CA2077967A1 - N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present - Google Patents
N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are presentInfo
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- CA2077967A1 CA2077967A1 CA002077967A CA2077967A CA2077967A1 CA 2077967 A1 CA2077967 A1 CA 2077967A1 CA 002077967 A CA002077967 A CA 002077967A CA 2077967 A CA2077967 A CA 2077967A CA 2077967 A1 CA2077967 A1 CA 2077967A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D233/56—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D233/70—One oxygen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D233/84—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- Hospice & Palliative Care (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
IN THE UNITED STATES PATENT & TRADEMARK OFFICE
PATENT APPLICATION
entitled: N-Substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present in the name of: Pierre PERREAUT
Claude MUNEAUX
Yvette MUNEAUX
Assignee: ELF SANOFI
ABSTRACT
The invention relates to N-substituted heterocyclic derivatives and its salts.
These derivatives have the formula (I) in which:
- R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C6 alkyl ; a C1-C4 alkoxy, an amino, an amino-methyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfo-nylamino, a tri-fluoromethylsulfonylaminomethyl, an N-cyano acetamide, an N-hydroxyacetamide, an N-(4-carboxy-1,3-thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyano-guanidinomethyl, an imi-dazol-l-yl carbonyl and a 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen ;
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C1-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cl-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;
-R4 is a C1-C6 alkyl which is unsubstituted ot substituted by one of more halogen atoms ; and - R5 is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms ;
- or R4 and R5 are each a cyclopropyl ;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one.
Application: Angiotensin II antagonists N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present.
PATENT APPLICATION
entitled: N-Substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present in the name of: Pierre PERREAUT
Claude MUNEAUX
Yvette MUNEAUX
Assignee: ELF SANOFI
ABSTRACT
The invention relates to N-substituted heterocyclic derivatives and its salts.
These derivatives have the formula (I) in which:
- R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C6 alkyl ; a C1-C4 alkoxy, an amino, an amino-methyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfo-nylamino, a tri-fluoromethylsulfonylaminomethyl, an N-cyano acetamide, an N-hydroxyacetamide, an N-(4-carboxy-1,3-thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyano-guanidinomethyl, an imi-dazol-l-yl carbonyl and a 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen ;
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C1-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cl-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;
-R4 is a C1-C6 alkyl which is unsubstituted ot substituted by one of more halogen atoms ; and - R5 is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms ;
- or R4 and R5 are each a cyclopropyl ;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one.
Application: Angiotensin II antagonists N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present.
Description
2~
N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present S
The present invention relates to N-substituted heterocyclic derivatives, to their preparation and to the pharmaceutical compositions in which they are present.
The compounds according to the invention antagonize the action of angiotensin II, which is a peptide hormone of the formula H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH
Angiotensin II is a potent vasopressor and the hiologically active product of the renin-angioterlsin system: renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angiotensin II by the action of the angiotensin I
converting enzyme.
The compounds of the present invention are non-peptide compounds which antagonize angio~ensin II. By inhibiting the action of angiotensin II on its receptors, the compounds according to the invention prevent especially the increase in blood pressure produced by the hormone-receptor interaction; they also have other physiological actions on the central nervous system and on the kidneys, for example.
Thus the compounds according to the invention are useful in the treatment of cardiovascular complaints such as hypertension and heart failure, as well as in the treatment of complaints of the central nervous system and in the treatment of glaucoma and diabetic retinopathy and renal insufficiency.
2~
Non-peptide compounds which antagonize -th~
action of angiotensin II are already describe in many patents or patent applications. Particularly, reference could be made to CA application 2 050 769 published on S March 11, 1992. Said CA application generally relates to compounds of formula :
N
in which notably :
~ X represents a group of formula :
-c(RIIIRIv-cc~Rv)RvI]p-[c(RvII )RVIII]q~
- RI represents an alkyl or an alkenyl group, said groups being unsubstituted or substituted by an halogen, - RII represen~s a carboxy or a tetrazolyl, - RIII and RIV represent each independently an alkyl unsubstituted or substituted by or more halogen atoms, a cycloalkyl or an aromatic radical.
Said CA application 2 050 769 does not specifically disclose compounds of formula 1 in which RIII is an alkyl and RIV is a cycloalkyl.
2~
The present invention relates to compounds of the formula R5 ~ H2) (CH2)z N ~ R3 R~ R1 (I) CH2 ~\
S in which:
- R1 and R2 ar similar or di~f~rent and are aach independently hydrogen or a group selected ~rom a Cl-C6 alkyl, a C1-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyano-acetamide, an N-hydroxyacetamide, an N-(4-carboxy-1,3 thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyano-guanidinomethyl, an imidazol-1-ylcarbonyl and a 3-cyano-2-methyliso-thioureidomethyl, with the proviso that at least one of the substituents Rl or R2 is other than hydrogen;
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by on~ or more halogen atoms ; a Cz-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cl-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cl-C4 alkyl, a Cl-C4 halogenoalkyl, a Cl-C~ polyhalogenoalkyl, a hydroxyl or a Cl-C4 alkoxy ;
- - ~
, ,: . ' , z~
- R4 is a Cl-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ;
- Rs is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C3-C7, which is unsubstitutecl or S substituted by one or more halogen atoms ;
- or R4 and R5 are each a cyclopropyl ~
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one ;
and their salts.
If a compound according to the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound and their racemic mi~ture.
The salts of the compounds of formula (I) lS according to the present inven~ion include those with mineral or organic acids which permit separation or suitable crystallizatlon of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or camphosulfonic acid, and acids which form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the methylsulfata, the maleate, the fumarate and the naphthalene-2-sulfonate.
The salts of the compounds of formula (I) also include the salts with organic or mineral bases, for example the salts of alkali or alkaline earth metals, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, or else the salts of arginine, lysine or any physiologically acceptable ~t~?~
amine.
According to the present description and in the claims which follow, halogen atom is understood as meaning a bromine, chlorine or fluorine atom; N-S protecting group (also designated by Pr) is understoodas meaning a group conventionally used in peptide chemistry for affording temporary protection of the amine group, for example a Boc, z or Fmoc group or a benzyl group; esterified carboxyl group is understood as meaning an ester which is labile under appropriate conditions, such as, for example, a methyl, ethyl, benzyl or tert-butyl ester. "Alkyl" denotes linear or branched saturated aliphatic hydrocarbon radicals.
The compounds of formula (I) in which R1 is in lS the ortAo position and is a carboxyl or tetrazolyl group and R2 is hydrogen are preferred compounds.
The compounds of formula (I) in which R4 is methyl and R5 is cyclohexyl are also preferred compounds.
Likewise, the compounds of formula (I) in which R3 is a linear C1-C6 alkyl group are preferred compounds.
The compounds of formula (I) in which X is an oxygen atom are also preferred compounds.
Finally, the compounds of formula (I) in which z = t = 0 are preferred compounds.
2-n-Butyl-4-methyl-4-cyclohexyl-1-[(2'-(tetrazol -5-yl)biphenyl-4-yl) methyl]-2-imidazolin-5-one or one of its salts with acids or bases are particularly preferred.
The following abbreviations are used in the description and in the Examples:
`s~
alcohol : ethyl alcohol Et : ethyl nBu, tBu n-butyl, tert-butyl DMF : dimethylformamide THF : tetrahydrofuran DCM : dichloromethane NBS : N-bromosuccinimide DCC : dicyclohexylcarbodiimide DIPEA : diisopropylethylamine ether : ethyl ether TFA : trifluoroacetic acid Z : benzyloxycarbonyl Boc : tert-butoxycarbonyl BOP : benzotriazolyloxytrisdimethylamino-phosphonium hexafluorophosphate Fmoc : fluorenylmethoxycarbonyl Lawesson's r~agent : [2,4-bis(4-methoxyphenyl)-1,3-dithia 2,4-diphosphetane 2,4-disulfide].
The present invention further relates to the 0 method of preparing the compounds (I). In said method :
al) a heterocyclic derivative of the formula S ~ (C~2)t (CH2)~ N
//~ N ~LL R3 O I , H
in which z, t, R3, R4 and R5 are as defined above for ~I), is reacted with a (biphenyl-4 yl)methyl. derivative of the formula 2~ 3~7 R'2 R 1 Hal-cH2 ~ ~ 3 in which Hal i5 a halogen atom and R'1 and R'2 are respectively either Rl and ~2 or a precursor group of Rl and/or R2;
bl) if appropriate, the resulting compound of the formula (CH2)t ~CH2)Z N
/~N~R3 R'~ R' 1~ _ r~" ~
is treated wi~h Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfideJ, and cl) the compound obtained in al) or bl), of the formula Z~
~ )t (CH2)~ ~ 5 /~ N ~ R3 R'2 R l CH 2 ' ~--`\
in which X is an o~ygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the groups R'l and/or R'2 to the groups R1 and/or R2 respectively ;
dl) the compound so obtained is converted if approprlate, into one of its salts, according to known method~ well known by the skilled in the art.
Among the compounds 2, some of them are prior art compounds, the others are new and belong to the scope o the invention.
EP patent application 144 748 discloses herbicides of formula :
lS
X
Y~\ 1~
H
in which one of X and Y may represent an alkyl and the other a cycloalkyl ; furthermore the phenyl group may be substituted.
Thus the present invention further relates to the compounds (II) of the formula - .
2'~
S " ~ H2)t ~(CH~ N fl X ~ N 3 H
in which:
- z and t are zero or one is zero and the other is one;
R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstltuted or monosubstituted or polysubs~ituted by a halogen atom, a C~-C4 alkyl, a Cl-C~ halogenoalkyl, a Cl-C4 polyhalogenoalkyl, a hydroxyl or a Cl-C~ alkoxy;
- R4 is a Cl-C6 alkyl which is unsubstituted or lS substituted by one or more halogen atoms ; and - R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms ;
- or else R4 and R5 are each a cyclopropyl ;
- X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z = t = 0, R5 represents a cycloalkyl.
Among the derivatives (II), the compounds in which z = t = 0 of the formula :
~5 N
X ~ \ ~ R3 H
in which X, R3, R4 and R5 are as defined above for (II~, with the proviso that R3 is other than a phenyl S or a substituted phenyl when R5 represents a cycloalkyl are preferred compounds.
The compounds (II) in which z = 0 and t = 1, of the formula R\4 R5- "^'N
xi ~ ~ -R3 in which R3, R4, R5 and X are as defined above for (II), are preferred compounds.
Finally, the compounds (II) in which z - 1 and t = 0, of the formula R ~ R5 N
H (II"') in which R3, R4, Rs and X are as defined above for (II), are preferred compounds.
The derivatives 2 are prepared by known .
2~
methods. For example, it is possible to use the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, ~, 1040-1051) and by Brunken and Bach (Chem.
Ber., 1956, ~9, 1363-1373) and to react an alkyl imidate with an amino acid or its ester in accordance with the following reaction scheme: -R4 (CH2)z~co2R ~NH
C ~ \
R5 (CH2)t-NH2 OR
_' _ R5 - ~ ~I2~t (CH2)z N 2 /~N~R3 O
H
in which R is a Cl-C4 alkyl, R' is hydrogen or a Cl-C4 alkyl and R3, R4, R5, z and t are as defined above for I).
This reaction is carried out in an acid medium by heating in an inert solvent such as xylene or toluene.
The compound 5' are known compounds or are prepared by known methods. ThP compounds ~' can be obtained optically pure using methods of asymetric synthesis or methods of resolving the racemic mixture, such as those described in "Synthesis of Optically Active Alpha-aminoacids, R.M. Williams, Pergamon Press, 1989".
2~ t~
According to another procedure, the compound 2 can be prepared by reacting an aminoalkylamide (5'') with an alkyl ortho-ester ~10) in an acid medium in accordance with the following react~on scheme:
R4 (CH~ CONH2 \ /
C ~ +R3~C(0R)3 -- ~ 2 ~5 (CH2)t~H2 in which R is a C1-C4 alkyl.
Using a procedure described by H. Takenaka et al. (Heterocycles, 1989, ~9(6), 1185 89), it is also possible to prepare the compound 2 by reacting an acid halide of the formula R3-CO-Hal 12 in which Hal is a halogen, preferably chlorine, with lS the deriv~tive 5'' ; ~he cyclization of the diamine is then carried out in a basic medium.
If z = t = O, a derivati~e 5" can be prepared from a ketone by a procedure described in US patent 4 017 510 or in Swiss patent 540 271 :
cyanure H+ ou OH
R ~ CO ~ R4-c-~N _ ~ 5 R5 NH40H ~5 NH~
", . -~
.
`
21~? ~
The ketone R4R5CO is treated with cyanide (hydrocyanic acid, sodium cyanide or potassium cyanide) and ammonium ions (aqueous ammonia and ammonium chloride) ; the aminonitrile compound 5"' i5 then S hydroly2ed to 5"', either in a strongly acidic medium or in a basic medium. If appropriate, the aminonitrile 5"' can be resolved with an optically active acid by the procedure in European patent 158 O00, in which case it is possible to prepare the compound 5" and then the compound 2 in optically pure form.
More particularly, according to another object of the present invention, the compound 2 is prepared by a method which comprises reacting a compound of the formula lS R3-B 14 in which B is - a group C~OR)3 NH~
- a group C or - a group COHal R being a Cl-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula R4 \ (CH2)zCOA l3 R5 (CH~)tNH2 in which A is an OH group, an NH2 group or a group OR', R' being hydrogen or a Cl-C4 alkyl.
