Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
Chemical Compounds
The present invention relates to new phenylacetic
acid derivatives, to processes for their preparation, and to
their effects on intermediate metabolism and the cardiac cir-
culatory system.
According to one feature of the present invention,
we provide compounds of general formula I
; - W~l -- CO - C~2 --~ ~}
[wherein
A represents a group of formula
R5 \ R6
14
- CH - or - C -
[wherein R4 represents an alkyl group containing 1 to 3 carbon
atoms substituted by an alkoxy group containing 1 to 3 carbon
atoms or by a phenyl group; a n-propyl group; an alkyl group
containing 4 to 7 carbon atoms; an alkenyl group containing 3
to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group con-
taining 4 to 6 carbon atoms in the alkylene moiety; an amino-
carbonyl group optionally mono- or disubs-titute~ by alkyl or
phenylalkyl groups each having 1 to 3 carbon atoms in the al~yl
moiety (the substituents in the case of disubstitution beillg
the same or different); an aryl group containing 6 or 10 carbon
~ r~
~i~
12~4~73
atoms mono- or disubstituted by halogen atoms, or by alkyl,
hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl
and/or alkylsulphonyl groups, the substituents in the case of
disubstitution being the same or different and each alkyl
moiety containing 1 to 3 carbon atoms; or a heteroaryl group
containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms;
or, when Rl represents a piperidino group and R2 repre-
sents in the 4-position a fluorine atom and R3 represents a
hydrogen atom and W represents a carboxy group or an alkoxycarb-
onyl group, wherein the alkyl part may contain 1 to 3 carbonatoms then R4 may also represent a methyl group;
or, when Rl represents a piperidino group substituted in
the 2- or 3-position by a methyl group,
or, when R2 represents in the 3-, 4-, or 6-position a
chlorine atom or in the 4- or 6-position a methyl group,
or when W represents a formyl t carboxyvinylene or alkoxy-
carbonylvinylene group, wherein the alkyl part may contain 1 to
3 carbon atoms then R4 may also represent a phenyl group;
R5 and R6 together with the carbon atom between them
represent an alkylidene group containing 3 to 9 carbon atoms or
a phenylalkylidene group containing 1 to 4 carbon atoms in the
alkylidene moiety~;
Rl represents an unbranched alkyleneimino group con-
taining 4 to 9 carbon atoms optionally mono- or disubstituted
by alkyl groups containing 1 to 3 carbon atoms (which in the
`';~
~2~4773
case of disubstitution may be the same or different); or a
dialk~lamino group containing 1 to 5 carbon atoms in each alkyl
component;
R2 represents a hydrogen, fluorine, chlorine, bromine,
or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino,
piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl,
alkylsulphonyl, phenylalkoxy, alkanoyloxy, alkanoylamino,
alkylamino or dialkylamino group wherein the alkyl component
may contain 1 to 3 carbon atoms in each case;
R3 represents an alkyl group containing 1 to 3 carbon
atoms or a hydrogen or halogen atom; and
W represents a carboxy group or an alkoxycarbonyl
group containing a total of 2 to 6 carbon atoms (wherein the
alkyl component may optionally be substituted by a phenyl group
and optionally, at any carbon atom except the a-carbon atom,
by one or two hydroxy groups or by an alkoxy, alkanoyloxy,
dialkylamino, alkyleneimino or pyridinecarbonyloxy group,
each alkyl component containing 1 to 3 carbon atoms and the
alkyleneimino group containing 4 to 6 carbon atoms); an
alkenyloxycarbonyl group containing a total of 4 to 6 carbon
atoms, an alkyl group containing 1 to 3 carbon atoms; or a
hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl,
?.-carboxyethyl, 2-carboxyethenyl, 2,2-bis-(carboxy)-ethyl,
alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycar-
bonyl-ethenyl or 2,2-bis-(alkoxycarbonyl)-ethyl group (each
alkoxy group containing from 1 to 3 carbon atoms )]
~2~773
-3a-
and tautomers ~hereof and optical enantiomers thereof
and salts of the aforementioned compounds.
The present invention is also directed to a process
for preparing the compoundsof gen~ral formula I which process
comprises
(a) reacting a compound of general formula II
/ ~ A - NH2
R2 t 11 (II)
~/\ Rl
~wherein A, Rl and R2 are as defined above or, if A represents
one of the vinylidene groups mentioned above, a tautomer thereof
or a lithium or magnesium halide complex thereof) with a compound
of general formula III
HO - CO - CH2 ~ ~ ~ W' (III)
~$J
R3
(wherein
R3 is as defined above and
W' has the meanings given for W above or represents
a carboxy group protected by a protecting group) or with a
reactive derivative thereof and, if necessary subsequently
cleaving any protecting group used;
(b~ for preparing a compound of formula I wherein W
represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-
carboxyethenyl group, subjecting a compound of general formula
IV
123.4773
-3b~
A - NH - CO - CH2 ~ ~ B
~\ ~ R3 (IV)
Rl
(wherein Rl to R3 and A are as defined above and B represents
a group which can be converted into a carboxy, carboxymethyl,
2-carboxy-ethyl or 2-carboxyethenyl group by hydrolysis,
thermolysis or hydrogenolysis) to hydrolysis, thermolysis or
hydrogenolysis;
(c) for preparing a compound of formula I wherein A re-
presents a group of formula
Rl 4
~ CH~
wherein R4~ has the meanings given for R4 above with the ex-
ception of an alkenyl group and a cyano group, reducing a com-
pound of general formula V
R2 ~ D - CO - CH2 ~ - W (V)
Rl R3
wherein
Rl to R3 and W are defined as above and
D represents a group of formula
R "
4 R5 \ / R6
or C
C~ N - - C ~
N--
~2~47~3
wherein R4" has the meanings given hereinbefore for R4' with
the exception of a cyano group and R5' and R6' together with
the carbon atoms between them represent an alkylidene group
containing 1 to 7 carbon atoms or a phenylalkylidene group
containing 1 to 3 carbon atoms in the alkylidene moiety;
(d) for preparing a compound of formula I wherein A
represents a group of formu].a
14
-- CH-
wherein R4" has the meanings given hereinbefore for R4' with
the exception of a cyano group; reacting a compound of gen-
eral formula VI R14"
~ CH OH
R2 ~ \ Rl (VI)
wherein
R4" represents R4 as defined above with the exception
of a cyano group and Rl and R2 are as defined above with a com-
pound of general formula VII
N-C - CH2 _ ~ W (VII)
wherein R3 and W are as defined above;
(e) Eor preparing a compound of formula I wherein R2
4~73
-3d-
represents a h~drogen atom, dehalogenating a compound of gen-
eral formula VIII
,~ " A - NH - CO - CH~ - ~ (VIII)
Rl R3
wherein Rl, R3, A and W are as defined above and Hal represents
a fluorine, chlorine, bromine or iodine atom;
(f) for preparing a compound of formula I where A
represents a group of formula
R14
- CH -
wherein R4 represents an alkyleneiminocarbonyl group containing
4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl
group optionally mono- or disubstituted by alkyl or phenylalkyl
groups each having 1 to 3 carbon atoms in the alkyl moiety, re-
acting a compound of general formula IX
COOH
2 ~ CH - NH - CO - CH2 -\r \~ W" (IX)
Rl R3
(wherein Rl, R2 and R3 are as defined above and W" represents
W as defined above with the exception of a carboxy group) with
an amine of general formula X
H - R7 (X)
~i4773
-3e-
wherein
R7 represents an alkyleneimino yroup containing 4
to 6 carbon atoms or an amino group optionally mono- or di-
substituted by alkyl or phenylalkyl groups each containing 1
to 3 carbon atoms in the alkyl moiety;
(g) for preparing a compound of formula I wherein A re-
presents a group of formula
14
- CH -
wherein R4 is as defined above and W represents a carboxy
group, oxidising a compound of general formula
R4
~ \ ~C~ NH - CO - CH2- / E (XI)
wherein
Rl to R4 are as defined above and
E represents a group which can be converted into a
carboxy group by oxidation;
(h) for preparing a compound of formula I wherein W
represents an alkoxycarbonyl group containing a total of 2 to
6 carbon atoms wherein the al~yl component may be substituted
at any carbon atom except the ~-carbon atom by one or two
hydroxy groups or by an alkoxy group containing 1 to 3 carbon
atoms, esterifying a carboxylic acid of general formula XII
~2~4773
-3f-
R2 ~ ~ A - NH - CO - CH2 ~ ~ COOH (XII)
Rl R3
(wherein Rl to R3 and A are as defined above, or a reactive
derivative thereof, with an alcohol of yeneral formula XIII
HO - Rg (XIII)
wherein
Rg represents an alkyl group containing 1 to 5
carbon atoms which may be substituted at any carbon atom except
the -carbon atom by one or two hydroxy groups or by an alkvxy
group containing 1 to 3 carbon atoms;
(i) for the preparing a compound of formula I wherein
W represents an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxy-
carbonylethyl or 2-alkoxycarbonylethenyl group and A represents
a group of formula
R14"
- CH -
wherein R4" represents R4 as hereinbefore defined with the ex-
ception of a cyano group, alcoholysing a compound of general
formula XIV
R14"
~ CH - NH - CO - CH2 ~ W"'
2 ~ \ Rl R3 ~XIV)
~;~4773
-3g
wherein R4" represents R4 as defined above with the exception
of a cyano group,
Rl to R3 are as defined above and
W"' represents a cyano, cyanomethyl, 2-cyanoethyl
or 2-cyanoethyenyl group;
and, if required converting an obtained compound of
formula I into a salt thereof.
It will be appreciated that the term "salts" as used
herein includes within its scope salts formed with organic and
inorganic acids and bases. Suitable acids include, for example,
hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric,
tartaric, succinic, maleic or fumaric acid. Suitable bases
include, for example, sodium hydroxide, potassium hydroxide,
cyclohexylamine, ethanolamine, diethanolamine, triethanolamine
or ethylenediamine.
For pharmaceutical use, the salts referred to above
will, of course, be physiologically compatible salts, but other
salts may find use, for example in the preparation of the
compounds of general formula I and their physiologically
compatible salts.
The term "tautomer" as used herein refers particularly
to the tautomeric ketimine form of the compounds of general
formula I wherein A represents a substituted viny~idene radical,
but the term is not restricted to this interpretation and covers
all possible tautomeric forms of the compounds of general
formula I.
~2~
- 3h -
The definitions given hereinbefore for the groups
Rl to R6 and W include the following, for example:
4773
-- 4 --
Rl may represent a dimethylamino, diethylamino,
di-n-propylamino, di-n-butylamino, di-n-pentylamino,
diisobutylamino, N-methyl-ethylamino, N-methyl-n-
propylamino, N-methyl-isopropylamino, N-isopropyl-
S n-propylamino, N-isobutyl-n-propylamino, N-methyl-
n-butylamino, N-ethyl-n-butylamino, N-ethyl-isopropyl-
amino, N-ethyl-n-pentylamino, N-propyl-n-butylamino,
pyrrolidino, piperidino, hexamethyleneimino, hepta-
methyleneimino, octamethyleneimino, nonamethyleneimino,
methyl-pyrrolidino, dimethyl-pyrrolidino, ethyl-pyrrol-
idino, methyl-piperidino, ethyl-piperidino, dimethyl-
piperidino, diethyl-piperidino, methyl-ethylpiperidino,
n-propyl-piperidino, methyl-n-propylpiperidino, isopropyl-
piperidino, or di-n-propyl-piperidino ~roup,
R2 may represent a hydrogen, fluorine, chlorine,
bromine or iodine atom or a methyl, ethyl, n-propyl,
isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy,
trifluoromethyl, nitro, amino, piperidino, methylmercapto,
ethylmercapto, n-propylmercapto, isopropylmercapto,
methylsulphinyl, ethylsulphinyl, methylsulphonyl,
n-propylsulphonyl, benzyloxy, l-phenyl-ethoxy, 2-
phenyl-ethoxy, 3-phenyl-propoxy, acetoxy, propionyloxy,
formylamino, acetylamino, propionylamino, methylamino,
ethylamino, n-propylamino, dimethylamino, diethylamino,
di-n-propylamino or methyl-ethylamino group,
R3 may represent a hydrogen, fluorine, chlorine
or bromine atom or a methyl, ethyl, n-propyl or isopropyl
group,
R4 may represent a methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-pentyl, n-hexyl, methoxymethyl,
ethoxymethyl, n-propoxymethyl, isopropoxymethyl,
2-methoxyethyl, 2-ethoxy-ethyl, 3-methoxy-propyl,
benzyl, l-phenylethyl, 2-phenylethyl, l-phenyl-n-
propyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl,
3-buten-1-yl, 2-buten-1-yl, 4-penten-1-yl, cyano,
lZ:14773
aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,
n-propylaminocarbonyl, dimethylaminocarbonyl, diethylamino-
carbonyl, di-n-propylaminocarbonyl, benzylaminocarbonyl,
2-phenyl-ethylaminocarbonyl, pyrrolidinocarbonyl,
piperidinocarbonyl, hexamethyleneiminocarbonyl, phenyl,
naphthyl, fluorophenyl, chlorophenyl, bromophenyl,
methylphenyl, ethylphenyl, isopropylphenyl, hydroxyphenyl,
methoxyphenyl, ethoxyphenyl, n-propoxyphenyl~ benzyloxy-
phenyl~ 2-phenyl-ethoxy-phenyl, 3-phenylpropoxy-phenyl,
methylsulphenyl-phenyl, ethylsulphenyl-phenyl, methyl-
sulphinyl-phenyl, n-propylsulphinyl-phenyl, methyl-
sulphonyl-phenyl, ethylsulphonyl-phenyl, isopropyl-
sulphonyl-phenyl, methyl-naphthyl, hydroxy-naphthyl,
methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl,
dimethyl-phenyl, di-isopropyl-phenyl, chloro-methyl-
phenyl, dimethoxy-phenyl, methyl-methoxyphenyl, chloro-
methoxy-phenyl, bromo-methoxy-phenyl, pyridyl, pyrimidyl,
quinolyl, isoquinolyl or quinazolyl group,
R5 and ~6 may represent a hydrogen atom or
a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec.butyl or n-pentyl group,
R5 and R6 together with the carbon atoms between
them may represent a benzylidene, l-phenyl-ethylidene,
2-phenyl-ethylidene, l-phenyl-n-propylidene, l-phenyl-
2,2-propylidene or 3-phenyl-n-propylidene group and
W may represent a hydroxymethyl, formyl, carboxy,
carboxymethyl, 2-carboxy-ethyl, 2-carboxy-ethenyl,
2,2-bis-(carboxy)-ethyl, methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
isobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl,
crotyloxycarbonyl, (2-hydroxyethoxy)carbonyl, (2-
hydroxy-n-propoxy)carbonyl, (l-hydroxy-2-propoxy)carbonyl,
(2-methoxyethoxy)carbonyl, (2-ethoxyethoxy)carbonyl,
(2-n-propoxyethoxy)carbonyl, (2-nicotinoyloxy-ethoxy)-
carbonyl, (2-isonicotinoyloxy-ethoxy)carbonyl, (2,3-
12~4773
-- 6 -- .
dihydroxy-n-propoxy)carbonyl, (2-dimethylamino-ethoxy)-
carbonyl, (2-diethylamino-ethoxy)carbonyl, (2-piperidino-
e~hoxy)carbonyl, methyl, ethyl, n-propyl, isopropyl,
cyano, aminocarbonyl, methoxycarbonyl-methyl, ethoxy-
carbonyl-methyl, n-propoxycarbonyl-methyl, 2-methoxy-
carbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxy-
carbonyl-ethyl, 2 methoxycarbonyl-ethenyl, 2-ethoxy-
carbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl, 2,2-
bis-(methoxycarbonyl)-ethyl, 2,2-bis-(ethoxycarbonyl)-
ethyl or 2,2-bis-(isopropoxycarbonyl)-ethyl group.
Preferred compounds of general formula I above
are those wherein
A represents a group of formula
5~ ~ 6
R4 C
11
- CH - or - C -
wherein R4 represents an alkyl group containing 1
to 3 carbon atoms substituted by an alkoxy group
containing 1 to 3 carbon atoms or by a phenyl group;
an n-propyl group; an alkyl group containing 4 to
6 carbon atoms; an alkenyl group containing 3 to
5 carbon atoms; a cyano or aminocarbonyl group; an
aryl group containing 6 or 10 carbon atoms mono-
or disubstituted by halogen atoms, or by alkyl, hydroxy,alkoxy, phenylalkoxy and/or alkylsulphenyl groups,
whilst the substituents may be the same or different
and each alkyl component may contain from 1 to 3
carbon atoms; or a naphthyl, pyridyl, quinolyl or
isoquinolyl group;
R5 and R6 together with the carbon atom between
them represent an alkylidene group containing 3 to
9 carbon atoms or a phenylalkylidene group containing
-- 7 --
1 to 3 carbon atoms in the alkylidene moiety;
Rl represents an unbranched alkyleneimino group containing
4 to S carbon atoms or a piperidino group mono- or disubstituted by
alkyl groups each having 1 to 3 carbon atoms;
R2 represents a hydrogen, fluorine, chlorine or bromine
atom or a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms,
or (if R5 ancl R6 are as hereinbefore defined or R4 represents an alkyl
group containing 1 to 3 carbon atoms substituted by an alkoxy group
with 1 to 3 carbon atoms or by a phenyl group, an n-propyl group, an
alkyl group containing 4 to 6 carbon atoms, an alkenyl group contain-
ing 3 to 5 carbon atoms, or a nitrile or aminocarbonyl group) R2 may
also represent an iodine atom or a hydroxy or amino group;
R3 represents a hydrogen or chlorine atom; and
W represents a methyl, hydroxymethyl, formyl, cyano,
carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group;
an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms
in which the alkyl component may be substituted at any carbon atom
except the c~-carbon atom by 1 or 2 hydroxy groups or by an alkoxy
group containing 1 to 3 carbon atoms or by a pyridinecarbc)nyloxy
group; or an alkoxycarbonyl-methyl, 2-alkoxycarbonylethyl or 2-
alkoxycarbonyl-ethenyl group, wherein each alkoxy group may contain
from 1 to 3 carbon atoms and
4-[N-(6-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbollyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
1214773
-- 8 --
4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-
cinnamic acid and Cl 3 alkyl esters ~hereof,
3-~4-[(N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-
phenyl]-propionic acid and Cl 3 alkyl esters thereof,
4-~N-(4-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyll-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(6-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl~-benzoic acid and Cl 3 alkyl esters thereof,
4-rN-(2-(2-methyl-piperidino)-a-phenyl-benzyl)-amino-
carbonylmethyl~-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(2-(3-methyl-piperidino)-~-phenyl-benzyl)-amino-
carbonyl-methyl~-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl-
benzaldehyde,
4-~11-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[~1-(3-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl]-benzoic acid and Cl_3 aikyl esters thereof,
and
4-[~1-(3-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof.
~4773
Particularly preferred are those compounds
of general formu}a I wherein
A represents a group of formula
5 ~ ~ 6
S R4 C
11
- CH - or - C -
wherein R4 represents an alkyl group containing 1
to 3 carbon atoms substituted by a methoxy or phenyl
group; an n-propyl, cyano or aminocarbonyl group;
an alkyl group containing 4 to 6 carbon atoms, an
alkenyl group containing 3 to 5 carbon atoms; a phenyl
group substituted by a fluorine, chlorine or bromine
atom or by a methyl, hydroxy, methoxy, benzyloxy
or methylsulphenyl group; or a pyridyl group;
R5 and R6 together with the carbon atom between
them represent an alkylidene group containing 3 to
9 carbon atoms or a phenylalkylidene group containing
1 to 3 carbon atoms in the alkylidene moiety,
Rl represents an unbranched alkyleneimino group
containing 4 to 8 carbon atoms or a piperidino group
mono- or disubstituted by methyl groups,
R~ represents a hydrogen, fluorine, chlorine
or bromine atom or a methyl or methoxy group; or
(if R5 and R6 are as hereinbefore defined or R4 represents
an alkyl group containing 1 to 3 carbon atoms sub tituted
by a methoxy or phenyl group, an n-propyl, nitrile
or aminocarbonyl group, an alkyl group containing
4 to 6 carbon atoms or an alkenyl group containing
3 to 5 carbon atoms) R2 may also represent an iodine
atom or a hydroxy or amino group,
~2147 73
- 10 -
R3 represents a hydrogen or chlorine atom; and
~ represents a methyl, hydroxymethyl, formyl, cyano, car-
boxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, an
alkoxycarbonyl group containing a total of 2 to 5 carbon atoms
wherein the alkyl component may be substituted at any carbon atom
except the ~-carbon atom by one or two hydroxy groups, by an
alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbonyl-
oxy group; or ~n alkoxycarbonyl-methyl, 2-alkoxycarbonylethyl or
2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may con-
lQ tain from 1 to 3 carbon atoms; and
4-[N-~6-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof with 1 to 3 carbon
atoms,
4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-
cinnamic acid and Cl 3 alkyl esters thereof J
3-[4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-
phenyl]-propionic acid and Cl 3 alkyl esters thereof,
- 4-[N-(4-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(3-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-(6-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid and Cl 3 alkyl esters thereof,
1~4~3
4-~N-(4-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl3-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-~2-~2-methyl-piperidino)-~-phenyl-benzyl)-amino-
carbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereofJ
4-[N-~2-~3-methyl-piperidino)-~-phenyl-benzyl)-aminocar-
bonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[N-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-
benzaldehyde,
4-[~ 4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbon-
yl-methyl]-benzoic acid and Cl 3 alkyl esters thereof,
4-[~ 3-chloro-2-piperidino-phenyl)-ethyl)-aminocarbon-
yl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, and
4-[~1-(3-methyl-2-piperidino-phenyl)-ethyl)-amino-carbon-
yl-methyl]-benzoic acid and Cl 3 alkyl esters thereof.
