl-C1-C4, polyhaloalkylcarbonyl-C1-C4, benzoyl, α-aminoacyl or N-protecting group, or R 4 and R 5 together with the carbon atom to which they are attached to form indan- or adamantane; - P + q = m - n is an integer with values from 2 to 11; - m is an integer with values from 2 to 5; - X is an oxygen atom or a sulfur atom; - z and t are zero or one of the indices is zero but the other is one; with the following limitations: - if z and t are zero, and X is oxygen then R4 and R5 are different from:. alkyl-C 1 -C 8, phenyl, phenylalkyl, in which alkyl is C 1 -C 3, alkyl, phenyl and phenylalkyl groups are unsubstituted or substituted with one or more halogen atoms or with a group selected from perfluoroalkyl C1-C4, hydroxy or alkoxy-C1-C4 groups; . or R4 and R5, taken together, are different from the group N-Rg, wherein R8 is hydrogen, alkyl-C1-C4, phenylalkyl, wherein alkyl is C1-C3; . n is different from 6; - when z = 1 and R3 is phenyl then R4 and R5 each differ from methyl. 12. Savienojums, atbilstoši izg.f. 11. punktam, ar formulu:12. Connection according to f.f. With the formula: H kurā X ir skābekļa atoms vai sēra atoms, bet R3 ir ūdeņradis, alkil- Cļ-Cg, neaizvietots vai aizvietots ar vienu vai vairākiem halogēna atomiem; alkenil- C2-Cg, cikloalkil- C3-C7, fenil-, fenilalkil-, kurā alkil- ir ar C1-C3, fenilalkenil-, kurā alkenil- ir ar C2-C3, uzrādītās fenilgrupas ir neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēnā atomiem, alkil- C1-C4, halogēnalkil- C4-C4, polihalogēnalkil-C1-C4, hidroksil- vai alkoksi- C4-C4 grupām.H wherein X is oxygen or sulfur, and R 3 is hydrogen, alkyl-C 1 -C 8, unsubstituted or substituted with one or more halogen atoms; alkenyl-C2-Cg, cycloalkyl-C3-C7, phenyl-, phenylalkyl- in which alkyl is C1-C3, phenylalkenyl- in which alkenyl is C2-C3, phenyl substituted with one or more halogen is unsubstituted or substituted atoms, alkyl-C1-C4, haloalkyl-C4-C4, polyhaloalkyl-C1-C4, hydroxy or alkoxy-C4-C4 groups. 13. Savienojums, atbilstoši izg.f. 11. punktam, ar formulu:13. Connection according to f.f. With the formula: H 01") 8 kurā R3, R4, R5 un X ir nozīmes, kuras uzrādītas savienojumam (11) izg.f.10. punktā.H 01 ") 8 in which R 3, R 4, R 5 and X are the meanings indicated for the compound (11). above. 14. Savienojums, atbilstoši izg.f. 11. punktam, ar formulu:14. Connection according to f.f. With the formula: H - R3 ir ūdeņradis, alkil- Cj-Cg, neaizvietots vai aizvietots ar vienu vai vairākiem halogēna atomiem, alkenil- Cļ-Cft, cikloalkil- C3-C7, fenil-, fenilalkil-, kurā alkil- ir ar C1-C3, fenilalkenil-, kurā alkenil- ir ar C2-C3, uzrādītās fenilgrupas ir neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēna atomiem, alkil- Cļ-C4, halogēnalkil- C1-C4, polihalogēnalkil- C1-C4, hidroksil- vai alkoksi- C1-C4 grupām; - R4 un R5 katrs, neatkarīgi viens no otra, ir alkil- Cļ-Cg, fenil-, fenilalkil-, kurā alkil- ir ar C1-C3, uzrādītās alkil-, fenil- un fenilalkil- grupas ir neaizvietotas vai aizvietotas ar vienu vai vairākiem halogēna atomiem vai ar grupu, kura izvēlēta no perfluoralkil- C1-C4, hidroksil-, alkoksi- C1-C4 grupām; - vai R4 un R5 kopā veido grupu ar formulu =CR7Rg, kurā R7 ir ūdeņradis, alkil-Cļ-C4 vai fenil-, bet Rg ir alkil- C4-C4 vai fenil-; - vai R4 un R5, kopā savienoti, ir grupa ar formulu (CH2)n* va* grupa ar formulu (CH2)pY(CH2>q, kurā Y ir skābekļa atoms, vai sēra atoms, vai oglekļa atoms, aizvietots ar alkil- C1-C4, fenil- vai fenilalkil-, kurā alkil- ir ar