Note: Descriptions are shown in the official language in which they were submitted.
- 1 2111~
60603.570
CarboxYlic acid derivatives
This invention relates to novel carboxylic acid
derivatives, their preparation, pharmaceutical
compositions containing them and their use.
In EP-A-478328 and EP-A-478363 various phenylalanyl
derivatives are described as fibrinogen antagonists. :
It has now been found that certain novel carboxylic acid
derivatives have valuable pharmacological properties,
particularly aggregation-inhibiting effects. These new
compounds differ structurally from the compounds
described in EP-A~478328 and EP-A-478363, in particular
in the group B in formula I below.
Thus viewed from one aspect the present invention
provides compounds of formula I
A - B - C - D - E - COORa (I)
(wherein
Ra denotes a hydrogen atom or a C15-alkyl, a C35-alkenyl,
phenyl(C13-alkyl~, C57-cycloalkyl or a R1-C0-0-(R2CH)- -
group;
Rl denotes a C~s-alkyl, C57-cycloalkyl, phenyl (C
alkyl), C15-alkoxy, C57-cycloalkoxy or phenyl group; ~
R2 denotes a hydrogen atom or a C14-alkyl, C57-cycloalkyl ~ :
or phenyl group; - ,
A denotes a C15-aminoalkyl group linked to group B via a
carbon atom of A, or A denotes a 5-, 6- or 7-membered ::~
azacycloalkyl group linked to group B via a carbon a om
of the azacycloalkyl group, or A denotes a quinuclidinyl
2- 2111Q35
or pyridyl group wherein, the nitrogen in the above-
mentioned aminoalkyl or azacycloalkyl groups is
optionally substituted by a group Rb, wherein the carbon
atoms of the azacycloalkyl group are optionally
substituted by 1 to 3 C13-alkyl groups or by an
aminocarbonyl, cyano, R30- or R30-C0- group,
wherein in a 6- or 7-membered azacycloalkyl group A a
>CH- unit in the 4-position relative to the ring
nitrogen is optionally replaced by a nitrogen atom,
wherein in a 5-, 6- or 7-membered azacycloalkyl group A
a -CHz-CH< unit is optionally replaced by a -CH=C< unit
and wherein in a piperazinyl or homopiperazinyl group A
a ring carbon adjacent to the nitrogen atom in the 4-
position is optionally oxo-substituted; ,~
Rb denotes a C13-alkyl, phenyl(C13-alkyl), C24-alkanoyl, ~- .
trifluoroacetyl, (C1s-alkoxy)carbonyl, phenyl(C13- -
alkoxy)carbonyl, (C3s-alkenyl)oxycarbonyl, or
R1-C0-0-(R2CH)-0-C0- group;
R3 denotes a hydrogen atom or a Cl3-alkyl or phenyl(C13-
alkyl) group; -~
::
B denotes a phenylene group optionally mono- or `~
disubstituted by fluorine, chlorine or bromine atoms, by
trifluoromethyl groups, or by C13-alkyl, C13-alkoxy, C13- ~:
alkylsulphenyl, C13-alkylsulphinyl or C13-alkylsulphonyl ~ :
groups, wherein the substituents m~y be identical or
different and wherein, additionally, 1 or 2 : ~
unsubstituted methine groups may each be replaced by an -
N-atom, or B denotes a piperidinylene group, -
C denotes a carbonyl, -CH2CH2-, -CH=CH-, -CH2-, -CH20-, : :
H2 ~ CONR4-, -CONR4-CH2-, -NR4CO-, -NR CO-NR -
CH2NR4 , NR4CH2-, -S02NR4-, -SO2NR4-CH2- or -NR4SO2- group;
2111~3~
3 --
R4 denotes a hydrogen atom or a C13-alkyl or phenyl(C13-
alkyl) group, or if C denotes a -CONR4- group bound to
group B via the carbonyl group, R4 may also denote a
methylene or 1,2-ethylene group bound to the carbon atom
of group B in the ortho-position relative to the point
of linkage of the -CONR4- group;
D denotes a phenylene group optionally mono- or
disubstituted by fluorine, chlorine or bromine atoms, by
trifluoromethyl groups, by C13-alkyl, C13-alkoxy, Cl3-
alkylsulphenyl, C13-alkylsulphinyl or C13-alkylsulphonyl
groups, wherein the substituents may be identical or
different, and wherein additionally 1 or 2 unsubstituted
methine groups may each be replaced by an N-atom, or D
denotes a C57-cycloalkylene group wherein one or two
>CH- units may be replaced by an N-atom and additionally
in an aza- or diazacyclohexylene ring thus formed, a
ring carbon adjacent to a ring nitrogen is optionally ~ -
oxo-substituted;
E denotes a bond, a Cl3-alkyleneoxy group bound to group
D through the oxygen atom, a straight-chain C15-alkylene
group optionally substituted by 1 or 2 C18-alkyl groups,
or by a hydroxy, C18-alkoxy, RsNH-, R5N(C18alkyl) or
R5N(phenylC13-alkyl) group, or E denotes a C25-alkenylene
group optionally substituted by one or two Cl8-alkyl
groups;
R5 denotes a hydrogen atom or a C18-alkyl, (Cl 4~
alkoxy)carbonyl, or phenyl(C13-alkoxy)carbonyl group~or
a carbonyl or sulphonyl group substituted by a Cl8-alkyl ~ --
group or by a C37-cycloalkyl, phenylCl3-alkyl or phenyl
group, wherein each phenyl moiety in R5 is optionally
mono- or disubstituted by fluorine, chlorine or bromine
atoms, by trifluoromethyl groups, or by C13-alkyl, Cl3-
alkoxy, Cl3-alkylsulphenyl, Cl3-alkylsulphinyl or Cl3-
alkylsulphonyl groups and the substituents may be
- ~ - 21~1~3~
identical or different;
wherein
(i) if the A-B- moiety denotes a phenyl group
substituted in the 4-position by an Rb-NH-CH2- group,
wherein Rb is a benzyloxycarbonyl group, then
RaOOC-E-D-C- does not denote a 3-carboxy-
phenylaminocarbonyl group (see EP-A-0372486 and J. Med.
Chem. 35: 4393-4407 (1992)), and
(ii) if the A-B- moiety denotes a phenyl group
substituted in the 4-position by an Rb-NH-CH2- group,
wherein Rb denotes a hydrogen atom or an acetyl group,
the RaOOC-E-D-C- does not denote a phenylcarbonyl group
substituted in the 4-position by a carboxymethyl,
methoxycarbonylmethyl, 2-carboxy-ethyl, 2-
methoxycarbonyl-ethyl or 2-ethoxycarbonylethyl group ~
(see EP-A-0044541, JP-A-5813553, JP-A-5939866, ~-
JP-A-S846051 and Chem. Pharm. Bull. 33: 5059-5061
(1985)), and
(iii) if the A-B- moiety denotes a phenyl group
substituted in the 4-position by an N~2-CH2-CH2- group,
then RaOOC-E-D-C- does not denote a 4-ethoxycarbonyl- -
phenylcarbonyl group (see DE-A-3718638~, and
-,
(iv) if the A-B- moiety denotes a 4-aminomethyl-phenyl-,
3-aminomethyl-phenyl-, 4-aminomethyl-3-methoxy-phenyl-
or 3-aminomethyl-4-methoxyphenyl group, then RaOOC-E-D-C-
does not denote a 4-ethoxycarbonylmethoxy-2,3-
dichlorophenylcarbonyl group (see J. Med. Chem. 27:
1579-1587 (1984) and Diuretics: Chem. Pharmacol., Clin.
Appl., Proc. Int. Conf. Diuretics, 1st, 21-29 ~1984)),
and
~ " 2111~3~
- 5 -
(v) if the A-B- moiety denotes a phenyl group
substituted in the 4-position by an NH2-CH2- or
(CH3)3C0-C0-NH-CH2- group, then RaOOC-E-D-C- does not
denote a 4-carboxyphenylmethoxy group (see Int. J. Pept.
Protein Res. 18: 451-458 (1981)), and
(vi) if the A-B- moiety denotes a phenyl group
substituted in the 4-position by an NH2-CH2- group, then
RaOOC-E-D-C- does not denote a 4-carboxy-
phenylaminosulphonyl group (see Chem. Pharm. Bull -
~Tokyo) 7: 734-739 (1959) and J. Chem. Phys. 32: 691-697 -
(1960)), and
(vii) if the A-B- moiety denotes a 4-(2-pyridyl)-phenyl- -
or 4-(3-pyridyl)-phenyl group, then RaOOC-E-D-C- does not
denote a 4-carboxy-phenylcarbonylamino, 4- -~
benzyloxycarbonyl-phenylcarbonylamino- or 2-(4-carboxy-
phenyl)-ethyl group (see J. Med. Chem. 11: 2a5 (1968)
and US-A-2837522), and
(viii) if the A-B- moiety denotes a 3-(4-pyridyl)-phenyl -- -
group, then RaOOC-E-D-C- does not denote a 2- ~ -
(carboxymethyl)-phenylcarbonylamino group (see Farmaco
44: 721-729 (1989))) ~ -
and the isomers (eg. tautomers and stereoisomers),
isomer mixtures and salts thereof.
In formula I, where group D denotes an aza- or
diazacyclohexylene ring this may be linked to groups C
and E via ring carbons and/or ring nitrogens of D.
Preferred compounds according to the invention include
those of formula I wherein:
Ra denotes a hydrogen atom or a C1s-alkyl, phenyl(Cl3-
alkyl) or Cs7-cycloalkyl group;
-`` 2111~3~
-- 6 --
A denotes a Czs-aminoalkyl group linked to group B via a .
carbon atom of A, or a piperidinyl group linked to group ~.
B via a carbon atom of the piperidinyl group, or A .-
denotes a quinuclidinyl or pyridyl group, wherein the : -:
nitrogen of the above-mentioned aminoalkyl or ~:
piperidinyl groups is optionally substituted by a group
Rb, wherein the carbon atoms of the piperidinyl group are
optionally substituted by methyl, cyano, carboxy,
methoxycarbonyl or aminocarbonyl groups,
¦ and wherein in a piperidinyl A group a >CH- unit in the
4-position may be replaced by a nitrogen atom or a ~ . -
-CH2-CH< unit may be replaced by a -CH=C< unit; -:~:
Rb denotes a C13-alkyl, benzyl, (C1s-alkoxy)carbonyl, ;~:
benzyloxycarbonyl or CH3-CO-O-(CHz)-O-CO- group; :-
.
B denotes a phenylene group optionally substituted by a
fluorine, chlorine or bromine atom or by a C12-alkyl, --
C12-alkoxy, C12-alkylsulphenyl, C12-alkylsulphinyl or :
C12-alkylsulphonyl group, or B denotes a pyridinylene or
piperidinylene group;
C denotes a -CO-, -CH2CH2-, -CH=CH-, -CH2-, -CH20-,
-OCH2-, -CONR4-, -NR4CO-, -NR4CO-NR4-, -CH2NR4-, -NR4CH2-,
-SO2NR4- or -NR4SO2- group;
R4 denotes a hydrogen atom or a C12-alkyl or phenyl(C12-
alkyl) group or, if C denotes a -CONR4 group bound to
group B via the carbonyl group, R4 may also denote a
methylene or l,2-ethylene group bound to the carbon atom
of group B in the ortho- position relative to the point
of linkage of the -CONR4 group;
D denotes a phenylene group optionally substituted by a
chlorine or bromine atom, or by a C12-alkyl or C12-alkoxy
group, or D denotes a cyclohexylene group in which one
:
7 21111~3~
or two >C~- units may be replaced by N-atoms, and
additionally, in a piperidinylene or piperazinylene D
group a ring carbon adjacent to a ring nitrogen is
optionally oxo-substituted;
E denotes a bond, a methyleneoxy group bound to group D
through the oxygen atom, a 1,2-ethenylene group or a ~ ,
straight-chain C1s-alkylene group which may be
substituted by a C17-alkyl group or by an R5NH- group;
and
R5 denotes a hydrogen atom or a C17-alkylcarbonyl, :
benzylcarbonyl, C15-alkylsulphonyl or benzylsulphonyl - ~-
group; .
wherein
(iii) if the A-B- moiety denotes a phenyl group
substituted in the 4-position by an NH2-CH2-CH2- group,
then RaOOC-E-D-C does not denote a 4-ethoxycarbonyl-
phenylcarbonyl group, and
(vii) if the A-B- moiety denotes a 4-(2-pyridyl)-phenyl-
or 4-(3-pyridyl)-phenyl group, then RaOOC-E-D-C- does not
denote a 4-carboxy-phenylcarbonylamino, 4-
benzyloxycarbonyl-phenylcarbonylamino- or 2-(4-carboxy-
phenyl)-ethyl group, and
(viii) if the A-B- moiety represents a 3-(4-pyridyl)-
phenyl group, then RaOOC-E-D-C- does not denote a 2-
~(carboxymethyl)-phenylcarbonylamino group;
and the tautomers, stereoisomers tincluding mixtures ::
thereof) and salts thereof. :;~
21~1~33~
In formula I, where yroup D denotes a piperidinylene or
piperazinylene ring this may be linked to groups C and E
via ring carbons and/or ring nitrogens of ~.
Particularly preferred compounds according to the
invention include those of formula I wherein:
Ra denotes a hydrogen atom or a C14-alkyl, 2-phenylethyl
or cyclohexyl group;
A denotes a C3s-aminoalkyl group linked to group B via a
carbon atom of A, or a piperidinyl group linked to group
B via a carbon atom of the piperidinyl group or A
denotes a quinuclidinyl or 4-pyridyl group, wherein the
nitrogen atom in the above-mentioned piperidinyl group
is optionally substituted by a group Rb, wherein the
carbon atoms of the piperidinyl group are optionally
substituted by methyl, cyano, carboxy, methoxycarbonyl
or aminocarbonyl groups,
and wherein in a piperidinyl A group a >CH- unit in the
4-position may be replaced by a nitrogen atom or a
-CH2-CH< unit may be replaced by a -CH=C< unit;
Rb denotes a C13-alkyl, benzyl, (C14-alkoxy)carbonyl or
CH3-CO-O-(CH2~-O-CO- group;
B denotes an optionally methyl- or methoxy- substituted ~ :
phenylene group or a 2,5-pyridinylene or 1,4-
piperidinylene group; ~
C denotes a -CO-, -CH2CH2-, -CH=CH-, -CH2-, -CH20-, ;;::
I -OCH2-, -CONR4-, -NR4CO-, -NR4CO-NR4- or -CH2NR4- group or
I an -SO2NR4- group wherein the SO2 moiety is linked to
group B;
: !~
2111~3~ .
g
R4 denotes a hydrogen atom or a methyl or 2-phenylethyl
group or, if C denotes a -CON~4- group bound to group B
via the carbonyl group, R4 may also denote a methylene or
l,2-ethylene group bound to the carbon atom of group B
in the ortho-position relative to the linkage point of
the -CONR4- group;
D denotes a phenylene group or a cyclohexylene group in
which one or two >CH- units may be replaced by N- atoms;
E denotes a bond, a methyleneoxy group bound to group D
through the oxygen atom, or a straight-chain C15-
alkylene group which may be substituted by an RsNH-
group;
R5 denotes a hydrogen atom or a (C1s-alkyl)carbonyl,
C14alkyl-sulphonyl, or benzylsulphonyl group;
and the tautomers, stereoisomers (including the mixtures
thereof) and salts thereof.
In formula I, where group D denotes a piperidinylene or
piperazinylene ring this may be linked to groups C and E
via ring carbons and/or ring nitrogens of D. -
~:
Especially preferred compounds according to the :
invention include those of formula I wherein -
Ra denotes a hydrogen atom or a C14-alkyl or cyclohexyl
group;
A denotes a piperidinyl or 3,4-dehydro-piperidinyl group
linked to group B via the 4-position, wherein the
nitrogen atom is optionally substituted by a group Rb or
A denotes a 4-piperazinyl group optionally substituted
by a group Rb in the l-position, or A denotes a
quinuclidinyl group:
2 ~ 3 ~
-- 10 --
Rb denotes a (C14-alkoxy)carbonyl group;
B denotes a phenylene group;
C denotes a -CONR4 group;
R4 denotes a hydrogen atom or a methyl group or, if C
denotes a -CONR4 group bound to group B via the càrbonyl
group, R4 may also represent a methylene or 1,2-ethylene
group bound to the carbon atom of group B in the
ortho-position relative to the point of linkage of the
-CONR4 group;
D denotes a 1,4-phenylene or 1,4-cyclohexylene group;
E denotes a bond or a 1,2-ethylene group optionally
substituted by an R5NH- group; and
denotes a ~C1s-alkyl)carbonyl or a C14-alkylsulphonyl
qroup;
and the tautomers, stereoisomers (including mixtures
thereof) and salts thereof.
More especially preferred compounds according to the
invention include: '~
4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyl]-phenyl~-piperidine, .;-
,
4-[4-[[4-[2-(n-butanesulphonylamino)-2- ::
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]-phenyl]~
piperidine, ~-
4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]- :
aminocarbonyl]-phenyl]-piperidine,
''1' '
,
~ 2111~35
4-[4-[[4-[2-(n-butanesulphonylamino)-2-carboxyethyl]-
phPnyl]-aminocarbonyl]-phenyl]-piperidine,
4-[3-[~4-[2-(n-butanesulphonylamino)-2-carboxyethyl]-
phenyl]-aminocarbonyl]-phenyl]-piperidine and
4-[3-[[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]-phenyl]-
piperidine,
and the tautomers, stereoisomers (including mixtures
thereof) and salts thereof.