Ilowever, another group of preferred compounds are those
wherein A, Rl to R3 and W are as hereinbefore defined, more parti-
cularly those wherein W represents a carboxy group or an alkoxy-
carbonyl group containing a total of 2 to 5 carbon atoms in which
the alkyl component may be substituted at any carbon atom except the
~-carbon atom by one or two hydroxy groups, and optically active
enantiomers and the salts thereof.
Particularly preferred compounds of general formula I above
are those wherein
A represents a group of formula
773
R5 R6
R4
11
- C~ - or - C -
wherein R4 represents an n-propyl group, an alkyl
group contsining 4 or 5 carbon atoms, a phenyl group
substituted by a methyl group or by a fluorine or
chlorine atom, or a pyridyl group,
R5 and R6 together with the carbon atom between
them represent an alkylidene group containing 3 to
5 carbon atoms or a phenylalkylidene group containing
1 to 3 carbon atoms in the alkylidene part;
Rl represents a piperidino group optionally
substituted by one or two methyl groups;
R2 represents a hydrogen, fluorine or chlorine
atom or a methyl or methoxy group:
R3 represents a hydrogen atom and
W represents a carboxy group or an alkoxycarbonyl
group containing a total of 2 to 4 carbon atoms;
particularly those wherein
A represents a group of formula
5~ ~ 6
14 C
- CH - or - C -
wherein R4 represents an n-propyl group or an alkyl
group containing 4 or 5 carbon atoms and R5 and R6
together with the carbon atom between them represent
an alkylidene group containing 3 to 5 carbon atoms
or a phenylalkylidene group containing 1 to 3 carbon
atoms in the alkylidene part, and optically active
enantiomers and salts thereof.
The compounds of general formula I as hereinbefore
defined and their optical enantiomers and salts thereof
may, for example, be prepared by the following processes,
which processes constitute further features of the
present invention:
73
a) Reacting a compound of general formula II
A - NH2
~2 t~ R1 (II)
(wherein A, Rl and R2 are as hereinbefore defined
or, if A represents one of the vinylidene groups
mentioned hereinbefore, the tautomers thereof or
a lithium or magnesium halide complex thereof)
with a compound of general formula III
H0 - CO - C~z ~ - W (I~I)
R3
(wherein R3 is as hereinbefore defined and
W' has the meanings given for W hereinbefore
or represents a carboxy group protected by a protecting
group), or with a reactive derivative thereof optionally
formed in the reaction mixture and, if necessary,
subsequently cleaving any protecting group used.
lS The reactive derivatives of a compound of general
formula III may be, for example, the esters thereof,
such as the methyl, ethyl or benzyl esters, the thio-
esters thereof such as the methylthio- or ethylthio-
ester~, the halides thereof 6uch as the acid chloride,
or the anhydrides or imidazolides thereof.
47173
- 14 -
The reaction is conveniently carried out in
a solvent such as methylene chloride, chloroform,
carbon tetrachloride, ether, tetrahydrofuran, dioxan,
benzene, toluene~ acetonitrile or dimethylformamide,
optionally in the presence of an agent which activates
the acid or a dehydrating agent, e.g. in the presence
of ethyl chloroformate, thionyl chloride, phosphorus
trichloride, phosphorus pentoxide, N,N'-dicyclohexyl-
carbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-
succinimide, N,N'-carbonyldiimidazole or N,~'-thionyldi-
imida~ole or triphenylphosphine/carbon tetrachloride,
or an agent which activates the amino gro~p, e.g.
phosphorus trichloride, and optionally in the presence
of an inorganic base such as sodium carbonate or
a tertiary organic base such as triethylamine or
pyridine, which may simultaneously serve as solvent,
at temperatures of between -25C and 250C, but prefer-
ably at temperatures of between -10C and ~he boiling
temperature of the solvent used. The reaction may
also be carried out without a solvent and furthermore
any water formed during the reaction may be removed
by azeotropic distillation, e.g. by heating with
toluene using a water separator, or by the addition
of a drying agent such as magnesium sulphate or a
molecular sieve.
If necessary, the subsequent cleaving of a
protecting group is preferably effected by hydrolysis,
conveniently either in the presence of an acid such
as hydrochloric, sulphuric, phosphoric or trichloroacetic
acid or in the pre~ence of a base such as sodium
hydroxide or potassium hydroxide in a suitable solvent
~uch as water, methanol, ethanol, ethanol/water,
water~isopropanol or water/dioxan at temperatures
of between -10C and 120C, e~g. at temperatures
of between ambient temperature and the boiling temper-
ature of the reaction mixture.
A tert.butyl group used as the protecting group
may also be cleaved thermally, possibly in an inert
~4773
solvent such as methylene chloride, chloroform, benæene,
toluene, tetrahydrofuran or dioxan and preferably
in the presence of a catalytic quantity of an acid
such as p-toluenesulphonic, sulphuric, pho~phoric
or polyphosphoric acid.
Moreover, a ~enzyl group used as a protecting
group may also be cleaved by hydrogenolysis 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, dioxan or dimethylformamide.
b) In order to prepare a compound of general formula
I wherein W represents a carboxy, carboxymethyl,
2-carboxyethyl or 2-carboxyethenyl group:
subjecting a compound of general formula IV
2 ~ - N H - CO - C~ ~ 3
(wherein
Rl to R3 and A are as hereinbefore defined,
and
B represents a group which can be converted
by hydrolysis, thermolysis or hydrogenolysis into
~ carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxy-
ethenyl group) to hydrolysis, thermolysis or hydrogeno-
lysis.
The hydrolysable groups in the compounds of
general formula IV may be, for example, functional
derivatives of carboxy, carboxymethyl, 2-carboxyethyl
121~773
- 16 -
or 2-carboxyethenyl qroups such as the unsubstituted
or substituted amides thereof, the nitriles, esters,
thiolesters, orthoesters, iminoethers, amidines or
anhydrides thereof, a malonic ester-(l)-yl group,
the tetrazolyl group, an optionally substituted 1,3-
oxazol-2-yl or 1,3-oxazolin-2-yl group, and
the thermolytically cleavable groups may be,
for example, esters with tertiary alcohols, e.g.
the tert.butyl ester,
the hydrogenolytically cleavable groups may
be, for example, esters with aralkanols, e.g. the
benzyl ester.
The hydrolysis is conveniently effected either
in the presence of an acid such as hydrochloric,
sulphuric, phosphoric or trichloroacetic acid or
in the presence of a base such as sodium hydroxide
or potassium hydroxide in a suitable solvent such
as water, water/methanol, ethanol, water/ethanol,
water/isopropanol or water/dioxan at temperatures
of between -10C and 120C, e.g. at temperatures
of between ambient temperature and the boiling temper-
ature of the reaction mixture.
If B in a compound of general formula IV represents
a cyano or aminocarbonyl group, these groups may
also be converted into a carboxy group using a nitrite,
e.g. ~odium nitrite, in the presence of an acid such
as sulphuric acid, which is conveniently also used
as the solvent, at temperatures of between 0 and
50C
If B in a compound of general formula IV represents
the tert.butyloxycarbonyl group, for example, the
tert.butyl group may also be cleaved thermally, option-
ally in an ~nert solvent such as methylene chloride,
chloroform, ben~ene, tolùene, tetrahydrofuran or
3S dioxan and preferably in the presence of a catalytic
quantity of an acid such as p-toluenesulphonic, sul-
phuric, phosphoric or polyphosphoric acid, preferably
at the boiling temperature of the solvent used, e.g.
at temperatures of between 40C and 100C.
121477~
If B in a compound of general formula IV represents
the benzyloxycarbonyl group, for example, the benzyl
group may also be cleaved hydrogenolytically 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, dioxan or dimethylformamide, preferably
at temperatures of hetween 0 and 50C, e.g. at ambient
temperature, and at a hydrogen pressure of from 1
to 5 bar. In the hydrogenolysis, other groups may
simultaneously be reduced as well (e.g. a nitro group
may be reduced to an amino group, a benzyloxy group
to a hydroxy group, a vinylidene group to the corres-
ponding alkylidene group or a cinnamic acid group
to the corresponding phenylpropionic acid group),
or may be replaced by hydrogen atoms, e.g. a halogen
atom may be replaced by a hydrogen atom.
c) In order to prepare compounds of general formula
I wherein A represents a group of formula
IR4'
- CH -
wherein R4' has the meanings given hereinbefore for
R4, with the exception of an alkenyl group and a
cyano group:
Reduction of a compound of general formula V
2 ~ D -CO - C~2 ~ W
~.21477~
- 18 -
wherein
Rl to R3 and W are as hereinbefore defined
and
D represents a group of formula
R4 C
- C~ or It
N - - C
H
wherein R4" has the meanings given hereinbefore for
R4, with the exception of a cyano group and R5' and
R6' together with the carbon atom between them represent
an alkylidene group containing 1 to 7 carbon atoms
or a phenylalkylidene group containing 1 to 3 carbon
atoms in the alkylidene moiety.
Reduction is preferably effected with hydrogen
in the presence of a hydrogenation catalyst such
as palladium/charcoal or Raney nickel in a suitable
solvent such as methanol, ethanol, isopropanol, ethanol/
water, glacial acetic acid, ethyl acetate, dioxan,
tetrahydrofuran, dimethylformamide, benzene or benzene/
ethanol at temperatures of between 0 and 100C, but
preferably at temperatures of between 20C and 50C,
and under a hydrogen pressure of 1 to 5 bar. When
a suitable chiral hydrogenation catalyst such as
a metal ligand complex is used, e.g. a complex of
~ dichloro-bis~1,5-cyclooctadiene-rhodium] and
(+)- or (-~ O,O-isopropylidene-2,3-dihydroxy-1,4-
bis(diphenylphosphino)-butane (= DIOP), the addition
of hydrogen occurs enantioselectively. Moreover,
during catalytic hydrogenation, other groups may
be reduced at the ~ame time, e.g~ a nitro group may
be reduced to the amino group, a benzyloxy group
to the hydroxy group or a cinnamic acid group to
1214~73
-- 19 --
the phenylpropionic acid group, or may be replaced
by hydrogen atoms, e.g. a halogen atom may be replaced
by a hydrogen atom.
d) In order to prepare compounds of g neral formula
I wherein A represents a gro~p of formula
R4~
I
- CH -
wherein R4~ has the meanings given hereinbefore for
R4, with the exception of a cyano group:
Reacting a compound of general formula VI
~ CH - OH (VI)
R
R~
(wherein
R4~ is defined as above and Rl and R2 are as
hereinbefore defined) with a com]pound of general
formula VII
N _ C - C~2 ~ W (VII)
wherein
lZ~4773
- 20 -
R3 and W are as hereinbefore defined.
The reaction is carried out in the presence
of a strong acid which may simultaneously serve as
solvent, prefer2bly in concentrated sulphuric acid,
at temperatures of between 0C and 150C, but preferably
at temperatures of between 20C and 100C.
e) for the preparation of compounds of general formula
~, wherein R2 represents a hydrogen atom:
dehalogenating a compound of general formula VIII
~ A - N H - C~ - CH2 ~ W
10 Hal ~ ~ (VIII)
R3
wherein
Rl, R3, A and W are as hereinbefore defined
and
Hal represents a fluorine, chlorine, bromine
or iodine atom.
The dehalogenation is conveniently effected
in a solvent such as methanol, ethanol, ethyl acetate,
glacial acetic acid or dimethylformamide by means
of catalytically activated hydrogen, e.g. with hydrogen
in the pre~ence of platinum or palladium/charcoal,
at temperatures of between 0 and 100C, but preferably
at ambient temperature, and under a hydrogen pressure
of from 1 to 5 bar. During the dehalogenation, other
groups may be reduced at the same time, e.g. a benzyloxy
group may be reduced ~o a hydroxy group, a vinylidene
group ~o the corresponding alkylidene group or a
cinnamic acid group to the corresponding phenylpropionic
12~4773
acid group, or may be replaced by hydrogen atoms,
e.g. a halogen atom may be replaced by a hydrogen
atom.
f) In order to prepare compounds of general formula
I, wherein A represents a group of formula
~4
I
- CH -
wherein
R4 represents an alkyleneiminocarbonyl group
containing 4 to 6 carbon atoms in the alkylene ring
or an aminocarbonyl group optionally mono- or disub-
stituted by alkyl or phenylalkyl groups each having
1 to 3 carbon atoms in the alkyl moiety:
Reacting a compound of general formula
COOH
R2 ~ H - NH - CO - CH2 ~ W
(wherein
Rl, R2 and R3 are as hereinbefore defined and
W~ has the meanings given hereinbefore for
W, with the exception of the carboxy group), with
` 20 an amine of general formula X
H - R7 ~X)
wherein
R7 represents an alkyleneimino group containing
~214773
- 22 -
4 to 6 carbon atoms or an amino group optionally
mono- or disubstituted by alkyl or phenylalkyl groups
each having 1 to 3 carb~n atoms in the alkyl moiety.
Amidation is conveniently effected in a solvent
such as methylene chloride, chloroform, carbon tetra-
chloride, ether, tetrahydrofuran, dioxan, benzene,
toluene, acetonitrile or dimethylformamide, preferably
in the presence of an agent which activates the acid
or a dehydrating agent, e.g. in the presence of ethyl
chloroformate, thionyl chloride, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
~,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole
or triphenylphosphine/carbon tetrachloride, or an
agent which activates the amino group, e.g. phosphorus
trichloride, and optionally in the presence of an
inorganic base such as sodium carbonate or a tertiary
organic base such as triethylamine or pyridine which
may simultaneously serve as solvent, at temperatures
of between -25C and 250C, but preferably at temper-
atures of between -10C and the boiling temperature
of the solvent used.
g) In order to prepare compounds ~f general formula
I wherein A represents a group of formula
R4
- CH -
as hereinbefore defined and W represents a carboxy
group:
Oxidising a compound of general formula XI
773
- 23 -
R2 ~ ~ - Nll - C0 - CH~ ~ E (XI)
wherein
Rl to R4 are as hereinbefore defined and
E represents a group which can be converted into a carboxy
group by oxidation.
An oxidisable group of this kind may be, for example, a
formyl group and the acetals thereof, a hydroxymethyl group and the
ethers thereof, a substituted or unsubstituted acyl group such as
an acetyl, chloroacetyl J propionyl or malonic acid-ll)-yl group
or a malonic ester-(l)-yl group.
The reaction may be carried out with an oxidising agent in
a suitable solvent such as water, glacial acetic acid, methylene
chloride, dioxan or glycol dimethyl ether at temperatures of between
0 and 100C, but conveniently at temperatures of between 20C and
50C. However, the reaction is preferably effected with silver oxide/
sodium hydroxide solution, manganese dioxide/acetone or methylene
chloride, hydrogen peroxide/sodium hydroxide solution, bromine or
chlorine/sodium or potassium hydroxide solution, chromium trioxide/-
pyridine or pyridinium chlorochromate.
h) In order to prepare compounds of general form-lla I w]lcrei
W represents an alkoxycarbollyl group containing a total o~ ~ to (~
carbon atoms wherein the alkyl componellt may be substitutcd at any
carbon atom except the ~-carbon atom
~2~7~3
_ 24 --
by one or two hydroxy groups or by an alkoxy group containing 1 to
3 carbon atoms:
Esterifying a carboxylic acid of general formula XII
R2 ~ ~ - ~H - CO - CH2 ~ COO~ (XII)
(wherein Rl to R3 and A are as hereinbefore defined) or a reactive
derivative thereof optionally prepared in the reaction mixture,
with an alcohol of general formula XIII
HO - Rg (XIII)
wherein
Rg represents an alkyl group containing 1 to 5 carbon atoms
which may be substituted at any carbon atom except the ~-carbon
atom by one or two hydroxy groups or by an alkoxy group containing
1 to 3 carbon atoms.
Examples of reactive derivatives of a compound of general
formula XII include the halides thereof, such as the acid chloride,
and the anhydrides and imidazolides.
The reaction is conveniently carried out using the
corresponding alcohol as solvent or in a suitable solvent such as
methylene chloride, chloroform, ether, tetrahydrofuran, dioxan,
benzene or toluene, optionally in the presence of an acid-
activating agent or a dehydrating agent, e.g. in the presence
of hydrogen
~2~4~73
chloride, sulphuric acid, ethyl chloroformate, thionyl
chloride, carbon tetrachloride/triphenylphosphine,
carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide
or the isourea ethers thereof, optionally in the
presence of a reaction accelerator such as copper
chloride, and optionally in the presence of an inorganic
base such as sodium carbonate or a tertiary organic
base such as triethylamine or pyridine, or by trans-
esterification, e.g. with a corresponding carbonic
acid diester, at temperatures of between -20C and
100C, but preferably at temperatures of between
-10C and the boiling temperature of the solvent
used.
i) In order to prepare a compound of general formula
I wherein W represents an alkoxycarbonyl, alkoxycarbonyl-
methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-
ethenyl group and A represents a group of formula
R4~
I
-- C~--
where R4" represents R4 as hereinbefore defined with
the exception of a cyano group:
Alcoholysis of a compound of general formula
XIV
RZ ~tl H - NH - CO - CHZ~ W
(XIV)
~4773
- 26 -
wherein
R4~ represents R4 as hereinbefore defined with
the exception of a cyano group and Rl to ~3 are as
hereinbefore defined and
wn~ represents a cyano, cyanomethyl, 2-cyanoethyl
or 2-cyanoethenyl group.
The alcoholysis is conveniently effected in
a corresponding alcohol as a solvent, such as methanol,
ethanol or propanol, preferably in the presence of
an acid such as hydrochloric or sulphuric acid at
temperatures of between 2~C and the boiling temperature
of the solvent used, preferably a$ temperatures of
between 50 and 100C.
If, according to the invention, a compound
of general formula I is initially obtained wherein
W represents a carboxy or alkoxycarbonyl group, this
may subsequently be converted by reduction into a
corresponding compound of general formula I wherein
W represents a formyl or hydroxymethyl group, and/or
20 if a compound of general formula I is initially obtained
wherein W represents a carboxy group, this may subse-
quently be converted by conversion into a sulphonic
acid hydrazide and subsequent disproportionation
into a corresponding compound of general formula
I wherein W represents a formyl group, and/or
if a compound of general formula :r is initially obtained
wherein W represents a formyl group, this may subsequently
be converted by condensation and optional subsequent
hydrolysis and/or decarboxylation into a corresponding
compound of general formula I wherein W represents
a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-ethenyl
group, and/or
if a compound of general formula I is initially obtained
wherein W represents a 2-carboxy-ethenyl or 2-alkoxy-
carbonyl-ethenyl group, this may subsequently be
~147 73
- 27 -
converted by catalytic hydrogenation into a corresponding compound
of general formula I wherein W represents a 2-carboxyethyl or 2-
alkoxycarbonyl-ethyl group, and/or
if a compound of general formula I is initially obtained wherein W
represents an alkoxycarbonyl group substitute~ at any carbon atom
except the ~-carbon atom by a hydroxy group, this may subsequently
be converted by acylation by means of a pyridine-carboxylic acid
into a corresponding (pyridine-carbonyloxyalkoxy)-carbonyl com-
pound of general formula I, and/or
if a compound of general formula I is initially obtained wherein W
represents a hydroxymethyl group, this may, after being converted
into a corresponding halo-methyl compound, subsequently be con-
verted by reaction with a malonic acid diester into a correspond-
ing compound of general formula I wherein W represents an ethyl
group substituted by two alkoxycarbonyl groups, and/or
if a compound of general formula I is initially obtained wherein W
represents an ethyl group substituted by two alkoxycarbonyl groups,
this may subsequently be converted by hydrolysis into a correspond-
ing compound of general formula I wherein W represents an ethyl
group substituted by two carboxy groups, and/or
if a compound of general formula I is initially obtained wherein W
represents an ethyl group substituted by two alkoxycarbonyl groups,
this may subsequently be converted by hydrolysis and decarboxylation
into a corresponding compound of general formula I wherein W repre-
sents a 2-carboxyethyl group, and/or
if a compound of general formula I is initially obtained wherein
R2 represents a nitro group, this may subse-
~2147~3
- 28 -
quently be converted by reduction into a corresponding
compo~nd of general formula I wherein R2 represents
an amino group, and/or
if a compound of general formula I is initially obtained
wherein R2 represents an amino group, this may subse-
quently be converted, via a corresponding diazonium
salt, into a corresponding compound of general f~rmula
I wherein R2 represents a hydrogen or halogen atom
or a hydroxy, alkoxy or alkylsulphenyl group, and/or
if a compound of general formula I is initially obtained
wherein R2 represents a hydroxy group, this may subse-
quently be converted by alkylation into a corresponding
compound of general formula I wherein R2 represents
an alkoxy group, and/or
if a compound of general formula I is initially obtained
wherein R2 represents a benzyloxy group and/or R4
represents an aryl group substituted by a benzyloxy
group, this may subsequently be converted by debenzyl-
ation into a corresponding compound of general formula
I wherein R2 represents a hydroxy group and/or R4
represents an aryl group substituted by a hydroxy
group, and/or
if a compound of general formula I is initially obtained
wherein R4 represents an aminocarbonyl group, this
may subsequently be converted by dehydration into
a corresponding compound of general formula I wherein
R4 represents a cyano group.