C1-C3, vai grupu N-Rg, kurā Rg ir ūdeņradis, alkil- C1-C4, fenilalkil-, kurā alkil- ir ar C1-C3, alkilkarbonil- CJ-C4, halogēnalkilkarbonil- C1-C4, polihalogēnalkilkarbonil- C1-C4, benzoil-, α-aminoacil- vai N-aizsarggrupa, vai R4 un R5, kopā ar oglekļa atomu, pie kura tie pievienot, veido indān- vai adamantān-; - p + q = m; - n ir vesels skaitlis ar vērtībām no 1 līdz 11; - m ir vesels skaitlis ar vērtībām no 2 līdz 5; - X ir skābekļa atoms vai sēra atoms; ar nosacījumu, ka R3 ir atšķirīgs no fenil-, ja R4 un R5 katrs ir metil-.H-R 3 is hydrogen, alkyl-C 1 -C 8, unsubstituted or substituted with one or more halogen atoms, alkenyl-C 1 -C 3 C, cycloalkyl-C 3 -C 7, phenyl, phenylalkyl, wherein alkyl is C 1 -C 3, phenylalkenyl - wherein the alkenyl is C2-C3, the phenyl groups shown are unsubstituted or substituted with one or more halogen atoms, alkyl-C 1 -C 4, haloalkyl-C 1 -C 4, polyhaloalkyl-C 1 -C 4, hydroxy or alkoxy-C 1 -C 4 groups; - R 4 and R 5 each independently of one another are alkyl-C 1 -C 8, phenyl, phenylalkyl- in which alkyl is C 1 -C 3, alkyl, phenyl and phenylalkyl groups are unsubstituted or substituted with one or more of the alkyl groups. several halogen atoms or a group selected from perfluoroalkyl-C1-C4, hydroxy, alkoxy-C1-C4; - R 4 and R 5 together form a group of the formula = CR 7 R 8, wherein R 7 is hydrogen, alkyl-C 1 -C 4 or phenyl, and R 8 is alkyl-C 4 -C 4 or phenyl; - whether R4 and R5, taken together, is a group of formula (CH2) n * va * with the formula (CH2) pY (CH2 > q in which Y is an oxygen atom or a sulfur atom or a carbon atom substituted with alkyl C1-C4, phenyl or phenylalkyl, in which alkyl is C1-C3, or a group N-Rg in which Rg is hydrogen, alkyl C1-C4, phenylalkyl, in which alkyl is C1-C3, alkylcarbonyl- CJ-C4, haloalkylcarbonyl-C1-C4, polyhaloalkylcarbonyl-C1-C4, benzoyl, α-aminoacyl or N-protecting group, or R4 and R5 together with the carbon atom to which they are attached form indan- or adamantane; - p + q = m; - n is an integer with values from 1 to 11, - m is an integer with values from 2 to 5, - X is an oxygen atom or a sulfur atom, provided that R 3 is different from phenyl; if R4 and R5 are each methyl. 15. Paņēmiens savienojuma iegūšanai, atbilstoši kādam vienam no izg.f. 11-14 punktiem, kas a t š ķ i r a s ar to, ka - uz savienojumu ar formulu:A method for obtaining a compound according to any one of the preceding claims. 11-14 points, that is - to connect to the formula: n kura R4 un R5 ir aizvietotāji, kuri uzradīti savienojumam (11) izg.f.10. punktā, A ir OH grupa, NH2 grupa vai OR' grupa, kurā R' ir ūdeņradis vai alkil- C1-C4, 14 9 14 9LV 10439 - iedarbojas ar savienojumu, kura formula ir: R3 - B kurā R3 ir aizvietotāji, kuri uzrādīti savienojumam (11) izg.f.10. punktā, bet B ir: - grupa C(OR)3; NH - grupa C- OR; - vai grupa COHal; kur R ir alkil- C1-C4, bet Hal ir halogēna atoms, vēlams hlors; - pēc tam, ja vajadzīgs, iegūto savienojumu apstrādā ar Lawesson'a reaktīvu: 2,4-bis-(4-metoksifenil)-1,3-ditia-2,4-difosfetān-2,4-disulfīdu. 16. Ārstnieciskais sastāvs, kurš satur kā aktīvo vielu savienojumu, atbilstoši · kādam vienam no izg.f.1-7 punktiem. 17. Ārstnieciskais sastāvs, kurš satur savienojumu, atbilstoši kādam vienam no izg.f.1-7 punktiem, kopā atbloķējošu savienojumu. 18.. Ārstnieciskais sastāvs, kurš satur savienojumu, atbilstoši kādam vienam no izg.f. 1 -7 punktiem, kopā ar diurētsku līdzekli. 