CA2098158A1 - Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents
Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing themInfo
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- CA2098158A1 CA2098158A1 CA002098158A CA2098158A CA2098158A1 CA 2098158 A1 CA2098158 A1 CA 2098158A1 CA 002098158 A CA002098158 A CA 002098158A CA 2098158 A CA2098158 A CA 2098158A CA 2098158 A1 CA2098158 A1 CA 2098158A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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Abstract
Abstract Biphenyl Derivatives The invention relates to biphenyl derivatives of formula I
Description
" 2098158 59730~000.562 Biphenyl Derivatives The present invention relates to biphenyl derivatives, processes for their preparation and pharmaceutical composi~tions containing them.
We have found that certain novel biphenyl derivatives have valuable pharmacological properties, in particular aggregation-inhibiting effects.
Thus, viewed from one aspect, the present invention provides compounds of formula I:
Rb Ra~A--B--E
(I) (wherein with the proviso that where E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra does not denote an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C16-alkoxy)carbonyl, phenyl(C1-6- ~
alkoxy)carbonyl, (C3s-alkenyl)oxycarbonyl or phenyl(C3s-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1s-alkyl or C1s-alkoxy group, or a Cs7-cycloalkyl, Cs 7-cycloalkyloxy, phenylalkyl, phenylalkoxy, phenyl or phenoxy group, : ~ ..
R2 denotes a hydrogen atom or a C16-alkyl, C3 7-cycloalkyl, or phenyl group and R3 denotes a hydrogen atom or a C16-alkyl group;
Rb denotes a hydrogen atom or an alkyl, hydroxy or alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, wherein the -CH2CO- and -O-CH2CO- groups are each connected to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2) n~ group (wherein X
denotes a bond or an -HCRs- or -NR5- group), or an NR4 CH2CH2 R6C CH , NR4 CO (CH2)m- or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, the above-mentioned Y
or -NR4- groups each being linked to the group A, and wherein n denotes the number O or l, m denotes the number 2, 3, 4 or 5, R4 denotes a hydrogen atom or an alkyl or - phenylalkyl group and R5 denotes a hydrogen atom, or R4 and Rs together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C25-alkylene group, in which the ethylene group may be substituted by a phenylalkylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and 2098~8 E denotes a (C26-alkoxy)carbonyl or phenylalkoxycarbonyl group, a (C4l0cycloalkyloxycarbonyl) group in which a C58-cycloalkyl moiety may additionally be substituted by l or 2 alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxy-carbonyl, or C26-alkanoyl group, and wherein the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (C58-cycloalkenyl)oxycarbonyl, (C35-alkenyl)-oxycarbonyl, phenyl(C35-alkenyl)oxycarbonyl, (C35-alkynyl)oxycarbonyl or phenyl(C35-alkynyl)oxycarbonyl group wherein the carbon attached to the oxycarbonyl moiety does not itself carry a double or triple bond, a (C38-cycloalkyl)alkoxy-carbonyl group, a (C810-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two alkyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C16-alkyl groups or by a C38-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkyl-piperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy-carbonyl group;
whilst unless otherwise specified any alkyl or alkoxy moiety contains 1 to 3 carbon atoms, and any phenyl nuclei mentioned above in the definitions of groups Ra~ B and E may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl, ethyl, , - :- ; , ' ~ -n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identicà~l or different);
and the stereoisomers thereof, including the mixtures and the salts thereof.
Preferred compounds according to the invention include those of formula I wherein, with the proviso that Ra does not represent an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group if E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C13-alkoxy)carbonyl, phenyl (C~ 3-alkoxy)carbonyl or (C34-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1s-alkyl -- group or a phenyl(C13-alkyl), C13-alkoxy, Cs 7-cycloalkyl, Cs7-cycloalkoxy, or phenyl group, R2 denotes a hydrogen atom or a C13-alkyl, Cs 7-cycloalkyl or phenyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a hydroxy or C13-alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the -CH2CO- and -O-CH2CO- groups are each - . ~
- -.. .
~.
20981~8 linked to the group B via the carbonyl group;
B denotes an -NR4-cH2cHz-x-(cH2) n~ group (wherein X
denotes a bond or an -HCR5- or -NR5- group), an -NR4-cH2cH2-R6c=cH-~ -NR4-CO-(CHz)m- or -Y-W- group~
wherein Y denotes an -NR4- group or, if A denotes a bond, Y may aiso denote an oxygen atom, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3, 4 or 5, , ~ n denotes the number O or 1, R4 denotes a hydrogen atom or a C13-alkyl or benzyl group and R5 denotes a hydrogen atom, or R4 and Rs together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2s-alkylene group, in which the ethylene group may be substituted in the - ~-position by a phenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C26-alkoxy)carbonyl group, a benzyloxycarbonyl group, a (C410cycloalkyloxycarbonyl) group wherein a Cs8-cycloalkyl moiety may additionally be substituted by 1 or 2 C13-alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or Cz4-alkanoyl group, .
' ~ ' ' ':
. ' ~
20981~8 a (Cs7-cycloalkyl)(C1.2alkoxy)carbonyl group, a (C89-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two methyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by l or 2 C13-alkyl groups or by a C57-cycloalkyl group, or E represents a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-methyl-piperazinyl group, or a l,3-dihydro-3-oxo-l-isobenzofuranyloxycarbonyl group;
whilst any phenyl nuclei mentioned above in the definitions of groups Ra~ B and E may each be mono- or disubstituted by fluorine, chlorine or bromine atoms or methyl, hydroxy, methoxy, trifluoromethyl, nitro, amino, methylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identical or different;
and the stereoisomers thereof, including the mixtures and the salts thereof.
More particularly preferred compounds according to the invention include those of formula I above wherein, with the proviso that Ra does not represent an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group if E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R~CR3)-O-CO-, (C13-alkoxy)carbonyl, benzyloxycarbonyl or allyloxycarbonyl group, wherein - ` ,, ~
2Q9~1~8 R1 denotes a straight-chained or branched C14-alkyl group, a C13-alkoxy group or a cyclohexyloxy group, R2 denotes a hydrogen atom or a methyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a methoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the ~CH2CO- and -O-CH2CO- groups are each linked to the group B via the carbonyl group; and B denotes an -NR4-CH2CH2-X-(CH2) n~ group (wherein X
denotes a bond or an -HCRs- or -NRs- group~, an -NR4-CH2CH2-R6C=CH-~ -NR4-CO-(CH2)m~ or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, whilst the above mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3 or 4, n denotes the number O or 1, R4 denotes a hydrogen atom, a C13-alkyl group or a benzyl group and R5 denotes a hydrogen atom, or R4 and Rs together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C25-alkylene group, in which the ethylene group may be substituted in the ~-position by a methoxyphenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and :
~ ' ~0~81~8 E denotes a (C26-alkoxy)carbonyl group, a (C610-cycloalkyloxycarbonyl) group in which the cyclohexyl moiety may additionally be substituted by l or 2 C13-alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which a methylene group in the 3- or 4-position in the cycloalkyloxy moiety is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or acetyl group, a (C56-cycloalkyl)(C12-alkoxy)carbonyl group, a (C8 bicycloalkyloxycarbonyl) group, an R1-CO-O-(RzCR3)-O-CO-group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by l or 2 methyl groups or by a cyclohexyl group, or E denotes a piperidinyl or morpholinyl group, or a l,3-dihydro-3-oxo-l-isobenzo~uranyloxycarbonyl group;
and the stereoisomers thereof, including the mixtures and the salts thereof.
Particularly preferred compounds according to the invention include those of formula I above wherein, with the proviso that Ra does not denote an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group, if E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, methoxycarbonyl or allyloxycarbonyl group, wherein R1 denotes a straight-chained or branched C14-alkyl , ~ .-2 ~
group, a C13-alkoxy group or a cyclohexyloxy group, R2 denotes a hydrogen atom or a methyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a methoxy group;
A denotes a -CH2- or -CO- group;
B denotes an -NR4-CH2CH2-X-CH2- group wherein X denotes an -NR5- group, or B denotes an -NR4-CH2CH2-R6C=CH- or -Y-W-group wherein Y denotes an -NR4- group, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein R4 denotes a hydrogen atom or a methyl group or R4 and R5 together or R4 and R6 together represent an ethylene group and W denotes a 1,4-cyclohexylene group;
E denotes an isopropyloxycarbonyl, isobutyloxycarbonyl, 2-butyloxycarbonyl, 2-amyloxycarbonyl, 3-amyloxycarbonyl or neopentyloxycarbonyl group, a (C69-cycloalkoxy-carbonyl) group wherein the cyclohexyl moiety may additionally be substituted by 1 or 2 C13-alkyl groups, a (C56-cycloalkyl)(C12alkoxy)carbonyl group, a (C8 bicycloalkyloxycarbonyl) group, or an R1-CO-O-(R2CR3)-O-CO- group in which R1, R2 and R3 are as hereinbefore defined;
and the stereoisomers thereof, including the mixtures and salts thereof.
The present invention particularly relates to the 20~o81~8 following compounds of formula I:
4-amidino-4'-t4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-3'-[4-trans-(cyclohexyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-3'-[4-trans-(cyclohexylmethoxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-4'-t4-(cycloheptyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-t4-((exo)-norbornyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-((-)-menthyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-amidino-biphenyl;
4-[N-allyloxycarbonyl-amidino]-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-tN-allyloxycarbonyl-amidino]-4'-t4-(carboxymethyl)-piperidinocarbonyl]-biphenyl; and 4-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl;
, . . ~ , - :.
: ~. .. .
-:
20~181~8 and the stereoisomers thereof, including the mixtures and the salts thereof.
Viewed from a further aspect, the invention provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps:
a) (to prepare compounds of formula I wherein E denotes a (C37-alkoxycarbonyl) group, a phenylalkoxycarbonyl group, a (C410-cycloalkyloxycarbonyl) group wherein a -^-Cs8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which in the cycloalkyloxy moiety a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl or C26-alkanoyl group, and the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (Cs8-cycloalkenyl)oxycarbonyl, a (C35-alkenyl)oxycarbonyl, phenyl(C35-alkenyl)oxycarbonyl, (C3s-alkynyl)oxycarbonyl or phenyl(C35-alkynyl)oxycarbonyl group in which he carbon attached to the oxycarbonyl moiety carries no double or triple bond, a (C38-cycloalkyl)alkoxycarbonyl group, or a (C810-bicycloalkyloxycarbonyl) group, which may additionally be substituted in the bicycloalkyl moiety by one or two alkyl groups) esterifying a carboxylic acid of formula II
Rb Ra ~ A-B-COOH
(II) (wherein Ra~ Rb, A and B are as hereinbefore defined) or a , . , t . ~ `
, :
209~1.58 reactive derivative thereof optionally formed in the reaction mixture, with an alcohol of formula III
HO - R8 (III) (wherein R8 denotes a C26-alkyl group, a phenylalkyl group, a C3 9-cycloalkyl group in which a Cs8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a Cs7-cycloalkyl group in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl, or C26-alkanoyl group, and the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a Cs8-cycloalkenyl, C35-alkenyl, phenyl(C35-alkenyl), C35-alkynyl or phenyl(C3s-alkynyl) group in which the carbon attached to the hydroxyl carries no double or triple bond, a (C38-cycloalkyl)alkyl group, or a C7~-bicycloalkyl group optionally substituted by one or two alkyl groups;
b) reacting a carboxylic acid of formula IV
Rb Ra~) ~A--B--COOH
(IV) (wherein Rb, A and B are as hereinbefore defined and Ral denotes an amidino group substituted by an R1-CO-O-(R2CR3)-O-CO-, (C16-alkoxy)carbonyl, phenyl(C16-alkoxyjcarbonyl, ( C3 5-alkenyl)oxycarbonyl or phenyl( C3 s-alkenyl)oxycarbonyl group, or Ral denotes an amidino group protected by a protecting group) or a carbanion thereof, with a compound of formula V
, .' ~ '' ;
2lQ98l~8 Z~ - R9 (V) (wherein R9 denotes a C26-alkyl group, a phenylalkyl group, a C39-cycloalkyl group wherein a C5 8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C57-cycloalkyl group in which a methylene group in the 3- or 4 position is replaced by an oxygen atom or by an ~;
imino group itself optionally substituted by an alkyl, phenylalkyl, phenyloxycarbonyl or C26-alkanoyl group and in which the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C58-cycloalkenyl group, a C3s-alkenyl, phenyl(C35-alkenyl), C35-alkynyl or phenyl(C35-alkynyl) group wherein the Zl attached carbon carries no double or triple bond, a (C38-cycloalkyl)alkyl group, or a C79-bicycloalkyl group optionally substituted by one or two alkyl groups, an Rl-CO-O-(R2CR3)- group wherein Rl, R2 and R3 are as hereinbefore defined, an R7-CO-CH2- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C16-alkyl groups or by a C38-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkylpiperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyl group and Z1 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom) and if necessary subsequently cleaving any protecting group used;
c) (to prepare compounds of formula I wherein Ra denotes an amidino group substituted by an Rl-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group) acylating a compound of formula VI
.:
, ~49~1~8 I b HN\C~A--B--E
(VI) (wherein Rb, A, B and E are as hereinbefore defined) with a compound of formula VII
:"~
.. Z2 ~ R10 (VII) (wherein R~o denotes an R1-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group and Z2 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom or a p-nitrophenyl group) d) resolving a compound of formula I thus obtained into the enantiomers and/or diastereomers thereof;
e) converting a compound of formula I obtained into 2 i salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid, or converting a salt of a compound of formula I into the free compound; and f) performing a process as defined in any one of steps (a) to (e) above on a corresponding protected compound and subsequently removing the protecting group used.
The esterification of step (a) is conveniently carried out in a solvent or mixture of solvents such as .. , . ~ . ~ .
,., . . , . , ,. :: . .
, ;: , ~: ~ , . : , - :
:. . . - . : -- - . : ~ ~ ~ --,: ,; ~ . . .. : .
methylene chloride, dimethylformamide, dimethylsulphoxide, toluene, chlorobenzene, tetrahydrofuran, toluene/tetrahydrofuran or dioxane, ~-optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of a chloroformate such as isobutylchloroformate, thionylchloride, trimethylchlorosilane, titanium tetrachloride, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide or l-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, optionally in the presence of a base such as a pyridine substituted in the 4-position by a secondary amino group such as 4-dimethylamino-pyridine or triphenylphosphine/carbon tetrachloride, at temperatures between -30 and 100C, preferably at temperatures between -10 and 60C.
In step (b), examples of protecting groups for the amidino groups include the tert.butyloxycarbonyl, allyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group and examples of protecting groups for the hydroxy group include the trimethylsilyl, tetrahydropyran-2-yl, benzyl, benzhydryl or triphenylmethyl group.
The reaction of step (b) is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide or dimethylformamide, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl-. ' - : :
`:' :
20~15~
diisopropylamine, N-methyl-morpholine, pyridine or 4-dimethylamino-pyridine, which may simultaneously be used as solvent, or possibly in the presence of silver carbonate or silver oxide, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 80C.
A protecting group used for the amino, amidino or hydroxy group is preferably cleaved hydrogenolytically, depending on the protecting group used and the particular group to be protected, e.g. using hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 50C, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably of 3 to S bar, using an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or sulphuric acid, with the aid of an organic acid such as formic acid or trifluoroacetic acid in a solvent such as methanol, ethanol, ethyl acetate, methylene chloride or glacial acetic acid, with the aid of a secondary amine such as piperidine or morpholine in a solvent such as dimethylformamide or methylene chloride or with the aid of a catalyst such as tetrakis-(triphenylphosphine)-palladium(0) and morpholine in a solvent such as tetrahydrofuran or dioxane, at temperatures between 0 and 50C, but preferably at ambient temperature.
The reaction of step (c) is conveniently carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform or dimethylformamide, appropriately in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-: , - : . ~
20~8158 morpholine or pyridine, which may simultaneously be used as solvent, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 80C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino, imino or amidino groups may be protected during the reaction by means of conventional protecting groups which may be cleaved again after the reaction.
For example, suitable protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl and tetrahydropyranyl groups, suitable protecting groups for a carboxyl group include trimethylsilyl, methyl, ethyl, tert.butyl and benzyl groups, and suitable protecting groups for an amino, alkylamino or imino group include acetyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, benzhydryl, trityl, methoxybenzyl, 2,4-dimethoxybenzyl, 9-fluorenylmethyloxycarbonyl and allyloxycarbonyl groups.
The optional subsequent cleaving of a protecting group used may, for example, be carried out hydrolytically in an aqueous sol~ent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between -10 and lOCC, preferably at temperatures between 0 and 60~C.
However, a benzyl, methoxybenzyl, benzyloxycarbonyl, benzhydryl or trityl group may for example be cleaved hydrogenolytically, eg. using hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial - . ~ ., . .. , ~: . -20981~8 acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 50C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presencè of an oxidising agent such as cerium(IV)-ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50C, but preferably at ambient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, or ether.
A 9-fluorenylmethyloxycarbonyl group is preferably cleaved using a secondary amine such as piperidine or morpholine in a solvent such as dimethylformamide or methylene chloride at temperatures between 0 and 50C, but preferably at ambient temperature, and an allyloxycarbonyl group is preferably cleaved in the presence of a catalyst such as tetrakis-(triphenylphosphine)-palladium(0) and morpholine in a solvent such as tetrahydrofuran or dioxane at temperatures between 0 and 50C, but preferably at ambient temperature.
Furthermore, the compounds of formula I obtained may be resolved into their enantiomers and/or diastereomers as mentioned hereinbefore. Thus, for example, cis/trans - : ~
- ~
20981~
mixtures may be resolved into their cis and trans isomers, and compounds having at least one optically active carbon atom may be resolved into their enantiomers. Thus, for example, the compounds of formula I which occur in racemate form may be separated by methods known er se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of formula I having at least 2 asymmetric carbon atoms may be separated on the basis of their physical-chemical differences using known methods, e.g.
by chromatography and/or fractional crystallisation, into the diastereomers thereof which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably effected by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound, especially acids and the activated derivatives or alcohols thereof, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. on the basis of their different solubilities, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids include, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols include for example (+)- or (-)-menthol and examples of optically active acyl groups in amides include for example (+)- or (-)-menthyloxycarbonyl.
~ ~ ' Moreover, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
The compounds used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature. In addition, some of them are described in EP-A-4~6378 (not previously published). Thus, for example, compounds of formulae II
and IV are obtained by acylating a corresponding amidine, whilst the amidine required for this is appropriately prepared by reacting a corresponding iminoester with a corresponding amine. A compound of formula II thus obtained is then converted by hydrolysis into a corresponding compound of formula VI.