Viewed from another aspect, the invention also provides
a process for preparing the compounds of the invention,
said process comprising at least one of the following
steps:
a) (to prepare compounds of formula I wherein Ra denotes
a hydrogen atom) .
hydrolysing, pyrrolysing or hydrogenolysing a compound
of formula II
A - B - C - D - E - COORa' (II) ~
(wherein - :
A, B, C, D and E are as hereinbefore defined and R~l has -~ ::
the meanings given for Ra hereinbefore, with the
exception of the hydrogen atom);
b) (to prepare compounds of formula I, wherein A is
substituted by a group Rb)
reacting a compound of formula III
2111~3~
- 12 -
Al - B - C - D - E - COORa (III)
(wherein
B, C, D, E and Ra are as hereinbefore defined and
A1 denotes a C15-aminoalkyl group linked to group B via a
carbon atom or a 5-, 6- or 7-membered azacycloalkyl
group linked to group B via a carbon atom, wherein the
carbon atoms of the azacycloalkyl group may be
substituted by 1 to 3 C~3-alkyl groups or by an
aminocarbonyl, cyano, R30~ or R30-CO- group, wherein R~
is as hereinbefore defined) with a compound of formula
IV
Rb Z1 (IV)
(wherein . ~
Rb is as hereinbefore defined and : -
Z1 denotes a nucleophilic leaving group such as a halogen
atom, e.g. a chlorine, bromine or iodine atom, or, if Z
is bound to a carbonyl group, Z1 may also denote a
hydroxy, alkanoyloxy or alkyioxycarbonyloxy group, or
in the presence of a reducing agent when Z1 together with
an adjacent hydrogen atom of the group Rb denotes an
oxygen atom); -~
c) (to prepare compounds of formula I, wherein Ra has the ~:
meanings given hereinbefore, with the exception of the
hydrogen atom) ~: -
'''~::'~ ~,
reacting a compound of formula V
: ~
A - B - C - D - E - COOH (V) ~:
' - -
(wherein :~
A, B, C, D and E are a6 hereinbefore defined) with a
, 2llln~s
- 13 -
compound of formula VI
Z - R ' (VI)
(wherein
Ral has the meanings given for Ra hereinbefore, with the
exception of the hydrogen atom, and
Z2 denotes a nucleophilic leaving group such as a halogen
atom, e.g. a chlorine or bromine atom, or a sulphonyloxy
group substituted at the sulphonyl group, e.g. a
methanesulphonyloxy, methoxysulphonyloxy or
toluenesulphonyloxy group, or a hydroxy group);
d) (to prepare compounds of formula I, wherein C denotes
a -CH2-NH- group)
reducing a compound of formula VII
A - B - CH=N - D - E - COORa (VII) --
(wherein
A, B, D, E and Ra are as hereinbefore defined);
e) (to prepare compounds of formula I, wherein C denotes
a -CO-NR4- group)
reacting a compound of formula VIII
A2 ~ B - COOH (VIII)
(wherein
B is as hereinbefore defined and
A2 denotes a group A substituted at the nitrogen atom by
an alkyl, aralkyl, alkanoyl, trifluoroacetyl or
alkoxycarbonyl group) with an amine of formula IX
- - 1" _ 21~1~3~
R - NH - D - E - COOR ' (IX)
(wherein
D, E and R4 are as hereinbefore defined and
Ral has the meanings given for Ra hereinbefore, with the
exception of the hydrogen atom);
f) (to prepare compounds of formula I, wherein C denotes
an -NR4-CO- group)
::, -
reacting a compound of formula X ~ ~:
A - B - NH-R4 (X)
(wherein
R4 and B are as hereinbefore defined and
A2 denotes a group A substituted at the nitrogen atom by
an alkyl, aralkyl, alkanoyl, trifluoroacetyl or
alkoxycarbonyl group) with a carboxylic acid of formula
HOOC - D - E - COORa' (XI) ;
(wherein
D and E are as hereinbefore defined and -
Ral has the meanings given for Ra hereinbefore with the
exception of the hydrogen atom); ~ -
g) (to prepare compounds of formula I, wherein A denotes
a C15-aminoalkyl group linked to group B via a carbon
atom)
reducing a compound of formula XII ~ :
A3 - B - C - D - E - COORa (XII)
twherein
B, C, D, E and Ra are as hereinbefore defined and
~:
2111~3~
- ~.5 -
A3 denotes a cyano yroup or cyanoC14alkyl group);
h) (to prepare a compound of formula I wherein R4 denotes
an optionally phenyl-substituted C12-alkyl group)
alkylating a compound of formula I (wherein R4 is a
hydrogen atom);
i) performing the process of any one of steps (a) to (h)
above on a reagent having a protecting group and
subsequently removing the protecting group used;
j) converting a compound of formula I into a salt
thereof; and
k) resolving a compound of formula I into its isomers.
The hydrolysis of step (a) is appropriately carried out
either in the presence of an acid such as hydrochloric
acid, sulphuric acid, phosphoric acid, acetic acid,
acetic acid/hydrochloric acid, trichloroacetic acid or
trifluoroacetic acid, or in the presence of a base such
as lithium hydroxide, sodium hydroxide or potassium
hydroxide in a suitable solvent such as water, methanol,
water/methanol, ethanol, water/ethanol,
water/isopropanol, water/tetrahydrofuran or
water/dioxane, at temperatures between -10C and 120C,
e.g. at temperatures between ambient temperature and the
boiling temperature of the reaction mixture. Upon -
treatment with an organic acid such as trichloroacetic -
acid or trifluoroacetic acid, any alcoholic hydroxy
groups present may simultaneously be converted into a
corresponding acyloxy group, such as a trifluoroacetoxy
group.
During acid hydrolysis, depending on the conditions
used, other hydrolytically cleavable groups present in a
compound of formula II, such as the acetyl,
213.1~3.
- 16 -
trifluoroacetyl, benzoyl, tert.butyloxycarbonyl or
benzyloxycarbonyl group may be simultaneously cleaved.
If a compound of formula II contains, for example, a
tert.butyloxycarbonyl group, the tert.butyl group may
also be cleaved by treating with an acid such as
trifluoroacetic acid, hydrochloric acid, formic acid, p- -- -
toluenesulphonic acid, sulphuric acid, phosphoric acid -
or polyphosphoric acid, optionally in an inert solvent ~
such as methylene chloride, chloroform, benzene, ~-
toluene, tetrahydrofuran or dioxane, preferably at
temperatures between -10C and 120C, e.g. at ~-
temperatures between 0 and 60C, or thermally,
optionally in an inert solvent such as methylene -,~
chloride, chloroform, benzene, toluene, tetrahydrofuran
or dioxane and optionally in the presence of a catalytic ~
amount of an acid such as p-toluenesulphonic acid, ~ --
sulphuric acid, phosphoric acid or polyphosphoric acid,
preferably at the boiling temperature of the solvent -~
used, e.g. at temperatures between 40C and 100C.
If a compound of formula II contains, for example, a
benzyloxycarbonyl group, the benzyl group may also be
hydrogenolytically cleaved in the presence of a ~--
hydrogenation catalyst such as palladium/charcoal, in a
suitable solvent such as methanol, ethanol,
ethanol/water, glacial acetic acid, ethyl acetate,
dioxane or dimethylformamide, preferably at temperatures
between 0 and 50C, e.g. at ambient temperature, under a -~
hydrogen pressure of 1 to 10 bar. During
hydrogenolysis, other groups may also be reduced at the
same time, e.g. a nitro group may be reduced to an amino
group or a benzyloxy group to a hydroxy group, or a
benzylamino group into an amino group. Furthermore, C=C
double bonds may simultaneously be hydrogenated into
single bonds.
2111~33~
- 17 -
The reaction of step (b) is preferably carried out in a
suitable solvent, optionally in the presence of a ba~e
or optionally in the presence of an acid activating
agent or in the presence of a reducing agent at
temperatures between -30 and 150C.
If Z1 denotes a nucleophilic leaving group, the reaction
of step (b) is conveniently carried out in a solvent or
mixture of solvents such as water, tetrahydrofuran,
tetrahydrofuran/water, dioxane, dioxane/water, methylene
chloride, chloroform, ethyl acetate or
dimethylformamide, conveniently 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-morpholine or pyridine, which
may simultaneously be used as solvent, optionally in the
presence of a reaction accelerator such as potassium
iodide at temperatures between -30 and 100C, but
preferably at temperatures between -10 and 80C.
If Zl denotes a hydroxy group, the reaction of step (b)
is conveniently carried out in a solvent or mixture of
solvents such as methylene chloride, dimethylformamide,
benzene, toluene, chlorobenzene, tetrahydrofuran,
benzene/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
isobutyl chloroformate, thionylchloride,
trimethylchlorosilane, hydrochloric acid, sulphuric
acid, methanesulphonic acid, p-toluenesulphonic acid, :
phosphorus trichloride, phosphorus pentoxide, N,N'-
dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodi- : -,
imide/N-hydroxysuccinimide, 2-(lH-benzotriazolyl)-
1,1,3,3-tetramethyl-uronium salts, N,N'-
carbonyldiimidazole, N,N'-thionyldiimidazole or ~ :~
triphenylphosphine/carbon tetrachloride, optionally in ~-
- 18 - 21110~5 - :-
,
the presence of dimethylaminopyridine or l-hydroxy-
benzotriazole, appropriately at temperatures between 0
and 150C, preferably at temperatures between 0 and -
50C.
If Z1 together with an adjacent hydrogen atom of the
group Rb denotes an oxygen atom, the reductive alkylation
of step (b) is conveniently carried out in a suitable
solvent such as methanol, ethanol, tetrahydrofuran, :
dioxane, acetonitrile or mixtures thereof with water, in
the presence of a suitable reducing agent such as formic -:~ :-
acid or a suitable complex metal hydride, but preferably
in the presence of sodium cyanoborohydride, or with :- :
hydrogen in the presence of a hydrogenation catalyst ~
such as palladium/charcoal, at temperatures between o -:
and 50C, but preferably at ambient temperature. . ~:
- :~:' '
If Z2 denotes a halogen atom or a sulphonyloxy group :~
substituted at the sulphonyl group, the reaction of step ~
(c) is expediently carried out in a solvent such as ~:
tetrahydrofuran, dioxane, methylene chloride,
chloroform, ethyl acetate, dimethylsulphoxide 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 or N-methyl-morpholine, which may
simultaneously serve as solvent, optionally in the
presence of a reaction accelerator such as potassium
iodide, at temperatures between -30 and 100C, but
preferably at temperatures between -10 and 80C.
If Z2 denotes a hydroxy group, the reaction of step (c)
is preferably carried out using the compound of formula
VI as solvent, in the presence of thionylchloride or an
acid such as hydrochloric acid or sulphuric acid, at
temperatures between -10C and 100C, preferably at
- 19 - 2111~
temperatures between 0C and 50C.
The reduction oE step (d) is preferably carried out in a
suitable solvent such as methanol, methanol/water,
methanolJammonia, methanol/water/ammonia,
methanol/hydrochloric acid, methanol/ethereal
hydrochloric acid, ethanol, ethyl acetate, ether,
tetrahydrofuran, dioxane, dimethylformamide or glacial
acetic acid, in the presence of catalytically activated
hydrogen, e.g. hydrogen in the presence of Raney nickel,
platinum or palladium/charcoal, or in the presence of a
metal hydride such as sodium borohydride, sodium -
cyanoborohydride or lithium borohydride, at temperatures
between -20'C and 100C, preferably at temperatures
between 0C and 60C.
The reaction of step (e) is conveniently carried out in
a solvent or mixture of solvents such as methylene
chloride, dimethylformamide, dimethylsulphoxide,
benzene, toluene, chlorobenzene, tetrahydrofuran,
benzene/tetrahydrofuran or dioxane, optionally in the
presence of a dehydrating agent, e.g. in the presence of
isobutyl chloroformate, thionylchloride,
trimethylchlorosilane, hydrochloric acid, sulphuric
acid, methanesulphonic acid, p-toluenesulphonic acid, ~ : ,
phosphorus trichloride, phosphorus pentoxide, N,N'- -~
dicyclohexylcarbodiimide, N,N'-
dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-(lH- -~
benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts, N,N'- .
carbonyldiimidazole, N,N'-thionyldiimidazole or
triphenylphosphine/carbon tetrachloride, optionally in
the presence of dimethylaminopyridine or l-hydroxy- ;. :
benzotriazole and/or a base such as triethylamine, N-
ethyl-diisopropylamine or N-methyl-morpholine,
conveniently at temperatures between -10 and 150C,
preferably at temperatures between 0 and 50C. ;~
~ ~,
'~'';' '~ ",
2 1 ~
- 20 -
The reaction of step (f) is conveniently carried out in
a solvent or mixture of solvents such as methylene
chloride, dimethylformamide, dimethylsulphoxide,
benzene, toluene, chlorobenzene, tetrahydrofuran,
benzene/tetrahydrofuran or dioxane, optionally in the
presence of a dehydrating agent, e.g. in the presence o~
isobutyl chloroformate, thionylchloride,
trimethylchlorosilane, hydrochloric acid, sulphuric .
acid, methanesulphonic acid, p-toluenesulphonic acid, -
phosphorus trichloride, phosphorus pentoxide, N,N'- ::
dicyclohexylcarbodiimide, N,N'-
dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-(lH-
benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts, N,N'-
carbonyldiimidazole, N,N'-thionyldiimidazole or
triphenylphosphine/carbon tetrachloride, optionally in -~
the presence of dimethylaminopyridine or l-hydroxy- ~.
benzotriazole and/or a base such as triethylamine, N- -
ethyl-diisopropylamine or N-methyl-morpholine,
conveniently at temperatures between -10 and 150C,
preferably at temperatures between 0 and S0C.
The reduction of step (g) is preferably carried out in a - .
suitable solvent such as methanol, methanol/water, -.
methanol/water/ammonia, ethanol, ether, tetrahydrofuran,
dioxane or dimethylformamide, optionally with the -
addition of an acid such as hydrochloric acid, in the .
presence of catalytically activated hydrogen, e.g. ~- ~
hydrogen in the presence of Raney nickel, platinum or .: ~:
palladium/charcoal, or in the presence of a metal
hydride such as sodium borohydride, lithium borohydride ~ :
or lithium aluminium hydride, at temperatures between 0
and 100C, preferably at temperatures between 20 and ~:
80C.
The alkylation of step (h) is conveniently carried out
with a suitable halide such as methyliodide,
ethylbromide, benzylchloride or phenylethylbromide, ~-
'''"'`
~ ~ . . " . .. . . . . ..... . .. . ..
:" 2111~5
- 21 -
preferably in a solvent such as methylene chloride,
tetrahydrofuran, dioxane, dimethylsulphoxide or
dimethylformamide, optionally 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-diisopropylamine or N-
methyl-morpholine, which may simultaneously be used as
solvent, at temperatures between -30 and 100C, but
preferably at temperatures between -10 and 80C.
During the reactions described hereinbefore, reactive
groups such as hydroxy, carboxy, amino, alkylamino or
imino groups may be protected by means of conventional
protecting groups which are removed by cleaving after
the reaction.
For example, the protective group for a hydroxy group '-
may be a trimethylsilyl, acetyl, benzoyl, tert.butyl,
trityl, benzyl or tetrahydropyranyl group,
the protecting group for a carboxyl group may be a
trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or `~ -
tetrahydropyranyl group, and the protecting group for an
amino, alkylamino or imino group may be an acetyl,
trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.- -
butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl
or 2,4-dimethoxybenzyl group and for the amino group a
phthalyl group may also be considered.
The optional subsequent cleaving of a protecting group
may, for example, be carried out hydrolytically in an
aqueous solvent, 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 lithium hydroxide, sodium hydroxide
or potassium hydroxide or by ether cleaving, e.g. in the
presence of iodotrimethylsilane, at temperatures between
- 22 _ 2 1 1 ~ ~ ,3 ~
0 and 100C, preferably at temperatures between 10 and
50C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl
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, dimethylformamide, -
dimethylformamide/acetone 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, under a hydrogen
pressure of 1 to 7 bar, preferably 3 to 5 bar. During
hydrogenolytic cleaving of benzyl groups, any CzC-
double bonds present in a compound of formula II may
simultaneously be hydrogenated. For example, an N-
benzyl-dehydro-piperidyl group may be converted into a
piperidyl group in this way. -
A methoxybenzyl group may also be cleaved in the
presence 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,
ether or dioxane/ether.
!
,
21~1133~
- 23 -
A phthalyl group is preferably cleaved in the presence
of hydrazine or a primary amine such as methylamine,
ethylamine or n-butylamine in a solvent such as
methanol, ethanol, isopropanol, toluene/water or
dioxane, at temperatures between 20 and 50C.
An allyloxycarbonyl group is cleaved by treating with a
catalytic amount of tetrakis-(triphenylphosphine)-
palladium(0), preferably in a solvent such as
tetrahydrofuran and preferably in the presence of an
excess of an allyl group acceptor such as morpholine or
1,3-dimedone, at temperatures between 0 and 100C, ~-
preferably at ambient temperature and under inert gas,
or by treating with a catalytic amount of tris- :
(triphenylphosphine)-rhodium(I)chloride, in a solvent ~ .
such as aqueous ethanol and optionally in the presence
of a base such as 1,4-diazabicyclo[2.2.2]octane, at -~
temperatures between 20 and 70C.
Furthermore, the compounds of formula I obtained may be
resolved into their enantiomers and/or diastereomers. ;~
Thus, for example, the cis/trans mixtures obtained may -:
be resolved by chromatography into the cis and trans ~ i~
isomers thereof and the compounds of formula I which ~:
occur in racemate form may be separated by conventional .
methods (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 stereogenic centres 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.
- 2~ _ 2 ~
The separation of enantiomers is preferably effected by
column separation on chiral phases or by
recrystallisation from an optically active solvent or by
reaction with optically active substances (especially
acids and the activated derivatives thereof or
alcohols), which form salts or derivatives such as
esters or amides with the racemic compound, and
separation of the diasteromeric 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 by the
action of suitable agents. Particularly useful,
optically active acids include, for example, the D- and ~
L-forms of tartaric acid, and dibenzoyltartaric acid, -
di-o-tolyl tartaric acid, malic acid, mandelic acid,
camphorsulphonic acid, glutamic acid, aspartic acid and ~ -
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 beconverted into the salts thereof, particularly for
pharmaceutical use into the physiologically acceptable
salts thereof with inorganic or organic acids. Examples
of suitable acids include hydrochloric acid, hydrobromic -
acid, sulphuric acid, phosphoric acid, acetic acid,
fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or maleic acid.
In addition, the compounds of formula I thus obtained,
if they contain a carboxyl group, may subsequently, if
desired, be converted into the addition salts thereof
with inorganic or organic bases, more particularly, for
pharmaceutical use, into the physiologically acceptable
addition salts thereof. Examples of suitable bases
include sodium hydroxide, potassium hydroxide, ammonia,
2 ~
- 25 -
cyclohexylamine, ethanolamine, diethanolamine and
triethanolamine.
The starting compounds used in the process of the
invention are known or may be obtained by conventional
techniques (see Examples I to XXIV).
As mentioned above, the compounds of the invention have -
valuable properties. Thus, the compounds of formula I,
wherein A represents an aminoalkyl, aza- or
diazacycloalkyl group optionally substituted at the
nitrogen, or represents a pyridyl or quinuclidinyl group
or a group which may optionally be converted in vivo ~-
into an aminoalkyl, aza- or diazacycloalkyl group, e.g. :
an amino, aza- or diazacycloalkyl group substituted at
the nitrogen by an alkoxycarbonyl, alkenyloxycarbonyl, :-
aralkoxycarbonyl, alkylcarbonyl, ~ :
trifluoromethylcarbonyl, alkanoyloxymethoxycarbonyl,
cycloalkanoyloxymethoxy-carbonyl or
aralkanoyloxymethoxycarbonyl group and -COORa denotes a .
carboxyl group or a group which may be converted in vivo
into a carboxyl group, e.g. an alkoxy, alkenyloxy,
phenylalkoxy, cycloalkyloxy, alkanoyloxyalkoxy,
cycloalkanoyloxyalkoxy, phenylalkanoyloxyalkoxy,
benzoyloxyalkoxy, alkoxycarbonyloxyalkoxy or
cycloalkyloxycarbonyloxy-alkoxycarbonyl group, have
valuable pharmacological properties, and in addition to
having an inhibitory effect on inflammation and bone
degradation, they have in particular antithrombotic,
antiaggregatory and tumour- or metastasis-inhibiting
effects.
Viewed from a further aspect the invention thus 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.
.~
21~1~3~j
- 26 -
Viewed from a still further aspect the invention also
provides the use of a compound of formula I or a
physiologically acceptable salt thereof, for the
manufacture of a medicament for use in combating .
inflammation, bone degradation, tumours, metastases,
thrombosis and aggregation-related conditions.
Viewed from a yet still further aspect the invention
provides a method of treatment of the human or non~
human, preferably mammalian body to combat inflammation, -
bone degradation, tumours, metastases, thrombosis and -:
aggregation-related conditions, said method comprising
administering to said body a compound of formula I or a
physiologically acceptable salt thereof.
By way of example, the biological activity of the
compounds according to the invention were investigated
as follows: :
211103~
- 27 -
1. Competitive binding of 3H-BIBU 52/test substance to
human thrombocytes:
A suspension of human thrombocytes in plasma is
incubated with 3H-BIBU 52 ~3H-sIBU 52, which is disclosed
in DE-A-4214245 is (3S,5S)-5-[(4'-amidino-4-
biphenylyl)oxymethyl]-3-[(carboxyl)methyl]-2- -
pyrrolidinone[3-3H-4-biphenylyl] and is used in place of
the conventional 12sI fibrinogen ligand] and various
concentrations of the test substance. The free and
bound ligand are separated by centrifuging and ~-
quantified by scintillation counting. The inhibition of
3H-BIBU 52 binding by the test substance is determined
from the measurements obtained.
In order to do this, donor blood is taken from an
anticubital vein and anticoagulated with trisodium
citrate (final concentration 13 mM). The blood is
centrifuged for 10 minutes at 170 x g and the
supernatant platelet-rich plasma (PRP) is removed. The
remaining blood is vigorously centrifuged once more in
order to obtain plasma. The PRP is diluted 1:10 with
autologous plasma. 750 ~l are incubated with 50 ~l of
physiological saline solution, 100 ~1 of test substance
solution, 50 ~l of l4C-sucrose (3,700 Bq) and 50 ~l of ;~
3H-BIBU 52 (final concentration: 5 nM) at ambient
temperature for 20 minutes. In order to measure the ~ -
non-specific binding, 5 ~l of BIBU 52 (final
concentration: 30 ~M) are used in place of the test -
substance. The samples are centrifuged for 20 seconds
at 10,000 x g and the supernatant is poured off. 100 ~l
thereof are measured in order to determine the free
ligand. The pellet is dissolved in 500 ~l of 0.2N NaOH,
450 ~l are mixed with 2 ml of scintillator and 25 ~1 of
5N HCl and measured. The residual plasma remaining in
the pellet is determined from the 14C-content and the ~-
bound ligand is determined from the 3H-measurement.
1, .,' ~`
2111~3~
~ 2~ -
After the non-specific binding has been deducted, the
pellet activity is plotted against the concentration of
the test substance and the concentration for a 50%
inhibition of binding is determined.
2. Antithrombotic activity
Method
Thrombocyte aggregation is measured using the method of
Born and Cross (J. Physiol. 170: 397 (1964)) in
platelet-rich plasma taken from healthy volunteers. To
inhibit coagulation, the blood is mixed with 3.14%
sodium citrate in a volume ratio of 1:10.
Collaqen-induced aqqreqation
The pattern of the decrease in optical density of the
platelet suspension is photometrically measured and
recorded after the addition of the aggregation-
triggering substance. The rate of aggregation is
determined from the angle of inclination of the density
curve. The point on the curve where there i5 maximum
light transmittance is used to calculate the optical
density.
The concentration of collagen used is as small as
possible but sufficient to produce an irreversible :~
reaction curve. Standard commercial collagen produced
by Hormonchemie of Munich is used. Before the addition
of the collagen the plasma is incubated for 10 minutes
with the substance at 37C.
From the concentration/activity curve the EC50 is
determined, which indicates the concentration giving a
50% change in the optical density in terms of the
inhibition of aggregation.
- 29 _ 2111~3~
The following table shows the results which were
obtained:
Substance Competitive binding Inhibition of
(Example No.) of 3H-BIBU 52/test platelet
substance to humanaggregation
thrombocytes EC50 [nM~
ICso [nM]
2 1 100 840
2.1>100 000 3 300
2.2 4 500 3 300
3 190 260
3.1 1 400 2 400 ~ -
3.3 17 260
3.4 2 000 5 800
3.6 14 12~
2 900 5 600
The inhibition of thrombocyte aggregation after oral
administration of the test substance is determined ex -~
vivo on Rhesus monkeys.
Directly before the oral administration of the test
substance suspended in Natrosol, a blood sample is taken
from the cubital vein of the animals to provide a ~ -~
reference value. At specified times after the
administration of the substance, fresh blood samples are ~
taken and investigated as follows. -- -
Whole blood, mixed with 3.14% sodium citrate in a ratio
by volume of 1:10 is centrifuged at 200 x g for 15
minutes. The supernatant, platelet-rich plasma, is
carefully removed. From the sediment which is rich in
erythrocytes, the platelet-depleted plasma is obtained -~
as supernatant, by centrifuging at 4000 x g for lO ;~
::~
~!x
_ 30 _ 2111~3~
minutes.
The thrombocyte aggregation triggered with collagen
(Hormonchemie, Munich; 2 ~g/ml final concentration in
platelet-rich plasma) in these ex vivo samples is
measured photometrically using the method of Born and
Cross ~J. Physiol. l70: 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 compounds of Examples 2 and 5(2) inhibit the
collagen-induced thrombocyte aggregation ex vivo for
more than 2 hours after the oral administration of
1 mg/kg.
The compounds according to the invention are well
tolerated because after intravenous administration of
30 mg/kg of the compounds of Examples 2 and 3 to three
mice in each case, no animals died.
., ~ ,
In the light of their inhibitory effect on cell-cell or
cell-matrix interactions, the compounds 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
metastasis 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
- 31 _ 2111~3~
fibrinolytics or vascular interventions such as
transluminal angioplasty or in the treatment of shock,
psoriasis, diabetes and inflammation.
For treating or preventing the diseases mentioned above,
the dosage is 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 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, 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 clotting
factors, may be incorporated together with one or more
inert conventional carriers and/or diluents, e.g. 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 following Examples are provided to illustrate the
invention in a non-limiting fashion. Percentages and
ratios are by weight unless otherwise indicated except
eluant ratios which are by volume~
- 32 - 21~1~3~
Preparation of the starting compounds:
Example I
4-(4-Carboxyphenyl)-piperidine-hydrochloride
157.4 g of oxalylchloride are added dropwise to a
solution of 63.0 g of 1-acetyl-4-phenyl-piperidine in
1000 ml of methylene chloride, with thorough stirring,
at -10 to -20C. Then 46.7 g of aluminium chloride are
added. The mixture is stirred for 1 hour at -10C and a
further 82.7 g of aluminium chloride are added. After
another 2 hours the cooling bath is removed and the
mixture is stirred for 24 hours at ambient temperature. -
The reaction solution is carefully stirred into about 4
litres of ice/water and the aqueous phase is extracted
twice with methylene chloride. The combined organic
phases are washed with water, dried over sodium sulphate
and the solvent is removed under reduced pressure. The
residue remaining is dissolved in 2.5 litres of 2N -~ -
sodium hydroxide solution with vigorous stirring. Ice -~
is added to the dark aqueous solution and it is
acidified with conc. hydrochloric acid. The precipitate
is suction filtered, washed with water and refluxed for
5 hours in 2 litres of 6N hydrochloric acid. The
solvent is removed under reduced pressure. The solid
remaining is triturated with a little water and suction
filtered.
Yield: 40.5 g (54% of theory),
Melting point: > 300C
Rf value: 0.07 (si.lica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
_ 33 _ 2111~3~
Example II
l-tert.Butyloxycarbonyl-4-(4-carboxyphenyl)-piperidine
-
47.5 g of 4-(4-carboxyphenyl)-piperidine-hydrochloride
are carefully added to 16.4 g of sodium hydroxide in
300 ml of water. The suspension is diluted with 500 ml
of dioxane and 250 ml of water. Then 54.6 g of di-
tert.butyl pyrocarbonate are added in batches. The
mixture is stirred for 16 hours at ambient temperature. :~
The precipitate is suction filtered and the filtrate is
partially concentrated by evaporation under reduced
pressure. The precipitate and the remaining aqueous ~ ~
filtrate are combined and diluted with 1 litre of water. - ~-
The aqueous phase is adjusted to pH 2 using saturated -:~
potassium hydrogen sulphate solution and extracted twice
with ethyl acetate. The combined ethyl acetate phases
are washed with saturated saline solution, dried over
sodium sulphate and the solvent is removed under reduced
pressure. The crude crystalline product is triturated :~
with a little ethyl acetate, suction filtered and dried.
Yield: 54.0 g (90% of theory),
Melting point: 172~174C
R~ value: 0.73 (silica gel; ethyl acetate/cyclohexane =
Example III
Methyl 3-(4-aminophenyl)-2-(n-butylsulphonylamino)-
propionate
19 g of methyl 2-(n-butanesulphonylamino)-3-(4-nitro-
phenyl)-propionate in 200 ml of ethyl acetate are
treated with hydrogen at 5 bars pressure in the presence
of 2 g of 10% palladium/charcoal for 1.5 hours at
ambient temperature. The catalyst is filtered off, the ~-~
filtrate is evaporated down and the residue is used
211 ~03~
- 3~ -
without further purification.
Yield: 17.8 g (100% of theory),
Rf value: 0.43 (silica gel; cyclohexane/ethyl acetate =
The following compound is obtained analogously:
(1) Methyl 3-(4-amino-phenyl)-propionate
Methyl 4-nitro-cinnamate, hydrogenated at 50C.
Rf value: 0.76 (silica gel; cyclohexane/ethyl acetate =
1:3)
Example IV
Methyl 2-(n-butanesulphonylamino)-3-(4-nitrophenyl)-
propionate
.
25.9 g of methyl 2-amino-3-(4-nitrophenyl)-propionate
hydrochloride are suspended in 100 ml of methylene
chloride and mixed with 32 g of N-ethyl-
diisopropylamine, whereupon the precipitate dissolves.
To the solution are added dropwise, at 8 to 15C, 17.1 g
of n-butanesulphonylchloride in 20 ml of methylene
chloride. After stirring for 16 hours at ambient
temperature, 10 g of N-ethyl-diisopropylamine are added
whilst cooling with ice and a further 8 g of n-
butanesulphonylchloride are added dropwise and stirred
for a further 2 hours at ambient temperature. The
mixture is combined with ice water, the organic phase is
washed successively with water, lN hydrochloric acid and
water and concentrated by evaporation. The residue is
purified over silica gel (eluant: methylene chloride).
Yield: 19.4 g (57% of theory),
Melting point: 100-102C
Rf value: 0.38 (silica gel; cyclohexane/ethyl acetate =
6:4~
211~0'~
- 35
Example V
Methyl 2-amino-3-(4-nitrophenyl)-propionate-
hydrochloride
'- : ' : ,,
21 g of 4-nitro-phenylalanine are suspended in 250 ml of ~ -
methanol and mixed with 10 ml of methanolic hydrochloric
acid, whereupon the solid product dissolves. The
mixture is left to stand for 60 hours at ambient
temperature and evaporated down in vacuo. The product
is used without any further purification. -
Yield: 25.9 g (99% of theory), -~
Melting point: 206-208C (decomp.)
Rf value: 0.67 (Reversed Phase Plate RP8; methanol/5% ~ ~
sodium chloride solution = 6:4) ; ~-
, " , ,
The following compound is obtained analogously: - ~-
(1) Methyl 3-(trans-4-amino-cyclohexyl)-propionate~
hydrochloride
Melting point: above 200C ~ -
ExamPle VI
: - '
3-(trans-4-Amino-cyclohexyl)-propionic acid- ;~
hydrochloride ~
26 g of 3-(trans-4-acetamino-cyclohexyl)-propionic acid ` -
are refluxed for 16 hours in 200 ml of 6N hydrochloric
I acid. The mixture is evaporated to dryness in vacuo and --
I evaporated down several more times after the addition of
toluene and methanol. The residue is used directly.
Yield: 26 g (100~ o~ theory)
`' ~;
~',
2il~3~
- 36 -
Example VII
3-(trans-4-Acetaminocyclohexyl)-propionic acid
112.7 g of 3-(4-acetaminophenyl)-propionic acid and 10 g
of platinum dioxide are treated in 350 ml of glacial
acetic acid at 60C with hydrogen at 5 bars pressure.
After 1.5 and 7 hours, the platinum dioxide is replaced
with fresh. The entire reaction time is 10 hours. The
mixture is evaporated to dryness ln vacuo and the
residue is recrystallised from 1800 ml of acetone. The
primary crystals are also recrystallised from 50 ml of
80% acetic acid.
Yield: 26 g (22.4% of theory),
Melting point: 200-201C
Rf value: 0.30 (silica gel; methylene chloride/ethyl
acetate/glacial acetic acid = 4:1:0.4)
After evaporation and recrystallisation from 100 ml of
water, 53.6 g (46% of theory) of cis-3-(4-acetamino-
cyclohexyl)-propionic acid are obtained from the acetone
mother liquor.
Example VIII -
1-Benzyl-4-(3-carboxyphenyl)-3,4-dehydro-piperidine-
hydrochloride
25 g of 1-benzyl-4-(3-bromo-phenyl)-3,4-dehydro-
piperidine are dissolved in 300 ml of tetrahydrofuran.
The mixture is cooled to below -65C and at this
temperature, within 30 minutes, 47.6 ml of a 1.6 molar
solution of n-butyllithium in hexane are added dropwise.
The resulting mixture is stirred for a further hour and
then a slow stream of carbon dioxide dried over conc. -~
sulphuric acid is passed over the reaction solution.
The temperature is first maintained for 1 hour at below
-65C and then slowly allowed to rise to ambient
- -- .. ,,....................................... :
` ~ 211103~
,
temperature and the reaction mixture is left to stand at
this temperature for 60 hours. It is then evaporated to
dryness, the residue is taken up in 500 ml of ethyl --
acetate and extracted with water. The aqueous phases -
are concentrated by evaporation in vacuo, cooled in an
ice bath and adjusted to pH 1 using 2N hydrochloric
acid. The precipitated crystals are filtered off and
washed with water.
Yield: 9 g (40~ of theory),
Melting point: from 185C (decomp.)
Rf value: 0.50 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) - -
Example IX
1-Benzyl-4-(3-bromophenyl)-3,4-dehydro-piperidine -~ -
' ':
29.6 g of 1-benzyl-4-(3-bromophenyl)-4-hydroxy-
piperidine, 32.5 g of p-toluenesulphonic acid hydrate ~ -
and 300 ml of toluene are heated for 2 hours using a ~-
water separator. After cooling, the mixture is diluted
with methylene chloride, ice water is added and the
resulting mixture is made alkaline with 30% sodium
hydroxide solution. The aqueous phase is extracted once -~
again with methylene chloride and the combined organic ~-
phases are evaporated down ln vacuo.
Yield: 25.2 g (90% of theory),
Rf value: 0.69 (silica gel; methylene chloride/methanol p
= 100:2)
Example X
1-Benzyl-4-(3-bromophenyl)-4-hydroxy-piperidine
To a solution of 35.7 g of 1,3-dibromo-benzene in 200 ml
of ether, 93.1 ml of a 1.6 molar solution of n-
2111~3~
- 38 -
butyllithium in hexane are added dropwise over 25
minutes at a temperature below 0C. The mixture is
stirred for a further 40 minutes and then, at a
temperature below 10C, a solution of 28.2 g of freshly
distilled l-benzyl-4-piperidone in 40 ml of ether is
added dropwise. The mixture is stirred for a further 30
minutes at this temperature and finally for 1 hour at
ambient temperature. 500 ml of saturated saline
solution are added, the aqueous phase is extracted twice
more with ethyl acetate, the organic phases are
evaporated down in vacuo and the residue is purified by
column chromatography over silica gel (eluant: methylene
chloride/methanol = 100:2)
Yield: 29.6 g (56% of theory),
Rf value: 0.34 (silica gel; methylene chloride/methanol
= 100:2
Example XI
3-(4-Acetaminophenyl)-propionic acid
155 g of methyl 3-(4-acetaminophenyl)-propionate are
dissolved in 1000 ml of methanol, heated to 50C and
mixed with 700 ml of 2N sodium hydroxide solution. The
mixture is cooled to ambient temperature and stirred for ~ '
another 3 hours. It is then cooled in an ice bath,
750 ml of 2N hydrochloric acid are added and the mixture
is stirred for another hour whilst cooling with ice.
The precipitate is filtered off and washed with a little ;
ice water.
Yield: 112.7 g (77.6% of theory),
Melting point: 144-147C
Rf value: 0.25 (silica gel; methylene chloride/ethyl
acetate/glacial acetic acid = 8:1:0.4)
2111~3~ `
- 39 -
Example XII
.
Methyl 3-(4-acetaminophenyl)-propionate `
138.4 g of methyl 3-(4-aminophenyl)-propionate are
dissolved in 1000 ml of methylene chloride and 119 ml of
triethylamine are added. The mixture is cooled to below
0C and within 35 minutes at 0 to 10C a solution of
58 ml of acetylchloride in 200 ml of methylene chloride
is added dropwise. The resulting mixture is stirred for
one hour at 0C, 300 ml of water are added, the organic -~-
phase is extracted twice more with water and evaporated
down in vacuo.
Yield: 155.5 g (91% of theory),
Melting point: 118-120C
Rf value: 0.50 (silica gel; cyclohexane/ethyl acetate =
1:3) ~ ~
.- :
Example XIII
4-[4-[[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-
iminomethyl]-phenyl]-l-trifluoroacetyl-piperidine
6.9 g of 4-(4-formylphenyl)-1-trifluoroacetyl-piperidine
and 4.33 g of methyl 3-(4-aminophenyl)-propionate are
refluxed for 5 hours in 50 ml of toluene using a water -~
separator. The mixture is evaporated down in vacuo and
the product is used without any further purification.
Yield: 10.8 g (100% of theory),
Rf value: 0.43 (silica gel; cyclohexane/ethyl acetate =
2:1)
::
~.', ~ .'
211103~
- 40 -
Example XIV
4-(4-Formylphenyl)-1-trifluoroacetyl-piperidine
To a solution of 8.3 g of 4-phenyl-1-trifluoroacetyl-
piperidine in 30 ml of methylene chloride, 7.8 ml of
titanium tetrachloride are added dropwise at a
temperature below 0C. After 10 minutes, 3.5 ml of
dichloromethylmethylether are added dropwise over 40
minutes whilst the temperature is maintained below O-C.
The mixture is left to stand for 16 hours at ambient
temperature, poured onto ice water and the aqueous phase
is extracted several times with methylene chloride. The
organic phases are evaporated down in vacuo and the
residue is purified by column chromatography over silica
gel (eluant: cyclohexane/ethyl acetate = 2:1)
Yield: 6.9 g (75% of theory),
Melting point: 76-77C
Rf value: 0.42 (silica gel; cyclohexane/ethyl acetate =
2:1)
Example XV
~ ..
4-Phenyl-l-trifluoroacetyl-piperidine
, ~ :
25 g of 4-phenyl-piperidine are dissolved in 250 ml of -~
methylene chloride, 29.8 ml of N-ethyl-diisopropylamine
are added and the mixture is cooled to 0C. 24.1 ml of ~-
trifluoroacetic acid anhydride are added dropwise to~the
solution so that the temperature does not exceed 10C.
It is stirred for a further 30 minutes at 0C, allowed
to warm to ambient temperature, 100 ml of water are
added and the organic phase is washed twice more with
water. The methylene chloride phase is evaporated down
and the residue is used without further purification. ;~
Yield: 40 g (100% of theory),
''''~';"
: ~:
2ill û3~
Rf value: 0.90 (silica gel; cyclohexane/ethyl acetate =
1 : 1 )
Example XVI
4-(4-AminophenYl)-l-trifluoroacetyl-pi~eridine
a) 4-Phenyl-l-trifluoroacetvl-PiPeridine
To a solution of 125 g (0.775 Mol) of 4-phenyl-
piperidine and 149 ml (0.775 Mol) of N,N-diisopropyl-
ethylamine in 1300 ml of dichloromethane, 120.5 ml -
~0.775 Mol) of trifluoroacetic acid anhydride are added
dropwise at 5C, with stirring, over a period of 2
hours. The mixture is then stirred for a further hour
whilst cooling with ice, left to stand overnight at
ambient temperature and then diluted with 400 ml of
water. The dichloromethane phase is separated off,
washed twice with 400 ml of water, dried over sodium
sulphate and evaporated to dryness ln vacuo.
Yield: 193 g (97% of theory)
Yellow crystals ~`
Rf value: 0.88 (silica gel; cyclohexane/ethyl acetate =
b) 4-(4-Nitro~henyl)-l-trifluoroacetyl-Piperidine
80 g (0.311 Mol) of the 4-phenyl-1-trifluoroacetyl- -~
piperidine obtained in a) are dissolved in a mixture of
400 ml of glacial acetic acid and 200 ml of acetic
anhydride. This solution is cooled to 10C in an ice
bath and 1.6 g of sodium nitrite are added, with
stirring, followed by the dropwise addition of 51.9 ml
(0.311 Mol) of fuming nitric acid. The mixture is left
to stand overnight at ambient temperature and then
poured onto 1000 ml of water which contains 200 g of
ice. The pH is adjusted to 8 using 8N sodium hydroxide
solution within 4.5 hours, with cooling to prevent the
.
` 21~1~3~
- ~2 -
temperature exceeding 20C. The mixture is extracted
with a total of 2000 ml of dichloromethane, the combined
dichloromethane extracts are washed with 100 ml o~ 0.1 N
sodium hydroxide solution and then twice with water,
dried over sodium sulphate and evaporated to dryness in
vacuo. The residue is crystallised from ethyl
acetate/cyclohexane.
Yield: 54.5 g (58% of theory)
Yellow crystals
Melting point: 100-102C
c) 4-(4-AminophenYl)-l-trifluoroacetvl-piperidine -
The compound prepared in b) is dissolved in 700 ml of
ethyl acetate and, after the addition of 7 g of
palladium on charcoal (10~), it is hydrogenated at
ambient temperature under 3 bars of hydrogen pressure.
The catalyst is filtered off and the ethyl acetate
solution is evaporated to dryness ln vacuo.
Yield: 39.7 g (quantitative)
Rf value: 0.25 (silica gel; cyclohexane:ethyl acetate =
:,
' - ,
ExamPle XVII
l-tert.Butyloxycarbonyl-4-[4-[[4-[2-(methoxycarbonyl)-
ethvl~-piperidino~-methvll-~henvll-piperidine
a) l-tert.Butyloxycarbonyl-4-(4-hydroxymethyl-phenyl)-
Piperidine
To a solution of 5 g (0.0164 Mol) of 1-
tert.butyloxycarbonyl-4-(4-carboxy-phenyl)-piperidine
and 1.66 g (0.0164 Mol = 2.28 ml) of triethylamine in
100 ml of tetrahydrofuran, a solution of 1.78 g
(0.0164 Mol = 1.57) ml of ethylchloroformate in 10 ml of
tetrahydrofuran is added dropwise with stirring at 5C
and the mixture is stirred at this temperature for a
~' 2111~3~
- ~3 -
further hour. The triethylamine-hydrochloride
precipitated is then suction filtered and washed with
tetrahydrofuran. The combined tetrahydrofuran phases
are then added dropwise, with stirring at 10 to 15C,
into a solution of 1.55 g (0.041 Mol) of sodium
borohydride. After stirring overnight at ambient
temperature the mixture is evaporated to dryness in
vacuo. The residue remaining is distributed between
ethyl acetate and lN sodium hydroxide solution. The
ethyl acetate phase is washed with water, dried over
sodium sulphate and evaporated to dryness in vacuo. The
residue remaining is crystallised from petroleum ether.
Yield: 4.05 g (84.7% of theory),
Melting point: 78-80C
b) l-tert.Butyloxycarbonyl-4-(4-chloromethylphenyl)- ~ -
PiPeridine
A solution of 3.95 g (0.0136 Mol) of compound a) and -
2.74 g (0.0271 Mol = 3.8 ml) of triethylamine in 80 ml -~ -~of dichloromethane are slowly combined, with stirring, -- ~
with 3.1 g (0.0271 Mol = 2.1 ml) of mesylchloride. ~-
After addition is complete the mixture is left to stand -~
overnight and the clear solution is then evaporated to `~
dryness. The residue remaining is chromatographed over -~
silica gel using dichloromethane as eluant. ~ -
Yield: 3.75 g (89% of theory), ~ ~
Melting point: 56-58C - ---
Rf value: 0.47 (silica gel; dichloromethane)
c) 1-tert.Butyloxycarbonyl-4-[4-[[4-[2- ~
(methoxycarbonyl)-ethyl]-piperidino]-methyl]-phenyl]- -
Piperidine
A mixture of 1.8 g (0.0058 Mol) of the compound prepared -~
under b), 1.44 g (0.007 Mol) of methyl piperidino-
propionate hydrochloride, 1.42 g (1.95 ml = 0.014 Mol)
of triethylamine and 3 g of sodium iodide in 150 ml of
2111~3~
- ~4 -
chloroform are refluxed for 36 hours. The undissolved
components are then removed by suction filtering. The
filtrate is washed twice with water, dried over sodium
sulphate and evaporated to dryness ln yacuo. The
residue remaining is purified by chromatography over
silica gel using methylene chloride/methanol (35:1) as
eluant.
Yield: 2.05 g (79.8% of theory)
Resin
Rf value: 0.41 (silica gel; dichloromethane/methanol =
9.5:0.5)
The following compound was prepared analogously:
(1) 1-tert.butyloxycarbonyl-4-[4-[[trans-4-[2- ~-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminomethyl]-
phenyl]-piperidine --
~::
,~
Prepared from l-tert.butyloxycarbonyl-4-(4-chloromethyl-
phenyl)-piperidine and methyl trans-3-[4-amino-
cyclohexane]-propionate
Resin -
Example XVIII
1-[tert.Butyloxycarbonyl]-4-[4-[[trans-4-
methoxycarbonylcyclohexyl]-aminocarbonylamino]-phenyl]-
piPeridineA solution of 1.2 g (0.0044 Mol) of 1-tert.-
butyloxycarbonyl-4-[4-aminophenyl]-piperidine and 0.8 g
(0.0044 Mol) of trans-[4-methoxycarbonylcyclohexyl]-
isocyanate in 20 ml of dioxane is heated at 50~C for 2
hours. The mixture is then evaporated to dryness under
reduced pressure and the solid residue is stirred with
tert.butylmethylether. The remaining solid is suction
filtered, washed with tert.butylmethylether and dried.
_~5_ 21103~j
Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate z
1 : 1 )
Example XIX
l-tert.Butyloxycarbonyl-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]~
piperidinol-piperidine
a) l-tert.Butyloxycarbonyl-4-[t4-ethoxycarbonyl~- -
~iperidinol-piperidine ~ .
A mixture of 24.9 g (0.1249 Mol) of N-
tert.butyloxycarbonyl-4-piperidone, 19.3 ml (0.1249 Mol)
of ethyl piperidino-4-carboxylate and 46.5 ml ~ -~
(0.1562 Mol) of titanium(IV)-isopropoxide is stirred for -~
one hour at ambient temperature. Then 170 ml of
anhydrous ethanol followed by 5.3 g (0.0837 Mol) of
sodium cyanoborohydride are added and the mixture is
stirred for a further 20 hours. Thereafter, 34 ml of ~ -
water are added, the inorganic solids obtained are
removed by suction filtering and washed with ethanol.
The combined filtrates are evaporated to dryness. The
residue remaining is dissolved in ethyl acetate. The
insoluble inorganic solids are filtered off and the
filtrate is evaporated to dryness in vacuo. The residue
is purified by chromatography over a silica gel column
using ethyl acetate/cyclohexane = 3:2 as eluant.
Yield: 32.9 g of an oily substance (77.3% of theory)
Rf value: 0.36 (silica gel; ethyl acetate)
b) l-tert.Butyloxycarbonyl-4-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
pi~eridinol-~i~eridine
3.4 g (0.01 Mol) of the compound prepared in a) are
stirred overnight in 20 ml of lN sodium hydroxide
solution. After this time, complete saponification of
'
:-``` 2111~3~
- 46 -
the ethylester had occurred. 20 ml of lN hydrochloric
acid are added and the mixture is washed with ethyl
acetate. The aqueous phase is evaporated to dryness in
vacuo, the residue remaining is taken up twice in
ethanol, evaporated down in vacuo and then dried at 80C
in vacuo. The residue is dissolved in 100 ml of
dimethylformamide. This solution is combined with 2 ml
(0.0102 Mol) of diphenyl-phosphorylchloride, cooled to
-5C, 1.4 ml (0.0102 Mol) of triethylamine are added --
with stirring and the mixture is stirred for a further
hour at -5C. Then 2.26 g (0.0102 Mol) of methyl trans-
3-[4-aminocyclohexyl]-propionate hydrochloride and
1.4 ml (0.0102 Mol) of triethylamine are added and the ~-
mixture is stirred for a further 4 hours at ambient ~--
temperature and then for one hour at 60C. In order to -
complete the reaction, another 1 ml of diphenyl-
phosphorylchloride and 1.4 ml of triethylamine are added
and the mixture is stirred overnight at ambient
temperature. It is then evaporated to dryness in vacuo,
the r6!sidue is taken up in ethyl acetate, the ethyl
acetate solution is washed twice with saturated sodium
hydrocren carbonate solution and once with water and
dried over sodium sulphate. After evaporation in vacuo,
4 g of a residue remain which are purified by column
chromatography over silica gel, using
dichloromethane/methanol = 20:1 and 10:1 as eluant. The
residue is triturated with ether/petroleum ether,
suction filtered and dried.
Yield: 2.98 g (62.1% of theory),
Melting point: 182-184'C
' :~ '
.
" '~.~.
211~03
- 47 -
Example XX
4-~4-[[trans-4-[2-(Methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyll-Phenvll-l-benzyl-piperazine
a) l-Benzyl-4-(4-cyanophenyl)-Piperazine
A mixture of 26 g (0.2147 Mol) of 4-fluorobenzonitrile,
37.3 ml (0~2147 Mol) of N-benzylpiperazine and 36.7 ml
(0.2147 Mol) of N-ethyl-diisopropylamine is heated to
140C for 8 hours. After cooling it is stirred into
water and extracted with dichloromethane. The combined ~
dichloromethane phases are dried over sodium sulphate ~ ~-
and evaporated down in vacuo. The residue remaining is
crystallised from ether/petroleum ether. -
Yield: 29.8 g (50.1% of theory),
Melting point: 106-108C
b) l-Benzvl-4-(4-carboxY~henvl~-Piperazine
29.8 g (0.1074 Mol) of l-benzyl-4-(4-cyanophenyl)-
piperazine are dissolved in 200 ml of ethyleneglycol.
After the addition of 48 g (0.8592 Mol) of potassium
hydroxide the mixture is refluxed for 8 hours. The
ethyleneglycol is then substantially distilled off in
vacuo and the remaining oil is diluted with water.
After acidifying with acetic acid, the solid precipitate
is suction filtered, washed with water and then with a
little acetone and dried.
Yield: 31.4 g (98.7% of theory),
Melting point: 225-227C (decomp.)
c) 4-[4-[[trans-4-[2-(Methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-l-benzyl-
piperazine
. -
To a solution of 1.5 g (0.051 Mol) of l-benzyl-4-(4-
carboxyphenyl)-piperazine in 80 ml of dimethylformamide
are added, at -5c and with stirring, 1 ml (0.0051 Mol)
¦ of diphenylphosphinic acid chloride and 0.7 ml ~;
21~ ~3~
` ` ~-.~EC-lY93 16:19 FRRNK 13. QEH~ ~ CU 071 240 07'76 P,0Z
,
.
- 4B -
~O.O~l Mol) of tr~othyl~ine ~md th~ mixture i~ et~rr-d
ror a ~urth-r hour a'c -5-C. Th~n 1.13 g ~O.OS1 Mol) o~
rothyl 3- (4-t~ ~inocyclohQxy~l -propio~?ltQ. '
hydrochlorid~ and O.~ ml (O.~Sl ~ol~ o~ trie~yl~ln~ .
ar ~dd~d ~nd ehe mixtur- i~ s~lrred o~rernlght ~t , :
~bi-n~ te,npsratur~. It is t~en ~r~porat~ to dryne~B
i,ll ~Q and th~ r~duo ~ pur~$ed by chro~a'cogr~p~y ;
over a ~lica g l colu~ lng dichlo ~ ~
I conta~n~ 2.5~ ~othanol a~ eluant. Th~ r~sldue re~alning -: - r'
a ~ evapo~at~on o~ tha aluant iB trlturat-d with
p-trol~u~ QthQr and ~uc~ion ril~rd.
Yî-ld: 1 . 04 g (44~ o~ ory),
eltlng polnt: 188-189-C
~
4-t2-~tr~ns-4-~2-~ethoxycarbonyl-ethyl)-cyclohexy~
oxo-2,3-dihydro-~solndol-6-yl~-eyricina -:
, a) ~Qthyl 2-m thyl-s-~ri~luorc~thylsulphonylox~
; ~o a solution o~ 10 g ~60 mMol) o~ ~ethyl 3-hydroxy-6- ~
~athyl-benzoat~ in 40 ml o~ dry p~r~dln~ ~r~ add~d ~ -
drop~ise, with 6tirr~ng, at -8 to 4~C, 18.2 ml (66
o~ ~rl~luoron-th~n-~ulphon~c acid anhydr~d~ wl~hin 35
I ~inut-~. A~ter the addition i~ Cempl~tQ th ~iXtNre iB
I ~tirr d ov sni~ht in an iCQ b~th and then pourQ~ onto
I wat~r. It ~- xtracted wttn tert.butyl-methy1QthRr, th~
¦ coDbined eYtract~ ar~ wa~h~d ~ith dilut- hydrochlor~c : --
I aaid ~nd th-n With watar, d~-d o~or sodium sulphato and -: ~
! ~v~porated to dryne~6 i~ v~uo. The orang--red oil :: ~
r-~inlng i0 puri~ied by colu~n chromatography over :~ :
lliQ gel, uslng cycloh-xan~/othyl ac-tat = ~:1 a~
el~ant.
Colourl~ss o~
Yield: 15.3 ~ (85.5$ of th~ory~
~: .
'., "-..,: ~
~92 ~ 3 5
Rf value: 0.60 (silica gel; ethyl acetate/cyclohexane =
9:1) ' ~'
b) Methyl 2-bromomethyl-5-trifluoromethylsulphonyloxy-
benzoate
A mixture of 8.3 g (27.8 mMol) of the compound prepared
under a), 5.3 g (30 mMol) of N-bromosuccinimide and
20 mg of 2,2'-azaisobutyronitrile in 100 ml of carbon
tetrachloride is irradiated for one hour with a 300 W W -
immersion lamp. The mixture is then cooled, the
undissolved succinimide is filtered off and the filtrate
is evaporated to dryness ln vacuo. The residue is
purified by column chromatography over silica gel using
cyclohexane/ethyl acetete = 9:1 as eluant.
Colourless oil.
Yield: 7.7 g (73.3% of theory),
Rf value: 0.55 (silica gel; ethyl acetate/cyclohexane =
9 : 1 )
c) 2-[trans-4-(2-Methoxycarbonyl-ethyl)-cyclohexyl]-l-
oxo-2,3-dihydro-6-trifluoromethylsulphonyloxy-
isoindole
To a solution of 2.2 g (10 mMol) of methyl trans-4-
aminocyclohexylpropionate-hydrochloride and 3.9 g
(5.1 ml = 30 mMol) of N,N-diisopropyl-ethylamine in
100 ml of dry dimethylformamide, a solution of 3.8 g
(10 mMol) of the compound obtained in b) in 10 ml of
dimethylformamide is added at ambient temperature with
stirring and stirring is continued for a further 16
hours at ambient temperature. Then the mixture is
evaporated down ln vacuo and the residue is distributed
between water and dichloromethane. The organic phase is
separated off, dried over sodium sulphate and evaporated
to dryness ln vacuo. The solid residue is triturated
with petroleum ether and suction filtered.
Yield: 1.9 g (42.2% of theory),
Melting point: 104-105C
I
'
_ 50 2111~3~
d) 4-[2-[trans-4-(2-Methoxycarbonyl-ethyl)-cyclohexyl]-
l-oxo-2,3-dihYdro-isoindol-6-yll-pvridine
A solution of 2.3 g (5.1 mMol) of the compound obtained
in c), 1 g (8 mMol) of 4-pyridyl-boric acid, 0.58 g
(0.5 mMol) of tetrakis-triphenylphosphine-palladium(0)
and 3.3 ml (24 mMol) of triethylamine in 35 ml of
dim~thylformamide is heated to 100C for 8 hours. After
cooling, the mixture is added to 150 ml of water, the
precipitate is suction filtered and washed with water.
After drying ln vacuo at 40C it is purified by column
chromatography over silica gel, using
dichloromethane/methanol = 19:1 as eluant.
Yield: 1.2 g (62.2% of theory),
Melting point: 210-211C
ExamPle XXII
1-Benzyl-4-[2-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-1-oxo-2,3-dihydro-isoindol-6-yl]-3,4
dehydro-piperidine
'' .:'' .
a) 1-Benzyl-4-[2-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-1-oxo-2,3-dihydro-isoindol-6-yl]-
Pvridinium-bromide
A mixture of 0.32 g (0.84 mMol) of 4-[2-[trans-4-(2- -~-
(methoxycarbonyl)-ethyl)-cyclohexyl]-1-oxo-2,3-dihydro~
isoindole-pyridine, 0.2 ml (1.68 mMol) of benzylbromide ~-~
and 3 ml of acetonitrile is refluxed for half an hour,
during which time a solid is precipitated. After ~
cooling and diluting with tert.butyl-methylether the ~ -
mixture is suction filtered and the solid is dried at
40C in vacuo.
Yield: 0.4 g (86.7% of theory),
Melting point: 252-255C ,~
` ~':-'
: : :
07~ 1993 16:20 FRRNK a. DEHN ~ C0 071 Z40 0776 P.03
21~1~33~
- 51 _
b) l-Bon~yl-4-t2~ n~ 2- ~m tboxyaarbon~rl) -~th~rl]-
oycloh ~yl] -1-o~2, 3-di hyd~o-i~olndo1-6-yll -3, ~-
360 ~ ~0,66 ~o:l) of the c~ou~ obt~inad ~
u~pended in ;.0 ~1 o~ ~nol~ 38 ~q (1 ~olJ o~ iuu
bo~n~ydrido ~ 4dl~d in 2 b~tche~ a~ ~lent
t~p r~t~re, wl~ ~rr$n~ q!hQ lll~XtlaS' i~ d ~or
a furth r 2 day- at ~blent t~ture an~ t~en ~t-r
ic ~ed, thQ ~ 1 ~ct~ w~ sthyl a~etat-,
the conblnod ~thyl ac-tat~ ~xtract~ a~ dr~-~l o~r
~phat~ an~ porat~d to dryn ~- ~ vaGuc~. The
cry-tal~ r~lnlng ar~ dri d at 60-C ~B Y~. ,
Yleld~ 27a ~g ~86~6% of theory)
Melting point: 142-1~,3-C ~ :~
.. . .
utyloxycarbonyl-3-~4-[ttr~ns-4-{2-
(~ thoxyo~rbo~yl)-ethyl]-cyclohexylJ-~minoc~bonyl3- -~
ph~nyl]-pyrrolldin : ,.,
a) ~
124.g g ~1.2 ~ol) o~ xalonic ac~d arQ dis~olved ln 180
~1 of pyr~d$ne. 16~.2 g ll ~ol) or ~-car~04eSh~xy-
bensald hyde ~nd 8.52 g (O.l Mol) o~ piporldine ar~
add-d So thi~ olution and the ~u~p~ns~on thus obta~d
~8 heat-d eO SOO-C Scr 1~ hours. A~ter coolin~ ~o
a~bient t mperatur the ~u~p-nsion i8 pou~-d into 800 ~1
o~ ic /w~ter ~nd aciq$ried with 200 ~1 concentr~d
hydroohloric ac~d. ~he preci~ltat~ i~ auctlon rlltOr-d,
w~h d care,~ully wlth w~t-r, d~ied, tr~tur~tod w~th
aceton-r furthet ~uct~on ~lt-rod and dried.
Yi~ld: le,s~,o g ~89.72% o~ theory)
~el~ing po~nt~ 23~-241-C
, '.
' .
.,' .
T!~TFL F. 03
- 52 - 21~1~3~
b) 1-Benzyl-4-[2-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-1-oxo-2,3-dihydro-isoindol-6-yl]-3,4-
dehydro-piPeridine
360 mg (0.66 mMol) of the compound obtained in a) are
suspended in 10 ml of ethanol. 38 mg (1 mMol) of sodium
borohydride are added in 2 batches at ambient
temperature, with stirring. The mixture is stirred for
a further 2 days at ambient temperature and then water
is added, the mixture is extracted with ethyl acetate,
the combined ethyl acetate extracts are dried over
sodium sulphate and evaporated to dryness in vacuo. The
crystals remaining are dried at 60C in vacuo.
Yield: 270 mg (86.6% of theory),
Melting point: 142-143C
- ': ,- .: -:-:
Exam~le XXIII ~ --
l-tert.butyloxycarbonyl-3-(4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-pyrrolidine
'::~'~ ;:. .
::
a) 4-methoxvcarbonyl-trans-cinnamic acid
124.9 g (1.2 Mol) of malonic acid are dissolved in 180 ;~
ml of pyridine. 164.2 g (1 Mol) of 4-carbomethoxy~
benzaldehyde and 8.52 g (0.1 Mol) of piperidine are -~
added to this solution and the suspension thus obtained
is heated to 100C for 1~ hours. After cooling to
ambient temperature the suspension is poured into 800 ml
of ice/water and acidified with 200 ml concentrated
hydrochloric acid. The precipitate is suction filtered,
washed carefully with water, dried, triturated with
acetone, further suction filtered and dried.
Yield: 185.0 g (89.72% of theory)
Melting point: 329-241C
- 53 - 2111~3~
b) methyl 4-methoxycarbonyl-trans-cinnamate
A mixture of 184.8 g (0.896 Mol) of 4-methoxycarbonyl-
trans-cinnamic acid, 10 ml of sulphuric acid and 3 l of
methanol is refluxed for 18 hours. After cooling with
an ice bath the resulting white crystals are suction
filtered, washed with methanol and dried.
Yield: 175.9 g (89.2% of theory)
Melting point: 121-123C
c) methyl 3-(4-methoxycarbonyl-phenyl)-3-(nitro- ~ -
methvl3-~ro~ionate
To a suspension of 22 g (0.1 Mol) of methyl 4-
methoxycarbonyl-trans-cinnamate in 59 g (0.966 Nol) = 52 -~-
ml of nitromethane, 2.4 g (0.021 Mol) ` 2.6 ml of
1,1,3,3-tetramethylguanidine are added. After heating
at 70C for 5 hours, the reaction mixture is cooled and
evaporated to dryness in vacuo. The residue is divided
between ethyl acetate and 2 N hydrochloric a~id. The
organic phase is washed with water, dried and evaporated
to dryness in vacuo. The remaining crude brown oil is
chromatographed over silica gel with cyclohexane/ethyl
acetate (7:3 to 3:2).
Yield: 20.~ g of a light yellow oil (74% of theory)
Rf value: 0.52 (silica gel; cyclohexane/ethyl acetate =
3:2)
d) 3-(4-methoxycarbonYl-phenyl)-~yrrolidin-5-one
20.3 g (0.72 Mol) of 3-(4-methoxycarbonyl-phenyl)-3-
(nitromethyl)-propionic acid are hydrogenated in 200 ml
of methanol in the presence of 2 g of Raney Nickel for 7
hours at 60C under a pressure of 3 bar. The catalyst
is then removed by suction filtering and the filtrate is
evaporated to dryness in vacuo. The remaining crude,
yellow material is triturated with dichloromethane. The
resulting precipitate is suction filtered, washed with
dichloromethane and dried.
Yield: 11.2 g (70.9% of theory)
- 54 211~33~
.
Melting point: 154-156C
e) 3-(4-methoxycarbonyl-phenyl)-pyrrolidine-
hydrochloride -
16.5 g t274 mMol) = 15.7 ml of glacial acetic acid are
slowly added to a solution of 6 g (27 mMol) of 3-(4-
methoxycarbonyl-phenyl)-pyrrolidin-5-one and 10.4 g (274
mMol) of sodium borohydride in 120 ml of dioxane with
stirring and at a temperature of 10 to 15C. The
resulting mixture is refluxed for 7 hours. After -~
stirring overnight at ambient temperature a further ~- -
quantity of 5.2 g of sodium borohydride is added
followed by 7.9 ml of glacial acetic acid in 30 ml of -
dioxane. After refluxing for a further 6 hours, the --
solution is evaporated to a small volume, diluted with - ~
500 ml of water and extracted with dichloromethane. The - ~-
organic phase is washed with water, dried and evaporated
to a small volume. The resulting solution is treated ~-~
with hydrogen chloride and evaporated to dryness.
Yield: 6.2 g of a colourless oil (93.9% of theory) -
Rf value: 0.63 tReversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
f) l-tert.butyloxycarbonyl-3-(4-methoxycarbonyl- ~-~
~henvl)-Pyrrolidine
9.0 g (41.17 mMol) of di-tert.butyl dicarbonate are
added to 6.2 g (25.6 mMol) of 3-(4-methoxycarbonyl- ~
phenyl)-pyrrolidine-hydrochloride dissolved in a mixture ~-
of 40 ml dioxane, 20 ml water and 14.3 ml triethylamine
after cooling with ice. After stirring overnight the
solution is evaporated to dryness. The remaining oily
substance is divided between dichloromethane and water.
The organic phase is washed with water, dried and
evaporated to dryness. The remaining oily substance is
chromatographed over silica gel with cyclohexane/ethyl
acetate (4~
Yield: 4.8 g of a light yellow oil (61.5% of theory)
,
2 1 ~
-- 55 --
Rf value: 0.62 (silica gel; cyclohexane/ethyl acetate -
3:2)
g) 1-tert.butyloxycarbonyl-3-(4-carboxyphenyl)-
yrrolidine
A mixture of 4.7 g (15.4 mMol) of 1-
tert.butyloxycarbonyl-3-(4-methoxycarbonyl-phenyl)-
pyrrolidine, 15.4 ml of 2 N sodium hydroxide, 100 ml of
tetrahydrofuran and 3.3 ml of water is stirred for 24
hours at ambient temperature. A second quantity of 15.4
ml of 2 N sodium hydroxide is then added and the
solution is heated to 50C for 7 hours. After cooling
to ambient temperature 31 ml of 2 N hydrochloric acid
and aqueous citric acid are added to give a pH of 3.
The resulting solution is evaporated to a small volume.
The resulting colourless precipitate is suction
filtered, washed with water and dried.
Yield: 3.8 g (84.4% of theory)
Melting point: 145-147C
h) 1-tert.butyloxycarbonyl-3-[4-C[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
Phenyll-~Yrrolidine
A mixture of 3.75 g (12.87 mMol) of 1-tert.butyloxy-
carbonyl-3-(4-carboxyphenyl)-pyrrolidine, 3.1 g (13.86
mMol) of methyl trans-(4-amino-cyclohexyl)-propionate,
7.9 g (77.67 mMol) = 10.8 ml of triethylamine and 4.45 g
(13.86 mMol) of 2-[(lH)-benzotriazol-l-yl]-1,1,3,3-
tetramethyluronium-tetra-fluoroborate in 100 ml of
absolute dimethylformamide is stirred for 2 hours at
ambient temperature. After diluting the suspension with
250 ml of water, the resulting colourless precipitate is
suction filtered, washed with water and dried.
Yield: 5.75 g (100% of theory)
Melting point: 99-103C
56 2111~3~
, ~
Example XXIV
1-tert.butyloxycarbonyl-3-[4-[[trans-4-(2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]- ~
phenyll-3-methvl-pYrrolidine ~-
' '-'
a) 2-(4-methoxvcarbonyl-phenyl)-pronionitrile
1.3 g of sodium hydride (5S-62% in oil) are added to a
solution of 5.3 g (30.25 mMol) of 4-methoxycarbonyl- ~
phenyl-acetonitrile in 50 ml of dimethylformamide whilst -
cooling with ice. After ten minutes 4.3 g (30.25 mMol~ ,
= l.9 ml of methyl iodide are added dropwise with
cooling maintained. The resulting suspension is stirred
for 1~ hours, diluted with water and evaporated to a -~
small volume. The remaining solution is diluted again -~
with water, acidified with citric acid and extracted ~ - -
with ethyl acetate. The combined organic phase is -~
washed with water, dried and evaporated to dryness in
vacuo. The remaining oily substance is chromatographed
over silica gel with cyclohexane/ethyl a~etate (17:3). --~
Yield: 32 g of a light yellow oil (47.1% of theory)
Rf value: 0.5 (silica, gel, cyclohexane/ethyl acetate =
7:3)
b) methyl 3-cyano-3-(4-methoxycarbonyl-phenyl)-
butyrate
0.72 g of sodium hydride (55-65% in oil) ars added to a
solution of 3.1 g (16.38 mMol) of 2-(4-methoxycarbonyl- -
phenyl)-propionitrile in 50 ml of dimethylformamide
whilst cooling with ice. After 15 minutes 2.5 g (16.4
mMol) = 1.55 ml of methyl bromoacetate is added dropwise
whilst cooling is maintained. The resulting suspension
is stirred for 2~ hours, diluted with water and
evaporated to a small volume. The resulting solution is
diluted again with water, acidified with citric acid and
extracted with ethyl acetate. The combined organic -
phase is washed with water, dried and evaporated to
211103~
- 57 -
dryness in vacuo. The remaining oily substance is
chromatographed over silica gel with cyclohexane/ethyl
acetate (7:3).
Yield: 3.6 g (83.7% of theory)
Melting point: 75-77C
c) 3-(4-methoxycarbonyl-phenyl)-3-methyl-pyrrolidin-5-
one
A solution of 3.3 g (12.6 mMol) of methyl 3-cyano-3-(4-
methoxycarbonyl-phenyl)-butyrate in 100 ml of methanol
is acidified with 12 ml of methanolic hydrochloric acid
and hydrogenated in the presence of 1 g of palladium on
charcoal (10%), at a pressure of 3 bar for 6 hours at
ambient temperature. After removing the catalyst by
suction filtering the filtrate is evaporated to dryness
in vacuo. The remaining solid is dissolved in ethyl
acetate and the organic phase is extracted with water.
The aqueous phase is adjusted to a pH >7 by adding a
solution of potassium carbonate and then extracted with
ethyl acetate. The organic phase is dried and
evaporated to dryness in vacuo. The remaining solid is
triturated with ethyl acetate, suction filtered, washed
with ethyl acetate and dried.
Yield: 2.2 g (75.9% of theory)
Melting point: 188-189C
d) 3-(4-methoxycarbonyl-phenyl)-3-methylpyrrolidine-
hvdrochloride
5.6 g (92.5 mMol) = 5.3 ml of glacial acetic acid are -
slowly added to a solution of 2.15 g (9.22 mMol) of 3-
(4-methoxycarbonyl-phenyl)-3-methylpyrrolidine-5-one and
3.5 g (92.5 mMol) of sodium borohydride in 60 ml of
dioxane with stirring and at temperature of 10 to 15C. ~ ~
The mixture is refluxed for 6 hours. After stirring ~; -
overnight at ambient temperature a further 1.8 g of
sodium borohydride is added followed by 2.7 ml of
glacial acetic acid in 10 ml of dioxane. After
2 ~ 3 ~
- 58 -
refluxing for a further 7 hours the solution is
evaporated to a small volume, diluted with 300 ml of
water and extracted with dichloromethane. The ; -
dichloromethane phase is washed with water, dried and
evaporated to a small volume. The resulting solution is
treated with hydrogen chloride and evaporated to
dryness.
Yield: 1.14 g of a colourless oil (48.6% of theory) ~ -
Rf value: 0.5 (Reversed Phase Plate RP8; methanol/5% ;
sodium chloride solution = 6:7)
e) 1-tert.butyloxycarbonyl-3-(4-methoxycarbonyl-
Phenyl)-3-methyl-Pvrrolidine
1.6 g (7.15 mMol) of di-tert.butyl dicarbonate are added
to a solution of 1.14 g (4.46 mMol) of 3-(4-
methoxycarbonyl-phenyl)-3-methyl-pyrrolidine-
hydrochloride in a mixture of 8 ml dioxane, 4 ml water
and 2.5 ml triethylamine after cooling with ice. After
stirring for 2 hours the solution is evaporated to
dryness and the remaining oily substance is triturated
between dichloromethane and water. The organic phase is
washed with water, dried and evaporated to dryness.
Yield: 1.18 g of a colourless oil (83.12% of theory)
Rf value: 0.62 (silica gel, cyclohexane/ethyl acetate =
3:2)
f) l-tert.butyloxycarbonyl-3-(4-carboxyphenyl)-3-
methvl-Pyrrolidine
A mixture of 1.1 g (3.44 mMol) of l-tert.butyloxy- ~-
carbonyl-3-(4-methoxycarbonyl-phenyl)-3-methyl-
pyrrolidine, 7 ml of 2 N sodium hydroxide, 20 ml
tetrahydrofuran and 1 ml water is stirred for 3 days.
After this time 7 ml of 2 N hydrochloric acid and citric
acid are added to give a pH of 2. The resulting
solution is evaporated to a small volume and extracted ~ -
with dichloromethane. The organic extract is washed
with water, dried and evaporated to dryness. The
~`~
2111~3~
~ig
remaining oily substance is chromatographed over silica
gel with cyclohexane/ethyl acetate (4:1 to 1:1).
Yield: 600 mg of a light yellow oil (51.1% of theory)
Rf value: 0.5 (silica gel; cyclohexane/ethyl acetate =
3:2)
g) l-tert.butyloxycarbonyl-3-[4[[trans~4-(2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl~-
phenyll-1-methyl-pyrrolidine
A mixture of 0.57 g (1.87 mMol) of 1-tert.butyloxy-
carbonyl-3-(4-carboxyphenyl)-3-methyl-pyrrolidine, 0.445
g (2.01 mMol) of methyl trans-(4-amino-cyclohexyl)-
propionate, 1.14 g (0.113 mMol) = 1.56 ml of
triethylamine and 0.645 g (2 mMol) of 2-[(lH)-
benzotriazol-l-yl]-1,1,3,3-tetramethyluronium-
tetrafluoroborate in 15 ml of absolute dimethylformamide
is stirred for 2 hours at ambient temperature. The
resulting suspension is diluted with water and
evaporated to dryness. The residue is divided between
ethyl acetate and a diluted potassium hydrogencarbonate ~-
solution. The organic phase is washed with water, dried
and evaporated to dryness. The remaining oily substance
is chromatographed over silica gel with cyclohexane/ -~
ethyl acetate = 4:1.
Yield: 300 mg of a colourless oil (37.5% of theory).
Rf value: 0.31 (silica gel; cyclohexane/ethyl acetate = --~
3:2) ~
: ~ '
'~
-`:` 211103~
- 60 -
Preparation of the end compounds:
Exam~le 1
1-tert.Butyloxycarbonyl-4-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-piperidine
A solution of 0.76 g of 1-tert.butyloxycarbonyl-4-(4-
carboxyphenyl)-piperidine, 0.90 g of 2-[(lH)-
benzotriazol-1-yl]-1,1,3,3-tetramethyluronium-
tetrafluoroborate, 0.55 g of mathyl 3-(trans-4-amino-
cyclohexyl)-propionate-hydrochloride, 0.38 g of 1-
hydroxy-(lH)-benzotriazole and 0.67 g of N-methyl-
morpholine in 50 ml of dimethylformamide is stirred for
16 hours at ambient temperature. The solvent is removed
under reduced pressure. 200 ml of water are added to
the residue and the aqueous phase is extracted with
ethyl acetate. The organic phase is dried over sodium
sulphate and filtered and the solvent is removed under
reduced pressure. 1.8 g of a solid are obtained which
is chromatographed with methylene chloride/methanol
(9:1) over silica gel.
Yield: 1.15 g (98% of theory),
Melting point: sintering from 169C
Rf value: 0.60 (sili~a gel; methylene chloride/methanol =
9 : 1 ) ,. :
The following compounds are obtained analogously:
(1) l~tert.butyloxycarbonyl-4-[4-[[4-[2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl~-phenyl]-
piperidine
Melting point: 157-162~C
Rf value: 0.53 (silica gel; cyclohexane/ethyl acetate =
1: 1 )
211103
- 61 -
(2) 4-[4-[[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl~-phenyl]-
l-tert.butyloxycarbonyl-piperidine
Rf value: 0.41 (silica gel; cyclohexane/ethyl acetate =
1 : 1 )
Mass spectrum: (M+Na)+ = 624
(3) 4-[4-L[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-quinuclidine
(4) 4-[4-[[trans-4-[2-methoxycarbonyl~-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-pyridine
(5) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
aminocarbonyl]-piperidino]-pyridine
(6) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-piperidino]-pyridine ~:.
(7) 4-[4-[[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]- :
piperidino]-pyridine ::
(8) 4-[4-[[4-[2-(n-hexanoylamino)-2-(methoxycarbonyl)-
ethyl]-phenyl]-aminocarbonyl]-piperidino]-pyridine
(9) 4-[4-[[trans-4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl~
piperidino]-pyridine
~'
(10) 4-[4-[[trans-4-[2-(n-hexanoylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]- ~:
piperidino]-pyridine -
(11) 1-tert.butyloxycarbonyl-4-[4-[[trans-4-
(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-phenyl]-
piperidine
-`` 21~103~
- 62 -
Melting point: 197-200C
Rf value: 0.20 (silica gel; methylene chloride/methanol =
20: 1)
(12) 4-[4-[[4-(tert.butyloxycarbonyl-methyloxy)-phenyl]- ,
carbonylamino]-phenyl]-l-trifluoroacetyl-piperidine
Prepared from 4-[4-amino-phenyl]-1-trifluoroacetyl-
piperidine and 4-[tert.butyloxycarbonyl-methyloxy]-
benzoic acid
Melting point: 177-178VC
,Example 2 -;
4-[4-[[trans-4-[ 2 - (Methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
A mixture of 1.1 g of 1-tert.butyloxycarbonyl-4-[4-
[[trans-4-[2-(methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine, 40 ml of dioxane and
40 ml of ethereal hydrochloric acid is stirred for 5 -'~
hours at ambient temperature, during which tims an oil
is precipitated. The mixture of solvents is decanted
off and the remaining oil is triturated with ether. The ,'",~,i
solids produced are suction filtered and dried.
Yield: 0.87 g (91% of theory),
Melting point: 225-232C
Rf value: 0.53 (silica gel; methylene chloride/methanol/ -~
conc. ammonia = 4:1:0.25) -,
Mass spectrum: M+ = 372
The following compounds are obtained analogously:
(1) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: 222-225C
Rf value: 0.54 (silica gel; methylene chloride/
, methanol/conc. ammonia = 4:1:0.25) ''
I Mass spectrum: M+ = 366
211103!3
63 -
(2) 4-[4-[[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]-phenyl]-
piperidine-hydrochloride
Melting point: sintering from 70C
Rf value: 0.63 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
Mass spectrum: (M+H)' = 502
(3) 4-[4-[[trans-4-[2-acetamino-2-(methoxycarbonyl)- :
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine- -
hydrochloride
(4) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-oxymethyl]-phenyl]-piperidine-hydrochloride
(5) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]- -
cyclohexyl]-methyloxy]-phenyl]-piperidine-hydrochloride '-~
(6) 4-[4-[[trans-4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]- :~
phenyl]-piperidine-hydrochloride ~--:
(7) 4-[4-[[trans-4-[2-(methanesulphonylamino)-2- -~-~
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]~
phenyl]-piperidine-hydrochloride
(8) 4-[4-[[trans-4-[2-(n-hexanoylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
(9) 4-[4-[[trans-4-[2-~methoxycarbonyl)-propyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(10) 4-[4-[N-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-N-methyl-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
2111~3~
- 64 -
(11) 4-[4-[[trans-4-[2-(methoxycarbonyl)~ethyl]-
cyclohexyl]-carbonylamino]-phenyl]-piperidine
hydrochloride
(12) 4-[4-[[trans-4-[3-(methoxycarbonyl)-propyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(13) 4-[4-[[trans-4-(methoxycarbonylmethyl)-cyclohexyl]-
aminocarbonyl]-phenyl~-piperidine-hydrochloride
Melting point: >250C --
Rf value: 0.4 (Reversed Phase Plate RP8; methanol/5% ~
sodium chloride solution = 6:4) ::
(14) 4-[4-[[4-[3-(methoxycarbonyl)-propyl]-piperidino]~
carbonyl]-phenyl]-piperidine-hydrochloride ;~ ~
(15) 4-[4-[[4-[4-(methoxycarbonyl)-butyl]-piperidino]- -
carbonyl]-phenyl]-piperidine-hydrochloride
: ~'
(16) 4-[4-[[4-[3-(methoxycarbonyl)-propyl]-piperazino]- ~ ~-
carbonyl]-phenyl]-piperidine-dihydrochloride ~; :
(17) 4-[4-[[1-[2-(methoxycarbonyl)-ethyl]-4-
piperidinyl]-aminocarbonyl]-phenyl]-piperidine-
dihydrochloride -.
(18) 4-[4-[[4-[3-(methoxycarbonyl)-propyl]-3-oxo- ~:
piperazino]-carbonyl]-phenyl]-piperidine-hydrochloride ~-
(19) 1-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperazine-
hydrochloride
Melting point: 190-192C
(20) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-3,4-dehydro-
21~103~
~ 65 -
piperidine-hydrochloride
(21) 4-~4-[[trans-4-[2-(methoxycarbonyl)-n-octyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(22) 4-[4-[[trans-4-[2-(benzylsulphonylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
(23) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-4-methyl-piperidine- -
hydrochloride
(24) 4-cyano-4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]- ~
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine- 1~ -
hydrochloride
(25) 4-aminocarbonyl-4-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-piperidine.-hydrochloride
(26) 4-(methoxycarbonyl)-4-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
(27) 3-[4-[[trans-4-[2-methoxycarbonyl)-ethyl]- ~:
cyclohexyl]-aminocarbonyl~-phenyl]-n-propylamine- -~
hydrochloride
(28) 5-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-n-pentylamine-
hydrochloride
(29) 5-[4-[[trans-4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-n-pentylamine-hydrochloride
2 ~ 3 3 '~
- ~6 -
(30) 5-[4-[[trans-4-[2-(n-hexanoylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-n-pentylamine-hydrochloride
(31) 1-[5-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-pyridin-2-yl]-piperazine-
dihydrochloride
(32) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-3-methyl-phenyl]-piperidine-
hydrochloride : :
(33) 4-[3-methoxy-4-[[trans-4-[2-(methoxycarbonyl)- : -- :ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine- -
hydrochloride -:
(34) 4-[4-[[trans-4-[2-amino-2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
dihydrochloride
(35) 4-[4-[[cis-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(36) 4-[4-[[cis-4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
(37) 4-[4-[[4-[2-(n-hexanoylamino)-2-(methoxycarbonyl)-
ethyl]-phenyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(38) 4-~4-[[trans-4-(methoxycarbonylmethoxy)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine- -~
hydrochloride
(39) 4-[3-[[4-[2-(benzylsulphonylamino)-2- ~ :
' ~
` 211103~
- 67 -
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]-phenyl]-
piperidine-hydrochloride
(40) 4-[3-[[4-[2-(n-hexanoylamino)-2-(methoxycarbonyl)-
ethyl]-phenyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(41) 4-[4-[[4-[2-(benzylsulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl~-phenyl]- - :
piperidine-hydrochloride
(42) 4-[3-fluoro-4-[[trans-4-[2-(methoxycarbonyl)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(43) 4-[3-ethoxy-4-[[trans-4-[2-(methoxycarbonyl)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(44) 1-[2-bromo-4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl~-piperazine-
hydrochloride . :
(45) 4-[3-chloro-4-[[trans-4-[2-(methoxycarbonyl)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(46) 4-[4-[[2-bromo-4-[2-(methoxycarbonyl)-ethyl]- :~
phenyl]-aminocarbonyl]-phenyl]-piperidine-hydrochloride
(47) 4-[4-[[2-methoxy-4-[2-(methoxycarbonyl)-ethyl]- : ~
phenyl]-aminocarbonyl]-phenyl]-piperidine-hydrochloride ::
(48) 4-[4-[[trans-4-~2-(methoxycarbonyl)-ethyl]- :
cyclohexyl]-aminocarbonyl]-2-methylthio-phenyl]-
piperazine-hydrochloride
2111035
- 68 -
(49) 1-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl~-
cyclohexyl]-aminocarbonyl]-2-methylsulphonyl-phenyl]-
piperazine-hydrochloride
(50) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-2-methyl- ;
phenyl]-aminocarbonyl]-phenyl]-piperidine-hydrochloride
(51) 4-[4-~[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
sulphonylamino3-phenyl]-piperidine-hydrochloride -
(52) 4-[4-[[4-[2-(methoxycarbonyl)-ethenyl]-phenyl]- ~
aminocarbonyl]-phenyl]-piperidine-hydrochloride -
(53) 4-[4-[[trans-4-(methoxycarbonyl)-cyclohexyl]- -
aminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: 260-265C
Rf value: 0.39 (æilica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
(54) 4-[4-[[4-[2-(methoxycarbonyl~-ethyl]-piperidino]-
methyl]-phenyl]-piperidine-dihydrochloride
Yield: 0.44 g (88 % of theory), resin;
Rf value: 0.65 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
H-NMR-Spectrum (200 MHz, DMS0-d6); signals at ppm:
1.2-1.6 (m, 4H); 1.6-2.05 (m, 6+1H); 2.25-2.4 (t, 2H);
2.8-3.1 (m, 4 +lH); 3.3-3.55 (t, 4H); 3.6 (s, 3H);
4.2 (d, 2H); 7.3 (d, 2H); 7.5 (d, 2H); 8.4-8.9 (m, 2H); -~
9.9 (s, lH)
(55) 1-[4-[[4-(methoxycarbonylmethoxy)-phenyl]-
carbonylamino]-phenyl]-piperazine-hydrochloride
(56) 4-[4-[[4-[2-(methoxycarbonyl)-ethenyl]-phenyl]-
carbonylamino]-phenyl]-piperazine-hydrochloride
(57) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
I
'1
21~10~
- 69 -
carbonylamino]-phenyl]-piperidine-hydrochloride
(58~ 4-[4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-
methylaminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: >250C
Rf value: 0.43 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
(59) 4-[4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-
methylaminocarbonyl]-phenyl]-piperidine-hydrochloride
R~ value: 0.43 (Reversed Phase Plate ~P8; methanol/5% ~-
sodium chloride solution = 6:4)
(60) 4-[4-[~trans-4-(methoxycarbonyl)-cyclohexyl]-
aminocarbonylamino]-phenyl]-piperidine-hydrochloride
(61) 4-[4-[[trans-4-(methoxycarbonylmethoxy)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
Rf value: 0.6 (Reversed Phase Plate RP8; methanol/5% -~
sodium chloride solution = 6:4) - -
(62) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-piperidinyl]-
carbonyl]-phenyl]-piperidine-hydrochloride -
Instead of hydrochloric acid, trifluoroacetic acid was
used. -~-
Melting point: 177-179C (decomp.) -
(63) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-piperidino]-piperidine-
dihydrochloride
Instead of hydrochloric acid, trifluoroacetic acid was
used. -~
Yield: 1.98 g (75.4 % of theory),
Melting point: 302-303C (decomp.)
.,~.
. , , , " .:, -, , ., , ~: ,, ,, . . ~ , .
- 211103~
- 70 -
Example 3
4-[4-[[trans-4-(2-Carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
0.41 g of 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride are stirred with 80 ml of 6N hydrochloric
acid for 4 hours at ambient temperature. The
precipitate formed is filtered off and washed with
water.
Yield: 0.33 g (84% of theory),
Melting point: 280-285C
Rf value: 0.07 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
Mass spectrum: M+ = 358
The following compounds are obtained analogously:
(1) 4-[4-[[4-(2-carboxyethyl)-phenyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride ~ -
Melting point: 290-293C
Rf value: 0.11 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
Mass spectrum: M+ = 352
.--.-.- '
(2) 4-[4-[[4-(2-carboxyethyl)-phenyl]-aminocarbonyl]~
phenyl]-1-methyl-piperidine-hydrochloride
Saponification is carried out with lithium hydroxide in
a 5:4 mixture of tetrahydrofuran and water, lN ~ ~-
hydrochloric acid is added and the tetrahydrofuran is
evaporated off in vacuo.
Melting point: above 300C
Rf value: 0.13 (silica gel; methylene chloride/
¦ methanol/conc. ammonia = 4:1:0.25)
l Mass spectrum: M+ = 366
-
- 71 - 2 1 ~ ~ ~ 3 ~
(3) 4-[4-[[4-[2-(n-butanesulphonylamino)-2-carboxy-
ethyl]-phenyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
Melting point: 130C (sintering from 120C)
Rf value: 0.15 (silica gel; methylene
chloride/methanol/conc. ammonia = 4:1:0.25)
Mass spectrum: (M-H) = 486
(4~ 4-[3-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride -~
A 1:1:0.5 mixture of water, conc. hydrochloric acid and
glacial acetic acid is used.
Rf value: 0.6Q (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
Mass spectrum: M' = 358 ;~
(5) 4-[3-[[4-(2-carboxyethyl)-phenyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
A 1:1:1 mixture of water, conc. hydrochloric acid and - -
glacial acetic acid is used. -- --
Rf value: 0.43 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
Calc. x HCl x 1.3 H20: C 60.47 H 6.67 N 6.71
Found : 60.25 6.77 6.65 ~
''' ~'~'
(6) 4-[3-[[4-[2-(n-butanesulphonylamino)-2-carboxy- -~-~
ethyl~-phenyl]-aminocarbonylJ-phenyl]-piperidine-
hydrochloride
The same procedure is used as in (4). ~-
Melting point: over 200C -
Rf value: 0.60 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
Mass spectrum: (M+H)f = 488
(7) 4-[4-[[trans-4-(2-acetamino-2-carboxyethyl)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
'~':
` ' ~ .
- 72 - 21~103~
(8) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-1-isopropyl-piperidine-
hydrochloride
(9) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
oxymethyl]-phenyl]-piperidine-hydrochloride
(10) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
methyloxy]-phenyl]-piperidine-hydrochloride
(11) 4-[4-[[trans-4-[2-(n-butanesulphonylamino)-2-
carboxyethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-
piperidine-hydrochloride
(12) 4-[4-[[trans-4-[2-carboxy-2-(methanesulphonyl-
amino)-ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-
piperidine-hydrochloride
(13) 4-[4-[[trans-4-[2-carboxy-2-(n-hexanoylamino)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(14) 4-[4-[[trans-4-(2-carboxypropyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
(15) 4-[4-[N-[trans-4-(2-carboxyethyl)-cyclohexyl]-N-
methyl-aminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: 245-247C
~16) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
carbonylamino]-phenyl]-piperidine-hydrochloride
(17) 4-[4-[[trans-4-(3-carboxypropyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
(18) 4-[4-[(trans-4-carboxymethyl-cyclohexyl)-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
211103~
- 73 -
Melting point: >250C
Rf value: 0.5 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
(19) 4-[4-[[4~(3-carboxypropyl)-piperidino]-carbonyl]-
phenyl]-piperidine-hydrochloride
(20) 4-[4-[[4-(4-carboxybutyl)-piperidino]-carbonyl]-
phenyl]-piperidine-hydrochloride
(21) 4-[4-t[4-(3-carboxypropyl)-piperazino]-carbonyl]-
phenyl]-piperidine-dihydrochloride
(22) 4-[4-[[1-(2-carboxyethyl)-4-piperidinyl]-
aminocarbonyl]-phenyl]-piperidine-dihydrochloride
(23) 4-[4-[[4-(3-carboxypropyl)-3-oxo-piperazino]- -
carbonyl]-phenyl]-piperidine-hydrochloride :~
(24) 1-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperazine-hydrochloride ,~
Melting point: 300-302C (decomp.)
(25) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-quinuclidine-hydrochloride
: - ::
(26) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-pyridine-hydrochloride -~
(27) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-3,4-dehydro-piperidine- -
hydrochloride
(28) 4-[4-[[trans-4-(2-carboxy-n-octyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
'I .,
.
~'
.
211103~
- 74 -
(29) 4-[4-[[trans-4-[(2-benzylsulphonylamino)-2-carboxy-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(30) 4-[4-[[trans-4-t2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-4-methyl-piperidine-hydrochloride
(31) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-4-cyano-piperidine-hydrochloride
(32) 4-aminocarbonyl-4-[4-~[trans-4-(2-carboxyethyl)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(33) 4-carboxy-4-[4-[[trans-4-(2-carboxyethyl)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(34) 3-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-n-propylamine-hydrochloride
(35) 5-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-n-pentylamine-hydrochloride
(36) 5-[4-[[trans-4-[2-(n-butanesulphonylamino~-2-
carboxyethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-n-
pentylamine-hydrochloride
(37) 5-[4-[[trans-4-[2-carboxy-2-(n-hexanoylamino)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-n-pentylamine-~ -,
hydrochloride
(38) 1-[5-[[trans-4-(2-carboxyethyl)-cyclohexyl]- ;~ ::
aminocarbonyl]-pyridin-2-yl]-piperazine-dihydrochloride~:
(39) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-3-methyl-phenyl]-piperidine-hydrochloride
- 75 - 2~ 3~
(40) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-3-methoxy-phenyl]-piperidine-
hydrochloride
The same procedure is used as in (2)
(41) 4-[4-[[trans-4-(2-amino-2-carboxyethyl)- ~-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
dihydrochloride -
(42) 4-[4-[[cis-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
(43) 4-[4-[[cis-4-[2-(n-butanesulphonylamino)-2-carboxy-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine- ~ -
hydrochloride
(44) 4-[4-[[4-E2-carboxy-2-(hexanoylamino)-ethyl]-
phenyl]-aminocarbonyl]-phenyl]-piperidine-hydrochloride
(45) 4-[4-[[trans-4-(carboxymethoxy)-cyclohexyl]- ~-
aminocarbonyl]-phenyl]-piperidine-hydrochloride -
(46) 4-[4-[[4-(2-carboxyethyl)-phenyl~-aminocarbonyl]-
piperidino]-pyridine-hydrochloride -
(47) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-piperidino]-pyridine-hydrochloride
(48) 4-[4-[[4-[2-(n-butanesulphonylamino)-2-carboxy- ~
ethyl]-phenyl]-aminocarbonyl]-piperidino]-pyridine- ~ : :
hydrochloride
(49) 4-[4-[[4-[2-carboxy-2-(n-hexanoylamino)-ethyl]- :~
phenyl]-aminocarbonyl]-piperidino]-pyridine-
hydrochloride
: ' :,- ~'
: ~
-' 211103
- 76 -
(50) 4-[4-~[trans-4-[2-(n-butanesulphonylamino)-2-
carboxyethyl]-cyclohexyl]-aminocarbonyl]-piperidino]-
pyridine-hydrochloride
(51) 4-[4-[[trans-4-[2-carboxy-2-(n-hexanoylamino)-
ethyl]-cyclohexyl]-aminocarbonyl]-piperidino]-pyridine-
hydrochloride
(52) 4-[3-[[4-[2-(benzylsulphonylamino)-2-carboxy-
ethyl]-phenyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(53) 4-[3-[[4-[2-carboxy-2-(n-hexanoylamino)-ethyl]-
phenyl]-aminocarbonyl]-phenyl]-piperidine-hydrochloride
(54) 4-[4-[[4-[2-(benzylsulphonylamino)-2-carboxy-
ethyl]-phenyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(55) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-3-fluoro-phenyl]-piperidine-hydrochloride
(56) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-3-ethoxy-phenyl]-piperidine-hydrochloride
The same procedure is used as in (2)
(57~ 1-[2-bromo-4-[[trans-4-(2-carboxyethyl)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperazine- -
hydrochloride ---~
(58) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-3-chloro-phenyl]-piperidine-hydrochloride
~,- -
(59) 4-[4-[[2-bromo-4-(2-carboxyethyl)-phenyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
2111~3~
- 77 -
(60) 4-[4-[[4-(2-carboxyethyl)-2-methoxy-phenyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
(61) 1-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-2-methylthio-phenyl]-piperazine-
hydrochloride
(62) 1-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-2-methylsulphonyl-phenyl]-piperazine-
hydrochloride
(63) 4-[4-[[4-(2-carboxyethyl)-2-methyl-phenyl]- :
aminocarbonyl]-phenyl]-piperidine-hydrochloride
(64) 4-[4-[[4-(2-carboxyethyl)-phenyl]-sulphonylamino]-
phenyl]-piperidine-hydrochloride
(65) 4-[4-[[4-(2-carboxyethenyl)-phenyl]-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
(66) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-l-methyl-piperidine-hydrochloride
Melting point: >300C -
Mass spectrum: M~ = 372 : -
(67) 4-[1-[[trans-4-~2-carboxyethyl)-cyclohexyl]-
aminocarbonyl3-piperidino]-piperidine-hydrochloride
~, ~
(68) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-piperidino]-piperidine-dihydrochloride .- .:.
Yield: 0.77 g (79.5% of theory), :~-~
Melting point: 297-300C (decomp.)
(69) 1-[4-[[4-(carboxymethoxy)-phenyl]-carbonylamino]-: :~
phenyl]-piperazine-hydrochloride ~;
- 78 - 2111~35
(70) 4-[4-[[4-(2-carboxyethenyl)-phenyl]-carbonylamino~-
phenyl]-piperidine-hydrochloride
(71) 4-[4-[[4-(2-carboxyethyl)-phenyl]-carbonylamino]-
phenyl]-piperidine-hydrochloride
(72) 4-[4-[~trans-4-(carboxy)-cyclohexyl]-methyl-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: 109-110C
(73) 4-[2-[4-(2-carboxyethyl)-phenyl]-1-oxo-2,3-dihydro-
isoindol-6-yl]-piperidine-hydrochloride --
Melting point: 291-293C
Rf value: 0.52 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) ~
(74) 2-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]- ~ ;
aminocarbonyl]-phenyl]-ethylamine-hydrochlor~de -
Melting point: >250C ~ :
Rf value: 0.65 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
(75) 4-[4-[[trans-4-(carboxymethoxy)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: >250C
Rf value: 0.65 (Reversed Phase Plate RP8; methanol/5% ~ ~.
sodium chloride solution = 6:4) ~-
(76) 4-[4-[[trans-4-carboxy-cyclohexyl]-
aminocarbonyamino]-phenyl]-piperidine-hydrochloride
Melting point: >200~C
Rf value: 0.70 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) :~
(77) 4-[4-[[4-(2-carboxyethyl)-phenyl]-aminomethyl]-
phenyl]-piperidine-hydrochloride
: .
21110.~
- 79 -
(78) 4-[4-[[4-(2-carboxyethyl)-piperidinyl]-carbonyl]-
phenyl]-piperidine-hydrochloride
Melting point: 207-208C (decomp.)
(79) 4-[2-[trans-4-(2-carboxyethyl)-cyclohexyl]-1-oxo-
2,3-dihydro-isoindol-6-yl]-piperidine-hydrochloride `
Rf value: 0.50 (Reversed Phase Plate RP8; methanol/5
sodium chloride solution = 6:4)
(80) 4-[2-[trans-4-(2-carboxyethyl)-cyclohexyl]-1-oxo-
2,3-dihydro-isoindol-5-yl]-piperidine-hydrochloride
Rf value: 0.50 (Reversed Phase Plate RP8; methanol/5% : -:
sodium chloride solution = 6:4)
Melting point: >300OC
(81) 4-[2-[4-(2-carboxyethyl)-phenyl]-1-oxo-2,3-dihydro-
isoindol-5-yl]-piperidine-hydrochloride ~-:
Melting point: 303-306C ~- .
(82) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-l-aza-bicyclo[2.2.1]heptane-
hydrochloride -`~
(83) 4-[4-[[trans-4-(carboxy)-cyclohexyl]-
methylaminocarbonyl]-piperidine-hydrochloride
Rf value: 0.56 (Reversed Phase Plate RP8i methanol/5%
sodium chloride solution = 6:4) ~ `:
': "' '' ~
Exam~le 4
4-[4-[[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-
aminocarbonyl]-phenyl]-1-methyl-piperidine-hydrochloride
0.8 g of 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride are
dissolved in 35 ml of methanol, mixed with 0.42 g of
paraformaldehyde and 0.45 g of sodium cyanoborohydride
~,
^` 2111~35
- 80 -
and stirred for 3 hours at ambient temperature, whil~t
the pH is maintained between 3 and 6 by the addition o~
lN hydrochloric acid. Then a further 0.5 g of
paraformaldehyde and 0.5 g of sodium cyanoborohydride
are added and the mixture is stirred for 16 hours at
ambient temperature whilst maintaining the above-
mentioned acidity of the solution. It is then made
alkaline with lON sodium hydroxide solution, extracted
with ethyl acetate, the organic phase is evaporated down -
and purified by chromatography on silica gel (eluant:
methylene chloride/methanol = 9:1).
Yiald: 0.58 g (76% of theory),
Melting point: 161-164C
Rf value: 0.17 (silica gel; methylene chloride/methanol =
9 : 1 ) , . :
Mass spectrum: M~ = 380 ~ -
The following compounds are obtained analogously: ~ -
(1) 1-isopropyl-4-[4-[[trans-4-[2-(methoxycarbonyl)- --
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine -
' :' '
(2) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]~
cyclohexyl]-aminocarbonyl]-phenyl~-1-methyl-piperidine
Melting point: 202-204C -
~,
(3) 4-[2-[trans-4-(2-carboxy-ethyl)cyclohexyl]-1-oxo-
2,3-dihydro-isoindol-5-yl]-1-methyl-piperidine-
hydrochloride
Melting point: 301-303C
Prepared from 4-[2-(trans-4-(2-carboxy-ethyl)-
cyclohexyl]-l-oxo-2,3-dihydro-isoindol-5-yl]-piperidine
with paraformaldehyde and formic acid.
(4) 3-[4-[[trans-4-(2-carboxyethyl)cyclohexyl]- ~-
aminocarbonyl]-phenyl]-l-methyl-pyrrolidine-
hydrochloride
::
`` -` 2111~3~
- 81 -
Melting point: 246-250C
Prepared from 3-[4-[[trans-4-(2-carboxy-ethyl)-
cyclohexyl]-aminocarbonyl]-phenyl]-pyrrolidine-
hydrochloride with paraformaldehyde and formic acid.
Example 5
4-[3-[[trans-4-[2-(Methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
1.7 g of 1-benzyl-4-[3-[[trans-4-[2-(methoxycarbonyl)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-3,4-dehydro-
piperidine are dissolved in 40 ml of methanol, mixed -
with 2 ml of methanolic hydrochloric acid and 0.5 g of -~
palladium hydroxide on charcoal and hydrogenated with
hydrogen under 5 bars of pressure at 50C. Then the ;~
catalyst is filtered off and the filtrate is evaporated ~ - -
down ln vacuo.
Yield: 1.30 g (87% of theory),
Rf value: 0.25 (Reversed Phase Plate RP8; methanol/5% -
sodium chloride solution = 6:4)
Mass spectrum: M' = 372
The following compounds are obtained analogously:
(1) 4-[3-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
aminocarbonyl]-phenyl]-piperidine
The work is done without the addition of hydrochloric
acid, using 10% palladium charcoal.
Rf value: 0.27 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
(2) 4-[3-[[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]-phenyl3-
j piperidine-hydrochloride
The same procedure is used as in (1) but at 60~C.
R~ value: 0.28 (Reversed Phase Plate RP8; methanol/5%
2ill~3~
- ~2 -
sodium chloride solution = 6:4)
Mass spectrum: (M+H)+ = 502
(3) 1-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperazine-
hydrochloride
Prepared by debenzylation of 4-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-l-benzyl-piperazine in the presence of 10%
palladium charcoal.
Melting point: 190-192C
(4) 4-[2-[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-1-oxo- ;~
2,3-dihydro-isoindol-6-yl]-piperidine-hydrochloride - ~:~
(5) 4-[2-[trans-4-[2-(methoxycarbonyl)-ethyl]- -d -
cyclohexyl]-l-oxo-2,3-dihydro-isoindol-6-yl]-piperidine- - :-
hydrochloride :
Melting point: 175-178C
Prepared from l-benzyl-4-~2-[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-l-oxo-2,3-dihydro-
I isoindol-6~yl]-3,4-dehydro-piperidine and palladium
hydroxide on charcoal as catalyst.
(6) 4-[2-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-1-oxo-2,3-dihydro-isoindol-5-yl]-piperidine-
hydrochloride ~-
Melting point: 260-262C
(7) 4-[2-[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-1-oxo-
2,3-dihydro-isoindol-5-yl]-piperidine-hydrochloride
Melting point: 232-235C
.
..'
. ~
' ~ :
2illO3~
- 83 -
Example 6
l-Benzyl-4-[3-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-3,4-dehydro-
piperidine -
2 g of 1-Benzyl-4-(3-carboxyphenyl)-3,4-dehydro- -
piperidine-hydrochloride are refluxed for 45 minutes in
3.5 ml of thionylchloride and then evaporated to dryness
in vacuo. The acid chloride thus obtained is added in
batches to a solution (cooled to 0C) of 1.3 g of methyl
3-(trans-4-amino-cyclohexyl)-propionate-hydrochloride
and 3.3 ml of N-ethyl-diisopropylamine in 50 ml of
methylene chloride. After 2 hours, 300 ml of methylene
chloride and 15 ml of methanol are added, the mixture is
washed successively with water, O.lN sodium hydroxide
solution, water, O.lN hydrochloric acid and water and
the organic phase is evaporated down. The product is
purified by column chromatography over silica gel
(eluant: methylene chloride/methanol = 9:1)
Yield: 1.8 g (64% of theory),
Rf value: 0.42 (silica gel; methylene chloride/methanol =
9 : 1 )
The following compounds are obtained analogously:
(1) 1-benzyl-4-[3-[[4-[2-(methoxycarbonyl)-ethyl]-
phenyl]-aminocarbonyl]-phenyl]-3,4-dehydro-piperidine
Melting point: 194-196C
Rf value: 0.66 (silica gel; methylene chloride/methanol =
9 : 1 )
(2) 1-benzyl-4-[3-[[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-aminocarbonyl]-phenyl]-
3,4-dehydro-piperidine-hydrochloride
Rf value: 0.25 (silica gel; methylene chloride/methanol =
20:1)
',:
-
` --" 21~1035
Example 7
4-[4-[[4-(2-Carboxyethyl)-phenyl]-aminomethyl]-phenyl]-
piperidine-hydrochloride
0.7 g of 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
aminomethyl]-phenyl]-l-trifluoroacetyl-piperidine, 10 ml
of glacial acetic acid and l ml of conc. hydrochloric
acid are stirred for 4 hours at 80C and for 16 hours at
ambient temperature. The mixture is evaporated to
dryness ln vacuo, evaporated down several times with
toluene and the residue is stirred with 50 ml of
acetone.
Yield: 0.39 g (66% of theory),
Rf value: 0.76 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 9:1)
Mass spectrum: M+ = 338
The following compounds are obtained analogously:
(1) 4-[2-[trans-4-(2-carboxyethyl)-cyclohexyl]-l-oxo-
2,3-dihydro-isoindol-6-yl]-piperidine-hydrochloride
(2) 4-[2-[4-[2-(n-butanesulphonylamino)-2-carboxy-
ethyl]-phenyl]-l-oxo-2,3-dihydro-isoindol-6-yl]-
piperidine-hydrochloride
(3) 4-[4-[~trans-4-(2-carboxyethyl)-cyclohexyl]-
aminomethyl]-phenyl]-piperidine-dihydrochloride -~
Melting point: 308-311C (decomp.)
(4) 4-[4-[N-[trans-4-(2-carboxyethyl)-cyclohexyl]-N-
methylaminomethyl]-phenyl]-piperidine-dihydrochloride
(5) 4-[4-[N-[trans-4-(2-carboxyethyl)-cyclohexyl]-N-(2- - -
phenyl-ethyl)-aminomethyl]-phenyl]-piperidine-
dihydrochloride
',' '~ :'
:, ,:
_ ~5 _ 211103~
(6) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl~-
aminosulphonyl]-phenyl]-piperidine-hydrochloride
(7) 4-[4-[2-[4-(2-carboxyethyl)-phenyl]-ethenyl]-
phenyl]-piperidine-hydrochloride
(8) 4-[2-[trans-4-(2-carboxyethyl)-cyclohexyl]-l-oxo-
2,3-dihydro-isoindol-5-yl]-piperidine-hydrochloride
(9) 4-[2-~4-(2-carboxyethyl)-phenyl]-1-oxo-2,3-dihydro-
isoindol-5-yl]-piperidine-hydrochloride
(10) 4-[2-[4-[2-(n-butanesulphonylamino)-2-carboxy-
ethyl]-phenyl]-1-oxo-2,3-dihydro-isoindol-5-yl]-
piperidine-hydrochloride
(11) 4-[2-[trans-4-(2-carboxyethyl)-cyclohexyl]-1-oxo-
~,4-dihydro-isoquinolin-7-yl]-piperidine-hydrochloride
(12) 4-[2-[4-(2-carboxyethyl)-phenyl]-1-oxo-3,4-dihydro-
isoquinolin-7-yl]-piperidine-hydrochloride
(13) 4-[2-[4-(2-carboxyethyl)-phenyl]-1-oxo-2,3-dihydro- :
isoindol-6-yl]-piperidine-hydrochloride ~
-.
(14) 4-[4-[2-[4-(2-carboxyethyl)-phenyl]-ethyl3-phenyl]-
piperidine-hydrochloride
(15) 4-[4-[[4-(2-carboxyethyl)-phenyl]-methylamino]-
phenyl]-piperidine-hydrochloride
(16) 4-[4-[(trans-4-carboxy-cyclohexyl)-aminocarbonyl]-
phenyl]-piperidine-hydrochloride
Melting point: above 310C
Rf value: 0.13 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
- ` 2 ~ 3 ~
- 86 -
(17) 4-[4-[[4-(carboxymethyloxy)-phenyl]-carbonylamino]-
phenyl]-piperidine-hydrochloride
Prepared from 4-[4-[[4-(tert.butyloxycarbonyl-
methyloxy)-phenyl]-carbonylamino]-phenyl]-1-
trifluoroacetyl-piperidine
Rf value: 0.10 (silica gel; methylene chloride/
methanol = 9:1)
Mass spectrum: (M+H)+ = 355
Exam~le 8
4-[4-[[4-~2-(Methoxycarbonyl)-ethyl]-phenyl]-
aminomethyl]-phenyl]-1-trifluoroacetyl-piperidine
8.6 g of 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
iminomethyl]-phenyl]-1-trifluoroacetyl-piperidine are
dissolved in 100 ml of ethyl acetate and hydrogenated
initially for 1.5 hours in the presence of 0.5 g of
platinum dioxide at ambient temperature using a hydrogen
pressure of 5 bar. A further 0.5 g of platinum dioxide ~ -
are added and the temperature is increased to 50C.
After 3 hours a further 0.5 g of platinum dioxide are
added and hydrogenation is continued for a further 4
hours. After the catalyst has been filtered off the
solvent is removed and the residue is purified by column
chromatography over silica gel (eluant~
cyclohexane/ethyl acetate = 3:1)
Yield: 3.6 g (42% of theory), ~ -
Rf value: 0.50 (silica gel; cyclohexane/ethyl acetate =
2:1) --~
- ~.
- 87 - 211103~
Example 9
4-[4-[[trans-4-[2-(Isopropyloxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
0.15 g of 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride are
suspended in a mixture of 100 ml of isopropanol and
50 ml of ethereal hydrochloric acid and stirred for 16
hours at ambient temperature. The product is obtained
by evaporating the solution down in vacuo.
Yield: 0.135 g (81% of theory),
Melting point: 255-260C
Rf value: 0.31 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
Mass spectrum: M' = 400
~he following compounds are obtained analogously: ;
(1) 4-[4-[[trans-4-[2-(sec.butyloxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
(2) 4-[4-[[trans-4-[2-(cyclohexyloxycarbonyl~-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine- -
hydrochloride
Melting point: 238-240C
(3) 4-[4-[[trans-4-[2-(isobutyloxycarbonyl)-ethyl]-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
Melting point: 238-240C
(4) 4-[4-[[trans-4-[2-[(2-phenylethyl)-oxycarbonyl]-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
2111~
- ~8 -
(5) 4-[2-[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-1-oxo-
2,3-dihydro-isoindol-6-yl]-piperidine-hydrochloride
(6) 4-~2-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-l-oxo-2,3-dihydro-isoindol-6-yl]-piperidine-
hydrochloride
(7) 4-[2-[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-l-oxo-2,3-dihydro-
isoindol-6-yl]-piperidine-hydrochloride
(8) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminomethyl]-phenyl]-piperidine-di-
trifluoroacetate :- -
Melting point: 77-79C (decomp.) ~:
(9) 4-[4-[N-[trans-4-[2-(methoxycarbonyl)-ethyl]- -~
cyclohexyl]-N-methyl-aminomethyl]-phenyl]-piperidine-
dihydrochloride -~ .
(10) 4-[4-[N-[trans-4-[2-(methoxycarbonyl)-ethyl]- -
cyclohexyl]-N-(2-phenylethyl)-aminomethyl]-phenyl]-
piperidine-dihydrochloride :~
(11) 4-[4-[[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-aminosulphonyl]-phenyl]-piperidine-
hydrochloride :~
(12) 4-[4-[2-[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
ethenyl]-phenyl]-piperidine-hydrochloride ::'-
(13) 4-[2-[trans-4-[2-(methoxycarbonyl)-e~hyl]- :~-
cyclohexyl]-l-oxo-2,3-dihydro-isoindol-5-yl]-piperidine-
hydrochloride
(14) 4-[2-[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-1-oxo-
2,3-dihydro-isoindol-5-yl]-piperidine-hydrochloride
- 89 - 211103~
(15) 4-[2-[4-[2-(n-butanesulphonylamino)-2-
(methoxycarbonyl)-ethyl]-phenyl]-l-oxo-2,3-dihydro-
isoindol-5-yl]-piperidine-hydrochloride
(16) 4-[2-[trans-4-[2-(methoxycarbonyl)-ethyl]-
cyclohexyl]-l-oxo-3,4-dihydro-isoquinolin-7-yl]-
piperidine-hydrochloride
(17) 4-[2-[4-[~-(methoxycarbonyl)-ethyl]-phenyl]-1-oxo-
3,4-dihydro-isoquinolin-7-yl]-piperidine-hydrochloride
(18) 4-[4-[2-[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
ethyl]-phenyl]-piperidine-hydrochloride
(19) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl]-
methylamino]-phenyl]-piperidine-hydrochloride
(20) 4-[4-[[4-[2-(methoxycarbonyl)-ethyl]-phenyl~- -
aminomethyl]-phenyl]-piperidine-hydrochloride
(21) 4-[4-[[trans-4-(isopropylcarbonyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-piperidine-hydrochloride
Melting point: 270C (sintering from 250~C)
Rf value: 0.38 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
(22) 4-[4-[[trans-4-[2-(ethoxycarbonyl)-ethyl~-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
Melting point: 246-248~C
(23) 4-[4-[[trans-4-(ethoxycarbonyl-meth,vloxy)-
cyclohexyl]-aminocarbonyl]-phenyl]-piperidine-
hydrochloride
, Rf value: 0.60 (Reversed Phase Plate RP8; methanol/5%
; sodium chloride soluti.on = 6:4)
2111035
-- 90
(24) 4-[4-[[4-(methoxycarbonyl~methyloxy)-phenyl]-
carbonylamino]-phenyl]-piperidine
(25) 4-[2-[trans-4-t2-(ethoxycarbonyl) ethyl]-
cyclohexyl]-l-oxo-2,3-dihydro-isoindol-5-yl]-piperidine-
hydrochloride
Melting point: 260-264C
Example 10
l-(Methoxycarbonyl)-4-[4-[[trans-4-[2-(methoxycarbonyl~- :
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine ~-
Prepared from 4-[4-[[trans-4-[2-(methoxycarbonyl)-
ethyl]-cyclohexyl]-aminocarbonyl]-phenyl]-piperidine and -
methylchloroformate in methylene chloride in the --
presence of 0.2N sodium hydroxide solution.
The following compound is obtained analogously~
(1) 1-(acetoxy-methoxycarbonyl)-4-[4-[[trans-4-[2- ,
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]- --
phenyl]-piperidine -
Exam~le 11 -~
2-[4-[[trans-4-[2-(Methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyl]-phenyl]-ethylamine-hydrochloride
A solution of 1.6 g (4.87 mMol) of 2-[4-[[trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-acetonitrile in 400 ml of methanol is acidified
with methanolic hydrochloric acid and then hydrogenated
in the presence of 0.5 g of palladium on charcoal (10~)
at ambient temperature under a pressure of 3 bar until
the uptake of hydrogen has ceased. Then the catalyst is
,, .
-~,,
::
211103~
-- 91 --
removed by suction filtering and the filtrate is
evaporated to dryness under reduced pressure. The
residue is triturated with a 1:1 mixture of tert.butyl-
methylether and ethyl acetate, heated, cooled down to
ambient temperature once more and suction filtered.
After decoction with acetone and suction filtering
again, 1.2 g = 66.7~ of a yellowish crystalline compound
are obtained.
Melting point: >250C -
Rf value: 0.45 (silica gel; dichloromethane/methanol =
Example 12
4-[1-[[trans-4-[2-(Methoxycarbonyl)-ethyl]-cyclohexyl]-
aminocarbonyl]-piperidino]-piperidine
To an equimolar solution of trans-4-[2-
(methoxycarbonyl)-ethyl]-cyclohexylamine and p-
nitrophenyl chloroformate in dry tetrahydrofuran, a
solution of 2 equivalents of triethylamine in
tetrahydrofuran is added dropwise with stirring at O-C
and the resulting mixture is stirred for another 2.5
hours at 0C. Then, as stirring continues, one
equivalent of 4,4'-bipiperidyl is added dropwise, the
mixture is then stirred for 16 hours at ambient
temperature and for another 4 hours at 50C. Then it is
evaporated to dryness under reduced pressure, the
residue is taken up in ethyl acetate and this ethyl !
acetate solution is washed with lN sodium hydroxide
solution and then with water, dried over sodium sulphate
and evaporated to dryness under reduced pressure. The
crude product remaining is chromatographed over silica
gel, using ethyl acetate as eluant.
-:`` 2111035
- 92 -
Example 13
4-[4-[[4-(2-Carboxyethyl)-piperidino]-methyl]-phenyl~-
piperidine dihydrochloride
1.3 g (0.0029 Mol) of l-tert.butyloxycarbonyl-4-[4-[[2-
(methoxycarbonylethyl)-piperidino]-methyl]-phenyl]-
piperidine are stirred for 15 minutes at ambient -
temperature in 80 ml of semiconcentrated hydrochloric
acid. Then the mixture is evaporated to dryness
vacuo and the residue remaining is digested three times
with acetone and the resinous residue remaining is dried
in vacuo. -
Yield: 0.82 g (77.1% of theory), ,
Rf value: 0.54 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
H-NMR spectrum (200 MHz, DMS0-d6); signals at ppm: -
1.3-1.7 (m, 5H), 1.7-2.0 (m, 6H); 2.15-2.3 (t, 2H); 2.7
3.1 (m, 4+1H); 3.2-3.55 (m, 4H); 4.15-4.2 (d, 2H); 7.3
(d, 2H); 7.6 (d, 2H); 9.1 (s, 2H); 10.7 (s, lH~; 12.05
(s, lH)
: ~
The following compounds are prepared analogously:
(1) 4-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]- ~-~
aminomethyl]-phenyl]-piperidine-dihydrochloride
Melting point: 308-311C (decomp.)
Prepared from 1-tert.butyloxycarbonyl-4-[4-[[trans-4-(2-
methoxycarbonyl-ethyl)-cyclohexyl]-aminomethyl]-phenyl]-
piperidine and semiconcentrated hydrochloric acid.
(2) 3-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl~-pyrrolidine-hydrochloride
(3) 3-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminocarbonyl]-phenyl]-3-methyl-pyrrolidine-
hydrochloride
`:` 2111~35
- 93 -
(4) 4-[2-[trans-4-(2-carboxyethyl)-cyclohexyl]-1-oxo-
2,3-dihydro-isoindol-6-yl~-pyridine
Rf value: 0.39 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4)
(5) 1-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-
aminomethyl]-phenyl]-piperazine-dihydrochloride
Melting point: 245-248C (decomp.)
Prepared from 1-tert.butyloxycarbonyl-4-[4-[[trans-4-(2-
methoxycarbonyl-ethyl~-cyclohexyl]-aminomethyl]-phenyl]-
piperazine and semiconcentrated hydrochloric acid.
(6) 3-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-amino-
carbonyl]-phenyl]-pyrrolidine-hydrochloride
Melting point: > 250C
Rf value: 0.55 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6/4)
Prepared from l-tert.butyloxycarboxyl-3-[4-[[trans-4-t2-
(methoxycarbonyl)-ethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-pyrrolidine and half-concentrated hydrochloric
acid.
(7) 3-[4-[[trans-4-(2-carboxyethyl)-cyclohexyl]-amino-
carbonyl]-phenyl]-3-methyl-pyrrolidine-hydrochloride
Melting point: >250C
Rf value: 0.5 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6/4)
Prepared from 1-tert.butyloxycarbonyl-3-[4-[[trans-4-[2-
(methoxycarbonylethyl]-cyclohexyl]-aminocarbonyl]-
phenyl]-3-methyl-pyrrolidine and semi-concentrated
hydrochloric acid. -~-
2111~3~
- 94 -
Example 14
Dry ampoule containing 2.5 mg of active substance per
1 ml
,
Composition:
: : -
Actîve substance 2.5 mg - -
Mannitol 50.0 mg
Water for injections ad1.0 ml -
Preparation~
The active substance and mannitol are dissolved in
water. After transferring the solution to the ampoule,
it is freeze-dried.
When required for use, the solution is made up with
water for injections.
Example 15 -
Dry ampoule containing 35 mg of active substance per
2 ml ~ -
Composition:
Active substance 35.0 mg
Mannitol lO0.0 mg
Water for injections ad2.0 ml
Preparation: -
¦ The active substance and mannitol are dissolved in -~
, water. After transferring the solution to the ampoule,
211103~
- 95 -
it is freez~-dried.
When required for use, the solution is made up with
water for injections.
ExamPle 16
Tablet containing 50 mg of active substance
-
Composition:
(1) Active substance 50.0 mg
(2) Lactose 9~.0 mg
(3) Corn starch 50.0 mg
(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesium stearate 2.0 mq
215.0 mg
Preparation:
Components (1), (2) and (3) are mixed together and
granulated with an aqueous solution of component (4).
Component (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.
~xample 17
Tablet containing 350 mg of active substance
. ~ .
Composition:
~.
211103~
- ~6 -
(1) Active substance 350.0 mg
(2) Lactose 136.0 my
(3) Corn starch 80.0 mg
(4) Polyvinylpyrrolidone30.0 mg
(5) Magnesium stearate 4.0 mg
600.0 mg
Preparation:
Components (l), (2) and (3) are mixed together and
granulated with an aqueous solution of component (4).
Component (S) is added to the dried granules. From this
mixture, compressed tablets are produced, biplanar,
~acetted on both sides and notched on one side.
Diameter of tablets: 12 mm.
Example 18
Capsules containing 50 mg of active substance
.:
Composition:
(l) Active substance 50.0 mg
(2) Dried corn starch 58.0 mg
(3) Powdered lactose 50.0 mg
(4) Magnesium stearate 2.0 mq
160.0 mg
Preparation:
Component (1) is triturated with component (3). This
triturate is added to the mixture of components (2) and
(4), with thorough mixing. ;
This powdered mixture is packed into size 3 hard gelatin ~ -
oblong capsules in a capsule filling machine. ;~
--~` 2 ~ 3 ~
- 97 -
Example 19
Capsules containing 350 mg of active substance
,
Composition:
tl) Active substance 350.0 mg
(2) Dried corn starch 46.0 mg
(3) Powdered lactose 30.0 mg
(4) Magnesium stearate 4.0 ma
430.0 mg
Preparation: : ,
.
Component (1) is triturated with component (3). This ~
triturate is added to the mixture of components (2) and -.-
t4), with thorough mixing. ~ -
This powdered mixture is packed into size O hard gelatin
oblong capsules in a capsule filling machine.
,.
.~
: ~ .