19. Ārstnieciskais sastāvs, kurš satur savienojumu, atbilstoši kādam vienam no izg.f.1-7 punktiem, kopā ar nesteroīdu pretiekaisuma savienojumu. 20. Ārstnieciskais sastāvs, kurš satur savienojumu, atbilstoši kādam vienam no izg.f.1-7 punktiem, kopā ar kalcija antagonistu. 21. Ārstnieciskais sastāvs, kurš satur savienojumu, atbilstoši kādam vienam no izg.f. 1-7 punktiem, kopā ar trankvilizatoru.n of which R4 and R5 are substituents on the compound (11). , A is an OH group, a NH 2 group or a OR 'group in which R' is hydrogen or alkyl-C 1 -C 4, 14 9 14 9LV 10439 - works with a compound of the formula: R 3 - B wherein R 3 is a substituent for connection (11) f.10. but B is: - group C (OR) 3; NH - group C-OR; - or a group COHal; wherein R is alkyl-C1-C4, and Hal is halogen, preferably chlorine; - then, if necessary, treating the resulting compound with Lawesson's reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide. 16. A therapeutic composition comprising a compound of the active substance according to one of the claims 1-7. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 7 together for an unblocking compound. 18. A pharmaceutical composition comprising a compound according to one of the claims. 1 -7 points with a diuretic. A pharmaceutical composition comprising a compound according to any one of claims 1-7 together with a non-steroidal anti-inflammatory compound. A pharmaceutical composition comprising a compound according to any one of claims 1-7 together with a calcium antagonist. 21. A pharmaceutical composition comprising a compound according to one of the formulas. 1-7 points with a tranquilizer.
LVP-93-147A 1990-03-20 1993-02-25 N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing them LV10439B (en)

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FR9010144A FR2665702B1 (en) 1990-08-08 1990-08-08 N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
PCT/FR1991/000224 WO1991014679A1 (en) 1990-03-20 1991-03-20 Heterocyclic n-substituted derivatives, their preparation and thepharmaceutical compositions containing them

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Families Citing this family (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL97219A (en) * 1990-02-19 1995-12-08 Ciba Geigy Ag Biphenyl substituted aliphatic amino compounds process for their preparation and pharmaceutical compositions containing them
CA2053148A1 (en) * 1990-10-16 1992-04-17 Karnail Atwal Dihydropyrimidine derivatives
AU656551B2 (en) * 1990-12-14 1995-02-09 Smithkline Beecham Corporation Angiotensin II receptor blocking compositions
FR2673427B1 (en) * 1991-03-01 1993-06-18 Sanofi Elf N-SUBSTITUTED DIAZOTATED HETEROCYCLIC DERIVATIVES BY A BIPHENYLMETHYL GROUP, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
AU1625192A (en) * 1991-05-31 1992-12-03 Zeneca Limited Heterocyclic derivatives
IL102183A (en) * 1991-06-27 1999-11-30 Takeda Chemical Industries Ltd Biphenyl substituted heterocyclic compounds their production and pharmaceutical compositions comprising them
EP0599999A1 (en) * 1991-08-19 1994-06-08 E.I. Du Pont De Nemours And Company Angiotensin ii receptor blocking imidazolinone derivatives
CA2115990A1 (en) * 1991-08-19 1993-03-04 George Albert Boswell Angiotensin ii receptor blocking imidazolinone derivatives
US5182288A (en) * 1991-11-13 1993-01-26 Ortho Pharmaceutical Corporation Substituted n-biphenylyl lactams
FR2685328B1 (en) * 1991-12-20 1995-12-01 Rhone Poulenc Agrochimie DERIVATIVES OF 2-IMIDAZOLINE-5-ONES AND 2-IMIDAZOLINE-5-THIONES FUNGICIDES.