As already mentioned, the new biphenyl derivatives of formula I and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have valuable properties.
Thus, the new compounds, in addition to having an inhibitory effect on inflammation and bone degradation, have in particular antithrombotic, antiaggregatory and tumour- or metastasis-inhibiting effects.
By way of example, the compounds of formula I were investigated for their biological effects as follows:
The inhibition of thrombocyte aggregation after oral administration of the test substance is determined ex vivo in Rhesus monkeys.
. ' ' ,, 209~8 Immediately before the oral administration of the test substance suspended in Natrosol, a blood sample is taken from the animal's cubital vein as a reference value. At defined times after administration of the substance, more blood samples are taken and investigated as follows . ~
The whole blood mixed with 3.14% sodium citrate in a volume ratio of 1:10 is centrifuged at 200 g for 15 minutes. The supernatant of platelet-rich plasma is carefully removed. The platelet-poor plasma is obtained as supernatant from the erythrocyte-rich sediment by centrifuging at 4000 g for 10 minutes.
The thrombocyte aggregation in these ex vivo samples initiated with collagen (Hormonchemie, Munich; 2 ~g/ml final concentration in platelet-rich plasma) is photometrically measured using the Born and Cross method (J. Physiol. 170: 397 (1964)). The maximum light transmittance of the platelet-rich plasma, measured after collagen stimulation, is compared with the reference value in order to determine the inhibition of aggregation at the various times of blood sampling after the administration of the substance relative to the reference value.
The compound of Example 1 inhibits the collagen-induced thrombocyte aggregation ex vivo after the oral administration of 3 mg/kg for more than 4 hours.
The compound according to the invention is well tolerated, since no toxic side effects were observed at the dosages administered.
In the light of their inhibitory effect on cell-cell or cell-matrix interactions, the new biphenyl derivatives of formula I and the physiologically acceptable addition salts thereof are suitable for combating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, e.g. in treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metàstasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures.
They are also suitable for parallel therapy in thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or in the treatment of shock, psoriasis, diabetes and inflammation.
Thus, viewed from a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with at least one physiologically acceptable carrier or excipient.
Viewed from a still further aspect the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for combating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part.
In particular, the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell .
:
- ~ .-: .
209~1~8 interactions with one another or with solid structures, in particular, for parallel therapy in thrombolysis with fibrinolytics or vascular interventions, or for the treatment of shock, psoriasis, diabetes or inflammation.
Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human animal body to combat or prevent diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
More particularly, the invention provides a method of treatment of the human or non-human animal body for treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures, in particular, for parallel therapy in thrombolysis with fibrinolytics or vascular interventions, or for the treatment of shock, psoriasis, diabetes or inflammation, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
For treating or preventing the diseases mentioned above the dosage is conveniently between 0.1 ~g and 30 mg/kg of body weight, preferably 1 ~g to 15 mg/kg of body weight, given in up to 4 doses per day. For this purpose the compounds of formula I produced according to the invention, optionally in conjunction with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, serotonin antagonists, ~-receptor antagonists, alkylnitrates such as glycerol trinitrate, :, . -' ' ' ~
2 0 9~ 5 8 27169-219 phospho-diesterase inhibitors, prostacyclin and the analogues thereof, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatane sulphate, activated protein C, vitamin K antagonists, hirudine, inhibitors of thrombin or other activated clottlng factors, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water-glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
- The invention also extènds to a commercial package containing a compound of the invention, together with instructions for its use in treating any of the above conditions.
The following non-limiting Examples are provided to illustrate the invention. All percentages and ratios are by weight, other than eluant or solvent ratios which are by volume.
-.;. :- :
: - ::
- - :. ~
: . :: :
- .. ~
2Q92~158 Example I
We have found that certain novel biphenyl derivatives have valuable pharmacological properties, in particular aggregation-inhibiting effects.
Thus, viewed from one aspect, the present invention provides compounds of formula I:
Rb Ra~A--B--E
(I) (wherein with the proviso that where E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra does not denote an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C16-alkoxy)carbonyl, phenyl(C1-6- ~
alkoxy)carbonyl, (C3s-alkenyl)oxycarbonyl or phenyl(C3s-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1s-alkyl or C1s-alkoxy group, or a Cs7-cycloalkyl, Cs 7-cycloalkyloxy, phenylalkyl, phenylalkoxy, phenyl or phenoxy group, : ~ ..
R2 denotes a hydrogen atom or a C16-alkyl, C3 7-cycloalkyl, or phenyl group and R3 denotes a hydrogen atom or a C16-alkyl group;
Rb denotes a hydrogen atom or an alkyl, hydroxy or alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, wherein the -CH2CO- and -O-CH2CO- groups are each connected to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2) n~ group (wherein X
denotes a bond or an -HCRs- or -NR5- group), or an NR4 CH2CH2 R6C CH , NR4 CO (CH2)m- or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, the above-mentioned Y
or -NR4- groups each being linked to the group A, and wherein n denotes the number O or l, m denotes the number 2, 3, 4 or 5, R4 denotes a hydrogen atom or an alkyl or - phenylalkyl group and R5 denotes a hydrogen atom, or R4 and Rs together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C25-alkylene group, in which the ethylene group may be substituted by a phenylalkylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and 2098~8 E denotes a (C26-alkoxy)carbonyl or phenylalkoxycarbonyl group, a (C4l0cycloalkyloxycarbonyl) group in which a C58-cycloalkyl moiety may additionally be substituted by l or 2 alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxy-carbonyl, or C26-alkanoyl group, and wherein the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (C58-cycloalkenyl)oxycarbonyl, (C35-alkenyl)-oxycarbonyl, phenyl(C35-alkenyl)oxycarbonyl, (C35-alkynyl)oxycarbonyl or phenyl(C35-alkynyl)oxycarbonyl group wherein the carbon attached to the oxycarbonyl moiety does not itself carry a double or triple bond, a (C38-cycloalkyl)alkoxy-carbonyl group, a (C810-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two alkyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C16-alkyl groups or by a C38-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkyl-piperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy-carbonyl group;
whilst unless otherwise specified any alkyl or alkoxy moiety contains 1 to 3 carbon atoms, and any phenyl nuclei mentioned above in the definitions of groups Ra~ B and E may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl, ethyl, , - :- ; , ' ~ -n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identicà~l or different);
and the stereoisomers thereof, including the mixtures and the salts thereof.
Preferred compounds according to the invention include those of formula I wherein, with the proviso that Ra does not represent an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group if E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C13-alkoxy)carbonyl, phenyl (C~ 3-alkoxy)carbonyl or (C34-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1s-alkyl -- group or a phenyl(C13-alkyl), C13-alkoxy, Cs 7-cycloalkyl, Cs7-cycloalkoxy, or phenyl group, R2 denotes a hydrogen atom or a C13-alkyl, Cs 7-cycloalkyl or phenyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a hydroxy or C13-alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the -CH2CO- and -O-CH2CO- groups are each - . ~
- -.. .
~.
20981~8 linked to the group B via the carbonyl group;
B denotes an -NR4-cH2cHz-x-(cH2) n~ group (wherein X
denotes a bond or an -HCR5- or -NR5- group), an -NR4-cH2cH2-R6c=cH-~ -NR4-CO-(CHz)m- or -Y-W- group~
wherein Y denotes an -NR4- group or, if A denotes a bond, Y may aiso denote an oxygen atom, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3, 4 or 5, , ~ n denotes the number O or 1, R4 denotes a hydrogen atom or a C13-alkyl or benzyl group and R5 denotes a hydrogen atom, or R4 and Rs together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2s-alkylene group, in which the ethylene group may be substituted in the - ~-position by a phenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C26-alkoxy)carbonyl group, a benzyloxycarbonyl group, a (C410cycloalkyloxycarbonyl) group wherein a Cs8-cycloalkyl moiety may additionally be substituted by 1 or 2 C13-alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or Cz4-alkanoyl group, .
' ~ ' ' ':
. ' ~
20981~8 a (Cs7-cycloalkyl)(C1.2alkoxy)carbonyl group, a (C89-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two methyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by l or 2 C13-alkyl groups or by a C57-cycloalkyl group, or E represents a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-methyl-piperazinyl group, or a l,3-dihydro-3-oxo-l-isobenzofuranyloxycarbonyl group;
whilst any phenyl nuclei mentioned above in the definitions of groups Ra~ B and E may each be mono- or disubstituted by fluorine, chlorine or bromine atoms or methyl, hydroxy, methoxy, trifluoromethyl, nitro, amino, methylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identical or different;
and the stereoisomers thereof, including the mixtures and the salts thereof.
More particularly preferred compounds according to the invention include those of formula I above wherein, with the proviso that Ra does not represent an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group if E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R~CR3)-O-CO-, (C13-alkoxy)carbonyl, benzyloxycarbonyl or allyloxycarbonyl group, wherein - ` ,, ~
2Q9~1~8 R1 denotes a straight-chained or branched C14-alkyl group, a C13-alkoxy group or a cyclohexyloxy group, R2 denotes a hydrogen atom or a methyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a methoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the ~CH2CO- and -O-CH2CO- groups are each linked to the group B via the carbonyl group; and B denotes an -NR4-CH2CH2-X-(CH2) n~ group (wherein X
denotes a bond or an -HCRs- or -NRs- group~, an -NR4-CH2CH2-R6C=CH-~ -NR4-CO-(CH2)m~ or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, whilst the above mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3 or 4, n denotes the number O or 1, R4 denotes a hydrogen atom, a C13-alkyl group or a benzyl group and R5 denotes a hydrogen atom, or R4 and Rs together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C25-alkylene group, in which the ethylene group may be substituted in the ~-position by a methoxyphenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and :
~ ' ~0~81~8 E denotes a (C26-alkoxy)carbonyl group, a (C610-cycloalkyloxycarbonyl) group in which the cyclohexyl moiety may additionally be substituted by l or 2 C13-alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which a methylene group in the 3- or 4-position in the cycloalkyloxy moiety is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or acetyl group, a (C56-cycloalkyl)(C12-alkoxy)carbonyl group, a (C8 bicycloalkyloxycarbonyl) group, an R1-CO-O-(RzCR3)-O-CO-group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by l or 2 methyl groups or by a cyclohexyl group, or E denotes a piperidinyl or morpholinyl group, or a l,3-dihydro-3-oxo-l-isobenzo~uranyloxycarbonyl group;
and the stereoisomers thereof, including the mixtures and the salts thereof.
Particularly preferred compounds according to the invention include those of formula I above wherein, with the proviso that Ra does not denote an amidino group optionally substituted by a (C23-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group, if E denotes a (C23-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, methoxycarbonyl or allyloxycarbonyl group, wherein R1 denotes a straight-chained or branched C14-alkyl , ~ .-2 ~
group, a C13-alkoxy group or a cyclohexyloxy group, R2 denotes a hydrogen atom or a methyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a methoxy group;
A denotes a -CH2- or -CO- group;
B denotes an -NR4-CH2CH2-X-CH2- group wherein X denotes an -NR5- group, or B denotes an -NR4-CH2CH2-R6C=CH- or -Y-W-group wherein Y denotes an -NR4- group, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein R4 denotes a hydrogen atom or a methyl group or R4 and R5 together or R4 and R6 together represent an ethylene group and W denotes a 1,4-cyclohexylene group;
E denotes an isopropyloxycarbonyl, isobutyloxycarbonyl, 2-butyloxycarbonyl, 2-amyloxycarbonyl, 3-amyloxycarbonyl or neopentyloxycarbonyl group, a (C69-cycloalkoxy-carbonyl) group wherein the cyclohexyl moiety may additionally be substituted by 1 or 2 C13-alkyl groups, a (C56-cycloalkyl)(C12alkoxy)carbonyl group, a (C8 bicycloalkyloxycarbonyl) group, or an R1-CO-O-(R2CR3)-O-CO- group in which R1, R2 and R3 are as hereinbefore defined;
and the stereoisomers thereof, including the mixtures and salts thereof.
The present invention particularly relates to the 20~o81~8 following compounds of formula I:
4-amidino-4'-t4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-3'-[4-trans-(cyclohexyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-3'-[4-trans-(cyclohexylmethoxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-4'-t4-(cycloheptyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-t4-((exo)-norbornyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-((-)-menthyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-amidino-biphenyl;
4-[N-allyloxycarbonyl-amidino]-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-tN-allyloxycarbonyl-amidino]-4'-t4-(carboxymethyl)-piperidinocarbonyl]-biphenyl; and 4-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl;
, . . ~ , - :.
: ~. .. .
-:
20~181~8 and the stereoisomers thereof, including the mixtures and the salts thereof.
Viewed from a further aspect, the invention provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps:
a) (to prepare compounds of formula I wherein E denotes a (C37-alkoxycarbonyl) group, a phenylalkoxycarbonyl group, a (C410-cycloalkyloxycarbonyl) group wherein a -^-Cs8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a (C68-cycloalkyloxycarbonyl) group in which in the cycloalkyloxy moiety a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl or C26-alkanoyl group, and the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (Cs8-cycloalkenyl)oxycarbonyl, a (C35-alkenyl)oxycarbonyl, phenyl(C35-alkenyl)oxycarbonyl, (C3s-alkynyl)oxycarbonyl or phenyl(C35-alkynyl)oxycarbonyl group in which he carbon attached to the oxycarbonyl moiety carries no double or triple bond, a (C38-cycloalkyl)alkoxycarbonyl group, or a (C810-bicycloalkyloxycarbonyl) group, which may additionally be substituted in the bicycloalkyl moiety by one or two alkyl groups) esterifying a carboxylic acid of formula II
Rb Ra ~ A-B-COOH
(II) (wherein Ra~ Rb, A and B are as hereinbefore defined) or a , . , t . ~ `
, :
209~1.58 reactive derivative thereof optionally formed in the reaction mixture, with an alcohol of formula III
HO - R8 (III) (wherein R8 denotes a C26-alkyl group, a phenylalkyl group, a C3 9-cycloalkyl group in which a Cs8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a Cs7-cycloalkyl group in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl, or C26-alkanoyl group, and the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a Cs8-cycloalkenyl, C35-alkenyl, phenyl(C35-alkenyl), C35-alkynyl or phenyl(C3s-alkynyl) group in which the carbon attached to the hydroxyl carries no double or triple bond, a (C38-cycloalkyl)alkyl group, or a C7~-bicycloalkyl group optionally substituted by one or two alkyl groups;
b) reacting a carboxylic acid of formula IV
Rb Ra~) ~A--B--COOH
(IV) (wherein Rb, A and B are as hereinbefore defined and Ral denotes an amidino group substituted by an R1-CO-O-(R2CR3)-O-CO-, (C16-alkoxy)carbonyl, phenyl(C16-alkoxyjcarbonyl, ( C3 5-alkenyl)oxycarbonyl or phenyl( C3 s-alkenyl)oxycarbonyl group, or Ral denotes an amidino group protected by a protecting group) or a carbanion thereof, with a compound of formula V
, .' ~ '' ;
2lQ98l~8 Z~ - R9 (V) (wherein R9 denotes a C26-alkyl group, a phenylalkyl group, a C39-cycloalkyl group wherein a C5 8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C57-cycloalkyl group in which a methylene group in the 3- or 4 position is replaced by an oxygen atom or by an ~;
imino group itself optionally substituted by an alkyl, phenylalkyl, phenyloxycarbonyl or C26-alkanoyl group and in which the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C58-cycloalkenyl group, a C3s-alkenyl, phenyl(C35-alkenyl), C35-alkynyl or phenyl(C35-alkynyl) group wherein the Zl attached carbon carries no double or triple bond, a (C38-cycloalkyl)alkyl group, or a C79-bicycloalkyl group optionally substituted by one or two alkyl groups, an Rl-CO-O-(R2CR3)- group wherein Rl, R2 and R3 are as hereinbefore defined, an R7-CO-CH2- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C16-alkyl groups or by a C38-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkylpiperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyl group and Z1 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom) and if necessary subsequently cleaving any protecting group used;
c) (to prepare compounds of formula I wherein Ra denotes an amidino group substituted by an Rl-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group) acylating a compound of formula VI
.:
, ~49~1~8 I b HN\C~A--B--E
(VI) (wherein Rb, A, B and E are as hereinbefore defined) with a compound of formula VII
:"~
.. Z2 ~ R10 (VII) (wherein R~o denotes an R1-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group and Z2 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom or a p-nitrophenyl group) d) resolving a compound of formula I thus obtained into the enantiomers and/or diastereomers thereof;
e) converting a compound of formula I obtained into 2 i salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid, or converting a salt of a compound of formula I into the free compound; and f) performing a process as defined in any one of steps (a) to (e) above on a corresponding protected compound and subsequently removing the protecting group used.
The esterification of step (a) is conveniently carried out in a solvent or mixture of solvents such as .. , . ~ . ~ .
,., . . , . , ,. :: . .
, ;: , ~: ~ , . : , - :
:. . . - . : -- - . : ~ ~ ~ --,: ,; ~ . . .. : .
methylene chloride, dimethylformamide, dimethylsulphoxide, toluene, chlorobenzene, tetrahydrofuran, toluene/tetrahydrofuran or dioxane, ~-optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of a chloroformate such as isobutylchloroformate, thionylchloride, trimethylchlorosilane, titanium tetrachloride, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide or l-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, optionally in the presence of a base such as a pyridine substituted in the 4-position by a secondary amino group such as 4-dimethylamino-pyridine or triphenylphosphine/carbon tetrachloride, at temperatures between -30 and 100C, preferably at temperatures between -10 and 60C.
In step (b), examples of protecting groups for the amidino groups include the tert.butyloxycarbonyl, allyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group and examples of protecting groups for the hydroxy group include the trimethylsilyl, tetrahydropyran-2-yl, benzyl, benzhydryl or triphenylmethyl group.
The reaction of step (b) is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide or dimethylformamide, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl-. ' - : :
`:' :
20~15~
diisopropylamine, N-methyl-morpholine, pyridine or 4-dimethylamino-pyridine, which may simultaneously be used as solvent, or possibly in the presence of silver carbonate or silver oxide, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 80C.