The subsequent alcoholysis is preferably carried
out in a corresponding alcohol such as ethanol, in
the presence of an acid such as hydrochloric or sulphuric
acid, at temperatures up to the boiling temperature
of the solvent used.
12~47~73
- 29 -
The subsequent reduction is preferably carried
out with a metal hydride, e.g. with a complex metal
hydride such as lithium aluminium hydride, in a solvent
such as diethyl ether, tetrahydrofuran or dioxan
at temperatures of between 0 and 100C, but preferably
at temperatures of-between 20C and 60C.
The subsequent disproportionation of a sulphonic
acid hydrazide, which is obtained by reacting a corres-
ponding hydrazine with a corresponding reactive carboxylic
acid derivative, is carried out in the presence of
a base such as sodium carbonate in a solvent such
as ethyleneglycol at temperatures of between 100C
and 200C, but preferably at 160 to 170~C.
The subsequent condensation of a formyl compound
is conveniently carried out in a solvent such as
pyridine or tetrahydrofuran with malonic acid, with
a malonic acid ester, with a dialkylphosphono-acetic
acid ester or an alkoxycarbonylmethylene-triphenyl-
phosphoran, optionally in the presence of a base
as the condensing agent, e.g. in the presence of
piperidine, potassium tert.butoxide or sodium hydride,
at temperatures of between 0 and 100C; the desired
compound is obtained by subsPquent acidification,
e.g. with hydrochloric or sulphuric acid, or by subse-
quent alkaline hydrolysis.
The subsequent catalytic hydrogenation is conveni-
ently effected in a solvent such as methanol, ethanol,
ethyl acetate, glacial acetic acid or dimethylformamide
with hydrogen in the presence of a hydrogenation
catalyst such as platinum or palladium/charcoal at
temperatures of between 0 and 75C, but preferably
at ambient temperature and under a hydrogen pressure
of 1 to ~ bar.
The subsequent O-acylation is conveniently
carried out in a solvent such as methylene chloride,
chloroform, carbon tetrachloride, ether, tetrahydrofuran,
dioxan, benzene, toluene, acetonitrile or dimethyl-
formamide, preferably with a reactive derivative
~214773
- 30 -
of the acid, for example a halide such as the acid
chloride, an anhydride or imidazolide and optionally
in the presence of an inorganic base such as sodium
carbonate or a tertiary organic base such as triethyl-
S amine or pyridine which may simultaneously serveas solvent, at teMperatures of between -25C and
250~C, but preferably at temperatures of between
-10C and the boiling temperature of the solvent
used.
The subsequent conversion of a hydroxymethyl
group into a halomethyl group is effected with a
halogenating agent such as thionyl chloride, phosphorus
trichloride, phosphorus tribromide or phosphorus
pentachloride in a solvent such as methylene chloride,
carbon tetrachloride, benzene or nitrobenzene and
subsequently reacting with a malonic acid ester,
e.g. with an alkali metal salt of diethyl malonate,
at temperatures of between 0 and 100C, but preferably
at temperatures of between 50C and 80C.
The subsequent hydrolysis or hydrolysis and
decarboxylation is conveniently effected in the presence
of an acid such as hydrochloric, sulphuric, phosphoric,
polyphosphoric or trifluoroacetic acid in a suitable
solvent such as water, ethanol, water/ethanol, waterJiso-
propanol or water/dioxan at elevated temperatures,
e.~. at the boiling temperature oE the reaction mixture.
The subsequent reduction of the nitro compound
is preferably effected in a solvent such as water,
water/ethanol, methanol, glacial acetic acid, ethyl
acetate or dimethylformamide, conveniently with hydrogen
in the presence of a hydrogenation catalyst such
as Raney nickel, platinum or palladium/charcoal,
with metals such as iron, tin or zinc in the presence
of an acid, with salts such as iron(II)sulphate,
tin(II)chloride or sodium dithionite or with hydrazine
in the presence of Raney nickel at temperatures of
between ~ and 50C, but preferably at ambient temper-
ature.
1~4773
- 31 -
The subsequent reaction of a diazonium salt,
e.g. the fluoroborate, the fluoride in 40~ hydrofluoric
acid, the hydrosulphate in sulphuric acid or the
hydrochloride, if necessary in the presence of copper
or a corresponding copper(I)salt such as copper(I)
chloride/hydrochloric acid or copper(I~bromide/hydro-
bromic acid, is carried out at slightly elevated
temperatures, e.g. at temperatures of between 1~C
and 100C; the subsequent reaction with hypophosphorous
acid is preferably carried out at -5C to 0C. The
diazonium salt required is conveniently prepared
in a suitable solvent, e.g. in water/hydrochloric
acid, methanol/hydrochloric acid, ethanol/hydrochloric
acid or dioxan/hydrochloric acid, by diazotising
a corresponding amino compound with a nitrite, e.g.
sodium nitrite or an ester of nitrous acid, at low
temperatures, e.g. at temperatures of between -10C
and 5C.
The subsequent O-alkylation is conveniently
effected with a corresponding halide, sulphonic acid
ester or diazoalkane, e.g. with methyl iodide, dimethyl-
sulphate, ethyl bromide, ethyl p-toluenesulphonate,
isopropylmethanesulphonate or diazomethan~, optionally
in the presence of a base such as sodium hydride,
potassium hydroxide or potassium tert.butoxide and
preferably in a solvent such as diethyl ether, tetrahydro-
furan, dioxan, methanol, ethanol, pyridine or dimethyl-
formamide at temperatures of between 0 and 75C,
preferably at ambient temperature.
The ~ubsequent debenzylation is conveniently
effected in a solvent such as methanol, ethanol,
ethyl acetate, glacial acetic acid or dimethylformamide
using catalytically àctivated hydrogen, e.g. using
hydrogen in the presence of platinum or palladium~char-
coal, at temperatures of between 0 and 75C, but
preferably at ambient temperature and at a hydrogen
pressure of from 1 to 5 bar.
1~14773
The subsequent dehydration is carried out with
a dehydrating agent such as phosphorus pentoxide,
sulphuric acid or p-toluenesulphonic acid chloride,
optionally in a solvent such as methylene chloride
S or pyridine at temperatures of between 0 and 100C,
preferably at temperatures of between 20 and 80C.
If they have a chiral centre, the compounds
of general formula I obtained can also be resolved
into their enantiomers by conventional methods.
This may, for example, be effected by column chromato-
graphy on a chiral phase.
A compound of general formula I or a tautomer
thereof, initially obtained, may subsequently be
converted into an addition salt thereof, for example
by conventional methods such as reacting the compound
of general formula I or tautomer thereof as a base
with an acid in a suitable solvent, or reacting the
compound of general formula I or tautomer thereof
as an acid with a base in a suitable solvent. A
salt of a compound of general formula I or a tautomer
thereof, initially obtained, may subsequently be
converted by conventional methods into a different
salt or into a compound of general formula I or tautomer
thereof.
The compounds of general formulae II to XIV
used as starting materials may be obtained by methods
known from the literature or are themselves known
from the literature.
Thus, for example, a compound of general formula
II wherein A represents a group of formula
C
Ic
or the tautomeric ketimine thereof is obtained by
reacting a corresponding nitrile with a corresponding
1214~3
Grignard or lithium compound and subsequently hydrolysing
or by reacting a corresponding ketone with ammonia
in the presence of titanium tetrachloride. For further
reaction with a compound of general formula I~I or
the reactive derivatives thereof, more particularly
the acid chlorides thereof, it is also possible to
use the organometalli~ ketimine complex.
A compound of general formula II wherein A
represents a group of formula
~4
- CH -
wherein R4n' has the meanings given hereinbefore
for R4 with the exception of the cyano and aminocarbonyl
groups, is obtained, for example, by reacting a corre-
sponding nitrile with a corresponding Grignard or
lithium compound and optionally subsequently carrying
out lithium aluminium hydride reduction or subsequent
hydrolysis to form the ketimine, which is then reduced
with catalytically activated hydrogen, with a complex
metal hydride or with nascent hydrogen, by hydrolysis
or hydrazinolysis of a corresponding phthalimido
compound, by reacting a corresponding ketone with
ammonium formate and subsequent hydrolysis or with
an ammonium salt in the presence of sodium cyanoboro-
hydride, by reduction of a corresponding oxime with
lithium aluminium hydride or with catalytically activated
or nascent hydrogen, by reduction of a corresponding
N-benzyl- or ~-(l-phenylethyl)-ketimine, e.g. with
catalytically activated hydrogen or with a complex
metal hydride in ether or tetrahydrofuran at temperatures
of between -78C and the boiling temperature of the
solvent used and subsequently cleaving the benzyl
or l-phenylethyl group by catalytic hydrogenation,
by ~itter reaction of a corresponding alcohol with
potassium cyanide in sulphuric acid, or by Hofmann,
~2~477~
- 34 -
Curtius, Lossen or Schmidt degradation of a corresponding
compound.
A compound of general formula II wherein A
represents the group
CN
I
- CH -
may be obtained by reacting a corresponding aldehyde
with ammonium cyanide or by reacting a corresponding
cyanohydrin with ammonia.
An amine of general formula II thus obtained,
having a chiral centre, wherein A represents a group
of formula
- CH -
wherein R4" has the meanings given hereinbefore with
the exception of the cyano group, may be resolved
into the enantiomers by racemate splitting, e.g.
by fractional crystallisation of the diastereomeric
salts with optically active acids and subsequent
decomposition of the salts or by column chromatography
on a chiral phase, or by forming diastereomeric compounds
and then eeparating and splitting them.
Moreover, an optically active amine of general
formula II may also be prepared by enantioselective
reduction of a corresponding ketimine using complex
boron or alu~inium hydrides wherein some of the hydride
hydrogen atoms are replaced by optically active alkoxide
radicals, or by means of hydrogen in the presence
of a su$table chiral hydrogenation catalyst or analo-
gously, gtarting from a corresponding N-benzyl- or
N-(l-phenethyl)-ketimine or from a corresponding
N-acyl-ketimine or enamide and optionally subsequently
cleaving the benzyl, l-phenethyl or acyl group.
121~773
- 35 -
Furthermore, an optically active amine of general
formula II may also be prepared by diastereoselective
reduction of a corresponding ketimine or hydrazone
chirally substituted at the nitrogen atom, by means
of complex or non-complex b~ron or aluminium hydrides
wherein, if desired, some of the hydride hydrogen
atoms have been replaced by corresponding alkoxide,
phenolate or alkyl radicals, or by means of hydrogen
in the presence of a suitable hydrogenation catalyst
and optional subse~uent cleaving of the chiral auxiliary
radical by catalytic hydrogenolysis or hydrolysis.
In addition, an optically active amine of general
formula II may also be prepared by dias.ereoselective
addition of a corresponding organometallic compound,
lS preferably a Grignard or lithium compound, to a corres-
ponding aldimine chirally substituted at the nitrogen
atom, by subsequent hydrolysis and optional subsequent
cleaving of the chiral auxiliary radical by catalytic
hydrogenolysis or hydrolysis.
The compounds of general formulae IV, VIII,
IX, XI, XII and XIV used as starting materials are
obtained by reacting a corresponding amine with a
corresponding compound of general formula III or
the reactive derivatives thereof, with optional subse-
quent hydrolysis.
A compound of general formula V used as starting
material is preferably obtained by acylating a corres-
ponding ketimine or the organometallic complex thereof
with a corresponding carboxylic acid or the reactive
derivatives thereof.
As already mentioned hereinbefore, the new
compounds of general formula I as hereinbefore defined,
the tautomers and optical enantiomers thereof and
acid and base addition salts of the aforementioned
compounds have valuable pharmacological properties,
namely an effect on the intermediate metabolism,
but particularly the hypoglycaemic effect of lowering
blood sugar and, to some extent, an effect on the
cardiac circulatory system.
773
- 36 -
For example, the following compounds have been
examined for their properties as follows:
A = (Z)-4-[(1~(2-piperidino-phenyl)-1-buten-1-yl)-
aminocarbonylmethyl]-benzoic acid,
B = ethyl (Z)-4-~(1-(2-piperidino-phenyl)-1-buten-
l-yl)-aminocarbonylmethyl]-benzoate,
C = (E)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-
aminocarbonylmethyl~-benzoic acid,
D = 4-[(2-methyl-1-(2-piperidino-phenyl)-1-propen-
l-yl)-aminocarbonylmethyl]-benzoic acid,
E = ethyl (Z)-4-~(1-(2-piperidino-phenyl)-1-hexen-
l-yl)-aminocarbonylmethyl]-benzoate,
F = (Z)-4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propen-
l-yl)-aminocarbonylmethyl~-benzoic acid,
G = (z)-4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-
l-buten-l-yl)-aminocarbonylmethyl~-benzoic acid,
H = 4-[(1-~2-pyrrolidino-phenyl)-1-butyl)-aminocarbonyl-
methyl]-benzoic acid,
J = (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-
carbonylmethyl]-benzoic acid,
R S (+) -4-1 ( 1- ( 2-piperidino-phenyl)-1-butyl)-amino-
carbonylmethyl]-benzoic acid,
L ~ ethyl (~)-4-[(1-~2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoate,
~2~4773
- 37 -
M - 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-amino-
carbonylmethyl]-benzoic acid,
N = 4-[(1-(2-pip~ridino-phenyl)-1-hexylj-aminocarbonyl-
methyll-benzoic acid,
O = 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propyl)-
aminocarbonylmethyl]-benzoic acid,
P = 4-~(2-methoxy-1-(2-piperidino-phenyl)-1-ethyl)-
aminocarbonylmethyl] benzoic acid,
Q = 4-~(~-cyan~-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzoic acid,
R = 4-[~1-(2-piperidino-phenyl)-1-butyl3-aminocarbonyl-
methyl]-benzyl alcohol,
S = 4-~(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-
methyl]-phenylacetic acid,
T = 4-~(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-
methyl]-cinnamic acid,
U = 2,3-dihydroxy-propyl 4-[(1-(2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate,
V = 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl~-benzoic acid,
W = 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid,
X 5 4-~(1-(2-octahydroazonino-phenyl)-1-ethenyl)-
aminocarbonylmethyl]-benzoic acid,
Y - 4-[(1-(3-chloro-2-piperidino-phenyl)-1-ethyl)-
aminocarbonylmethyl~-benzoic acid,
~Z~4773
- 38 -
Z = 4-[tl-(3-methyl-2-piperidino-phenyl)-1-ethyl)-
aminocarbonylmethyl~-benzoic acid,
AA = 4-~(~-(4-methyl-phenyl)-2-piperidino-benzyl1-
5aminocarbonylmethyl]-benzoic acid,
AB = 4-[(-(3-methyl-phenyl)-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid,
AC = 4-[~a-(4-fluoro-phenyl)-2-piperidino-benzyl)-
aminocarbonylmethyl3-benzoic acid,
AD = 4-[(~-~2-fluoro-phenyl)-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid,
AE = 4-[(Q-(4-chloro-phenyl)-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid,
AF = 4-[(a-(3-chloro-phenyl)-2-piperidino-benzyl)-
15aminocarbonylmethyl]-benzoic acid,
AG = 4-[(2-piperidino-a-(2-pyridyl)-benzyl)-amino-
carbonylmethyl]-benzoic acid,
AH = 4-[(2-piperidino-a-(4-pyridyl3-benzyl)-amino-
carbonylmethyl~-benzoic acid,
AJ = 4-[~6-chloro-a-phenyl-2-piperidino-benzyl)-amino-
carbonylmethyl~-benzoic acid,
AX = 4-l(-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl~-cinnamic acid,
AL - 3-[4~[(-phenyl-2-piperidino-benzyl)-aminocarbonyl-
25methyl]-phenyl~-propionic acid,
AM = 4-[t4-chloro-~-phenyl-2-piperidino-benzyl)-amino-
carbonylmethyl]-benzoic acid,
12~773
- 39 -
AN = 4-[(6-methyl-~-phenyl-2-piperidino-benzyl)-amino-
carbonylmethyl]-benzoic acid,
AO = 4-~(4-methyl--phenyl-2-piperidino-benzyl)-amino-
carbonylmethyl~-benzoic acid,
AP = 4-[(~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzaldehyde,
AQ = 4-[(2-(2-methyl-piperidino)-~-phenyl-benzyl)-
aminocarbonylmethyl~-benzoic acid,
AR = 4-[(2-(3-methyl-piperidino)-a-phenyl-benzyl)-
aminocarbonylmethyl~-benzoic acid and
AS = 4-[(3-chloro--phenyl-2-piperidino-benzyl~-amino-
carbonylmethyl]-benzoic acid:
1. HyPoql~caemic activity
- The hypoglycaemic activity of the test substances
was tested on female rats of a single strain weighing
from 180 to 220 9, which had been kept without food
or drink for 24 hours before the start of the test.
The substances to be tested were suspended in 1.5%
methylcellulose immediately before the start cf the
test and administered by oesophageal tube.
Blood samples were taken immediately before
the administration of the substance and then 1, 2,
3 and 4 hours afterwards, in each case from the retro-
orbital venous plexus. From each sample, 50 ~1 were
deproteinated with 0.5 ml of 0.33 N perchloric acid
and then centrifuged. The glucose in the supernatant
phase was determined by the hexokinase method using
an analytical photometer. The results were evaluated
statistically using the t test according to Student,
taking p - 0.05 as the limit of significance.
The following Table contains the values found
in percent, compared with the controls:
~Z~4773
- 40 -
_ -
5 mg/kg 1 mg/kg
Substance 1 2 3 4 1 2 3 4
_
A -43 -40 -33 -35
B -44 -39 -26 -35 -39 -19 -26 -30
C -43 -43 -37 -38
D -36 -32 -27 -25
E -46 - -40 -3B -26 -23 -23 -12 -18
F -43 -42 -39 -32
G -44 -42 -37 -31
H -50 -46 -44 -45
J -44 -37 -42 -42 -38 -32 -34 -29
K -41 -43 -38 -31
L -42 -45 -31 -22 -14 -18 -14 n.s
M -46 -43 -40 -36 -33 -30 -21 n.s
N -42 -42 -37 -33
O -38+ -31+ n.s.+ n.s.+
P -49 -43 -34 -22 -37 ~19n.s. n.s
Q -28 -13 n.s.n.s.
R -38 -40 -35 -29 -39 -34 -29 -24
S -49 -42 -30 -17 -29 -20 -10 n.s
T -48 -46 -42 -40 -42 -42 -40 -32
U -43 -43 -49 -45 -39 -35 -29 -24
~ -45 -41 -46 -40 -37 -23 -30 -18
W -46 -45 -39 -37 -36 -25 -16 n.s
X -34+ -21+ -17+ -14
Y -32 -24 -16 -18
Z -22 -33 -28 -26
30 AA -30 -33 -14 n.s. -15 -15 -13 n.s
AB -43 -38 -36 -27 -26 -15 n.s. n.s
AC -36 -37 -36 -33
AD -28 -32 -27 -28 -16 -20 -17 -14
AE -3Q -28 -39 -36 -21 -20 -22 n.s
~Z~4773
~ 41 -
5 mg/kg 1 mg/kg
Substance1 2 3 4 1 2 3 4
_
AF -43 -39 -30 -26 -17-19 n. 5. n. s
AG -49 -50+ -36 -31+ -18n.s. n.s. n.s
AH -41 -37 -20 n.s. -26 -14 n.s. n.s
AJ -44 -40 -39 -40 -35 -34 -28 -20
AK -48 -47+ -40+ -45+ -32 -19 -10 -17
AL -43+ -41+ -38+ -34 -40 -31 -23 -12
AM -34 -35 -32 -29 -11 -13 n.s. n. s
AM -39 -35 -27 -26 -27 -24 n. s. n.s
AO -37 -34 -32 -31 -21 -17 -15 -11
AP -26 -28 -22 -17
AQ -32 -31 -24 -19 -16 -11 n.s. n. s
AR -35 -30 -29 -31 -13 - 9 n.s. n.s
AS I-45 -44 -42 -32 -21 -13 n.s. n. s
+ = at lQ mg/kg
n.s. = statistically not significant
2. Acute toxicitY
The toxic effect was tested in male and female
mice of the same strain weighing from 20 to 26 9,
after oral administration of a single dose (suspended
in 1% methylcellulose) over an observation period
of 14 days:
~2~ 73
~ 42 ~
Substance Approximate acute toxicity
A > 1 000 mg/kg p.o. (0 out of 6 animals died)
C ~2 000 mg/kg p.o. (0 out of 6 animals died)
D > soO mg/kg p.o. (0 out of 6 animals diPd)
J >2 000 mg/kg p.o. (0 out of 10 animals died)
AA >1 000 mg/kg p.o. (0 out of 10 animals died)
AB ~l 000 mg/kg p.o. (0 out of 10 animals died)
AC ~1 000 mg/kg p.o. (0 out of 10 animals died)
AD >1 oon mg/kg p.o. (0 out of 10 animals died)
AE ~1 000 mg/kg p.o. (0 out of 10 animals died)
AG >1 000 mg/kg p.o. (0 out of 10 animals died)
In view of their pharmacological properties,
the compounds prepared according to the invention
are suitable for the treatment of diabetes mellitus.
According to a yet further feature of the present
invention, we provide pharmaceutical compositions
comprising, as active ingredient, at least one compound
of general formula I as hereinbefore defined or a
tautomer thereof or a physiologically compatible
salt of these compounds, in association with one
or more pharmaceutical carriers or excipients.
For pharmaceutical administration the compounds
of general formula I or tautomers thereof or their
physiologically compatible salts may be incorporated
into conventional preparations in either solid or
liquid formr optionally in combination with other
active ingredients. ~he compositions may, for example,
be presented in a form suitable for oral or parenteral
admini~tration. Preferred forms include, for example,
tablets, coated tablets, capsules, powders or suspensions.
The active ingredient may be incorporated in
excipients customarily employed in pharmaceutical
~2~4773
- 43 -
compositions such as, for example, corn starch, lactose,
celulose, magnesium stearate, citric acid, aqueous
or non-aqueous vehicles, fatty substances of animal
or vegetable origin, paraffin derivatives, glycols,
various wetting, dispersing or emulsifying agents
and/or preservatives.
Advantageously, the compositions may be formulated
as dosage units, each dosage unit being adapted to
supply a fixed dose of active ingredient.
A suitable single dose for adults is 1-50 mg,
preferably 2.5-20 mg of active ingredient, once or
twice per day. The total daily dosage may, however,
be varied according to the compounds used, the subject
treated and the complaint concerned.
According to a still further feature of the
present invention, we provide a method of treating
a patient suffering from or susceptible to diabetes
mellitus or disorders of the intermediate metabolism
or the cardiac circulatory system, which comprises
administering to the said patient an effective amount
of a compound of general formula I as hereinbefore
defined or a tautomer thereof or a physiologically
compatible salt thereof.
~.214773
- 44 -
The following non-limiting Examples are intended
to illustrate the invention:
Example 1
Ethyl 4-[N-~-(4-methYl-phenyl)-2-pi~eridino-ben~l]-
5 aminocarbonYlmethyl]-benzoate
4.7 9 (18 mmol) of triphenylphosphine, 3 9
(30 mmol) of triethylamine and 1.5 mm (15 mmol) of
carbon tetrachloride are added successively to 4.2 g
(15 mmol) of a-(4-methyl-phenyl)-2-piperidino-benzylamine
and 3.4 9 (16.5 mmol) of 4-ethoxycarbonyl-phenylacetic
acid, dissolved in 40 ml of acetonitrile. The reaction
mixture is stirred at 50C for 2 hours, then concentrated
by evaporation and, after acidification with 6N hydro-
chloric acid, extracted with ethyl acetate. The
acidic aqueous phase is then extracted several times
with methylene chloride. The methylene chloride
extracts are washed with sodium bicarbonate solution,
dried over magnesium sulphate and concentrated by
evaporation. The evaporation residue is triturated
20 with ethanol and suction filtered.
Yield: 4.55 9 (65~ of theory),
M.p.: 177-178C
Calculated: C 76.57 H 7.28 N 5.9S
Found: 76.19 7.16 5.82
The following were prepared analogously to
Example 1:
(a~ Ethyl 4-[N-I-(3-methyl-phenyl)-2-piperidino-
benzyl~-aminocarbonyl-methyl]-benzoate
Yield: 48% of theory,
.p.: 159-160C
Calculated: C 76.57 H 7.28 N 5.g5
Found: 76.80 7.35 5.76
(b) Ethyl 4-[N-1-(2-methyl-phenyl)-2-piperidino-
benzyl~-aminocarbonylmethyl~-benzoate
Yield: 35.4~ of theory,
M.p.: 196-198C
~21~
- 45 -
Calculated: C 76.57 H 7.28 N 5.95
Found: 76.65 7.35 5.90
(c) Ethyl 4-[N-1-(4-methoxy-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 45% of theory,
M.p.: 167-168C
Calculated: C 74.05 H 7.04 N 5.76
Found: 73.72 6.99 5.62
(d) Ethyl 4-~N-[a-~4-benzyloxy-phenyl)-2-piperidino-
benzyl)-aminocarbonylmethyl~-benzoate
Yield: 96% of theory,
M.p.: 154-155C
Calculated: C 76.84 6.81 N 4.98
Found: 76.68 6.68 S.03
(e) Ethyl 4-~N-[a-(4-fluoro-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethyl]benzoate
Yield: 58% of theory,
M.p.: 174-176C
Calculated: C 73.40 H 6.58 N 5.90
Found: 73.55 6.72 5.91
2S (f) Ethyl 4-~N-[a-(2-fluoro-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 83% of theory,
M.p.: 173-175C
Cal~ulated: C 73.40 H 6.58 N 5.90
Found: 73.61 S.62 5.85
lg) Ethyl 4-[N-~-(4-chloro-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 57~ of theory,
M.p.: 178-181~C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22
Found: 71.10 6.56 5.26 7.11
~Z14773
- 46 -
(h) Ethyl 4-~N-~-(3-chloro-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 71~ of theory,
M.p.: 153-156C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22
Found: 70.86 6.26 5.65 7.25
li) Ethyl 4-[N-la-(2-chloro-phenyl)-2-piperidin
benzyl~-aminocarbonylmethyl]-benzoate
Yield: 66% of theory,
M.p.: 196-198C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22
Found: 70.90 6.30 5.61 7.10
(k) Ethyl 4-[N-Ea-(4-methylmercapto-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 84% of theory,
M.p,: 173-175~C
Calculated: C 71.68 ~ 6.82 N 5.57 C1 6.38
Found: 71.92 6.97 5.45 6.21
(1) Ethyl 4-~N-[5-chloro-a-(2-chloro-phenyl~-2-piperidino-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 92% of theory,
M.p.: 213-215C
Calculated: C 66.28 H 5.75 N 5.33 Cl 13.49
Found: 66.45 5.86 5.25 13.51
(m) ~thyl 4-~N-12-piperidino-a-(2-pyridyl)-benzyl]-
aminocarbonylmethyl~-benzoate
Yield: 51% of theory,
M.p.: 158-159C
Calculated: C 73.50 H 6.83 N 9.18
Found: 73.40 6.95 9.10
(n~ ~thyl 4-tN-~2-piperidino-3-(3-pyridyl)-benzyl]-
aminocarbonylmethyl]-benzoate
1~14773
- 47 -
Yield: 85~ of theory,
M~p.: 172C
Calculated: C 73.50 H 6.83 N 9.18
Found: 73.42 6.76 9.25
(o) Ethyl 4-~N-[2-piperidino-~-(4~pyridyl)-benzyl]-
aminocarbonylmethyl]-benzoate
Yield: 20% of theory,
M.p.: 150-152C
Calculated: C 73.50 H 6.83 N 9.18
Found: 73.61 6.91 9.15
(p) Ethyl 4-~N-(6-chloro-~-phenyl-2-piperidinO-ben
aminocarbonylmethyl~-benzoate
Yield: 12% of theory,
M.p.: Oil
Calculated: molecular ion peak m/e - 490/492
Found: molecular ion peak m/e = 490/492
(q) Ethyl 4-[N-(4-chloro-~-phenyl~2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoate
Yield: 37~ of theory,
M.p.: 148-150C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22
Found: 70.81 6.25 5.61 7.12
(r) Ethyl 4-[N-(3-chloro-~-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoate
Yield: 74% of theory,
M~pr 176-178C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22
~ound: 70.59 6.25 5.68 7.16
(~ Ethyl 4-~N-(6-methyl-~-phenyl-2-piperidinD-benzyl)-
aminocarbonylmethyl]-benzoate
Yield: 65% of theory,
M.p.: Oil
1;~4773
- 48 -
Calculated: molecular ion peak m/e = 470
Found: molecular ion peak m/e = 470
~t) Ethyl 4-[N-~5-methyl-~-phenyl-2-piperidino-benzyl)-
S aminocarbonylmethyl]-benzoate
Yield: 48% of theory,
M.p : 171-173C
Calc~lated: C 76.57 H 7.28 N 5.95
Found: 76.75 7.35 5.72
(u) Ethyl 4-~N-(4-methyl-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl~-benzoate
Yield: 76% of theory,
M.p.: 133-135C
Calculated: C 76.57 H 7.28 N 5.~5
Found: 76.51 7.16 5.83
(v) Ethyl 4-~N-(5-methoxy-a-phenyl-2-piperidino-
benzyl)-aminocarbonylmethyl]-benzoate
Yield: 10% of theory,
M.p.: 122-125C
Calculated: molecular ion peak m/e = 486
Found: molecular ion peak m/e = 486
(w) Ethyl 4-lN-(6-methoxy-~-phenyl-2-piperidino-
benzyl)-aminocarbonylmethyl]-benzoate
Yield: 97~ of theory,
M.p.: Oil
Calculated: molecular ion peak m/e = 486
Found: molecular ion peak m/e - 486
(x) ~thyl 3-chloro-4-tN-~n-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoate
Yield: 42% of theory,
M.p.: 175-176C
Calculated: C 70.93 H 6.36 N 5.71 Cl 7.22
Found: 70.65 6.36 5.50 7.29
~l2~4~73
- 49 -
(y) Ethyl 4-[N-(2-dimethylamino-~-phenyl-benzyl)-
aminocarbonylmethyl]-benzoate
Yield: 67% ~f theory,
M.R.: 116-118C
Calculated: C 74.97 H 6.77 N 6.73
Found: 75.13 6.60 6.78
(z) Ethyl 4-lN-(2-di-n-propylamino-a-phenyl-benzyl)-
aminocarbonylmethyl~-benzoate
Yield: 76~ of theory,
M.p.: 38-139C
Calculated: C 76.2~ ~ 7.6~ N 5.93
Found: 76.41 7.79 5.81
lS (aa) Ethyl 4-~N-[2-(octahydro-lH-azonino)~-phenyl-
benzyl]-aminocarbonylmethyl]-benzoate
Yield: 71% of theory~
M.p.: Oil
Calculated: molecular ion peak m/e = 498
Found: molecular ion peak m/e = 498
(ab) Ethyl 4-[N-[5-chloro-2-(2-methyl-piperidino)-
-phenyl-benzyl]-aminocarbonylmethyl]-benzoate
Yield: 36.5% of theory,
M.p.: 171-173C
Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01
Found: 71.45 6.68 5.59 7.20
(ac~ Ethyl 4-~N-[2-(3,3-dimethyl-piperidino)-~-phenyl-
benzyl]-aminocarbonylmethyl~-benzoate
Yield: 91% of theory,
M.p. 146-148C
Calculated: C 76.82 H 7.49 N 5.78
Found: 76.91 7.55 5.61
1214773
- 50 -
Example 2
Ethyl 4- [N- ~a- ( 4-chloro-phenyl~-2-piperidino-benzyl]-
aminocarbonyl-methYl~-benzoate
A solution of 5 9 (22.1 mmol) of 4-ethoxycarbonyl-
phenylacetyl chloride in 20 ml of chloroform is added
dropwise, whilst cooling with ice, to a solution
of 6.02 9 (20 mmol) of -(4-chloro-phenyl)-2-piperidino-
benzylamine and 3.5 ml (25 mmol) of triethylamine
in 50 ml of chloroform. The mixture is stirred for
2 hours at ambient temperature then added to water
and extracted with chloroform. The extracts are
dried and concentrated by evaporation. The evaporation
residue is chromatographed on silica gel using toluene/
ethyl acetate (5:1) as eluant.
Yield: 5.6 9 (57% of theory),
M.p.: 178-181C
Calculated: C 70.94 6.36N 5.71Cl 7.22
Found: 71.09 6.47 5.61 7.10
The following was prepared analogously to Example 2:
(a) Ethyl 4-tN-[5-chloro-2-(3-methyl-piperidino)-
a-phenyl-benzyl]-aminocarbonylmethyl]-benzoate
Yield: 54% of theory,
M.p.: 178-lB0C
Calculated: C 71.24 H 6.58N 5.54 Cl 7.01
Found: 70.91 6.64 5.75 7.01
Example 3
4-[N-~-(4-methyl-phenyl)-2-piperidino-benzyl]-amin~-
carbonyl-methYl]-benzoic acid
4.4 9 (9.35 mmol) of ethyl 4-tN-t~-(4-methyl-
phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl)-
benzoate are dissolved in 150 ml of ethanol, with
heating. Then 20 ml of lN sodium hydroxide solution
~2147 73
- 51 -
are added and the mixture is stirred for 3 hours
at 50~C. 29 ml of lN hydrocloric acid are then added
to the reaction mixture and any excess ethanol is
eliminated by evaporation in a rotary evaparator.
The remaining aqueous suspension is filtered and
the precipitate is thoroughly washed with water.
It is then recrystallised from acetonitrile.
Yield: 2.45 9 (59.3% of theory)
M.p.: 226-228C
Calculated: C 75.99 H 6.83 N 6.33
Found: 75.60 6.75 6.29
The following were prepared analogously to Example 3:
(a) 4-[N-ta-(3-Methyl-phenyl)-2-piperidino-benzyl]-
aminocarbonylmethyl~-benzoic acid
Yield: 72% of theory,
M.p.: 202-203C
Calculated: C 75.99 H 6.83 N 6.33
Found: 75.64 6.91 6.37
(b) 4-tN-ta-(2-methyl-phenyl)-2-piperidino-benzyl]-
aminocarbonylmethyl~-benzoic acid
Yield: 42.6% of theory,
M.p.: 285-290C
Calculated: C 75.99 ~ 6.83 N 6.33
Found: 76.05 6.98 6.25
lc) 4-LN-ta-t4-methoxy-phenyl)-2-piperidino-benzyl~-
aminocarbonylmethyl]-benzoic acid
Yield: 72.4 of theory,
M.p.: 228-230C
Calculated: C 73.34 H 6.59 N 6.11
Found: 73.22 6.61 6.13
12~4773
(d) 4~[N-~-(4-benzyloxy-phenyl)-2-piperidino-benzyl~-
aminocarbonylmethyl~-benzoic acid
Yield: 57~ ~f theory,
M.p.: 219-221C
Calculated: C 76.38 6.41 N 5.24
Found: 76.05 6.44 5.24
(e, 4-[N-[-(4-fluoro-phenyl)-2-piperidino-benzyl]-
- aminocarbonylmethyl]benzoic acid
Yield: 75% of theory,
M.p.: 238-240C
Calculated: C 72.63 H 6.09 N 6.27
Found: 72.9B 6.29 6.32
~f) 4-lN-[~-(2-fluoro-phenyl)-2-piperidino-benzyl]-
aminocarbonylmethyl]-benzoic acid
Yield: 87% of ~heory,
M.p.: 280 283C
Calculated: C 72.63 H 6.09 N 6.27
Found: 72.70 6.10 6.37
(g) 4-[N-[~-(4-chloro-phenyl)-2-piperidino-benzyl]-
aminocarbonylmethyl~-benzoic acid
Yield: 89% of theory,
M.p.: 241-242C
Calculated: C 70.05 R 5.88 N 6.05 Cl 7.66
Found: 69.74 6.05 6.01 7.64
(h) 4-~N-~-(3-chloro-phenyl)-2-piperidino-benzyl]-
~minocarbonylmethyl]-benzoic acid
Yield: 53% of theory,
M.p.: 223-225C
Cal~ulated: C 70.05 H 5.88 N 6.05 Cl 7.66
Found: 70.28 5.98 5.78 7.84
(i~ 4-[N-~-52-chloro-phenyl)-2-piperidino-benzyl]-
aminocarbonylmethyl~-benzoic acid
~147~3
- 53 -
Yield: 98% of theory,
M.p.: 303-305C
Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66
Found: 69.88 6.05 ~.87 7.74
(kJ 4-~N-[-(4-methylmercapto-phenyl)-2-piperidin~-
ben~yl]-aminocarbonylmethyl]-benzoic acid
Yield: 84.6% of theory,
M.p.: 225-227C
Calculated: C 70.86 H 6.37 N 5.90 Cl 6.75
Found: 70.34 6.37 5.68 6.82
(1) 4-[N-[5-chloro-a-(2-chloro-phenyl)-2-piperidino-
benzyl~-aminocarbonylmethyl]-benzoic acid
~ield: 90% of theory,
M.p,: 317-320C
Calculated: C 65.19 H 5.27 N 5.63 Cl 14.25
Found: 64.87 5.34 5.69 14.22
(m) 4-[N-[2-piperidino-~-(2-pyridyl)-benzyl]-amino-
carbonylmethyl]-benzoic acid
Yield: 81% of theory,
M.p,: 160-161C
Calculated: C 72.71 H 6.34 N 9.78
Found: 72.43 6.39 10.00
(n) 4-tN-[2-piperidino-a-(3-pyridyl)-benzyl~-amino-
carbonylmethyl3-benzoic acid
Yield: 72% of theory,
M.p.: 252-253C
Calculated: C 72.71 H 6.34 N 9.78
Found: 72.56 6.53 9.60
(o) 4-[N-~2-piperidino-a-(4-pyridyl)-benzyl]-amino-
carbonylmethyl]-benzoic acid
Yield: 68.5~ of theory,
.p.: from 260C (decomposition)
~14773
- 54 -
Calculated: C 72.71 H 6.34 N 9.7B
Found: 72.31 6.29 9.63
~p) 4-~N-(6-chloro-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 82% of theory,
M.p.: 91-94C
Calculated: C 70.04 ~ 5.88 N 6.05 Cl 7.66
Found: 69.61 5.77 5.967.78
(q) 4-~N-(4-chloro-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl~-benzoic acid
Yield: 61~ of theory,
M.p.: 221-223~C
Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66
Found: 69.73 5.89 5.87 7.52
(r) 4-~N-(3-chloro-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 83~ of theory,
M.p.: 210-213C
Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66
Found: 70.31 6.03 5.90 7.79
(s) 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-ben%oic acid
Yield: 64% of theory,
M.p.: 165-170C (sintering from 150C)
Calculated: C 75.99 H 6.83 N 6.33
Found~ 75.73 6.96 6.14
(t3 ~-~N-(5-methyl-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid
~ield: 97~ of theory,
M.p.: 243-245C
C~lculated: C 75.g9 H 6.83 N 6.33
Found: 75.60 7.01 6.31
~2~477;~
(u) 4-[N-(4-methyl--phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 96% of theory,
M.p.: 202-203~C
Calculated: C 75.99 H 6.83 N 6.33
Found: 76.04 6.78 6.23
(v) 4-[N-(5-methoxy-a~phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl)-benzoic acid
Yield: 27% of theory,
M.p.: 217-220~C (sintering from 203C)
Calculated: C 73.34 H 6.5~ N 6.11
Found: 72.92 6.68 5.99
(w) 4-[N-(6-methoxy-a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 51.5% of theory,
M.p.: 90-95C
Calculated: C 73.34 H 6.59 N 6.11
Found: 73.03 6.42 5.86
(x) 4-1N-[5-chloro-2-(3,5-cis-dimethyl-piperidino)-
c-phenyl-benzyl]-aminocarbonylmethyl]-benzoic
acid
Yield: 81~ of theory,
M.p.: 253-255C
Calculated: C 70.93 H 6.36 N 5.71 Cl 7.22
Found: 70.68 6.51 5.73 7.36
ty) ~-tN-(2-dimethylamino-a-phenyl-benzyl)-aminocarbonyl-
methyl~-benzoi~ acid
Yield: 83~ of theory,
M.p.: 183-lô4C
Calculated: C 74.20 ~ 6.23 N 7.21
Found: 74.31 6.27 7.16
(z) 4-[N-(2-di-n-propylamino-a-phenyl-benzyl)-amino-
carbonylmethyl]-benzoic acid
~Z14773
- 56
Yield: 79% of theory,
M.p,: 202-204C
Calculated: C 75.64 H 7.2~ N 6.30
Found: 75.74 7.31 6.15
(aa~ 4-[N-[5-chloro-2-(2-methyl-piperidino)-~-phenyl-
benzyl]-aminocarbonylmethyl]-benzoic acid
Yield: 52% of theory,
M.p.: 280-282C
Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43
Found: 70.14 6.10 5.75 7.45
(ab) 4-[N-[5-chloro-2-(3-methyl-piperidino)--phenyl-
benzyl~-aminocarbonylmethyl~-benzoic acid
Yield: 66% of theory,
M.p.: 246-248~C
Calculated: C 70.50 ~ 6.13 N 5.87 Cl 7.43
Found: 70.16 6.07 5.87 7.30
(ac) 4-~N-[2-(3,3-dimethyl-piperidino)-a-phenyl-
benzyl]-aminocarbonylmethyl~-benzoic acid
Yield: s9% of theory,
M.p.: 238-240C
Calculated: C 76.28 H 7.07 N 6.14
Found: 76.38 7.28 6.11
(ad) 3-chloro-4-[N-(a-phenyl-2-piperidino-benzyl)-
aminocarbonylmethyl)-benzoic acid
Yield: ~6~ of theory,
M.p.: 236-239C
- Calculated: C 70.04 H 5.88 N 6.05 Cl 7.66
Found: 69.88 5.77 5.86 7.ôl
~ae) 4-lN-[2-(3,5-cis-dimethyl-piperidino)-5-niero-
~-phenyl-benzyl]-aminocarbonylmethyl~-benzoic acid
Yield: 81% of theory,
M.p~: from 255C ~decomposition)
47~3
- 57 -
Calculated: C 69.44 H 6.23 N 8 . 38
Found: 68.95 6.44 8.53
(af) 4-lN-~2-(octahydro-lH-azonino)-~-phenyl-benzyl]-
amino-carbonylmethyl~-benzoic acid
Yield~ 62.5% of theory,
M.p.: 235-237C
Calculated: C 76.56 H 7.28 N 5.95
Found: 76.50 7. 30 5 . 9 4
(ag) 4-[N-(5-hydroxy--phenyl-2-piperidino-benzyl)-
amino-~arbonylmethyl]-benzoic acid
Yield: 71% of theory,
M.p.: 98-101C
Calculated: C 72.95 H 6.35 N 6.30
Found: 72.98 6.406.47
Example 4
4-~N-[~-(4-hydroxv-phenyl)-2-piperidino-benzyl]-amino-0 carbonYl-methyl]-benzoic acid
1.1 9 (2 mmol) of 4-[N-[a- (4-benzyloxy-phenyl)-
2-piperidino-benzyl] aminocarbonylmethyl~-benzoic
acid are suspended in 200 ml of ethanol and catalytically
debenzylated at 50C, under a hydrogen pressure of
S bar, in the presence of 0.4 9 of 10% palladium/charcoal.
Then the catalyst is filtered off, and the filtrate
is concentrated by evaporation and recrystallised
from acetonitrile.
Yield: 720 mg (66.7% of theory),
M.p.: 202-204C
Calculated: C 72.95 ~ 6.35 N S.30
Found: 72.65 6.176.20
~2147 73
- 58 -
The following was prepared analogously to Example 4:
~a) Ethyl 4-[N-(5-hydroxy-a-phenyl-2-piperidino-
benzyl)-aminocarbonylmethyl~-benzoate
Yield: 93~ of theory,
M.p.: 191-193C
Calculated: C 73.70 H 6.82 N 5.93
Found: 73.52 6.57 5.61
Example 5
4-[N-[~-(4-Methyl-phenyl)-2-Pi~eeridino-benzyl]-amino-
carbonylmethYl]-benzyl alcohol
2.5 9 (5.3 mmol) of ethyl 4-[N-~-(4-methyl-
phenyl)-2-piperidino-benzyl~-aminocarbonylmethyl]-
benzoate are added in batches to a suspension of
0.5 9 (13.2 mmol) of lithium aluminium hydride in
50 ml of absolute tetrahydrofuran. The mixture is
stirred for a further 30 minutes at ambient temperature,
decomposed by the dropwise addition of 4 N sodium
hydroxide solution and filtered to remove the sodium
aluminate formed. The filtrate is concentrated by
evaporation and the residue is recrystallised from
a little toluene.
Yield: 0.98 9 ~43~ of theory)
M.P. 144-146C
Calculated: C 78.47 H 7.53N 6.54
Found: 78.20 7.39 6.58
The following was prepared analogously to Example
5:
(a) 4-[N-[~-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzyl alcohol
Yield: 31.S% of theory
; M.p. 143-145C
Calculated: C 78.23 H 7.29 N 6.76
Found: 78.13 7.30 6.62
12~4 773
- 59 -
ExamPle 6
4-tN-ta-~4-methYl-phenyl1-2-piperidino-benzYll-amino-
carbonyl-methyl]-benzaldehyde
8.85 9 (20 mmol) of 4-[N-[-(4-methyl-phenyl)-
2-piperidino-benzyl]-aminocarbonylme~hyl]-benzoic
acid and 3.25 9 (20 mmol) of N,N'-carbsnyldiimidazole
are refluxed in 100 ml of absolute tetrahydrofuran
for 2 hours. Then the mixture is concentrated by
evaporation and after the addition of 50 ml of pyridine
and 3.7 9 (20 mmol) of 4-toluenesulphonic acid hydrazide,
the mixture is refluxed for a further 2 hours. It
is then poured on to ice water and suction filtered
and the precipitate is dried. The resulting crude
toluenesulphonic acid hydrazide of the carboxylic
acid used is mixed with 20 g of anhydrous sodium
carbonate and heated to 170C in 50 ml of ethylene
glycol for 2 hours. Then it is added to water and
extracted with chloroform. The concentrated extracts
are purified by column chromatography on silica gel
using toluene/ethyl acetate 5:1 as eluant.
Yield: 1.73 9 (21% of theory)
M.p.: 144-146C
Calculated: C 78.84 H 7.09N 6.57
Found: 78.95 7.19 6.50
The following was prepared analogously to Example
6:
(a) 4-[N-[a-Phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl~-benzaldehyde
Yield: 29~ of theory
M.p.: 168-170C
Calculated: C 78.61 H 6.84 N 6.79
Found: 78.60 7.00 6.72
3S Example 7
4-tN-~a-~4-Methyl-phen~-2-piperidino-benzyl~-amino-
carbonyl-methYl~-benzaldehyde
0.5 9 ~1.2 mmol) of 4-tN-ta-(4-methyl-phenyl)-
~Z~4~73
- 60 -
2-piperidino-benzyl]-aminocarbonylmethyl]-benzyl
alcohol are added to a suspension of 0.4 9 (1.5 mmol)
of pyridinium chlorochromate in 2 ml of chloroform.
After 12 hours at ambient temperature, ether is added,
the mixture is filtered and the concentrated filtrate
is purified by column chromatography on silica gel
(eluant: toluene/ethyl acetate = S:1).
Yield: 0.3 9 (60~ of theory)
M.p.: 145-146C
Calculated: C 78.84 H 7.09 N 6.57
Found: 78.97 7.12 6.57
The following was prepared analogously to Example
7:
(a) 4-tN-(~-Phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-benzaldehyde
Yield: 40% of theory
M.p.: 170C
Calculated C 78.61 H 6.84 ~ 6.79
Found: 78.59 6.87 6.61
Example 8
Ethyl 4-[N-ta-(4-methY1-phenyl)-2-piperidino-benzyl~-
aminocarbonyl-methyl]-cinnamate
427 mg (1 D ol) of 4-[N-[~-(4-methyl-phenyl)-
2-piperidino-benzyl]-aminocarbonylmethyl]-benzaldehyde
are added to an ethereal solution of 450 mg (2 mmol)
of ethyl diethylphosphonoacetate and 100 mg (2 mmol)
of 50% sodium hydride. After the mixture has been
stirred overnight, water is added and the resulting
mixture is extracted with chloroform and purified
by column chromatography on silica gel using toluene/ethyl
acetate (5:1) as eluant.
Yield: 0.18 9 ~36% of theory)
M.p.: 176-180C
Calculated: C 77~39 ~ 7.31 N 5.64
Found: 77.64 7.25 5.71
~2~ 73
- 61 -
The following was prepared analogously to Example
8:
~a) Ethyl 4-[N-(a-phenyl-2-piperidino-benzyl)-amino-
carbonylmethyl]-cinnamate
Yield: 28.6~ of theory
M.p~: 159-161C
Calculated- C 77.14 H 7.10 N 5.80
Found: 77.28 7.21 5.65
Example 9
4-[N-[a-(4-Methyl-ehenyl)-?-pi~eridino-benzyl)-amin
carbonyl-methyl~-cinnamic acid
Prepared by alkaline saponification of ethyl
4-[N-Cc-(4-methyl-phenyl)-2-piperidino-benzyl]-amino-
carbonyl-methyl~-cinnamate analogously to ~xample
3.
Yield: 84~ of theory
M.p.: 173-176C
Calculated: C 76.90H 6.88N 5.98
Found: 77.24 7.01 5.64
The following was prepared analogously to Example
9:
(a) 4-[N-(a-Phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl]-cinnamic acid
Yield: 75~ of theory
M.p.: 177-180C
Calculated: C 76.62 H 6.~5 N 6.16
Found:76.75 6.57 6.07
Exa~le 10
Ethyl 4-~N-~-(3-methyl-~e~nvl~-2-piperidino-benzyl~-
aminocarbonylmethyl~-benzoate
A mixture of 0.22 9 ~0.8 mmol) of ~-(3-methyl-
phenyl-2-piperidino-benzyl alcohol and 0.15 9 (0.8 mmol)
of ethyl 4-cyanomethyl-benzoate ~n 2 ml of o-dichloro-
benzene i~ added dropwise, at ambient temperature,
to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated
~2147~3
sulphuric acid. After 2 hours' stirring, the mixture
is poured onto ice-water, extracted once with ether,
made alkaline with dilute sodium hydroxide solution
and extracted with chloroform. The chloroform extract
is concentrated by evaporation and the residue is
recrystallised from ethanol.
Yield: 0.22 9 (60% of theory)
M.p.: 158-159C
Calculated: C 76.57 H 7.28 N 5.95
Found: 76.41 7.39 5.76
The following was prepared analogously to Example
10:
(a) Ethyl 4-[N-~2-(3,5-cis-dimethyl-piperidino)-
5-nitro-a-phenyl-benzyl~-aminocarbonylmethyl~-
benzoate
Yield: 57~ of theory
M.p.: 170-173C
, Calculated: C 70.30 H 6.66 N 7.93
Found: 70.05 6.687.81
Example 11
4-tN-la-(4-methYl-Phen~l)-2-piperidino-benzyl]-amin
carbonyl-methyl3-benzoic acid
240 mg (5 mmol) of 4-[N-t5-chloro-~-(4-methyl-
phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-
benzoic acid are catalytically dehalogenated in 80 ml
of ethanol/dioxan (1/1) in the presence of 0.1 9
of 10~ palladium on charcoal at 50C and under a
hydrogen pressure of 5 bar. After cooling, the catalyst
is filtered off. The filtrate is concentrated by
evaporation and the residue is recrystallised from
ethanol.
Yield: 0.16 g (72% of theory)
M.p.: 226-228C
Calculated: C 75.99 H 6.83 N 6.33
Found: 75.81 6.736.10
~2~4773
The following was prepared analogou~ly to Example
11:
(a) 4-[N-L2-(2-methyl~piperidino)-~-phenyl-benzyl]-
aminocarbonylmethyl)-benzoic acid
From 4-[N-[5-chloro-2-(2-methyl-piperidino)-
a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic
acid
Yield: 68% of theory
M.p.: 246-248C
Calculated C 75.~9 H 6.83 N 6.33
Follnd: 75.57 7.10 6.44
(b) 4-[N-[2-(3-Methyl-piperidino)-Q-phenyl-benzyl]-
aminocarbonylmethyl]-benzoic acid
From 4-[N-~5-chloro-2-(3-methyl-piperidino)-
a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic
acid
Calculated: 43% of theory
M.p.: 22B-230C
Calculated: C 75.99 H 6.83 N 6.33
Found: 75.91 Ç.82 6.33
Example 12
Ethyl 4-tN-[~-(4-methyl-phenyl)-2-~iperidino-benzyl] -
aminocarbonyl-methyl] -benzoate
A solution of 2.78 9 (10 mmol) of freshly prepared
(4-methyl-phenyl)-(2-piperidinophenyl)-ketimine in
50 ml of methylenechloride is mixed with 1.5 ml (11 mmol)
of triethylamine and thPn a solution of 2.5 9 (11 mmol)
of 4-ethoxycarbonyl-phenylacetic acid c:hloride in
20 ml of methylene chloride is added dropwise thereto,
whilst the mixture is cooled with ice. After 1 hour
at ambient temperature it is poured onto ice-water
and extr~acted with methylene chloride. The extracts
are dried and concentrated by evaporation and the
evaporation residue is purified by column chromatography
on ~ilica gel (eluant: toluene/ethyl acetate 10:1).
The crude acylimine is dissolved in dimethylformamide
and, after the addition of 0.5 g of palladium (10%
1~14773
~ - 64 -
on charcoal), it is hydrogenated at ambient temperature
under a hydrogen pressure of 5 bar. After the calculated
quantity of hydrogen has been taken up the catalyst
is removed by filtering, the filtrate is concentrated
by evaporation and the residue is recrystallised
from a little alcohol.
Yield: 2.8 g (60% of theory)
M.p.: 175-177C
Calculated: C 76.57 H 7.28 N 5.95
Found: 76.41 7.19 5.76
ExamPle 13
4-[N-[a-(4-methyl-~henyl)-2-piperidino-~enzyl]-aminocarbonyl-
methyl]-benzonitrile
Prepared from ~-(4-methyl-phenyl)-2-piperidino-
benzylamine and 4-cyano-phenylacet;c acid analogously
to Example 1.
Yield: 64% of theory
M.p.: 144-146C
Calculated: C 79.40R 6.90N 9.92
Found: 79.10 6.90 9.78
The following was prepared analogously to Example
13:
(a) 4-~N-(a-Phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl~-benzonitrile
Yield: 53% of theory
M.p. 178-181C
Calculated: C 79.18R 6.65 N 10.26
Found: 78.84 6.55 10.24
Example 14
Ethyl 4-[N-~a-(4-methyl-phenYl)-2-Piperidino-benzyl]
minocarbonylmethyl~-benzoate
4.2 9 (10 mmol) of 4-~N-~a-(4-methyl-phenyl)-
2-piperidino-benzyl]-aminocarbonylmethyll-benzonitrile
are refluxed for 24 hours with 50 ml of ethanolic
hydrochloric ~cid. The mixture is then concentrated
~14773
- 65 -
by evaporation and the evaporation residue is mixed
with aqueous sodium bicarbonate solution and extracted
with chloroform. The chloroform extract i6 concentrated
by evaporation and the residue is triturated with
ethanol and suction filtered.
Yield: 2.9 9 (61.6% of theory)
M.p.: 177-179C
Calculated: C 76.57 H 7.28N 5.95
Found: 76.41 7.35 5.76
The following was prepared analogously to Example
14:
(a~ Ethyl 4-[N-(5-methyl-~-phenyl-2-piperidin~-
benzyl)-aminocarbonylmethyl]-benzoate
Yield: 57% of theory
M.p.: 170-173C
Calculated: C 76.57 H 7.28 N 5.95
Found: 76.41 7.19 5.65
ExamPle 15
Ethyl 4-[N-[5-chloro-~-(2-chloro-phenyl)-2-piperidino-
benzyl]-aminocarbonylmethYl]-benzoate
10 mmol of ethyl 4-[N-[~-(2-chloro-phenyl)-
5-nitro-2-piperidino-benzyl]-aminocarbonylmethyl]-
benzoate are dissolved in 50 ml of dimethylformamideand, after the addition of 1 9 of Raney nickel, hydro-
genated at 60C under a hydrogen pressure of 6 bar.
Then the catalyst is filtered off, the filtrate is
concentrated by evaporation and the residue, consisting
of ethyl 4-~N-[5-amino-~-(2-chloro-phenyl)-2-piperidino-
benzyl]-amino-carbonylmethyl]-benzoate is dissolved
in 100 ~1 of ~oncentrated hydrochloric acid. Whilst
the mixture is cooled with ~ce, a solution of 1.0 9
~14 mmol) of sodium nitrite in 10 ml of water is
added dropwise thereto and the resulting mixture
is stirred for 1 hour at 0 to 5C. The reaction
mixture is then added dropwise to a solution of 3 g
of copper ~I) chloride in 2~ ml of concentrated hydro-
~2~4~73
- 66 -
chloric acid. After 1 hour's stirring, the mixture
is made alkaline with sodium hydroxide solution and
extracted with chloroform~ The concentrated chloroform
extracts are purified by column chr~mat~graphy on
silica gel using toluene/ethyl acetate (5:1) as eluant.
Yield: 1.5 g ~28.6~ of theory)
M.p.: 213-215C
Calculated: C 66.28 H 5.75N 5.33Cl 13.49
Found: 66.40 5.91 5.41 13.40
The followinq was prepared anal~g~usly t~ Example
1~
(a) Ethyl 4-[N-15-chloro-2-(3,5-cis-dimethyl-piperidino)-
a-phenyl-benzylj-aminocarbonylmethyl]-benzoate
~ield: 28% of theory
M.p.: 188-191C
Calculated: C 71.72 H 6.80 N 5.40 Cl 6.83
Found: 71.95 6.85 5.35 6.77
Example 16
3-[4-~N-(a-(4-MethYl-PhenYl)-2-piperidino-benzyl)
aminocarbon~lmethyl]-phenyl]-pro~ionic acid
0.91 9 (2 mmol) of 4-[N-(a-(4-methyl-phenyl)-
2-piperidino-benzyl)-aminocarb~nylmethyl]-cinnamic
acid are dissolved in 50 ml of methanol and, after
the addition of 0.5 g of palladium (10% on charcoal),
the mixture is catalytically hydrogenated at ambient
temperature under a hydrogen pressure of 3 bar.
After the hydrogen uptake has ended, the catalyst
ls filtered off and recrystallised from a little
acetonitrile.
Y~eld: 0.68 9 (74% of theory)
M.p.: 146-148C
Calculated: C 76.57 H 7.28N 5.95
Found: 76.41 7.19 5.61
The following was prepared analogously to Example
16:
121~773
- 67 -
(a) 3-[4-[N-(-phenyl-2-piperidino-benzyl)-aminocarbonyl-
methyl3-phenyl]-propionic acid
Yield: 65~ of theory
M.p.: 97-99C
CalculatedO C 76.30H 7.06 N 6.13
Found: 76.35 6.95 5.91
Example 17
Sodium salt of 4-[N-(a-(4-methyl-phenyl~-2-piperidino-0 benzyl)-aminocarbonylmethyl]-benzoic acid
442 mg (1 mmol) 4-~N~(a-(4-methyl-phènyl)-2-
piperidino-benzyl)-aminocarbonylmethyl~-benzoic acid
are dissolved in 25 ml of ethanol and mixed with
1 ml of 1 N sodium hydroxide solution. The mixture5 is then concentrated by evaporation in vacuo, 20 ml
of acetone are added, the precipitate obtained is
suction filtered and washed with ethyl acetate.
Yield: 410 mg ~85% of theory)
M.p.: 295-300C
Calculated: C 72.40 H 6.29 N 6.03
Found: 72.15 6.46 5.93
The following was prepared analogously to Example
17:
(a) Ethanolamine salt of 4-tN-(-(4-methyl-phenyl)-
2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic
acid
Yield: 75% of theory
M.p.: 188-191C
Cal~ula~ed: C 71.55~ 7.41 N 8.34
Found: 71.16 7.48 8.52
b) Diethanolamine salt of 4-tN-(a-(4-methyl-phenyl)-
2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic
acid
Yield: 81~ of ~heory
M.p.: 178-180C
Calculated: C 70.70~ 6.86 N 7.73
Found: 70.25 6.75 7.58
~Z147~73
- 68 -
(c) Triethanolamine salt of 4~[N-(-(4-methyl-phenyl)-
2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic
acid
Yield: 76~ of theory
M.p.: 160-165C
Calculated: C 69.01 H 7.67 N 7.10
Found: 68.91 7.64 7.45
(d) Ethylenediamine salt of 4-~N- (a- (4-methyl-phenyl)-
2-piperidino-benzyl)-aminocarbonylmethyl~-benzoic
acid
Yield: 65% of theory
M.p.: 160-163C
Calculated: C 71.69 H 7.62 N 11.15
Found: 72.04 7.80 10.96
Example 18
Ethyl 4-[N-(5-methoxy-a-Phenyl-2-piperidino-ben
aminocarbonyl-methYl]-benzoate
472 mg ~1 mmol) of ethyl 4-[N-(5-hydroxy-~-
phenyl-2-piperidino-benzyl~-aminocarbonylmethyl)-
benzoate are dissolved in 25 ml of absolute dimethyl-
formamide. After the addition of 50 mg of 50% sodium
hydride the mixture is stirred for 30 minutes. Then
0.5 9 of methyl iodide are added dropwise and the
resulting mixture is stirred overnight. To work
it up, it is poured onto ice-water and extracted
with methylene chloride. The concentrated extracts
are purified by column chromat~graphy on silica gel
using toluene/ethyl acetate 4:1 as eluant.
Yield: 260 mg (53% of theory)
M.p.: 123-125C
Calculated: C 74.05 H 7.04 N 5.76
Found: 73.ô6 6.95 5.61
Example 19
Ethyl 4-~(2-methoxY-1-(2-piperidino-phenyl)-ethyl)-
aminocarbonyl methyl~-benzoate
0.49 9 ~2.34 mmol) of 4-ethoxycarbonyl-phenylacetic
~214773
- 69 -
acid, 0.73 9 (2.78 mmol) of triphenylphosphine, 0.50 ml
(3.66 mmol) of triethylamine and 0.23 ml (2.34 mmol)
of carbontetrachloride are added successively to
a solution of 0.55 9 (2.34 mmol) of 2-methoxy-1-(2-
piperidino-phenyl)-ethylamine in 5 ml of acetonitrile
and the resultin~ mixture is stirred for 20 hours
at ambient temperature. It is then concentrated
by evaporation in vacuo and distributed between ethyl
acetate and water. The organic extract is dried
and filtered and evaporated in vacuo. The evaporation
residue is purified by column chromatography on silica
gel (toluene/acetone = 10/2).
Yield: 0.45 9 (45% of theory)
M.p.: 122-123C
Calculated: C 70.73 H 7.60N 6.60
Found: 71.04 7.48 6.39
The following was prepared analogously to Example
19:
(a) Ethyl 4-~ (3-chloro-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 55% of theory
M.p.: 141-143C
Calculated: C 68.33 H 7. 20 Cl 7.76 N 6.13
Found: 68.30 7.16 8.03 6.20
(b) Ethyl 4-[(1-(6-chloro-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 73.9% of theory
M.p.: 79-82~C
Calcula ed: C 68.33 R 7.28 Cl 7.76 N 6.13
Found: 68.45 7.24 7.ôO 6.09
(c) Ethyl 4-1(1-(4-bromo-2-piperidino-phenyl)-1-
butyl)-aminocarbonylmethyl~-benzoate
Yield: 62.1~ of theory,
M.p.: 116-118C
Calculated: C 62.27 ~ 6.63 Br 15.93 N 5.58
Found: 62.53 6.48 15.38 5.66
~d~ Ethyl 4-1(1-(4-nitro~2-piperidino-phenyl)-1-
butyl)-aminocarbonylmethyl~-benzoate
~Z~4773
- 70
Yield: 74.6% of theory,
M.p.: 127-130C
Calculated: C 66.79 H 7.11 N 8.99
Fou~d: 66.88 7.08 9.15
(e) Ethyl 4-[(1-(3-methyl-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 68% of theory,
M.p.: 145-147C
Calculated: C 74.28 ~ 8.31 N Ç.42
Found: 74.40 8.30 6.41
(f~ Ethyl 4-[(1-(4-methyl-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 54.7 of theory,
M.p.: 113-114C
Calculated: C 74.28 H 8031 N 6.42
Found: 74.23 8.30 6.55
(g) Ethyl 4-[(1-(5-methyl-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 67.g~ of theory,
M.p.: 149-150C
Calculated: C 74.28 H 8.31 N 6.42
Found: 74.38 8.21 6.49
(h) Ethyl 4-[(1-(6-methyl-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 47~ of theory,
M.p.: 92-93C
Calculated: C 74.28 ~ 8.31 N 6.42
Found: 74.50 8.46 6.48
~ thyl 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-
aminocarbonylmethyl-benzoate
Yield: 57.3% of theory,
M.p.: 122-125~C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.63 8.07 7.015 (k) Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-
amin~-carbonylmethyl]-benzoate
Yield: -71.5~ of theory,
M.p.: 127-128C
~14773
71 -
Calculated: C 73.90 H 8.11 N 6.63
Found: 73.9~ 8.~6 6.72
(1) Ethyl 4-[(1-(2-(4-methyl-piperidino)-phenyl)-
l-butyl)-aminocarbonylmethyl3-benzoate
S Yield: 51.1~ of theory,
M.p.: 153-155C
Calculated: C 74.28 H 8.31 N 6.42
Found: 74.55 8.33 6.45
(m) Ethyl 4-~(1-(2-hexahydr~azepino-phenyl~-1-butyl)-
aminocarbonylmethyl]-benzoate
Yield: 42.7~ of theory,
M.p.: 145-147C
Calculated: C 74.28 H 8.31 N 6.42
Found: 73.98 8.26 6.58
(n) Ethyl 4-lll-(5-fluoro-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 55% of theory,
M.p.: 128-130C
Calculated: C 70.88 H 7.55 ~ 6.36
Found: 71.14 7.57 6.49
(o) Methyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-
amino-carbonylmethyl~-benzoate
Yield: 63.2% of theory,
M.p.: 147-148C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.66 7.ô8 6.80
(p) n-Butyl 4-[1-(2-piperidino-phenyl)-1-butyl)-
amino-carbonylmethyl]-benzoate
Yield: 50.9% of theory,
M.p.: 117-119C (ether)
Calculated: C 74.63 H ô.50 N 6.22
Found: 74.49 8.46 6.14
(q) Ethyl 3-chloro-4-[(1-~2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 14.9~ of theory,
M.p.: ~20C
Calculated: m/e = 456/458 (1 chloro)
Found: m/e = 456/450 (1 chloro)
12~4773
- 72 -
tr) Ethyl 4-[(1-(2-piperidino-phenyl)-4-penten-
1 yl)-aminocarbonylmethyl]-benzoate
Yield: 18.9% of theory,
M.p.: 103-105C
S Calculated: C 74.62 H 7.89 N 6.45
F~und: 75.01 8.10 6.26
(s) Ethyl 4-~ 3-chloro-2-piperidino-phenyl)-
l-ethyl)-aminocarbonylmethyl~-benzoate
Yield: 58.~% of theory,
M.p.: 166-168C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53
Found: 67.17 6.858.17 6.45
Example 20
Ethyl 4-[(1-~5-nitro-2-piperidino-PhenYl)-l-butyl)-
aminocarbonylmethy~-benzoate
A solution of 14.6 g (64.6 mmol) of 4-ethoxy-
carbonyl-phenyl acetic acid chloride in 20 ml of
methylene chloride is added dropwise to a ~tirred
solution of lS.l 9 (54.4 mmol) of 1-(5-nitro~2-piperidino-
phenyl)-l-butylamine and 8.46 ml (61.4 mmol) of triethyl-
amine in 55 ml of dry methylene chloride within 30
minutes in such a way that the temperature does not
exceed 30C. The mixture is stirred for a further
2 hours at ambient temperature, 300 ml of methylene
chloride are added and the result~ng mixture is extracted
twice, each time with S0 ml of water. The organic
phase is dried over sodium sulphate, filtered and
concentrated by evaporation in vacuo. The reddish-
brown oily evaporation residue is purified by columnchromatography on silica gel (toluene/acetone = 10:1).
Yield: 17.7 g (69.7% of theory),
M.p.: 135-137C (ether)
Calculated: C 66.79 H 7.11 N 8.99
Found: 66.73 6.99 9.09
~he following ~ere prepared analogously to Example 20:
(a) ~thyl 4~ (2-piPeridino-phenyl)-l-butyl)-
aminocarbonylmethyl~-benzoate
12~4773
- 73 -
Yield: 80.2~ of theory,
M.p.: 127-129C
Calculated: C 73.90 H 8.11 N 6.63
Found: 73.98 8.26 6.89
(b) ~thyl 4-[(1-(4-hydroxy-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 13.5% of theory,
M.p.: 178-180C
Calculated: C 71.21 H 7.al ~ 6.39
Found: 71.27 7.82 6.40
~c) Ethyl 4~ -hydroxy-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 37.4% of theory,
M.p.- 188-190C
Calculated: C 71.21 H 7.81 N 6.39
Found: 71.34 7.89 6.38
Example 21
4-[~1-(2-piperidino-~henYl)-l-butyl)-aminocarbonylmethYl]-0 phenvl acetic acid3.0 9 (15.45 mmol) of p-phenylene-diacetic
acid and 10 ml of thionyl chloride are refluxed for
90 minutes and then concentrated by evaporation in
vacuo. The crude diacid chloride is dissolved in
100 ml of methylene chloride. Then a solution of
3.6 g (15.45 mmol) of 1-(2-piperidino-phenyl)-1-butyl-
amine is slowly added dropwise to this solution,
with stirring, at an internal temperature of 10 -
15C. After 2 hours at ambient temperature, the
mixture is concentrated by evaporation in vacuo and
the evaporation residue is distributed between 100
ml of ice cold 5% sodium hydroxide solution and ethyl
acetate. It is filtered through kieselguhr and the
organic phase is separated off. The alkaline-aqueous
phase i8 adjusted to pH 5~5 with semi-concentrated
hydrochloric acid and extracted with ethyl acetate.
The extract i6 dried over sodium sulphate and filtered
and the filtrate is concentrated by evaporation in
12~4773
vacuo. The evaporation residue is purified by column
chromatography on silica gel ~chloroform/methanol
= 20/1)-
Yield: 0.10 9 (1.6% of theoryJ,
M.p.: 136-140C (acetonitrile/ether)
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.17 8.10 6.85
~xample 22
Ethyl 4-[(2-methyl-1-(2-piperidino-phenyl)-1-~ropen-
l-yl)-aminocarbonylmethyl]-benæoate
5.58 9 (26.8 mmol) of 4-ethoxycarbonyl-phenylacetic
acid, 8.43 g (32.2 mmol) of triphenylphosphine, 11.2
ml (80.4 mmol) of triethylamine and 2.6 ml (~.0268
mol) of carbon tetrachloride are successively added
to a solution of 6.17 9 (26.8 mmol) of freshly prepared
isopropyl-(2-piperidino-phenyl)-ketimine in 62 ml
of acetonitrile and the resulting mixture is stirred
for 20 hours at an ambient temperature. It is then
concentrated by evaporation in vacuo and distributed
between ethyl acetate and water. The dried and filtered
ethyl acetate extract is evaporated in vacuo. The
evaporation residue is purified by column chromatography
on silica gel (toluene/ethyl acetate = 5/1).
Yield: 3.0 9 126.6~ of theory),
M.p.: 82-84C (ether)
Calculated: C 74.26 H 7.67 N 6.66
Found: 74.20 7.49 6.~6
The following were prepared analogously to Example 22:
(a) Ethyl 4-t(l-2-piperidino-phenyl)-1-penten-1-
yl)-amino~arbonylmethyl~-benzoate
Yield 16% of theory,
M,p.: 94-97C (ethanol)
Calculated: C 74.62 H 7.89 N 6.45
Found: 74.75 7.71 6.24
5b) Ethyl 4-[(1-2-piperidino-phenyl)-1-hexen-1-
yl)-aminocarbonylmethyl]-benzoate
Yield: 27.4% of theory,
7~3
- 75 -
M.p.: 83-85C (ethanol)
Calculated: C 74.97 H 8.09 N 6.24
Found: 75.42 7.95 6.00
(c) Ethyl 4-[(1-2-piperidino-phenyl)-1-buten-1-
yl)-aminocarbonylmethyl)-benzoate
Yield (more lipophilic isomer; probably E form):
4.1~ of theory,
M~p.: <20C
Calculated: m/e = 42
Found: m/e = 420
Yield (less lipophilic isomer; probably Z form):
~1.9% of theory,
M.p.: 115-117C (ethanol)
Calculated: C 74.26 H 7.67 N 6.66
Found: 73.85 7.59 6.44
(d) Ethyl 4-[(2-phenyl-1-(2-piperidino-phenyl)-
ethen-l-yl)-aminocarbonylmethyl3-benzoate
Yield (more lipophilic isomer; probably E form):
4% of theory,
M.p.: 75-77C (ether/petroleum ether3
Calculated: C 76.90 H 6.88 N 5.98
Found: 77.31 7.20 5.93
Yield (less lipophilic isomer; probably Z form):
42.7~ of theory,
M.p.: lS7-160C tethanol)
Found: C 77.19 H 6.95 N 6.02
(e) Ethyl 4-[(3-phenyl-1-(2-piperidino-phenyl)-
l-propen-l-yl)-aminocarbonylmethyl)-benzoate
Yield: 62.6~ of theory,
M.p.: <20C
Calculated: m/e = 482
Found: m/e - 482
(f) Ethyl 4-~(1-(2-~3,3-dimethyl-piperidino-phenyl)-
3S l-buten~l-yl)-aminocarbonylmethyl]-benzoate
Yield: 33~ of theory,
M~p.: 113-116C tethanol)
1~14773
- 76 -
Calculated: C 74.97 H 8.09 N 6.24
Found: 75.37 7.93 6.03
(g) Ethyl 4-~(1-(6-methyl-2-piperidino-phenyl)-
l-buten-l-yl)-aminocarbonylmethyl3-benzoate
Yield: S0.4% of theory (probably ~ form)
M.p.: 95-96C
Calculated: C 74.62 H 7.89 N 6.45 m/e = 434
Found: 74.44 B.OO 6.59 m/e = 434
ExamPle 23
Ethyl 4-t(1-(2-piPeridino-~henyl)-l-buten-l-yl)-amin
carbonYlmethy~]-benzoate
A stirred solution of 19.0 9 (82.46 mmol) of
freshly prepared (2-piperidino-phenyl)-propyl-ketimine
and 11.5 ml ~82.46 mmol) of triethylamine in 190 ml
of anhydrous toluene is heated to an internal temperature
of 85C, then a solution of 18.7 g (82.46 mmol) of
4-ethoxycarbonyl-phenylacetic acid chloride in 95 ml
of anhydrous toluene is added dropwise thereto within
10 minutes and the resulting mixture is stirred for
30 minutes at an internal temperature of 95C. It
is then cooled to 20C and extracted twice with water.
The organic phase is dried over sodium sulphate,
fil~ered and concentrated by evaporation in vacuo.
The evaporation residue is purified by repeated column
chromatography (toluene/acetone = 20/1 and 50/1).
Yield: (more lipophilic isomer; probably E form):
11.2 g (23.6% of theory),
M.p.: <20C (honey-yellow viscous oil)
Calculated: C 74.26 H 7.67 N 6.66
Found: 73.90 7.92 6.91
Yield (less lipophilic isomer; probably Z form):
15.9 9 ~33.5% of theory),
M.p.: 114-116C
Found: C 74.02 H 7.69 N 6.85
~;~14773
- 77 -
Example 24
Ethyl (E)- and (Z)-4-~(1-(2-piperidino-Phenyl)-l-
buten-l-yl)-aminocarbonylmethyl]-benzoate
1.0 9 of Z ester (see Example 22c) is heated
for 30 minutes in a pre-heated oil bath at 230C.
After cooling, the product obtained is purified by
column chromatography on silica gel (toluene/acetone
= 20/1).
Yield (E ester): 0.36S 9 (36.5% of theory),
M.p.: <20C
Yield (z esterl: 0.380 9 ~38.0~ of theory),
M.p.: 115-117C
If the (E)-ester is heated for 3.5 hours with
catalytic quantities of iodine in benzene, a 1/1
mixture of (E) and (Z) esters is obtained, according
to thin layer chromatography (toluene/acetone = 10/1).
The following compounds were obtained analogously
to Example 24:
(a) Ethyl (E)- and (Z)-4-~(1-(6-methYl-2-piperidino-
phenYl)-l-buten-l-Yl)-aminocarbonylmethyl)-
benzoate
According to thin layer chromatography, a 1/1
mixture of (E) and (Z) esters is obtained from
the (Z) ester (see Example 229).
Upper spot (E): Calculated: m/e = 434
Found: m/e = 434
lower spot (Z): Found: m/e = 434
ExamPle 25
Ethyl 4-[(1-(2-Piperidino-phenyl~ butyl)-aminocarbon
methyl]-benzoate
2.9 9 (~.90 mmol) of ethyl 4-[(1-(2-piperidino-
phenyl),-l-buten-l-yl)-aminocarbonylmethyl~-benzoate
in 100 ml of ethanol is hydrogenated on 0.77 9 of
10% palladium/charcoal at 50C under a hydrogen pressure
~LZ1~773
- 78 -
of 1 bar After 2 hours, the catalyst is filtered
off over kieselguhr and the filtrate is concentrated
by evaporation in vacuo. The evaporation residue
.
is crystallised from ethanol.
5Yield: 1.5 9 (51.5% of theory3,
M .p.: 126-128 C
Calculated: C 73.90 H 8 .11 N 6 . 63
Found: 73.97 8.22 6.57
The following compounds were obtained analogously
to Example 25:
(a) Ethyl 4-~ (2-piperidino-phenyl)-1-pentyl)-
aminocarbonylmethyl~-benzoate
Yield: 45~ of theory,
M.p.: 117-120C (ether)
Calculated: C 74.28 H 8.31 N 6.42
Found: 74.60 8.13 6.27
0 (b) Ethyl 4-[(1-(2-piperidino-phenyl)-1-hexyl)-
aminocarbonylmethyl]-benzoate
Yield: 50% of theory,
M.p.: 108-110C (ether)
Calculated: C 74.63 H 8.50 N 6.22
Found: 74.85 8.33 6.01
(c) Ethyl 4-[(2-phenyl-1-(2-piperidino-phenyl)-
l-ethyl)-aminocarbonylmethyl]-benzoate
Yield: 87.6% of theory,
M p.: 161-162C (ethanol)
Calculated: C 76.57 ~ 7.28 N 5.95
Found: 76.71 7.19 5.99
(d) Ethyl 4-t(3-phenyl-1-(2-piperidino-phenyl)-
l-propyl)-aminocarbonylmethyl]-benzoate
Yield: 57.6% of theory,
M.p.: 118-119C (ethanol)
4773
- 79 -
Calculated: C 76.83 H 7.49 N 5.78
F~und: 76.70 7.49 5.90
(e) Ethyl 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 36.S% of theory,
M.p.: 140-141C (ethanol)
- Calculated: C 74.63 H 8.50 N 6.22
Found: 74.30 8.23 6.12
Example 26
4-~[1-(2-P~peridino-phenyl)-l-butyl)-aminocarbonylmethvl~-
benzoic acid
A mixture of 1.2 g (2.84 mmol) of ethyl 4-~(1-
1~ (2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-
benzoate and 4.26 ml of lN sodium hydroxide solution
in 12 ml of ethanol is stirred for 1 hour at 60~C,
then neutralised with 4.26 ml of lN hydrochloric
acid and the ethanol is evaporated off in vacuo.
The residue is distributed between ethyl acetate
and water; the organic extract is dried and filtered
and concentrated by evaporation in vacuo. The evaporation
residue is crystallised from ethanol.
Yield: 0.50 9 (44.6% of theory),
M.p.: 213-215C
Calculated: C 73.07 H 7.66 N 7.10
Found: 73.18 7.51 7.10
The following compounds were obtained analogously
to Example 26:
(a) 4-t(1-(2-PiPeridino-phenyl)-l-Pentyl)-aminocarbonyl-
methyl~-benzoic acid
Yield: 70.~% of theory,
M.p.: 213-215C (acetone)
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.71 7.70 6.90
~Z~4773
- 80 -
(b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonyl-
methyl~-benzoic acid
Yield: 72.6~ of theory,
M.p.: 197-200CC (acetone)
Calculated: C 73.90 H 8.11 N 6.63
Found: 73.83 7.93 6.77
(c) 4-~(2-phenyl-1-(2-piperidino-phenyl)-1-ethyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 68.7% of theory,
M.p.: 214-215C (acetone)
Calculated: C 7~.99 H 6.83 N 6.33
Found: 75.70 6.60 6.32
(d) 4-[(3-Phenyl-1-(2-piperidino-phenyl)-1-propyl)-
aminocarbonylmethyl~-benzoic acid
Yield: 67.7% of theory,
M.p.: 167-170C (ethyl acetate)
Calcula~ed: C 76.29 H 7.06 N 6.14
Found: 76.56 7.06 6.23
(e) 4-[2-Methoxy-1-(2-piperidino-phenyl)-1-ethyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 60.8% of theory,
M.p.: 196-198C (ether)
Calculated: C 69.68 H 7.12 N 7.07
Found: 69.72 6.52 6.71
(f) 4-1(1-(2-PiPeridino-phenyl)-4-penten-1-yl)-
aminocarbonylmethyl]-benzoic acid x 0.67 H20
Yield: 30.7~ of theory,
M.p.: 193-197C (ether/petroleum ether)
Calculated: C 71.74 ~ 7.38 N 6.69
Found: 71.63 7.21 6.34
(9) 4-1(1-(2-(3,3-Dimethyl-piperidino)-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoic acid
Yield: 48.2% of theory,
lZ14773
-- %l --
M.p.: 168-170C ~petroleum ether)
Calcula~ed: C 73.91 H 8.11 N 6.63
Found: 73.51 7.89 6.32
(h) 4-[(1-(3-Methyl-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 53% of theory,
M.p.: 179-182C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.50 7.82 7.01
(i) 4~ 4-Methyl-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl~-benzoic acid
Yield: 85.6% of theory,
~.p.: 17~-172C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.25 7.64 6.89
(k) 4-t~l-(5-Methyl-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 62.1% of theory,
M.p.: 219-221C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.20 7.74 6.89
(1) 4-[(1-(6-Methyl-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl)-benzoic acid x 0.3 H20
Yield: 89~ of theory,
M.p.: 158-160C
Calculated: C 72.53 H 7.93 N 6.77
Found: 72.40 7.91 6.92
(m) 4-[(1-(3-Chloro-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 70% of theory,
M.p.~ 189-191C
Calculated: C 67.2Q ~ 6.81 Cl 8.27 N 6.53
Found: 67.30 6.858.36 6.58
lZ~4773
- 82 -
(n) 4-[ (1- ~4-Chloro-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]~benzoic acid
Yield: 57.8% of theory,
~.p.: 188-189C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53
Found: 66.90 7.00 8.Z2 6.53
(o~ 4~ 5-Chloro-2-piperidino-phenyl)-1-bu~yl)- ;
aminocarbonylmethyl]-benzoic acid
Yield: 81.6% of theory,
M.p.: 226-229C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53
Found: 67.17 6.59 8.51 6.60
(p) 4-[(1-(6-Chloro-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 69.4% of theory,
M.p.: 150-153C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53
2Q Found: 67.18 6.91 8.42 6.77
(q) 4-[(1-(4-Bromo-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 84.4% of theory,
M.p.: 198-201C
Calculated: C 60.89 H 6.17 Br 16.88 N 5.92
Found: 60.88 5.98 17.20 5.98
(r~ 4-t(1~(5-8romo-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 90.7% of theory,
M.p.: 232-235~C
Calculated: C 60.89 H 6.17 Br 16.88 N 5.92
Found: 60.96 6.13 16.85 5.90
~5
~s) 4-t~l-(4-Nitro-2-p$peridino-pheny~ -butyl)
aminocarbonylmethyl~-benzoic acid
Yield: 70.9% of theory,
~2~4773
- 83 -
M.p.: 188-190C
Calculated: C 65.59 H 6.65 N 9.56
Found: 65.30 6.44 9.53
(t) 4-[(1-(5-Nitro-2-piperidino-phenyl)-1-butyl)-
aminocarb~nylmethyl~-benzoic acid
Yield: 90.7% of theory,
M.p.: 225-227C
Calculated: C 65.59 H 6.65 N 9.56
Found: 65.80 6.61 9.72
(u) 4-[(1-(4-Hydroxy-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid x 0.5 H20
Yield: 85.7% of theory,
M.p.: softening from 70C (foam)
Calculated: (x 0.5 H20) C 68.71 H 7.45 N 6.68
Found: 68.63 7.55 6.26
(v) 4-[(1-(5-~ydroxy-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl~-benzoic acid
Yield: 89.3% of theory,
M.p.: 186-190C
Calculated: C 70.22 H 7.37 N 6.82
Found: 70.31 7.58 6.51
(w) 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic: acid
Yield: 78.6% of theory,
M.p.: 185-187C
Calculated: C 70.73 H 7.60 N 6.60
Found: 70.46 7.77 6.56
(x) 4-~(1-(5-Methoxy-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 75% of theory,
M.p.: 182-185C tdecomp.)
Calculated: C 70.73 ~ 7.60 N 6.60
Found: 70.52 7.50 6.70
4773
- 84 -
(y) 4-[(1-~2-Pyrrolidino-phenyl)-l-butyl)-aminocarbonyl-
methyl]-benzoic acid
Yield: 64.5~ of theory,
M.p.: 200-203C
Calculated: C 72.61 H 7 42 N 7.36
Found: 72.64 7.50 7.38
(z) 4-1(1-(2-(4-Methyl-piperidino)-phenyl)-l-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 81.4% of theory,
M.p.: 197-201~C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.90 8.06 7.00
(aa) 4-[(1-(2-Hexahydroazepino-phenyl)-l-butyl)-
aminocarbonylmethyl~-benzoic acid
Yield: 65.6% of theory,
M.p.: 199-202~C
Calculated: C 73.50 H 7.90 N 6.86
Found: 73.50 7.90 6.76
(ab) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl~-benzoic acid
Yieldo 87.1% of theory,
M.p.: 204-207C
Calculated: C 69.88 H 7.09 N 6.79
Found: 70.25 7.02 7.12
(ac) 4-[(1-(5-Fluoro-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoic acid
Yield: 53.9% of theory,
M.p.: 200-202C
Calculated: C 69.88 H 7.09 N 6.79
Found: 69.67 7.24 6.90
(ad) ~-Chloro-4-~ 2-piperidino-phenyl)-1-butyl)-
- aminocarbonylmethyl~-benzoic acid
Yield: 51~ of theory,
1214~73
- 85 -
M.p.: 165-168~C
Calculated: C 67.20H 6.81 N 6.53 m/e - 428/430
(1 chlorine)
Found^ 66.92 6.696.55 m/e = 428/430
(1 chlorine)
(ae) 4-[(1-(3-Methyl-2-piperidino-phenyl)-1-ethyl)-
aminocarbonylmethyl)-benzoic acid
Yield: 79% of theory,
M.p.: 230-231C
Calculated: C 72.60 H 7.42 N 7.36
Found: 72.75 7~58 7.30
(af ) 4-[ (1- (3-Chloro-2-piperidino-ph~nyl)-1-ethyl-
aminocarbonylmethyl]-benzoic acid
Yield: 54~ of theory,
M.p.: 192-195C (75% aqueous ethanol)
Calculated: C 65.91 H 6.28 Cl 8.84 ~ 6.99
Found: 66.00 6.44 8.67 6.78
Example 27
4-[(2-Methyl-1-(2-piperidino-phenyl)-l-propen-l-yl)
aminocarbonylmethyl~-benzoic acid
A mixture of 3.5 g (8.3 mmol) of ethyl 4-[(2-
methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-
carbonylmethyl]benzoate and 12.5 ml of lN sodium
hydroxide solution in 35 ml of ethanol is stirred
at 60C for 2 hours. It is neutralised with 12.5 ml
of lN hydrochloric acid, concentrated by evaporation
in vacuo and distributed between ethyl acetate and
water~ The dried, filtered organic extract is evaporated
in vacuo. The evaporation residue is crystallised
from ethanol.
Yield: 2.4 9 (73.6~ of theory),
M.p.: 188-191C
Calculated: C 73.44 B 7.19 ~ 7.14
Found: 73.60 7.19 7.02
~2~4773
- 86 -
The following compounds were obtained analogously
to Example 27:
(a) (E)-4-[(1-(2-Piperidino-phenyl)-l-buten-l-yl)-
aminocarbonylmethyl~-benzoic acid
Yield: 71.5~ of theory,
M.p.: lB8-190C
Calculated: C 73.44 H 7.19 N 7.14
Found: 73.15 7.13 7.10
Olefinic proton: lH-NMR (CDC133:~= 6.42 ppm
(b) (Z)-4-~(1-(2-Piperidino-phenyl)-l-buten-l-yl)-
aminocarbonylmethyl]-benzoic acid
Yield: 57.8% of theory,
lS M.p.: 174-175C (ethanol)
Calculated: C 73.44 H 7.19 N 7.14
Found: 73.54 6.97 7.17
Olefinic proton: lH-NMR ~CDC13):~= 5.60 ppm
0 (c) (E)-4-[(2-Phenyl-1-(2-piperidino-phenyl)-ethen-
l-yl)-aminocarbonylmethyl]-benzoic acid x 0.4
H20
Yield: 33.2% of theory,
M.p.: 165-167C (ether/petroleum ether)
25 Calculated: (x 0.4 H20) C 75.11 H 6.48 N 6.26
Found: 75.22 6.39 6.26
olefinic proton: lH-NMR (CDC13):~ ~6.9 ppm
(d) (z)-4-t(2-phenyl-l-(2-piperidino-phenyl)-ethen
l-yl)-aminocarbonylmethyl]-benzoic acid x 1
~2
Yield: 72~ of theory,
M.p.: 182-185C ~methanol)
Calculated: (x 1 H20): C 73.34H 6.60 N 6.11
Found: 73.55 6.45 6.00
olefinic proton: lH-NMR (CDC13): ~ = 6.50 ppm
1214773
- ~7 -
(e) 4-t(3-Phenyl-l-t2-piperidino-phenyl)-1-propen-
l-yl)-aminocarbonylmethyl]-benzoic acid
Yield: 48.3% of theory,
M.p.: 162-164~C (ether); probably (z) form
Calculated: C 76.63 H 6.65 N 6.16
Found: 76.30 6.47 6.31
Olefinic proton: 1H-NMR (CDC13): ~ = S80 PPm
(f) 4-[(1-(2-(3,3-Dimethyl-piperidino)-phenyl)-
l-buten-l-yl~-aminocarbonylmethyl~-benzoic:
acid
Yield: 64.1% of theory,
M.p.: 152-153C (ethyl acetate); probably (Z) form
Calculated: C 74.26 ~ 7.67 N 6.67
Found: 73.93 7.57 6.50
O1efiniC PrOtOn: 1H-NMR (CDC13): ~ = 5.55 ppm
(g) lZ)-4-[(1-(6-Methyl-2-piperidino-phenyl)-1-
buten-l-yl)-aminocarbonylmethyl]-benzoic acid
Yield: 53.3~ of theory,
M.p.: 142-145C
Calculated: C 73.66 H 7.44 N 6.89
Found: 73.56 7.73 7.15
olefinic proton: lH-~M~ (CDC133: S = 5.38 ppm
Example 28
4-[~1-(2-Piperidino-Phenyl)-l-butyl)-aminocarbonylmethyl]-
benzoic acid
200 mg (0.51 mmol~ of 4-[(1-(2-piperidino-phenyl)-
l-buten-l-yl)-aminocarbonylmethyl]-benzoic acid in
10 ml of absolute ethanol are hydrogenated over 100 mg
of palladium/charcoal (10%) at 50C and under 1 bar
of hydrogen, with shaking. After 1.5 hours the mixture
is f iltered and concentrated by evaporation in vacuo.
Yield: 68% of theory,
M.p.: 213-214C
Calculated: C 73.07 H 7.6S N 7.10
Found: 73.21 7.82 7.02
~14773
- 88 -
The yield is 56~ of theory if hydrogenation is carried
out at 50 DC and under 1 bar of hydrogen on Raney
nickel.
Example 29
Sodium salt of 4-[(1-(2-Piperidino-Phenyl)-l-butyl)-
aminocarbonylmethyl]-benzoic acid x 0.5 H20
_
10.0 9 (25.3~ mmol) of 4-[(1-(2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl~-benzoic acid
are dissolved at 50C in 200 ml of ethanol and 25.35 ml
of lN sodium hydroxide solution are added thereto.
The mixture is evaporated to dryness in vacuo and
the evaporation residue is dissolved in the minimum
amount of ethanol, whilst being heated over a steam
bath. The solution is cooled in an ice bath, the
crystals precipitated are filtered off and washed
with ether and dried at 140C/15 torr.
Yield: 9 9 (85.3% of theory),
M.p.: 280-285C (decomp.); softening from 255C
Calculated: (x 0.5 H20) C 67.74 H 6.87 N 6.58
Found: 67.86 7.13 6.49
Example 30
EthYl (+~-4-l~1-(2-Piperidino-phenyl)-l-butyl)-amino-
carbonyl~ethYl~-benzoate
To a stirred solution of 2.58 9 (11.1 mmol)
of (+)-1-(2-piperidino-phenyl)-1-butylamine [Bp 0 03:
87C; ee = 86 (HPLC, after derivatising with (+)-
l-phenethyl-isocyanate)] in 26 ml of acetonitrile,
there are added, at 20C, one after another, 2.31 9
(11.1 mmol) of 4-ethoxycarbonyl-phenyl acetic acid,
3.50 9 (13.3 mmol1 of triphenylphosphine, 4.60 ml
(33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol)
of carbon tetrachloride. After 14 hours at 20C
and 1.5 hours at 40C the mixture is concentrated
by evaporation in vacuo and distributed between water
and ether. The organic phase is dried over sodium
lZ14773
- 89 -
sulphate, then filtered, and concentrated by evaporation
in vacuo. The evaporation residue is purified by
column chromatography on silica gel (toluene/acetone
= 6:1).
Yield: 2.63 9 (56% of theory),
M.p.: 118-120~C
Calculated: C 73.90 H 8.11 N 6.63
Found: 74.02 7.97 6.51
[~]20 = +9.2 (c = l; methanol)
The foll~wing compound was obtained analogously to
Example 30:
(a) Ethyl (-)-4-[(1-(2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoate
Prepared from (-)-1-(2-Piperidino-phenyl)-l-
butylamine x 1.4 HCl [[]D0 = -20.0 (c = 1,
methanol ),
Mel~ing range: 90-100C; ee = 80 (HPLC, after
derivatising the base with (+)-l-phenethyl-
isocyanate)]
Yield: 52.6% of theory,
M.p.: 115-120C
Calculated: C 73.90 H ô.llN 6.63
Found: 73.83 8.01 6.47
~a]20 = _g,o (c = 1, methanol)
~'~14773
-- 90 --
Example 31
Ethyl (+)-4-[(1-~2-piperidino-Phen~l)-l-butYl)-amino-
carbonvlmethyl]-benzoate
1.0 9 (3.27 mmol) of (~0-1-(2-piperidino-phenyl)-
l-butylamine-dihydrochloride [~a) 20= +18.7 (c ~
1, methanol); m.p.: decomposition from 115C; ee
= 91.6 (HPLC, after derivatising the base with (+)-
l-phenethyl-isocyanate)3 is suspended in 6 ml of
methylene chloride, then 1.4 ml (10 mmol) of triethylamine
are added, with stirring, and then the solution of
0.82 9 (3.64 mmol) of 4-ethoxycarbonyl-phenylacetic
acid chloride in 2.4 ml of methylene chloride is
added dropwise thereto, whereupon the reaction temperature
rises from 22C to 38C. The mixture is stirred
for 6 hours at ambient temperature and then extracted
successively:
twice with 10 ml of water,
once with 10 ml of 2N hydrochloric acid and
once with 10 ml of water.
The organic phase is dried over sodium sulphate,
filtered and concentrated by evaporation in vacuo.
The evaporation residue is purified by column chromat-
ography on silica gel (toluene/acetone = 6/1).
Yield: 0.53 9 (38.2~ of theory),
M.p.: 120-122C
Calculated: C 73.90 H 8.11 N 6.63
Found: 73.96 7.98 6.61
~]20 = +g o (c = 1, methanol)
xamPl-e 32
(+)-4-[tl-~-PiPeridino-phenyl)-l-butyl)-aminocarbonyl-
methyl]-benzoic acid
2.0 9 ~4.73 mmol) of ethyl (+)-4-1(1-(2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate ¦~]20
= l9.2 (c = 1, methanol)] in 20 ml of ethanol are
stirred with 7.0 ml of lN sodium hydroxide solution
for 2.5 hours in a bath at 65C. The mixture is
cooled and 7.0 ml of lN hydrochloric acid are added.
1214773
-- 91 --
The crystals which are slowly precipitated are filtered
off, washed with water and dried at 100C/4 torr.
Yield: 1.65 9 (88.2% of theory),
M.p.: 185-187C
Calculated: C 73.07 ~ 7.66N 7.10
Found: ~2.90 7.80 7.17
t]20 = +7.9 (c = 1, methanol)
The following compound was obtained analogously to
iO Example 32:
(a) (-)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-amino-
carbonylmethyl]-benzoic acid
Yield: 80% of theory,
M.p.: 187-190C
Calculated: C 73.07 H 7.66 N 7.10
Found: 72.98 7.44 7.22
[a]20 = _7.9 (c = 1, methanol)
Exam~le 33
4-[(1-(2-Piperidino-phenYl)-l-butYl)~aminocarbonyl-
Prepared from 1-(2-piperidino-phenyl)-1-butylamine
and 4-cyano-phenylacetic acid analogously to Example
19.
Yield: 57.3% of theory,
M.p.: 147-148C
Calculated: C 76.76H 7.78N 11.19
Found: 7Ç.46 7.81 11.10
The following compound was obtained analogously to
Example 33:
(a) 4-~(1-(2-Piperidino-phenyl)-l-butyl)-aminocarbonyl-
methyl~-toluene
Prepared with 4-tolyl-acetic acid.
Yield: 60.4~ of theory,
M.p.: 150-153~C
lZ147~3
- 92 -
Calculated: C 79.08 H 8.85 N 7.68
Found: 78.97 8.58 7.77
Example 34
Ethyl 4~ (2-piPeridino-phenyl)-l-butyl)-aminocar-bon
methyl]-benzoate
Prepared from 4-~(1-(2-piperidino-phenyl)-1-
butyl)-aminocarbonylmethyl]-benzonîtrile with ethanolic
hydrochloric acid analogously to Example 14.
10 Yield: 58% of theory,
M.p.: 127-12BC
Calculated: C 73.90H 8.11N 6.63
Found: 74.07 8.23 6.87
Example 35
Ethyl 4-[(1-(2-~iperidino-phenyl)-1-butyl)-aminocarbonyl-
meth~l]-benzoate
Prepared analogously to Example 10 from 1-(2-
piperidino-phenyl)-l-butanol and ethyl 4-cyanomethyl-
benzoate with concentrated sulphuric acid in o-dichloro-
benzene at ambient temperature.
Yield: 21% of theory,
M.p.: 126-128C
Calculated: C 73.90 H 8.11N 6.63
Found: 74.12 8.20 6.45
The following compound was obtained analogously to
Example 35:
0 (a) 4-t(1-(2-Piperidino-phenyl)-l-butyl)-aminocarbon
methyl]-benzoic acid
Prepared from 1-(2-piperidino-phenyl)-1-butanol
and 4-cyanomethyl-benzoic acid. Extraction
at pH 5.5.
Yield: 29~ of theory,
M.p.: 215-217C
Calculated: C 73.07 H 7.66 N 7.10
Found: 72.82 7.69 6.95
lZ1~773
- 93 -
Example 36
4-[~1-(4-Amino-2-~iPeridino-PhenYl)-l-butyl)-aminocarbonyl-
methyl~-benzoic acid x O.S H20
-
0.60 9 (1.365 mmol) of 4-[(1-(4-nitro-2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid
in 10 ml of dimethylformamide are hydrogenated on
0.1 9 of 10% palladium/charcoal for 3 hours at 25C
and under a hydrogen pressure of 1 bar. The catalyst
is filtered off using kieselguhr and the filtrate
i5 concentrated by evaporation in vacuo. The evaporation
residue is crystallised from ether.
Yield: 0.41 9 (73.2~ of theory),
M.p.: 118-120C
Calculated: (x 0.5 H20): C 68.87 H 7.71 N 10.04
Found: 68.62 7.64 10.08
The following compounds were obtained analogously
to Example 36:
(a) Ethyl 4-[(1-(4-amino-2-piperidino-phenyl)-1-
- butyl)-aminocarbonylmethyl]-benzoate
Yield: 81.7% of theory,
M.p.: 145-146C (ether/petroleum ether)
Calculated: C 71.37 H 8.06 N 9.60
Found: 71.50 8.08 9.68
(b) 4-[(1-(5-Amino-2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl~-benzoic acid
Yield: 64% of theory,
M.p.: 227-230C
Calculated: C 70.39 H 7.63 N 10.26
Found: 70.54 7.S4 10.36
(c) Ethyl 4-t(1-(5-amino-2-piperidino-phenyl)-1-
butyl)-aminocarbonylmethyl]-benzoate
Yield: 84.3% of theory,
M.p.: 162-16SC
1214773
- 94 -
Calculated: C 71.37 H 8.06 N 9.60
Found: 71.58 7.83 9.65
Example 37
Eth~l 4-~(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-
aminocar~ylmethyl~-benzoate
A cold diazonium salt solution (0C) is prepared
from 2.0 9 (4.57 mmol) of ethyl 4-[(1-(5-amino-2-
piperidino-phenyl)-l-butyl)-aminocarbonylmethyl)-
benzoate in 4.8 ml of semiconcentrated hydrochloric
acid and 0.31S 9 (4.57 mmol) of sodium nitrite in
1.66 ml of water. This solution is added dropwise,
at 0 to 5C, to a stirred mixtur~ of 0.59 9 (5.94 mmol)
of copper(I)chloride and 2.4 ml of conc. hydrochloric
acid and the resulting mixture is then heated in
a bath at 50C. Af ter the development of gas has
ended (about 15 minutes), the mixture is cooled,
added to ice/conc. ammonia and extracted four times,
each time with 100 ml of ethyl acetate. The combined
organic extracts are shaken with water, dried and
filtered and evaporated in vacuo. The evaporation
residue is purified by column chromatography on silica
gel (toluene/ethyl acetate = 10/1).
Yield: 0.80 9 (40% of theory),
M.p.: 137-140~C (ether)
Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13
Found: 68.42 7.09 8.06 6.05
The followin~ compounds were obtained analogously
to Example 37:
(a) Ethyl 4-t(1-(4-chloro-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 21.9% of theory,
M.p.: 123-125C
Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13
Found: 68.70 7.18 7.77 6.08
~2~47~3
- 95 -
(b) Ethyl 4-[(1-(5~bromo-2-piperidino-phenyl~-1-
butyl)-aminocarbonylmethyl3-benzoate
Yield: 53.8% of theory,
M.p.: 140-142C
Calculated: C 62.27 H 6.63 Br 1~.93 ~ 5.58
Found: 62.39 6.78 15.85 5.59
(c~ Ethyl 4-[(1-(4-fluoro-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl)-benzoate
Yield: 21.6~ of theory,
M.p.: 110-112C
Calculated: C 70.88 H 7.55 N 6.36
Found: 71.01 7.53 6.21
15 In addition, 40% of ethyl 4-~(1-(4-hydroxy-2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate are
isolated (solid foam).
(d) Ethyl 4-l(1-(5-fluoro-2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl]-benzoate
Yield: 2% of theory,
Mop~ 127-129C
Calculated: m/e = 440
Found: m/e = 440
(e) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-ethyl)-
~minocarbonylmethyl~-benzoic acid
Yield: 16.9% of theory,
M.p.: 172-175C
Calculated: C 68.73 H 6.55 N 7.29
Found: 68.78 6.62 7.31
4-[(1-(2-Piperidino-phenyl~-l-butyl)-aminocarbonyl-5 methyl~-benzoic acid
1.0 g ~2.33 mmol) of 4-~(1-(5-chloro-2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl]-benzQic acid
in 40 ml of absolute ethanol are hydrogenated on
~214773
- 96 -
0.5 9 of 10% palladium/charcoal at 50~C and under
5 bar of hydrogen. After 2 hours, the catalyst is
filtered off over kieselguhr and the filtrate is
concentrated by evaporation in vacuo. The evaporation
residue is distributed at pH 6 between water and
ethyl acetate. The organic extract is washed with
water, dried and filtered and evaporated in vacuo.
Yield: 0.61 y (66% of theory),
M.p.: 213-215C
Calculated: C 73.07 H 7.66 N 7.10
Found: 73.18 7.42 7.27
The same compound is also obtained from the corresponding
4-chlorine-, 3-chlorine- or 6-chlorine-substituted
lS starting products.
Example 39
Ethyl 4-[(1-(4-Meth~y-2-piPeridino-pheny~ -butyl)
aminocarbonYlmethyl]-benzoate
A solution of 5.0 g (11.4 mmol) of ethyl 4-
[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-
methyl]-benzoate in 45 ml of absolute dimethylformamide
is added dropwis~, with stirring, at ambient temperature,
to 548 mg (11.4 mmol) of sodium hydride (50% in
oil) in 10 ml of absolute dimethylformamide. The
mixture is stirred for a further 15 minutes and then
a solution of 0.71 ml (11.4 mmol) of methyliodide
in 8 ml of absolute dimethylformamide is slowly added
dropwise thereto. The mixture is stirred for a further
2.5 hours at ambient temperature, evaporated in vacuo
and distributed between water and ether. The ether
phase i5 dried and filtered and concentrated by evapor-
ation in vacuo. The evaporation residue is purified
by column chromatography on silica gel (toluene/acetone
= 20/1).
Yield: 1.8 9 (34.9~ of theory),
M.p.: 115-117C
~2~47~3
- 97 -
Calculated: C 71.65 H 8.02 N 6.19
Found: 71.47 7.86 6.19
The following compound was obtained analogously to
Example 39:
(a) Ethyl 4-~(1-(5-me~hoxy-2-piperidino-phenyl)-
l-butyl~-aminocarbonylmethyl~-benzoate
Yield: 68.4~ of theory,
M.p.: 142-145C
Calculated: C 71.65 H 8.02 N 6.19
Found: 71.87 8.06 6.38
Exam~le 40
2,3-Dih~droxy-propyl 4-l(l (2-piperidino-phenyl?-
l-butyl)-aminocarbonylmethyl]-benzoate
A solution of 2.0 9 (5.07 mmol) of 4-[(1-(2-
piperidino-phenyl~-l-butyl)-aminocarbonylmethyl]-
benzoic acid and 0.85 g (5.27 mmol) of N,~'-carbonyldi-
imida~ole in 20 ml of absolute tetrahydrofuran i~refluxed for 1 hour, then 3.7 ml (50.7 mmol) of glycerol
are added and the resulting mixture is refluxed for
a further 15 hours. It is then concentrated by evapor-
ation _ vacuo, distributed between water and ethyl
acetate, the organic solution is dried and filtered
and evaporated in vacuo. The evaporation residue
is purified by column chromatography on silica gel
(toluene/acetone = 1:1).
Yield: 1.1 g ~46.2% of theory),
M.p.: 120-122C
Calculated: C 69.21 ~ 7.74 N 5.98
Found: 69.23 7.73 5.g3
The following compounds were obtained analogously
to Example 40:
(a) 2-hydroxy-ethyl 4-[(1-(2-piperidino-phenyl~-
l-butyl)-aminocarbonylmethyl]-ben~oate
7 73
- 98 -
Yield: 80~ of theory,
M.p.: 125-127~C
Calculated: C 71.21 H 7.81 N 6.39
Found: 71.35 7.54 6.33
(b) 2-methoxy-ethyl 4-[(1-(2-piperidino-phenyl)-
l-butyl)-aminocarbonylmethyl~-benzoate
Yield: 55.9~ of theory,
M.p.: 120-123~C
Calculated: C 71.65 H 8.02 N 6.19
Fo~nd: 72.03 8.03 6.24
Example 41
2-nicotinoyloxy-ethY1 4-r(l-(2-piperidino-phenyl)-5 l-butyl)-aminocarbonYlmethyl~-benzoate
A solution of 0.7 9 (4.68 mmol) of nicotinic
acid chloride in 20 ml of methylen~ chloride is rapidly
added dropwise to a stirred solution of 2.0 g (4.56 mmol)
of 2-hydroxyethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-
aminocarbonylmethyl]-benzoate in 40 ml of methylene
chloride and 0.7 ml ~4.81 mmol) of triethylamine.
The res~lting mixture is stirred at 20C for 2.5
hour~, extracted with water, then the organic phase
is dried and filtered and evaporated in vacuo. The
evaporation residue is purified by column chromatography
on silica gel (toluene/acetone = S/l).
Yield: 1.1 9 (44~ of theory),
M.p.: 132-135C
Calculated: C 70.70 H 6.86 N 7.73
Found: 70.82 6.82 7.91
Exam~le 42
4-[(1-~2-Pi~eridino-phenvl)-l-butyl)-aminocarbonylmethyl~-
benzYl alcohol
A ~olution of 5.0 9 (11.83 mmol) of ethyl 4-
[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-
benzoate in 7S ml of absolute tetrahydrofuran is
added dropwi~e, at an internal temperature of 0C,
12~4773
99
to a stirred suspension of 0.68 9 (17.95 mmol) of
lithium aluminium hydride in 25 ml of absolute tetrahydro-
furan. The mixture is stirred for 20 hours at ambient
temperature then cooled to 0C and 4N sodium hydroxide
solution is slowly added dropwise thereto until a
filterable precipitate has formed. The mixture is
filtered and the precipitate is decocted several
times with ether. The combined organic solutions
are concentrated by evaporation in vacuo. The evaporation
residue is distributed between water and ether.
The ether phase is dried and filtered and concentrated
by evaporation in vacuo. The evaporation residue
is purified by column chromatography on silica gel
(toluene/acetone = 5/1).
15 Yield: 1.0 g (22% of theory),
M.p.: 152-154C
Calculated: C 75.75 H 8.48 N 7.36
Found: 75.90 8.45 7.28
Example 43
4-~(1-(2-Piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-
benzaldehyde
6.6 9 (62 mmol) of sodium carbonate are heated
together with 62 ml of ethylene glycol in a bath
at 170C and, within 1 minute, 6.2 g (11 mmol) of
Nl-~4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-
methyl~-benzoyl]-N2-tosyl-hydrazine (melting point
195C (decomposition~) are added thereto, with rapid
stirring, whereupon there is a vigorous development
of gas. The mixture is then heated for a further
2.5 minutes at 170C and then immediately poured
onto ice. It is extracted with ether and the ether
solution is dried, filtered and concentrated by evapor-
ation in vacuo. The evaporation residue is purified
by column chromatography on silica gel (chloroform/
acetone = 20/1).
Yield: 2.2 9 (S2.g% of theory),
M.p.: 142-145C
1214773
-- 100 --
Calculated:C 76.16 H 7.99 N 7.40
Found: 76.26 7.96 7.37
ExamPle 44
Ethyl 4-[(1-(2-PiPeridino-phenyl)-l-butYl)-aminocarbonyl-
methvl]-cinnamate
A s~lution of 2.80 9 (12.5 mmol) of ethyl diethyl-
phosphonoacetate in 10 ml of absolute dimethylformamide
is added dropwise, at ambient temperature, to 0.60 9
(12.5 mmol) of sodium hydride (50% in oil) in 15 ml
of absolute dimethylformamide. The mixture is stirred
for 15 minutes (until the development of gas ceases)
and then a solution of 2.4 ~ (6.34 mmol) of 4-[(1-
(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-
benzaldehyde in 10 ml of absolute dimethylformamideis added dropwise thereto. The mixture is stirred
for 2 hours at ambient temperature, concentrated
by evaporation in vacuo and distributed between water
and ether. The ether phase is dried and filtered
and then evaporated in vacuo. The evaporation residue
is purified by column chromatography on silica gel
(toluene/acetone = 10/1).
Yield: 0.8S g (29.9% of theory),
M.p.: 135-137C (ether/petroleum ether)
2S Calculated: C 74.97 H 8.09 N 6.24
Found: 74.91 7.89 6.29
ExamPle 45
4-[(1-(2-Piperidino-phenyl)-l-butYl)-aminocarbonYlmethyl]-
cinnamic acid
Prepared by alkaline saponification of ethyl4-t(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]
c~nnamate analogou~ly to Example 26.
Yield: 64% of theory,
M.p.: 180-183~C
Calcula~ed: C 74.26 H 7.67 N 6.66
Found: 74.03 7.47 6.80
12~4773
-- 101 --
ExamPle 46
Ethyl 3-r4-r~1-(2-Piperidino-phenyl)-l-butvl)-amin
carbonYlmethYl]-Phenyl]-PrOpiOnate
0.60 9 (1.34 mmol) of ethyl 4-[tl-(2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl]-cinnamate are
hydrogenated in lO ml of ethanol on 0.20 9 of 10%
palladium/charcoal at ambient temperature under 5
bar of hydrogen. The mixture is filtered and concentrated
by evaporation in vacuo.
Yield: 0.53 g ~88% of theory),
M.p.: 98-99C (petroleum ether)
Calculated: C 74.63 H 8.50 N 6.22
Found: 74~64 8.58 6.23
The following compound was obtained analogously to
Example 46:
(a) 3-[4-[(1-(2-Piperidino-phenyl)-l-butyl)-amino-
carbonylmethyl]-phenyl]-propionic acid
Yield: 63% of theory,
M.p.: 131-133C
Calculated: C 73.90 H 8.11 N 6.63
Found: 73.96 8.30 6.56
Example 47
3-[4-[(1-(2-Piperidino-phenYl)-l-butYl)-aminocarbonyl-
methyl~-phenyl~-proPionic acid
Prepared by alkaline saponification of ethyl
3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-
methyl]-phenyl]-propionate analogously to Example
; 26.
Yield: 50~ of theory,
M.p.: 131-133C
Calculated: C 73.90 H 8.11 N 6.63
Found: 73.82 8.07 6.41
1~14773
- 102 -
Example 48
Ethyl 4-[~-aminocarbonyl-2-piperidino-benzYl)-amin
carbonylmethYl~-benzoate
At 20C, 0.90 9 (5.5 mmol~ of N,N'-carbonyldi-
imidazole are added to a stirred solution of 2.0 9
(4.7 mmol) of ethyl 4-[(a-carboxy-2-piperidino-benzyl)-
aminocarbonylmethyl~-benzoate x 0.167 H20 (melting
point 156-159~C~ in 20 ml of anhydrous tetrahydrofuran
and the mixture is then heated for half an hour in
a bath at 80C. The mixture is then cooled to 60C
and at this temperature a vigorous current of dry
ammonia is introduced over a period of half an hour.
Then the re6ulting mixture is evaporated in vacuo,
distributed between water and chloroform, then the
combined chloroform extracts are shaken with a little
water, dried, filtered and evaporated in vacuo.
The evaporation residue is purified by column chromat-
ography on silica gel tchloroform/methanol = S/l).
Yield: 1.0 9 (S0.2~ of theory),
M.p.: 160-162C (acetone)
Calculated: C 68.07 H 6.90 N 9.92
Found: 68.40 6.92 9.84
Example 49
Ethvl 4-[(a-cYano-2-Piperidino-benzyl)-aminocarbonyl-
methYl]-benzoate
234 mg (1.22 mmol) of 4-toluenesulphochloride
are added in two batches to 520 mg (1.22 mmol) of
ethyl 4-[(u-aminocarbonyl-2-piperidino-benzyl)-amino-
carbonylmethyl]-benzoate in 0.22 ml of pyridine and
the mixture is heated to 50C. ~fter 2 hours and
then 1 hour later, the same quantities of pyridine
and 4-toluenesulphochloride are again added and the
resulting mixture is heated for a further hour at
50C. After it has been left to stand for 2 days
at 20C, 2N ammonia is added and the mixture is extracted
with chloroform. The chloroform solution is extracted
twice with water. After drying and filtering, it
~ 214773
- 103 -
is concentrated by evaporation in vacuo. The evaporation
residue is purified by column chromatography on silica
gel (chloroform/methanol = 10/1~.
Yield: 325 mg (6S.7% of theory),
M.p.: 114-117C (ether/petroleum ether)
Cal~ulated: C 71.09 H 6.71 N 10.36
Found: 70.79 6.56 10.10
Example 50
4-[(a-CYano-2-PiPeridino-benzvl)-aminocarbonYlmeth~l]
benzoic acid
1.5 9 (3.7 mmol) of ethyl 4-[(~-cyano-2-piperidino-
benzyl)-aminocarbonylmethyl3 benzoate in 15 ml of
dioxan are stirred together with 3.7 ml of lN sodium
hydroxide solution for 45 minutes in a bath at 60C
and for a further 45 minutes in a bath at 80~C.
After cooling with ice, the mixture is combined with
3.7 ml of lN hydrochloric acid, the dioxan is evaporated
off in vacuo and the residue is distributed between
water and chloroformr The organic solution is extracted
with a little water, then dried and filtered and
concentrated by evaporation in vacuo. The evaporation
residue is purified by column chromatography on silica
gel (chloroform/ethanol - 5/1).
Yield: 0.50 9 (35.7% of theory),
M.p.: 176-180C (decomposition)
Calculated: C 70.01 H 6.14 N 11.13
Found: 70.02 6.19 11.05
ExamPle 51
4-~(1-(2-piPeridino-pheny~ butyl)-aminocarbonylmethyl]
benzoic acid x H SO
- 2 - 4
5 ml (2.50 mmol) of lN sulphuric acid are added
to a solution of 1.0 9 l2.53 mmol) of 4-[(1-(2-piperidino-
phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid
in 50 ml of ethanol, the mixture is concentrated
to dryness in vacuo and triturated with acetone~
~Z14773
- 104 -
Yield: 0.80 9 (65~ of theory),
M.p.: 192~197C (decomposition).
Calculated: C 58.53 H 6.55 N 5.69 S 6.49
Found: 58.05 6.54 5.49 6.35
The following addition salt was obtained analogously
to Example 51:
(a) 4-[(1-(2-Piperidino-phenyl)-l-butYl)-aminocarbonYl-
methyl]-benzoic acid x 0.5 H2SO1 x 1.5 H20
Prepared analogously to Example 51 with half
the quantity of sulphuric acid.
Yield: 59.3~ of theory,
M.p.: 180-185C decomposition at 207-210C
Calculated C 61.26 H 7.28 N 5.95 S 3.40
Found: 61.28 6.99 6.10 3.23
1~14773
- 105 -
Example A
Tablets containing 5 mg of 4-[(1-(2-Piperidino-phenyl)
l-butyl)-aminocarbonylmethyl]-benzoic acid
5 Composition:
1 tablet contains:
Active substance (1)5.0 mg
Corn starch (2)62.0 mg
Lactose (3)48.0 mg
10 Polyvinylpyrrolidone (4)4.0 mg
Magnesium stearate (5)1.0 mg
120.0 mg
Method of preparation:
1, 2, 3 and 4 are mixed together and moistened
with water. The moist mixture is pressed through
a screen with a mesh width of 1.5 mm and dried at
about 45C. The dry granulate is passed through
a screen with a mesh width of 1.0 mm and mixed with
5. The finished mixture is compressed in a tablet
press, using punches 7 mm in diameter provided with
a dividing slot, to form tablets.
Weight of tablet: 120 mg
Exam~e B
Coated tablets containinq 2.5 mg of 4-[(1-(2-piperidino-
~hen~ bu~ aminocarbonYlmethyl]-benzoic acid
1 tablet core contains:
30 Active substance (1)2.5 mg
Potat~ starch (2)44.0 mg
Lactose (3)30.0 mg
Polyvinylpyrrolidone (4)3.0 mg
Magnesium stearate ~5)0.5 mg
80.0 mg
121~773
- 106 -
Method of pre~aration:
1, 2, 3 and 4 are thoroughly mixed and moistened
with water. The moist mass is passed through a screen
with a mesh width of 1 mm, then dried at 45C and
the granulate is again passed through the same screen.
After the addition of 5, convex tablet cores 6 mm
in diameter are produced in a tablet-making machine
by compression. The tablet cores thus produced are
coated in known manner with a coating consisting
essentially of sugar and talc. The finished coated
tablets are polished with wax.
Weight of coated tablet: 120 mg
Example C
Tablets containinq 10 mg of 4-[(1-(2-piPeridino-phenYl)-
l-but~ aminocarbonylmethyl]-benzoic acid
Composition:
1 tablet contains:
20 Active substance 10.0 mg
Powdered lactose 70.0 mg
Corn starch 31.0 mg
Polyvinylpyrrolidone 8.0 mg
Magnesium stearate 1.0 mq
120.0 mg
Method of Preparation
A mixture of the active substance, lactose
and corn starch is moistened with a 20~ solution
of polyvinyl pyrrolidone in water. The moist mass
is granulated through a screen with a mesh width
of 1.5 mm and then dried at 45C. The dried granulate
is rubbed through a screen with a mesh size of 1 mm
and homogeneously mixed with magnesium stearate.
Weight of tablet: 120 mg
Punch: 7 mm in diameter with dividing slot.
~.214773
- 107 -
Example D
Coated tablets containinq 5 m~ of 4-[(1-(2-piPeridin
-
E~henyl)-l-butyl)-aminocarbonylmethYl]-benzoic acid
5 1 tablet core contains:
Active substance 5.0 mg
Secondary calcium phosphate70.0 mg
Corn starch 50.0 mg
Polyvinylpyrrolidone 4.0 mg
10 Magnesium stearate 1.0 mq
130.0 mg
Method of ~reparation
A mixture of active substance, calcium phosphate
and corn starch is moistened with a 15% solution
of polyvinylpyrrolidone in water. The moist mass
is passed through a screen with a mesh size of 1 mm,
then dried at 45~C and passed through the same screen
again. After the specified amount of magnesium stearate
has been added, tablet cores are compressed from
the mixture.
Weight of core: 130 mg
Punch: 7 mm in diameter~
A coating of sugar and talc is applied to the
tablet cores thus produced in known manner. The
finished coated tablets are polished with wax.
Weight of coated tablet: 180 mg