IL104755A0 (en) * 1992-02-17 1993-06-10 Ciba Geigy Ag Treatment of glaucoma
WO1993017681A1 (en) * 1992-03-02 1993-09-16 Abbott Laboratories Angiotensin ii receptor antagonists
FR2688781B1 (en) * 1992-03-23 1994-07-01 Sanofi Elf IMIDAZOLINES N-SUBSTITUTED BY A BIPHENYLMETHYL GROUP, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
EP0577025A3 (en) * 1992-07-01 1998-02-04 Hoechst Aktiengesellschaft Angiotensin-ii-receptorantagonist for the treatment and prophylaxis of coronary heart diseases
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
EP0603712B1 (en) * 1992-12-22 2001-08-16 Takeda Chemical Industries, Ltd. Heterocyclic compounds having angiotensin II antagonistic activity and use thereof
FR2711367B1 (en) * 1993-10-19 1995-12-01 Roussel Uclaf New process for the preparation of sulfur derivatives of imidazole and the new intermediates obtained.
US5338740A (en) * 1993-07-13 1994-08-16 Pfizer Inc. Angiotensin II receptor antagonists
US5411641A (en) * 1993-11-22 1995-05-02 E. I. Du Pont De Nemours And Company Electrochemical conversion of anhydrous hydrogen halide to halogen gas using a cation-transporting membrane
US5994348A (en) 1995-06-07 1999-11-30 Sanofi Pharmaceutical compositions containing irbesartan
TW442301B (en) * 1995-06-07 2001-06-23 Sanofi Synthelabo Pharmaceutical compositions containing irbesartan
DE69624253T2 (en) * 1995-10-06 2003-08-07 Novartis Ag, Basel ATI RECEPTOR ANTAGONISTS FOR PREVENTING AND TREATING POSTICEMICAL NERVOUS FAILURE AND PROTECTING ISCHEMICAL KIDNEYS
CA2196263C (en) * 1996-02-09 2004-10-26 Barry Jackson Process for the preparation of 4-oxoimidazolinium salts
DK0883401T3 (en) 1996-02-29 2003-05-05 Novartis Ag AT1 receptor antagonist to stimulate apoptosis
SK283295B6 (en) * 1996-03-14 2003-05-02 Warner-Lambert Company Substituted cyclic amino acid, use and pharmaceutical composition based on it
HU218681B (en) 1997-07-25 2000-10-30 Sanofi-Synthelabo Process for the preparation of 1,3-diaza-spiro(4,4)non-1-en-4-one derivatives and 1-cyano-1-acylamino-cyclopentane intermediates
US6162922A (en) * 1998-01-30 2000-12-19 Bristol-Myers Squibb Co. Method for preparing N-substituted heterocyclic derivatives using a phase-transfer catalyst
WO1999048873A1 (en) * 1998-03-25 1999-09-30 Bristol-Myers Squibb Company Imidazolone anorectic agents: i. acyclic derivatives
FR2780403B3 (en) 1998-06-24 2000-07-21 Sanofi Sa NOVEL FORM OF IRBESARTAN, METHODS FOR OBTAINING SAID FORM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
US6638937B2 (en) 1998-07-06 2003-10-28 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
TR200605471T2 (en) 1998-12-23 2006-11-21 Novartis Ag Use of the at-1 receptor antagonist or at-2 receptor modulator for the treatment of diseases caused by increased AT-1 or AT-2 receptors.