A protecting group used for the amino, amidino or hydroxy group is preferably cleaved hydrogenolytically, depending on the protecting group used and the particular group to be protected, e.g. using hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 50C, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably of 3 to S bar, using an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or sulphuric acid, with the aid of an organic acid such as formic acid or trifluoroacetic acid in a solvent such as methanol, ethanol, ethyl acetate, methylene chloride or glacial acetic acid, with the aid of a secondary amine such as piperidine or morpholine in a solvent such as dimethylformamide or methylene chloride or with the aid of a catalyst such as tetrakis-(triphenylphosphine)-palladium(0) and morpholine in a solvent such as tetrahydrofuran or dioxane, at temperatures between 0 and 50C, but preferably at ambient temperature.
The reaction of step (c) is conveniently carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform or dimethylformamide, appropriately in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-: , - : . ~
20~8158 morpholine or pyridine, which may simultaneously be used as solvent, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 80C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino, imino or amidino groups may be protected during the reaction by means of conventional protecting groups which may be cleaved again after the reaction.
For example, suitable protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl and tetrahydropyranyl groups, suitable protecting groups for a carboxyl group include trimethylsilyl, methyl, ethyl, tert.butyl and benzyl groups, and suitable protecting groups for an amino, alkylamino or imino group include acetyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, benzhydryl, trityl, methoxybenzyl, 2,4-dimethoxybenzyl, 9-fluorenylmethyloxycarbonyl and allyloxycarbonyl groups.
The optional subsequent cleaving of a protecting group used may, for example, be carried out hydrolytically in an aqueous sol~ent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between -10 and lOCC, preferably at temperatures between 0 and 60~C.
However, a benzyl, methoxybenzyl, benzyloxycarbonyl, benzhydryl or trityl group may for example be cleaved hydrogenolytically, eg. using hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial - . ~ ., . .. , ~: . -20981~8 acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 50C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presencè of an oxidising agent such as cerium(IV)-ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50C, but preferably at ambient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, or ether.
A 9-fluorenylmethyloxycarbonyl group is preferably cleaved using a secondary amine such as piperidine or morpholine in a solvent such as dimethylformamide or methylene chloride at temperatures between 0 and 50C, but preferably at ambient temperature, and an allyloxycarbonyl group is preferably cleaved in the presence of a catalyst such as tetrakis-(triphenylphosphine)-palladium(0) and morpholine in a solvent such as tetrahydrofuran or dioxane at temperatures between 0 and 50C, but preferably at ambient temperature.
Furthermore, the compounds of formula I obtained may be resolved into their enantiomers and/or diastereomers as mentioned hereinbefore. Thus, for example, cis/trans - : ~
- ~
20981~
mixtures may be resolved into their cis and trans isomers, and compounds having at least one optically active carbon atom may be resolved into their enantiomers. Thus, for example, the compounds of formula I which occur in racemate form may be separated by methods known er se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of formula I having at least 2 asymmetric carbon atoms may be separated on the basis of their physical-chemical differences using known methods, e.g.
by chromatography and/or fractional crystallisation, into the diastereomers thereof which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably effected by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound, especially acids and the activated derivatives or alcohols thereof, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. on the basis of their different solubilities, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids include, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols include for example (+)- or (-)-menthol and examples of optically active acyl groups in amides include for example (+)- or (-)-menthyloxycarbonyl.
~ ~ ' Moreover, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
The compounds used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature. In addition, some of them are described in EP-A-4~6378 (not previously published). Thus, for example, compounds of formulae II
and IV are obtained by acylating a corresponding amidine, whilst the amidine required for this is appropriately prepared by reacting a corresponding iminoester with a corresponding amine. A compound of formula II thus obtained is then converted by hydrolysis into a corresponding compound of formula VI.
As already mentioned, the new biphenyl derivatives of formula I and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have valuable properties.
Thus, the new compounds, in addition to having an inhibitory effect on inflammation and bone degradation, have in particular antithrombotic, antiaggregatory and tumour- or metastasis-inhibiting effects.
By way of example, the compounds of formula I were investigated for their biological effects as follows:
The inhibition of thrombocyte aggregation after oral administration of the test substance is determined ex vivo in Rhesus monkeys.
. ' ' ,, 209~8 Immediately before the oral administration of the test substance suspended in Natrosol, a blood sample is taken from the animal's cubital vein as a reference value. At defined times after administration of the substance, more blood samples are taken and investigated as follows . ~
The whole blood mixed with 3.14% sodium citrate in a volume ratio of 1:10 is centrifuged at 200 g for 15 minutes. The supernatant of platelet-rich plasma is carefully removed. The platelet-poor plasma is obtained as supernatant from the erythrocyte-rich sediment by centrifuging at 4000 g for 10 minutes.
The thrombocyte aggregation in these ex vivo samples initiated with collagen (Hormonchemie, Munich; 2 ~g/ml final concentration in platelet-rich plasma) is photometrically measured using the Born and Cross method (J. Physiol. 170: 397 (1964)). The maximum light transmittance of the platelet-rich plasma, measured after collagen stimulation, is compared with the reference value in order to determine the inhibition of aggregation at the various times of blood sampling after the administration of the substance relative to the reference value.
The compound of Example 1 inhibits the collagen-induced thrombocyte aggregation ex vivo after the oral administration of 3 mg/kg for more than 4 hours.
The compound according to the invention is well tolerated, since no toxic side effects were observed at the dosages administered.
In the light of their inhibitory effect on cell-cell or cell-matrix interactions, the new biphenyl derivatives of formula I and the physiologically acceptable addition salts thereof are suitable for combating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, e.g. in treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metàstasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures.
They are also suitable for parallel therapy in thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or in the treatment of shock, psoriasis, diabetes and inflammation.
Thus, viewed from a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with at least one physiologically acceptable carrier or excipient.
Viewed from a still further aspect the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for combating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part.
In particular, the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell .
:
- ~ .-: .
209~1~8 interactions with one another or with solid structures, in particular, for parallel therapy in thrombolysis with fibrinolytics or vascular interventions, or for the treatment of shock, psoriasis, diabetes or inflammation.
Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human animal body to combat or prevent diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
More particularly, the invention provides a method of treatment of the human or non-human animal body for treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures, in particular, for parallel therapy in thrombolysis with fibrinolytics or vascular interventions, or for the treatment of shock, psoriasis, diabetes or inflammation, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
For treating or preventing the diseases mentioned above the dosage is conveniently between 0.1 ~g and 30 mg/kg of body weight, preferably 1 ~g to 15 mg/kg of body weight, given in up to 4 doses per day. For this purpose the compounds of formula I produced according to the invention, optionally in conjunction with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, serotonin antagonists, ~-receptor antagonists, alkylnitrates such as glycerol trinitrate, :, . -' ' ' ~
2 0 9~ 5 8 27169-219 phospho-diesterase inhibitors, prostacyclin and the analogues thereof, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatane sulphate, activated protein C, vitamin K antagonists, hirudine, inhibitors of thrombin or other activated clottlng factors, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water-glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
- The invention also extènds to a commercial package containing a compound of the invention, together with instructions for its use in treating any of the above conditions.
The following non-limiting Examples are provided to illustrate the invention. All percentages and ratios are by weight, other than eluant or solvent ratios which are by volume.
-.;. :- :
: - ::
- - :. ~
: . :: :
- .. ~
2Q92~158 Example I
4'-Cyano-biphenylyl-4-acetic acid A mixture of 11.3 g of 4'-bromo-biphenylyl-4-acetic acid (melting point: 172-175C, prepared from 4-acetyl-4'-bromo-biphenyl by treating with morpholine and sulphur and subsequent hydrolysis with potassium hydroxide), 3.48 g of copper(I)-cyanide and 100 ml of dimethylformamide is refluxed for 12 hours and evaporated down after cooling. The residue is distributed between lN sodium hydroxide solution and `~i~ methylene chloride to which some methanol is added. The aqueous phase is acidified and extracted with methylene chloride. The methylene chloride phase is treated with activated charcoal and evaporated down, the solid residue is triturated with a mixture of ether and petroleum ether and filtered off.
Yield: 5.1 g (55% of theory), Rf value: 0.46 (silica gel; methylene chloride/ethanol =
9 : 1 ) The following compound is obtained analogously:
(1) Methyl 4-cyano-biphenylyl-4'-carboxylate Melting point: 140-142C
The necessary starting compound, methyl 4-bromo-biphenylyl-4'-carboxylate (melting point: 140-142C), is obtained by esterifying the acid with methanolic hydrochloric acid. 4-Bromo-4'-biphenylyl-carboxylic acid is obtained by reacting 4-acetyl-4'-bromo-biphenyl with bromine and sodium hydroxide solution.
.. . .
2Q92~l~8 Example II
4-Cyano-4'-hydroxymethyl-biphenyl A solution of 5 g (0.0224 mol) of 4'-cyano-biphenyl-4-carboxylic acid and 2.27 g (0.0224 mol) of triethylamine in 100 ml of tetrahydrofuran is mixed at 5C with a solution of 2.43 g (0.024 mol) of ethylchloroformate in 20 ml of tetrahydrofuran, within 5 minutes, with stirring. The mixture is then stirred at 5C for another hour. The triethylamine-hydrochloride precipitated is suction filtered and the mother liquor is added dropwise to a solution of 2.12 g (0.056 mol) of sodium borohydride in 20 ml of water at 10-15C with stirring. After another 4 hours stirring at ambient temperature the mixture is acidified to pH 2-3 using 2N
hydrochloric acid, the aqueous phase produced is separated off and extracted with ethyl acetate. The organic phases are combined, washed with 10% sodium hydroxide solution and then with water. After drying over sodium sulphate the mixture is evaporated to dryness under reduced pressure.
Yield: 2.5 g (53.3% of theory) of an amorphous product.
Example III
4-Chloromethyl 4'-cyano-biphenyl 2.5 g (0.0119 mol) of 4-cyano-4'-hydroxymethyl-biphenyl are dissolved in 70 ml of dichloromethane and after the addition of 2.4 g (0.0239 mol) of triethylamine the mixture is slowly combined with 2.7 g (0.024 mol~ of mesylchloride at ambient temperature with stirring.
After standing overnight the clear solution is evaporated to dryness under reduced pressure and the residue is chromatographed over silica gel, using methylene chloride as eluant.
.. . .
.
- :' ~` "'' ~
- , ., - .
20~781~8 Yield: 2.6 g (96% of an amorphous solid) Example IV
4-Cyano-4'-iodomethyl-biphenyl 2.4 g (0.0087 mol) of 4-chloromethyl-4'-cyano-biphenyl are refluxed together with 6.26 g (0.042 mol) of sodium iodide in 100 ml of acetone for 3 hours. The suspension is then evaporated to dryness in vacuo and the residue is extracted several times with dichloromethane. The combined dichloromethane solutions are evaporated to dryness. The crude residue thus obtained is used in Example V without any further purification.
Exam~le V
4-Cyano-4'-[4-(methoxycarbonylmethyl)-piperidinomethyl]-biphenyl The crude product obtained in Example V is dissolved in 100 ml of chloroform. After the addition of 2.5 g of methyl piperidinoacetate hydrochloride and 2.57 g of triethylamine this solution is refluxed for 4 hours.
After cooling, the precipitated triethylamine-hydrochloride is suction filtered and the mother liquor is evaporated to dryness. The residue is chromatographed over silica gel using dichloromethane/methanol t40:1) as eluant.
Yield: 2.2 g (59.6% of theory) : ~' :' ' ' . ,' ' ', ' ~ . , " ~ :
20981~8 Exam~le VI
4-Amidino-4'-[4-(methoxycarbonylmethyl)-piperidinomethyl]-biphenyl HCl gas is introduced for 2 hours into a suspension of 2.1 g (0.006 mol) of 4-cyano-4'-[4-(methoxycarbonyl-methyl)-piperidinomethyl]-biphenyl in 100 ml of absolute methanol whilst cooling with ice and stirring. The reaction mixture is then left to stand for 4 hours at ambient temperature. The solution is evaporated to dryness in vacuo, the residue is dissolved in methanol and the solution thus obtained is mixed with sodium carbonate until a basic reaction is achieved. The suspension thus produced is evaporated to dryness ln vacuo. The residue is chromatographed over silica gel, using dichloromethane/methanol/conc. ammonia in the ratio 9:1:0.1 as eluant.
Yield: 0.72 g (29.7% of theory), Melting point: 148-150C
Example VII
4-Amidino-4'-~4-(hydroxycarbonylmethyl)-piperidinomethyl]-biphenyl 0.59 g of 4-amidino-4'-[4-(methoxycarbonylmethyl)-piperidinomethyl]-biphenyl are dissolved in 15 ml of tetrahydrofuran and 11 ml of water. 8.1 ml of a lN
a~ueous lithium hydroxide solution are added to this solution wit~ stirring. After another 3 hours, 433 mg of ammonium chloride are added, whereupon a colourless substance is precipitated. The tetrahydrofuran is distilled off in vacuo and the substance precipitated is then filtered off.
Yield: 420 mg (74.7% of theory), Melting point: 318-320C (decomp.) - - :. , , . :-- -~ , , .
, 2092981~8 Example VIII
3-Carboxy-4'-cyano-4-hydroxy-biphenyl A solution of 12 g of 4-cyano-4'-methoxy-biphenyl in 75 ml of methylene chloride is added dropwise to a mixture of 25 ml of oxalylchloride, 50 ml of methylene chloride and 25 g of aluminium chloride which is stirred for 30 minutes at -20C. The resulting mixture is stirred for 5 hours at -20C, initially whilst cooling with ice, and then allowed to come up to ambient temperature in the course of 16 hours, after which it is stirred for a further 3 hours. It is poured onto ice water, stirred for 30 minutes, extracted with ethyl acetate and the ethyl acetate phase is evaporated down until crystallisation occurs.
Yield: 10.3 g (75% of theory), Melting point: 244-246C
Example IX
4-(tert.Butyloxycarbonylmethyloxy)-4'-cyano-biphenyl . _ Prepared analogously to Example 13 from 4-cyano-4'-hydroxy-biphenyl and tert.butyl-bromoacetate.
Melting point: 110-112C
Example X
4-(Carboxymethyloxy)-4'-cyano-biphenyl 32.9 g of 4-(tert.butyloxycarbonylmethyloxy)-4'-cyano-biphenyl are dissolved in 250 ml of methylene chloride and slowly combined with 137 ml of trifluoroacetic acid.
The resulting mixture is stirred for 3 hours at ambient temperature, evaporated to dryness and the residue is '~
20~o~158 triturated with water.
Yield: 26.3 g (98% of theory), Melting point: 202-204C
Example XI
4-Cyano-4'-[[[3-(2-methoxycarbonyl-ethyl)-phenyl]-aminocarbonyl]-methyl]-biphenyl ... . _ _ A solution of 1.4 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is added dropwise, whilst cooling with ice, to a mixture of 1 g of 4'-cyano-biphenylyl-4-acetic acid, 1.2 g of methyl 3-(3-aminophenyl)-propionate, 0.57 g of l-hydroxy-lH-benzotriazole-hydrate and 100 ml of tetrahydrofuran. The mixture is stirred for a further hour, allowed to come up to ambient temperature and the dicyclohexylurea precipitated is filtered off. The filtrate is evaporated down and the residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol = 30:1).
Yield: 1.58 g (95% of theory), Melting point: 166-168~C
Example ~II
4-Cyano-4'-[(2-ethoxycarbonyl-ethylamino)-carbonyl]-biphenyl A mixture of 2 g of 4'-cyano-biphenylyl-4-acetic acid, 1.9 ml of N-methyl-morpholine and 100 ml of tetrahydrofuran is cooled to -30C and mixed with 1.1 ml of isobutylchloroformate. The mixture is stirred for one hour, 1.3 g of ~-alanine ethylester-hydrochloride is added and the resulting mixture is stirred for 50 hours at ambient temperature. The solution obtained is stirred into 300 ml of 0.5 molar potassium hydrogen .
, . -:
- , ~: . ~ . . :
, ,, :
20981~8 sulphate solution and extracted with ethyl acetate. The ethyl acetate phase is evaporated down and mixed with ether, whereupon the product is obtained in crystalline form.
Yield: 1.1 g (39% of theory), Melting point: 132-136C
Exam~le XIII
[4-Amidino-4'-(5-methoxycarbonyl-pentyloxy)-biphenyl]-dihydrogen carbonate 75 ml of methanol are covered with 30 ml of petroleum ether and hydrogen chloride gas is piped in, whilst cooling with ice, until saturation point is reached.
Then 2.1 g of 4-cyano-4'-(5-ethoxycarbonyl-pentyloxy)-biphenyl are added and the mixture is stirred for 18 hours at ambient temperature. It is evaporated to dryness in vacuo, the residue is suspended in methanol, 5.3~ g of ammonium carbonate are added and the mixture is stirred for 16 hours at ambient temperature. The precipitate obtained is filtered off and purified by stirring with methylene chloride/methanol (85:15) and water.
Yield: 1.75 g (75% of theory), Melting point: 185-189~C (decomp.) 20981~8 Exam~le l 4-Amidino-4'-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride Hydrochloric acid gas is piped into a suspension of 1 g (0.0027 mol) of 4-amidino-4'-[4-(carboxymethyl)-piperidinocarbonyl]-biphenyl in 20 ml of dichloromethane and 20 ml of cyclohexanol at ambient temperature until saturation is reached. Then the clear solution thus obtained is left to stand for one hour and heated to 40C for 3 hours. The solution is evaporated down under reduced pressure and the solid residue remaining is crystallised from ether, suction filtered and washed with ether.
Yield: 1.1 g (83.1% of theory), Melting point: 227-230C
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-(cycloheptyloxycarbonyl)-butyrylamino]-biphenyl-hydrochloride (2) 4-amidino-4'-[4-(2-cyclohexyl-ethoxycarbonyl)-butyryl-N-methyl-amino]-biphenyl-hydrochloride (3) 4-amidino-4'-tN-(3-(cyclopentylmethyloxycarbonyl)-propyl)-aminocarbonyl]-biphenyl-hydrochloride (4) 4-amidino-4'-[N-(3-(cyclopentylmethyloxycarbonyl)-propyl)-N-benzyl-aminocarbonyl]-biphenyl-hydrochloride (5) 4-amidino-4'-[4-(2-cyclohexyloxycarbonyl-ethyl)-piperazinocarbonyl]-biphenyl-dihydrochloride (6) 4-amidino-4'-[4-(cyclooctyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride - .,-- ~, ;
--.
209815~
Yield: 5.1 g (55% of theory), Rf value: 0.46 (silica gel; methylene chloride/ethanol =
9 : 1 ) The following compound is obtained analogously:
(1) Methyl 4-cyano-biphenylyl-4'-carboxylate Melting point: 140-142C
The necessary starting compound, methyl 4-bromo-biphenylyl-4'-carboxylate (melting point: 140-142C), is obtained by esterifying the acid with methanolic hydrochloric acid. 4-Bromo-4'-biphenylyl-carboxylic acid is obtained by reacting 4-acetyl-4'-bromo-biphenyl with bromine and sodium hydroxide solution.
