IE910913A1 - N-substituted heterocyclic derivates, their preparation¹and pharmaceutical compositions containing them - Google Patents

N-substituted heterocyclic derivates, their preparation¹and pharmaceutical compositions containing them

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Publication number
IE910913A1
IE910913A1 IE091391A IE91391A IE910913A1 IE 910913 A1 IE910913 A1 IE 910913A1 IE 091391 A IE091391 A IE 091391A IE 91391 A IE91391 A IE 91391A IE 910913 A1 IE910913 A1 IE 910913A1
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alkyl
compound
formula
phenyl
ppm
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IE091391A
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Sanofi Sa
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26227935&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IE910913(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from FR9003563A external-priority patent/FR2659967B1/en
Priority claimed from FR9010144A external-priority patent/FR2665702B1/en
Application filed by Sanofi Sa filed Critical Sanofi Sa
Publication of IE910913A1 publication Critical patent/IE910913A1/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
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D403/02—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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/02—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
    • 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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    • C07D471/00—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
    • 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
    • C07D471/10—Spiro-condensed systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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

This invention relates to N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing them.
The compounds in accord with the invention antagonise the action of angiotensine II which is a peptide hormone with the formula: H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-QH Angiotensine II is a powerful vasopressor agent which is the active biological product of the renin-angiotensine system.
Senin acts on angiotensinogen in plasma to produce angiotensine I, the latter being converted into angiotensine II by the action of the angiotensine I conversion enzyme.
The compounds in this invention are non-peptide compounds, antagonists of angiotensine II. By inhibiting the action of angiotensine II on its receptors, the compounds in accord with the invention prevent in particular the increase in blood pressure produced by the hormone-receptor interaction, they also have other physiological effects on the central nervous system.
Thus, compounds in accord with the invention are useful in the treatment of cardiovascular ailments like hypertension, heart failure as well as in the treatment of the central nervous system and in the treatment of glaucoma and diabetic retinopathy.
The subject of this invention is compounds of formula: in which: - Ri and R2 are alike or different and each independently represents 1’ IE 91913 hydrogen or a group selected from, a Ci-Cs alkyl, a C1-C4 alkoxy, amino, aminoethyl, carboxy, an alkoxycarbanyl in which the alkoxy is C1-C4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, H-cyano-acetamide, N-hydroxy-acetamide, N-(4-carboxy-l,3-thiazol2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-l-yl-carbonyl, 3-cyano-2-methylisothioureidomethyl, with the condition that at least one of the substituents Ri or R2 is different from hydrogen; - Rs represents hydrogen, a Ci-Cs alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is CiCe, a phenylalkenyl in which the alkenyl is C2-C3, the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalky, hydroxyl or a C1-C4 alkoxy; - R4 and Rs each independently represent a Ci-Cs alkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a Ci-C4 perfluoroalkyl, hydroxyl, C1-C4 alkoxy; - or R4 and Rs together form a group of formula =CR7Re, in which R7 represents hydrogen, a C1-C4 alkyl or a phenyl and Rs represents a C1-C4 alkyl or a phenyl; - or again R4 and Rs linked together represent either a group with formula (CH2>n, or a group of formula (CH2>PY(CH2>q, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or an N-Rs group in which Rs represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C4, a C,-C4 alkylcarbonyl, a C1-C4 haloalkylcarbonyl, a C1-C4 polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an N-protecting group, or R4 and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p + q = m; - 2 IE 91913 - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; - z and t are zero or one is zero and the other is unity; - and their salts.
When a compound in accord with the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound.
The salts of compounds of formula (I) in accord with this invention consist of those with organic or inorganic acids which permit appropriate separation or crystallization of compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a camphosulphonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, naphthalene-2-suIfonate.
The salts of compounds of formula (I) also consist of salts with organic or inorganic bases, for example salts of alkali or alkaline earth metals like salts of sodium, potassium, calcium, the salts of sodium and potassium being preferred, or with a tertiary amine, such as trometamol, or even salts of arginine, lysine, or any physiologically acceptable amine.
According to this description and in the claims which follow, a halogen atom is understood to be a bromine, chlorine or fluorine atom. An N-protecting group (also denoted by Pr) is understood to be a group classically used in peptide chemistry for temporary protection of the amine function, for example a Boc, Z or Fmoc group or a benzyl group. An esterified carboxy group is understood to be an ester which is labile under the approriate conditions, like for example a methyl, ethyl, benzyl or tertiary butyl ester. Alkyl means straight-chain or branched aliphatic hydrocarbon radicals.
Confounds of formula (I) in which Ri is in the ortho position and is a carboxy group or tetrazolyl and R2 is hydrogen are IE 91913 Et nBu,tBu DMF THF DCM MBS DCC DI PEA Ether TFA Z Boc BOP Fmoc preferred compounds.
Compounds of formula (I) in which Ri and Rs linked together as one unit with the carbon to which they are bonded constitute a cyclopentane or a cyclohexane are preferred compounds.
Similarly, compounds of formula (I) in which R3 Is a straight-chain Ci-Ce alkyl group are preferred compounds.
Compounds of formula (I) in which'X is an oxygen atom are likewise preferred compounds.
Finally, compounds of formula (I) in which z = t = 0 are preferred compounds.
The fallowing abbreviations are used in the description and in the examples: : ethyl : n-butyl, tert-butyl : dimethylformamide : tetrahydrofuran : dichloromethane : M-bromo-succinimide : dicylcohexylcarbodiimide : diisopropylethylamine : ethyl ether : trifluoroacetic acid : benzyloxycarbony1 : tert-butoxycarbonyl : benzotriazolyloxy trisdimethylamino phosphonium hexa f1u orophosphate : fluorenylmethyloxycarbonyl This invention also has for its subject the method of preparation of compounds (I). The said method comprises; al) a heterocyclic derivative of formula; -r 4 ί4 E5zL(CH2)t z(CH2) N X.A IE 91913 in which z, t, S3, R4 and Rs have the meanings indicated above for (I), reacting with a derivative of 4-methylbiphenyl of formula; in which Hal is a halogen atom and R‘ i and R'2 are either Ri and R2 or a grouping which is a precursor of Ri and Rj respectively; bl) optionally, the compound thus obtained of formula; is treated with Lawesson's reagent 2,4-bis<4-methoxyphenyl)-l,330 dithia-2,4-diphosphetan 2,4-disulfide; cl) the compound obtained from al) or bl) of formula; - 5 IE 91913 in which X is an oxygen atom or a sulfur atom, is treated by converting the R* i and/or Ε'ϊ groups into Ri and/or Ri groups respectively in order to prepare compound (I).
Amongst compounds 2., the compounds (II) as defined below are novel.
Thus this invention also has as its subject the compounds (II) of formula; \4 S5d-(CH2)t z(dH2) N A A83 n χ/ N I H in which; - R3 represents hydrogen, a Ci-Cs alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C>Ce, a phenylalkenyl in which the alkenyl is C2-C3, the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a C)-C4 alkoxy; - R4 and Rs each independently represent a Ct-Ce alkyl, a phenyl, a phenylalkyl in which the alkyl is C,-C3, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or - ϋ IE 91913 several halogen atoms or with a group selected from, a C1-C4 perfluoroalkyl, hydroxyl, C1-C4 alkoxy; - or R4 and Rs together form a group of formula =CR7Rs, in which R7 represents hydrogen, a C1-C4 alkyl or a phenyl and Re represents a C1-C4 alkyl or a phenyl; - or again R4 and Rs linked together represent either a group of formula (CHPn, or a group of formula PY(CH2>q, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or an 1T-Rs group in which Rs represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C4, a C1-C4 alkylcarbonyl, a Ci-C4 haloalkylcarbonyl, a C1-C4 polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an Ϊprotectinggroup, or R4 and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p + q = m; - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; - z and t are zero or one is zero and the other is unity; with the restriction that - when z and t are zero and X is an oxygen atom, Ra and Rs are other than; ® a Ci-Cs alkyl, a phenyl, a phenylalkyl in which the alkyl is Ci25 Ca, the said alkyl, phenyl and phenylalkyl being unsubstituted or substituted with one or several halogen atoms or with a group selected from a C1-C4 perfluoroalkyl, hydroxyl, C1-C4 alkoxy; » or R4 and Rs linked together are other than an H-Rs group in which Rs is a hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is Ci-C3! w n is different from 6 and, when z=l and R3 is a phenyl, R4 and Rs are each different from methyl.
Amongst the derivatives (II), compounds in which z = t = 0 and Ra and Rs together with the carbon to which they are bonded - 7 IE 91913 constitute a cyclopentane, are preferred compounds. These compounds correspond to formula; in which X is an oxygen atom or a sulfur atom and R3 is hydrogen, a Ci-Ce alkyl, either unsubstituted or substituted with one or several halogen atoms, a C2-Ce alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Ci-C3, a phenylalkenyl in which the alkenyl is C2-C3, the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a C1-C4 alkoxy.
Compounds (II) in which z = 0 and t = 1 of formula; in which R3, R4, Rb and X have the definitions given above for (II) are preferred compounds.
Finally, compounds (II) in which z = 1 and t = 0 with formula; - 8 IE 91913 R4 R5 (Π’") in which; " Rs represents hydrogen, a Ci-Cs alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is CtC6, a phenylalkenyl in which the alkenyl is C2-C3, the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a C1-C4 alkoxy; - S4 and Rs each independently represent a Ci-Cfi alkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a C1-C4 perfluoroalkyl, hydroxyl, C1-C4 alkoxy; - or R4 and Rs together form a group of formula =CR7Rs, in which R7 represents hydrogen, a C1-C4 alkyl or a phenyl and Rs represents a Ci-C4 alkyl or a phenyl; - or again R4 and Rs linked together represent either a group of formula „, or a group of formula PY)<,, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or an Μ-Rs group in which Rs represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is Ci-Ctp a C1-C4 alkylcarbonyl, a C1-C4 haloalkylcarbonyl, a C1-C4 polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an M-protecting group, or R4 and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p + q = m; IE 91913 - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; with the restriction that R3 is other than a phenyl when R4 and Rs each represent methyl; are preferred compounds.
The derivatives 2. are prepared by known methods. For example, the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, 2., 1040-1051) and by Brunken and Bach (Chem. Ber., 1956, 22., 1363-1373) may be used by reacting an alkyl imidate with an amino acid or its ester in accord with the fallowing reaction scheme: R4^ ^CH2)z-C02R· Ks ^CH2)t.-NH2 NH + R3 - --OR ’ I4 Rsy-CCh^t z(CH2) N Ο N in which R is a Ci-C4 alkyl, R' is hydrogen or a Ci-CZ alkyl and Rs, R4, Rs, z and t are as defined previously for (I).
This reaction is performed in acid medium, by heating in an inert solvent such as xylene or toluene.
According to another method of working, a compound 2. nay be prepared by the effect in acid medium of an aminoalkylamide (5.'*) on an alkyl ortho-ester (lfi.) in accord with the following reaction scheme: IE 91913 • Ϊ ----- > R4 (CH2)z-C0NH2 /C\ R5 (CH2)t-NH2 + R3-C(0R)3 —> 2 where R is a C1-C4 alkyl.
The compound 2. may also be prepared by using a method of working described by H. Takenaka et al. (Heterocycles, 1989, 22 (6>, 1185-89), by reacting the derivative 5'1 with an acid halide of formula: R3 - CO - Hal 22 in which Hal is a halogen, preferably chlorine.
The reaction is carried out in a basic medium.
More particularly, a compound 2., in accord with another subject of this invention, is prepared by a- method comprising reacting a compound of formula: R4 (CH2)zC0A X 12 R5 (CH2)tNH2 in which A is an OH group, an UH2 group or an OR' group, R' being hydrogen or a C1-C4 alkyl, with a compound of formula: R3 - B 24 in which B is: C (0R)3 ,NH OR grouping grouping IE 91913 ' or - a COHal grouping, R being a C1-C4 alkyl and Hal representing a halogen atom, preferably chlorine, then optionally the compound thus obtained is treated with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3dithia-2,4-diphosphetan 2,4-disulfide.
The derivative of 4-methylbiphenyl (2.) is prepared in accord with a method described in patent application EP 324 377.
The conversion of an R* 1 and/or R'2 group into an Ri and/or Rs group is carried out using methods which are well known to the specialist in the field. Thus, when the compound (I) to be prepared has an Ri and/or R2 group = carboxy, R'1 and/or R*2 is an esterified carboxy group. When the compound (I) to be prepared has an Rt and/or R2 group = tetrazolyl, R'1 and/or R'2 may be either a tetrazolyl protected for example by a trityl group, or a cyano group which will then be replaced by a tetrazolyl optionally protected by a trityl. Conversion of the cyano group into tetrazolyl may be carried out by an azide, for example tributyl tin azide or sodium aside.
R'i and/or R‘2 groups such as nitro, carboxy, cyano or acid chloride groups may also be used and these may then be converted using reactions which are well-known to the specialist in the field in order to obtain Ri and/or R2 groups such as those described for compound I.
Thus, when R'i and/or R'2 represent a carboxy, it may be converted into Ri and/or R2 representinf an imidazol-l-yl-carbonyl, or even N-C(4-carboxy)-l,3-thiazol-2-yl]acetamide.
The R’i and/or R*2 representing an acid chloride may be converted int Ri and/or R2 representing 5-hydroxyacetamide, Ncyanoacetamide, ureido or 2-cyanoguanidinocarbonyl.
R'ι and/or R‘2 representing a nitro may be converted into an amino from which R, and/or R2 such as methylsulfonylamino, trifluoromethylsulfonylamine and trifluoromethylsulfonylaminomethyl may be prepared.
R'i and/or Rl2 representing a cyano may be converted into IE 91913 aminomethyl from which can be prepared 3-cyano-2methylisothioureidomethyl (in accord wirh C. Gordon et al., J. Org. Chem., 1970, 35. (6), 2067-2069) or a 2-cyanoguanidomethyl (in accord with R.V. Turner, Synthesis, 1975, 332) Stage al) is performed in an inert solvent such as DMF, DMSO or THF, in a basic medium, for example in the presence of potash, a metal alcoholate, a metal hydride, calcium carbonate or triethylamine.
Stage bl) is performed by heating under nitrogen in a solvent such as toluene, in accord with the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061.
The method comprising stages al, bl, and cl is called method 1 in the fallowing description.
Alternatively, compounds (I) may be prepared in accord with another method which is likewise a subject of this invention. This method comprises: a2) reacting an aminoacid of formula; R4 (CH2)fNHPr (CH2)z COOH' in which z, t, R4 and Rs have the meanings indicated above for (I) and whose amine function is protected with the Pr group with a 4-methylamine-biphenyl derivative of formula: in which R’i and/or R’2 represent either Ri and Rz respectively, or a precursor of Ri and R2; IE 91913 b2> after deprotecting the amine, the compound thus obtained of formula: is then treated with an alkyl ortho-ester of formula 10 R3C(0R>3 (10) in which R3 has the meaning indicated above for (I) and R is a C1-C4 alkyl; c2> optionally, the compound thus obtained of formula: is treated with Lawesson's reagent 2,4-bis<4-methoxyphenyl)-l,3dithia-2,4-diphosphetan 2,4-disulphide; d2> the compound thus obtained in b2 or in c2 of formula: IE 91913 is then treated under appropriate conditions to prepare compound Compounds Z. are known or prepared by known methods 15 (Chemistry of the Amino Acids, Greenstein and Vinitz, John Viley ed., 1961, vol. 1, p. 697).