The (biphenyl-4-yl)methyl derivative (~) is prepared by a method described ~n European patent 30 application 324 377.
The conversion of a group R'1 and/or R'2 to a group R1 and/or R2 is effected by methods well known to those skilled in the art. Thus, i~ the compound (I) to be prepared possesses a group Rl and/or R2 = carboxyl, S R'l and/or R'2 are an esterified carboxyl group. If the compound (I) to be prepared possesses a group Rl and/or R2 - tetrazolyl, R'l and/or R'2 can be either a tetrazolyl protected for example by a trityl group, or a cyano group which will subsequently be replaced with a tetrazolyl group protected if necessary by a trityl.
The conversion of the cyano group to a tetrazolyl can be effected with an azide, for example tributyltin azide or sodium azide.
It is also possible to use groups R'l and/or R'2 such as nitro, carboxyl, cyano or acid chloride groups and ~hen to convert them by reactions well known to those skilled in the art to give groups R1 and/or R2 as defined ~or the compound ~I).
Thus, if R'1 and/or R'~ are a carboxyl, they can be converted to R1 and/or R2 in the form of an imidazol-l-ylcarhonyl or elsa an N-(4-carboxy-1,3-thiazol-2-yl)acetamide.
The group R'1 and/or R'2 in the form of an acid chloride can be converted to Rl and/or R2 in the form of N-hydroxyacetamide, N-cyanoacetamide, ureido or 2-cyanoguanidinocarbonyl.
The group R'l and/or R'2 in the form of a nitro can be converted to amino, from which Rl and/or R2 is prepared in the form of methylsulfonylamino, trifluoro-methylsulfonylamino or trifluoromethylsulfonylamino-methyl.
The group R'1 and/or R'2 in the form of a cyano . - ' 2~?~
can be converted to aminomethyl, from which a 3-cyano-2-methylisothioureidomethyl is prepared (according to C. Gordon et al., J. Org. Chem.~ 1~70, ~(6~, 2067-2069) or a 2-cyanoguanidinomethyl is prepared S (according to R.W. Turner, Synthesis, 1975, 332).
Step al) is carried out in an inert solvent such as DMF, DMSO or THF, in a basic medium, for example in the presence of potassium hydroxide, a m~tal alcoholate, a metal hydride, calcium carbonat~ or triethylamine.
Step bl) is carried out by heating under nitrogen in a solvent such as toluene, according to the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061.
In the description below, the method camprising steps al, bl and cl is referred to as method 1.
Alternatively, the compounds (I) can be prepared by another method, which is also a sub~ect of the present invention. In this method:
a2) an amino acid of the formula 4 \ / (CH2)t NHPr S (CH2)z COOH
in which z, t, R4 and R5 are as defined above for (I), and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methylamine derivative of the formula .
- , :
R'2 R' in which R'l and R'2 are respectively either Rl and R2 or a precursor group of Rl and R2;
S b2) a~ter deprotection of the amina, the resulting compound of the formula R'~ R' R5 / ¦ Z CH2 ~ ~\ ~ 2 is then treated wlth an alkyl ortho-ester of the formula R3C(OR)3 (lO), in which R3 is as defined above for (I) and R is a C1-C4 alkyl;
c2~ if appropriate, the resulting compound of the ~ormula : 15 : R4 : R5 ~ (CH ) (C~I2)z N 4 /~ N ~ R3 ~ 2 R'1 CH2--~\
is treated with Lawesson's reagent [2,4-~is(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disul-fide];
~ . ' ' ' ': . , .
s~
and d2) the compound thus obtained in b2 or c2, of the formula R~
S--~ ~CH2)t (CH2)z N S
/~ N ~ R3 R 2 R'1 X CH2 ~ ~ \>
is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'l to the groups R2 and/or Rl respectively ;
e2) the compound so obtained is converted if appropriate, into one of its salts according to known methods well known by the skilled in the art.
The compounds 7 are known or are prepared by known methods (Chemistry of the Amino Acids, Greenstein lS and Winitz, published by ~ohn Wiley, 1961, vol. I, p.
697). If appropriate, these compounds can be obtained : optically pure using methods of asymetric synthasi~ or methods of resolving the racemic mixture, such as those : : dsscribed in 'ISynthesis of Optically Active Alpha-aminoacids, R.M. Williams, Pergamon Press, 1989".
The compounds 8 are prepared according to European patent application 324 377. Step a2~ is carried out under the usual conditions for the coupling of an acid with an amine, for example in the presence of BOP and DIPEA.
Step b2), which is the cyclization of the ~,~ 3 i~
compound 9 in the presence of 10, is carried out according to Jacquier et al. (Bull. Soc. Chim. France, 1971, (3), 1040-1051) and according to srunken and Bach (Chem. Ber., 1956, ~9, 1363-1373).
S In the description below, the method comprising steps a2 to d2 is referred to as method 2.
In one variant of method 2, in step b2, it is possible, if appropriate, to isolate an intermediate 9 of the formula -(CH2)z ~0 - NH- CH2 ~ \
(CH2)t- NH-C0-R3 and then to prepare the compound 4 by cyclization in an acid or alkaline medium.
The affinity of the products according to the invention for angiotensin II receptors was studied in a test for the binding of angiotensin II, labeled with iodine 125, to rat liver mambrane receptors. The method used is the one described by S. KEPPENS et al.
20 in Bio~hem. J., 1982, 20~, 80~-817.
The IC50, namely the concentration which gives a 50~ displacement of the labeled angiotensin II bound speaifically to the receptor, is measured. The IC50 f the compounds according to the invention is less than 25 10-6 M.
Also, the effect of the products according to the invention as angiotensin II antagonists was observed on different animal species in which the renin-angiotensin system had been activated befor~hand ~,t~ 3~t~
(C. LACOUR et al., J. Hypertension, 1989, 7 (suppl~ 2), S33-S35).
The compounds according to the invention are active after administration by diffarent routes, especially after oral administration.
No signs of toxicity are observed with these compounds at the pharmacologically active doses.
Thus the compounds accordin~ to the invention can be used in the treatment of various cardiovascular complaints, especially hypertension, heart failure and venous insufficiency, as well as in the treatment of ~laucoma, diabetic retinopathy and various complaints of the central nervous system, for example anxiety, depression, memory deficiencies or Alzheimer's disease~
lS The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the inven~ion, or of a pharmaceutically acceptable salt, and suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the activa principles of formula I above, or their salts if appropriate, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, 2~, ,j~
gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous S administration and forms for recta:L administration.
For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
To achieve the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg o~ body weight per day.
Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit lS dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0~5 to 5000 mg, preferably 1 to 2500 mg.
When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceu~ical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a ~rolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in th~ form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
I A preparation in the form of a syrup or elixir or for administration in the form of drops can contain
N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present S
The present invention relates to N-substituted heterocyclic derivatives, to their preparation and to the pharmaceutical compositions in which they are present.
The compounds according to the invention antagonize the action of angiotensin II, which is a peptide hormone of the formula H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH
Angiotensin II is a potent vasopressor and the hiologically active product of the renin-angioterlsin system: renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angiotensin II by the action of the angiotensin I
converting enzyme.
The compounds of the present invention are non-peptide compounds which antagonize angio~ensin II. By inhibiting the action of angiotensin II on its receptors, the compounds according to the invention prevent especially the increase in blood pressure produced by the hormone-receptor interaction; they also have other physiological actions on the central nervous system and on the kidneys, for example.
Thus the compounds according to the invention are useful in the treatment of cardiovascular complaints such as hypertension and heart failure, as well as in the treatment of complaints of the central nervous system and in the treatment of glaucoma and diabetic retinopathy and renal insufficiency.
2~
Non-peptide compounds which antagonize -th~
action of angiotensin II are already describe in many patents or patent applications. Particularly, reference could be made to CA application 2 050 769 published on S March 11, 1992. Said CA application generally relates to compounds of formula :
N
in which notably :
~ X represents a group of formula :
-c(RIIIRIv-cc~Rv)RvI]p-[c(RvII )RVIII]q~
- RI represents an alkyl or an alkenyl group, said groups being unsubstituted or substituted by an halogen, - RII represen~s a carboxy or a tetrazolyl, - RIII and RIV represent each independently an alkyl unsubstituted or substituted by or more halogen atoms, a cycloalkyl or an aromatic radical.
Said CA application 2 050 769 does not specifically disclose compounds of formula 1 in which RIII is an alkyl and RIV is a cycloalkyl.
2~
The present invention relates to compounds of the formula R5 ~ H2) (CH2)z N ~ R3 R~ R1 (I) CH2 ~\
S in which:
- R1 and R2 ar similar or di~f~rent and are aach independently hydrogen or a group selected ~rom a Cl-C6 alkyl, a C1-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyano-acetamide, an N-hydroxyacetamide, an N-(4-carboxy-1,3 thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyano-guanidinomethyl, an imidazol-1-ylcarbonyl and a 3-cyano-2-methyliso-thioureidomethyl, with the proviso that at least one of the substituents Rl or R2 is other than hydrogen;
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by on~ or more halogen atoms ; a Cz-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is Cl-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a Cl-C4 alkyl, a Cl-C4 halogenoalkyl, a Cl-C~ polyhalogenoalkyl, a hydroxyl or a Cl-C4 alkoxy ;
- - ~
, ,: . ' , z~
- R4 is a Cl-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ;
- Rs is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C3-C7, which is unsubstitutecl or S substituted by one or more halogen atoms ;
- or R4 and R5 are each a cyclopropyl ~
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one ;
and their salts.
If a compound according to the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound and their racemic mi~ture.
The salts of the compounds of formula (I) lS according to the present inven~ion include those with mineral or organic acids which permit separation or suitable crystallizatlon of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or camphosulfonic acid, and acids which form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the methylsulfata, the maleate, the fumarate and the naphthalene-2-sulfonate.
The salts of the compounds of formula (I) also include the salts with organic or mineral bases, for example the salts of alkali or alkaline earth metals, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, or else the salts of arginine, lysine or any physiologically acceptable ~t~?~
amine.
According to the present description and in the claims which follow, halogen atom is understood as meaning a bromine, chlorine or fluorine atom; N-S protecting group (also designated by Pr) is understoodas meaning a group conventionally used in peptide chemistry for affording temporary protection of the amine group, for example a Boc, z or Fmoc group or a benzyl group; esterified carboxyl group is understood as meaning an ester which is labile under appropriate conditions, such as, for example, a methyl, ethyl, benzyl or tert-butyl ester. "Alkyl" denotes linear or branched saturated aliphatic hydrocarbon radicals.
The compounds of formula (I) in which R1 is in lS the ortAo position and is a carboxyl or tetrazolyl group and R2 is hydrogen are preferred compounds.
The compounds of formula (I) in which R4 is methyl and R5 is cyclohexyl are also preferred compounds.
Likewise, the compounds of formula (I) in which R3 is a linear C1-C6 alkyl group are preferred compounds.
The compounds of formula (I) in which X is an oxygen atom are also preferred compounds.
Finally, the compounds of formula (I) in which z = t = 0 are preferred compounds.
2-n-Butyl-4-methyl-4-cyclohexyl-1-[(2'-(tetrazol -5-yl)biphenyl-4-yl) methyl]-2-imidazolin-5-one or one of its salts with acids or bases are particularly preferred.
The following abbreviations are used in the description and in the Examples:
`s~
alcohol : ethyl alcohol Et : ethyl nBu, tBu n-butyl, tert-butyl DMF : dimethylformamide THF : tetrahydrofuran DCM : dichloromethane NBS : N-bromosuccinimide DCC : dicyclohexylcarbodiimide DIPEA : diisopropylethylamine ether : ethyl ether TFA : trifluoroacetic acid Z : benzyloxycarbonyl Boc : tert-butoxycarbonyl BOP : benzotriazolyloxytrisdimethylamino-phosphonium hexafluorophosphate Fmoc : fluorenylmethoxycarbonyl Lawesson's r~agent : [2,4-bis(4-methoxyphenyl)-1,3-dithia 2,4-diphosphetane 2,4-disulfide].
The present invention further relates to the 0 method of preparing the compounds (I). In said method :
al) a heterocyclic derivative of the formula S ~ (C~2)t (CH2)~ N
//~ N ~LL R3 O I , H
in which z, t, R3, R4 and R5 are as defined above for ~I), is reacted with a (biphenyl-4 yl)methyl. derivative of the formula 2~ 3~7 R'2 R 1 Hal-cH2 ~ ~ 3 in which Hal i5 a halogen atom and R'1 and R'2 are respectively either Rl and ~2 or a precursor group of Rl and/or R2;
bl) if appropriate, the resulting compound of the formula (CH2)t ~CH2)Z N
/~N~R3 R'~ R' 1~ _ r~" ~
is treated wi~h Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfideJ, and cl) the compound obtained in al) or bl), of the formula Z~
~ )t (CH2)~ ~ 5 /~ N ~ R3 R'2 R l CH 2 ' ~--`\
in which X is an o~ygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the groups R'l and/or R'2 to the groups R1 and/or R2 respectively ;
dl) the compound so obtained is converted if approprlate, into one of its salts, according to known method~ well known by the skilled in the art.
Among the compounds 2, some of them are prior art compounds, the others are new and belong to the scope o the invention.
EP patent application 144 748 discloses herbicides of formula :
lS
X
Y~\ 1~
H
in which one of X and Y may represent an alkyl and the other a cycloalkyl ; furthermore the phenyl group may be substituted.
Thus the present invention further relates to the compounds (II) of the formula - .
2'~
S " ~ H2)t ~(CH~ N fl X ~ N 3 H
in which:
- z and t are zero or one is zero and the other is one;
R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstltuted or monosubstituted or polysubs~ituted by a halogen atom, a C~-C4 alkyl, a Cl-C~ halogenoalkyl, a Cl-C4 polyhalogenoalkyl, a hydroxyl or a Cl-C~ alkoxy;
- R4 is a Cl-C6 alkyl which is unsubstituted or lS substituted by one or more halogen atoms ; and - R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms ;
- or else R4 and R5 are each a cyclopropyl ;
- X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z = t = 0, R5 represents a cycloalkyl.
Among the derivatives (II), the compounds in which z = t = 0 of the formula :
~5 N
X ~ \ ~ R3 H
in which X, R3, R4 and R5 are as defined above for (II~, with the proviso that R3 is other than a phenyl S or a substituted phenyl when R5 represents a cycloalkyl are preferred compounds.
The compounds (II) in which z = 0 and t = 1, of the formula R\4 R5- "^'N
xi ~ ~ -R3 in which R3, R4, R5 and X are as defined above for (II), are preferred compounds.
Finally, the compounds (II) in which z - 1 and t = 0, of the formula R ~ R5 N
H (II"') in which R3, R4, Rs and X are as defined above for (II), are preferred compounds.
The derivatives 2 are prepared by known .
2~
methods. For example, it is possible to use the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, ~, 1040-1051) and by Brunken and Bach (Chem.
Ber., 1956, ~9, 1363-1373) and to react an alkyl imidate with an amino acid or its ester in accordance with the following reaction scheme: -R4 (CH2)z~co2R ~NH
C ~ \
R5 (CH2)t-NH2 OR
_' _ R5 - ~ ~I2~t (CH2)z N 2 /~N~R3 O
H
in which R is a Cl-C4 alkyl, R' is hydrogen or a Cl-C4 alkyl and R3, R4, R5, z and t are as defined above for I).
This reaction is carried out in an acid medium by heating in an inert solvent such as xylene or toluene.
The compound 5' are known compounds or are prepared by known methods. ThP compounds ~' can be obtained optically pure using methods of asymetric synthesis or methods of resolving the racemic mixture, such as those described in "Synthesis of Optically Active Alpha-aminoacids, R.M. Williams, Pergamon Press, 1989".
2~ t~
According to another procedure, the compound 2 can be prepared by reacting an aminoalkylamide (5'') with an alkyl ortho-ester ~10) in an acid medium in accordance with the following react~on scheme:
R4 (CH~ CONH2 \ /
C ~ +R3~C(0R)3 -- ~ 2 ~5 (CH2)t~H2 in which R is a C1-C4 alkyl.
Using a procedure described by H. Takenaka et al. (Heterocycles, 1989, ~9(6), 1185 89), it is also possible to prepare the compound 2 by reacting an acid halide of the formula R3-CO-Hal 12 in which Hal is a halogen, preferably chlorine, with lS the deriv~tive 5'' ; ~he cyclization of the diamine is then carried out in a basic medium.
If z = t = O, a derivati~e 5" can be prepared from a ketone by a procedure described in US patent 4 017 510 or in Swiss patent 540 271 :
cyanure H+ ou OH
R ~ CO ~ R4-c-~N _ ~ 5 R5 NH40H ~5 NH~
", . -~
.
`
21~? ~
The ketone R4R5CO is treated with cyanide (hydrocyanic acid, sodium cyanide or potassium cyanide) and ammonium ions (aqueous ammonia and ammonium chloride) ; the aminonitrile compound 5"' i5 then S hydroly2ed to 5"', either in a strongly acidic medium or in a basic medium. If appropriate, the aminonitrile 5"' can be resolved with an optically active acid by the procedure in European patent 158 O00, in which case it is possible to prepare the compound 5" and then the compound 2 in optically pure form.
More particularly, according to another object of the present invention, the compound 2 is prepared by a method which comprises reacting a compound of the formula lS R3-B 14 in which B is - a group C~OR)3 NH~
- a group C or - a group COHal R being a Cl-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula R4 \ (CH2)zCOA l3 R5 (CH~)tNH2 in which A is an OH group, an NH2 group or a group OR', R' being hydrogen or a Cl-C4 alkyl.
The (biphenyl-4-yl)methyl derivative (~) is prepared by a method described ~n European patent 30 application 324 377.
The conversion of a group R'1 and/or R'2 to a group R1 and/or R2 is effected by methods well known to those skilled in the art. Thus, i~ the compound (I) to be prepared possesses a group Rl and/or R2 = carboxyl, S R'l and/or R'2 are an esterified carboxyl group. If the compound (I) to be prepared possesses a group Rl and/or R2 - tetrazolyl, R'l and/or R'2 can be either a tetrazolyl protected for example by a trityl group, or a cyano group which will subsequently be replaced with a tetrazolyl group protected if necessary by a trityl.
The conversion of the cyano group to a tetrazolyl can be effected with an azide, for example tributyltin azide or sodium azide.
It is also possible to use groups R'l and/or R'2 such as nitro, carboxyl, cyano or acid chloride groups and ~hen to convert them by reactions well known to those skilled in the art to give groups R1 and/or R2 as defined ~or the compound ~I).
Thus, if R'1 and/or R'~ are a carboxyl, they can be converted to R1 and/or R2 in the form of an imidazol-l-ylcarhonyl or elsa an N-(4-carboxy-1,3-thiazol-2-yl)acetamide.
The group R'1 and/or R'2 in the form of an acid chloride can be converted to Rl and/or R2 in the form of N-hydroxyacetamide, N-cyanoacetamide, ureido or 2-cyanoguanidinocarbonyl.
The group R'l and/or R'2 in the form of a nitro can be converted to amino, from which Rl and/or R2 is prepared in the form of methylsulfonylamino, trifluoro-methylsulfonylamino or trifluoromethylsulfonylamino-methyl.
The group R'1 and/or R'2 in the form of a cyano . - ' 2~?~
can be converted to aminomethyl, from which a 3-cyano-2-methylisothioureidomethyl is prepared (according to C. Gordon et al., J. Org. Chem.~ 1~70, ~(6~, 2067-2069) or a 2-cyanoguanidinomethyl is prepared S (according to R.W. Turner, Synthesis, 1975, 332).
Step al) is carried out in an inert solvent such as DMF, DMSO or THF, in a basic medium, for example in the presence of potassium hydroxide, a m~tal alcoholate, a metal hydride, calcium carbonat~ or triethylamine.
Step bl) is carried out by heating under nitrogen in a solvent such as toluene, according to the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061.
In the description below, the method camprising steps al, bl and cl is referred to as method 1.
Alternatively, the compounds (I) can be prepared by another method, which is also a sub~ect of the present invention. In this method:
a2) an amino acid of the formula 4 \ / (CH2)t NHPr S (CH2)z COOH
in which z, t, R4 and R5 are as defined above for (I), and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methylamine derivative of the formula .
- , :
R'2 R' in which R'l and R'2 are respectively either Rl and R2 or a precursor group of Rl and R2;
S b2) a~ter deprotection of the amina, the resulting compound of the formula R'~ R' R5 / ¦ Z CH2 ~ ~\ ~ 2 is then treated wlth an alkyl ortho-ester of the formula R3C(OR)3 (lO), in which R3 is as defined above for (I) and R is a C1-C4 alkyl;
c2~ if appropriate, the resulting compound of the ~ormula : 15 : R4 : R5 ~ (CH ) (C~I2)z N 4 /~ N ~ R3 ~ 2 R'1 CH2--~\
is treated with Lawesson's reagent [2,4-~is(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disul-fide];
~ . ' ' ' ': . , .
s~
and d2) the compound thus obtained in b2 or c2, of the formula R~
S--~ ~CH2)t (CH2)z N S
/~ N ~ R3 R 2 R'1 X CH2 ~ ~ \>
is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'l to the groups R2 and/or Rl respectively ;
e2) the compound so obtained is converted if appropriate, into one of its salts according to known methods well known by the skilled in the art.
The compounds 7 are known or are prepared by known methods (Chemistry of the Amino Acids, Greenstein lS and Winitz, published by ~ohn Wiley, 1961, vol. I, p.
697). If appropriate, these compounds can be obtained : optically pure using methods of asymetric synthasi~ or methods of resolving the racemic mixture, such as those : : dsscribed in 'ISynthesis of Optically Active Alpha-aminoacids, R.M. Williams, Pergamon Press, 1989".
The compounds 8 are prepared according to European patent application 324 377. Step a2~ is carried out under the usual conditions for the coupling of an acid with an amine, for example in the presence of BOP and DIPEA.
Step b2), which is the cyclization of the ~,~ 3 i~
compound 9 in the presence of 10, is carried out according to Jacquier et al. (Bull. Soc. Chim. France, 1971, (3), 1040-1051) and according to srunken and Bach (Chem. Ber., 1956, ~9, 1363-1373).
S In the description below, the method comprising steps a2 to d2 is referred to as method 2.
In one variant of method 2, in step b2, it is possible, if appropriate, to isolate an intermediate 9 of the formula -(CH2)z ~0 - NH- CH2 ~ \
(CH2)t- NH-C0-R3 and then to prepare the compound 4 by cyclization in an acid or alkaline medium.
The affinity of the products according to the invention for angiotensin II receptors was studied in a test for the binding of angiotensin II, labeled with iodine 125, to rat liver mambrane receptors. The method used is the one described by S. KEPPENS et al.
20 in Bio~hem. J., 1982, 20~, 80~-817.
The IC50, namely the concentration which gives a 50~ displacement of the labeled angiotensin II bound speaifically to the receptor, is measured. The IC50 f the compounds according to the invention is less than 25 10-6 M.
Also, the effect of the products according to the invention as angiotensin II antagonists was observed on different animal species in which the renin-angiotensin system had been activated befor~hand ~,t~ 3~t~
(C. LACOUR et al., J. Hypertension, 1989, 7 (suppl~ 2), S33-S35).
The compounds according to the invention are active after administration by diffarent routes, especially after oral administration.
No signs of toxicity are observed with these compounds at the pharmacologically active doses.
Thus the compounds accordin~ to the invention can be used in the treatment of various cardiovascular complaints, especially hypertension, heart failure and venous insufficiency, as well as in the treatment of ~laucoma, diabetic retinopathy and various complaints of the central nervous system, for example anxiety, depression, memory deficiencies or Alzheimer's disease~
lS The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the inven~ion, or of a pharmaceutically acceptable salt, and suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the activa principles of formula I above, or their salts if appropriate, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, 2~, ,j~
gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous S administration and forms for recta:L administration.
For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
To achieve the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg o~ body weight per day.
Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit lS dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0~5 to 5000 mg, preferably 1 to 2500 mg.
When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceu~ical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a ~rolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in th~ form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
I A preparation in the form of a syrup or elixir or for administration in the form of drops can contain
3,~
the active ingredient in conjunction with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring and an appropriate color.
S The water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example cacao butter or polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and in~ectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In addition to the products of formula I above or one of their pharmaceutically acceptable salts, the compositions of the present invention can contain other active principIes such as, for example, tranquilizers or other drugs which can be useful in the treatment of the disorders or diseases indicated above.
Thus the present invention relates to pharmaceutical compositions containing several active principles in association, one being a compound according to the invention and it being possible for the other or others to be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal antiinflammatory or a tranguilizer.
The following Examples illustrate the invention without however implying a limitation. The following abbreviations are used in these Examples: d denotes density, RT denotes room temperature, KHS04-K2S04 denotes an aque3us solution containing 16.6 g of potassium bisulfate and 33.3 g of potassium sulfate per liter.
The melting points (m.p.) are given in degrees Celsius; unless indicated otherwise, they were measured without recrystallization of the product.
The purity of the products is checked by thin layer chromatography (TLC) or HPLC. The products are characterized by their NMR spectra run at 200 MHz in deuterated DMS0 with tetramethylsilans as the internal reference.
The specific optical rotation ~]D are measured at 22'C ; path length : lO cm, concentration l g per 100 ml.
The following abbreviations are used in the lnterpretation of the NMR spectra:
s : singlet sb : broad singlet d : doublet t : triplet q : quadruplet quint : quintuplet sext : sextuplet m ; unresolved signals or multiplet In addition, im denotes imidazole.
(R,S)-2-n-Butyl~ (2'-carboxybiphenyl-4-yl)-methyl]-4-cyclohexyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate S A) 5-Cyclohexyl-5-methylhydantoin This compound is prepared accordin~ to J. Org.
Chem., lg60, 2S, 1920-1924.
A solution of 50 g of cyclohexyl methyl ketone in 4~0 ml of 95- alcohol is added over 30 minutes to 29.4 g of sodium cyanide and 192 g of ammonium carbonate in 400 ml of water. The mixture is heated at 55-60- C for 4 hours and then evaporated to half its volume under vacuum and left to stand overni~ht at +4~ C. The precipitate formed is filtered off, washed with wa~er and then dried under vacuum over phosphorus pentoxide to give 65.5 g of the expected hydantoin, wh~ch is identified by its IR and NMR spectra.
M.p. = 220- C.
B) tR,S)-2-Amino-2-cyclohexylpropionic acid This compound is prepared according to J. Org.
Chem., 1960, 2~, 1920-1924.
A mixture containing 7 g of the hydantoin prepared in the previous step and 28 g of barium hydroxide octahydrate in 150 ml of water is heated at 160- C for 5 hours in a steel tube. The reaction medium is saturated with dry ice, the insoluble.
material formed is filtered off and the -filtrate is then concentrated under vacuum. The solid residue is taken up in acetone, filtered off and dried to give 5.25 g of the expected acid, which is identified by its IR and NMR spectra. The product melts at 350- C
with decomposition.
C) Ethyl ester of (R,S)-2-amino-2-cyclohexylpropionic acid 3 g of the acid prepared in the previous step are added to 40 ml of absolute alcohol saturated with S gaseous hydrochloric acid and the mixture is then refluxed for 20 hours, with stirring. The reaction medium is evaporated under vacuum and the residue is taken up in an ether/water mixture, which is brought to pH 9 by the addition of a saturated solution of sodium bicarbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride and then evaporated under vacuum to give 2.1 g of the expected ester in the form of an oil. Identification by IR and NMR spectra.
lS D) Ethyl valerimidate This compound is prepared in the form of the hydrochloride according to Mac Elvain (J. Amer. Chem.
Soc., 1942, 64, 1825-1827)o It is freed from its hydrochloride by reaction with potassium carbonate and then extracted with DCM.
E) (R,S)-2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one 2 g of the ester prepared in step C and 2.35 g of ethyl valerimidate are mixed in 6 ml of xylen~, to which 6 drops of acetic acid are added; the reaction medium is re1uxed for 6 hours. It is then concen-trated under vacuum and the residue is chromatographed on fine silica gel using a chloroform/methanol/acetic acid mixture (95/9/3; v/v/v) as the eluent. The ~ractions containing the desired product are com~ined and then evaporated under vacuum; the residue is taken up in an ethyl acetate/water mixture and the pH is brought to 9 by the addition of a solution of sodium hydroxide. The organic phase is decanted, washed with water and then with a saturated solution of sodium chloride, dried over sodium sulfate and then S evaporated to dryness. The expected product is obtained in the form of a thick oil, which solidifies to give an amorphous solid.
m = 1.56 mg.
- IR (chloroform):
1720 cm~1 : C=0 1640 cm~1 : C=N
- NMR consis~ent.
F) 4-Bromomethyl-2'-tert-butoxycarbonylbiphenyl This compound is prepared by the method described in European patent application 324 377.
G) (R,S)-2-n-Butyl-4-cyclohexyl-4~methyl-1-C(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl~-2-imidazolin-5-one 1.5 g of the imidazolinone prepared in the previous step are dissolved in 20 ml of DMF. 250 mg of sodium hydride as an 80% dispersion in oil are added. After stirring for 20 minutes, 2.48 g of the compound prepared in step F) are added and the reaction medium is left to stand for 2 hours at RT.
It is taken up in an ethyl acetate/water mixture; tha organic phase is decan~ed washed with water and with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum.
The residue is chromatographed on silica using an ethyl acetate/toluene mixture ~1/4; v/v~ as the eluent to give 1.8 g of the expected product in the ~orm of a white wax.
- IR (chloroform):
1710 1730 cm~l : ester and imidazolinone C=0 1630 cm~1 : C=N
H) (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-
the active ingredient in conjunction with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring and an appropriate color.
S The water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example cacao butter or polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and in~ectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In addition to the products of formula I above or one of their pharmaceutically acceptable salts, the compositions of the present invention can contain other active principIes such as, for example, tranquilizers or other drugs which can be useful in the treatment of the disorders or diseases indicated above.
Thus the present invention relates to pharmaceutical compositions containing several active principles in association, one being a compound according to the invention and it being possible for the other or others to be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal antiinflammatory or a tranguilizer.
The following Examples illustrate the invention without however implying a limitation. The following abbreviations are used in these Examples: d denotes density, RT denotes room temperature, KHS04-K2S04 denotes an aque3us solution containing 16.6 g of potassium bisulfate and 33.3 g of potassium sulfate per liter.
The melting points (m.p.) are given in degrees Celsius; unless indicated otherwise, they were measured without recrystallization of the product.
The purity of the products is checked by thin layer chromatography (TLC) or HPLC. The products are characterized by their NMR spectra run at 200 MHz in deuterated DMS0 with tetramethylsilans as the internal reference.
The specific optical rotation ~]D are measured at 22'C ; path length : lO cm, concentration l g per 100 ml.
The following abbreviations are used in the lnterpretation of the NMR spectra:
s : singlet sb : broad singlet d : doublet t : triplet q : quadruplet quint : quintuplet sext : sextuplet m ; unresolved signals or multiplet In addition, im denotes imidazole.
(R,S)-2-n-Butyl~ (2'-carboxybiphenyl-4-yl)-methyl]-4-cyclohexyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate S A) 5-Cyclohexyl-5-methylhydantoin This compound is prepared accordin~ to J. Org.
Chem., lg60, 2S, 1920-1924.
A solution of 50 g of cyclohexyl methyl ketone in 4~0 ml of 95- alcohol is added over 30 minutes to 29.4 g of sodium cyanide and 192 g of ammonium carbonate in 400 ml of water. The mixture is heated at 55-60- C for 4 hours and then evaporated to half its volume under vacuum and left to stand overni~ht at +4~ C. The precipitate formed is filtered off, washed with wa~er and then dried under vacuum over phosphorus pentoxide to give 65.5 g of the expected hydantoin, wh~ch is identified by its IR and NMR spectra.
M.p. = 220- C.
B) tR,S)-2-Amino-2-cyclohexylpropionic acid This compound is prepared according to J. Org.
Chem., 1960, 2~, 1920-1924.
A mixture containing 7 g of the hydantoin prepared in the previous step and 28 g of barium hydroxide octahydrate in 150 ml of water is heated at 160- C for 5 hours in a steel tube. The reaction medium is saturated with dry ice, the insoluble.
material formed is filtered off and the -filtrate is then concentrated under vacuum. The solid residue is taken up in acetone, filtered off and dried to give 5.25 g of the expected acid, which is identified by its IR and NMR spectra. The product melts at 350- C
with decomposition.
C) Ethyl ester of (R,S)-2-amino-2-cyclohexylpropionic acid 3 g of the acid prepared in the previous step are added to 40 ml of absolute alcohol saturated with S gaseous hydrochloric acid and the mixture is then refluxed for 20 hours, with stirring. The reaction medium is evaporated under vacuum and the residue is taken up in an ether/water mixture, which is brought to pH 9 by the addition of a saturated solution of sodium bicarbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride and then evaporated under vacuum to give 2.1 g of the expected ester in the form of an oil. Identification by IR and NMR spectra.
lS D) Ethyl valerimidate This compound is prepared in the form of the hydrochloride according to Mac Elvain (J. Amer. Chem.
Soc., 1942, 64, 1825-1827)o It is freed from its hydrochloride by reaction with potassium carbonate and then extracted with DCM.
E) (R,S)-2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one 2 g of the ester prepared in step C and 2.35 g of ethyl valerimidate are mixed in 6 ml of xylen~, to which 6 drops of acetic acid are added; the reaction medium is re1uxed for 6 hours. It is then concen-trated under vacuum and the residue is chromatographed on fine silica gel using a chloroform/methanol/acetic acid mixture (95/9/3; v/v/v) as the eluent. The ~ractions containing the desired product are com~ined and then evaporated under vacuum; the residue is taken up in an ethyl acetate/water mixture and the pH is brought to 9 by the addition of a solution of sodium hydroxide. The organic phase is decanted, washed with water and then with a saturated solution of sodium chloride, dried over sodium sulfate and then S evaporated to dryness. The expected product is obtained in the form of a thick oil, which solidifies to give an amorphous solid.
m = 1.56 mg.
- IR (chloroform):
1720 cm~1 : C=0 1640 cm~1 : C=N
- NMR consis~ent.
F) 4-Bromomethyl-2'-tert-butoxycarbonylbiphenyl This compound is prepared by the method described in European patent application 324 377.
G) (R,S)-2-n-Butyl-4-cyclohexyl-4~methyl-1-C(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl~-2-imidazolin-5-one 1.5 g of the imidazolinone prepared in the previous step are dissolved in 20 ml of DMF. 250 mg of sodium hydride as an 80% dispersion in oil are added. After stirring for 20 minutes, 2.48 g of the compound prepared in step F) are added and the reaction medium is left to stand for 2 hours at RT.
It is taken up in an ethyl acetate/water mixture; tha organic phase is decan~ed washed with water and with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum.
The residue is chromatographed on silica using an ethyl acetate/toluene mixture ~1/4; v/v~ as the eluent to give 1.8 g of the expected product in the ~orm of a white wax.
- IR (chloroform):
1710 1730 cm~l : ester and imidazolinone C=0 1630 cm~1 : C=N
H) (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-
4-cyclohexyl-4-methyl-2-imidazolin-5-one trifluoro-acetate 1.5 g of the compound obtained in the previous step are stirred for 40 minutes in 7 ml of TFA and 7 ml of ~CM. The reaction medium is concentrated under vacuum and taken up in ether to give a white solid, which is filtered off, washed with ether and dried under vacuum.
m = 1.40 g.
M.p. = 171- C.
MH+ : 447.
- NMR:
7.10-7.70 ppm : m : 8 aromatic H
4.45 ppm : s : 2 H : N-C~2-C6H4-1.25 ppm : s : CH3 in the 4 position (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclohexyl-methyl-4-m~thyl-2-imidazolin-5-one trifluoroacetate The ~ollowing compounds are prepared from cyclohexyl methyl ketone according to the procedures described in Example 1:
A) 5-Cyclohexylmethyl-5-methylhydantoin M.p. = 205-206- C.
B~ (R,S)-2-Amino-3-cyclohexyl-2-methylpropionic acid Characterized by its IR and NMR spectra.
2~
C) Ethyl ester of (R,S)-2-amino-3-cyclohexyl-2-methyl-propionic acid Characterized by its IR and NMR spectra.
D) (R,S)-2-n-Butyl-4-cyclohexylmethyl-4-methyl-2-S imidazolin-5-one This product is obtained in the form of an oil, which solidifies. Identification by I~ and NMR.
- IR (chloroform):
1720 cm~1 : imidazolinone C=0 1630 cm~1 : C=N
E) (R,S)-2-n-Butyl-4-cyclohexylmethyl-4-methyl-1-[(2'-tert-butoxycarbonylbi-phenyl-4-yl)methyl]-2-imicla-zolin-5-one This product is obtained by treatiny the compound of step D with 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl in the presenca of sodium hydride. After purification by ahromatography, the product is in the form of an oil, which crystallizes in the refrigerator.
Yield : 51%.
M.p. = 73-75- C.
- IR tKBr):
1700-1730 cm~1 : imidazolinone and ester C=0 1630 cm~1 : C=N
F) (R,S)-2-n-Butyl-1-~(2'-carboxybiphenyl-4-yl)methyl]-4-cyclohexylmethyl-4-methyl-2-imidazolin-5-one trifluoroacetate Yield : 90~.
M.p. = 143-146- C.
- NMR:
7.20-7.80 ppm : 8 H : aromatic protons 4.85 ppm : m : 2 H : N-CH2-C6H4-2 ~ ~3'~ 7 2-70 ppm : t : 3 H : -cH2-cH2-cH2-cH3 1.80-0.85 ppm : m : 20 H : 4-methyl 4-cyclohexylmethyl 0.80 ppm : t : 3 H : CH2-CH2-CH2-CH3 (R,S)-2-n-Butyl-1-[(2' carboxybiphenyl-4-yl)-methyl]
-4-cyclohexyl-4-ethyl-2-imidazolin-5-one trifluoro-acetate A) (R,S)-2-Amino-2-cyclohexylbutyronitrile hemioxalate 1.18 g of ammonium chloride and 1.5 ml of a 32~ aqueous solution of ammonia are added successively to a solution of 1.03 ~ of sodium cyanide in 6 ml of lS water, followed, over 15 minutes, by 2.8 g of cyclohexyl ethyl ketone in 5 ml of methanol, and tha reaction medium is heated at 60- C for 6 hours. It is cooled and extracted 4 times with DCM and the extracts are then evaporated under vacuum. The residue is treated again with the same amounts of cyanide, ammonium chloride, aqueous ammonia, water and methanol at 60- C for 6 hours. The reaction medium i5 then cooled and extracted 4 times with DCM and the extracts are dried and then evaporated under vacuum. The residue is taken up in 30 ml of acetone, and a solution of 1.1 g of o~alic acid dihydrate in 10 ml of acetone is added dropwise. After 15 minutes, the precipitate formed is filtered off, washed with acetone and then with ether and dried under vacuum to give 2.87 g of product, which becomes pasty at 120- C.
Identification by IR and NMR.
- IR of the free base: -J.t 2220 cm~l : C-N
B) (R,S)-2-Amino-2-cyclohexylbutyramide 2.84 g of the nitrile ob~ained in step A are added over 30 minutes to 6 ml of pure sulfuric acid.
S The mixture is heated for 1 hour at 85- C and then 30 minutes at 100- C. After cooling, the reaction medium is added dropwise to 20 ml of iced 32% aqueous ammonia. The mixture is extracted with chloroform and the extract is then dried over sodium sulfate and evaporated under vacuum to give 2.5 g of the expected product in the form of a wax. Identification by IR
and NMR.
C) (R,S)-2-n-Butyl-4-cyclohexyl-4-ethyl-2-imidazolin-
m = 1.40 g.
M.p. = 171- C.
MH+ : 447.
- NMR:
7.10-7.70 ppm : m : 8 aromatic H
4.45 ppm : s : 2 H : N-C~2-C6H4-1.25 ppm : s : CH3 in the 4 position (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclohexyl-methyl-4-m~thyl-2-imidazolin-5-one trifluoroacetate The ~ollowing compounds are prepared from cyclohexyl methyl ketone according to the procedures described in Example 1:
A) 5-Cyclohexylmethyl-5-methylhydantoin M.p. = 205-206- C.
B~ (R,S)-2-Amino-3-cyclohexyl-2-methylpropionic acid Characterized by its IR and NMR spectra.
2~
C) Ethyl ester of (R,S)-2-amino-3-cyclohexyl-2-methyl-propionic acid Characterized by its IR and NMR spectra.
D) (R,S)-2-n-Butyl-4-cyclohexylmethyl-4-methyl-2-S imidazolin-5-one This product is obtained in the form of an oil, which solidifies. Identification by I~ and NMR.
- IR (chloroform):
1720 cm~1 : imidazolinone C=0 1630 cm~1 : C=N
E) (R,S)-2-n-Butyl-4-cyclohexylmethyl-4-methyl-1-[(2'-tert-butoxycarbonylbi-phenyl-4-yl)methyl]-2-imicla-zolin-5-one This product is obtained by treatiny the compound of step D with 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl in the presenca of sodium hydride. After purification by ahromatography, the product is in the form of an oil, which crystallizes in the refrigerator.
Yield : 51%.
M.p. = 73-75- C.
- IR tKBr):
1700-1730 cm~1 : imidazolinone and ester C=0 1630 cm~1 : C=N
F) (R,S)-2-n-Butyl-1-~(2'-carboxybiphenyl-4-yl)methyl]-4-cyclohexylmethyl-4-methyl-2-imidazolin-5-one trifluoroacetate Yield : 90~.
M.p. = 143-146- C.
- NMR:
7.20-7.80 ppm : 8 H : aromatic protons 4.85 ppm : m : 2 H : N-CH2-C6H4-2 ~ ~3'~ 7 2-70 ppm : t : 3 H : -cH2-cH2-cH2-cH3 1.80-0.85 ppm : m : 20 H : 4-methyl 4-cyclohexylmethyl 0.80 ppm : t : 3 H : CH2-CH2-CH2-CH3 (R,S)-2-n-Butyl-1-[(2' carboxybiphenyl-4-yl)-methyl]
-4-cyclohexyl-4-ethyl-2-imidazolin-5-one trifluoro-acetate A) (R,S)-2-Amino-2-cyclohexylbutyronitrile hemioxalate 1.18 g of ammonium chloride and 1.5 ml of a 32~ aqueous solution of ammonia are added successively to a solution of 1.03 ~ of sodium cyanide in 6 ml of lS water, followed, over 15 minutes, by 2.8 g of cyclohexyl ethyl ketone in 5 ml of methanol, and tha reaction medium is heated at 60- C for 6 hours. It is cooled and extracted 4 times with DCM and the extracts are then evaporated under vacuum. The residue is treated again with the same amounts of cyanide, ammonium chloride, aqueous ammonia, water and methanol at 60- C for 6 hours. The reaction medium i5 then cooled and extracted 4 times with DCM and the extracts are dried and then evaporated under vacuum. The residue is taken up in 30 ml of acetone, and a solution of 1.1 g of o~alic acid dihydrate in 10 ml of acetone is added dropwise. After 15 minutes, the precipitate formed is filtered off, washed with acetone and then with ether and dried under vacuum to give 2.87 g of product, which becomes pasty at 120- C.
Identification by IR and NMR.
- IR of the free base: -J.t 2220 cm~l : C-N
B) (R,S)-2-Amino-2-cyclohexylbutyramide 2.84 g of the nitrile ob~ained in step A are added over 30 minutes to 6 ml of pure sulfuric acid.
S The mixture is heated for 1 hour at 85- C and then 30 minutes at 100- C. After cooling, the reaction medium is added dropwise to 20 ml of iced 32% aqueous ammonia. The mixture is extracted with chloroform and the extract is then dried over sodium sulfate and evaporated under vacuum to give 2.5 g of the expected product in the form of a wax. Identification by IR
and NMR.
C) (R,S)-2-n-Butyl-4-cyclohexyl-4-ethyl-2-imidazolin-
5-one 2.45 g of the product obtained in the previous step are dissolved in 30 ml of THF; 1.84 ml of triethylamine are added, followed, over 25 minutes, by a solution of 1.73 ml of valeroyl chloride in 10 ml of THF. After stirring for 2 hours, 3.57 g of potassium hydroxide pellets, then 4 ml of water and then 10 ml of methanol are added and the mixture is refluxed for 3 hours. After cooling, 6 g of ammonium chloride are added and the reaction medium is concentrated to half its volu.ne and then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum. The residue is taken up in 10 ml of hexane and left to stand for 4 hours at 0- C.
The solid formed is filtered off and dried.
m = 2.62 g.
M.p. = 80-85- C.
Identification by NMR and IR (chloroform and KBr).
2 ~'3~
D) (R,S)-2-n-Butyl-1-[(2'- tert -butoxycarbonylbiphenyl-4-yl)methyl]-4-cyclohexyl-4-ethyl-2-imidazolin-5-one The procedure described in Example 1, step G), is followed; 1.50 g of the expected product are obtained, after chromatography, by treating 1 g of the product of step C) with 4-bromomethyl-2'-tert-butoxycarbonylbiptlenyl.
- IR (chloroform):
17G0-1720 cm~l : imidazolinone and ester C=0 1635 cm~1 : C=N
E) (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]- -4-cyclohexyl-4-ethyl-2-imidazolin-5-one tri~luoroacetate The expected product is obtained by treating lS the compound obtained in the previous step by the mathod described in Example 1, step H).
Yield : 85%.
M.p. = 159-161- C.
- NMR:
7.10-7.7Q ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : -N-CH2-C6H4-2.60 ppm : t : 2 H : -CH2-~H2-CH2-CH3 0.90-1.90 ppm : m : 17 H : cyclohexyl + -CH2-CH3 +
-CH2-cH2-cH2-cH3 0.80 ppm : t : 3 H : -C~3 0.60 ppm : t : 3 H : -CH3 (R,S)-2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5~one A) 4-Methyl-2'-(tetrazol-5-yl)biphenyl 2'-Cyano-4-methylbiphenyl is prepared according to European patent application 324 377.
2 g of this compound are placed in a round-bottomed flask in the presence of 4 g of tributyltin azide and 20 ml of xylene and the mixture is reflu~ed S for 110 hours. After it has returned to RT, the reaction medium is diluted with toluene and the organic phase is then extracted 3 times with 50 ml of 1 N sodium hydroxide solution. The aqueous phases are combined, washed with ether and then cooled in a bath of iced water and acidified to pH 1-2 by the addition of concentrated hydrochloric acid. The precipitate formed is filtered off, washed with water and dried under vacuum over phosphorus pentoxide to give 2.18 g of the expected product.
M.p. = 146-148- C after recrystallization from ethyl acetate.
B) 4-Methyl-2'-(triphenylmethyltetra~ol-5-yl)biphenyl 5.46 g of the compound obtained in step A,
The solid formed is filtered off and dried.
m = 2.62 g.
M.p. = 80-85- C.
Identification by NMR and IR (chloroform and KBr).
2 ~'3~
D) (R,S)-2-n-Butyl-1-[(2'- tert -butoxycarbonylbiphenyl-4-yl)methyl]-4-cyclohexyl-4-ethyl-2-imidazolin-5-one The procedure described in Example 1, step G), is followed; 1.50 g of the expected product are obtained, after chromatography, by treating 1 g of the product of step C) with 4-bromomethyl-2'-tert-butoxycarbonylbiptlenyl.
- IR (chloroform):
17G0-1720 cm~l : imidazolinone and ester C=0 1635 cm~1 : C=N
E) (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]- -4-cyclohexyl-4-ethyl-2-imidazolin-5-one tri~luoroacetate The expected product is obtained by treating lS the compound obtained in the previous step by the mathod described in Example 1, step H).
Yield : 85%.
M.p. = 159-161- C.
- NMR:
7.10-7.7Q ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : -N-CH2-C6H4-2.60 ppm : t : 2 H : -CH2-~H2-CH2-CH3 0.90-1.90 ppm : m : 17 H : cyclohexyl + -CH2-CH3 +
-CH2-cH2-cH2-cH3 0.80 ppm : t : 3 H : -C~3 0.60 ppm : t : 3 H : -CH3 (R,S)-2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5~one A) 4-Methyl-2'-(tetrazol-5-yl)biphenyl 2'-Cyano-4-methylbiphenyl is prepared according to European patent application 324 377.
2 g of this compound are placed in a round-bottomed flask in the presence of 4 g of tributyltin azide and 20 ml of xylene and the mixture is reflu~ed S for 110 hours. After it has returned to RT, the reaction medium is diluted with toluene and the organic phase is then extracted 3 times with 50 ml of 1 N sodium hydroxide solution. The aqueous phases are combined, washed with ether and then cooled in a bath of iced water and acidified to pH 1-2 by the addition of concentrated hydrochloric acid. The precipitate formed is filtered off, washed with water and dried under vacuum over phosphorus pentoxide to give 2.18 g of the expected product.
M.p. = 146-148- C after recrystallization from ethyl acetate.
B) 4-Methyl-2'-(triphenylmethyltetra~ol-5-yl)biphenyl 5.46 g of the compound obtained in step A,
6.9 g of trityl chloride, 100 ml of DCM and 4 ml o triethylamine are mixed in a round-bottomed flask.
The medium is refluxed for 4 hours and then evaporated. The residue is taken up in ethyl acetate and washed with water, a 3% solution of potassium hydrogensulfate, 1 N sodium hydroxide solution, water and then a saturated solution of sodium chloride. It is dried over sodium sulfate, filtered and avaporated to give 11 g of the expected product.
M.p. = 161-164- C.
C) 4-Bromomethyl-2'-(triphenylmethyltetrazol-5-yl) biphenyl A mixture containing 11 g of the compound prepared in step B, 140 ml of carbon tetrachloride, 4.12 g of NBS and 0.4 g of benzoyl peroxide is refluxed for 3 hours. After it has returned to RT, it is filtered and the filtrate is then evaporated. The residue is taken up in 30 ml of isopropyl ether. The precipitate ormed is filtered off and then dried under vacuum, The product obtained is used as such in the next step.
D) ~R,S)-2-n-Butyl-4-cyclohexyl-4-msthyl-1-[(2'-~tri-phenyl-methyltetrazol-5-yl)biphenyl-4-yl)me~hyl]-2-imidazolin-5-one 394 mg of sodium hydride as an 80% dispersion in oil are suspended in 100 ml of anhydrous DMF under nitrogen, 1.71 g of 2-n-butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one in 10 ml of anhydrous DMF, prepared in Example 1, step E), are added gradually, with stirring, and the mixture is stirred for 30 minutes.
4.86 g of the compound prepared in step C) are added and the mixture is stirred for 3 hours at RT. It is evaporated to dryness, the residue is then taken up in 60 ml of ethyl acetate and the medium is filtered and evaporated to dryness. The oil obtained is chromato-graphed on silica using an ethyl acetate/hexane mixture (1/3; v/v) as the eluent. ~fter evaporation of the solvents, 3.45 g of the expected product .~re obtained in the form of a solid foam.
- NMR (CDC13):
0.9 ppm m : 3 H : -CH2-CH2-CH2-cH3 1-1.8 ppm : m : 18 H : 4-methyl + 4-cyclohexyl 2.35 ppm : distorted t : 2 H : CH2-CH2-CH2-CH3 4.5 pprn : s : 2 H : N-CH2-C6H4-.
2~ 3'7 6.70-8 ppm : m : 23 H : aromatic protons E) (R,S)-2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 3.38 g of the compound prepared in step D) are S dissolved in a mixture of 40 ml of methanol and 20 ml of THF. 3.5 ml of 4 N hydrochloric acid are added and the mixture is stirred for 3 hours at RT. After evaporation ~o dryness, the residue is taken up in lO
ml of 2 N sodium hydroxide solution and 10 ml of ether and the mixture is then stirred until a solution is formed. The aqueous phase is extracted twice with ether. The a~ueous phase is acidified to pH 6 with dilute hydrochloric acid and then extracted 3 times with ethyl acetate and the extracts are dried over sodium sulfate and evaporated to dryness to give 1.72 g of the expected product in the form of a white solid ~oam.
- NMR (CDCl3):
0.9 ppm : t : 3 ~ : C~2-CH2-CH2-CH3 0.95-2.7 ppm : m o 18 H : 4-cyclohaxyl ~ 4-methyl +
-CH2-CH2-C~2-cH3 2.1 ppm : t : 2 H : -CH2-CH2-CH2-CH3 4.4-4.7 ppm : AB system : 2 H : N-CH2-C6H4-6.95-7.1 ppm : q : 4 H : aromatic protons
The medium is refluxed for 4 hours and then evaporated. The residue is taken up in ethyl acetate and washed with water, a 3% solution of potassium hydrogensulfate, 1 N sodium hydroxide solution, water and then a saturated solution of sodium chloride. It is dried over sodium sulfate, filtered and avaporated to give 11 g of the expected product.
M.p. = 161-164- C.
C) 4-Bromomethyl-2'-(triphenylmethyltetrazol-5-yl) biphenyl A mixture containing 11 g of the compound prepared in step B, 140 ml of carbon tetrachloride, 4.12 g of NBS and 0.4 g of benzoyl peroxide is refluxed for 3 hours. After it has returned to RT, it is filtered and the filtrate is then evaporated. The residue is taken up in 30 ml of isopropyl ether. The precipitate ormed is filtered off and then dried under vacuum, The product obtained is used as such in the next step.
D) ~R,S)-2-n-Butyl-4-cyclohexyl-4-msthyl-1-[(2'-~tri-phenyl-methyltetrazol-5-yl)biphenyl-4-yl)me~hyl]-2-imidazolin-5-one 394 mg of sodium hydride as an 80% dispersion in oil are suspended in 100 ml of anhydrous DMF under nitrogen, 1.71 g of 2-n-butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one in 10 ml of anhydrous DMF, prepared in Example 1, step E), are added gradually, with stirring, and the mixture is stirred for 30 minutes.
4.86 g of the compound prepared in step C) are added and the mixture is stirred for 3 hours at RT. It is evaporated to dryness, the residue is then taken up in 60 ml of ethyl acetate and the medium is filtered and evaporated to dryness. The oil obtained is chromato-graphed on silica using an ethyl acetate/hexane mixture (1/3; v/v) as the eluent. ~fter evaporation of the solvents, 3.45 g of the expected product .~re obtained in the form of a solid foam.
- NMR (CDC13):
0.9 ppm m : 3 H : -CH2-CH2-CH2-cH3 1-1.8 ppm : m : 18 H : 4-methyl + 4-cyclohexyl 2.35 ppm : distorted t : 2 H : CH2-CH2-CH2-CH3 4.5 pprn : s : 2 H : N-CH2-C6H4-.
2~ 3'7 6.70-8 ppm : m : 23 H : aromatic protons E) (R,S)-2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one 3.38 g of the compound prepared in step D) are S dissolved in a mixture of 40 ml of methanol and 20 ml of THF. 3.5 ml of 4 N hydrochloric acid are added and the mixture is stirred for 3 hours at RT. After evaporation ~o dryness, the residue is taken up in lO
ml of 2 N sodium hydroxide solution and 10 ml of ether and the mixture is then stirred until a solution is formed. The aqueous phase is extracted twice with ether. The a~ueous phase is acidified to pH 6 with dilute hydrochloric acid and then extracted 3 times with ethyl acetate and the extracts are dried over sodium sulfate and evaporated to dryness to give 1.72 g of the expected product in the form of a white solid ~oam.
- NMR (CDCl3):
0.9 ppm : t : 3 ~ : C~2-CH2-CH2-CH3 0.95-2.7 ppm : m o 18 H : 4-cyclohaxyl ~ 4-methyl +
-CH2-CH2-C~2-cH3 2.1 ppm : t : 2 H : -CH2-CH2-CH2-CH3 4.4-4.7 ppm : AB system : 2 H : N-CH2-C6H4-6.95-7.1 ppm : q : 4 H : aromatic protons
7.3-7.6 ppm : m : 3 H : aromatic protons 7.8 : d : 1 H : aromatic protons 2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one, levorotatory A) 5-Methyl-5-phenylhydantoin 2~ 3~
30 g of acetophenone diluted in 250 ml of 95-alcohol are added over 30 minutes to a mixture of 18.35 g of sodium cyanide and 125 g of ammonium bicarbonate in 250 ml of water and the reaction medium S is heated at 60-65- C for 22 hours, with stirring. It is concentrated to half its volume under vacuum and the solld which has precipitated is filtered off, washed with watsr and ether and then dried under vacuum to give 38 g of a white solid, which is identified by IR.
M.p. = 190-192- C.
B) ~R,S)-2-Amino-2 phenylpropionic acid 20 g of the compound prepared in the previous step are added to a mixture of 75 g of barium hydroxide octahydrate and S00 ml of water and the reaction madium is then heated at 160- C for S hours in a steel tube. It is saturated with dry ice and the precipitate is then filtered off. The filtrate is concentrated under vacuum and the white solid formed is taken up in acetone, filtered off, washed with acetone and ether and then dried to give 15.3 g of the expected acid.
M.p. = 260-265~ C (with decomposition).
C) EthyI ester of (R,S)-2-amino-2-phenylpropionic acid Using a spatula, 24 g of the acid prepared in the previous step are added to a solution of 80 g of gaseous hydrochloric acid in 210 ml of absoluta ethanol, with stirring, and the mixture is refluxed for 6 snd a half hours. It is concentrated under vacuum, the residue is taken up in 600 ml of ethyl acetate and 100 ml of water, and 2 N sodium hydroxide solution is added until the pH is 9. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 25.5 g of the expected product in the form of an oil.
Identification by IR.
D) Dextrorotatory ethyl ester of 2-amino-2-phenylpro-pionic acid The enantiomers of the ester prepared in the previous step are separated by the method described by Y. Sugi and S. Mitsui in Bull. Chem. Soc. Japan, 1969, 42, 2984-2988. 19.8 g of (L)(+)-tartaric acid are added to th~ 25.5 g of ester obtained in step C, diluted in 210 ml of absolute ethanol. The mi~ture is heated to 60- C to give a total solution, ~hich is then left to stand at RT for 4 hours. The precipitate formed is filtered off, then rinsed with twice 70 ml of absolute alcohol and then redissolved in ~00 m:L of alcohol at the boil and the solution is then left to stand at RT for 72 hours. The acicular crystals formed are filtered off, rinsed twice with 30 ml of alcohol and then dried under vacuum to give 11.9 g of the tartaric acid salt of the expected dextrorotatory ester.
M.p. = 172-173- C.
[~]D = ~44-5 (C = 1, water).
The remaining alcoholic solu~ion is enriched in the tartaric acid salt of the levorotatory ester.
6.1 g of the tartaric acid salt of the dextro-rotatory ester are taken up in 30 ml of water and then 200 ml of ethyl acetate, and 5 N sodium hydroxide solution is added until the pH is 9. The organic phase is decanted, washed with water and a saturated f solution of sodium chloride, dried over sodium sulfate and than concentrated under vacuum to give 3.33 g of the expected product in the form of an oil.
[~]D = +24- (C = 2, ethanol). Identification S by NMR.
E) Dextrorotatory ethyl ester of 2-amino-2-cyclohexyl-propionic acid 3.30 g of the dextrorotatory ester obtain~d in the previous step are diluted in 120 ml of acetic acid; 1.5 g of platinum oxide are added and the mixture is then hydrogenated at atmospheric pressure.
After hydrogenation for 40 hours, the reaction medium is filtered and then concentrated under vacuum. The residue is taken up in an ether/water mixture and 6 N
lS hydrochloric acid is added until the pH is 2. The organic phase is separated from the agueous phase.
Ethyl acetate is added, followed by 5 N sodium hydroxide solution until the pH is 9.5. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 3.10 g of the expected product.
[~]D = +18- (C = 2, ethanol). Literature :
W~A. Bonner et al., J. Amer. Chem. Soc., 1956, 7~, 3218-3221.
Identification by NMR.
F) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, levorotatory A mixture containing 3 g of the dextrorotatory ester obtained in the previous step, 4.7 g of ethyl valerimidate and 8 drops of acetic acid in 15 ml of xylene is brought to the reflux point, with stirring.
3~
After refluxing for 7 hours, the reaction medium is concentrated under vacuum. The residue is chromatographed on silica using a chloroform/methanol/
acetic acid mixture (95/9/3) as the eluen-t; the S fractions containing the product are combined and concentrated under vacuum. The residue is taken up in an ethyl acetate/water mixture and the pH is brought to 9 by the addition of 5 N sodium hydroxide solution.
The organic phase is decanted, washed wi-th water and a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum to give an oil, which changes to an amorphous solid.
m = 2.36 g.
~]D = -57-2- (G = 1, chloroform).
lS ~ IR (chloroform):
1720 cm~l : C=0 1640 cm~1 : C=N
The IR spectrum confirms the 5-one form of the imidazolinone in solution.
G~ 2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2l-(triphenyl-methyl-tetrazol-5-yl)biphenyl-4-yl) methyl]-2-imida-zoline-5-one, levorotatory This compound is prepared from the product prepared in step F by following the procedure 2S described in Example 4, step D.
Yield : 73%.
[~]D = -22.8- (C = 1, chloroform).
- NMR: superimposable on that of the compound of Example 4, step D.
H) 2-n-Butyl-4-cyclohexyl-4-methyl-l-[(2'-(tetrazol-5-yl) biphenyl-4-yl)methyl]-2-imidazolin-5-one, levo-rotatory This compound is prepared from the product prepared in step G by following the procedure described in Example 4, step E.
Yield : 85%.
S [~D = -25.9- (C - 1, methanol).
- NMR: superimposable on that of the compound of Example 4, step E.
2-n-Butyl-4-cyclohexyl-4-methyl-1~[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one, dextrorotatory A) Levorotatory ethyl ester of 2-amino-2-phenylpropio-nic acid The alcoholic solution obtained in Example 5, step D), i5 concentrated after separation of the crystals of the tartaric acid salt of the dextrorota-tory ethyl ester of 2.-amino-2-phenylpropionic aaid.
The solid residue is ~aken up in 150 ml of water and 600 ml of ethyl aceta~e and the pH is brought to g by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 20.6 g of the ester enriched in the levorotatory form.
15.9 g of (D)(-~-tartaric acid are added to 20.5 g of this ester diluted in 200 ml of absolute ethanol, and a solution is formed at the boiling point of the alcohol. After 5 hours at RT, the acicular crystals formed are filtered off, washed twice with 50 ml of absolute alcohol and then dried under vacuum to give 16.3 g or the tartaric acid salt of the expected product.
M.p. = 172-173- C.
[a]~ = -45.2- (C = 1, water).
S 6 g of- the salt obtained are taken up in 50 ml of water and 200 ml of ethyl acetate and the pH is brought to 9.5 by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride and then dried over sodium sulfate and concentrated under vacuum to give 3.31 g of the expected product in the form of an oil, which is identified by NMR.
[a]D = -25.5- (C = 2, ethanol).
B~ Levorotatory ethyl ester o~ 2-amino-2-cyclohexyl-propionic acid The procedure of Example 5, step E), is followed to give 3.20 g of the expected product from 3.30 g of the compound of step A.
[a]D = -19.2- (C = 1, ethanol).
20 C) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, dextrorotatory The procedure of Example 5, step F), is followed.
t~]D = +56.9- (C = 1, chloroform).
The NMR and IR spectra are superimposable on those of the levorotatory isomer prepared in Example 5, step F).
D) 2-n-Butyl-4-cyclohexyl-4-methyl-1-~(2'-(triphenyl-methyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imida-zolin-5-one, dextrorotatory The procedure described in Example 5, step G), is followed to give 2.3 g of the expected product in the form of a white solid from 1.1 g of the. compound prepared in step C.
[~]D = -23.8- (C = 1, methanol) and NMR
spectrum superimposable on that of the compound S prepared in Example 4, step D.
E) 2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-~tetrazol-5-yl~ biphenyl-4-yl)methyl]-2-imidazolin-5-one, dextro-rotatory The procedure described in Example 5, step H, is followed to give 1.1 g of the expected produc~ in the form of a white solid from 2.15 g of the compound prepared in step D.
t~]D = +27.1' (C = 1, methanol~.
The NMR spectrum is superimposable on that of lS the compound prepared in Example 4.
~ ikewise, the following compounds according to the invention were prepared according to the procedure described in Example 3:
(R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl~-methyll 4~cyclopropyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate M.p. = 149-150J C.
- NMR:
7.05-7.80 ppm : m : 8 H : aromatic proton.s 4.70 ppm : s : 2 H N-CH2-C6H4-2.45 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.05-1.45 ppm : m + s : 8 H : -CH2-CH2-CH2-CH3 + CH3 in the 4 position +
cyclopropane CH
0.70 ppm : t : 3 H : CH3-(C~2)3-~:?~3' 3 ~3 0.05-0.45 ppm : m : 4 H : 2 cyclopropane CH2 (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)-S methyl]-4,4-dicyclopropyl-2-imidazolin-5-one trifluorQ-acetate M.p. = 132-134- C.
- Mass spectrum:
MH+ : 431 - NMR:
7.15-7.80 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 ~ : N-CH2-C6H4-2.50 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.1-1.60 ppm : m : 6 H : CH2-CH2-CH2-CH3 ~ 2 cyc propane CH
0.80 ppm : t : 3 H : (CH2)~-CH3 0.10-0.80 ppm : m : 8 H : 4 cyclopropane CH2 EXAMPL~ 9 (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclopentyl-4-methyl-2-imidazolin-5-one trifluoroacetate M.p. = 104-107- C.
- NMR:
7.20-7.80 ppm : m : 8 H : aromatic protons 4.85 ppm : AB system : 2 H : N-CH2-C6H4-2.75 ppm : distorted t : 2 H : CH2-CH2-CH2-CH3 2.20-1.00 ppm : m + s : 16 H : cyclopentane + CH3 in the 4 position + -C~2-0.80 ppm : t : 3 H : CH3-(CH2)3-.
(R,S)-2-n-Butyl-4-cyclopentyl-4-methyl-1-[(2'-t~trazol-5-yl)-biphenyl-4-yl) methyl]-2-imidazolin-5-one.
S This compound is prepared by following the procedure described in Example 4.
M.p. = 78-80-C
- NMR : (CDC13) 7.05-7.8 ppm : m : 8H : aromatic protons 4.70 ppm : s : 2 H : -N-CH2-C6H4-2.40 ppm : t : 2 H : -CH2-CH2-CH2-CH3 2.15-1.20 ppm : m : 13 H : -CH2-CH2-CH2-CH3 +
4-cyclopentyl 1.20 ppm : s . 3 H : C~13-4 0.95 ppm : t : 3 H : -CH2-CH2-CH2-C~3
30 g of acetophenone diluted in 250 ml of 95-alcohol are added over 30 minutes to a mixture of 18.35 g of sodium cyanide and 125 g of ammonium bicarbonate in 250 ml of water and the reaction medium S is heated at 60-65- C for 22 hours, with stirring. It is concentrated to half its volume under vacuum and the solld which has precipitated is filtered off, washed with watsr and ether and then dried under vacuum to give 38 g of a white solid, which is identified by IR.
M.p. = 190-192- C.
B) ~R,S)-2-Amino-2 phenylpropionic acid 20 g of the compound prepared in the previous step are added to a mixture of 75 g of barium hydroxide octahydrate and S00 ml of water and the reaction madium is then heated at 160- C for S hours in a steel tube. It is saturated with dry ice and the precipitate is then filtered off. The filtrate is concentrated under vacuum and the white solid formed is taken up in acetone, filtered off, washed with acetone and ether and then dried to give 15.3 g of the expected acid.
M.p. = 260-265~ C (with decomposition).
C) EthyI ester of (R,S)-2-amino-2-phenylpropionic acid Using a spatula, 24 g of the acid prepared in the previous step are added to a solution of 80 g of gaseous hydrochloric acid in 210 ml of absoluta ethanol, with stirring, and the mixture is refluxed for 6 snd a half hours. It is concentrated under vacuum, the residue is taken up in 600 ml of ethyl acetate and 100 ml of water, and 2 N sodium hydroxide solution is added until the pH is 9. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 25.5 g of the expected product in the form of an oil.
Identification by IR.
D) Dextrorotatory ethyl ester of 2-amino-2-phenylpro-pionic acid The enantiomers of the ester prepared in the previous step are separated by the method described by Y. Sugi and S. Mitsui in Bull. Chem. Soc. Japan, 1969, 42, 2984-2988. 19.8 g of (L)(+)-tartaric acid are added to th~ 25.5 g of ester obtained in step C, diluted in 210 ml of absolute ethanol. The mi~ture is heated to 60- C to give a total solution, ~hich is then left to stand at RT for 4 hours. The precipitate formed is filtered off, then rinsed with twice 70 ml of absolute alcohol and then redissolved in ~00 m:L of alcohol at the boil and the solution is then left to stand at RT for 72 hours. The acicular crystals formed are filtered off, rinsed twice with 30 ml of alcohol and then dried under vacuum to give 11.9 g of the tartaric acid salt of the expected dextrorotatory ester.
M.p. = 172-173- C.
[~]D = ~44-5 (C = 1, water).
The remaining alcoholic solu~ion is enriched in the tartaric acid salt of the levorotatory ester.
6.1 g of the tartaric acid salt of the dextro-rotatory ester are taken up in 30 ml of water and then 200 ml of ethyl acetate, and 5 N sodium hydroxide solution is added until the pH is 9. The organic phase is decanted, washed with water and a saturated f solution of sodium chloride, dried over sodium sulfate and than concentrated under vacuum to give 3.33 g of the expected product in the form of an oil.
[~]D = +24- (C = 2, ethanol). Identification S by NMR.
E) Dextrorotatory ethyl ester of 2-amino-2-cyclohexyl-propionic acid 3.30 g of the dextrorotatory ester obtain~d in the previous step are diluted in 120 ml of acetic acid; 1.5 g of platinum oxide are added and the mixture is then hydrogenated at atmospheric pressure.
After hydrogenation for 40 hours, the reaction medium is filtered and then concentrated under vacuum. The residue is taken up in an ether/water mixture and 6 N
lS hydrochloric acid is added until the pH is 2. The organic phase is separated from the agueous phase.
Ethyl acetate is added, followed by 5 N sodium hydroxide solution until the pH is 9.5. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 3.10 g of the expected product.
[~]D = +18- (C = 2, ethanol). Literature :
W~A. Bonner et al., J. Amer. Chem. Soc., 1956, 7~, 3218-3221.
Identification by NMR.
F) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, levorotatory A mixture containing 3 g of the dextrorotatory ester obtained in the previous step, 4.7 g of ethyl valerimidate and 8 drops of acetic acid in 15 ml of xylene is brought to the reflux point, with stirring.
3~
After refluxing for 7 hours, the reaction medium is concentrated under vacuum. The residue is chromatographed on silica using a chloroform/methanol/
acetic acid mixture (95/9/3) as the eluen-t; the S fractions containing the product are combined and concentrated under vacuum. The residue is taken up in an ethyl acetate/water mixture and the pH is brought to 9 by the addition of 5 N sodium hydroxide solution.
The organic phase is decanted, washed wi-th water and a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum to give an oil, which changes to an amorphous solid.
m = 2.36 g.
~]D = -57-2- (G = 1, chloroform).
lS ~ IR (chloroform):
1720 cm~l : C=0 1640 cm~1 : C=N
The IR spectrum confirms the 5-one form of the imidazolinone in solution.
G~ 2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2l-(triphenyl-methyl-tetrazol-5-yl)biphenyl-4-yl) methyl]-2-imida-zoline-5-one, levorotatory This compound is prepared from the product prepared in step F by following the procedure 2S described in Example 4, step D.
Yield : 73%.
[~]D = -22.8- (C = 1, chloroform).
- NMR: superimposable on that of the compound of Example 4, step D.
H) 2-n-Butyl-4-cyclohexyl-4-methyl-l-[(2'-(tetrazol-5-yl) biphenyl-4-yl)methyl]-2-imidazolin-5-one, levo-rotatory This compound is prepared from the product prepared in step G by following the procedure described in Example 4, step E.
Yield : 85%.
S [~D = -25.9- (C - 1, methanol).
- NMR: superimposable on that of the compound of Example 4, step E.
2-n-Butyl-4-cyclohexyl-4-methyl-1~[(2'-(tetra-zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one, dextrorotatory A) Levorotatory ethyl ester of 2-amino-2-phenylpropio-nic acid The alcoholic solution obtained in Example 5, step D), i5 concentrated after separation of the crystals of the tartaric acid salt of the dextrorota-tory ethyl ester of 2.-amino-2-phenylpropionic aaid.
The solid residue is ~aken up in 150 ml of water and 600 ml of ethyl aceta~e and the pH is brought to g by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 20.6 g of the ester enriched in the levorotatory form.
15.9 g of (D)(-~-tartaric acid are added to 20.5 g of this ester diluted in 200 ml of absolute ethanol, and a solution is formed at the boiling point of the alcohol. After 5 hours at RT, the acicular crystals formed are filtered off, washed twice with 50 ml of absolute alcohol and then dried under vacuum to give 16.3 g or the tartaric acid salt of the expected product.
M.p. = 172-173- C.
[a]~ = -45.2- (C = 1, water).
S 6 g of- the salt obtained are taken up in 50 ml of water and 200 ml of ethyl acetate and the pH is brought to 9.5 by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride and then dried over sodium sulfate and concentrated under vacuum to give 3.31 g of the expected product in the form of an oil, which is identified by NMR.
[a]D = -25.5- (C = 2, ethanol).
B~ Levorotatory ethyl ester o~ 2-amino-2-cyclohexyl-propionic acid The procedure of Example 5, step E), is followed to give 3.20 g of the expected product from 3.30 g of the compound of step A.
[a]D = -19.2- (C = 1, ethanol).
20 C) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, dextrorotatory The procedure of Example 5, step F), is followed.
t~]D = +56.9- (C = 1, chloroform).
The NMR and IR spectra are superimposable on those of the levorotatory isomer prepared in Example 5, step F).
D) 2-n-Butyl-4-cyclohexyl-4-methyl-1-~(2'-(triphenyl-methyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imida-zolin-5-one, dextrorotatory The procedure described in Example 5, step G), is followed to give 2.3 g of the expected product in the form of a white solid from 1.1 g of the. compound prepared in step C.
[~]D = -23.8- (C = 1, methanol) and NMR
spectrum superimposable on that of the compound S prepared in Example 4, step D.
E) 2-n-Butyl-4-cyclohexyl-4-methyl-1-[(2'-~tetrazol-5-yl~ biphenyl-4-yl)methyl]-2-imidazolin-5-one, dextro-rotatory The procedure described in Example 5, step H, is followed to give 1.1 g of the expected produc~ in the form of a white solid from 2.15 g of the compound prepared in step D.
t~]D = +27.1' (C = 1, methanol~.
The NMR spectrum is superimposable on that of lS the compound prepared in Example 4.
~ ikewise, the following compounds according to the invention were prepared according to the procedure described in Example 3:
(R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl~-methyll 4~cyclopropyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate M.p. = 149-150J C.
- NMR:
7.05-7.80 ppm : m : 8 H : aromatic proton.s 4.70 ppm : s : 2 H N-CH2-C6H4-2.45 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.05-1.45 ppm : m + s : 8 H : -CH2-CH2-CH2-CH3 + CH3 in the 4 position +
cyclopropane CH
0.70 ppm : t : 3 H : CH3-(C~2)3-~:?~3' 3 ~3 0.05-0.45 ppm : m : 4 H : 2 cyclopropane CH2 (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)-S methyl]-4,4-dicyclopropyl-2-imidazolin-5-one trifluorQ-acetate M.p. = 132-134- C.
- Mass spectrum:
MH+ : 431 - NMR:
7.15-7.80 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 ~ : N-CH2-C6H4-2.50 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.1-1.60 ppm : m : 6 H : CH2-CH2-CH2-CH3 ~ 2 cyc propane CH
0.80 ppm : t : 3 H : (CH2)~-CH3 0.10-0.80 ppm : m : 8 H : 4 cyclopropane CH2 EXAMPL~ 9 (R,S)-2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclopentyl-4-methyl-2-imidazolin-5-one trifluoroacetate M.p. = 104-107- C.
- NMR:
7.20-7.80 ppm : m : 8 H : aromatic protons 4.85 ppm : AB system : 2 H : N-CH2-C6H4-2.75 ppm : distorted t : 2 H : CH2-CH2-CH2-CH3 2.20-1.00 ppm : m + s : 16 H : cyclopentane + CH3 in the 4 position + -C~2-0.80 ppm : t : 3 H : CH3-(CH2)3-.
(R,S)-2-n-Butyl-4-cyclopentyl-4-methyl-1-[(2'-t~trazol-5-yl)-biphenyl-4-yl) methyl]-2-imidazolin-5-one.
S This compound is prepared by following the procedure described in Example 4.
M.p. = 78-80-C
- NMR : (CDC13) 7.05-7.8 ppm : m : 8H : aromatic protons 4.70 ppm : s : 2 H : -N-CH2-C6H4-2.40 ppm : t : 2 H : -CH2-CH2-CH2-CH3 2.15-1.20 ppm : m : 13 H : -CH2-CH2-CH2-CH3 +
4-cyclopentyl 1.20 ppm : s . 3 H : C~13-4 0.95 ppm : t : 3 H : -CH2-CH2-CH2-C~3
Claims (21)
1. A compound of the formula (I) in which:
- R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C6 alkyl, a C1-C4 alkoxy, an amino, an amino-methyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a tri-fluoromethylsulfonylamino, a trifluoromethyl-sulfonylaminomethyl, an N cyanoacatamide, an N-hydroxyacetamide, an N-(4-carboxy- 1j3-thiazol-2-yl) acetamide, a ureido, a 2-cyano-guanidino-carbonyl, a 2-cyano-guanidino-methyl, an imida-zol-l-ylcarbonyl and a 3-cyano-2-methylisothiou-reido-methyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen;
- R3 is a hydrogen ; a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C6 alkenyl, a C3-C7 cycloaikyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti-tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy; and - R4 is a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and - R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms;
- or R4 and R5 are each a cyclopropyl;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
and its salts.
- R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C6 alkyl, a C1-C4 alkoxy, an amino, an amino-methyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a tri-fluoromethylsulfonylamino, a trifluoromethyl-sulfonylaminomethyl, an N cyanoacatamide, an N-hydroxyacetamide, an N-(4-carboxy- 1j3-thiazol-2-yl) acetamide, a ureido, a 2-cyano-guanidino-carbonyl, a 2-cyano-guanidino-methyl, an imida-zol-l-ylcarbonyl and a 3-cyano-2-methylisothiou-reido-methyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen;
- R3 is a hydrogen ; a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C6 alkenyl, a C3-C7 cycloaikyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti-tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy; and - R4 is a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and - R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms;
- or R4 and R5 are each a cyclopropyl;
- X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one;
and its salts.
2. A compound according to claim 1 wherein R1 is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen.
3. A compound according to claim 1 or claim 2 wherein R4 is methyl and R5 is cyclohexyl.
4. A compound according to any one of claims 1 to 3 wherein R3 is a linear C1-C6 alkyl group.
5. A compound according to any one of claims 1 to 4 wherein X is oxygen.
6. A compound according to any one of claims 1 to 5 wherein z = t = 0.
7. A compound according to claim 1 which is 2-n-butyl-4 -methyl-4-cyclohexyl-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one or one of its salts with acids or bases.
8. A method of preparing a compound (I) according to any one of claims 1 to 7, wherein:
a1) a heterocyclic derivative of the formula 2 in which X, z, t, R3, R4 and R5 are as defined for (I) in claim 1, is reacted with a (biphenyl-4-yl) methyl derivative of the formula 3 in which Hal is a halogen atom and R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2;
b1) if appropriate, the resulting compound of the formula 4 is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide] ;
and cl) the compound obtained in a1) or b1), of the formula 5 in which X is an oxygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the groups R'l and/or R'2 to the groups R1 and/or R2 respectively d1) the compounds so obtained is converted, if appropriate, into one of its salts.
a1) a heterocyclic derivative of the formula 2 in which X, z, t, R3, R4 and R5 are as defined for (I) in claim 1, is reacted with a (biphenyl-4-yl) methyl derivative of the formula 3 in which Hal is a halogen atom and R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2;
b1) if appropriate, the resulting compound of the formula 4 is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide] ;
and cl) the compound obtained in a1) or b1), of the formula 5 in which X is an oxygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the groups R'l and/or R'2 to the groups R1 and/or R2 respectively d1) the compounds so obtained is converted, if appropriate, into one of its salts.
A method of preparing a compound (I) according to any one of claims 1 to 7, wherein:
a2) an amino acid of the formula 7 in which z, t, R4 and R5 are as defined for (I) in claim 1, and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4 yl) methylamine derivative of the formula 8 in which R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2;
b2) after deprotection of the amine, the resulting compound of the formula 9 is then treated with an alkyl ortho-ester of the formula R3C(OR)3 (10), in which R3 is as defined for (I) in claim 1 and R is a C1-C4 alkyl;
c2) if appropriate, the resulting compound of the formula 4 is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide];
and d2) the compound thus obtained in b2 or c2, of the formula 5 is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'1 to the groups R2 and/or R1 respectively e2) the compounds so obtained is converted, if appropriate, into one of its salts.
a2) an amino acid of the formula 7 in which z, t, R4 and R5 are as defined for (I) in claim 1, and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4 yl) methylamine derivative of the formula 8 in which R'1 and R'2 are respectively either R1 and R2 or a precursor group of R1 and R2;
b2) after deprotection of the amine, the resulting compound of the formula 9 is then treated with an alkyl ortho-ester of the formula R3C(OR)3 (10), in which R3 is as defined for (I) in claim 1 and R is a C1-C4 alkyl;
c2) if appropriate, the resulting compound of the formula 4 is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide];
and d2) the compound thus obtained in b2 or c2, of the formula 5 is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'1 to the groups R2 and/or R1 respectively e2) the compounds so obtained is converted, if appropriate, into one of its salts.
10. A compound of the formula II
in which:
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenyl alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti-tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;
either - R4 is a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, and R5 is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms;
- or R4 and R5 are each a cyclopropyl;
z and t are zero or one is zero and the other is one, - X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z = t = 0, R5 represents a cycloalkyl.
in which:
- R3 is a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenyl alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti-tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy;
either - R4 is a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, and R5 is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms;
- or R4 and R5 are each a cyclopropyl;
z and t are zero or one is zero and the other is one, - X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z = t = 0, R5 represents a cycloalkyl.
11. A compound according to claim 10 of the formula (II') in which R3, R4, R5 and X ara as defined for II in claim 10 and R3 is a C1-C6 alkyl.
12. A compound according to claim 11 of the formula in which X is an oxygen atom and R3 is a C1-C6 alkyl.
13. A compound according to claim 10 of the formula (11") in which R3, R4, R5 and X are as defined above for (II) in claim 10.
14. A compound according to claim 10 of the formula (II"') in which X, R3, R4 and R5 are as defined for (II) in claim 10.
15. A method of preparing a compound according to any one of claims 10 to 14, which comprises reacting a compound of the formula in which R3 is as defined above for (II) in claim 10 and B is - a group C(OR)3 - a group or - a group COHal R being a C1-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula 13 in which R4 and R5 are as defined above for (II) in claim 10 and A is an OH group, an NH2 group or a group OR', R' being hydrogen or a C1-C4 alkyl.
16. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present as the active principle.
17. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present ln association with a beta-blocking compound.
18. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a diuretic.
19. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a non-steroidal antiinflammatory.
20. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a calcium antagonist.
21. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a tranquilizer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9111161A FR2681067B1 (en) | 1991-09-10 | 1991-09-10 | N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| FR9111161 | 1991-09-10 |
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| Publication Number | Publication Date |
|---|---|
| CA2077967A1 true CA2077967A1 (en) | 1993-03-11 |
Family
ID=9416798
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002077967A Abandoned CA2077967A1 (en) | 1991-09-10 | 1992-09-10 | N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0532410A1 (en) |
| JP (1) | JPH05213894A (en) |
| KR (1) | KR930006008A (en) |
| AU (1) | AU661017B2 (en) |
| CA (1) | CA2077967A1 (en) |
| CZ (1) | CZ275992A3 (en) |
| FR (1) | FR2681067B1 (en) |
| HU (1) | HUT63616A (en) |
| IL (1) | IL103116A (en) |
| LT (1) | LT3148B (en) |
| LV (1) | LV10255B (en) |
| MX (1) | MX9205155A (en) |
| MY (1) | MY108089A (en) |
| NO (1) | NO180678C (en) |
| NZ (1) | NZ244258A (en) |
| PL (1) | PL171524B1 (en) |
| RU (1) | RU2107062C1 (en) |
| TW (1) | TW218871B (en) |
| ZA (1) | ZA926899B (en) |
Families Citing this family (21)
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| KR100222252B1 (en) * | 1990-12-14 | 1999-10-01 | 스튜어트 알. 수터 | Angiotensin II Receptor Blocking Composition |
| US5484939A (en) * | 1993-03-12 | 1996-01-16 | Lonza Ltd. | 2-substituted 5-chlorimidazoles |
| US5721263A (en) * | 1993-06-07 | 1998-02-24 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition for angiotensin II-mediated diseases |
| HU218681B (en) * | 1997-07-25 | 2000-10-30 | Sanofi-Synthelabo | Process for the preparation of 1,3-diaza-spiro(4,4)non-1-en-4-one derivatives and 1-cyano-1-acylamino-cyclopentane intermediates |
| HU218680B (en) | 1997-07-25 | 2000-10-30 | Sanofi-Synthelabo | Process for the preparation of 1,3-diaza-spiro(4,4)non-1-en-4-one derivatives and 1-cyano-1-acylamino-cyclopentane intermediates |
| NZ508118A (en) | 1998-07-06 | 2003-07-25 | Bristol Myers Squibb Co | Heteroaryl substituted biphenyl sulfonamides useful as dual angiotensin endothelin receptor antogonists |
| US6638937B2 (en) | 1998-07-06 | 2003-10-28 | Bristol-Myers Squibb Co. | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
| DE19832429A1 (en) * | 1998-07-18 | 2000-01-20 | Hoechst Marion Roussel De Gmbh | New imidazolylmethyl-biphenyl-sulfonylcyanamides, are sodium-dependent bicarbonate/chloride exchanger inhibitors used e.g. for treating cardiovascular disorders such as cardiac infarction |
| DE19832428A1 (en) * | 1998-07-18 | 2000-01-20 | Hoechst Marion Roussel De Gmbh | New imidazolylmethyl-biphenyl-sulfonylcyanamides, are sodium-dependent bicarbonate/chloride exchanger inhibitors used e.g. for treating cardiovascular disorders such as cardiac infarction |
| US7091232B2 (en) * | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
| BRPI0406987A (en) | 2003-01-31 | 2006-01-10 | Sankyo Co | Medicament for the prevention and / or treatment of atherosclerosis, medicaments for inhibiting vascular smooth muscle cell proliferation, neointimal formation of blood vessels and vascular remodeling, medicament for the prevention of restenosis following percutaneous coronary intervention, and, medicines for the prophylaxis and / or treatment of hypertension or diseases caused by hypertension or diseases caused by hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney diseases, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular diseases, cerebral infarction, and cerebral hemorrhage |
| AU2005249794A1 (en) | 2004-06-04 | 2005-12-15 | Teva Pharmaceutical Industries, Ltd. | Pharmaceutical composition containing irbesartan |
| AP2007004161A0 (en) * | 2005-04-28 | 2007-10-31 | Pfizer Ltd | Amino acid derivatives |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| CN103601792B (en) | 2007-06-04 | 2016-06-29 | 协同医药品公司 | It is effective to the guanylate cyclase agonist of gastrointestinal dysfunction, inflammation, cancer and other diseases treatment |
| CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| SI3004138T1 (en) | 2013-06-05 | 2024-07-31 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
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|---|---|---|---|---|
| CH540271A (en) | 1970-05-29 | 1973-08-15 | Agripat Sa | Herbicidal triazines-2-substd-4-amino-6-(1'-cyclopropyl-1'-cyano - -alkyl-amino)-s-triazines |
| US4017510A (en) | 1975-11-12 | 1977-04-12 | American Cyanamid Company | Imidazoisoindolediones and the use thereof as herbicidal agents |
| DE3545597A1 (en) * | 1985-12-21 | 1987-07-02 | Celamerck Gmbh & Co Kg | NEW HERBICIDE EFFECTIVE IMIDAZOLINONES |
| EP0303863A3 (en) * | 1987-08-17 | 1991-10-23 | American Cyanamid Company | Benzenesulfonyl carboxamide compounds, intermediate compounds and methods of preparation thereof and use of said compounds and intermediate compounds as herbicidal agents |
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| CA2020073A1 (en) * | 1989-07-03 | 1991-01-04 | Eric E. Allen | Substituted quinazolinones as angiotensin ii antagonists |
| EP0412594B1 (en) * | 1989-07-28 | 1996-01-03 | Merck & Co. Inc. | Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists |
| IL99372A0 (en) * | 1990-09-10 | 1992-08-18 | Ciba Geigy Ag | Azacyclic compounds |
| JP2004247578A (en) | 2003-02-14 | 2004-09-02 | Kawasaki Microelectronics Kk | Semiconductor device and method of manufacturing semiconductor device |
-
1991
- 1991-09-10 FR FR9111161A patent/FR2681067B1/en not_active Expired - Fee Related
-
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- 1992-08-26 TW TW081106738A patent/TW218871B/zh active
- 1992-09-04 MY MYPI92001566A patent/MY108089A/en unknown
- 1992-09-04 CZ CS922759A patent/CZ275992A3/en unknown
- 1992-09-04 LV LVP-92-109A patent/LV10255B/en unknown
- 1992-09-08 NZ NZ244258A patent/NZ244258A/en unknown
- 1992-09-08 LT LTIP119A patent/LT3148B/en not_active IP Right Cessation
- 1992-09-09 HU HU9202889A patent/HUT63616A/en unknown
- 1992-09-09 RU SU5052773A patent/RU2107062C1/en active
- 1992-09-09 EP EP92402459A patent/EP0532410A1/en not_active Withdrawn
- 1992-09-09 IL IL103116A patent/IL103116A/en not_active IP Right Cessation
- 1992-09-09 PL PL92295874A patent/PL171524B1/en unknown
- 1992-09-09 NO NO923509A patent/NO180678C/en unknown
- 1992-09-09 KR KR1019920016618A patent/KR930006008A/en not_active Ceased
- 1992-09-09 MX MX9205155A patent/MX9205155A/en unknown
- 1992-09-10 JP JP4242126A patent/JPH05213894A/en not_active Withdrawn
- 1992-09-10 AU AU22868/92A patent/AU661017B2/en not_active Ceased
- 1992-09-10 ZA ZA926899A patent/ZA926899B/en unknown
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Also Published As
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|---|---|
| LV10255A (en) | 1994-10-20 |
| AU661017B2 (en) | 1995-07-13 |
| JPH05213894A (en) | 1993-08-24 |
| MX9205155A (en) | 1993-03-01 |
| KR930006008A (en) | 1993-04-20 |
| NZ244258A (en) | 1996-10-28 |
| LTIP119A (en) | 1994-07-15 |
| IL103116A0 (en) | 1993-02-21 |
| NO180678B (en) | 1997-02-17 |
| LT3148B (en) | 1995-01-31 |
| NO923509L (en) | 1993-03-11 |
| RU2107062C1 (en) | 1998-03-20 |
| FR2681067A1 (en) | 1993-03-12 |
| FR2681067B1 (en) | 1993-12-17 |
| TW218871B (en) | 1994-01-11 |
| HUT63616A (en) | 1993-09-28 |
| PL171524B1 (en) | 1997-05-30 |
| AU2286892A (en) | 1993-03-11 |
| NO923509D0 (en) | 1992-09-09 |
| EP0532410A1 (en) | 1993-03-17 |
| MY108089A (en) | 1996-08-15 |
| HU9202889D0 (en) | 1992-11-30 |
| LV10255B (en) | 1995-04-20 |
| PL295874A1 (en) | 1993-04-19 |
| IL103116A (en) | 1998-04-05 |
| CZ275992A3 (en) | 1993-03-17 |
| ZA926899B (en) | 1993-03-16 |
| NO180678C (en) | 1997-05-28 |
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