.. . .
2Q92~l~8 Example II
4-Cyano-4'-hydroxymethyl-biphenyl A solution of 5 g (0.0224 mol) of 4'-cyano-biphenyl-4-carboxylic acid and 2.27 g (0.0224 mol) of triethylamine in 100 ml of tetrahydrofuran is mixed at 5C with a solution of 2.43 g (0.024 mol) of ethylchloroformate in 20 ml of tetrahydrofuran, within 5 minutes, with stirring. The mixture is then stirred at 5C for another hour. The triethylamine-hydrochloride precipitated is suction filtered and the mother liquor is added dropwise to a solution of 2.12 g (0.056 mol) of sodium borohydride in 20 ml of water at 10-15C with stirring. After another 4 hours stirring at ambient temperature the mixture is acidified to pH 2-3 using 2N
hydrochloric acid, the aqueous phase produced is separated off and extracted with ethyl acetate. The organic phases are combined, washed with 10% sodium hydroxide solution and then with water. After drying over sodium sulphate the mixture is evaporated to dryness under reduced pressure.
Yield: 2.5 g (53.3% of theory) of an amorphous product.
Example III
4-Chloromethyl 4'-cyano-biphenyl 2.5 g (0.0119 mol) of 4-cyano-4'-hydroxymethyl-biphenyl are dissolved in 70 ml of dichloromethane and after the addition of 2.4 g (0.0239 mol) of triethylamine the mixture is slowly combined with 2.7 g (0.024 mol~ of mesylchloride at ambient temperature with stirring.
After standing overnight the clear solution is evaporated to dryness under reduced pressure and the residue is chromatographed over silica gel, using methylene chloride as eluant.
.. . .
.
- :' ~` "'' ~
- , ., - .
20~781~8 Yield: 2.6 g (96% of an amorphous solid) Example IV
4-Cyano-4'-iodomethyl-biphenyl 2.4 g (0.0087 mol) of 4-chloromethyl-4'-cyano-biphenyl are refluxed together with 6.26 g (0.042 mol) of sodium iodide in 100 ml of acetone for 3 hours. The suspension is then evaporated to dryness in vacuo and the residue is extracted several times with dichloromethane. The combined dichloromethane solutions are evaporated to dryness. The crude residue thus obtained is used in Example V without any further purification.
Exam~le V
4-Cyano-4'-[4-(methoxycarbonylmethyl)-piperidinomethyl]-biphenyl The crude product obtained in Example V is dissolved in 100 ml of chloroform. After the addition of 2.5 g of methyl piperidinoacetate hydrochloride and 2.57 g of triethylamine this solution is refluxed for 4 hours.
After cooling, the precipitated triethylamine-hydrochloride is suction filtered and the mother liquor is evaporated to dryness. The residue is chromatographed over silica gel using dichloromethane/methanol t40:1) as eluant.
Yield: 2.2 g (59.6% of theory) : ~' :' ' ' . ,' ' ', ' ~ . , " ~ :
20981~8 Exam~le VI
4-Amidino-4'-[4-(methoxycarbonylmethyl)-piperidinomethyl]-biphenyl HCl gas is introduced for 2 hours into a suspension of 2.1 g (0.006 mol) of 4-cyano-4'-[4-(methoxycarbonyl-methyl)-piperidinomethyl]-biphenyl in 100 ml of absolute methanol whilst cooling with ice and stirring. The reaction mixture is then left to stand for 4 hours at ambient temperature. The solution is evaporated to dryness in vacuo, the residue is dissolved in methanol and the solution thus obtained is mixed with sodium carbonate until a basic reaction is achieved. The suspension thus produced is evaporated to dryness ln vacuo. The residue is chromatographed over silica gel, using dichloromethane/methanol/conc. ammonia in the ratio 9:1:0.1 as eluant.
Yield: 0.72 g (29.7% of theory), Melting point: 148-150C
Example VII
4-Amidino-4'-~4-(hydroxycarbonylmethyl)-piperidinomethyl]-biphenyl 0.59 g of 4-amidino-4'-[4-(methoxycarbonylmethyl)-piperidinomethyl]-biphenyl are dissolved in 15 ml of tetrahydrofuran and 11 ml of water. 8.1 ml of a lN
a~ueous lithium hydroxide solution are added to this solution wit~ stirring. After another 3 hours, 433 mg of ammonium chloride are added, whereupon a colourless substance is precipitated. The tetrahydrofuran is distilled off in vacuo and the substance precipitated is then filtered off.
Yield: 420 mg (74.7% of theory), Melting point: 318-320C (decomp.) - - :. , , . :-- -~ , , .
, 2092981~8 Example VIII
3-Carboxy-4'-cyano-4-hydroxy-biphenyl A solution of 12 g of 4-cyano-4'-methoxy-biphenyl in 75 ml of methylene chloride is added dropwise to a mixture of 25 ml of oxalylchloride, 50 ml of methylene chloride and 25 g of aluminium chloride which is stirred for 30 minutes at -20C. The resulting mixture is stirred for 5 hours at -20C, initially whilst cooling with ice, and then allowed to come up to ambient temperature in the course of 16 hours, after which it is stirred for a further 3 hours. It is poured onto ice water, stirred for 30 minutes, extracted with ethyl acetate and the ethyl acetate phase is evaporated down until crystallisation occurs.
Yield: 10.3 g (75% of theory), Melting point: 244-246C
Example IX
4-(tert.Butyloxycarbonylmethyloxy)-4'-cyano-biphenyl . _ Prepared analogously to Example 13 from 4-cyano-4'-hydroxy-biphenyl and tert.butyl-bromoacetate.
Melting point: 110-112C
Example X
4-(Carboxymethyloxy)-4'-cyano-biphenyl 32.9 g of 4-(tert.butyloxycarbonylmethyloxy)-4'-cyano-biphenyl are dissolved in 250 ml of methylene chloride and slowly combined with 137 ml of trifluoroacetic acid.
The resulting mixture is stirred for 3 hours at ambient temperature, evaporated to dryness and the residue is '~
20~o~158 triturated with water.
Yield: 26.3 g (98% of theory), Melting point: 202-204C
Example XI
4-Cyano-4'-[[[3-(2-methoxycarbonyl-ethyl)-phenyl]-aminocarbonyl]-methyl]-biphenyl ... . _ _ A solution of 1.4 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is added dropwise, whilst cooling with ice, to a mixture of 1 g of 4'-cyano-biphenylyl-4-acetic acid, 1.2 g of methyl 3-(3-aminophenyl)-propionate, 0.57 g of l-hydroxy-lH-benzotriazole-hydrate and 100 ml of tetrahydrofuran. The mixture is stirred for a further hour, allowed to come up to ambient temperature and the dicyclohexylurea precipitated is filtered off. The filtrate is evaporated down and the residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol = 30:1).
Yield: 1.58 g (95% of theory), Melting point: 166-168~C
Example ~II
4-Cyano-4'-[(2-ethoxycarbonyl-ethylamino)-carbonyl]-biphenyl A mixture of 2 g of 4'-cyano-biphenylyl-4-acetic acid, 1.9 ml of N-methyl-morpholine and 100 ml of tetrahydrofuran is cooled to -30C and mixed with 1.1 ml of isobutylchloroformate. The mixture is stirred for one hour, 1.3 g of ~-alanine ethylester-hydrochloride is added and the resulting mixture is stirred for 50 hours at ambient temperature. The solution obtained is stirred into 300 ml of 0.5 molar potassium hydrogen .
, . -:
- , ~: . ~ . . :
, ,, :
20981~8 sulphate solution and extracted with ethyl acetate. The ethyl acetate phase is evaporated down and mixed with ether, whereupon the product is obtained in crystalline form.
Yield: 1.1 g (39% of theory), Melting point: 132-136C
Exam~le XIII
[4-Amidino-4'-(5-methoxycarbonyl-pentyloxy)-biphenyl]-dihydrogen carbonate 75 ml of methanol are covered with 30 ml of petroleum ether and hydrogen chloride gas is piped in, whilst cooling with ice, until saturation point is reached.
Then 2.1 g of 4-cyano-4'-(5-ethoxycarbonyl-pentyloxy)-biphenyl are added and the mixture is stirred for 18 hours at ambient temperature. It is evaporated to dryness in vacuo, the residue is suspended in methanol, 5.3~ g of ammonium carbonate are added and the mixture is stirred for 16 hours at ambient temperature. The precipitate obtained is filtered off and purified by stirring with methylene chloride/methanol (85:15) and water.
Yield: 1.75 g (75% of theory), Melting point: 185-189~C (decomp.) 20981~8 Exam~le l 4-Amidino-4'-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride Hydrochloric acid gas is piped into a suspension of 1 g (0.0027 mol) of 4-amidino-4'-[4-(carboxymethyl)-piperidinocarbonyl]-biphenyl in 20 ml of dichloromethane and 20 ml of cyclohexanol at ambient temperature until saturation is reached. Then the clear solution thus obtained is left to stand for one hour and heated to 40C for 3 hours. The solution is evaporated down under reduced pressure and the solid residue remaining is crystallised from ether, suction filtered and washed with ether.
Yield: 1.1 g (83.1% of theory), Melting point: 227-230C
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-(cycloheptyloxycarbonyl)-butyrylamino]-biphenyl-hydrochloride (2) 4-amidino-4'-[4-(2-cyclohexyl-ethoxycarbonyl)-butyryl-N-methyl-amino]-biphenyl-hydrochloride (3) 4-amidino-4'-tN-(3-(cyclopentylmethyloxycarbonyl)-propyl)-aminocarbonyl]-biphenyl-hydrochloride (4) 4-amidino-4'-[N-(3-(cyclopentylmethyloxycarbonyl)-propyl)-N-benzyl-aminocarbonyl]-biphenyl-hydrochloride (5) 4-amidino-4'-[4-(2-cyclohexyloxycarbonyl-ethyl)-piperazinocarbonyl]-biphenyl-dihydrochloride (6) 4-amidino-4'-[4-(cyclooctyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride - .,-- ~, ;
--.
209815~
(7) 4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: >240C, sintering from 219C
(8) 4-amidino-3'-[4-trans-(cyclohexyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl-hydrochioride Melting point: 238-241~C (decomp.) (9) 4-amidino-3'-[4-trans-(cyclohexylmethoxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl-hydrochloride Melting point: 247-250C (decomp.) (10) 4-amidino-4'-[4-(cycloheptyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: >240C, sintering from 215C
(11) 4-amidino-4'-[4-(cyclohexyloxycarbonylmethyl)-piperidinomethyl]-biphenyl-hydrochloride (12) 4-amidino-4'-[4-[(2,2-dimethyl-propyloxy)-carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 235-240C
Rf value: 0.73 (silica gel, methylene chloride/methanol = 4:1) (13) 4-amidino-4'-t4-[(3-pentyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 205-207C
R~ value: 0.52 (silica gel, methylene chloride/methanol = 4:1) (14) 4-amidino-4'-[4-[((R)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 203-205C
Rf value: 0.56 (silica gel, methylene chloride/methanol = 4:1~
~15) 4-amidino-4'-[4-[((S)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 205-208C
Rf valuè~ 0.56 (silica gel, methylene chloride/methanol = 4 1) (16) 4-amidino-4'-[4-[(2-methyl-propyloxy)-carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride This is done without the addition of methylene chloride and the mixture is left to stand for 18 hours at ambient temperature.
Melting point: 218-223C
Rf value: 0.64 (silica gel, methylene chloride/methanol = 4:1) (17) 4-amidino-4'-[4-trans-(isopropyloxycarbonyl)-cyclo-hexylaminocarbonyl]-biphenyl-hydrochloride This is done without the addition of methylene chloride and, after the introduction of hydrogen chloride, the mixture is left to stand for 5 days at ambient temperature.
Rf value: 0.41 (silica gel, methylene chloride/methanol = 8:2) (18) 4-amidino-4'-[4-(isopropyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride The same procedure is used as in (16).
Melting point: 248-250C
Rf value: 0.25 (Reversed Phase Plate RP18, methanol/5%
sodium chloride solution = 6:4) , ~ : ` . -'~.,. .: :
~;, ~ ' ' . .
Example 2 4-Amidino-4'-[4-(cyclohexylmethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl A suspension of 4-amidino-4'-[4-carboxymethyl-piperidinocarbonyl]-biphenyl, hydroxymethylcyclohexane and trimethylchlorosilane in a molar ratio of 1:4:10 is refluxed for 36 hours in dry tetrahydrofuran. It is then evaporated to dryness under reduced pressure, diluted with dichloromethane and washed with 2N ammonia and then with water. After drying over sodium sulphate ` the mixture is evaporated to dryness under reduced pressure. The residue is purified by chromatography over a silica gel column.
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-(N-methyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (2) 4-[4-(N-acetyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-4'-amidino-biphenyl (3) 4-amidino-4'-[4-(tetrahydro-4H-pyran-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (4) 4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (5) 4-amidino-4'-[5-(N-benzyl-piperidin-4-yloxycarbonyl)-pentyloxy]-biphenyl (6) 4-amidino-4'-t4-(tetrahydrofuran-3-yloxycarbonyl)-butyloxy]-biphenyl (7) 4-amidino-4'-[4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl ` ., ~ ~:
~' ' : ' :
' (8) 4-amidino-3'-[4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl Example 3 4-Amidino-4'-[4-(N-methyl-piperidin-3-yloxycarbonyl)-piperidinocarbonylmethyloxy]-biphenyl-dihydrochloride a) 4-[N-Benzyloxycarbonyl-amidino]-4'-[4-(N-methyl-piperidin-3-yloxycarbonyl)-piperidinocarbonyl-`~ methyloxyl-bi~henyl A solution of 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonylmethyloxy]-biphenyl and N-methyl-piperidin-3-ol in a molar ratio of 1:2 in dichloromethane/dimethylformamide is mixed with a solution of 1.1 molar equivalent of dicyclohexyl-carbodiimide in dichloromethane, with stirring, in the presence of a catalytic amount of 4-dimethylamino-pyridine. After standing overnight at ambient temperature, the dicyclohexylurea precipitated is filtered off and the solution is evaporated to dryness under reduced pressure. The residue is taken up in ethyl acetate and washed with 5% sodium bicarbonate solution and then with water and dried over sodium sulphate. The remaining solution is evaporated down under reduced pressure and the residue is purified by chromatography over a silica gel column.
The following compounds are obtained analogously:
(1) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(cycloheptyloxycarbonyl)-piperidinocarbonylmethyl]-biphenyl (2) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(dimethylaminocarbonylmethyloxycarbonylmethyl)-.. ~ -~ .
: . : ~. . , ,~ r 20~81~8 piperidinocarbonyl]-biphenyl (3) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(cyclohexylaminocarbonylmethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (4) 4-[4-(aminocarbonylmethyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl (5) 4-[N-benzyloxycarbonyl-amidino]-3'-[4-trans-(dimethylaminocarbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl (6) 4-[N-ben2yloxycarbonyl-amidino]-4'-methoxy-3'-[4-trans-(piperidinocarbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl (7) 4-[N-benzyloxycarbonyl-amidino]-4'-methoxy-3'-[4-trans-(morpholinocarbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl b) 4-Amidino-4'-[4-(N-methyl piperidin-3-yloxycarbonyl)-~ iperidinocarbonvlmethyloxy]-biphenYl-dihydrochloride The product obtained in a) is hydrogenated in a solution consisting of dimethylformamide, water and lN
hydrochloric acid, in a ratio by volume of 20:1:1, in the presence of (10%) palladium on charcoal for one hour under a pressure of 5 bar. After the catalyst has been suction filtered the remainder is evaporated down under reduced pressure and the residue is suspended in acetone and suction filtered.
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-(cycloheptyloxycarbonyl)-piperidino-carbonylmethyl]-biphenyl-hydrochloride . , . :
.. : .. . .
. . . . .. ::: : :
- -: '~
.. . .
(2) 4-amidino-4'-[4-(dimethylaminocarbonylmethyloxy-carbonylmethyl)-piperidinocarbonyl]-biphenyl (3) 4-amidino-4'-[4-(cyclohexylaminocarbonylmethyloxy-carbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride (4) 4-amidino-4'-[4-(aminocarbonylmethyloxycarbonyl-methyl)-piperidinocarbonyl]-biphenyl-hydrochloride (5) 4-amidino-3'-[4-trans-(dimethylaminocaxbonyl-methyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl-hydrochloride (6) 4-amidino-4'-methoxy-3'-[4-trans-(piperidino-carbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl-hydrochloride (7) 4-amidino-4'-methoxy-3'-[4-trans-(morpholino-carbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl-hydrochloride Example 4 4-Amidino-4'-[4-((exo)-norbornyloxycarbonylmethyl)-piperidino-carbonyl]-biphenyl-hydrochloride A suspension of 0.4 g (0.0011 mol) of 4-amidino-4'-[4-carboxymethyl-piperidinocarbonyl] biphenyl in 10 ml of thionylchloride is refluxed for 2 hours. The solution thus obtained is evaporated to dryness in vacuo and the residue remaining is mixed with 30 ml of dichloromethane and 0.3 g of (exo)-norborneol. After heating to 40C
for 12 hours the mixture is evaporated down in vacuo and the residue remaining is purified over a silica gel column, using dichloromethane/methanol mixtures as eluant.
:. ~-20~98l58 Yield: 150 mg (26.6% of theory),Melting point: 175-180C
The following compound is obtained analogously:
(1) 4-amidino-4'-[4-((-)-menthyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: >260C
Example 5 4-Amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride a) 4-(N-Benzyloxycarbonyl-amidino)-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidino-carbonyl]-bi~henyl A mixture of 1.7 g (0.0034 mol~ of 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonyl]-biphenyl, 1 ml (0.0068 mol) of chloromethyl-pivalate, 1.1 g (0.0068 mol) of potassium iodide, 0.7 g (0.0068 mol) of potassium bicarbonate and 1 g (0.0068 mol) of potassium carbonate in 40 ml of dimethylformamide is stirred for 2 days at ambient temperature. Then it is poured into 150 ml of water and the suspension thus produced is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue remaining is purified by chromatography over a silica gel column, using cyclohexane-ethyl acetate mixtures as solvents.
In this way 1.45 g (68.5% of theory) is obtained in the form of a foamy product which is used for the following stage of synthesis without any further purification.