Compounds S_ are prepared in accord with European patent application 324 377. Stage a2) is carried out under the normal conditions for coupling an acid and an amine, for example in the presence of BOP and of DIPEA.
Stage b2) which is the cyclisation of compound 2. in the presence of 10 is performed in accord with Jacquier et al. (Bull. Soc. Chim. France, 1971, (3), 1040-1051) and in accord with Brunken and Bach (Chem. Ber., 1956, £2., 1363-1373).
In the following description the method comprising stages a2 to d2 is called method 2.
According to one variant of method 2, in stage b2, an intermediary 9' of formula: may optionally be isolated and then compound ί may be prepared by cyclisation in acid medium.
According to another variant of method 2 and to prepare a compound I in which R4R5 is one group =CR7Ra an amino acid of formula: CH2-(CH2)t-NHCOR3 (CH2)z-C00H 2' may be reacted in acid medium with an aldehyde or a ketone of 10 formula: IE 91913 R7CORS in which R7 and Re have the meanings given above for (I), then a 15 compound of formula: R’l R’20 z-h R7R8C=C-(CH2)z-C-NH-CH2-\X \ (CH2)t-NHC0R3 \=/ \~z 20 22 is obtained by action with compound Cyclisation of this compound in acid medium leads to 25 compound 4..
In this method, to prepare a compound (I) in which Ri and/or R2 is a carboxy group, the substituent R'1 and/or R’2 is preferentially a tert-butoxycarbonyl.
Finally, another alternative for the preparation of 30 compounds (I) in accord with the invention in which z and t are zero, is the photooxidation method which is likewise a subject of this invention.
This last method comprises: a3> reacting an imidazole derivative of formula: IE 91913 in which. R3, R4, Rs have the meanings indicated above for (I) with a derivative of 4-methylbiphenyl of formula: in which Hal is a halogen atom and R'ι and/or R'2 represents 20 either Ri and R2 respectively or a precursor of Ri and R2, in the presence of oxygen and UV irradiation, in a basic medium; b3) optionally, the compound thus obtained of formula: IE 91913 is treated, with Lawesson's reagent 2,4-bis(4-methoxy)-l,3-2,4diphosphetan 2,4-disulfide; c3> the compound thus obtained from b3 or from c3 of formula: is then treated under appropriate conditions to prepare compound (I) by converting the R'i and/or R'2 groups into Ri and/or R2 groups respectively.
The imidazole derivative 11 is either commercially available, or known, or prepared by known methods as indicated above for the preparation of compunds 2.· Stage a3) is performed in an inert solvent such as DMF for example. To facilitate the reaction, a photosensitizing product such as methylene blue may be added.
In the following description, the method comprising stages a3> to c3> is called method 3.
Compounds (I) in accord with the invention, in which Ri ®91913 and Rs linked together represent a group of formula (CH2)PY(CH2)q in which Y is an MH group, may be prepared by catalytic hydrogenolysis of a corresponding compound (I) in which Y is an M-Rs group, Rs being benzyl.
The affinity of products in accord with the invention for angiotensine II receptors was studied in a linkage test of angiotensine II labelled with iodine 125 to membrane receptors in rat livers. The method used was that described by S. MS et al., in Biochem. J., 1982, 208. 809-817.
CIso was measured. This was the concentration which produced 50% displacement of the labelled angiotensine II, linked specifically to the receptor. The CIso of the compounds in accord with the invention is less than 10~s M.
In addition, the angiotensine II antagonistic effect of the products in accord with the invention has been confirmed in various animal species in which the renin-angiotensine system had been activated previously (C. LACOUR et al. , J, Hypertension, 1989, Z. (suppl.2>, S33-S35).
Compounds in accord with the invention are active after administration by various routes, particularly the oral route.
Mo sign of toxicity was observed with these compounds at pharmacologically active doses.
Thus the compounds in accord with the invention may be used in the treatment of various cardiovascular ailments, particularly hypertension, heart failure, venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathy, and various ailments of the central nervous system, anxiety, depression, memory disorders or Alzheimer's disease, far example.
This invention likewise has as its subject pharmaceutical compositions containing an efficacious dose of a compound in accord with the invention or a pharmaceutically acceptable salt and appropriate excipients. The said excipients are chosen in accord with the pharmaceutical form and the desired method of administration.
In pharmaceutical compositions of this invention for IE 91913 oral, sublingual, percutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermic or rectal administration, the active principles of formula I above, or optionally their salts, may be administered in the form of administration units, mixed with classical pharmaceutical supports, to animals and to humans for the prevention or treatment of the illnesses or diseases above. The appropriate forms of administration units include forms for the oral route such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal forms of administration, percutaneous, intramuscular or irftravenous forms of adminstration and rectal forms of adminstration. For topical application, the compounds in accord with the invention may be used in creams, ointments or lotions.
In order to obtain the preventive or therapeutic effect desired, the dose of active principle may vary between 0.01 and 50 mg per kg body weight and per day.
Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, active ingredients in combination with a pharmaceutical support. This unit dose may be administered 1 to 5 times per day in such a way as to administer a daily dosage of from 0.5 to 5000 mg, preferably from 1 to 2500 mg.
When a solid composition is prepared in the form of tablets, the principal active ingredient is mixed with a pharmaceutical vehicle such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic or similar. The tablets may be coated with sucrose, a cellulose derivative, or other appropriate material or again they may be treated in such a way that they have a prolonged or retarded activity and they release a predetermined quantity of active principle continuously.
A preparation in capsules is obtained by mixing the active ingredient with a diluant and pouring the mixture obtained into soft or hard capsules.
A preparation in the form of syrup or elixir or for IE 91913 adminstration in the form of drops may contain the active ingredient together with a sweetener, preferably with no calorie content, methylparaben and propylparaben as antiseptics, as well as an agent to give a suitable taste and colour.
Powders or granules which can be dispersed in water may contain the active ingredient mixed with dispersion or wetting agents, or suspension agents like polyvinylpyrrolidone, again with sweeteners or taste correctors.
For rectal administration, suppositories which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethyleneglycols, are used.
For parenteral administration, aqueous solutions, isotonic saline soutions or sterile and injectable solutions which contain pharmacologically compatible dispersion and/or wetting agents, for example propyleneglycol or butyleneglycol, are used.
The active principle may also be formulated in the form of microcapsules, optionally with one or several supports or additives.
The compositions of this invention may contain, alongside the products of formula I above or one of the pharmaceutically acceptable salts, other active principles such as, for example, tranquillisers or other drugs which may be used in the treatment of the illnesses or ailments indicated above.
Thus, this invention has for its subject pharmaceutical compositions containing several active principles in association, one of which is a compound in accord with the invention and the other(s> may be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal anti-inflammatory agent or a tranquilliser.
The following examples illustrate the invention without limiting it in any way. In these examples, the fallowing abbreviations are used; d means density, TA means ambient temperature, KHS04-K2S04 means an aqueous solution containing 16.6 g potassium bisulfate and 33.3 g potassium sulfate per IE 91913 litre.
The melting points (M.pt.) are given in degrees Celcius; unless indicated to the contrary, they were measured without recrystallizing the product.
Purity of the products was checked using thin layer chromatography (TLC) or HPLC. The products are characterised by their EUR spectra recorded at 200 KHz in deuterated DMSO, the internal reference being tetramethylsilane.
To interpret the IfMR spectra, the following were used: s for a singlet s.e. for a broadened singlet d for a doublet t for a triplet q for a quadruplet quint for a quintuplet sext for a sextuplet m for for a very broad band or multiplet Moreover, im means imidazole.
In the classic manner, the hydrogen atoms are numbered on the biphenyl as shown in the following formula: (I) In the fallowing compounds, z and t are zero, except when the compound prepared is a pyrimidinone.
IE 91913 EXAMPLE 1 2-n-butyl-4-spirocyclopentane-l-[(2'-tertbutoxycarbonylbiphenyl-4-yl)methyl] -2-imidazolin-5-one 5 and 2-n-butyl-l-[2,-carboxybiphenyl-4-yl)methyll-4spirocyclopentane-2-imidazolin-5-ane trifluoroacetate. Method 2.
A) 1-(N-Fmoc-amino)-cyclopentane ccarboxylic acid was prepared in IQ accord with the method described by CHI-ODEU CHANG et al. (Int.
J. Peptide Protein Res., 1980, 15., 59-66). M.pt. = 89-91’C) B) N-(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl-l-(N-Fmocami no)cyclopentanecarboxamide-1. 700 mg of the product prepared in the preceding stage were dissolved in 8 ml DMF and 576 mg 4-aminoethyl-(2' butoxycarbonyl)biphenyl, 970 mg BOP and enough DIPEA to give a pH of 6 were added in succession.
After stirring for 1 hour, the reaction medium was diluted with 100 ml ethyl acetate and 20 ml water. The organic phase was washed successively with a saturated sodium bicarbonate solution, then with a KHSCG-KiSCL solution and finally with a saturated sodium chloride solution. After drying over sodium sulfate, the solution was evaporated to dryness. An oil was obtained with m = 1.2 g. c> N-(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl-l-aminocyc1opentanecarboxamide-1.
The product obtained in the preceding stage was dissolved in 10 ml DMF, then 1 ml diethylamine was added and the mix stirred for 1¼ hours at TA. The reaction medium was 30 absorbed by 100 ml ethyl acetate and 20 ml water and the organic phase was washed once with water, once with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness.
The residue was chromatographed on silica gel by eluting with an ethyl acetate/methanol/30% ammonia solution mixture IE 91913 (99/1/0.5 ; v/v/v). 600 mg expected product were obtained.
IR (CHC1»> · 3350 cm-» : H (amide et amine) 1700 cm-» : C = 0 (CQjtBu) 5 1650 cm-» : C = 0 (CONH) OR spectrum : 1,25 ppm : s : 9 H : tBu 2.15 - 1,40 ppm : m : 10 H : (C5H8, NH2) 4,40 ppm : d : 2 H : CH2-NH 7.15-7.75 ppm : m : 8 H : biphenyl 8.60 : t : 1 H : NH - CHj D) 2-n-butyl-4-spirocyclopentane-l-[ (2’-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one. 394 mg product prepared in the preceding stage and 250 mg ethyl orthovalerate were mixed in 2 ml DCM. 1 drop of acetic acid was added and then the mix was heated to 90’C allowing the DCM to evaporate. After 1¼ hours, the reaction medium was absorbed by 50 ml ethyl acetate, 10 ml water and 1 ml saturated 2q sodium bicarbonate solution. The organic phase was then washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel by eluting with an ethyl acetate/toluene mixture (1/2, v/v). 390 mg expected product was obtained, which crystallized. M.pt. = 63-65’C.
IR (CHCls) : 1710-1720 era-» : C = 0, C = 0 (ester et imidazoline) 1625 cm-»: 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-CH21,58 ppm : quint : 2 H : CH3-CH2-CH21.95-1,65 ppm : a : 8 H : cyclopentane 2.42 ppm : t : 2 H : CH3-CH2-CH2-CH24.78 ppm : s : 2 H : CHj-CgH*24 IE 91913 7.20-7.80 ppm : m : 8 H : aromatic H mass spectrum : MH* : 461 E) 2-n-butyl-l-[(2'-carbaxybiphenyl-4-yl) methyl 3-4spirocyclopentane-2-imidazolin-5-one trifluoroacetate. 180 mg of product prepared in the preceding stage were treated with 3 ml DCM and 4 ml TFA for 45 minutes. After evaporation under vacuum, the residue was absorbed in ether. A white solid was obtained which was filtered, washed with ether and then dried under vacuum.
NMR spectrum : 0.78 ppm : t ; 3 H : CH3 (nBu) 1.25 ppm ; sext : 2 H : CH3-CH2 1.50 ppm : quint : 2 H : CH3-CH2-CH2 1.75-2,00 : m, 8 H : cyclopentane 2.65 ppm : t : 2 H : CH3-CH2-CH2-CH24.83 ppm : s : 2 H : CH2-C6H420 7.20-7.75 ppm : m 8 H : aromatic H mass spectrum : MH* : 405 EUHELE.2. 2-n-butyl-l-E(2'-carboxybiphenyl-4-yl)methyl3-4spirocyclopentane-2-imidazolin-5-one trifluoroacetate. Method 1.
A) 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one.
The ethyl ester of l-aminacyclopentahe carboxylic acid was prepared in accord with ADKINS and BILLICA (J. amer. Chem. Soc., 1948, Ζϋ. 3121).
Ethyl valerimidate was prepared in accord with Mac ELVAIN (J. Amer. Chem. Soc., 1942, £11825-1827) and then released from its hydrochloride by the action of potassium IE 91913 carbonate and extraction with DCM.
The ethyl ester of 1-aminocyclopentane carboxylic acid (1.57 g) and ethyl valerimidate (1.56 g) were dissolved in 12 ml xylene containing 6 drops of acetic acid. After 6¾ hours of heating under reflux, the reaction medium was concentrated under vacuum and the residue was then chromatographed on silica gel by eluting with a chloroform/methanol/acetic acid mixture (94/4/2 ; v/v/v). The fraction containing the expected product was evaporated several times in the presence of xylene and then of benzene to remove acetic acid. 1.91 g product was obtained in the form of a thick ail.
IR (CHCls) : 1720 cm*1 : C = 0 1635 cm*1 : C = N Note: the fact that no band is visible between 1500 and 1600 cm'1 indicates that, in chloroform solution, the product is an imidazolin-5-one.
NMR spectrum : 0,92 ppm : t : 3 H : CH3 (nBu) 1.35 ppm : sext : 2 H : CH3-CH21.50-1,93 ppm : m : 10 H : CH3-CH2-CH2 et cyclopentane 2.33 ppm : t : 2 H : CH3-CH2-CH2-CH2- .7 ppm : ra : NH mass spectrum : MH* : 195 The 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one prepared in stage A, may also be obtained in accord with another method of working, described below, by using cyclopentanone as the starting material. a) 1-aminocyclopentanenitrile This stage is carried out in accord with A. Strecker (Org. Synth., 1955, 2.)· 1.97 g sodium cyanide was dissolved in 3.9 ml water in a round-bottomed flask and a solution containing 2.33 g ammonium chloride in 5.9 ml water and 3.5 ml 20% ammonia solution was added, then 3 g cyclopentanone in 3,8 ml methanol were added to IE 91913 the flask. After 1¾ hours stirring, the flask was warmed to 60’C for 45 minutes, then the heating was turned off and the stirring continued for 45 minutes and the flask cooled to 25’C.
The contents were extracted several times with methylene chloride, dried over sodium sulfate, filtered and concentrated under vacuum. 4 g expected product was obtained in an oily form.