US6211217B1 (en) 1999-03-16 2001-04-03 Novartis Ag Method for reducing pericardial fibrosis and adhesion formation
SE9903028D0 (en) 1999-08-27 1999-08-27 Astra Ab New use
PE20020617A1 (en) 2000-08-22 2002-08-05 Novartis Ag COMPOSITION INCLUDING AN AT1 RECEPTOR ANTAGONIST AND AN INSULIN SECRETION POTENTIAL OR AN INSULIN SENSITIZER
US8168616B1 (en) 2000-11-17 2012-05-01 Novartis Ag Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension
FR2831446B1 (en) * 2001-10-26 2004-03-05 Sanofi Synthelabo USE OF IRBESARTAN FOR THE PREPARATION OF MEDICINES USEFUL FOR THE PREVENTION OR TREATMENT OF PULMONARY HYPERTENSION
US7232828B2 (en) 2002-08-10 2007-06-19 Bethesda Pharmaceuticals, Inc. PPAR Ligands that do not cause fluid retention, edema or congestive heart failure
DE10335027A1 (en) 2003-07-31 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of telmisartan and simvastatin for treatment or prophylaxis of cardiovascular, cardiopulmonary and renal diseases e.g. hypertension combined with hyperlipidemia or atherosclerosis
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
GB0316546D0 (en) 2003-07-15 2003-08-20 Novartis Ag Process for the manufacture of organic compounds
JP2007512359A (en) 2003-11-19 2007-05-17 メタバシス・セラピューティクス・インコーポレイテッド Novel phosphorus-containing thyroid hormone-like substance
GB0327839D0 (en) 2003-12-01 2003-12-31 Novartis Ag Organic compounds
GB0402262D0 (en) 2004-02-02 2004-03-10 Novartis Ag Process for the manufacture of organic compounds
TW200605867A (en) 2004-03-17 2006-02-16 Novartis Ag Use of organic compounds
JP4880591B2 (en) 2004-06-04 2012-02-22 テバ ファーマシューティカル インダストリーズ リミティド Pharmaceutical composition comprising irbesartan
WO2005122699A2 (en) * 2004-06-16 2005-12-29 Matrix Laboratories Ltd An improved process for the preparation of n-substituted hetero cyclic derivatives
SI21849A (en) 2004-07-29 2006-02-28 Krka, Tovarna Zdravil, D.D., Novo Mesto Preparation of hydrochloride salts of tetrazole derivative
TWI346108B (en) 2004-08-23 2011-08-01 Bristol Myers Squibb Co A method for preparing irbesartan and intermediates thereof
ES2384637T3 (en) 2004-10-08 2012-07-10 Novartis Ag Use of renin inhibitors for the prevention or treatment of diastolic dysfunction or diastolic heart failure
GB2419592A (en) 2004-10-26 2006-05-03 Cipla Ltd Process for the preparation of irbesartan hydrochloride
AU2005297984B2 (en) 2004-10-27 2009-11-12 Daiichi Sankyo Company, Limited Benzene compound having 2 or more substituents
FR2886642B1 (en) * 2005-06-06 2008-05-30 Sanofi Aventis Sa IRBESARTAN ALKALINE-EARTH SALTS AND THEIR PREPARATION
EP1749828A1 (en) 2005-08-04 2007-02-07 Farmaprojects S.L. Process for preparing an angiotensin II receptor antagonist
WO2007049293A1 (en) 2005-10-28 2007-05-03 Alembic Limited An improved process for preparation of irbesartan
PL1806130T3 (en) 2006-01-09 2010-08-31 Krka D D Novo Mesto Solid pharmaceutical composition comprising irbesartan
EP1908469A1 (en) 2006-10-06 2008-04-09 Boehringer Ingelheim Vetmedica Gmbh Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
EP1918288A1 (en) 2006-11-02 2008-05-07 Cadila Pharmaceuticals Limited A novel and improved process for the preparation of Irbesartan, an angiotensin-II receptor antagonist for the treatment of hypertension
EP2117540A1 (en) 2007-03-01 2009-11-18 Probiodrug AG New use of glutaminyl cyclase inhibitors
JP5667440B2 (en) 2007-04-18 2015-02-12 プロビオドルグ エージー Thiourea derivatives as glutaminyl cyclase inhibitors
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2998314B1 (en) 2007-06-04 2020-01-22 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8034782B2 (en) 2008-07-16 2011-10-11 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US7786155B2 (en) 2007-10-16 2010-08-31 Novartis Ag Organic compounds
EP2065035B1 (en) 2007-11-28 2010-07-21 Laboratorios Lesvi, S.L. Pharmaceutical formulations containing irbesartan
ES2627848T3 (en) 2008-06-04 2017-07-31 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2009149734A1 (en) * 2008-06-13 2009-12-17 Ratiopharm Gmbh Process for the preparation of irbesartan and intermediate products
EP2194050A1 (en) 2008-12-08 2010-06-09 KRKA, tovarna zdravil, d.d., Novo mesto A new process for the preparation of irbesartan
US20120046364A1 (en) 2009-02-10 2012-02-23 Metabasis Therapeutics, Inc. Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
HUP0900788A2 (en) 2009-12-16 2011-11-28 Sanofi Aventis Process for producing 4-bromomethyl-biphenyl derivatives
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
EA022420B1 (en) 2010-03-10 2015-12-30 Пробиодруг Аг Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
EP2560953B1 (en) 2010-04-21 2016-01-06 Probiodrug AG Inhibitors of glutaminyl cyclase
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
US8530670B2 (en) 2011-03-16 2013-09-10 Probiodrug Ag Inhibitors
WO2013090196A1 (en) 2011-12-15 2013-06-20 Takeda Pharmaceuticals U.S.A., Inc. Combinations of azilsartan and chlorthalidone for treating hypertension black patients
PL223830B1 (en) 2012-04-03 2016-11-30 Univ Jagiellonski Derivatives of aromatic imidazolidinones and their use
US9708367B2 (en) 2013-03-15 2017-07-18 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase and their uses
CA2905435A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
PL3004138T3 (en) 2013-06-05 2024-07-29 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase c, method of making and using same
ES2847904T3 (en) 2013-07-23 2021-08-04 Daiichi Sankyo Co Ltd Medicine for the prevention or treatment of hypertension
KR20180123021A (en) 2016-03-24 2018-11-14 다이이찌 산쿄 가부시키가이샤 Medicines for the treatment of kidney disease
BR112020000194A2 (en) 2017-07-07 2020-07-07 Boehringer Ingelheim Vetmedica Gmbh angiotensin ii receptor antagonist for the prevention or treatment of systemic diseases in cats
PL3461819T3 (en) 2017-09-29 2020-11-30 Probiodrug Ag Inhibitors of glutaminyl cyclase

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3340595A1 (en) * 1983-11-10 1985-05-23 Hoechst Ag, 6230 Frankfurt IMIDAZOLINONES, METHOD FOR THEIR PRODUCTION AND THEIR USE IN PLANT PROTECTION
DE3545597A1 (en) * 1985-12-21 1987-07-02 Celamerck Gmbh & Co Kg NEW HERBICIDE EFFECTIVE IMIDAZOLINONES
CA1334092C (en) * 1986-07-11 1995-01-24 David John Carini Angiotensin ii receptor blocking imidazoles
US4820843A (en) * 1987-05-22 1989-04-11 E. I. Du Pont De Nemours And Company Tetrazole intermediates to antihypertensive compounds
EP0303863A3 (en) * 1987-08-17 1991-10-23 American Cyanamid Company Benzenesulfonyl carboxamide compounds, intermediate compounds and methods of preparation thereof and use of said compounds and intermediate compounds as herbicidal agents
US5015651A (en) * 1988-01-07 1991-05-14 E. I. Du Pont De Nemours And Company Treatment of hypertension with 1,2,4-angiotensin II antagonists
CA1338238C (en) * 1988-01-07 1996-04-09 David John Carini Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids
EP0407342A3 (en) * 1989-07-06 1991-07-10 Ciba-Geigy Ag Pyrimidine derivatives
DE69024556T2 (en) * 1989-07-28 1996-10-17 Merck & Co Inc Substituted triazolinones, triazolinthiones and triazolinimines as angiotensin II antagonists
EP0411507B1 (en) * 1989-08-02 1994-10-26 Takeda Chemical Industries, Ltd. Pyrazole derivatives, their production and use
US5100897A (en) * 1989-08-28 1992-03-31 Merck & Co., Inc. Substituted pyrimidinones as angiotensin ii antagonists
IL99372A0 (en) * 1990-09-10 1992-08-18 Ciba Geigy Ag Azacyclic compounds

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