Rf value: 0.5 (silica gel; methylene chloride/ethanol =
9/1) : `' ~: ` ` ` ' :
2400981~8 The following compounds are obtained analogously:
(1) 4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl Oil, Rf value 0.65 (silica gel; methylene chloride/ethanol = 9:1) (2) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(pivaloyloxymethyloxycarbonylmethylidene)-piperidinocarbonyl]-biphenyl (3) 4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinomethyl]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl (4) 4-[N-benzyloxycarbonyl-amidino]-4'-[(2-(pivaloyloxymethyloxycarbonyl)-ethyl)-aminocarbonylmethyl]-biphenyl (5) 4-[2-(1-ethoxycarbonyloxy)-ethoxycarbonyl)-aminocarbonylmethyloxy]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl (6) 4-[N-benzyloxycarbonyl-amidino]-4'-[1-[2-(4-methoxyphenyl)-ethylaminocarbonyl]-2-(pivaloyloxymethyloxycarbonyl)-ethylamino]-carbonylmethyl]-biphenyl (7) 4-[benzyloxycarbonyl-amidino]-4'-[4-[1-(cyclohexyloxycarbonyloxy)-ethyloxycarbonylmethyl]-piperidinocarbonyl]-biphenyl (8) 4-[benzyloxycarbonyl-amidino]-4'-methoxy-3'-[4-trans-(pivaloyloxymethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl .. -.. : :
2 04~8 1~
(9) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(pivaloyloxymethyl-oxycarbonylmethylidene)-piperidinocarbonyl]-biphenyl (10) 3-[4-trans-[1-(ethoxycarbonyloxy)-ethoxycarbonyl]-cyclohexylaminocarbonyl]-4'-[N-benzyloxycarbonyl-amidino~-4-methoxy-biphenyl b) 4-Amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-~iperidinocarbonyll-biphenyl-hydrochloride The product obtained in a) (1.43 g = 0.0023 mol) is dissolved in a mixture of 20 ml of dimethylformamide and 2.3 ml of 0.5N hydrochloric acid. This solution is hydrogenated at ambient temperature in the presence of 0.2 g of (10%) palladium on charcoal under a pressure of 5 bar for 2.5 hours. After the catalyst has been removed by suction filtering, the solution is adjusted to a pH of 3 and evaporated to dryness under reduced pressure. The residue is suspended in acetone. The solid product is suction filtered.
Yield: 0.8 g (69.8% of theory), Melting point: 168-172C
The following compounds are obtained analogously:
(1) 4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-amidino-biphenyl- ;
hydrochloride with l-chloroethyl-ethyl-carbonate Melting point: 178-182~C
(2) 4-amidino-[4'-[4-(pivaloyloxymethyloxycarbonyl-methylidene)-piperidinocarbonyl]-biphenyl-hydrochloride with pivalate-chloromethylester (3) 4-[4-[(1-(ethoxycarbonyloxy)-athoxycarbonyl)-methyl]-piperidinomethyl~-4'-amidino-biphenyl-hydrochloride 20981~8 (4) 4-amidino-4'-[(2-(pivaloyloxymethyloxycarbonyl)-ethyl)-aminocarbonylmethyl]-biphenyl (5) 4'-amidino-4-[2-(1-ethoxycarbonyloxy)-ethoxycarbonyl)-aminocarbonylmethyloxy]-biphenyl-hydrochloride (6) 4-amidino-4'-[1-[2-(4-methoxyphenyl)-ethylaminocarbonyl]-2-(pivaloyloxymethyloxycarbonyl)-ethylamino]-carbonylmethyl]-biphenyl (7) 4-amidino-4'-[4-[1-(cyclohexyloxycarbonyloxy)-ethyloxy-carbonylmethyl]-piperidinocarbonyl]-biphenyl with 1-chloroethyl-cyclohexyl-carbonate (8) 4-amidino-4'-methoxy-3'-[4-trans-(pivaloyloxymethyloxy-carbonyl)-cyclohexylaminocarbonyl]-biphenyl (9) 4'-amidino-3-[4-trans-[1-(ethoxycarbonyloxy)-ethoxycarbonyl]-cyclohexylaminocarbonyl]-4-methoxy-biphenyl Example 6 4-Amidino-4'-[4-(phthalid-3-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl a) 4-[N-Allyloxycarbonyl-amidino]-4'-~4-(methoxycarbonylmethyl ? -piperidinocarbonyl~-biphenyl To a solution of 2.5 g (0.006 mol) of 4-amidino-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl in 250 ml of dichloromethane are added, at ambient temperature and with stirring, 0.75 ml (0.007 mol) of allylchloroformate and 13 ml (0.013 mol) of lN sodium hydroxide solution. This mixture is stirred for 3 hours .
- : .-: .. :
: . - , ~,- :
.
.
.
20~81~8 at ambient temperature, then left to stand overnight at ambient temperature. The organic phase is separated off, dried over sodium sulphate and stirred with 2 g of activated charcoal. After the drying agent and activated charcoal have been filtered off the solution is evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane/methanol = 1:1;
20 ml of~isopropanol are added and the mixture is concentrated down to 20 ml. After the addition of ether crystallisation sets in. The crystals are suction filtered and washed with water.
Yield: 2.4 g (86.3% of theory), Melting point: 148-152C
The following compound is obtained analogously:
(1) 4-[N-allyloxycarbonyl-amidino]-4'-[[1-[2-(4-methoxy-phenyl)-ethylaminocarbonyl]-2-methoxycarbonyl-ethyl]-aminocarbonyl]-biphenyl b) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonyll-biphenyl 1.95 g (0.042 mol) of the compound prepared in a) are dissolved in 20 ml of tetrahydrofuran and 4 ml of water.
To this solution are added 21 ml of a 1 molar lithium hydroxide solution (0.021 mol) and the mixture is left to stand for 2 hours at ambient temperature. It is then poured into an aqueous potassium hydrogen sulphate solution, the pH is adjusted to 6.S and the mixture is extracted exhaustively with ethyl acetate. The combined ethyl acetate phases are dried and evaporated down. The residue is triturated with ether and suction filtered.
Yield: 1.2 g (63.6~ of theory), Melting point: 189-192C (decomp.) The following compound is obtained analogously:
.: , .
.
~0~8~58 (1) 4-[N-allyloxycarbonyl-amidino]-4'-[[1-[2-(4-methoxy-phenyl)-ethylaminocarbonyl]-2-hydroxycarbonyl-ethyl]-aminocarbonyl]-biphenyl c) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(phthalid-3-vloxy-carbonylmethyl)-piperidinocarbonyl~-biphenyl 0.3 g (0.0007 mol) of the compound prepared under b) are dissolved in 30 ml of dimethylformamide. This solution is mixed with 0.4 g (0.004 mol) of potassium hydrogen carbonate and 0.71 g (0.00~3 mol) of 3-bromophthalide are added thereto with stirring at 0-5C and stirring is continued for 3 hours at this temperature. After this time, the mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate phases are washed with water, dried over sodium sulphate and evaporated down under reduced pressure. The residue is purified by chromatography over silica gel.
The following compound is obtained analogously: -(1) 4-[N-allyloxycarbonyl-amidino]-4'-t[1-[2-(4-methoxy-phenyl)-ethylaminocarbonyl]-2-(phthalid-3-yloxycarbonyl)-ethyl]-aminocarbonyl]-biphenyl d) 4-Amidino-4'-[4-(phthalid-3-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl The compound obtained in c) is dissolved in tetrahydrofuran. Under an inert gas atmosphere, 1 equivalent of morpholine and 0.1 equivalent of tetrakis-(triphenylphosphine)-palladium(o) are added dropwise, with stirring, and stirring is continued for a further hour.
The following compound is obtained analogously:
(1) 4-amidino-4'-[[1-[2-(4-methoxyphenyl)-ethylamino-carbonyl]-2-(phthalid-3-yloxycarbonyl)-ethyl]-~ . ' ~ , ,'- , ..~ . - -'~ . .
204~81~8 aminocarbonyl]-biphenyl Example 7 4-[4-(Cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl -0.6 g (0.0012 mol) of 4-amidino-4'-[4-(cyclohexyloxycarbonylmsthyl)-piperidinocarbonyl]-biphenyl-hydrochloride are suspended in 200 ml of dichloromethane. 0.1 g (0.0012 mol) of methylchloroformate and 24.8 ml (0.0025 mol) of O.lN
sodium hydroxide solution are added with stirring and the mixture is then stirred for a further 2 hours, thereby forming a solution. The aqueous phase is separated off, the dichloromethane solution is dried over sodium sulphate and evaporated to dryness. The residue is triturated with ether, suction filtered and washed with ether.
Yield: 0.44 g (76.2% of theory), Melting point: 218-220C
The following compounds are obtained analogously:
(1) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (2) 4-[N-methoxycarbonyl-amidino]-4'-[4-(N-methyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (3) 4-[N-methoxycarbonyl-amidino]-4'-[4-(tetrahydro-4H-pyran-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (4) 4-[N-(cyclohexylmethyloxycarbonylmethyl)-. , . ,: :
:-.
:
piperidinocarbonyl]-biphenyl (5) 4-t4-(cyclopentyloxycarbonylmethylidene)-piperidinocarbonyl]-4'-tN-methoxycarbonyl-amidino]-biphenyl (6) 4'-[4-(4-cycloheptyloxycarbonyl-butyrylamino)]-4-~N-methoxycarbonyl-amidino]-biphenyl (7) 4-[4-(cyclohexyloxycarbonylmethyl)-piperazino-carbonyl]-4'-tN-methoxycarbonyl-amidino]-biphenyl (8) 4-tN-methoxycarbonyl-amidino]-4'-t4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl (9) 3-t4-trans-cyclohexyloxycarbonyl-cyclohexylamino-carbonyl]-4-methoxy-4~-tN-methoxycarbonyl-amidino]-biphenyl ~10) 4-tN-methoxycarbonyl-amidino]-4'-methoxy-3'-t4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl (11) 4-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-(pivaloyloxymethoxycarbonyl)-amidino]-biphenyl (Pivaloyloxy-methyl)-(4-nitrophenyl)-carbonate and N-ethyl-diisopropylamine are used.
(12) 4-[N-(acetyloxymethoxycarbonyl)-amidino]-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl Acetyloxymethyl-(4-nitrophenyl)-carbonate and N-ethyl-diisopropylamine are used.
(13) 4-[N-~l-acetyloxy-ethoxycarbonyl)-amidino]-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl Acetyloxyethyl-(4-nitrophenyl)-carbonate and N-ethyl-.- -diisopropylamine are used.
(14) 4-[4-[~2,2-dimethyl-propyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino~-biphenyl Melting point: 168-170C
Rf valuè: 0.50 (silica gel, ethyl acetate) (15) 4-(N-methoxycarbonyl-amidino)-4'-[4-[(3-pentyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl Melting point: 148-152C
Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1) (16) 4-[4-[((R)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino)-biphenyl Melting point: 135-138C
Rf value: 0.56 (silica gel, methylene chloride/methanol = 9:1) (17) 4-[4-[((S)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino)-biphenyl Melting point: 130-132C
Rf value: 0.51 (silica gel, methylene chloride/methanol = 9:1) (18) 4-(N-methoxycarbonyl-amidino)-4'-[4-[(2-methyl-propyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl Melting point: 146-152C
Rf value: 0.51 (silica gel, methylene chloride/methanol = 9:1) (19) 4-[4-(isopropyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino)-biphenyl '-: ~ ~ - : . ' 24~9-~l58 Melting point: 146-148~C
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Example a 4-Amidino-4'-[4-(piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride a) 4-Amidino-4'-[4-(N-benzyloxycarbonyl-piperidin-4-' yloxycarbonylmethyl)-piperidinocarbonyll-biPhenyl A suspension of 4-amidino-4'-[4-carboxymethyl-piperidinocarbonyl]-biphenyl, N-benzyloxycarbonyl-piperidin-4-ol and trimethylchlorosilane in a molar ratio of 1:4:10 is refluxed for 36 hours in absolute tetrahydrofuran. It is then evaporated to dryness in vacuo, taken up in dichloromethane and the organic phase is washed with 2N ammonia and then with water. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo and the residue obtained is purified by chromatography over silica gel.
b) 4-Amidino-4'-[4-(piperidin-4-yloxycarbonylmethyl)-piperidino arbonyll-biphenyl-hydrochloride The product prepared in a) is dissolved in dimethylformamide/0.5N hydrochloric acid (10:1) and then hydrogenated in the presence of 10% palladium on charcoal at ambient temperature under a hydrogen pressure of 5 bar.
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-trans-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl `
, - : - , : ' , :
- ~g81S8 (2) 4-amidino-4'-[4-trans-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonyl)-cyclohexyl-N-methyl-aminocarbonyl]-biphenyl (3) 4-amidino-4'-[4-trans-(piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl-dihydrochloride (4~ 4-amidino-4'-[4-trans-(piperidin-4-yloxycarbonyl)-cyclohexyl-N-methyl-aminocarbonyl]-biphenyl-dihydrochloride Example 9 4-[N-Methoxycarbonyl-amidino~-4'-[4-(piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride a) 4-[4-(N-Benzyloxycarbonyl-piperidin-4-yloxycarbonyl-methyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl __ 4-Amidino-4'-[4-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl is suspended in dichloromethane and reacted, with stirring, with an equimolar amount of methylchloroformate in the presence of an equivalent quantity of O.lN sodium hydroxide solution at amhient temperature. The dichloromethane solution is washed with water, dried and evaporated down. The residue is purified by column chromatography over silica gel.
The following compound is obtained analogously:
(1) 4'-[4-trans-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-4-[N-methoxycarbonyl-amidino]-biphenyl .
2098~8 b) 4-[N-Methoxycarbonyl-amidino]-4-[4-(piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride ___ The product obtained in c) is hydrogenated, as described in Example 8b, in the presence of (10%) palladium/charcoal.
The following compound is obtained analogously:
(1) 4-[N-methoxycarbonyl-amidino]-4'-[trans-(piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl Exam~le 10 Dry ampoule containing 2.5 mg of active substance per 1 ml Composition:
Active substance 2.5 mg Mannitol 50.0 mg Water for injections ad 1.0 ml Preparation:
The active substance and mannitol are dissolved in water. After transferring the solution to the ampoule, it is freeze-dried.
At the point of use, the solution is made up with water for injections.
. .
- . . ~ ~ .. .~
.
. ... . . -: . . , ~ ;, .
Example 11 Dry ampoule containing 35 mg of active substance per 2 ml Composition:
Active substance 35.0 mg Mannitol 100.0 mg Water for injections ad 2.0 ml Preparation:
The active substance and mannitol are dissolved in water. After transferring the solution to the ampoule, it is freeze-dried.
At the point of use, the solution is made up with water for injections.
Example 12 Tablet containing 50 mg of active substance . ~ ~
Composition:
(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mq 215.0 mg :.; : ~ .. - : . . :. - :
. .. . , . :: .
~: . . . : ;
: . . ~ :
Rf value: 0.73 (silica gel, methylene chloride/methanol = 4:1) (13) 4-amidino-4'-t4-[(3-pentyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 205-207C
R~ value: 0.52 (silica gel, methylene chloride/methanol = 4:1) (14) 4-amidino-4'-[4-[((R)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 203-205C
Rf value: 0.56 (silica gel, methylene chloride/methanol = 4:1~
~15) 4-amidino-4'-[4-[((S)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: 205-208C
Rf valuè~ 0.56 (silica gel, methylene chloride/methanol = 4 1) (16) 4-amidino-4'-[4-[(2-methyl-propyloxy)-carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride This is done without the addition of methylene chloride and the mixture is left to stand for 18 hours at ambient temperature.
Melting point: 218-223C
Rf value: 0.64 (silica gel, methylene chloride/methanol = 4:1) (17) 4-amidino-4'-[4-trans-(isopropyloxycarbonyl)-cyclo-hexylaminocarbonyl]-biphenyl-hydrochloride This is done without the addition of methylene chloride and, after the introduction of hydrogen chloride, the mixture is left to stand for 5 days at ambient temperature.
Rf value: 0.41 (silica gel, methylene chloride/methanol = 8:2) (18) 4-amidino-4'-[4-(isopropyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl-hydrochloride The same procedure is used as in (16).
Melting point: 248-250C
Rf value: 0.25 (Reversed Phase Plate RP18, methanol/5%
sodium chloride solution = 6:4) , ~ : ` . -'~.,. .: :
~;, ~ ' ' . .
Example 2 4-Amidino-4'-[4-(cyclohexylmethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl A suspension of 4-amidino-4'-[4-carboxymethyl-piperidinocarbonyl]-biphenyl, hydroxymethylcyclohexane and trimethylchlorosilane in a molar ratio of 1:4:10 is refluxed for 36 hours in dry tetrahydrofuran. It is then evaporated to dryness under reduced pressure, diluted with dichloromethane and washed with 2N ammonia and then with water. After drying over sodium sulphate ` the mixture is evaporated to dryness under reduced pressure. The residue is purified by chromatography over a silica gel column.
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-(N-methyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (2) 4-[4-(N-acetyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-4'-amidino-biphenyl (3) 4-amidino-4'-[4-(tetrahydro-4H-pyran-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (4) 4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (5) 4-amidino-4'-[5-(N-benzyl-piperidin-4-yloxycarbonyl)-pentyloxy]-biphenyl (6) 4-amidino-4'-t4-(tetrahydrofuran-3-yloxycarbonyl)-butyloxy]-biphenyl (7) 4-amidino-4'-[4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl ` ., ~ ~:
~' ' : ' :
' (8) 4-amidino-3'-[4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl Example 3 4-Amidino-4'-[4-(N-methyl-piperidin-3-yloxycarbonyl)-piperidinocarbonylmethyloxy]-biphenyl-dihydrochloride a) 4-[N-Benzyloxycarbonyl-amidino]-4'-[4-(N-methyl-piperidin-3-yloxycarbonyl)-piperidinocarbonyl-`~ methyloxyl-bi~henyl A solution of 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonylmethyloxy]-biphenyl and N-methyl-piperidin-3-ol in a molar ratio of 1:2 in dichloromethane/dimethylformamide is mixed with a solution of 1.1 molar equivalent of dicyclohexyl-carbodiimide in dichloromethane, with stirring, in the presence of a catalytic amount of 4-dimethylamino-pyridine. After standing overnight at ambient temperature, the dicyclohexylurea precipitated is filtered off and the solution is evaporated to dryness under reduced pressure. The residue is taken up in ethyl acetate and washed with 5% sodium bicarbonate solution and then with water and dried over sodium sulphate. The remaining solution is evaporated down under reduced pressure and the residue is purified by chromatography over a silica gel column.