The 1-aminocyclopentanenitrile obtained was made into a solution with 300 ml acetone and a solution of 2.25 g oxalic acid dihydrate in 200 ml acetone was added with stirring. The precipitate which formed was centrifuged, washed with acetone and then dried. m = 4.71 g M.pt. = 220’C This compound is 1-aminocyclopentanenitrile hemioxalate. b) 1-aminocyclopentaneacetamide.
This stage was carried out in accord with J. Zabicky, (The Chemistry of Amides, Intersciences, New York, 1970, 119). .1 g of the oxalate obtained in the preceding stage were treated with 7.65 ml concentrated sulfuric acid (d = 1.84) for 45 minutes with stirring. A gas was evolved and the temperature increased to 100’C. The mix was cooled to 35*C and poured into a mixture of ice and concentrated ammonia solution (10 g/2.8 ml). The suspension which formed was extracted 6 times in succession with chloroform containing 5% methanol. 3 ml ammonia solution (d = 0.92) were added to the aqueous phase and this was then extracted again with chloroform containing methanol (1/0.5 ; v/v). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The expected product was obtained in the form of a white solid, n = 3.79 g M.pt. = 95*C The analysis results and the IR spectrum confirmed the structure. c) 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one This stage was carried out in accord with H. Taneka et al., Heterocycles, 1989, 29. 1185-89. g of the compound prepared in the preceding stage were placed in 70 ml anhydrous THF and 3.3 ml triethylamine and 3 ml valeryl chloride in 10 ml anhydrous THF were added with stirring. A white suspension was produced. The intermediate compound which was formed, but not isolated, was 1- (N-valeryl Jaminocyclopentanecarboxamide. 6 g potassium hydroxide in pellet form, 7 ml water and 16 ml methanol were added. Heating under reflux was performed for two and a half hours and then 9 g ammonium chloride were added. After 15 minutes stirring, the mix was concentrated under vacuum. The residue obtained was absorbed in 40 ml water and extracted with 10 ml ethyl acetate and then twice with 5 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness. 4.85 g expected product were obtained. The NMR spectrum was similar to that described previously. The hydrochloride of this compound may be prepared by addition of concentrated hydrochloric acid.
The hydrochloride melts at 240*C while subliming.
B) 2-n-butyl-4-spirocyclopentane-l-[ (2'-tert-butoxycarbonylbiphenyl-4-ylJmethyll-2-imidazolin-5-one. 970 mg product obtained in stage A) were dissolved in 10 ml DMF. 270 mg sodium methylate were added and left at TA for 15 minutes with stirring. 2.08 g 4-bromomethyl-<2'- tertbutoxycarbonyl) bimethyl were added to the suspension then, after 30 minutes, the mix was heated at 40’C for 3¾ hours under nitrogen. The reaction medium was absorbed by a mixture of 100 ml ethyl acetate, 10 ml water and 1 ml saturated sodium bicarbonate solution. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel by eluting with an ethyl acetate/toluene mixture (1/2 ; v/v). 1.25 expected product which crystallized was IE 91913 obtained. M.pt. = 63-66’C.
The IS, NMR and mass spectra as well as the Rf were identical with those obtained in stage D) of example 1.
C) 2-n-butyl-l-[ (2'-carboxybiphenyl-4-yl)methyl]-4-spiro5 cyclapentane-2-imidazolin-5-one trifluroacetate. 1.22 g product obtained in the preceding stage were stirred for 40 minutes in a solution containing 6 ml DCM and 8 ml TFA. After concentration under vacuum, the residue was absorbed in ethyl ether, the white precipitate which formed was filtered, washed with ether and then dried under vacuum. 1.15 g expected product was obtained. M.pt. = 176-178*C.
The IR, NMR and mass spectra were identical to those obtained in example IE. Moreover, the Rf measured in CCM was identical.
EXAMPLE 3 2-n-butyl-l-[<2’-carboxybiphenyl-4-yl) methyl]-4-spirocyclapentane-2-imidazolin-5-one trifluroroacetate. Method 3 A) 2-n-butylbenzimidazole was prepared in accord with W.O. POOL (J. Arner. Chem. Soc., 1937, 52, 178) and then 2-n-butyl-4,5,6,7tetrahydrobenzimidazole was prepared in accord with M. HARTMANN and L.PANIZZON (Hel. Chim. Acta, 1938, 21, 1692-1694). M.pt. = 145’C.
NMR spectrum : 0,82 ppm : t : 3 H : CH3 (nBu) 1.23 ppm : sext : 2 H : CH3-CH2’ 1,50 ppm : quint : 2 H : CH3-CH2’CH2* I. 65 ppm : s : 4 H : H5, H$ (tetrahydrobenzimidazole) 30 2.35 ppm : s; 4 H : H4, H7 (tetrahydrobenzimidazole) 2.45 ppm : t : 2 H : CH3-CH2-CH2-CH2II. 1 ppm : m : NH mass spectrum : M’ : 178 B) 2-n-butyl4-spirocyclopentane-l-t(2' tert-butoxycarbonyl29 IE 91913 biphenyl4-yl)methyll -2-imidazolin-5-one. g product prepared in the preceding stage was dissolved in 45 ml DMF with 303 mg sodium methylate and a few mg methylene blue. Oxygen was bubbled into the reaction medium which was illuminated with a UV lamp. After 15 minutes, 2.14 g 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl was added and then, after 1 hour, the reaction medium was absorbed in 300 ml ethyl acetate containing 50 ml water and 5 ml saturated sodium bicarbonate solution. The organic phase was then washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gell by eluting with an ethyl acetate/toluene mixture (1/2 ; v/v). 610 mg expected product which crystallized was obtained. M.pt. = 62-65’C.
The IS, NMR and mass spectra as well as the Rf were identical to those obtained previously for the same compound.
C) 2-n-butyl-l-I (2'-carboxybipenyl-4-yl)methyl1-4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate.
This compound was obtained by treatment in acid medium as described in the last stage of example 1 and example 2. The physicochemical data are identical to those obtained for the same compound prepared using methods 1 or 2.
EXAMPLE 4 2-n-butyl-4,4-dimethyl-l-I (2‘-tert-butoxycarbonylbiphenyl-4-yl)methyl I -2-imidazolin-5-one. and 2-n-butyl-l-t (2'-carboxybiphenyl-4-yl)methyl]-4,4dimethyl-2-imidazolin-5-one trifluoroacetate. Method 1.
The ethyl ester of alpha-aminoisobutyric acid was prepared in accord with R. Jacquier et al. (Bull. Soc. Chim., France, 1971, (3), 1040-1051). 650 mg of this compound and 780 mg ethyl valerimidate were dissolved in 8 ml xylene containing 4 drops of acetic acid and heated under reflux for 7 IE 91913 hours. The reaction medium was then concentrated under vacuum and the residue chromatographed on silica gel by eluting with a chloroform/methanol/acetic acid mixture <95/5/2 ; v/v/v). After several evaporations of xylene and then of benzene, to remove the acetic acid, 560 mg expected product which crystallized were obtained. M.pt. = 35-38 °C.
IS (CHCI3) 1725 cm*1 : C = 0 1635 cm*1 : C = N Note: the absence of a signal between 1500 and 1600 cm'’ confirms that the compound present in chloroform solution was a 2-imidazolin-5-one.
NMR spectrum : 0.92 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : s : 6 H : C (CH3)2 1.38 ppm : sext : 2 H : CH3-CH2 1.63 ppm : quint : 2 H : CH3-CH2-CH22.38 ppm : t : 2 H : CH3-CH2-CH2-CH210,7 ppm : m : 1 H : N-H mass spectrum : MH* : 169 B) 2-n-butyl-4, 4-dimethyl-l-C(2'-tert-butoxycarbonylbiphenyl-4y1)methy1-2-imidazolin-5-one. 520 mg product prepared in the preceding stage were dissolved in 10 ml DMF. 167 mg sodium methylate was added and stirred for 15 minutes under nitrogen. Then 1.25 g 4-bromomethyl-2'- tert-butoxycarbonylbiphenyl was added and the mix was stirred for 3¾ hours at 40‘C. The reaction medium was absorbed in 150 ml ethyl acetate and then 20 ml water and 2 ml saturated sodium bicarbonate solution. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel by eluting with an ethyl acetate/toluene mixture (1.2/2 ; v/v). 570 mg expected product which crystalliszed were obtained. M.pt. = 98-100°C, IR (CHCLs) : 1710-1720 cm-i : C = 0, C = 0 (imidazolinone, ester) IE 91913 1625 cm-i : C = N NMR spectrum : 0.78 ppm : t : 3 H : (¾ (nBu) 1.08 ppm : s : 9 H, C(CH3)3 1,15 ppm : s : C (CH3)2 et 1,20 ppm : sext : CH3-CH2- ) 8 H 1.45 ppm : quint : 2 H : CH3-CH2-CH22.30 ppm : t : 2 H : CH3-CH2-CH2-CH^4.65 ppm : s : 2 H : CH2-C6H47.15-7.65 ppm : m : 8 H : aromatic H A Nuclear Overhauser Effect study confirmed the position of the 5-one and 4,4-dimethyl substitutions on the imidazoline. mass spectrum : MH* : 435 C) 2-n-butyl-l-E <2'-carboxybiphenyl-4-yl)methyl3-4,4-dimethl-2imidazolin-5-one trifluoroacetate. 460 mg product prepared in the preceding stage were treated with 3 ml DCM and 4 ml TFA for 45 minutes. After concentration under vacuum, the residue was absorbed in ether and the precipitate which formed was filtered, washed with ether and then dried under vacuum. 450 mg expected product were obtained in the form of a white solid. M.pt. = 168-171’C.
NMR spectrum : 0,82 ppm : t : 3 H : CH3 (nBu) 1.30 ppm : sext : CH3-CH2") 1.35 ppm. s : C(CH3)2" ) 8 H 1.55 ppm : quint : 2 H : CH3-CH2-CH22.62 ppm : t : 2 H : CH3"CH2-CH2-CH2- 4.82 ppm : s : 2 H : CH2C8H4" 7.20 - 7.75 ppm : m : 8H aromatic mass spectrum : MH* : 379 EXAMPLE 5 1-E(2'-cyanobiphenyl-4-yl)methyl3-2-n-butyl-430 IE 91913 spirocyclopentane-2-imidazolin-5-one and 2-n-butyl-4-spirocyclopentane-l-[ (2’-(5tetrazolyl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. Method 1.
A) 1-C(2'-cyanobiphenyl-4-yl) methyl]-2n-butyl-4-spiro5 eye1opent ane-2-i mi dazο1i n-5-one.
A mixture containing 250 mg sodium hydride (an 80% dispersion in mineral oil) and 5 ml DMF was prepared under an atmosphere of nitrogen and a solution containing 0.97 g 2-n10 butyl-4-spirocyclopentane-2-imidazolin-5-one (prepared as in example 2, stage A) in 10 ml DMF was added dropwise. This was stirred for 30 minutes at TA and then a solution of 1.5 g 4bromomethyl-2'-cyanobiphenyl in 10 ml DMF was added. After stirring for 1 hour at TA, the DMF was evaporated off under reduced pressure and the residue was absorbed in ethyl acetate.
The organic phase was washed with water and then dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel by eluting with a DCM/ethyl acetate mixture (9/1 ; v/v). 1.68 g expected product was recovered.
M.pt. = 92-93*C.
B) 2-n-butyl-4-spirocyclopentane-l-[2’-(5-triphenylmethyltetrazolyl)biphenyl-4-yl)methyl)-2-imidazolin-5-one. 1.56 g preceding product, 2.6 g tributyltin azide and 30 ml xylene were heated under reflux for 66 hours. The xylene was then evaporated off and the residue was dissolved in 20 ml DCM and 5 ml THF, while adding 0.8 ml ION soda and, after 30 minutes stirring, 2.5 g trityl chloride and then the mix was stirred for 26 hours. After evaporating off the solvents, the residue was absorbed in ethyl acetate and washed well with a 3% solution of potassium hydrogen sulfate and water. This was dried and evaporated. The residue was chromatographed on alumina by eluting with a hexane/ethyl acetate mixture (9/1 ; v/v). 1.97 g expected product was obtained. M.pt. = 150152‘C.
C) 2-n-butyl-4-spirocyclopentane-l-[ (2'-(5-tetrazolyl)biphenyl33 IE 91913 4-yl)methyl]-2-imidazolin-5-one. 1.96 g product prepared ln the preceding stage were dissolved in 10 ml methanol and 10 ml THF. After cooling the reaction medium to 5’C, 1.5 ml 4N hydrochloric acid were added and the mix was stirred for 3 hours at TA and 30’C. After evaporation of the solvents, the residue was absorbed in water and adjusted to pH 12 by adding ION soda. The aqueous phase was extracted with ether, toluene and then ether again, The aqueous phase was acidified to pH 2 by the addition of IN hydrochloric acid and then extracted into ethyl acetate, dried and evaporated. The white solid which was obtained was dried at 50’C under a reduced pressure of 0.05 mm mercury. 840 mg expected product was obtained. M.pt. = 180-181’C.
NMR spectrum : 0,75 ppm : t : 3 H : CH3 (nBu) 1.10 ppm : sext : 2 H : CH3-CH2" 1,20 ppm : quint : 2 H : CHj-CHi-CH^1,5-2 ppm : m : 8 H : "CsHe 2.2 ppm : t : 2 H : CH3-CH2-CH2-CH24.6 ppm : s : 2H : CH2-CgH4" ppm : s : 4 H : CHj-CeJL 7.35-7.7 ppm : m: 4H: 3', 4', 5', 6' H aromatic A Nuclear Overhauser Effect study confirmed the position OK of the 5-one substitution on the imidazole.
D) Potassium salt of 2-n-butyl-4-spirocyclopentane-l-[ (2'-(5tetrazolyl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. 970 mg of the compound obtained in the preceding stage were dissolved in 40 ml of an isopropanol-methanol mixture (1/1 ; v/v) and the pH was adjusted to pH 12 by adding an 85% potash solution in a methanol-water mixture (20/1 ; v/v). This was evaporated, the residue was absorbed in isopropanol and evaporated again. The residue was dissolved in 20 ml isopropanol by heating gently and then left to return to ambient temperature. The mix was decanted, the filtrate evaporated and - 34 IE 91913 then the residue absorbed in heptane. After grinding up, the product solidified. It was filtered off, washed again with heptane and dried under vacuum. 945 mg of the expected potassium salt was obtined. M.pt. 142-144’C.
Elemental analysis: C2&H27KN6O. H2O calc: : C : 61.95 H : 6,03 N : 17.34 found: % 62.02 6,13 17.14 EXAMPLE 6 2-n-butyl-l-C(2’-carboxybiphenyl-4-yl)methyl I -4-(4spirotetrahydropyran)-2-imidazolin-5-one trifluoroacetate, and 2-n-butyl-4-<4-spirotetrahydropyran)-l-[ (2'-tert-butoxycarbonyl )biphenyl-4-yl) methyl! -2-imidazolin-5-ane. Method 2.
A) 4-amina-tetrahydrapyran~4-carboxylic acid was prepared starting from tetrahydropyran-4-one in accord with the method described in the German patent DE - 2 215 721.
B) 4- 1.015 g compound from stage A was placed in 12 ml water and treated at 10’C with 1.22 ml diisopropylethylamine and then 3.33 g N-(benzyloxycarbonyloxy)succinimide dissolved in 12 ml acetonitrile. After 1¼ hours, the reaction medium was diluted with 70 ml ethyl acetate and 10 ml water and adjusted to pH 2 using a saturated solution of potassium bisulfate.
After decanting, the organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. The residue was diluted in 60 ml ether and then 7 mmole dicycohexylamine was added. The precipitate which formed was filtered and washed with ether. It was then dissolved in a mixture of ethyl acetate and water and adjusted to pH 1.5 with a saturated solution of potassium bisulfate. The organic phase was decanted off, washed with a saturated solution of sodium chloride, evaporated under vacuum and 1.9 g of a white solid was obtained. M.pt. 110-115’C.
IE 91913 Ο Μ-ί <2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-4-(Νbenzyloxycarbonylamino)-tetrahydropyran-4-carboxamide. 850 ng of the compound prepared in stage B were dissolved in 15 ml DMF and equimolar amounts of 4-aminoethyl5 (2'-tert-butoxycarbonyl)biphenyl, DIPEA and BOP <10% excess) were added. After 40 minutes, the medium was absorbed in 200 ml ethyl acetate and 200 ml water. The organic phase was decanted and washed twice with a saturated solution of sodium bicarbonate and then once with a saturated solution of sodium chloride.
After drying over sodium sulfate, the organic phase was evaporated off under vacuum. 1.8 g expected product was obtained.
D) 4-N-l<2*-tert-butoxycarbonylbiphenyl-4-ylJmethyl]aminot et rahydropyran-4-carboxami de.
The product obtained in stage C was dissolved in 30 ml methanol. 400 mg 10% palladium on charcoal were added and hydrogen was passed through at atmospheric pressure. After 1 hour, the catalyst was filtered off and the filtrate was concentrated under vacuum. The residue was chromatographed on silica by eluting with an ethyl acetate/methanol/33% ammonia solution mixture <99/1/0.5 ; v/v/v). 0.93 g expected product was obtained in the form of a white solid. M.pt. = 125-127^0.
HMS spectrum : 8.50 ppm : t : 1 H : H amide 7.60-7.05 ppm : m : 8 H : H aromatiq 4-25 ppm : d : 2 H : CH2 - C6H4" 3.70-3.50 ppm : m : 4 H : CH2 en 2 et 6 du tetrahydropyran 2.00-1.80 ppm : m : 4 H : CH2 en 3 et 5 du tetrahydropyran 1.05 ppm : s : 9 H : tBu E) 2-n-butyl-4-<4-spirotetrahydropyran)-l-t <2’-tert-butoxycarbonyl biphenyl-4-ylJmethyl1-2-imidazolin-5-one A mixture containing 0.9 g of the compound obtained in stage D, 327 mg methyl orthovalerate and 2 drops of acetic acid IE 91913 were heated for 3 hours at 110°C. The reaction medium was absorbed in 100 ml ethyl acetate and 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 evaporated off, the residue which was obtained was chromatographed on silica by eluting with an ethyl acetate/toluene mixture <2/1 ; v/v). 550 mg expected product was obtained in the form of a wax.
ME spectrum : 7.05-7.60 ppm : m : 8 H : H aromatic 4,63 ppm : s : 2 H .' CH2 - CgRj3,85-3.55 ppm : m : 4 H, CH2 en 2 et 6 du tetrahydropyran 2.30 ppm : t : 2 H : CH2 - C3H7 1.05-1.80 ppm : m : 8 S’ : CH2-CH2-CH2-CH3. et CH2 en 3 et 5 du tetrahydropyran; 1.03 ppm : s : 9 H : tBu 0,75 ppm : t : 3 H : (CH2)3-CH3 IR (CHCls) : 1710-1720 cm-’ : C = 0, C = 0 1625 cm-’ : C = N F) 2-n-butyl-4-<4-spirotetrahydropyran)-l-[ (2'-tert-butoxycar bony 1 bi phenyl-4-yl) methy II -2-imidazolin-5-one 530 mg of. the product obtained in the preceding stage were treated with 4 ml dichloromethane and 5 ml TFA for 45 minutes. After evaporation under vacuum, the residue was absorbed in ether, the precipitate which was formed was filtered, washed with ether and then dried under vacuum. 510 mg expected product was obtained. M.pt. 159-162°C.
NMR spectrum : 7.80-7.10 ppm : m : 8 H : H aromatic 4,80 ppm : s : 2 H : CH2 - C6H4" 4.00-3.75 ppm : m : 4 H, CH2 en 2 et 6 du tetrahydropyran 2.60 ppm : t : 2 H : 0¾ - C3H7 1.45-2,00 ppm : m : 6 H : CH2-CH2-CH2-CH3. et CH2 en 3 et 5 du tetrahydropyran - 37 IE 91913 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-t (2'-carboxybiphenyl-4-yl)methyl]-4-tspirod-benzyl4-piperidine)]-2-imidazolin-5-one trifluoroacetate. and 2-n-butyl-4-tspiro(l-benzyl-4-piperine)]-l-t <2’tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one Method 1.
A) 4-amino-l-benzyl-piperinin-4-carboxylic acid was prepared from N-benzypiperid-4-one in accord with the method described in the German patent DE 2 215 721, B) Ethyl 4-amino-l-benzylpiperidin-4-carboxylate. 3.80 g of the compound prepared in stage A were added to a solution of 13 g hydrochloric acid in 50 ml ethanol at O’C and then heated under reflux for 5 hours. After concentration under vacuum, the residue was washed with ether and then dissolved in am ether-water mixture to which was added a saturated solution of potassium carbonate until pH 9 was reached. The ethereal phase was decanted, washed with a saturated solution nf sodium chloride, dried over sodium sulfate and then evaporated to dryness. 3.50 g expected product was obtained in the form of an oil.
NMR spectrum : 7.20- 7.40 ppm : m : 5 H : H aromatic-. . 4,10 ppm : q : 2 H : CH2-CH3 3,45 ppm : s : 2 H : CH2 du benzyle 2.25-2.60 ppm : m : 4 H : CH2 en 2 et 6 de piperidine 1.80-2.05 ppm : m : 2 H : ) CH2 en 3 et 5 de piperidine 1.20- 1.40 ppm : b : 2 H : j 1.12 ppm : t : 3 H : Q&-CH230 C) 2-n-butyl-4-[spiro(l-benzyl-4-piperidine)]-2-imidazolin-5-one Ethyl valerimidate was prepared as in example 2, stage A. 2.06 g ethyl valerimidate, 3.40 g of the compound prepared in stage B and δ drops of acetic acid, in 15 ml xylene, were mixed and heated under reflux for 6 hours. After concentration under vacuum, the residue was chromatographed on silica gel by eluting with a chloroform/methanol/acetic acid mixture (82/15/3 ; v/v/v). 2.80 g expected product was obtained after extraction with chloroform at pH 9 to remove acetic acid. M.pt. 170-172‘C.
IR (CHCls) : 1725 cm-1 C = 0 1640 cm*1 C = N .15 NMR spectrum : 7.10- 7.30 ppm ; m : 5 H : H aromatic 3„45 ppm : s ; 2 H : -0¾-¾¾ 1.10- 2.75 ppm : 5 m, 14 H ; CH2 en 2,3,5,6 de piperidine et 20 (ch2)3-ch3 0.80 ppm : t : 3 H : D) 2-n-butyl-4-[spiro(l-benzyl-4-piperidine)]-4-[(2'-tertbutoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 513 g sodium methylate were added to 2.78 g of the compound prepared in stage C dissolved in 25 ml DMF, and after 15 minutes, 4.16 g 4-bromomethyl(2'-tert-butoxycarbanyl)biphenyl were also added. The mix was heated at 40°C for 5 hours and then the reaction mediumwas absorbed in 300 ml ethyl acetate, 50 ml water and 5 ml saturated solution of sodiumbicarbonate. The organic phase was decnatedoff, washed once with a saturated solution osf sodium chloride, dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed onsilica by eluting·' with an ethylacetate/methanol mixture (995/5 ; v/v). 0.98 g expected product was obtined. M.pt. = 10339 IE 91913 106*C, IR (CHCI3) : 1710-1725 cm-’ C = 0, C = 0 (imidazoline, ester) 1630 cm·’ C = N NMR spectrum : 7.70-7-10 ppm : m : 13 H : H aromatic 4.70 ppm : s : 2 H : CHj-CgKj3,55 ppm : s : 2 H : CH2-C6H5 1,20-2,75 ppm : 5 m : 14 H : CH2 en 2,3,5,6, de la piperidine et (CH2)3-CH3 1,15 ppm : s : 9 H : tBu 0,85 ppm : t : 3 H : (CH2)3-CH3 E) 2-n-butyl-l-[2’carboxybiphenyl-4-yll-4-[spiro(l-benzyl-4piperidine)]-2-imidazolin-5-one trifluoroacetate. 350 mg of the compound obtained in stage D were dissolved in 4 ml dichloromethane and 5 ml TFA. After 45 minutes, the medium was concentrated under vacuum and the residue absorbed in an ether-hexane mixture. The precipitate which was formed was filtered off, washed with ether and dried under vacuum. 350 mg expected product was obtained. M.pt. 198200*C.
NMR spectrum : 7.05-7,75 ppm : m : 13 H : H aromatic 4,75 ppm : s : 2 H : CH2-C6H44.40 ppm : s : 2 H : CI^-CeHj 3.20- 3,60 ppm : m : 4 H : CH2 en 2 et 6, de la piperidine 2,35 ppm : t : 2 H : CH2-CH2-CH2-CH3 2.20- 1,40 ppm : 3 massifs : CH2 en 3 et 5 de la piperidine et 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-i(2’carboxybiphenyl-4-yl)methyl3-4-(440 IE 91913 spiropiperidine)-2-1midazolin-5-one ditrifluoroacetate. and 2-n-butyl-4-(spiropiperidine)-t (2'-tert-butoxycarbonylbiphenyl-4-yl) methylJ-2-imidazclin-5-one 300 mg of the compound from example 7, stage D, were dissolved in 10 ml methanol. 180 mg 10% palladium on charcoal were added and hydrogen was passed through for 3 hours at atmospheric pressure. The catalyst ewas filtered off and the filtrate was concentrated under vacuum. 200 mg expected product was obtained.
NMR spect rum : 7,20· -7,75 ppm : m : 8 H : H aromatic. 4.75 ppm : s : 2 H : CHrCgHr 3,00· -1,70 ppm : 3 massifs pour les 4 CH2 de la piperidine 2,40 ppm : t : 2 H : CH2-CH2-CH2-CH3 1,60 PP® : quint : 2 H : CH2"CH2"CH2CH3 1,35 PP® : sext : 2 H : CH2CH2-CH2-CH3 1.20 PP® : s : 9 H : tBu 0,90 ppm : t : 3 H : (CH2)3-CII3 B) 2-n-butyl-l-[ (2’-carboxybiphenyl-4-yl)methyl)-4-)4-spiropiperidine)-2-imidazolin-5-one ditrifluoroacetate. 160 mg product obtained in stage A were stirred in 3 ml dichloromethane and 4 ml trifluoroacetic acid for 45 minutes. This was concentrated under vacuum and the residue was absorbed in ether. A gum was obtained which turned into a foam after drying under vacuum (150 mg). M/pt. 80-85’C.
NMR spectrum : 7.15-7,80 ppm : m : 8 H : H aromatiques 4.75 ppm : s : 2 H : CH^-Cgftj3,20-1,60 ppm : 3 massifs : 4 0¾ de la piperidine 2.40 ppm : t : 2 H : CHj-CHj-CHj-CHa 1.50 ppm : quint : 2 H : CH2-CH2-CH2"CH3 1,30 ppm : sext : 2 H : CH2"CH2CH2-CH3 0,80 ppm : t : 3 H : (CH2)3-CH3 IE 91913 EXAMPLE 9 2-n-butyi-l-t (2* carboxybiphenyl-4-yl)meethyl] -4,4-d.iphenyl.-2imidazolin-5-one trifluoroacetate and 2-n-butyl-4,4-diphenyl-l-[ <2'-tert-butoxycarbonylbiphenyl-4yl)methyl]-2-imidazolin-5-one. Method 1.
A) Valerimidine hydrochloride g ethyl valerimidate hydrochloride were added to a solution of 6.75 g ammonia in 80 ml methanol at 0’C. After 18 hrs, the reaction medium was concentrated under vacuum and the expected product was obtained in the form a of a white solid.
B) 2-n-butyl-4, 4-diphenyl-2-imidazolin-5-one This compound was prepared in accord with the working method described by J. NYITRAI and K. LEMPERT in Tetrahedron, 1969, 25.» 4265-4267, starting with benzil and valerimidine hydrochloride. M. pt. = 135*C.
IR (CHCla) : 1725 cm-» C = 0 1640 cm-» C = N NMR spectrum : 7.20-7,50 ppm : m : 10 H : H aromatic 2,50 ppm : t : 2 H : CH2-CH2-CH2-CH3 1,65 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1,35 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0,90 ppm : t : 3 H : CH2-CH2-CH2-CH3 ppm : s.e. : NH C> 2-n-butyl-4,4-diphenyl-l-I (2'-tert-butoxycarbonylbiphenyl-430 yl)methyl]-2-imidazolin-5-one This compound was prepared in accord with the usual procedure by the reaction of 4-bromomethyl-2'-tert-butoxy carbonylbiphenyl on the compound prepared in stage B in DMF in the presence of sodium methylate.
IR (CHCls) : 1715-1725 cm-1 C = 0, C = 0 (ester, imidazolinone) IE 91913 1635 cm*1 C = N MNR spectrum : 7*25-7,80 ppm : m : 18 H : H aromatic 5 4,85 ppm : s : 2H : N-CHj-CelU2,60 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 du n-butyl D) 2-n-butyi-l-C 2'-carboxybiphenyl-4-yl)methyll-4,4-diphenyl-2imidazolin-5-one trifluaroacetate. 500 mg of the product prepared in stage C were treated i5 with 2.5 ml dichloromethane and 2.5 ml trifluoroacetic acid at ’C, for 20 minutes. After concentration under vacuum, the residue was absorbed in an ether-hexane mixture, the precipitate which formed was filtered, washed with hexane and dried. 440 mg expected product was obtained. M.pt. = 55-60’C. 2Q NMR spectrum: 7,15· 7,80 ppm : m : 18 H : H aromatic 4,85 ppm : s : 2 H : N-CH2-C6H4- 2,60 ppm : t : 2 H : CH2^CH2-CH2-CH3 1.70 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.40 ppm : sext ; : 2 H : CH2-CH2-CH2-CH3 0,90 ppm : t : 3 H : CH3 du butyl EXAMPLE 10 2-n-butyl-3-[<2'-carboxybipheny1-4-y1) methyl]-6spirocyclopentane-5,6-dihydro-l-H-pyrimid-4-one trifluroacetate.