The following compounds are obtained analogously:
(1) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(cycloheptyloxycarbonyl)-piperidinocarbonylmethyl]-biphenyl (2) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(dimethylaminocarbonylmethyloxycarbonylmethyl)-.. ~ -~ .
: . : ~. . , ,~ r 20~81~8 piperidinocarbonyl]-biphenyl (3) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(cyclohexylaminocarbonylmethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (4) 4-[4-(aminocarbonylmethyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl (5) 4-[N-benzyloxycarbonyl-amidino]-3'-[4-trans-(dimethylaminocarbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl (6) 4-[N-ben2yloxycarbonyl-amidino]-4'-methoxy-3'-[4-trans-(piperidinocarbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl (7) 4-[N-benzyloxycarbonyl-amidino]-4'-methoxy-3'-[4-trans-(morpholinocarbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl b) 4-Amidino-4'-[4-(N-methyl piperidin-3-yloxycarbonyl)-~ iperidinocarbonvlmethyloxy]-biphenYl-dihydrochloride The product obtained in a) is hydrogenated in a solution consisting of dimethylformamide, water and lN
hydrochloric acid, in a ratio by volume of 20:1:1, in the presence of (10%) palladium on charcoal for one hour under a pressure of 5 bar. After the catalyst has been suction filtered the remainder is evaporated down under reduced pressure and the residue is suspended in acetone and suction filtered.
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-(cycloheptyloxycarbonyl)-piperidino-carbonylmethyl]-biphenyl-hydrochloride . , . :
.. : .. . .
. . . . .. ::: : :
- -: '~
.. . .
(2) 4-amidino-4'-[4-(dimethylaminocarbonylmethyloxy-carbonylmethyl)-piperidinocarbonyl]-biphenyl (3) 4-amidino-4'-[4-(cyclohexylaminocarbonylmethyloxy-carbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride (4) 4-amidino-4'-[4-(aminocarbonylmethyloxycarbonyl-methyl)-piperidinocarbonyl]-biphenyl-hydrochloride (5) 4-amidino-3'-[4-trans-(dimethylaminocaxbonyl-methyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl-hydrochloride (6) 4-amidino-4'-methoxy-3'-[4-trans-(piperidino-carbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl-hydrochloride (7) 4-amidino-4'-methoxy-3'-[4-trans-(morpholino-carbonylmethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl-hydrochloride Example 4 4-Amidino-4'-[4-((exo)-norbornyloxycarbonylmethyl)-piperidino-carbonyl]-biphenyl-hydrochloride A suspension of 0.4 g (0.0011 mol) of 4-amidino-4'-[4-carboxymethyl-piperidinocarbonyl] biphenyl in 10 ml of thionylchloride is refluxed for 2 hours. The solution thus obtained is evaporated to dryness in vacuo and the residue remaining is mixed with 30 ml of dichloromethane and 0.3 g of (exo)-norborneol. After heating to 40C
for 12 hours the mixture is evaporated down in vacuo and the residue remaining is purified over a silica gel column, using dichloromethane/methanol mixtures as eluant.
:. ~-20~98l58 Yield: 150 mg (26.6% of theory),Melting point: 175-180C
The following compound is obtained analogously:
(1) 4-amidino-4'-[4-((-)-menthyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride Melting point: >260C
Example 5 4-Amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride a) 4-(N-Benzyloxycarbonyl-amidino)-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidino-carbonyl]-bi~henyl A mixture of 1.7 g (0.0034 mol~ of 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonyl]-biphenyl, 1 ml (0.0068 mol) of chloromethyl-pivalate, 1.1 g (0.0068 mol) of potassium iodide, 0.7 g (0.0068 mol) of potassium bicarbonate and 1 g (0.0068 mol) of potassium carbonate in 40 ml of dimethylformamide is stirred for 2 days at ambient temperature. Then it is poured into 150 ml of water and the suspension thus produced is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue remaining is purified by chromatography over a silica gel column, using cyclohexane-ethyl acetate mixtures as solvents.
In this way 1.45 g (68.5% of theory) is obtained in the form of a foamy product which is used for the following stage of synthesis without any further purification.
Rf value: 0.5 (silica gel; methylene chloride/ethanol =
9/1) : `' ~: ` ` ` ' :
2400981~8 The following compounds are obtained analogously:
(1) 4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl Oil, Rf value 0.65 (silica gel; methylene chloride/ethanol = 9:1) (2) 4-[N-benzyloxycarbonyl-amidino]-4'-[4-(pivaloyloxymethyloxycarbonylmethylidene)-piperidinocarbonyl]-biphenyl (3) 4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinomethyl]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl (4) 4-[N-benzyloxycarbonyl-amidino]-4'-[(2-(pivaloyloxymethyloxycarbonyl)-ethyl)-aminocarbonylmethyl]-biphenyl (5) 4-[2-(1-ethoxycarbonyloxy)-ethoxycarbonyl)-aminocarbonylmethyloxy]-4'-[N-benzyloxycarbonyl-amidino]-biphenyl (6) 4-[N-benzyloxycarbonyl-amidino]-4'-[1-[2-(4-methoxyphenyl)-ethylaminocarbonyl]-2-(pivaloyloxymethyloxycarbonyl)-ethylamino]-carbonylmethyl]-biphenyl (7) 4-[benzyloxycarbonyl-amidino]-4'-[4-[1-(cyclohexyloxycarbonyloxy)-ethyloxycarbonylmethyl]-piperidinocarbonyl]-biphenyl (8) 4-[benzyloxycarbonyl-amidino]-4'-methoxy-3'-[4-trans-(pivaloyloxymethyloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl .. -.. : :
2 04~8 1~
(9) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(pivaloyloxymethyl-oxycarbonylmethylidene)-piperidinocarbonyl]-biphenyl (10) 3-[4-trans-[1-(ethoxycarbonyloxy)-ethoxycarbonyl]-cyclohexylaminocarbonyl]-4'-[N-benzyloxycarbonyl-amidino~-4-methoxy-biphenyl b) 4-Amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-~iperidinocarbonyll-biphenyl-hydrochloride The product obtained in a) (1.43 g = 0.0023 mol) is dissolved in a mixture of 20 ml of dimethylformamide and 2.3 ml of 0.5N hydrochloric acid. This solution is hydrogenated at ambient temperature in the presence of 0.2 g of (10%) palladium on charcoal under a pressure of 5 bar for 2.5 hours. After the catalyst has been removed by suction filtering, the solution is adjusted to a pH of 3 and evaporated to dryness under reduced pressure. The residue is suspended in acetone. The solid product is suction filtered.
Yield: 0.8 g (69.8% of theory), Melting point: 168-172C
The following compounds are obtained analogously:
(1) 4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-amidino-biphenyl- ;
hydrochloride with l-chloroethyl-ethyl-carbonate Melting point: 178-182~C
(2) 4-amidino-[4'-[4-(pivaloyloxymethyloxycarbonyl-methylidene)-piperidinocarbonyl]-biphenyl-hydrochloride with pivalate-chloromethylester (3) 4-[4-[(1-(ethoxycarbonyloxy)-athoxycarbonyl)-methyl]-piperidinomethyl~-4'-amidino-biphenyl-hydrochloride 20981~8 (4) 4-amidino-4'-[(2-(pivaloyloxymethyloxycarbonyl)-ethyl)-aminocarbonylmethyl]-biphenyl (5) 4'-amidino-4-[2-(1-ethoxycarbonyloxy)-ethoxycarbonyl)-aminocarbonylmethyloxy]-biphenyl-hydrochloride (6) 4-amidino-4'-[1-[2-(4-methoxyphenyl)-ethylaminocarbonyl]-2-(pivaloyloxymethyloxycarbonyl)-ethylamino]-carbonylmethyl]-biphenyl (7) 4-amidino-4'-[4-[1-(cyclohexyloxycarbonyloxy)-ethyloxy-carbonylmethyl]-piperidinocarbonyl]-biphenyl with 1-chloroethyl-cyclohexyl-carbonate (8) 4-amidino-4'-methoxy-3'-[4-trans-(pivaloyloxymethyloxy-carbonyl)-cyclohexylaminocarbonyl]-biphenyl (9) 4'-amidino-3-[4-trans-[1-(ethoxycarbonyloxy)-ethoxycarbonyl]-cyclohexylaminocarbonyl]-4-methoxy-biphenyl Example 6 4-Amidino-4'-[4-(phthalid-3-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl a) 4-[N-Allyloxycarbonyl-amidino]-4'-~4-(methoxycarbonylmethyl ? -piperidinocarbonyl~-biphenyl To a solution of 2.5 g (0.006 mol) of 4-amidino-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl in 250 ml of dichloromethane are added, at ambient temperature and with stirring, 0.75 ml (0.007 mol) of allylchloroformate and 13 ml (0.013 mol) of lN sodium hydroxide solution. This mixture is stirred for 3 hours .
- : .-: .. :
: . - , ~,- :
.
.
.
20~81~8 at ambient temperature, then left to stand overnight at ambient temperature. The organic phase is separated off, dried over sodium sulphate and stirred with 2 g of activated charcoal. After the drying agent and activated charcoal have been filtered off the solution is evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane/methanol = 1:1;
20 ml of~isopropanol are added and the mixture is concentrated down to 20 ml. After the addition of ether crystallisation sets in. The crystals are suction filtered and washed with water.
Yield: 2.4 g (86.3% of theory), Melting point: 148-152C
The following compound is obtained analogously:
(1) 4-[N-allyloxycarbonyl-amidino]-4'-[[1-[2-(4-methoxy-phenyl)-ethylaminocarbonyl]-2-methoxycarbonyl-ethyl]-aminocarbonyl]-biphenyl b) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonyll-biphenyl 1.95 g (0.042 mol) of the compound prepared in a) are dissolved in 20 ml of tetrahydrofuran and 4 ml of water.
To this solution are added 21 ml of a 1 molar lithium hydroxide solution (0.021 mol) and the mixture is left to stand for 2 hours at ambient temperature. It is then poured into an aqueous potassium hydrogen sulphate solution, the pH is adjusted to 6.S and the mixture is extracted exhaustively with ethyl acetate. The combined ethyl acetate phases are dried and evaporated down. The residue is triturated with ether and suction filtered.
Yield: 1.2 g (63.6~ of theory), Melting point: 189-192C (decomp.) The following compound is obtained analogously:
.: , .
.
~0~8~58 (1) 4-[N-allyloxycarbonyl-amidino]-4'-[[1-[2-(4-methoxy-phenyl)-ethylaminocarbonyl]-2-hydroxycarbonyl-ethyl]-aminocarbonyl]-biphenyl c) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(phthalid-3-vloxy-carbonylmethyl)-piperidinocarbonyl~-biphenyl 0.3 g (0.0007 mol) of the compound prepared under b) are dissolved in 30 ml of dimethylformamide. This solution is mixed with 0.4 g (0.004 mol) of potassium hydrogen carbonate and 0.71 g (0.00~3 mol) of 3-bromophthalide are added thereto with stirring at 0-5C and stirring is continued for 3 hours at this temperature. After this time, the mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate phases are washed with water, dried over sodium sulphate and evaporated down under reduced pressure. The residue is purified by chromatography over silica gel.
The following compound is obtained analogously: -(1) 4-[N-allyloxycarbonyl-amidino]-4'-t[1-[2-(4-methoxy-phenyl)-ethylaminocarbonyl]-2-(phthalid-3-yloxycarbonyl)-ethyl]-aminocarbonyl]-biphenyl d) 4-Amidino-4'-[4-(phthalid-3-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl The compound obtained in c) is dissolved in tetrahydrofuran. Under an inert gas atmosphere, 1 equivalent of morpholine and 0.1 equivalent of tetrakis-(triphenylphosphine)-palladium(o) are added dropwise, with stirring, and stirring is continued for a further hour.
The following compound is obtained analogously:
(1) 4-amidino-4'-[[1-[2-(4-methoxyphenyl)-ethylamino-carbonyl]-2-(phthalid-3-yloxycarbonyl)-ethyl]-~ . ' ~ , ,'- , ..~ . - -'~ . .
204~81~8 aminocarbonyl]-biphenyl Example 7 4-[4-(Cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl -0.6 g (0.0012 mol) of 4-amidino-4'-[4-(cyclohexyloxycarbonylmsthyl)-piperidinocarbonyl]-biphenyl-hydrochloride are suspended in 200 ml of dichloromethane. 0.1 g (0.0012 mol) of methylchloroformate and 24.8 ml (0.0025 mol) of O.lN
sodium hydroxide solution are added with stirring and the mixture is then stirred for a further 2 hours, thereby forming a solution. The aqueous phase is separated off, the dichloromethane solution is dried over sodium sulphate and evaporated to dryness. The residue is triturated with ether, suction filtered and washed with ether.
Yield: 0.44 g (76.2% of theory), Melting point: 218-220C
The following compounds are obtained analogously:
(1) 4-[N-allyloxycarbonyl-amidino]-4'-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (2) 4-[N-methoxycarbonyl-amidino]-4'-[4-(N-methyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (3) 4-[N-methoxycarbonyl-amidino]-4'-[4-(tetrahydro-4H-pyran-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl (4) 4-[N-(cyclohexylmethyloxycarbonylmethyl)-. , . ,: :
:-.
:
piperidinocarbonyl]-biphenyl (5) 4-t4-(cyclopentyloxycarbonylmethylidene)-piperidinocarbonyl]-4'-tN-methoxycarbonyl-amidino]-biphenyl (6) 4'-[4-(4-cycloheptyloxycarbonyl-butyrylamino)]-4-~N-methoxycarbonyl-amidino]-biphenyl (7) 4-[4-(cyclohexyloxycarbonylmethyl)-piperazino-carbonyl]-4'-tN-methoxycarbonyl-amidino]-biphenyl (8) 4-tN-methoxycarbonyl-amidino]-4'-t4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl (9) 3-t4-trans-cyclohexyloxycarbonyl-cyclohexylamino-carbonyl]-4-methoxy-4~-tN-methoxycarbonyl-amidino]-biphenyl ~10) 4-tN-methoxycarbonyl-amidino]-4'-methoxy-3'-t4-trans-(N-methyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl (11) 4-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-(pivaloyloxymethoxycarbonyl)-amidino]-biphenyl (Pivaloyloxy-methyl)-(4-nitrophenyl)-carbonate and N-ethyl-diisopropylamine are used.
(12) 4-[N-(acetyloxymethoxycarbonyl)-amidino]-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl Acetyloxymethyl-(4-nitrophenyl)-carbonate and N-ethyl-diisopropylamine are used.
(13) 4-[N-~l-acetyloxy-ethoxycarbonyl)-amidino]-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl Acetyloxyethyl-(4-nitrophenyl)-carbonate and N-ethyl-.- -diisopropylamine are used.
(14) 4-[4-[~2,2-dimethyl-propyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino~-biphenyl Melting point: 168-170C
Rf valuè: 0.50 (silica gel, ethyl acetate) (15) 4-(N-methoxycarbonyl-amidino)-4'-[4-[(3-pentyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl Melting point: 148-152C
Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1) (16) 4-[4-[((R)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino)-biphenyl Melting point: 135-138C
Rf value: 0.56 (silica gel, methylene chloride/methanol = 9:1) (17) 4-[4-[((S)-2-butyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino)-biphenyl Melting point: 130-132C
Rf value: 0.51 (silica gel, methylene chloride/methanol = 9:1) (18) 4-(N-methoxycarbonyl-amidino)-4'-[4-[(2-methyl-propyloxy)carbonylmethyl]-piperidinocarbonyl]-biphenyl Melting point: 146-152C
Rf value: 0.51 (silica gel, methylene chloride/methanol = 9:1) (19) 4-[4-(isopropyloxy)carbonylmethyl]-piperidinocarbonyl]-4'-(N-methoxycarbonyl-amidino)-biphenyl '-: ~ ~ - : . ' 24~9-~l58 Melting point: 146-148~C
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Example a 4-Amidino-4'-[4-(piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride a) 4-Amidino-4'-[4-(N-benzyloxycarbonyl-piperidin-4-' yloxycarbonylmethyl)-piperidinocarbonyll-biPhenyl A suspension of 4-amidino-4'-[4-carboxymethyl-piperidinocarbonyl]-biphenyl, N-benzyloxycarbonyl-piperidin-4-ol and trimethylchlorosilane in a molar ratio of 1:4:10 is refluxed for 36 hours in absolute tetrahydrofuran. It is then evaporated to dryness in vacuo, taken up in dichloromethane and the organic phase is washed with 2N ammonia and then with water. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo and the residue obtained is purified by chromatography over silica gel.
b) 4-Amidino-4'-[4-(piperidin-4-yloxycarbonylmethyl)-piperidino arbonyll-biphenyl-hydrochloride The product prepared in a) is dissolved in dimethylformamide/0.5N hydrochloric acid (10:1) and then hydrogenated in the presence of 10% palladium on charcoal at ambient temperature under a hydrogen pressure of 5 bar.
The following compounds are obtained analogously:
(1) 4-amidino-4'-[4-trans-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl `
, - : - , : ' , :
- ~g81S8 (2) 4-amidino-4'-[4-trans-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonyl)-cyclohexyl-N-methyl-aminocarbonyl]-biphenyl (3) 4-amidino-4'-[4-trans-(piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl-dihydrochloride (4~ 4-amidino-4'-[4-trans-(piperidin-4-yloxycarbonyl)-cyclohexyl-N-methyl-aminocarbonyl]-biphenyl-dihydrochloride Example 9 4-[N-Methoxycarbonyl-amidino~-4'-[4-(piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride a) 4-[4-(N-Benzyloxycarbonyl-piperidin-4-yloxycarbonyl-methyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl __ 4-Amidino-4'-[4-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl is suspended in dichloromethane and reacted, with stirring, with an equimolar amount of methylchloroformate in the presence of an equivalent quantity of O.lN sodium hydroxide solution at amhient temperature. The dichloromethane solution is washed with water, dried and evaporated down. The residue is purified by column chromatography over silica gel.
The following compound is obtained analogously:
(1) 4'-[4-trans-(N-benzyloxycarbonyl-piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-4-[N-methoxycarbonyl-amidino]-biphenyl .
2098~8 b) 4-[N-Methoxycarbonyl-amidino]-4-[4-(piperidin-4-yloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl-hydrochloride ___ The product obtained in c) is hydrogenated, as described in Example 8b, in the presence of (10%) palladium/charcoal.
The following compound is obtained analogously:
(1) 4-[N-methoxycarbonyl-amidino]-4'-[trans-(piperidin-4-yloxycarbonyl)-cyclohexylaminocarbonyl]-biphenyl Exam~le 10 Dry ampoule containing 2.5 mg of active substance per 1 ml Composition:
Active substance 2.5 mg Mannitol 50.0 mg Water for injections ad 1.0 ml Preparation:
The active substance and mannitol are dissolved in water. After transferring the solution to the ampoule, it is freeze-dried.
At the point of use, the solution is made up with water for injections.
. .
- . . ~ ~ .. .~
.
. ... . . -: . . , ~ ;, .
Example 11 Dry ampoule containing 35 mg of active substance per 2 ml Composition:
Active substance 35.0 mg Mannitol 100.0 mg Water for injections ad 2.0 ml Preparation:
The active substance and mannitol are dissolved in water. After transferring the solution to the ampoule, it is freeze-dried.
At the point of use, the solution is made up with water for injections.
Example 12 Tablet containing 50 mg of active substance . ~ ~
Composition:
(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mq 215.0 mg :.; : ~ .. - : . . :. - :
. .. . , . :: .
~: . . . : ;
: . . ~ :
20~81~g Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granules. From this mixture, compressed tablets are produced, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 9 mm.
Example 13 Tablet containing 350 mg of active substance Composition:
(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Corn starch 80.0 mg (4) Polyvinylpyrrolidone30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granules. From this mixture, compressed tablets are produced, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 12 mm.
209~1~8 Example 14 Capsules containing 50 mg of active substance Com~osition:
(1) Actlve substance 50.0 mg (2) Dried corn starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg Pre~aration:
(1) is triturated with (3). This triturate is added to the mixture of (2) and (4), with thorough mixing.
This powdered mixture is packed into size 3 hard gelatin oblong capsules in a capsule filling machine.
Example 15 Capsules containing 350 mg of active substance ; .. _.
Composition:
(1) Active substance 350.0 mg (2) Dried corn starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation:
(1) is triturated with (3). This triturate is added to the mixture of (2) and (4), with thorough mixing.
-: : , : - : , ~ :
2098~58 This powdered mixture is packed into size O hard gelatin oblong capsules in a capsule filling machine.
, - , : , ~
- -- : .. ~ ;: .
. . .
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granules. From this mixture, compressed tablets are produced, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 9 mm.
Example 13 Tablet containing 350 mg of active substance Composition:
(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Corn starch 80.0 mg (4) Polyvinylpyrrolidone30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granules. From this mixture, compressed tablets are produced, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 12 mm.
209~1~8 Example 14 Capsules containing 50 mg of active substance Com~osition:
(1) Actlve substance 50.0 mg (2) Dried corn starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg Pre~aration:
(1) is triturated with (3). This triturate is added to the mixture of (2) and (4), with thorough mixing.
This powdered mixture is packed into size 3 hard gelatin oblong capsules in a capsule filling machine.
Example 15 Capsules containing 350 mg of active substance ; .. _.
Composition:
(1) Active substance 350.0 mg (2) Dried corn starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation:
(1) is triturated with (3). This triturate is added to the mixture of (2) and (4), with thorough mixing.
-: : , : - : , ~ :
2098~58 This powdered mixture is packed into size O hard gelatin oblong capsules in a capsule filling machine.
, - , : , ~
- -- : .. ~ ;: .
. . .
Claims (16)
1. Compounds of formula I:
(I) (wherein, with the proviso that if E denotes a (C2-3-alkoxy-carbonyl) group or a benzyloxycarbonyl group, Ra does not denote an amidino group optionally substituted by a (C2-3-alkoxycarbonyl) group or by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C1-6-alkoxy)carbonyl, phenyl(C1-6-alkoxy)carbonyl, (C3-5alkenyl)oxycarbonyl or phenyl(C3-5-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1-5-alkyl or C1-5-alkoxy group, or a C5-7-cycloalkyl, C5-7-cycloalkyloxy, phenylalkyl, phenylalkoxy, phenyl or phenoxy group, R2 denotes a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl, or phenyl group and R3 denotes a hydrogen atom or a C1-6-alkyl group;
Rb denotes a hydrogen atom or an alkyl, hydroxy or alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, wherein the -CH2CO- and -O-CH2CO- groups are each connected to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2)n- group (wherein X
denotes a bond or an -HCR5- or -NR5- group), or an -NR4-CH2CH2-R6C=CH-, -NR4-CO-(CH2)m- or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, the above-mentioned Y
or -NR4- groups each being linked to the group A, and wherein n denotes the number 0 or 1, m denotes the number 2, 3, 4 or 5, R4 denotes a hydrogen atom or an alkyl or phenylalkyl group and R5 denotes a hydrogen atom, or R4 and R5 together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2-5-alkylene group, in which the ethylene group may be substituted by a phenylalkylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C2-6-alkoxy)carbonyl or phenylalkoxycarbonyl group, a (C4-10cycloalkyloxycarbonyl) group in which a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl, or C26-alkanoyl group, and wherein the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (C5-8-cycloalkenyl)oxycarbonyl, (C3-5-alkenyl)oxycarbonyl, phenyl(C3-5-alkenyl)oxycarbonyl, (C3-5-alkynyl)oxycarbonyl or phenyl( C3-5-alkynyl)oxycarbonyl group wherein the carbon attached to the oxycarbonyl moiety does not itself carry a double or triple bond, a (C3-8-cycloalkyl)alkoxycarbonyl group, a (C8-10-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two alkyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group, wherein R7 denotes an amino group optionally substituted by 1 or 2 C1-6-alkyl groups or by a C3-8-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkyl-piperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy-carbonyl group;
whilst unless otherwise specified any alkyl or alkoxy moiety contains 1 to 3 carbon atoms, and any phenyl nuclei mentioned above in the definitions of groups Ra, B and E may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identical or different);
and the stereoisomers thereof, including the mixtures and the salts thereof.
(I) (wherein, with the proviso that if E denotes a (C2-3-alkoxy-carbonyl) group or a benzyloxycarbonyl group, Ra does not denote an amidino group optionally substituted by a (C2-3-alkoxycarbonyl) group or by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C1-6-alkoxy)carbonyl, phenyl(C1-6-alkoxy)carbonyl, (C3-5alkenyl)oxycarbonyl or phenyl(C3-5-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1-5-alkyl or C1-5-alkoxy group, or a C5-7-cycloalkyl, C5-7-cycloalkyloxy, phenylalkyl, phenylalkoxy, phenyl or phenoxy group, R2 denotes a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl, or phenyl group and R3 denotes a hydrogen atom or a C1-6-alkyl group;
Rb denotes a hydrogen atom or an alkyl, hydroxy or alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, wherein the -CH2CO- and -O-CH2CO- groups are each connected to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2)n- group (wherein X
denotes a bond or an -HCR5- or -NR5- group), or an -NR4-CH2CH2-R6C=CH-, -NR4-CO-(CH2)m- or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, the above-mentioned Y
or -NR4- groups each being linked to the group A, and wherein n denotes the number 0 or 1, m denotes the number 2, 3, 4 or 5, R4 denotes a hydrogen atom or an alkyl or phenylalkyl group and R5 denotes a hydrogen atom, or R4 and R5 together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2-5-alkylene group, in which the ethylene group may be substituted by a phenylalkylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C2-6-alkoxy)carbonyl or phenylalkoxycarbonyl group, a (C4-10cycloalkyloxycarbonyl) group in which a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl, or C26-alkanoyl group, and wherein the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (C5-8-cycloalkenyl)oxycarbonyl, (C3-5-alkenyl)oxycarbonyl, phenyl(C3-5-alkenyl)oxycarbonyl, (C3-5-alkynyl)oxycarbonyl or phenyl( C3-5-alkynyl)oxycarbonyl group wherein the carbon attached to the oxycarbonyl moiety does not itself carry a double or triple bond, a (C3-8-cycloalkyl)alkoxycarbonyl group, a (C8-10-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two alkyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group, wherein R7 denotes an amino group optionally substituted by 1 or 2 C1-6-alkyl groups or by a C3-8-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkyl-piperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy-carbonyl group;
whilst unless otherwise specified any alkyl or alkoxy moiety contains 1 to 3 carbon atoms, and any phenyl nuclei mentioned above in the definitions of groups Ra, B and E may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identical or different);
and the stereoisomers thereof, including the mixtures and the salts thereof.
2. Compounds of formula I as claimed in claim 1, wherein, with the proviso that if E denotes a (C2-3-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra does not represent an amidino group optionally substituted by a (C2-3-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C1-3-alkoxy)carbonyl, phenyl(C1-3-alkoxy)carbonyl or (C3-4-alkenyl)oxycarbonyl group, wherein R1 denotes a straight-chained or branched C1-5-alkyl group or a phenyl(C1-3-alkyl), C1-3-alkoxy, C5-7-cycloalkyl, C5-7-cycloalkoxy, or phenyl group, R2 denotes a hydrogen atom or a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a hydroxy or C1-3-alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the -CH2CO- and -O-CH2CO- groups are each linked-to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2)n- group (wherein X
denotes a bond or an -HCR5- or -NR5- group), an -NR4-CH2CH2-R6C=CH-, -NR4-CO-(CH2)m- or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3, 4 or 5, n denotes the number 0 or 1, R4 denotes a hydrogen atom or a C1-3-alkyl or benzyl group and R5 denotes a hydrogen atom, or R4 and R5 together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2-5-alkylene group, in which the ethylene group may be substituted in the .alpha.-position by a phenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C2-6-alkoxy)carbonyl group, a benzyloxycarbonyl group, a (C4-10-cycloalkyloxycarbonyl) group wherein a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 C1-3-alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or C2-4-alkanoyl group, a (C5-7-cycloalkyl)(C1-2-alkoxy)carbonyl group, a (C8-9-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two methyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C13-alkyl groups or by a C5-7-cycloalkyl group, or E represents a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-methyl-piperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy-carbonyl group;
whilst any phenyl nuclei mentioned above in the definitions of groups Ra, B and E may each be mono- or disubstituted by fluorine, chlorine or bromine atoms or methyl, hydroxy, methoxy, trifluoromethyl, nitro, amino, methylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identical or different;
and the stereoisomers thereof, including the mixtures and the salts thereof.
Rb denotes a hydrogen atom or a hydroxy or C1-3-alkoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the -CH2CO- and -O-CH2CO- groups are each linked-to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2)n- group (wherein X
denotes a bond or an -HCR5- or -NR5- group), an -NR4-CH2CH2-R6C=CH-, -NR4-CO-(CH2)m- or -Y-W- group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y may also denote an oxygen atom, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3, 4 or 5, n denotes the number 0 or 1, R4 denotes a hydrogen atom or a C1-3-alkyl or benzyl group and R5 denotes a hydrogen atom, or R4 and R5 together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2-5-alkylene group, in which the ethylene group may be substituted in the .alpha.-position by a phenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C2-6-alkoxy)carbonyl group, a benzyloxycarbonyl group, a (C4-10-cycloalkyloxycarbonyl) group wherein a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 C1-3-alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which, in the cycloalkyloxy moiety, a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or C2-4-alkanoyl group, a (C5-7-cycloalkyl)(C1-2-alkoxy)carbonyl group, a (C8-9-bicycloalkyloxycarbonyl) group which may additionally be substituted by one or two methyl groups in the bicycloalkyl moiety, an R1-CO-O-(R2CR3)-O-CO- group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C13-alkyl groups or by a C5-7-cycloalkyl group, or E represents a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-methyl-piperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy-carbonyl group;
whilst any phenyl nuclei mentioned above in the definitions of groups Ra, B and E may each be mono- or disubstituted by fluorine, chlorine or bromine atoms or methyl, hydroxy, methoxy, trifluoromethyl, nitro, amino, methylamino, acetamino, methanesulphonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl groups, and the substituents may be identical or different;
and the stereoisomers thereof, including the mixtures and the salts thereof.
3. Compounds of formula I as claimed in claim 1 or claim 2, wherein, with the proviso that if E denotes a (C2-3-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra does not denote an amidino group optionally substituted by a (C2-3-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, (C1-3-alkoxy)carbonyl, benzyloxycarbonyl or allyloxycarbonyl group, wherein R1 denotes a straight-chained or branched C1-4-alkyl group, a C1-3-alkoxy group or a cyclohexyloxy group, R2 denotes a hydrogen atom or a methyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a methoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the -CH2CO- and -O-CH2CO- groups are each linked to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2)n- group (wherein X
denotes a bond or an -HCR5- or -NR5- group), an -NR4-CH2CH2-R6C=CH-, -NR4-CO-(CH2)m or -Y-W group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y ,may also denote an oxygen atom, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3 or 4, n denotes the number 0 or 1, R4 denotes a hydrogen atom, a C1-3-alkyl group or a benzyl group and R5 denotes a hydrogen atom, or R4 and R5 together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2-5-alkylene group, in which the ethylene group may be substituted in the .alpha.-position by a methoxyphenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C2-6-alkoxy)carbonyl group, a (C6-10-cycloalkyloxycarbonyl) group in which the cyclohexyl moiety may additionally be substituted by 1 or 2 C1-3-alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which a methylene group in the 3- or 4-position in the cycloalkyloxy moiety is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or acetyl group, a (C5-6-cycloalkyl)(C1-2-alkoxy)carbonyl group, a (C8-bicycloalkyloxycarbonyl) group, an R1-CO-O-(R2CR3)-O-CO-group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by 1 or 2 methyl groups or by a cyclohexyl group, or E denotes a piperidinyl or morpholinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxycarbonyl group;
and the stereoisomers thereof, including the mixtures and the salts thereof.
Rb denotes a hydrogen atom or a methoxy group;
A denotes a bond or a -CH2-, -CO-, -CH2CO- or -O-CH2CO-group, whilst the -CH2CO- and -O-CH2CO- groups are each linked to the group B via the carbonyl group;
B denotes an -NR4-CH2CH2-X-(CH2)n- group (wherein X
denotes a bond or an -HCR5- or -NR5- group), an -NR4-CH2CH2-R6C=CH-, -NR4-CO-(CH2)m or -Y-W group, wherein Y denotes an -NR4- group or, if A denotes a bond, Y ,may also denote an oxygen atom, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein m denotes the number 2, 3 or 4, n denotes the number 0 or 1, R4 denotes a hydrogen atom, a C1-3-alkyl group or a benzyl group and R5 denotes a hydrogen atom, or R4 and R5 together or R4 and R6 together denote an ethylene group, and W denotes a straight-chained C2-5-alkylene group, in which the ethylene group may be substituted in the .alpha.-position by a methoxyphenylethylaminocarbonyl group, or W denotes a 1,4-cyclohexylene group; and E denotes a (C2-6-alkoxy)carbonyl group, a (C6-10-cycloalkyloxycarbonyl) group in which the cyclohexyl moiety may additionally be substituted by 1 or 2 C1-3-alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which a methylene group in the 3- or 4-position in the cycloalkyloxy moiety is replaced by an oxygen atom or by an imino group optionally substituted by a methyl, benzyl, benzyloxycarbonyl or acetyl group, a (C5-6-cycloalkyl)(C1-2-alkoxy)carbonyl group, a (C8-bicycloalkyloxycarbonyl) group, an R1-CO-O-(R2CR3)-O-CO-group wherein R1, R2 and R3 are as hereinbefore defined, an R7-CO-CH2-O-CO- group wherein R7 denotes an amino group optionally substituted by 1 or 2 methyl groups or by a cyclohexyl group, or E denotes a piperidinyl or morpholinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxycarbonyl group;
and the stereoisomers thereof, including the mixtures and the salts thereof.
4. Compounds of formula I according to claim 1 wherein, with the proviso that if E denotes a (C2-3-alkoxycarbonyl) group or a benzyloxycarbonyl group, Ra does not denote an amidino group optionally substituted by a (C2-3-alkoxycarbonyl) group or an amidino group substituted by a benzyloxycarbonyl group, Ra denotes an amidino group optionally substituted by an R1-CO-O-(R2CR3)-O-CO-, methoxycarbonyl or allyloxycarbonyl group, wherein R1 denotes a straight-chained or branched C1-4-alkyl group, a C1-3-alkoxy group or a cyclohexyloxy group, R2 denotes a hydrogen atom or a methyl group and R3 denotes a hydrogen atom;
Rb denotes a hydrogen atom or a methoxy group;
A denotes a -CH2- or -CO- group;
B denotes an -NR4-CH2CH2-X-CH2- group wherein X denotes an -NR5- group, or B denotes an -NR4-CH2CH2-R6C=CH- or -Y-W- group wherein Y denotes an -NR4- group, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein R4 denotes a hydrogen atom or a methyl group or R4 and R5 together or R4 and R6 together represent an ethylene group and W denotes a 1,4-cyclohexylene group;
E denotes an isopropyloxycarbonyl, isobutyloxycarbonyl, 2-butyloxycarbonyl, 2-amyloxycarbonyl, 3-amyloxycarbonyl or neopentyloxycarbonyl group, a (C6-9-cycloalkoxy-carbonyl) group wherein the cyclohexyl moiety may additionally be substituted by 1 or 2 C1-3-alkyl groups, a (C5-6-cycloalkyl)(C1-2-alkoxy)carbonyl group, a (C8-bicycloalkyloxycarbonyl) group, or an R1-CO-O-(R2CR3)-O-CO- group in which R1, R2 and R3 are as hereinbefore defined;
and the stereoisomers thereof, including the mixtures and the salts thereof.
Rb denotes a hydrogen atom or a methoxy group;
A denotes a -CH2- or -CO- group;
B denotes an -NR4-CH2CH2-X-CH2- group wherein X denotes an -NR5- group, or B denotes an -NR4-CH2CH2-R6C=CH- or -Y-W- group wherein Y denotes an -NR4- group, whilst the above-mentioned Y or -NR4- groups are each linked to the group A, and wherein R4 denotes a hydrogen atom or a methyl group or R4 and R5 together or R4 and R6 together represent an ethylene group and W denotes a 1,4-cyclohexylene group;
E denotes an isopropyloxycarbonyl, isobutyloxycarbonyl, 2-butyloxycarbonyl, 2-amyloxycarbonyl, 3-amyloxycarbonyl or neopentyloxycarbonyl group, a (C6-9-cycloalkoxy-carbonyl) group wherein the cyclohexyl moiety may additionally be substituted by 1 or 2 C1-3-alkyl groups, a (C5-6-cycloalkyl)(C1-2-alkoxy)carbonyl group, a (C8-bicycloalkyloxycarbonyl) group, or an R1-CO-O-(R2CR3)-O-CO- group in which R1, R2 and R3 are as hereinbefore defined;
and the stereoisomers thereof, including the mixtures and the salts thereof.