A) Cyclopentylidenoacetic acid was prepared in accord with G.A.R. KON and R.P. LINSTEAD, J. Chem Soc., 1925, 127. 616. 740 mg of this acid and 5 ml 20% ammonia solution were placed in an - 43 IE 91913 autoclave and heated at 150’C for 24 hours. After evaporation of the solvents, the residue was chromatographed on a silica column by eluting with a mixture of DCM/methanol/20 aqueous ammonia solution (70/30/1 ; v/v/v). 330 mg expected acid was obtained.
B) Ethyl (l-aminocyclopentyl)acetic acetate 330 mg of the acid were dissolved in 10 ml ethanol. This was cooled on an ice bath and saturated with gaseous hydrochloric acid. After 24 hours under reflux, the reaction medium was 2.Q evaporated down and the residue absorbed in a solution of sodium carbonate and extracted into ethyl acetate, then dried over sodium sulfate, filtered and evaporated. 312 mg expected ester was obtained.
C) 2-n-butyl-6-spirocyclopentane-5,6-dihydro-l-H-pyrimidin-4-one.
A mixture containing 310 mg of the compound obtained in stage B, 248 mg ethyl valerimidate, 10 ml zxylene and 6 drops of acetic acid were heated under reflux. After 2 hours and 18 hours, another 348 mg ethyl valerimidate were added, and after 24 hours total under reflux the reaction medium was evaporated down and then chromatographed on silica by eluting with a DCM/methanol mixture <97/3 ; v/v). 153 mg expected product was obtained.
D) 2-n-butyl-3-[ (2'-tert-butoxycarbonylbiphenyl-4-yl)methyl)5,6-dihydro-l-H-pyrimid-4-one.
A mixture of 10 ml DMF and 40 mg sodium hydride as an 80% mix in oil was prepared under an atmosphere of nitrogen. 144 mg of the compound prepared in stage C, dissolved in 5. ml DMF, were added slowly, dropwise, at ambient temperature. After 30 minutes with stirring, 288 mg 4-bromomethy1-2’-tertbutoxycarbonylbiphenyl dissolved in 5 ml DMF were added. The mix was left with stirring for 2 hours and then evaporated down, the residue absorbed in water and extracted into ethyl acetate. This was dried over sodium sulfate, filtered and evaporated, then purified by column chromatography by eluting with a hexane/ethyl acetate mixture <85/5 ; v/v). 174 mg expected product was obtained.
IE 91913 E) 2-n-butyl-3-[ (2'-carboxybiphenyl-4-yl)methyl]-6-spirocyclapentane-5,6-dihydro-l-B-pyrimid-4-ane trifluoroacetate. ml trifluoroacetic acid was cooled on an ice-bath and 161 mg of the compound prepared in stage D were added. This was left for 30 minutes with stirring and then evaporated down. The residue was absorbed in ethyl ether and then evaporated down again. This operation was repated and then the residue was dried under vacuum. 140 mg expected compound was obtined in the form of an amorphous powder. M/.pt. = 108-115’C.
RMS spectrum : 0.9 ppm : t : 3 H : (CH2)3-CH3 1.1 a 2,1 ppm : m : 12 H : cyclopentane et CH2-CH2-CH2-CH3 2,7 ppm : t : 2 H : CH2-CH2-CH2-CH3 3.1 ppm : s : 2 H : -CHg-CO · 5.1 ppm : s : 2 H : N-CH2-C6H5 7.2 a 7,8 ppm : m : 8 H : H aromatic .
EXAMPLE 11 2-n-butyl-4-spirocyclopentane-l-[ (2'-tertbutoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thione and 2-n-butyl-l-[ 2'-carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-thione A) 2-n-butyl-4-spirocyclopentane-l-C(2'-tertbutoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thione .63 g of the compound prepared in example 1, stage D, were dissolved in 40 ml anhydrous< toluene and reacted with 3 g of Lawesson's reagent under nitrogen at 80’C. After 6 hours, the reaction medium was filtered and concentrated. The residue was chromatographed an silica by eluting with a DCM/ethylacetate mixture (95/5 ; v/v). The expected product was obtained in the form of an oil which crystallized in the cold, m = 4.5 g. M.pt. = 77-79’C.
NMS spectrum : IE 91913 0.90 ppm : t : 3 H ; CH3 (n-Bu) 1,20 ppm : s : 9 H : tBu 1,35 ppm : sext : : 2 H : CHj-CH2- 1.60 ppm .* quint ; 2 H : CHyCH2-CH2- 1,80· 2,10 ppm : m : 8 H : cyclopentane 2,60 ppm : t : 2 H : CH3-CH2-CH2-CH2 5*35 ppm : s : 2 H : CH2-C6H4- 7,25- •7,80 ppm · it i : 8 H : H aromatic Β) 2-n-butyl-l-t (2’carboxybiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-thione trif luoroacetate 225 mg of the compound obtained in stage A were treated with 5 ml DCM and 5 ml TFA for 30 minutes. After concentration, the residue was absorbed in ether. The expected compound was obtained in the form of a yellow powder which was centrifuged and then rinsed with hexane, m = 160 mg. M.pt. = 185-190’C.
NMR spectrum : Mass spectrum : MH+ : 421 0*78 ppm : t : 3 H : CH3 (n-Bu) 1.20 ppm : sext : 2 H : CH3-CH2 1,50 ppm : quint : 2 H : CH3-CH2-CH2la75-2,00 ppm : m : 8 H : cyclopentane 2,40 ppm : t ; 2 H : CH3-CH2-CH2-CH2 .20 ppm ; s : 2 H : CH2-C6H47,00-7,65 ppm : m : 8 H : H aromatic EXAMPLE 12 2-n-butyl-4-<2-spiroindane)-l-[ (2* -tert-butoxycarbonylbiphenyl4-yl)methyl]-2-imidazolin-5-one. 3θ and 2-n-butyl-l-t(2'-carboxybiphenyl-4-yl)methyl]-4-(2spiroindane)-2-imidazolin-5-one. Method 1.
A) 2-amino-2-indane-2-carboxylic acid was prepared in accord with R.M. Pinder, J. Med. Chem., 1971, H, 9, 892 and the corresponding ethyl ester was then prepared in accord with Adkins - 46 IE 91913 (ref. cited in example 2Δ).
B) 2-n-butyl-4-(2-spiroindane)-2-imidazolin-5-one 2.78 g of the ethyl ester prepared in stage A and 2.5 g ethyl valerimidate were dissolved in 20 ml toluene in the presence of 60 micro-1 acetic acid and heated under reflux for 3 hours. 500 mg ethyl valerimidate were added again and the reflux maintained for'3 additional hours. The reaction medium was concentrated and then chromatographed on silica by eluting with a hexane/ethyl acetate/acetic acid mixture (3/8/0.3 ; £0 v/v/v). The pure fractions were combined and evaporated from toluene. 3.07 g expected product was obtained in the form of a white solid. M.pt. = 148-150’C.
NMR spectrum : 0.90 ppm : t : 3 H : CH3 (n-Bu) 1,2-1,7 ppm : m : 4 H : CH2-CH2-CH3 2,4 ppm : t : 2 H : CH2-(CH2)2-CH3 2,8-3,2 ppm : q : 4 H : 2CH2 (indane) 4,90 ppm is, 2 H : Cl^-CgH,»7,2 ppm : m : 4 H : H aromatic.
C) 2-n-butyl-4-(2-spiroindane)-l-C(2'-tert-butoxycarbonylbiphenyl-4-yl>methyl]-2-imidazolin-5-one.
The compound obtained in the preceding stage was dissolved in 20 ml anhydrous DMF and treated with 450 mg sodium methylate under nitrogen. After 20 minutes at ambient temperature, 3.6 g 4-bromomethy-2'-tert-butoxycarbonylbiphenyl were added and the mix was left with stirring at 40’C for 6 hours. The reaction medium was concentrated and then the normal washings were carried out and the product was chromatographed on 3Q silica by eluting with a dichloromethane/ethyl acetate mixture (95/5 ; v/v). The expected compound was obtained in the form of a foam.
NMR spectrum : •Ε 91913 0,80 ppm : t : 3 Η : CH3 n-Bu 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 : 2CH_2 (indane) 4,80 ppm : s : 2 H : N-CH2-C6H47.20- 7,80 ppm : m : 12 H : H aromatic D) 2-n-butyl-l-[2'-carboxybiphenyl-4-ylJmethyl]-4-spiroindane-2imidazolin-5-one trifluoroacetate 1.71 g of the compound obtained in the preceding stage was dissolved in 15 ml DCM and treated with 20 ml TFA. After 30 minutes, the reaction medium was concetrated and absorbed in ether. After grinding up, the solid obtained was centrifuged, rinsed with ether and dried. 1.42 g expected product was obtained. M. pt. = 217-218*C.
NMR spectrum : 0.70 ppm : t : 3 H : CH3 (n-Bu) 1.10- 1,50 ppm : m : 4 H : CH2-CH2-CH3 2.30 ppm : t : 2 H : ΟΗ2-(θϊζ)2-ΟΗ3 2,8-3.3 ppm : q : 4 H : 2CH2 (indane) 4,70 ppm : s : 2 H : N-CH2-C6H47,1-7.7 ppm : m : 12 H : H aromatic Other compounds in accord with the invention have been prepared in accord with one of the methods described above.
They are summarised in table I. The structure, of each of these compounds is in accordance with their IMS spectra.
EXAMPLE 13 2-n-butyl-l-[ (2’-<1-imidazolylcarbony1)biphenyl-4-yl)methyl]-4spi rocyc1opentane-2-imi daz oli n-5-one IE 91913 (I : 81 = -C-N_ 'k R2 - H, R3 = 11-C4H9, CR4R5 = cyclopentane, X = 0) A mixture containing 404 mg of the compound prepared in example 1, stage E, 15 ml THF and 260 mg carbonyldiimidazole was stirred for 72 hours at ambient temperature. The reaction medium was evaporated, absorbed in ethyl acetate and washed with water and then a solution of sodium chloride. 420 mg product were obtained which were purified by chromatography on silica by eluting with a DCM/ethyl acetate mixture (70/30 ; v/v) to obtain the expected compound. m = 230 mg M.pt. = 120*C EXAMPLE 14 2-n-butyl-i-[ (2' -(3-cyano-2-methyl-isothioureidamethyl)biphenyl4-yl)methyl]-4-spirocyclopentane-2-imidazalin-5-ane. sch3 (I : Ri = -CH2-NH-C=N-CN, R2 = H, R3 = n-C4Hg, CR4 R5 = cyclopentane, X = 0) A) 1-C(2'-aminomethylbiphenyl-4-yl)methyl]-2-n-butyl-4spi rocyc1opentane-2-i mi daz 01i n-5-one.
This compound was obtained by hydrogenation of the compound prepared in example 5. g of the compound prepared inexample 5 stage A was placed in 15 ml absolute methanol and 2.3 ml ethanol in the presene of (0.5 g) 5% palladium on cahrcoal and hydrogen was passed through at ambient temperature for 24 hours. After treatment, 730 mg expected product was obtained in an oily form.
B) A mixture containing 300 mg compound prepared in the preceding stage and 113 mg N-cyanimido-S,S-dimethyl- 49 IE 91913 dithiacarbonate in 3 ml ethanol was refluxed for 24 hours.
After the usual treatment, the reaction medium was purified by chromatography on silica by eluting with a DCM/ethyl acetate mixture (50/50 ; v/v/). The expected product was isolated in the form of a white solid. m = 307 mg M.pt. = 83X.
EXAMPLE 15 2-n-butyl-l-[(2'-(2-cyanoguanidinomethyl)biphenyl-4-yl)methyl]4-spirocyclopentane-2-imidazolin-5-one NH2 (I : Ri = CH2-NH-C=N-CN, R2 = H, R3 = η-Ο^, CR4R5 = cyclopentane, X = 0) This compound was obtained by starting with the compound prepared in the preceding example. 200 mg of the compound were placed in 10 ml absolute ethanol, saturated with ammonia at about 10X and then heated in an autoclave at 80X for 1 night. After concentration of the reaction medium to dryness, chromatography was performed on silica by eluting with a DCM/methanol mixture (95/5 ; v/v). 130 mg expected product was obtained.
M.pt. = 100X.
EXAMPLE 16 2-n-butyl-4-spirocyclopentane-l-[ (2'-trifluoromethylsulfonylaminobiphenyl-4-yl)methylJ-2-imidazolin-5-one trifluoromethylsulfonate (I : Rj = -NHSO2CF3, R2 = H, R3 = n-C4H9, CR4R5 = cyclopentane, X = 0) A) 4-methyl-2' -nitrobiphenyl IE 91913 11.2 g 2-nitrobromobenzene and 15 g 4-iodotoluene were mixed together, heated to 195’C and left at this temperature with stirring for 3¾ hours. After cooling to ambient temperature, the mix was absorbed in DCM and refluxed. The warm solution was filtered on Celite® and then the DCM was evaporated off. m = 6.5 g B.pt. = 80-120’C at 0.2 mm Hg, nD24& =1.6042 B) 4-bromomethyl-2' nitrobiphenyl.
A mixture containing 6.5 g 4-methy1-2'-nitrobiphenyl, .42 g MBS, 118 rag azo-bis-isobutyronitrile and 500 ml tetrachloromethane were refluxed. The mix was cooled to O’C, centrifuged, and the filtrate concentrated to obtain 9 g of an oily product which was used as such in the next stage.
C) 2-n-butyl-l-E (2*-nitrobiphenyl-4-yl)methyl)-4-spirocyclo15 pentane-2-imidazolin-5-one.
A mixture containing 260 mg 80% sodium hydride in 5 ml DMF was made up and 500 mg 2-n-butyl-4-spirocyclopentane-2imidazolin-5-one, prepared as in example 2, stage A was added at ambient temperature and under nitrogen. After, :15 minutes with stirring, 901 mg 4-bromommethyl-2'-nitrobiphenyl in 5 ml DMF were added and left for 24 hours with stirring. The reaction medium was concentrated to dryness, and absorbed in a water-ethyl acetate mixture. The organic phase was decanted off, dried over sodium sulfate, filtered and then the ethyl acetate evaporated off. The product which was obtained was chromatographed on silica by eluting with a DCM/ethyl acetate mixture (9/1 ; v/v). 500 mg expected product was obtained.
D) l-[(2'anminobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one. 450 mg of product obtained in the preceding stage were placed in 10 ml methanol, in the presence of 5% palladium on charcoal, at ambient temperature, to be hydrogenated. After filtration of the catalyst and evaporation, 240 mg expected product was obtained.
E) 2-n-butyl-4-spirocyclopentane-l-E <2*-trifluoromethyl- 51 IE 91913 sulfonylaminobiphenyl-4-yl)methyl3-2-imidazolin-5-one trifluoromethylsulfonate 225 mg product obtained in the preceding stage and 0.1 ml triethylamine were mixed in 4 ml DCM and to this was added 0.2 ml trifluoromethylsulfonic acid anhydride, under argon, at -78’C and then left to return to ambient temperature. The reaction medium was washed with water and a solution of sodium bicarbonate and then dried and concentrated. 150 mg of an amorphous white solid was obtained.
NMR spectrum : 0,4-1,3 ppm : m, 7 H : CH3-CH2-CH21.4-2,3 ppm : m, 10 H : C^-C^-C^-CHg et cyclopentane 4-4.8 ppm : systeme AB, 2H : N-Cfy-Cgltr 7-7,6 ppm : m, 8 H : aromatic. 8.3 ppm : s, 1 H : -NH ppm : s.e., 1 H : CF3SO3H^ EXAMPLE 17 2-n-butyl-4-spirocyclopentane-l-[(2'trifluoromethylsulfanylaminomethyl-biphenyl-4-yl)methyl]-2imidazolin-5-one trifluoromethylsulfonate (I : Rl = CH2NHSO2CF3s R2 = H, R3 = 11-C4H9, CR4R5 = cyclopentane, X = 0) The preparation took place starting with 1-[2'25 aminomethylbiphenyl-4-yl)methyl3-2-n-butyl-4-spirocyclopentane2-imidazolin-5-one, prepared in example 14, stage A. 322 mg of this compound and 0.122 ml triethylamine were placed in 3.4 ml DCM at -70’C and to this was added 0.294 ml trifluoromethylsulfonic acid anhydride. This was allowed to return to ambient temperature, poured into dilute acetic acid and extracted with DCM. The solution was dried over sodium sulfate, filtered and the DCM evaporated off. The residue was chromatographed twice on silica by eluting with DCM/ethyl acetate <95/5 ; v/v, then 99.5/0.5 ; v/v). m = 90 mg was obtained.
« IE 91913 M.pt. = 90’C.
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 et cyclopentane 4.1-5 ppm : m 4 H : N-CH2-C6H4- et NH-CHj-Ce^7.1-7,7 ppm : m, 8 H : H aromatic' 8.4 ppm : s, 1 H : NH EXAMPLE 18 10 2-n-butyl-l-[ (2*-(N-hydroxyacetamide)biphenyl-4-yl)methyl]-4splrocyclopentane2-imidazolin-5-one (I : Rj = -CO-NHOH, R2 = H, R3 = n-C4H9, CR4R5 = cyclopentane, X = 0) The compound prepared in example 2 was released from its trifluoroacetic acid salt by absorbing this compound in an ethyl 15 acetate-water mixture and by adjusting the pH of the solution to pH 6 by adding a saturated solution of sodium bicarbonate. The organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and. concentrated to give the free base in the farm of a white solid. 2θ 450 mg of this compound were dissolved in chloroform, 860 ml thionyl chloride was added at O’C and the mix left with stirring at ambient temperature for 2 hours. The solution was concentrated and traces of thionyl chloride removed by azeotropic distillation with toluene. The acid chloride thus obtained was added dropwise to a DMF solution containing 200 mg hydroxylamine hydrochloride and 700 micro-1 DIPEA in 10 ml DMF. After 2 hours at O’C, the reaction medium was concentrated and absorbed in 100 ml DCM and 50 ml water. The pH was adjusted to 7 and the organic phase extracted and dried over sodium sulfate. After 30 filtration, the solution was concentrated. The product obtained was recrystallized from an ethyl acetate/ethyl ether/hexane mixture. m = 360 mg M.pt. = 85’C.
IE 91913 EXAMPLE 19 2-n-butyl-4-spirocyclopentane-l-C (2'-ureidobiphenyl-4yl)methyl]-2-imidazolin-5-one (I : R, = NHCONHj, R2 = H, R3 = n-C4H9, CR4R5 = cyclopentane, X = 0) This compound was prepared by using the method described by B.B. Kobu et al. in Org. Synth., 1957, 37. 52 starting with l-t(2'aminobiphenyl-4-yl) methyl]-2-n-butyl-4-spirocyclapentane-2imidazolin-5-one, prepared in example 14 stage A. g of the latter was dissolved in 50 ml 6N hydrochloric acid and treated with potassium isocyanate for 1 hour at 5’C.
The reaction medium was concentrated, absorbed by ethyl acetate, washed with sodium bicarbonate and then with a saturated solution of sodium chloride. After drying over sodium sulfate and filtration, the solution was concentrated and the oil obtained was purified by chromatography on silica by eluting with a DCM/methanol mixture (9/1 ; v/v). in = 600 mg NMR spectrum : 0,85 ppm : t, 3 H : CH2-CH3 1,35 ppm : sext, 2 H : CH2-CH3 1,6 ppm : quint, 2 H : CH2-CH2-CH3 1,7-2 ppm : m, 8 H : cyclopentane 2,45 ppm : t, 2 H : CH2-CH2-CH2-CH3 4,8 ppm : s, 2 H : -CH2-C6H46,05 ppm : s, 2 H : NH2 7-8 ppm : m, 9 H : 8 H aromatic . + NHCO EXAMPLES 20 and 21 l-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one and 1-C (2'-(N-cyanocarboxyamide)biphenyl)methyl]-2-n-propy1-4spirocyclohexane-2-imidazolin-5-one - 54 IE 91913 A) ethyl butyrimidate hydrochloride /« CH3 - CH2 - CH2 - ’ HC1 OC2H5 This compound was prepared in. accord with McElvain (J. Amer. Chem. Soc., 1942, Si, 1825-1827). 2_q 23 ml butyronitrile were added to a solution of 10.6 g gaseous hydrogen chloride in 20 ml anhydrous ethanol and left for 4 days at O’C, Then the mix was poured, with stirring, into 200 ml anhydrous ether at O’C. The precipitate which formed was filtered, washed with ether and then dried under vacuum. 25.8 g expected product was obtained.
B) Ethyl butyrimidate g imidate obtained in stage A were dissolved in 100 ml dichloromethane and 50 ml water and 15 g potassium carbonate were added. After decanting, the dichloromethane was dried over potassium carbonate and then evaporated to dryness without being heated.
C) The ethyl ester of 1-aminocyclohexanoic acid 1-aminocylohexanoic acid is available commercially. 15 g of this aminoacid were added to a solution of 23 g gaseous hydrogen chloride in 150 ml anhydrous ethanol at O’C. This was heated under reflux for 5 hours, then the reaction medium was concentrated to dryness and absorbed in ether. The white solid which was obtained was filtered, washed with ether and then dissolved in a mixture of 300 ml ether and 100 ml water. A solution of potassium carbonate was added to adjust the pH to 9.
The organic phase was decanted off, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. 14 g expected product was obtained in the form of an oil.
D) 2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one IE 91913 g of the product obtained in stage C were dissolved in 200 ml xylene containing 0.6 ml acetic acid. Half the imidate obtained in stage B was added and the mix was heated under reflux. After 1¾ hours, half of the remaining imidate was added and then the last quarter was added after 4 hours. After a total of 7 hours refluxing, the medium was evaporated to dryness. The solid which was obtained was absorbed in hexane, filtered, washed in ether and then dried. .3 g expected imidazoline was obtained.
M.pt. = 124-125’C.
IR (CHCI») : 1715 cm-1 ; C = 0 1635 cm-1 : C = N Nate : The compound present in solution is actually an imidazolin-5-one, from the positions of the IR bands.1 E) 2-n-propyl-4-spirocyclohexane-l-I <2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 970 mg imidazoline obtained in stage D was added to 0.25 g sodium hydride in an 80% mix with oil in suspension in ml dimethylformamide. After stirring for 20 minutes, 1.91 g 4-bromomethyl-2’-tert-butoxycarbonylbiphenyl, prepared in accord with European patent 324 377, was added over 5 minutes. After 1 hour's stirring, the medium was concetrated under vaccum and half was absorbed in 100 ml ethyl acetate and then in 20 ml water, The organic phase was decanted off, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum. The residue was chromatographed on silica by eluting with an ethyl acetate/toluene mixture. 2.10 g expected product was obtained in the form of a wax.
IK (CHCls) : 1705-1715 cm-1 : C = 0, C = 0 (ester, imidazolinone) 1635 cm-» : C = N Analysis of the NMR spectrum confirmed the structure.
F) l-[(2'-carboxybiphenyl-4-yl)methyl]-l-n-propyl-4spirocyclohexane-2-imidazolin-5-one (Example 20).
IE 91913 1.25 g tertiarybutyl ester obtained in stage Ξ were stirred for 45 minutes in a mixture of 11 ml dichloromethane and ml trifluoroacetic acid. After concentration under vacuum, the residue was absorbed in ether. The solid which farmed was filtered, washed with ether and then dried. 1.04 g of white soid was obtained.
M.pt. = 170-172’C.
NMR spectrum : 7,10-7,80 ppm : m, 8 H : aromatic; 4,90 ppm : s, 2 H : N-C^-CgHj2,45 ppm : t, 2 H : CH3-CH2-CH2 1,40-1,80 ppm : m, 12 H : spirocyclohexane + CH3-CH2CH2" 0,90 ppm : t, 3 H : CH3-CH2-CH2" 1.60 g trifluoroacetate obtained as above were dissolved in 150 ml ethyl acetate plus 20 ml water. IN soda solution was added to obtain pH 5. The organic phase was decanted off, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. The residue obtained was absorbed in ethyl ether, filtered and dried, m = 1.14 g M.pt. = 208-210’C G) 1-L(2'-(N-carboxyamide)biphenyl-4-yl)methyl]-2-propyl-4spiracyclohexane-2-imidazolin-5-one. (Example 21) To 300 mg of compound prepared in the preceding stage, in suspension in 5 ml DCM, were added 0.54 ml thionyl chloride. After l'>2 hours, the reaction medium was concentrated under vacuum, then evaporated twice from benzene. The acid chloride thus obtained was dissolved in 2 ml dioxan and added to 42 mg cyanamide in solution in 1 ml dioxan containing 0.2 ml 10N soda solution. After 1 *2 hours, the reaction medium was diluted with 1450 ml ethyl acetate and 20 ml water and adjusted to pH 5 with acetic acid. The organic phase was decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. The residue was chromatographed IE 91913 on silica by eluting with a chloroform/methanol/acetic acid mixture <90/8/2 ; v/v/v). 160 mg expected product was obtained as a solid.
IR(KBr) : 2150 cm-1 : C 2 N mass spectrum : MH* : 429 NMR spectrum : 7,20-7,70 ppm : m, 8 H : aromatic 4.75 ppm : s, 2 H : N-CHj-CelU" 2,40 ppm : t, 2 H : CH3-CH2-CH21,30-1,80 ppm : m, 12 H : CH3-CH2-CH2- et spirocyclohexane 0.85 ppm : t, 3 H : CH3-CH2"CH2 EXAMPLE 22 15 l-[(2’-{N-(4-carboxy-l,3-thiazol-2-yl)acetamide)biphenyl4-yl) methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one.
N —-j—COOH (I : Ri = -CONH-l^ J) , R2 = H, R3 = n-C3H7, s CR4R5 = cyclohexane, X = 0 This compound was prepared from the compound obtained in example 20.
The 2-amino-4-ethaxycarbonyl-l,3-thiazole was prepared 30 in accord with B. Plouvier et al., J. Heterocycl. Chem., 1989, 2S. (6), 1646.
A) l-[2'-{N-<4-carbethaxy)-l,3-thiazol-2-yl>carboxamide) biphenyl-4-yl)methyl! -2-n-propyl-4-spirocyclohexane-2imidazolin-5-one.
To a solution of 404 mg of compound prepared in example •Ε 91913 and 190 mg of the thiazole derivative in 4 ml DCM and 1 ml DMF, were added 500 mg BOP and 0.14 ml triethylamine. This was stirred for 40 hours at ambient temperature and then for 7 hours at 50°C. The reaction medium was absorbed in 50 ml ethyl acetate and washed twice with a KHS04-K2SQ4 solution, then twice with a saturated solution of sodium bicarbonate and then once with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase was concentrated under vacuum and the residue was chromatographed on silica by eluting with an ethyl acetate/toluene mixture. 120 mg expected product was obtained.
M.pt. = 96-98’C. Β) 1-E <2'-{N-(4-carboxy-l,3-thiazol-2-yl)acetamide)biphenyl4-yl>methyl! -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one.
To 110 mg of product obtained in the preceding stage, dissolved in 1 ml methanol and 1 ml diaxan, was added 0.5 ml 2N soda solution. After 35 minutes stirring, the reaction medium was diluted with 10 ml water and 60 ml ethyl acetate and adjusted to pH 5 by the addition of IN hydrochloric acid. ·, The organic phase was decanted, washed with a saturatedd solution of sodium chloride, dried over sodium sulfate and then, concentrated. The residue was absorbed in ether, filtered and dried. m = 100 mg M.pt. = 145-148’C NMR spectrum : 8.0 ppm : s, 1 H : H en 5 du thiazole 7.1-7,7 ppm : m, 8 H : H aromatiques 4.7 ppm : s, 2 H : N-CH2-C6H42.25 ppm : t, 2 H : CH2-CH2-CH3 1*2-1,8 ppm : m, 12 H : cyclohexane et CH2-CH2-CH3 0.85 ppm : t, 3 H : CH2-CH2-CH3 EXAMPLE 23 2-n-butyl-l-E <2’-<2-cyanoguanidinocarbonyl>biphenyl-459 IE 91913 yl) methyl 1 -4-spirocyclopentane-2-imidazolin-5-one.
NH2 (I : Ri = CONH-ON-CN, R2 = H, R3 = 11-C4H9, CR4R5 = cyclopentane, X = 0).
The acid chloride of compound A obtained in example 2 was prepared. 1 g of this compound was placed in 20 ml DCM in the presence of 1.8 ml thionyl chloride and stirred at ambient temperature for 2 hours. After concentration of the medium, it was absorbed in benzene and then concentrated again. The crude product which was isolated was then used. It was mixed with 417 mg dicyanodiamide, 0.5 ml ION soda solution, 0.5 ml water and 10 ml dioxan and left with stirring for 5 hours. The reaction medium was absorbed in water and ethyl acetate, potassium carbonate was added and then it was concentrated. The residue obtained was chromatographed on silica by eluting with a DCM/methanol mixture* <95/5 ; v/v). 100 mg expected product was isolated.
M.pt. = 105*C.
EXAMPLE 24 4-benzylidene-2-n-butyl-l-[<2'carboxybiphenyl-4-ylJmethyl3-2imidazolin-5-one trifluoroacetate.
(I : Ri = CO2H, R2 = H, R3 = n-C4H9, R4R5 = =CH-C6H5, X = 0).
A) 4- CO2tBu n-C4H9-C0-NH-C-C0-NH-CH2-C6H4 CH-C6H5 Starting from N-Boc-alpha-dehydro-(L)-phenylalanine, the - 60 IE 91913 N-carboxyanhydride of alpha-dehydro-(L)-phenylalanine was prepared in accord with R. Jacquier et al., Tetrahedron Lett., 1984, 25 (26), 2775. To 430 ng of this compound in solution in ml THF, were added 644 mg 4-aminomethyl-2'5 tertbutylcarboxylate. This was stirred for 2 hours at ambient temperature and then 1 ml methyl orthovalerate was added and the mix evaporated to dryness under vacuum without external heat.
The residue was heated for 3 hours at 100*C, concentrated under vacuum and then chromatographed on silica by eluting With a hexane/ethyl acetate mixture (4/1 ; v/v). 580 mg of a white solid was obtained.
M.pt. = 154’C NMR spectrum : 1.3 ppm : s, 9 H : t-Bu 0r65 ppm : t, 3 H : CH3 (n-Bu) ppm : t, 2 H : CH3"CH2"CH2"CH2"CO 4.4 ppm : d, 1 H : CH2"NH 6,8 ppm : s, 1 H : CH ^CH-CgHs) B) 4-benzylidene-2-n-butyl-l-E(2' - tert-butoxycarbonylbiphenyl-4yl) methyl!-2-imidazolin-5-one 440 mg of compound obtained in stage A were dissolved in 1 ml acetic acid and heated for 30 minutes at 100’C.
The mix was evaporated to dryness under vacuum and the residue was chromatographed on silica by eluting with a hexane/ethyl acetate mixture (4/1 ; v/v). 130 mg of expected product was obtained in an oily form.
NMR spectrum : 4.9 ppm : s, 2 H : CH2 ( N-CH2-C6H4-) C) 4-benzylidene-2-n-butyl-l-E(2'carboxybiphenyl-4-yl)methyl]-2imidazolin-5-one trifluoroacetate. 100 mg compound obtained in the preceding stage were dissolved in 1 ml DCM and 1 ml trifluoroacetic acid was added and then left with stirring for 40 minutes at ambient temperature and - 61 IE 91913 evaporated, under vacuum. The residue was absorbed in DCM and then evaporated several times. On the addition of ethyl ether, a white solid precipitated. m = 101 mg M.pt. = 85°C Mass spectrum : MH* : 439 NMR spectrum : 0,82 ppm : t, 3 H : CH3 (n-Bu) 1.3 ppm : sext, 2 H : CH3-CH21.6 ppm : m, 2 H : CH3-CH2-CH22.6 ppm : t, 2 H : CH3-CH2-CH2-CH24.82 ppm : s, 2 H : CH2-C6H47.05 ppm : s, 1 H, =CH-C6H5 7.2-8,2 ppm : m, 13 H : aromatic EXAMPLE 25 4-benzylidene-l-[ <2'-carboxybiphenyl-4-yl)methyl]-2-phenyl-2imidazolin-5-one (I : R, = C02H, R2 = H, R3 = C6H5, R4R5 = =CH-C6H5, X = 0).
A) 4-benzyl-2-phenyl-oxazol-5-one. 1.8 g hippuric acid and 0.4 g potassium bicarbonate were dissolved in 4 ml acetic anhydride and heated for a few minutes at 50°C, then cooled to ambient temperature and 1.49 g benzaldehyde added. After 1 hour at ambient temperture, 20 ml distilled v/ater at 80’C were added. The solid which precipitaed was centrifuged, washed with water and then with ethanal and dried. 1.24 g expected product in the form of a yellow solid was formed.
M.pt. = 215 °C.
NMR spectrum : 7.4 ppm : s, 1 H : =CH-C6Hs 8.1-8.4 ppm : m, 10 H : aromatic - 62 IE 91913 Β) 4-(1-benzoylamino-1-benzylidene-methylamidomethyl)-2’ tertbutyl carboxylate biphenyl.
A mixture containing 500 mg of the compound obtained in the preceding stage, 570 mg 4-aminomethyl-2‘tert5. butylcarboxuylate biphenyl and 10 ml pyridine was heated at 110*C for 3 hours. It was then evaporated under vacuum, absorbed in chloroform and then evaporated again. The residue was chromatographed on silica by eluting with a hexane/ethyl acetate mixture (3/1 and then 2/1 ; v/v). 106 mg expected product was obtained in the form of a yellow solid.
NMR spectrum : 1.1 ppm : s, 9 H : t-Bu 4,35 ppm : t, 2 H : -CH2-NH 7·°·5·7,06 ppm : m, 19 H : H aromatic + C6HS-CH= 158’65 PP™ : t, 1 H : NH-CH2 9.9 ppm : s, 1 H : NH-CH= C) 4-benzylidene-l-[ <2‘-carboxybiphenyl-4-yl)methyl1-2-phenyl-2imidazolin-5-one A mixture of 1.2 g compound obtained in the preceding stage and 1.1 g freshly melted sodium acetate in 5 ml acetic acid were heated under reflux for 6 hours. This was allowed to cool and then an insoluble material was precipitated by the addition of chloroform. The filtrate was evaporated and the residue was chromatographed on silica by eluting with a chloroform/methanol mixture (98/2 ; v/v). The solid which was obtained was recrystallized from ethyl ether. m = 692 mg M.pt. = 120 cC NMR spectrum : 4,95 ppm : s, 2 Η i CH2-C$H4" 7,1-8,3 ppm : m, 19 H : H aromatic- + =CH-C6H5 EXAMPLES 26 and 27 2-n-butyl-l-E(2' -(2-methyltetrazol-5-yl)biphenyl-4-yl) methyl]-4spirocyclopentane-2-imidazolin-5-one (Example 26) - 63 IE 91913 and 2-n-butyl-l-E(2’-(l-methyltetrasol-5-yl) biphenyl-4-yl)methyl!-4-spiracyclopentane-2-imidasolin-5-one (Example 27). 500 mg of the compound prepared in example 5 and 58 mg sodium hydride were mixed in 10 ml DMF and stirred for 30 minute; before adding 179 mg methyl iodide and 2 ml DMF and leaving with stirring at ambient temperature for 4 hours. The reaction medium was concentrated, absorbed in water and then extracted with ethyl acetate. This was dried over sodium sulfate, filtered and the solvent evaporated off. The residue was chromatographed on silica by eluting with a hexane/ethyl acetate mixture (6/4 ; v/v). 2 fractions were isolated: mg compound in example 26 and 184 mg compound in example 27 NMR spectra Example 26 0.7 ppm : t, 3 H : CH3- (n-Bu) 1,2 ppm : sext, 2 H : CH3-CH21,4 ppm : quint, 2 H : CH3-CH2-CH21,5-1,9 ppm : m, 8 H : cyclopentane 2.25 ppm : t, 2 H : CH3-CH2-CH2-CH24,15 ppm : s, 3 H : N-CH3 4,6 ppm : s, 2 H : -N-Ci^-CgM;7 ppm : systeme AA’, BB*, 4 H : 7,3-7.75 ppm : m, 4 H : CH2-C6H4-C6H4Example 27 0,7 ppm : t, 3 H : CH3 (n-Bu) 1,15 ppm : sext, 2 H : CH3-CH21,38 ppm : quint, 2 H : CH3-CH2-CH21,5-1,9 ppm : m, 8 H : cyclopentane 2.2 ppm : t, 2 H : CH3-CH2-CH2-CH2- 64 IE 91913 3,35 ppm : s, 3 H : N-CH3 4,6 ppm : s, 2 H : N-CH^-CgHa ppm : systeme AA*, BB‘, 4 H : N-CHj-Cg^7,4-7,8 ppm : m, 4 H : CH2-C6H4-C6H4 EXAMPLE 28 5 2-n-butyl-6-spirocyclopentane-3-[ (2'-(tretazol-5-yl)biphenyl-4yl) methyl]-4 (lH)-5,6-dihydropyrimidin-4-one.
A) ethyl cyclopentylidenacetate g sodium hydride in an 80% mix with oil was placed in 40 ml benzene and 57.1 ml ethyl triethylphosphonoacetate were added dropwise at a temperature below 35’C. After 1 hour at ambient temperature, 24.3 ml cyclopentanone were added dropwise. The mix was then heated to 65’C for 15 minutes and then cooled to ambient temperature and the supernatant liquid decanted off. 25 ml benzene were added, heated to 65’C for 15 minutes, coaled dawn and then the supernatant liquid was recovered. The operation was repeated once more. By evaporation of the liquors, 42 g expected product was obtained and this was distilled.
B.pt. = 102’C at 11 mm Hg m = 22.8 g B) (1-aminocyclopentyl)acetamide. 150 ml gaseous ammonia was added to 20 g ethyl cyclopentylideneacetate prepared in the preceding stage and heated to 150’C for 72 hours. The product obtained after evaporation was purified by chromatography on silica by eluting with a DCM/methanol/20% ammonia mixture (90/10/1 ; v/v/v/). The product obtained was dissolved in DCM and dried over sodium sulfate. It was then filtered and the DCM evaporated to obtain 7.2 g expected product; C) 2-n-butyl-6-spirocyclopentane-4(lH)-5,6-dihydroprimidin-4-one A mixture containing 4.57 g (1-aminocyclopentyl) acetamide prepared previously, 25 ml methyl orthovalerate and a few drops of acetic acid was heated for 18 hours at 100’C.
After evaporation of excess orthovalerate, the residue was - 65 IE 91913 absorbed in an ethyl acetate/sodium bicarbonate mixture and then washed with an aqueous solution of sodium chloride, dried over sodium sulfate and then purified by chromatography on silica by eluting with a DCM/methanol mixture (98/2 ; v/v). m = 5 g NMR spectrum : 0,75 ppm : t, 3 H : CH3 (nBu) 1.2 ppm : sext, 2 H : CH3-CH21.3-1,8 ppm : m, 10 H : CH3-CH2-CH2 et cyclopentane i0 2 ppm : t, 2 H : CH3-CH2-CH2-CH22,15 ppm : s, 2 H : CH2-CO 9.95 ppm : s.e., 1 H : NH This compound is that obtained in example 10, stage C.
D) 2-n-butyl-6-spirocyclopentane-3-C(2‘15 (triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-pyrimidin-4one, 327 mg 80% sodium hydride were mixed under nitrogen for 30 minutes in 30 ml DMF with 1.5 g of the preceding pyrimidinone and 5.27 g 4-bromomethyl-2'-(triphenylmethyltetrazol-520 yl)biphenyl were added. After 4 hours with stirring at ambient temperature, the solvents were evaporated, the residue was absorbed in ethyl acetate and water, dried over sodium sulfate and concentrated. The product obtained was purified by chromatography on silica by eluting with an ethyl acetate/hexane mixture (3/7 ; v/v). m = 3.2 g E) 2-n-butyl-6-spirocyclopentane-3-C(2*-(tretazol-5-yl)biphenyl4-yl) methyl]-4(1H)-5,6-dihydropyrimidin-4-one. g of the compound obtained in the preceding stage were placed in methanol and cooled on a water-ice bath, 2.2 ml 4N HCI were added and left for 5 hours at ambient temperature. After evaporation the residue was absorbed in ethyl acetate and water and soda solution was added until the pH reached 11. The mix was decanted and the aqueous phase washed with ethyl ether and toluene and then again with ether. This phase was adjusted to IE 91913 pH 5 by the addition of dilute hydrochloric acid and then extracted with ethyl acetate, dried and concentrated. The product obtained was purified on silica by eluting with a DCM/methanol mixture (95/5 ; v/v). 800 mg expected product was obtained.
NMR spectrum : 0.85 ppm : t, 3 H : CH3 (nBu) l»30 ppm : sext, 2 H ; CH3-CH2 1,40-1,95 ppm : m, 10 H : cyclopentane et CH2-CH2-CH2-CH310 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-CHj-C^7,05 ppm : m, 4 H : CH2-C6H47,55-7,82 ppm : m, 4 H : CH2-C6H4-C6H415 EXAMPLE 29 2-n-butyl-3-E(2'-carboxybiphenyl-4-yl)methyl]-5spirocyclopentane-5(lH)-5,6-dihydropryrimidin-4-one 20 trifluoroacetate A) ethyl 1-cyanocyclopentanecarboxylate This compound was prepared in accord with Helv. Chim.
Acta, 1952, 25. (7), 2561. 9.2 g sodium were dissolved in 200 ml absolute ethanol.
Half of the solution of sodium ethylate formed was poured into an ampoule. To the remainder were added 24.88 g ethyl cyanoacetate and the mix was refluxed.
Into another ampoule were poured 43.19 g 1,430 dibromobutane and then the sodium ethylate and 1,4-dibromobutane were added simultaneously and dropwise to the reaction medium. When the addition had finished, reflux was maintained for 2 hours. Then it was evaporated, absorbed in an ethyl ether water mixture, washed with a saturated solution of sodium chloride and then dried. The product obtained distilled at IE 91913 115-120’C at 11 mm Hg. m = 24 g.
B) ethyl 1-aminomethylcyclopentanecarboxylate This compound was prepared by catalytic hydrogenation of 5 the ethyl 1-cyanocyclopentanecarboxylate. se 20 g of the ethyl 1-aminocyanocyclopentanecarboxylate were placed in 200 ml ethanol with 10% ammonia and hydrogenated for 72 hours at 60°C under a pressure of 100 bars in the presence of rhodium on alumina. After filtration on Cellite®, and evaporation, the residue was chromatographed on silica by eluting with a DCM/methanol/20% ammonia mixture (98/2/0.5 ; v/v/v). m = 12.8 g C) 2-n-butyl-5-spirocyclopentane-4(lH)-5,6-dihydropyrimidin-4one.
A mixture containing 13.12 g of the compound obtained in the preceding stage and 13.5 g ethyl valerimidate in 100 ml xylene containing a few drops of acetic acid was refluxed for 13 hours. The reaction medium was evaporated, absorbed in ethyl acetate and a 10% sodium carbonate solution and then dried and concentrated. m = 14 g.
M.pt. = 89-91 °C IMS spectrum : 0,80 ppm : t, 3 H : CH3 (nBu) 25 1.10-1,80 ppm : m, 12 H : CH3"CH2-CH2- et cyclopentane 2,05 ppm : t, 2 H : CH3-CH2-CH2-CH23,20 ppm : s, 2 H : CH2 (pyrimidinone) ppm : 1 H, s : NH-CO D) 2-n-butyl-5-spirocyclopentane-3-C(2' - tert-butoxycarbonyl biphenyl-4-yl) methyl]-5,6-dihydropyrimidin-4-one. 500 mg of product obtained in the preceding stage were placed in 40 ml DMF, in the presence of 115 mg sodium hydride at 80% in oil, under argon, and stirred at ambient temperature for half an hour. 1.08 g 4-bromomethyl-2’-tert-butoxy - 68 IE 91913 carbonylbiphenyl were added and the mix was stirred for another 2 hours. After evaporation, the residue was absorbed in an ethyl acetate - water mixture, washed with a saturated solution of sodium chloride, concentrated and chromatographed on silica by eluting with an ethyl acetate/hexane mixture <3/7 ; v/v). m = 280 mg E) 2-n-butyl-3-[ <2'-carboxybiphenyl-4-yl)methyl]-5spirocyclopentane-5 250 ml of the tertiarybutyl ester prepared in the preceding stage were dissolved in 10 ml DCM. This was cooled in an iced water bath and then 5 ml cold trifluoroacetic acid wereadded and left for one hour with stirring in the cold, then for 1 hour at ambient temperature. The mix was evaporated under reduced pressure. The residue was absorbed in ethyl ether and then evaporated. The operation was repeated 3 times and then the residue from evaporation was absorbed in hexane, ground up and the hexane decanted. The product was absorbed in ethyl ether and the precipitate was filtered. m = 190 mg M.pt. = 153-155*C NMR spectrum : 0.85 ppm : t, 3 H : CH3 (nBu) 1.35 ppm : sext, 2 H : CH3-CH21,45-2,20 ppm : m, 10 H : CH3-CH2-CH2- et cyclopentane 2.80 ppm : t, 2 H : CH3-CH2-CH2-CH23.80 ppm : s, 2 H : CH2 (pyriraidinone) .15 ppm : s, 2 H : N-CH27,25 ppm : m, 8 H : aromatic - 69 IE 91913 Table 1 (I) (ex.) Rl : R3 Salt K. pt. ’C (30) CO2H 11-C4H9 cyclohexane TFA 172-174 (31) CO2CH3 11-C4H9 cyclopentane — 86-87 (32) CO2H 11-C4H9 C(CH3)C6H5 TFA 55-60 (33) CO2H n-C4H9 C(C2H5)2 TFA 82-84 (34) CO2H n-C3H7 cyclopentane TFA 164 (35) (**) n-C4Hg cyclopentane — 163-164 (36) co2h C6H5 cyclopentane TFA 178 (37) CO2H 11-C4H9 cycloheptane TFA 160-162 (38) CO2H ch3 cyclopentane TFA 140 (39) CO2H n-C4H9 cyclopropane — 204-205 (40) tetrazolyl-5 -CH2-CH2- CH=CH2 cyclopentane — « 110 IE 91913 (41) tetrazolyl-5 P-C4H9 cyclohexane - 130 (42) tetrazolyl-5 I1-C3H7 cyclohexane — 141 05 (43) co2h cyclopen. -tyl cyclopentane TFA 82-88 (44) co2h n-CsHu cyclopentane TFA 151 10 (45) co2h CH2-C6H5 cyclopentane TFA 88 (46) co2h H cyclopentane — 230 (47) co2h n-C4.H9 cyclobutane TFA 178 15 (48) co2h n-C4H9 cyclododecane TFA 130-135 (49) co2h n-C4H9 adamantane-2 TFA 164-166 20 (SO) co2h n-C4Hg (phenyl-4) cyclohexane TFA 155-157 (51) co2h n-C4Hg (methyl-4) cyclohexane TFA 198-200 qo-q< 25 (52) co2h n-C4Hg (N-acetyl) piperidine-4 TFA 30 (53) co2h C3F7 cyclopentane — 141-143 (54)*- co2h n-C4Hg C_# V-CF3 ch3\=/ - 207-209 IE 91913 (55) CO2H n-C4H9 C-/T-C1 TFA 105 05 (56) CO2H 11-C4H9 /¼ \-/ cf3 TFA 10 (57) CO2H n-C4H9 _/ n-co-(j:h-nh2 \_/ GH-C2H5 ch3 TFA iK-u'M· (58) CO2H 11-C4H9 -/ N-CO C6H5 TFA : Rj = H et R2 = C02H * These compounds have an asymmetric carbon atom and were isolated 1 in the form of a mixture of optical isomers

Claims (26)

1. A compound of formula : (I) in which: - Si and R
2. Are alike or different and each independently represents hydrogen or a group selected from, a Ci-Ce alkyl, 20 a C1-C4 alkoxy, amino, aminoethyl, carboxy, an alkoxycarbonyl in which the alkoxy is C1-C4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyano-acetamide, N25 hydroxy-acetamide, N-(4-carboxy-l,
3. -thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyano-guanidinomethyl, imidazol-l-yl-carbonyl, 3-cyano-2-methyl-isothioureidomethyl, with the condition that at least one of the substituents Ri or R 2 is different from hydrogen; 30 - Ra represents hydrogen, a Ci-C« alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Ci-Ce, a phenylalkenyl in which the alkenyl is C 2 -Ca, the said phenyl groups being unsubstituted or substituted once or several times with a 73 IE 91913 halogen atom, a Ci-Ca alkyl, a Ci-Ca haloalkyl, a Ci-Ca polyhaloalkyl, hydroxyl or a Ci-Ca alkoxy; - Ra and Rs each independently represent a Ci-Cs alkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a Ci-C 4 perfluoroalkyl, hydroxyl, Ci-Ca alkoxy; - or Ra and Rs together form a group with the formula =CR7Ra, in which R7 represents hydrogen, a C1-C4 alkyl or a phenyl and Re represents a C1-C4 alkyl or a phenyl; - or again Ra and Rs linked together represent either a group with formula (CH2>n, or a group with formula (CH2)pY(CH2> q , in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or an N-Rs group in which Rs represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is Ci-Ca, a C1-C4 alkylcarbonyl, a Ci-Ca haloalkylcarbonyl, a Ci-Ca polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an N-protecting group, or Ra and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p + q = m; - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; - z and t are zero or one is zero and the other is unity; - and its salts. A compound as claimed in claim 1 in which Ri is in the ortho position and represents a carboxy or tetrazolyl group and R2 is hydrogen. A compound as claimed in any one of claims 1 or 2 in which Ra and Rs linked together constitute with the carbon to which 3. - 74 IE 91913 they are banded a cyclopentane or a cylcohexane.
4. A compound as claimed in any one of claims 1 to 3 in which R 3 is a straight-chain C»-Ce alkyl group.
5. A compound as claimed in any one of claims 1 to 4 in which X is oxygen.
6. A compound as claimed in any one of claims 1 to 5 in which 10 2 = t = 0.
7. A compound as claimed in claim 1 in which it is 2-n-butyl4-spirocyclopentane-l-[ (2'-(5-tetrazolyl)biphenyl4-yl) methyl]-2-imidazolin-5-one 15
8. A method for the preparation of a compound (I) as claimed in any one of claims 1 to 6 comprising : al) reacting a heterocyclic derivative of formula : R4 R 5? U (CH 2 ) t z(CH 2 ) N in which z, t, R3, R< and Re have the meanings indicated for (I) in claim 1, with a (biphenyl-4-yl)methyl derivative of formula : in which Hal represents a halogen atom and R'i and R' 2 - 75 IE 91913 represent either Rt and Ri, ar a precursor grouping for Ri and R 2 , respectively ; bl) optionally, the compound, thus obtained with formula : is treated with Lawesson's reagent 2,4-bis(4-methoxyphenyl)1,3-dithia-2,4-diphosphetan 2,4-disulfide ; 15 cl) the compound obtained in al) or bl), of formula: R 4 25 in which X represents an oxygen atom or a sulfur atom, is treated to prepare compound (I) by converting the R'ι and/or R' 2 groups into Ri and/or R 2 groups respectively .
9. A method for the preparation of a compound (I) in accord with 30 any one of the claims 1 to 6 comprising : a2) reacting an aminoacid of formula : IE 91913 Κ4κ .(CH2) t -NHPr R5 /Z (CH 2 ) 2 COOH in which z, t, R* and Rs have the meanings indicated for (I) in claim 1 and whose amine function is protected by the Pr group, with a (biphenyl-4-yl)methylamine derivative of formula : in which R’i and R' 2 represent either Ri and R 2 or precursors of Ri and R 2 respectively ; b2> after deprotection of the amine, the compound thus obtained of formula : R*2 R’l R4 \ s ^C- (CH 2 ) z -C-NH-CH 2 _γ \V U \\ R5 (CH 2 )t-NH 2 \ \ —/ is then treated with an alkyl ortho-ester of formula RsC(0R>3 (10) in which R3 has the meaning indicated for (I) in claim 1 and R is a Ci-C« alkyl : c2) optionally, the compound thus obtained of formula : 77 IE 91913 r 4 R 5/ L(CH2)t is treated with. Lawesson's reagent 2,4-bis(4-methoxyphenyl)1,3-dithia-2,4-diphosphetan 2,4-disulfide ; d2> the compound thus obtained in b2> or c2) of formula : R 4 R 5/-(CH 2 )t z(CH 2 ) N is then treated under appropriate conditions to prepare compound (I) by converting the S'i and/or R'. 2 groups into R 2 and/or Ri groups respectively.
10. A method for the preparation of a compound in accord with claims 1 to 7 comprising : a3> reacting an imidazole derivative of formula : in which Ra, R 4 and Rs have the meanings indicated for (I) in claim 1, with (biphenyl-4-yl)methyl derivative of formula: 78 IE 91913 5 in which Hal represents a halogen atom and R'1 and R' 2 represent either Ri and R 2 or precursors of Ri and R 2 respectively, in the presence of oxygen and UV irradiation, in a basic medium ; b3)optionally, the compound thus obtained of formula is treated with Lawesson's reagent 2, 4-bis(4-methoxyphenyl)l,3-dithia-2,4-diphosphetan 2,4-disulfide ; c3) the compound thus obtained in b3) or c3) of formula : 79 IE 91913 is then treated under appropriate conditions to prepare compound (I) by converting the R'i and/or R' 2 groups into Ri and/or R 2 groups respectively.
11. A compound of formula : R 5 y-(CH2)t z(CH 2 ) N II in which : 20 - R3 represents hydrogen, a Ct-Ce alkyl which is unsubstituted or substituted with one or several halogen atoms, a C 2 -Cs alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Ct-C 6 , a phenylalkenyl in which the alkenyl is C 2 -Cs, the said phenyl groups being 25 unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a C1-C4 alkoxy; - R 4 and Rs each independently represent a Ci-Cs alkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, the said 30 alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a C1-C4 perfluoroalkyl, hydroxyl, C1-C4 alkoxy; - or R 4 and Rs together form a group with the formula =CR7Rs, in which R7 represents hydrogen, a C1-C4 alkyl or a phenyl 80 IE 91913
12. and Re represents a C,-C 4 alkyl ar a phenyl; - or again R 4 and Rs linked together represent either a group with formula (CH2> n , or a group with formula (CH 2 ) p Y(CHi)q, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a Ci-C 4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or an N-Rs group in which Re represents hydrogen, a Ci-C 4 alkyl, a phenylalkyl in which the alkyl is Ci-C 4 , a C1-C4 alkylcarbonyl, a Ci-C 4 haloalkylcarbonyl, a Ci-C 4 polyhaloalkylcarbonyl, bensoyl, alpha-aminoacyl or an N-protecting group, or R 4 and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p + q = m; - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; - z and t are zero or one is zero and the other is unity; with the restriction that, -when z and t are zero and X is an oxygen atom, R 4 and Rs are other than a Ci-Cs alkyl, a phenyl, a phenyl alkyl in which the alkyl is C1-C3, the said alkyl, phenyl and phenyl alkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group chosen from a Ci-C 4 perfluoroalkyl, hydroxyl, a Ci-C 4 alkoxy > or R 4 and Rs linked together are other than an N-R& group in which Rs is hydrogen, a Ci-C 4 alkyl, a phenylalkyl in which the alkyl is C1-C3, ® n is different from 6 ; and, when z = 1 and Rs is a phenyl, R 4 and'Rs are each different from methyl. A compound in accord with claim 11 of formula : IE 9191® X^N I H in which X is an oxygen atom or a sulfur atom and R 3 is hydrogen, a Ci-Cs alkyl, unsubstituted or substituted with one or several halogen atoms, a Cx-Ce alkenyl, a C 3 -C7* cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Ci-C 3 , a phenylalkenyl in which the alkenyl is C2-C 3 , the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a Ci-C* alkyl, a Ci-Ca haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a C1-C4 alkoxy.
13. A compound in accord with claim 11, of formula : in which R 3 , R4, Rs and X have the definitions given above for (II) in claim 11.
14. A compound in accord with claim 11, of formula : R4 R5 // (II*”) X 82 IE 91913 in which ; 5 - Rs represents hydrogen, a Ci-Ce alkyl which is unsubstituted or substituted with one or several halogen atoms, a C 2 -C e alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Ci-Ce, a phenylalkenyl in which the alkenyl is C2-C3, the said phenyl groups being 10 unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a C1-C4 alkoxy; - R4 and Rb each independently represent a Ct-Ce alkyl, a phenyl, a phenylalkyl in which the alkyl is C,-C 3) the said
15. Alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a C1-C4 perfluoroalkyl, hydroxyl, C1-C4 alkoxy; - or R4 and Rb together form a group with the formula =CR7Rs, 20 in which R? represents hydrogen, a C1-C4 alkyl or a phenyl and Re represents a C1-C4 alkyl or a phenyl; - or again R» and Ss linked together represent either a group with formula (CH 2 ) n , or a group with formula (CH 2 ) P Y(CH 2 ) q , in which Y is either an oxygen atom, a sulfur atom, or a 25 carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1-C3, or an N-Rs group in which Re represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is C1-C4, a C1-C4 alkylcarbonyl, a C1-C4 haloalkylcarbonyl, a Cj-C4 polyhaloalkylcarbonyl, benzoyl, 30 alpha-aminoacyl or an N-protecting group, or R4 and Rs linked together with the carbon atom to which they are banded, constitute an indane or an adamantane; - p + q = m; - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - 83 IE 91913 - X is an oxygen atom or a sulfur atom; with the restriction that R3 is other than a phenyl when Ra and Rs are each methyl. 5 15. A method for the preparation of a compound in accord with one of the claims 11 to 14 comprising reacting a compound of formula : «4 (CH 2 ) z COA (CH 2 ) t NH 2
16. in which Ra and Rs have the definitions indicated above for (II) in claim 11, A is an OH group, an NHi group or an OR’ group, R' being hydrogen or a C1-C4 alkyl, with a compound of formula : Rs - B 11 in which R 3 has the definition given above for (II) in claim 11 and B is : - a C(OR)s group .NH - a k group X 0R -or a COHal group, R being a Ci-Ca alkyl and Hal being a halogen atom, preferably chlorine ; then optioanll.y, the compound thus obtained is treated with Lawesson's reagent, 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4diphosphetan 2,4-disulfide, A pharmaceutical preparation which comprises as the active - 84 IE 91913 ε» principle a compound, in accord with any one of the claims 1 to 7.
17. A pharmaceutical preparation containing a compound in accord 5 with any one of the claims 1 to 7 in association with a beta-blocking compound.
18. A pharmaceutical preparation containing a compound in accord with any one of the claims 1 to 7 in association with a 10 diuretic.
19. A pharmaceutical composition containing a compound in accord with any one of the claims 1 to 7 in association with a nonsteroid anti-inflammatory agent.
20. A pharmaceutical composition containing a compound in accord with any one of the claims 1 to 7 in association with a calcium antagonist. 20
21. A pharmaceutical composition containing a compound in accord with any one of the claims 1 to 7 in association with a tranquillizer.
22. A compound of. formula (I) given and defined in claim OR l.or a salt thereof, substantially as hereinbefore described and exemplified.
23. A method for the preparation of a compound of formula (I) given and defined in claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.
24. A compound of formula (I) given and defined in claim 1 or a salt thereof, whenever prepared by a method claimed in any one of claims 8-10 or 23.
25. A compound of formula (II) given and defined in claim 11, substantially as hereinbefore described and exemplified. IE 91913 _ J
26. A pharmaceutical preparation according to claim 16, substantial ly as hereinbefore described.
IE091391A 1990-03-20 1991-03-19 N-substituted heterocyclic derivates, their preparation¹and pharmaceutical compositions containing them IE910913A1 (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.

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