5. Compounds as claimed in claim 1 being:
4-amidino-4'-[4 (cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-3'-[4-trans-(cyclohexyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-3'-[4-trans-(cyclohexylmethoxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-4'-[4-(cycloheptyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-((exo)-norbornyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-((-)-menthyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-amidino-biphenyl;
4-[N-allyloxycarbonyl-amidino3-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-[N-allyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonyl]-biphenyl; or 4-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl;
and the stereoisomers thereof, including the mixtures and the salts thereof.
4-amidino-4'-[4 (cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(cyclopentyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-3'-[4-trans-(cyclohexyloxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-3'-[4-trans-(cyclohexylmethoxycarbonyl)-cyclohexylaminocarbonyl]-4'-methoxy-biphenyl;
4-amidino-4'-[4-(cycloheptyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-((exo)-norbornyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-((-)-menthyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-amidino-4'-[4-(pivaloyloxymethyloxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-[4-[(1-(ethoxycarbonyloxy)-ethoxycarbonyl)-methyl]-piperidinocarbonyl]-4'-amidino-biphenyl;
4-[N-allyloxycarbonyl-amidino3-4'-[4-(methoxycarbonylmethyl)-piperidinocarbonyl]-biphenyl;
4-[N-allyloxycarbonyl-amidino]-4'-[4-(carboxymethyl)-piperidinocarbonyl]-biphenyl; or 4-[4-(cyclohexyloxycarbonylmethyl)-piperidinocarbonyl]-4'-[N-methoxycarbonyl-amidino]-biphenyl;
and the stereoisomers thereof, including the mixtures and the salts thereof.
6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable salt of a compound of formula I as claimed in any one of claims 1 to 5.
7. A pharmaceutical composition containing a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.
8. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:
a) (to prepare compounds of formula I wherein E denotes a (C3-7-alkoxycarbonyl) group, a phenylalkoxycarbonyl group, a (C4-10-cycloalkyloxycarbonyl) group wherein a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which in the cycloalkyloxy moiety a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl or C2-6-alkanoyl group, and the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (C5-8-cycloalkenyl)oxycarbonyl, a (C3-5-alkenyl)oxycarbonyl, phenyl(C3-5-alkenyl)oxycarbonyl, (C3-5-alkynyl)oxycarbonyl or phenyl(C3-5-alkynyl)oxycarbonyl group in which the carbon attached to the oxycarbonyl moiety carries no double or triple bond, a (C3-8-cycloalkyl)alkoxycarbonyl group, or a (C8-10-bicycloalkyloxycarbonyl) group, which may additionally be substituted in the bicycloalkyl moiety by one or two alkyl groups) esterifying a carboxylic acid of formula II
(II) (wherein Ra, Rb, A and B are as defined in any one of claims 1 to 5) or a reactive derivative thereof optionally formed in the reaction mixture, with an alcohol of formula III
HO - R8 (III) (wherein R8 denotes a C2-6-alkyl group, a phenylalkyl group, a C3-9-cycloalkyl group in which a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-7-cycloalkyl group in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl, or C2-6-alkanoyl group, and the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-8-cycloalkenyl, a C3-5-alkenyl, phenyl(C35-alkenyl), C3-5-alkynyl or phenyl(C3-5-alkynyl) group in which the carbon attached to the hydroxyl carries no double or triple bond, a C3-8-cycloalkyl)alkyl group, or a C7-9bicyclcalkyl group optionally additionally substituted by one or two alkyl groups in the bicycloalkyl moiety;
b) reacting a carboxylic acid of formula IV
(IV) (wherein Rb, A and B are as defined in any one of claims 1 to 5 and Ra' denotes an amidino group substituted by an R1-CO-O-(R2CR3)-O-CO-, (C1-6-alkoxy)carbonyl, phenyl(C1-6-alkoxy)carbonyl, (C3-5-alkenyl)oxycarbonyl or phenyl (C3-5-alkenyl)oxycarbonyl group, or Ra' denotes an amidino group protected by a protecting group) or a carbanion thereof with a compound of formula V
Z1 - R9 (V) (wherein R9 denotes a C2-6-alkyl group, a phenylalkyl group, a C3-9-cycloalkyl group wherein a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-7-cycloalkyl group in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenyloxycarbonyl or C2-6-alkanoyl group and in which the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-8-cycloalkenyl group, a C3-5-alkenyl, phenyl(C3-5-alkenyl), C3-5-alkynyl or phenyl(C3-5-alkynyl) group wherein the Z1 attached carbon carries no double or triple bond, a (C3-8-cycloalkyl)alkyl group, or a C7-9-bicycloalkyl group optionally substituted by one or two alkyl groups, an R1-CO-O-(R2CR3)- group wherein R1, R2 and R3 are as defined in any one of claims 1 to 5, an R7-CO-CH2- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C1-6-alkyl groups or by a C3-8-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkylpiperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyl group and Z1 denotes a nucleophilic leaving group) and subsequently, if desired, any protecting group used is cleaved;
c) (to prepare compounds of formula I wherein Ra denotes an amidino group substituted by an R1-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group) acylating a compound of formula VI
(VI) (wherein Rb, A, B and E are as defined in any one of claims 1 to 5) with a compound of formula VII
Z2 - R10 (VII) (wherein R10 denotes an R1-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group and Z2 denotes a nucleophilic leaving group) and d) resolving a compound of formula I thus obtained into the enantiomers and/or diastereomers thereof;
e) converting a compound of formula I obtained into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid, or converting a salt of a compound of formula I into the free compound; and f) performing a process as defined in any one of steps (a) to (e) above on a corresponding protected compound and subsequently removing the protecting group used.
a) (to prepare compounds of formula I wherein E denotes a (C3-7-alkoxycarbonyl) group, a phenylalkoxycarbonyl group, a (C4-10-cycloalkyloxycarbonyl) group wherein a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a (C6-8-cycloalkyloxycarbonyl) group in which in the cycloalkyloxy moiety a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl or C2-6-alkanoyl group, and the cycloalkyloxy moiety may additionally be substituted by 1 or 2 alkyl groups, a (C5-8-cycloalkenyl)oxycarbonyl, a (C3-5-alkenyl)oxycarbonyl, phenyl(C3-5-alkenyl)oxycarbonyl, (C3-5-alkynyl)oxycarbonyl or phenyl(C3-5-alkynyl)oxycarbonyl group in which the carbon attached to the oxycarbonyl moiety carries no double or triple bond, a (C3-8-cycloalkyl)alkoxycarbonyl group, or a (C8-10-bicycloalkyloxycarbonyl) group, which may additionally be substituted in the bicycloalkyl moiety by one or two alkyl groups) esterifying a carboxylic acid of formula II
(II) (wherein Ra, Rb, A and B are as defined in any one of claims 1 to 5) or a reactive derivative thereof optionally formed in the reaction mixture, with an alcohol of formula III
HO - R8 (III) (wherein R8 denotes a C2-6-alkyl group, a phenylalkyl group, a C3-9-cycloalkyl group in which a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-7-cycloalkyl group in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenylalkoxycarbonyl, or C2-6-alkanoyl group, and the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-8-cycloalkenyl, a C3-5-alkenyl, phenyl(C35-alkenyl), C3-5-alkynyl or phenyl(C3-5-alkynyl) group in which the carbon attached to the hydroxyl carries no double or triple bond, a C3-8-cycloalkyl)alkyl group, or a C7-9bicyclcalkyl group optionally additionally substituted by one or two alkyl groups in the bicycloalkyl moiety;
b) reacting a carboxylic acid of formula IV
(IV) (wherein Rb, A and B are as defined in any one of claims 1 to 5 and Ra' denotes an amidino group substituted by an R1-CO-O-(R2CR3)-O-CO-, (C1-6-alkoxy)carbonyl, phenyl(C1-6-alkoxy)carbonyl, (C3-5-alkenyl)oxycarbonyl or phenyl (C3-5-alkenyl)oxycarbonyl group, or Ra' denotes an amidino group protected by a protecting group) or a carbanion thereof with a compound of formula V
Z1 - R9 (V) (wherein R9 denotes a C2-6-alkyl group, a phenylalkyl group, a C3-9-cycloalkyl group wherein a C5-8-cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-7-cycloalkyl group in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group itself optionally substituted by an alkyl, phenylalkyl, phenyloxycarbonyl or C2-6-alkanoyl group and in which the cycloalkyl moiety may additionally be substituted by 1 or 2 alkyl groups, a C5-8-cycloalkenyl group, a C3-5-alkenyl, phenyl(C3-5-alkenyl), C3-5-alkynyl or phenyl(C3-5-alkynyl) group wherein the Z1 attached carbon carries no double or triple bond, a (C3-8-cycloalkyl)alkyl group, or a C7-9-bicycloalkyl group optionally substituted by one or two alkyl groups, an R1-CO-O-(R2CR3)- group wherein R1, R2 and R3 are as defined in any one of claims 1 to 5, an R7-CO-CH2- group wherein R7 denotes an amino group optionally substituted by 1 or 2 C1-6-alkyl groups or by a C3-8-cycloalkyl group, a pyrrolidinyl, piperidinyl, hexamethyleneimino, morpholinyl or N-alkylpiperazinyl group, or a 1,3-dihydro-3-oxo-1-isobenzofuranyl group and Z1 denotes a nucleophilic leaving group) and subsequently, if desired, any protecting group used is cleaved;
c) (to prepare compounds of formula I wherein Ra denotes an amidino group substituted by an R1-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group) acylating a compound of formula VI
(VI) (wherein Rb, A, B and E are as defined in any one of claims 1 to 5) with a compound of formula VII
Z2 - R10 (VII) (wherein R10 denotes an R1-CO-O-(R2CR3)-O-CO-, alkoxycarbonyl, alkenyloxycarbonyl, phenylalkoxycarbonyl or phenylalkenyloxycarbonyl group and Z2 denotes a nucleophilic leaving group) and d) resolving a compound of formula I thus obtained into the enantiomers and/or diastereomers thereof;
e) converting a compound of formula I obtained into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid, or converting a salt of a compound of formula I into the free compound; and f) performing a process as defined in any one of steps (a) to (e) above on a corresponding protected compound and subsequently removing the protecting group used.
9. Use of a compound of formula I as claimed in any one of claims l to 5 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for combating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part.
10. Use of a compound as claimed in claim 9 for treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures.
11. Use of a compound as claimed in claim 9 for parallel therapy in thrombolysis with fibrinolytics or vascular interventions, or for the treatment of shock, psoriasis, diabetes or inflammation.
12. A method of treatment of the human or non-human animal body to combat or prevent diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof.
13. A method of treatment as claimed in claim 12 for treating or preventing venous and arterial thrombosis, cerebrovascular diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures.
14. A method of treatment as claimed in claim 12 for parallel therapy in thrombolysis with fibrinolytics or vascular interventions, or for the treatment of shock, psoriasis, diabetes or inflammation.
15. A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples.
16. Each and every novel compound, composition, process, use and method as herein disclosed.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4219158.0 | 1992-06-11 | ||
| DE4219158A DE4219158A1 (en) | 1992-06-11 | 1992-06-11 | Biphenyl derivatives, pharmaceutical compositions containing them and processes for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2098158A1 true CA2098158A1 (en) | 1993-12-12 |
Family
ID=6460811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002098158A Abandoned CA2098158A1 (en) | 1992-06-11 | 1993-06-10 | Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0574808A1 (en) |
| JP (1) | JPH0673038A (en) |
| KR (1) | KR940005554A (en) |
| CN (1) | CN1080917A (en) |
| AU (1) | AU4120193A (en) |
| CA (1) | CA2098158A1 (en) |
| DE (1) | DE4219158A1 (en) |
| FI (1) | FI932649L (en) |
| HU (1) | HU9301700D0 (en) |
| IL (1) | IL105976A0 (en) |
| MX (1) | MX9303466A (en) |
| NO (1) | NO932120L (en) |
| PL (1) | PL299260A1 (en) |
| ZA (1) | ZA934090B (en) |
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| US8323671B2 (en) | 2006-06-26 | 2012-12-04 | Akebia Therapeutics Inc. | Prolyl hydroxylase inhibitors and methods of use |
| US8865748B2 (en) | 2011-06-06 | 2014-10-21 | Akebia Therapeutics Inc. | Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer |
| US9987262B2 (en) | 2013-11-15 | 2018-06-05 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
| US10150734B2 (en) | 2015-01-23 | 2018-12-11 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
| US10246416B2 (en) | 2011-06-06 | 2019-04-02 | Akebia Therapeutics, Inc. | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides |
| US11324734B2 (en) | 2015-04-01 | 2022-05-10 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
| US11524939B2 (en) | 2019-11-13 | 2022-12-13 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid |
| US11713298B2 (en) | 2018-05-09 | 2023-08-01 | Akebia Therapeutics, Inc. | Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid |
| US11857543B2 (en) | 2013-06-13 | 2024-01-02 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
| US12419877B2 (en) | 2023-05-17 | 2025-09-23 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
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| EP0690847A1 (en) * | 1993-03-29 | 1996-01-10 | Zeneca Limited | Heterocyclic compounds as platelet aggregation inhibitors |
| PT825184E (en) * | 1993-03-29 | 2001-11-30 | Astrazeneca Ab | HETEROCYCLIC DERIVATIVES AS PLATELET INHIBITORS |
| US5750754A (en) * | 1993-03-29 | 1998-05-12 | Zeneca Limited | Heterocyclic compounds |
| US5753659A (en) * | 1993-03-29 | 1998-05-19 | Zeneca Limited | Heterocyclic compouds |
| US5652242A (en) * | 1993-03-29 | 1997-07-29 | Zeneca Limited | Heterocyclic derivatives |
| GB9313268D0 (en) * | 1993-06-28 | 1993-08-11 | Zeneca Ltd | Chemical compounds |
| GB9313285D0 (en) * | 1993-06-28 | 1993-08-11 | Zeneca Ltd | Acid derivatives |
| US5463011A (en) * | 1993-06-28 | 1995-10-31 | Zeneca Limited | Acid derivatives |
| DE4424974A1 (en) * | 1994-07-15 | 1996-01-18 | Thomae Gmbh Dr K | Urea and carbamic acid derivatives, medicaments containing these compounds and process for their preparation |
| DE19636689A1 (en) | 1996-09-10 | 1998-03-12 | Boehringer Ingelheim Kg | New benzamidine derivatives |
| CN1150162C (en) * | 1997-11-20 | 2004-05-19 | 帝人株式会社 | Biphenylamidine derivatives |
| DE19819548A1 (en) | 1998-04-30 | 1999-11-04 | Merck Patent Gmbh | Biphenyl derivatives |
| AU2868601A (en) * | 2000-01-27 | 2001-08-07 | Ribotargets Ltd | Biaryl compounds, their preparation and their use in therapy |
| US7534894B2 (en) | 2003-09-25 | 2009-05-19 | Wyeth | Biphenyloxy-acids |
| JP2008516989A (en) * | 2004-10-19 | 2008-05-22 | コンパス ファーマシューティカルズ リミティド ライアビリティ カンパニー | Compositions and their use as antitumor agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5084466A (en) * | 1989-01-31 | 1992-01-28 | Hoffmann-La Roche Inc. | Novel carboxamide pyridine compounds which have useful pharmaceutical utility |
| DE4035961A1 (en) * | 1990-11-02 | 1992-05-07 | Thomae Gmbh Dr K | CYCLIC IMINODERIVATES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DE4102024A1 (en) * | 1991-01-24 | 1992-07-30 | Thomae Gmbh Dr K | BIPHENYL DERIVATIVES, MEDICAMENTS CONTAINING THESE COMPOUNDS, AND METHOD FOR THE PRODUCTION THEREOF |
| DE69203797T2 (en) * | 1991-06-11 | 1996-02-08 | Ciba Geigy Ag | Amidino compounds, their production and use as medicines. |
| DE4127404A1 (en) * | 1991-08-19 | 1993-02-25 | Thomae Gmbh Dr K | CYCLIC IMINODERIVATES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
-
1992
- 1992-06-11 DE DE4219158A patent/DE4219158A1/en not_active Withdrawn
-
1993
- 1993-06-08 EP EP93109190A patent/EP0574808A1/en not_active Ceased
- 1993-06-09 PL PL93299260A patent/PL299260A1/en unknown
- 1993-06-10 JP JP5138438A patent/JPH0673038A/en active Pending
- 1993-06-10 NO NO932120A patent/NO932120L/en unknown
- 1993-06-10 ZA ZA934090A patent/ZA934090B/en unknown
- 1993-06-10 FI FI932649A patent/FI932649L/en not_active Application Discontinuation
- 1993-06-10 MX MX9303466A patent/MX9303466A/en unknown
- 1993-06-10 CN CN93106962A patent/CN1080917A/en active Pending
- 1993-06-10 HU HU9301700A patent/HU9301700D0/en unknown
- 1993-06-10 CA CA002098158A patent/CA2098158A1/en not_active Abandoned
- 1993-06-10 KR KR1019930010494A patent/KR940005554A/en not_active Withdrawn
- 1993-06-10 IL IL93105976A patent/IL105976A0/en unknown
- 1993-06-11 AU AU41201/93A patent/AU4120193A/en not_active Abandoned
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| US11426393B2 (en) | 2006-06-26 | 2022-08-30 | Akebia Therapeutics, Inc. | Prolyl hydroxylase inhibitors and methods of use |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU4120193A (en) | 1993-12-23 |
| JPH0673038A (en) | 1994-03-15 |
| EP0574808A1 (en) | 1993-12-22 |
| PL299260A1 (en) | 1994-03-07 |
| DE4219158A1 (en) | 1993-12-16 |
| NO932120D0 (en) | 1993-06-10 |
| HU9301700D0 (en) | 1993-09-28 |
| MX9303466A (en) | 1994-01-31 |
| FI932649A0 (en) | 1993-06-10 |
| KR940005554A (en) | 1994-03-21 |
| CN1080917A (en) | 1994-01-19 |
| NO932120L (en) | 1993-12-13 |
| FI932649A7 (en) | 1993-12-12 |
| IL105976A0 (en) | 1993-10-20 |
| ZA934090B (en) | 1994-12-11 |
| FI932649L (en) | 1993-12-12 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |