CARBOXYLIC ACID AMIDES, THEIR PREPARATION AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

AMIDES DE L'ACIDE CARBOXYLIQUE, PROCEDE DE PREPARATION ET UTILISATION COMME COMPOSES PHARMACEUTIQUES

English Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of general formula I

Image ,(I)

wherein R1 and R2 represent alkyl or cycloalkyl groups
or together with the nitrogen atom to which they are
attached, represent a cyclic imino group, R2 represents
a hydrogen or a halogen atom, an optionally substituted
hydroxy, mercapto, amino, carboxy or aminocarbonyl group, or
a nitro, alkanoyl, aminosulfonyl, trifluoromethyl or cyano
group, R4 represents a hydrogen atom or an alkyl group.
R5 represents a hydrogen or a halogen atom or an alkyl
group, A represents a bond or an optionally substituted
methylene, ethylene or vinylidene group, B represents
a methylene or ethylene group optionally substituted
by an alkyl group and W represents a hydrogen or a
halogen atom, a cyano, alkanoyl or nitro group, an
optionally substituted amino or aminocarbonyl group.
a carboxy group or an ester thereof, a formyl group
or an acetal thereof or an optionally substituted
alkyl group); and salts thereof formed with acids and
bases. Processes for the preparation of the new
compounds as well as pharmaceutical compositions containing
them are also objects of this invention.
The new compounds show valuable pharmaceutical
properties, especially effects on intermediary metabolism
and a blood-sugar lowering activity.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of general formula I

Image (I)

[wherein R1 and R2, which may be the same or different, each represents an
alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing 5
to 7 carbon atoms, or R1 and R2 together with the nitrogen atom to which they
are attached represent an unbranched alkyleneamino group containing 3 to 6 car-
bon atoms optionally substituted by 1 or 2 alkyl groups, each containing 1 to
3 carbon atoms, or by a hydroxy group and in which a methylene group may op-
tionally be replaced by a carbonyl group, by an oxygen or sulfur atom or by
an imino group (which may optionally be substituted by an alkyl group containing
1 to 3 carbon atoms, an aralkyl group containing 7 to 10 carbon atoms or by a
phenyl or halophenyl group) or an ethylene group may optionally be replaced by
an O-phenylene group; and unbranched alkenyleneimino group containing 4 to 6
carbon atoms; a saturated or partly unsaturated azabicycloalkyl group contain-
ing 6 to 10 carbon atoms; an aza-1,4-dioxaspiro-alkyl group containing 6 to 8
carbon atoms; or a heptamethyleneimino, octamethyleneimino, nonamethyleneimino
or decamethyleneimino group, R3 represents a hydrogen or halogen atom, a tri-
fluoromethyl, alkyl, hydroxy, alkoxy, alkanoyloxy, mercapto, alkylmercapto,
nitro, amino, cyano, alkanoyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkyl-
aminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino or alkylsulfonylamino group (wherein each

121

alkyl moiety in the above mentioned groups contains from 1 to 3 carbon atoms),
an aralkoxy group containing 7 to 10 carbon atoms or an arylcarbonylamino group;
R4 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon
atoms; R5 represents a hydrogen atom, a halogen atom or an alkyl group containing
1 to 3 carbon atoms; A represents a bond, a methylene or ethylene group
optionally substituted by a methyl, ethyl or isopropyl group, a methylene or
ethylene group substituted by two alkyl groups each containing 1 to 3 carbon
atoms, a methylene group substituted by a cycloalkyl group containing 3 to 7
carbon atoms or by a hydroxyalkyl, carboxyl, alkoxycarbonyl, or phenyl group,
wherein each of the alkyl moieties contains from 1 to 3 carbon atoms, a
cycloalkylidene group containing 3 to 7 carbon atoms or a vinylidene group of
formula


Image



wherein R6 and R7, which may be the same or different, each represents a
hydrogen atom or one of the radicals R6 and R7 represents a methyl group or
a cycloalkyl group containing 3 to 7 carbon atoms and the other is a hydrogen
atom, or R6 and R7 together with the carbon atom to which they are attached
represent a cycloalkylidene radical containing 5 to 7 carbon atoms; B represents
a methylene or ethylene group optionally substituted by an alkyl group
containing 1 to 3 carbon atoms; and W represents a hydrogen or halogen atom,
a nitro group, an amino group (optionally substituted by an alkanoyl group
containing 1 to 3 carbon atoms), an alkyl group containing 1 to 3 carbon atoms
(optionally substituted by a hydroxy or carboxy group or by one or two
alkoxycarbonyl groups containing 2 to 4 carbon atoms each), an alkenyl group

122


containing 2 to 5 carbon atoms substituted by a carboxy or alkoxycarbonyl group
containing 2 to 4 carbon atoms, an alkanoyl group containing 1 to 3 carbon
atoms, a dialkoxymethyl or trialkoxymethyl group containing 1 to 3 carbon
atoms in each alkyl part, an alkylenedioxymethyl group containing 2 or 3 carbon
atoms in the alkylene part, a 1,3-oxazoline-2-yl or cyano group, an aminocarbonyl
group (optionally substituted by one or two alkyl groups containing 1 to 4
carbon atoms in each alkyl moiety), an unbranched alkyleneiminocarbonyl group
containing 5 to 8 carbon atoms, a morpholinocarbonyl group, a (dialkyldioxolan-
yl)-alkoxycarbonyl group containing 7 to 10 carbon atoms or a carboxy group or
esterified carboxy group, wherein if the said ester group consists of an alkyl
group containing 1 to 6 carbon atoms this may be substituted, in any but the .alpha. -
position, by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, 1,3-
dimethylxanthine-7-yl, alkanoyloxy, aroyloxy, aralkanoyloxy or pyridine-
carbonyloxy group or by two hydroxy groups - except in the case of any methyl
or methylene group in the above cases, which can only be substituted by one
hydroxy group or by a group of formula

Image

wherein A, B, R1, R2, R3, R4 and R5 are as hereinbefore defined[wherein each
alkyl moiety of the above alkyl ester contains from 1 to 3 carbon atoms], or a
physiologically compatible salt thereof, which process comprises
(a) reacting an amine of general formula II

123


Image (II)

wherein A, R1, R2, R3 and R4 are as defined above (or if A represents one of
the above mentioned vinylidene groups one of its tautomers, or a lithium or
magnesium-halide complex thereof) with a carboxylic acid of general formula III

Image (III)

wherein R5 and B are as defined above and W' represents W as defined above or
represents a carboxyl group protected by a protective radical, or with a
reactive derivative thereof, optionally prepared in the reaction mixture, and
if necessary cleaving off a protective radical;
(b) for the preparation of a compound of general formula I wherein
W represents a carboxy group, hydrolytically, thermolytically or hydrogeno-
lytically reacting a compound of general formula IV

Image (IV)

wherein R1, R2, R3, R4, R5, A and B are as defined above and D represents a
group being transformable into a carboxy group by means of hydrolysis, thermo-
lysis or hydrogenolysis;

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(c) alkylating a compound (optionally formed in the reaction
mixture) of general formula


(V)


Image




wherein R3, R4, R5, A, B and W are as defined above and R2' represents a
hydrogen atom or is as defined above for R2, with a compound of general formula
VI
R1' - E (VI)
wherein R1' represents R1 as defined above or together with the radical R2' in
the above compound of formula V represents a straight-chained alkylene group
containing 4 to 6 carbon atoms (optionally substituted by one or two alkyl
groups containing 1 to 3 carbon atoms) or an n-pentylene group wherein the third
methylene group is replaced by an oxygen or sulfur atom, and E represents a
nucleophillically exchangeable group or (if in the radical R1' a methylene
group is replaced by an aldehyde or ketone carbonyl group) a hydrogen atom, if
necessary in the presence of a reducing agent and optionally subsequently
hydrolyzing the product obtained;
(d) for the preparation of a compound of general formula I, wherein
W represents a carboxy group, an alkanoyl group, an alkanoyl group containing
1 to 3 carbon atoms or an alkyl group containing 1 to 3 carbon atoms, reacting
a compound of general formula VII

Image (VII)

125

wherein R1, R2, R3, R4, R5, A and B are as defined above with phosgene, an
oxalyl halide, an alkyl or alkanoyl halide containing 1 to 3 carbon atoms each
in the alkyl moiety or with hydrogen cyanide and a hydrogen halide in the
presence of a Lewis acid;
(e) for the preparation of a compound of general formula I wherein
W represents a carboxy group, reacting a compound of general formula VIII

Image (VIII)

wherein R1, R2, R3, R4, R5, A and B are as defined above with a hypohalite
(optionally formed in the reaction mixture) in the presence of an alkali base;
(f) for the preparation of a compound of general formula I, wherein
W represents a carboxy group, oxidizing a compound of general formula IX

Image (IX)

wherein K1, K2, K3, K4, K5, A and B are as defined above and G represents
a group which may be converted into a carboxy group by means of oxidation;
(g) for the preparation of a compound of general formula I, wherein
R3 represents a nitro group, reacting a compound of general formula X

(X)
Image

126


wherein R4, R5, A, B and W are defined above, R3 represents a nitro group and
Y represents a nucleophilically exchangeable radical, with an amine of general
formula XI

Image (XI)

wherein R1 and R2 are as defined above, and optionally subsequently hydrolyzing
the product obtained;
(h) for the preparation of a compound of general formula I, wherein
A represents a group of formula



Image

wherein R6 and R7 are as defined above, reducing a compound of general formula

XII Image (XII)

wherein R1, R2, R3, R4, R5, R6, R7, B and W are as defined above, with hydrogen
in the presence of a hydrogenation catalyst;
(i) for the preparation of a compound of general formula I [wherein
R4 represents a hydrogen atom and A represents a methylene or ethylene group
(optionally substituted by a methyl, ethyl or isopropyl group), a methylene or
ethylene group substituted by two alkyl groups containing 1 to 3 carbon atoms
each, a methylene group substituted by a cycloalkyl group contain-

127

ing 3 to 7 carbon atoms, by a carboxyl group, by an alkoxycarbonyl group wherein
the alkyl moiety contains from 1 to 3 carbon atoms, or by a phenyl group, or a
cycloalkylidene group containing 4 to 7 carbon atoms], reacting a compound of
general formula XIII

Image (XIII)

wherein R1, R2 and R3 are as defined above, and A' represents a methylene or
ethylene group (optionally substituted by a methyl, ethyl or isopropyl group), a
methylene or ethylene group substituted by two alkyl groups containing 1 to 3
carbon atoms each, a methylene group (substituted by a cycloalkyl group
containing 3 to 7 carbon atoms, or a carboxyl group, or an alkoxycarbonyl
group wherein the alkyl moiety contains from 1 to 3 carbon atoms, or a phenyl
group), or a cycloalkylidene group containing 4 to 7 carbon atoms, with a
compound of general formula XIV

Image (XIV)

wherein R5, B and W are as defined above, in the presence of a strong acid;
(j) converting a compound of formula I wherein W represents a
carboxy group, initially obtained, by means of esterification or amidation into
an ester or amide derivative thereof;
(k) reducing a compound of formula I, wherein R3 and/or W represent
nitro groups, initially obtained, to a compound of formula I wherein R3 and/or
W represent amino groups;
(l) convering a compound of formula I initially obtained, wherein
R3 and/or W represent an amino group, via a diazonium salt into a compound of

128


formula I wherein R3 represents a hydrogen or a halogen atom, a hydroxy, alkoxy,
mercapto, alkylmercapto, chlorosulfonyl or cyano group and/or W represents a
hydrogen or a halogen atom or a cyano group;
(m) alkylating a compound of formula I wherein R3 represents a
hydroxy group, to yield a compound of formula I wherein R3 represents an alkoxy
group;
(n) converting a compound of formula I wherein R3 represents a
chlorosulfonyl group by means of ammonia to a compound of formula I wherein R3
represents an aminosulfonyl group;
(o) acylating a compound of formula I initially obtained wherein
R3 represents an amino group to yield a compound of formula I wherein R3 re-
presents an alkanoylamino, aroylamino, alkoxycarbonylamino or alkylsulfonylamino
group;
(p) converting a compound of formula I initially obtained wherein
R3 represents an amino group, by alkylation to a compound of formula I wherein
R3 represents an alkyl- or dialkylamino group;
(q) converting a compound of formula I initially obtained wherein
R3 represents a chlorine or a bromine atom by dehalogenation to a compound of
formula I wherein R3 represents a hydrogen atom;
(r) converting a compound of formula I initially obtained wherein
R3 represents a nitrile group by hydrolysis or alcoholysis to a compound of
formula I wherein R3 represents an aminocarbonyl, carboxycarbonyl or alkoxy-
carbonyl group;
(s) reducing a compound of formula I initially obtained wherein R3
represents a carboxycarbonyl or alkoxycarbonyl group and/or W represents a
carboxy or esterified carboxy group, to a compound of formula I wherein R3
and/or W represents a formyl or hydroxymethyl group;

129

(t) acylating a compound of formula I initially obtained, wherein
W represents an alkoxycarbonyl group (wherein the alkoxy group may contain from
2 to 6 carbon atoms) substituted in any but the .alpha.-position by a hydroxy group,
to a compound of formula I wherein W represents an acyloxy group;
(u) halogenating a compound of formula I initially obtained, where-
in W represents a hydroxymethyl group, and then reacting the product with a
malonic acid diester to form a compound of formula I wherein W represents an
ethyl group substituted by two alkoxycarbonyl groups;
(v) converting a compound of formula I initially obtained, wherein
W represents a formyl group, by means of condensation and optional subsequent
hydrolysis and/or decarboxylation to a compound of formula I wherein W represents
a vinyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group;
(w) converting a compound of formula I initially obtained, wherein
W represents an ethyl group substituted by two alkoxycarbonyl groups, by
hydrolysis and decarboxylation to a compound of formula I wherein W represents
an ethyl group substituted by one carboxy group;
(x) converting a compound of formula I initially obtained, wherein
W represents a carboxy group, via a sulfonic acid hydrazide and subsequent dis-
proportionation into a compound of formula I wherein W represents a formyl group;
(y) hydrolysing a compound of formula I initially obtained, wherein
R1 and R2 together with the nitrogen atom to which they are attached represent
an aza-1,4-dioxaspiro-alkyl group containing 6 to 8 carbon atoms, to a compound
of formula I wherein R1 and R2 together with the nitrogen atom to which they
are attached represent an unbranched alkyleneimino group containing 4 to 6
carbon atoms wherein a methylene group is replaced by a carbonyl group;
(z) reducing a compound of formula I initially obtained, wherein R1
and R2 together with the nitrogen atom to which they are attached represent an
unbranched alkyleneimino group containing 4 to 6 carbon atoms wherein a

130



methylene group is replaced by a carbonyl group, to a corresponding hydroxy-
alkyleneimino compound of formula I:
(aa) dehydrating a compound of formula I initially obtained,
wherein W represents an aminocarbonyl group, to a compound of formula I wherein
W represents a cyano group; or
(bb) converting a compound of formula I initially obtained into a
physiologically compatible salt thereof with an organic or inorganic acid or base,
or converting a salt of a compound of formula I initially obtained into a
compound of formula I.


2. A process as claimed in claim 1(a), wherein the reaction is carried
out in a solvent at a temperature between -25 and 250°C.


3. A process as claimed in claim 1(a) or 2 wherein the reaction is
carried out in the presence of an acid-activating or dehydrating agent.


4. A process as claimed in claim 1(a) or 2 wherein the reaction is
carried out in the presence of an amine-activating agent.


5. A process as claimed in claim 1(a) or 2 wherein the reaction is
carried out in the presence of an inorganic or tertiary organic base.


6. A process as claimed in claim 1(a) or 2 wherein water formed
during the reaction is removed by azeotropic distillation or by addition of a
drying agent.


7. A process as claimed in claim 1(b) wherein the reaction is carried

out in a solvent at a temperature between room temperature and the boiling
temperature of the reaction mixture.


8. A process as claimed in claim 1(b) or 7, wherein the hydrolysis
or thermolysis is carried out in the presence of an acid or base.

131




9. A process as claimed in claim 1(b), wherein, if in the compound of
formula IV, D represents a nitrile or aminocarbonyl group, the reaction is
carried out in the presence of a nitrite and an acid.


10. A process as claimed in claim 9 wherein the nitrite is sodium
nitrite and the acid is sulfuric acid.


11. A process as claimed in claim 1(c), wherein the reaction is car-
ried out in a solvent at a temperature between 0 and 150°C.


12. A process as claimed in claim 1(c) or 11, wherein the reaction is
carried out in the presence of an inorganic or tertiary organic base.


13. A process as claimed in claim 1(c), wherein the alkylation is
carried out with a carbonyl compound in the presence of a hydride at pH 7.


14. A process as claimed in claim 13 wherein the hydride is sodium
cyanoborohydride.


15. A process as claimed in claim 1(c) or 11, wherein a methylation
reaction is carried out using formaldehyde in the presence of formic acid, or
hydrogen in the presence of a hydrogenation catalyst.


16. A process as claimed in claim 1(d), wherein the reaction is car-
ried out in a solvent at a temperature between 0 and 120°C.



17. A process as claimed in claim 1(d) or 16, wherein the Lewis acid
is aluminium chloride.


18. A process as claimed in claim 1(e) wherein the reaction is carried
out in a solvent at a temperature between 0 and 80°C.


19. A process as claimed in claim 1(f) wherein the reaction is carried

132




out in a solvent at a temperature between 0 and 100°C.


20. A process as claimed in claim 1(g), wherein the reaction is carried
out in a solvent at a temperature between 20 and 150°C.


21. A process as claimed in claim 1(g) or 20, wherein the reaction is
carried out at the boiling temperature of the reaction mixture.


22. A process as claimed in claim 1(g) or 20, wherein the reaction is
carried out in the presence of an excess of the amine of formula XI and/or the
N-formyl derivative thereof.


23. A process as claimed in claim 1(g), wherein the reaction is carried
out in the presence of an inorganic or tertiary organic base and/or a reaction
accelerator and/or in a pressure vessel.


24. A process as claimed in claim 23 wherein the reaction accelerator
comprises copper or a copper salt.


25. A process as claimed in claim 1(h) wherein the reaction is carried
out in a solvent.


26. A process as claimed in claim 1(h) or 25, wherein the reaction is
carried out at a hydrogen pressure of 1 to 5 bar.



27. A process as claimed in claim 1(h) or 25, wherein the reaction is
carried out at a temperature between 0 and 100°C.


28. A process as claimed in claim 1(i), wherein the strong acid is
sulfuric acid.


29. A process as claimed in claim 1(i) or 28, wherein the reaction is

133




carried out in a solvent at a temperature between 20 and 150°C.


30. A process as claimed in claim 1, wherein starting compounds are
chosen in which R1 and R2 together with the nitrogen atom to which they are
attached, represent a dialkylamino or N-alkylcyclohexylamino group (wherein
each alkyl moiety may contain from 1 to 4 carbon atoms), an unbranched alkylene-
imino group containing 3 to 6 carbon atoms (optionally substituted by one or
two methyl groups), a hydroxypiperidino, piperidone-1-yl, tetrahydro-pyridino,
morpholino, thiomorpholino, N-methyl-piperazino, N-benzyl-piperazino, N-chloro-
phenyl-piperazino, heptamethyleneimino or octamethyleneimino group, a saturated
or partyl unsaturated azabicycloalkyl group containing 7 to 9 carbon atoms, an
unbranched alkyleneimino group containing 4 to 6 carbon atoms (wherein an
ethylene group is replaced by an o-phenylene group), or a 1,4-dioxa-azaspiro-
alkyl group containing 7 to 8 carbon atoms; R3 represents a hydrogen, fluorine,
chlorine, bromine, or iodine atom or a methyl, trifluoromethyl, hydroxy, methoxy,
benzyloxy acetoxy, mercapto, methylmercapto, nitro, amino, dimethylamino,
acetylamino, methylsulfonylamino, benzoylamino, ethoxycarbonylamino, cyano,
carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, acetyl or aminosulfonyl
group, R4 represents a hydrogen atom or a methyl group; R5 represents a hydrogen
atom, a chlorine atom or a methyl group; A represents a bond, a methylene group
(optionally substituted by a methyl, ethyl or isopropyl group, or by a
phenyl, cyclohexyl, carboxy, methoxycarbonyl or hydroxymethyl group), a
dimethylmethylene, cyclopropylidene or ethylene group, or a vinylidene group of
formula

Image

wherein R6 and R7 each represents a hydrogen atom or one of the radicals R6 and
R7 represents a methyl group and the other of the radicals R6 and R7 represents

134



a hydrogen atom, or R6 and R7 together with the carbon atom to which they are
attached represent a cycloalkylidene radical containing 5 or 6 carbon atoms; B
represents a methylene, ethylidene or ethylene group; and W represents a
hydrogen atom, a methyl, ethyl, hydroxymethyl, cyano or carboxyvinylene group,
an alkyl group containing 1 to 3 carbon atoms substituted by a carboxy group
or by one or two alkoxycarbonyl groups containing 2 to 4 carbon atoms each, a
carbonyl group (substituted by a hydrogen atom, a methyl, ethyl, hydroxy,
alkoxy, (2,2-dimethyldioxolan-4-yl)-methoxy, benzyloxy, pyridylmethoxy, amino,
alkylamino, dialkylamino, piperidino or morpholino group, each alkyl moiety in
the above groups containing from 1 to 3 carbon atoms) or a group of formula

Image

wherein n is 2, 3 or 4, and R8 represents a hydroxy, methoxy, ethoxy, acetoxy,
benzoyloxy, or pyridinecarbonyloxy group, a dialkylamino group containing 1 to 3
carbon atoms in each alkyl moiety, a 1,3-dimethylxanthine-7-yl group, or a group
of formula

Image

wherein A, B and R1, R2, R3, R4 and R5 are as defined above.



31. A process as claimed in claim 30, wherein starting compounds are
chosen in which the radical

Image

is present in the 2-position and the radical W is present in the 4'-position.

135





32. A process according to claim 1 for preparing a compound of general
formula Ia
Image (Ia)


wherein R1 and R2 together with the nitrogen atom to which they are attached,
represent a dimethylamino, pyrrolidino, methylpyrrolidino, piperidino, methyl-
piperidino, dimethylpiperidino, tetrahydro-pyridino, 2-octahydro-isoindolo, or
hexamethyleneimino group, R3 represents a hydrogen, fluorine or chlorine atom
or a methyl group, A represents a methylene group (optionally substituted by a
cyclohexyl, phenyl, methoxycarbonyl or ethoxycarbonyl group or a methyl, ethyl
or isopropyl group), a dimethylmethylene group or a vinylidene group of formula

Image

wherein R6 and R7 each represents a hydrogen atom or together with the carbon
atom to which they are attached represent a cyclohexylidene group, and W
represents a methyl, hydroxymethyl or carboxymethyl group, a carbonyl group
(substituted by a hydrogen atom or by a methyl, hydroxy, methoxy9 ethoxy,
propoxy, isopropoxy, 2-hydroxyethoxy, 2-methoxyethoxy, (2,2-dimethyl-dioxolan-
4-yl)-methoxy or 2-diethylaminoethoxy group) or a physiologically compatible
salt thereof, wherein appropriately substituted starting compounds are chosen.



33. A process as claimed in claim 32 wherein starting compounds are
chosen in which R1 and R2 together with the nitrogen atom to which they are
attached, represent a pyrrolidino, piperidino, methylpiperidino, hexamethylene-
imino, tetrahydro-pyridino or 2-octahydro-isoindolo group, R3 represents a

136




hydrogen, fluorine or chlorine atom or a methyl group, A represents a methylene
group (optionally substituted by a methyl, isopropyl, phenyl or methoxycarbonyl
groups or a dimethyl-methylene or vinylidene group and W represents a methyl,
hydroxymethyl, carboxymethyl, formyl or carboxy group or an alkoxycarbonyl
group optionally substituted by a (2,2-dimethyl-dioxolan-4-yl) group and
wherein the alkoxy moiety contains from 1 to 3 carbon atoms.


34. A process as claimed in claim 1, wherein starting compounds are
chosen in which R1 and R2, which may be the same or different, each represents
an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing
5 to 7 carbon atoms, or R1 and R2 together with the nitrogen atom to which they
are attached, represent an alkyleneimino group containing 4 to 10 carbon atoms
in the alkylene ring (optionally substituted by one or two alkyl groups each
containing 1 to 3 carbon atoms) a morpholino or a thiomorpholino group, R3
represents a hydrogen or a halogen atom, a trifluoro-methyl, alkyl, hydroxy,
alkoxy, mercapto, alkylmercapto, cyano, nitro, amino, aminocarbonyl, alkylamino,
dialkylamino, or alkylsulfonylamino group, wherein each alkyl moiety in the
above mentioned groups contains from 1 to 3 carbon atoms, A represents a
methylene or ethylene group optionally substituted by one or two alkyl groups
each containing 1 to 2 carbon atoms, R4 and R5 each represent a hydrogen atom,
B is as defined in claim 1, and W, which is in the para position, represents a
carboxy group or an ester thereof.


35. A process for preparing 4-[(1-(2-piperidino-phenyl)-ethyl)-amino-
carbonylmethyl]-benzoic acid or the methyl or ethyl ester thereof or a physiolo-
gically compatible salt thereof, which comprises (a) reacting 4-methoxycarbcnyl-
phenylacetic acid with 1-(2-piperidino-phenyl)-ethylamine; (b) reacting 4-
ethoxycarbonylphenylacetic acid with 1-(2-piperidino-phenyl)-ethylamine di-

137




hydrochloride; (c) reacting 4-ethoxycarbonyl-phenylacetic acid with (2-
piperidinophenyl)-methyl-ketimine; (d) if desired, hydrolysing a methyl or
ethyl ester obtained in step (a), (b) or (c) to the acid; (e) oxidizing 4-[(1-
(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl] benzaldehyde; (f) hydrogenating
4-[(1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid or
the ethyl ester thereof; and (g) if desired, converting an ester or the acid
to a physiologically compatible salt thereof.


36. A process for preparing 4-[(2-piperidino-benzhydryl)-aminocarbonyl-
methyl]-benzoic acid or the methyl or ethyl ester thereof or a physiologically
compatible salt thereof, which comprises (a) reacting 1-(2-piperidino-benz-
hydryl)-ethylamine with 4-methoxycarbonyl or 4-ethoxycarbonyl-phenylacetic acid;
and (b) if desired, hydrolysing the methyl or ethyl ester to form the acid and
(c) if desired converting the acid or ester to a physiologically compatible
salt thereof.


37. A compound of general formula (I) defined in claim 1 or a
physiologically compatible salt thereof, whenever prepared by the process
claimed in claim 1, or by an obvious chemical equivalent thereof.


38. A compound of formula (I) defined in claim 1 wherein R1, R2, R3, R4,
R5, A, B and W are as defined in claim 30, or a physiologically compatible
salt thereof, whenever prepared by the process claimed in claim 30, or by an
obvious chemical equivalent thereof.


39. A compound of formula (I) defined in claim 1 wherein R1, R2, R3, R4,
R5, A, B and W are as defined in claim 30, wherein the radical

Image

138





is present in the 2-position and the radical W is present in the 4'-position,
or a physiologically compatible salt thereof, whenever prepared by the process
claimed in claim 31, or by an obvious chemical equivalent thereof.


40. A compound of formula (Ia) defined in claim 32 or a physiologically
compatible salt thereof, whenever prepared by the process claimed in claim 32,
or by an obvious chemical equivalent thereof.

41. A compound of formula (I) as defined in claim 1 wherein B, R4 and
R5 are as defined in claim 1 and A, R1, R2, R3 and W are as defined in claim 33
or a physiologically compatible salt thereof, whenever prepared by the process
claimed in claim 33, or by an obvious chemical equivalent thereof.

42. A compound of formula (I) as defined in claim 1, wherein A, B, R1,
R2, R3, R4, R5 and W are as defined in claim 34, or a physiologically
compatible salt thereof, whenever prepared by the process claimed in claim 34,
or by an obvious chemical equivalent thereof.

43. 4-[(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic
acid or the methyl or ethyl ester thereof or a physiologically compatible salt
thereof, whenever prepared by the process claimed in claim 35, or by an obvious
chemical equivalent thereof.


44. 4-[(2-Piperidino-benzhydryl)-aminocarbonylmethyl]-benzoic acid,
or the methyl or ethyl ester thereof or a physiologically compatible salt
thereof, whenever prepared by the process claimed in claim 36, or by an
obvious chemical equivalent thereof.

139

Description

- 1 ~1762~6

ClrEMICAL CO.MPOUNDS

This invention relates to new carboxylic acid
amides, to processes .for their preparation and to
pharmaceutical compositions containing them, and also to
their use in the treatment of disorders of irtermediary
metabolism.
According to one feature of the present invention
there are provided compounds of general formula I
~4 ~ W
3 ~ A - N - C0 - B ~ ,(I)

~ 1 5
N~R2

[wherein Rl and R2, which may be the same or di.tterent,
each represents an alkyl aroup containina 1 to 6 carbon
atoms or a cycloalkyl aroup containina 5 to 7 carbon
atoms, or Rl and X2 together with the nitroaen atom to
which they are attached represent an unbranched alkyleneimino
group containing 3 to 6 carbon atoms optionally substituted
by 1 or 2 alkyl aroups, each containina 1 to 3 carbon atoms,
or by a hydroxy aroup and in which a meth~lene ~roup may
optionally be replaced by a carbonyl aroup, by an oxyaen
or sulfur atom or by an imino group (which may optionallv
be substituted by an alkyl group containina 1 to 3
carbon atom, ~n aralkyl aroup containing 7 to 10 carbon
atoms or by a phenyl or halophenyl group) or an ethylene
group mav optionally be replaced by an O-phenylene croup;
and unbranched alkenyleneimino qroup containinq 4 to 6 carbon
atoms; a saturated or partly unsaturated azabicvcloalkyl
group containing 6 to 10 carbon atoms an aza-1,4-dioxa-
spiro-alkyl aroup containin~ 6 to ~ carbon atoms; or
a heptamethyleneimino, octamethyleneimino, nonamethyleneimino
or decamethyleneimino qroup; R3 represents a hydroaen or
haloaen atom, a trifluorometh~], alkyl, hvdroxy, alkoxy,
alkanoyloxy, mercapto, alkylmercanto, nitro, amino, cvano,

1 ~762~

alkanoyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylamino-
carbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylamino, dialkyl-
amino, alkanoylamino, alkoxycarbonylamino or alkylsulfonylamino
group (wh~rein each alkyl part in the above mentioned groups may
contain from 1 to 3 carbon atoms), an aralkoxy group containing 7
to 10 carbon atoms or an arylcarbonylamino group; R4 represents a
hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; R5
represents a hydrogen atom, a halogen atom or an alkyl group con-
taining 1 to 3 earbon atoms; A represents a bond, a methylene or
ethylene group optionally substituted by a methyl, ethyl or
isopropyl group, a methylene or ethylene group substituted by two
alkyl groups each containing 1 to 3 carbon atoms, a methylene group
substituted by a cycloalkyl group containing 3 to 7 carbon atoms or
by a hydroxyalkyl, carboxyl, alkoxycarbonyl, or phenyl group,
wherein each of the alkyl parts may contain from 1 to 3 carbon atoms,
a cycloalkylidene group containing 3 to 7 carbon atoms or a
vinylidene group of formula


/
C
--C --
wherein R6 and R7, whieh may be the same or different, eaeh
represents a hydrogen atom or one of the radieals R6 and R7
represents a methyl group or a cycloalkyl group containing 3 to 7
earbon atoms and the other is as defined above or R6 and R7
together with the earbon atom to which they are attaehed, represent
a cycloalkylidene radical containing 5 to 7 carbon atoms; B
represents a methylene or ethylene group optionally substituted by
an alkyl group containing 1 to 3 carbon atoms and W represents a
hydrogen or halogen atom, a nitro group, an amino group ~optionally
..~
--2--

- 3 - 1~624~

substituted by an alkanoyl qroup containina 1 to 3 carbon
atoms) an alkyl aroup containina 1 to 3 carbon atoms
~optionally substituted by a hydroxy or carboxy ~roup
or by one or two alkoxycarbonyl ~roups containina 2 to 4
carbon atoms each), an alkenyl group containinq 2 to 5
carbon atoms substituted by a carboxy or alkoxycarbonyl
group containing 2 to 4 carbon atoms, an alkanoyl qroup
containinq 1 to 3 carbon atoms, a dialkoxymethyl or
trialkoxymethyl group containinq 1 to 3 carbon atoms in
each alkyl part, an alkylenedioxymethyl group containinq
2 or 3 carbon atoms in the alkylene part, a 1,3-oxazoline-
2-yl or cyano aroup, an aminocarbonyl group (optionally
substituted by one or two alkyl qroups containing 1 to 4
carbon atoms in each alkyl part), an unbranched alkyl-
eneiminocarbonyl aroup containing 5 to 8 carbon atoms
a morpholinocarbonyl aroup, a (dialkyldioxolane-yl)-
alkoxycarbonyl group containing 7 to 10 carbon atoms or
a carboxy group or esterfied carboxy ~roup wherein if the
said ester group consists of an alkyl qroup containina 1 to
6 carbon atoms this may be substituted, in any but the
~-position, by a hydroxy, alkoxy, amino, alkylamino,
dialkylamino, 1,3-dimethylxanthin~7-yl, alkanolyoxy, aroyl-
oxy, aralkanoyloxy or pyridine-carbonyloxy group or by
two hydroxy groups - except in the case of any methyl
or methylene aroup in the above cases, which can only
be substituted by one hydroxy aroup or bv a aroup of
formula


B - CO - N - A ~


R5 R1 \ R2

_ 4 _ 1~7624~

wherein A~ B~ Rl, R2, R3~ R4 and R5 are as hereinbefore
defined whereby each alkyl part of the above alk~l ester
substitutents ~ycontain from 1 to 3 carbon atoms), and
salts thereof.
The new compounds posses~ interesting ~harmacoloaical
properties, especially in qeneral an e~fect an inter-
medlary metab~lism and in particular a blood-su~ar lowerin~
activity.
~ or ~harmaceutical use, the salts referred to above
will of course be physiolo~ically compatible salts formed
with acids or ~ases, but other salts may find use in the
preparation of the compounds of formula I and the~r
physiologically compatible salts. The term "sa~ts
formed with acids or bases" inclu~es salts formed with
inor~anic or or~anic acids or bases.
The invention extends to all ~ossible iso~ers,
including optional isomers, of compo~nds of formula I.
Rl and R2 together with the nitroqen atom ma-~ represent
for example, dimethylamino, diethylamino,di~ropyl~no, dibutyl~no
diisobutylamino, dipentylamino, dihexylamino, N-methyl-
N-ethylamino, N-methyl-N-propylamino, N-isopropyl-N-
propylamino, N-isobutyl-N-propylamino, N-methyl-N-iso-
propyla~ino, N-methyl-N-butylamino, N-ethyl-N-butylamino,
N-ethyl-N-isopropylamino, N-ethyl-N-pentylamino,
N-propyl-N-butylamino, N-methyl-N-cyclopentylamino,
N-ethyl-N-cyclopentylamino, N-methyl-N-cyclohe~ylamino,
N-ethyl-N-cyclohexylamino, N-propyl-N-cyclohexylamino,
N-isobutyl-N-cyclohexylamino, pyrrolidino, piperidino,
he~amethyleneimino, heptamethyleneimino, octamethylen-
imino, nonamethyleneimino, decamethyleneimino, dimethyl_
azetidino, methyl-pyrrolidino, dimethyl-pyrrolidino,
ethyl-pyrrolldino, methyl-piperidi~o, dimethyl-piperidino J
ethyl-piperidino, di~thyl-piperidino, methyl-ethyl-piperi-
dino, propyl-piperidino, methyl-propyl-piperidino, iso-
propyl-piperidino, cis-3,5-dimethyl-piperidino, tr~ns-
3,5-dimethyl-piperidino, morpholino, thiomorpholino,
piperazino, N-methyl-piperazino, N-ethyl-piperazino,

1 176246

N-propyl-piperazino, N-isopropyl-piperazino, N-benzyl-
piperazino, N-(2-phenyl-ethyl)-piperazino, N-(3-phenyl-
propyl) piperazino, N-phenyl-piperazino, N-fluorophenyl-
piperazino, N-chlorophenyl-piperazino, N-bromophenyl-pipera-
zino, hydroxy-pyrrolidino, hydroxy-piperidino, hydroxy-hexamethy~
leneimino, pyrrolidone-1-yl, piperidone-1-yl, hexahydroazepino-
ne-1-yl, tetrahydro-isoquinoline-2-yl, octahydro-isoquinoline-
2-yl, decahydro-iso~uinoline-2-yl, dihydro-isoindole-2-yl,
hexahydro-isoindole-2-yl, octahydro-isoindole-2-yl,
tetrahydro-3-benzazepine-3-yl, decahydro-3-benzazepine-
3-yl, 3-aza-bicyclo ~ .2._7heptane-3-yl, 3-az~-bicyclo-
.2. ~ octane-3-yl, 3-aza-bicyclo ~ .3.3 nonane-3-yl,
1,4-dioxa-7-aza-spîro ~ , g nonane-7-yl, 1,4-dioxa-7-aza-
spiro ~ ,~ decane-7-yl, 1,4-dioxa-8-aza-spiro ~ , ~ decane-
8-yl, 1,4-dioxa-8-aza-spiro ~ , 0 undecane-8-yl, pyrrolino
or tetrahydropyridine group;
R3 may represent, for example, a hydroaen,
fluorine, chlorine, bromi.ne or iodine atom, or
a methyl, eth~l, pro~yl, iso~ropyl, hydroxy, methoxy,
2~ ethoxy, propoxy, isopropoxy, acetoxy, propionyloxy,
mercapto, methylmercapto, ethylmercapto, propylmer-
capto, isopropylmercapto, trifluoromethyl, nitro,
cyano, formyl, acetyl, propionyl, aminosul~onyl,
amino, methylamino, ethylamino, propylamino, di-
methylamino, diethylamino, dipropylaminc, diisopropyl-
amino, N-methyl-N-ethyl-amino, N-methyl-N-isopropyl-
~mino, N-ethyl-N-propylamino, formylamino, acetylamino,
propionylami~o, methylsulfonylamino, ethylsulfonyl-
amino, propylsulfonylamino, isopropylsulfonylamino,
carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycar-
bonyl, isopropoxycarbonyl, methoxycarbonylamino, ethoxy_
carbonylamino, propoxycarbonylamino, isopropoxy-
carbonylamino, ben~oylamino, benzyloxy, 1-phenyl-
ethoxy, 2-phenyl-ethoxy, 3-phenyl-propoxy, aminocar-
bonyl, methylaminocarbonyl, ethylaminocarbonyl, iso-
propylaminocarbonyl, dimethylaminocarbonyl, diethyl-
aminocarbonyl, dipropylaminocarbonyl, methyl-ethyl-


~ 176246
aminocarbonyl, or methyl-propylaminocarbonyl group;
R4 may represent a hydrogen atom, or a methyl, ethyl, propyl
or an isopropyl group;
R5 may represent a hydrogen, fluorine, chlorine, bromine or an
iodine atom, or a methyl, ethyl, propyl or an isopropyl group;
A may represent, for example, a single bond, or a methylene,
ethylidene, ethyl-methylene, isopropyl-methylene, dimethyl-
methylene, diethyl-methylene, dipropyl-methylene, methyl-ethyl-
methylene, methyl-propyl-methylene, ethyl-propyl-methylene,
ethyl-isopropyl-methylene, ethylene, methyl-ethylene, ethyl-
ethylene, propyl-ethylene, dimethyl-ethylene, cyclopropyl-methvlene,
cyclobutyl-methylene, cyclopentyl-methylene, cyclohexyl-methylene,
cycloheptyl-methylene, cyclopropylidene, cyclobutylidene,
cyclopentylidene, cyclohexylidene, cycloheptylidene, carboxymethy-
lene, methoxycarbonyl-methylene, ethoxycarbonyl-methylene,
propoxycarbonyl-methylene, hydroxymethyl-methylene, l-hydroxyethyl-
methylene, 2-hydroxyethyl-methylene, l-hydroxypropyl-methylene, 3-
hydroxypropyl-methylene, phenyl-methylene, vinylidene, methyl-
vinylidene, cyclopentyl-vinylidene, cyclohexyl-vinylidene,
cyclopropylidene-methylene, cyclopentylidene-methylene,
cyclohexylidene-methylene or cycloheptylidene-methylene group;




,~

- 7 - 1176246

R may represent, for exam~le, a methylene, ethylene, ethyl-
idene, propyl-methylene or isopropyl-methylene aroup; and
may represent, for example, a hydroaen, chlorine, bromine
or iodine atom, or a methyl, ethvl, ?ropyl, isopro~yl, hydroxy-
methyl, l-hydroxyethyl, 2-hydroxyethyl, l-hydroxyPropyl,
3-hydroxypropyl, carboxymethyl, 1-carboxyethyl, 2-carb-
oxy~thyl, 3-carboxy-propyl, methoxycarbonyl-methyl,
ethoxycarbonyl-methyl, propoxycarbonyl-methyl, 2-meth-
oxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 3-ethoxy-
carbonylpropyl, bi~-(methoxycarbonyl)-methyl, bis-(ethoxy-
carbonyl)-methyl, 2,2-bi 5-( ethoxycarbonyl)-ethyl,
carboxy-~inyl, carboxy-propenyl, carboxy-pentenyl,
~etho~ycarbonyl-vinyl, ethoxycarbonyl-~inyl, propoxy-
carbonyl-vinyl, formyl, acet~l, propionyl, dimethoxy-
methyl, diethoxy-methyl, dipropoxy-methyl, trimethoxy-
methyl, triethoxy-methyl, 1,2-ethylenedioxy-methyl,
1,3-prop~lenedioxy-mothyl, cyano, nitro, amino, formyl-
amino, aceta~ino, propionylamino~ 1,3-oxazoline-2-yl,
aminocarbonyl, methyla~inocarbonyl, ethylaminocarbonyl,
propylaminocarbonyl, isopropylaminocarbonyl, butylamino-
carbo~yl, dimethylamlnocarbonyl, diethylaminocarbo~yll
dipropylaminocarbonyl, dibutylaminocarbonyl, pyrrolidino-
carbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl,
hepta~ethyleneiminocarbonyl, morphol~nocarbonyl, carboxy,
methoxycarbonyl, ethoxyc~rbonyl, propoxycarbonyl, iso-
propoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl,
pentoxycarbonyl, hexoxycarbonyl, heptoxycarbonyl, octoxy-
carbonyl, allyloxycarbonyl, butenyloxycarbonyl~ benzyl-
oxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxy-
carbonyl, 3-phenylpropoxycarbonyl, 2-hydroxyethoxy-
carbonyl, 2-hydroxypropoxycarbonyl, 3-hydroxypropoxycar-
bonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl,
(2,2-dimethyl-dioxolane-4-yl)-methoxycarbonyl, 2-(2,2-di-
methyl-dioxolane-4-yl)-ethoxycarbonyl, (2,2-diethyl-dioxo-
lane-4-yl)-methoxy-carbo~yl, 2-(2,2-diethyl-dioxolan-4-yl)-
ethoxycarbonyl, 3-(2,2-dimethyl-dioxolane-4-yl)-propoxy-
carbonyl, 2-aminoethoxycarbonyl, 2-dimethylamino-
ethoxycarbonyl, 2-diethylamino-ethoxycarbonyl, 2-(1,3-di-
methyl-xanthine-7-yl)-ethoxycarbonyl, 2-acetoxy-ethoxy-

2 4 6

carbonyl~ 2-benzyloxy-ethoxycarbonyl, 2-phenylacetoxy-ethoxycarbonyl,
2-pyridinecarbonyloxy-ethoxycarbonyl, 2,3-dihydroxy-propoxycarbonyl,
3,4-dihydroxy-butoxycarbonyl, 2-[4-[(1-(2-piperidino-phenyl)-ethyl)-
aminocarbonylmethyl]benzoyloxy]ethoxycarbonyl or 3-[4-[(1-(2-
piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoyloxy]propoxy-
carbonyl group.
Preferred compounds of the above general formula I are,
however, those wherein Rl and R2 together with nitrogen atom to
which they are attached represent a dialkylamino or N-alkyl-

cyclohexylamino group, wherein each alkyl part may contain from1 to 4 carbon atoms, an unbranched alkyleneimino group containing
3 to 6 carbon atoms (optionally substituted by one or two methyl
groups)/ a hydroxypiperidino, piperidone-1-yl, tetrahydro-pyridino,
morpholino, thiomorpholino, N-methylpiperazino, N-benzyl-piperazino,
N-chlorophenyl-piperazino, heptamethyleneimino or octamethylene-
imino group, a saturated or partly unsaturated azabicycloalkyl group
containing 7 to 9 carbon atoms, an unbranched alkyleneimino group
containing 4 to 6 carbon atoms wherein one ethylene group is
replaced by a o-phenylene group, or a 1,4-dioxa-aza-spiro-alkyl
group containing 7 or 8 carbon atoms;
R3 represents a hydrogen, fluorine, chlorine, bromine or iodine
atom, or a methyl, trifluoromethyl, hydroxy, methoxy, benzyloxy,
acetoxy, mercapto, methylmercapto, nitro, amino, dimethylamino,
acetylamino, methylsulfonylamino, benzoylamino, ethoxy-
carbonylamino, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl,
aminocarbonyl, acetyl or aminosulfonyl group;
R4 represents a hydrogen atom ox a methyl group;
R5 represents a hydrogen atom, a chlorine atom or a methyl group;




~ -8-
.~

1 1~6246
A represents a bond, or a methylene group (optionally substituted
by methyl, ethyl, isopropyl, phenyl, cyclohexyl, carboxy,
methoxycarbonyl or a hydroxymethyl group), a dimethyl-methylene,
cyclopropylidene or ethylene group or a vinylidene group of
formula
C

--C
wherein R6 and R7, which may be the same or different, each
represents a hydrogen atom or one of the radicals R6 and R7
represents a methyl group and the other is as defined above, or
R6 and R7 together with the carbon atom to which they are attached
represent a cycloalkylidene radical containing 1 to 3 carbon atoms;
B represents a methylene, ethylidene or ethylene group; and
W represents a hydrogen atom, or a methyl, ethyl, hydroxymethyl,
cyano or carboxyvinylene group, an alkyl group containing 1 to 3
carbon atoms substituted by a carboxy group or by one or two
alkoxycarbonyl groups containing 2 to 4 carbon atoms each, a
carbonyl group (substituted by a hydrogen atom, a methyl, ethyl,
hydroxy alkoxy, (2,2-dimethyl-dioxolane-4-yl)-methoxy, benzyloxy,
pyridyl-methoxy, amino, alkylamino, dialkylamino, piperidino or
morpholino group), whereby any alkyl part in the aforementioned
groups may contain from 1 to 3 carbon atoms, or a group of formula
o
- C - O - (CH2)n 8
wherein n is 2, 3, or 4; and
R8 represents a hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy,
pyridinecarbonyloxy group, a dialkylamino group containing
1 to 3 carbon atoms in each alkyl part, a 1,3-dimethyl-


_g _

l 17824G
xanthine-7-yl group or a group of formula



/ Z~ ~B - CO - N - A ~ 3
N




R5 / \



wherein A, s, Rl, R2, R3, R4 and R5 are as hereinbefore defined;
and especially those compounds of general formula I wherein the
radical

R




\ R




is in the 2-position and the radical W is in the 4'-position.
Especially preferred are compounds of general formula Ia


A - N - CO - CH2 ~ - W

3 ~ ~ R ,(I~)




wherein Rl and R2 together with the nitrogen atom to which they
are attached, represent a dimethylamino, pyrrolidino, methyl-

pyrrolidino, piperidino, methylpiperidino, dimethylpiperidino,
tetrahydro-pyridino, 2-octahydroisoindolo or hexamethyleneimino
group; R3 represents a hydrogen, fluorine or a chlorine atom or a
methyl group;
A represents a methylene group (optionally substituted by a
cyclohexyl, phenyl, methoxycarbonyl, ethoxycarbonyl, methyl,
ethyl or isopropyl group), or a dimethylmethylene group or a



',~ -1 ~-

1 17~24~

vinylidene group of formula
C

C
wherein R6 and R7 each represents a hydrogen atom or together with
the carbon atom to which they are attached represent a
cyclohexylidene group; and W represents a methyl, hydroxymethyl
or a carboxymethyl group, or




-lOa-

1 i762~6

a carbonyl group (substituted by a hydro~en atom, a methyl,
hydroxy, methoxy, ethoxy, propoxy, isopropoxy~ 2-hydroxyethoxy,
2-methoxyethoxy, (2,2-dimethyl-dioxolane-4-yl)-methoxy,
or a 2--diethvlaminoethoxv qroup).
The compounds of formula I may, for examPle, be
prepared by the following processes, which ~rocesses constitute
further features of the present invention:
a) Acylation of an amine of general formula II
R4
~ A - N ,(II)

3 ~ J
~X, 1
N ~R




wherein A, Rl, R2, R3 and R4 are as hereinbefore defined,
(or if A represents one of the above mentioned vinylidene
groups one of its tautomers~or its lithium or
magnesium halide complex) with a carboxylic acid of
general formula III

HOOC- B ~ ,(III)
R5

wherein R5 and B are as hereinbefore defined and rA~ represents
W as hereinbefore defined or represents a carboxvl ~roup
protected by a protective radical, or with reactive
derivatives thereof optionally ~repared in the reaction
mixture.
Suitable reactive derivatives of a compound of aeneral
formula III include, for example, esters (such as the
methyl, ethyl or benzyl ester), thioesters (such as the
methylthio or ethylthioester), halides (such as the
acid chloride~, anhydrides or imidazolides thereof.
The reaction is convenientlv carried out in a solvent,
such as for example methylene chloride, chloroform, carbon
tetrachloride, ether, tetrahydrofuran, dioxan, benzene,

- 12 ~ 6 2 4 ~

toluene, acetonitrile or dimethylformamide, optionally
in the presence of an acid-activatina or a dehvdratina a~ent,
(e.a. in the presence of ethyl chloroformate, thionvl
chloride, phosphorous trichloride, phosphorus pentoxide,
N,N'-dicyclohexylcarbodiimide, N,N-dicyclohexvlcarbodiimide/N-
hydroxy-succinimide, N,N'-carbonyldiimidazole, N,N'~
thionyldiimidazole, or triphenyl phosphine/carbon
tetrachloride), or of an a~ent activatin~ the amino ~roup
(e.g. phosphorous chloride) and optionally in the presence
of an inorrsanic base such as, for example, sodium carbonate
or a tertiary or~anic base such as triethyl-amine or
pyridine, which simultaneously may serve as a solvent,
at temperatures between -25 and 250C, preferably, however,
at temperatures between -10C and the boilin~ temperature
of the used solvent. The reaction mav also be carried
out without a solvent. Furthermore, the water which
is formed during the reaction may be removed by
azeotropic distillation (e.g. bv heatina with toluene in
a water separator funnel) or by addition of a dryina a~.~ent
such as maanesium sulfate or a molecular sieve.
If necessary, the subse~suent removal of a ~rotective
radical is preferably carried out hydrolytically,conveniently
in the presence of either an acid (such as, for example,
hydrochloric, sulfuric,phosphoric or trichloroacetic acid)
or a base such as sodium hydroxide or potassium hydroxide
in a solvent such as for examnle water, methanol, ethanol,
ethanol/water, water/isopropanol or water/dioxan at
temperature between -10 and 120C, e.a. at temperatures
between room temperature and the boilina temperature
3~ of the reaction mixture. A tert.hut~l radical used as
protective radical may also be removed thermolytically
(optionally in an inert solvent such as methylene
chloride, chloroform, benzene, toluene, tetrahydrofuran
or dioxan) and preferably in the presence of a catalytic
3~ amount of an acid such as,for example, p-toluenesulonic,
sulfuric, phosphoric or polyphosphoric acid.
Furthermore, a benzyl radical used as protective
radical may also be removed ilydro~enolytically
(in the presence of a hydroaenation catalyst such as

1 17624~
- 13 -

palladium/charcoal) in a solvent such as, for example,
methanol, ethanol/water, glacial acetic acid, ethyl
acetate, dioxan or dimethyl formamide.
b~ For the preparation of compounds o.f general formula
I, wherein W represents a carboxy group:
Cleavage of a compound of aeneral formula IV
R




~ A - N - CO - B ~ D


R~ ~ ~ R2 R5 ,(IV)


wherein Rl, R2, R3, R4, P~5, A and B are defined as mentioned
before and D represents a aroup which
nay be converted into a carboxy group by means of
hydrolysis, thermolysis or hydrogenolysis.
Suitable hydrolysable aroups include, for example,
carboxy derivatives (such as unsubstituted or substituted
amides, esters, thioesters, orthoesters, iminoethers,
1~ amidines or anhydrides), a nitrile group, a malonic ester-
tl)-yl group, a tetrazolyl group or an optionally
substituted 1,3-oxazole-2-yl or 1,3-oxazoline-2-yl group.
Suitable thermolytically cleavable groups include,
for example, esters with tertiary alcohols, e.g. the tert.
butyl ester.
Suitable hydrogenolytically cleavable qroups include,
for example, aralkyl groups, e.g. the benzvl aroup.
The hydrolysis is conveniently carried out either
in the presence o~ an acid (such as for example,
hydrochloric,sulfuric, phosphoric or trichloroacetic acid)
or a base (such as sodium hydroxide or potassium hydroxide)
in a solvent such as, for example, water/methanol, ethanol,
water/ethanol, water/isopropanol or water/dioxan at

- 14 - 117624~

temperatures between -lO and 120C, e.a. at temperatures
between room temperature and the boiling temperature of
the reaction mixture.
Thus if, for example, D in a compound of general
formula IV represents a nitrile or aminocarbonyl group,
these groups may be converted into a carboxy group
with a nitrite, e.a. sodium nitrite, in the presence of
an acid (such as sulfuric acid~, whereby conveniently
this acid is simultaneously used as a solvent, at
temperatures between 0 and 50C; if for example , D
represents a tert.butyloxycarbonyl group, the tert.butyl
group may be split off thermolytically (optionally in an
inert solvent such as methylene chloride, chloroform,
benzene, toluene, tetrahydrofuran or dioxan~ and
preferably in the presence of a catalytic amount of an
acid such as p-toluenesulfonic, sulfuric, phosphoric
or polyphosphoric acid preferably at the boilina
temperature of the used solvent, e.g. at temperatures
between 40 and 100C; or if for example D represents a
benzyloxycarbonyl group, the benzyl aroup may be split
off hydroaenolytically in the presence of a hydro~enation
catalyst such as palladium/charcoal in a solvent such as
for example, methanol, ethanol, ethanol/water, glacial
acetic acid, ethyl acetate, dioxan or dimethyl formamide
preferably at temperatures between 0 and 50C, e.a.
at room temperature, and at a hydroaen pressure of 1 to
5 bar. During the hydrogenolysis other qroups may
optionally simultaneously be reduced, e.g. a halogen
compound may be dehalogenated, a nitro aroup may be
converted into the corresponding amino group, or a vinvli-
dene group into the corresponding alkylidene group .
c) Reaction of a compound, optionally formed in the
reaction mixture, of general formula V


3 ~ 4 ~ 5

N - R '

- 15 ~ 62~5

wherein R3, R4, R5, A, B, and W are as hereinbefore
defined and, R2' represents a hydrogen atom or has the
meanings mentioned before for R2, with a compound of general
formual VI
Rl' - E (VI)
[wherein Rl' has the meanings mentioned before for Rl or
together with the radical R2' of formula V represents a
straight-chained alkylene group containing 4 to 6 caxbon
atoms (optionally substituted by one or two alkyl aroups
containing 1 to 3 carbon atoms) or an n--pentylene group
in which the third methylene aroup is replaced by an oxygen
or sulfur atom, and E represents a nucleophilically
exchangeable aroup such as a halogen atom or a sulfonyloxy
aroup (e.g. a chloxine, bromine or an iodine atom or a
15 methanesulfonyloxy or p-toluenesulfonyloxy group), or
also a hydrogen atom if in Rl' one methylene group is
replaced by an aldehyde or ketone carbonyl group], if
necessary in the presence of a reducina agent,and optional
subsequent hydrolysis.
Suitable alkylating agents of formula VI include,
for example, the corresponding halides or sulfates such as
methyl iodide, ethyl iodide, propyl bromide, dimethyl sulfate
or diethyl sulfate.
The reaction is conveniently carried out in a solvent
such as,for example, acetone, tetrahydrofuran, dimethyl
formamide, dimethylsulfoxide or hexamethyl phosphoric acid
triamide, optionally in the presence of an inoraanic base
(such as sodium carbonate, potassium carbonate or potassium
tert.butylate) or tertiary oraanic base (such as pyridine)
at temperatures between 0 and 150C; preferably, however,
at temperatures between 20 and 75C. If a compound of
general formula V is used wherein W represents a carboxyl
group, this carboxyl group may simultaneously be converted
into the correspondina ester depending on the reaction
conditions, e.g. at temperatuxes above room temperature
and in the presence of a base, for example sodium
carbonate.
The methylation may optionally also be carried out

- 16 -
1 1~62~
so that a compound of aeneral formula V is reaeted with
formalin in the presenee of a reducina aaent, e.a. formic
aeid or hydroqen in the presenee of a hydrogenation eatalyst
(e.q. palladium or platinum), optionally in a solvent such
as formie acid or alacial acetie aeid at temperatures up
to the boiling temperature of the reaction mixture.
Moreover, the alkylation may oPtionally also be
carried out with a corresponding carbonyl compound in the
presence of a hydride such as sodium cyanoborohydride
in a solvent such as for example acetonitrile/glacial acetic
aeid or dimethyl formamide/aeetic aeid preferably at pH
7 and at temperatures between 0 and 50C.
The subsequent hydrolysis is preferably earried out
in an aqueous solvent sueh as water/methanol, water/ethanol
or water/dioxan in the presenee of an aeid (sueh as
hydroehlorie or sulfuric acid) or a base (such as sodium
or potassium hydroxide) at temperatures between 50 and
1 0 0 C .
d) For the preparation of compounds of general formula
I wherein W represents a carboxy aroup, an alkanoyl aroup
eontaining 1 to 3 earbon atoms or an alkyl group containing
1 to 3 carbon atoms:
Reaction of a compound of general formula VII

A - N - C0 - ~ ~ ,(VII)
N
R2




wherein Rl, R2, R3, R~, R5, A and B are as hereinbefore
defined, with phosaene, an oxalyl halide, an alkyl or
alkanoyl halide containing 1 to 3 carbon atoms in the
alkyl part or with hydrogen cyanide and a hydroaen
halide (preferably hydrogen chloride), in the presence
of a ~ewis acid.
Suitable halides inelude ehlorides and bromides, and

- 17 - 117624~

the L.ewis acid is preferably aluminium chloride.
The reaction is preferably carried out in a solvent
such as methylene chloride, nitrobenzene, chlorobenzene,
dichlorobenzene, tetrachloroethane or carbon disulfide or
in polyphosphoric acid at temperatures between 0 and 120C,
preferably, however at temperatures between 20 and 80C.
If in a compound of,general formula VII,R3 represents a
hydrogen atom, this may simultaneously be replaced by a
corresponding alkyl or acyl radical.
e) For the preparation of compounds of general formula
I wherein W represents a carbox~ group;
Reaction of a compound of general formula VIII


R3 ~ A - - CO - B ~ COCH3
N
~ R2




wherein Rl, R2, R3, R4, R5, A and ~ are as hereinbefore
defined, with a hypohalite optionally prepared in the
reaction mixture. The reaction is conveniently carried
out in a solvent ~such as for examnle water/tetrahydrofuran
or water/dioxan) and in the presence of a base (such
as sodium hydroxide or potassium hydroxide) at temperatures
between 0 and 80C; preferably, however, at temperatures
between 25 and 50C.
f) For the preparation of compounds of general formula
I wherein W represents a carboxy group:
Oxidation of compound of general formula IX

R3 ~ R4 ~ ,(IX)
N
~ R2

- 18 - ~ 17~4~

wherein Rl, R2, R3, R4, R5, A and B are as hereinbefore defined
and G represents a aroup which may be converted by means of
oxidation into a carboxy group.
Such an oxidizable group includes for example a
formyl group or one of its acetals, a hydroxymethyl aroup
or one of its ethers, or an unsubstituted or substituted
acyl group ( such as an acetyl, chloroacetyl, propionyl,
malonic acid-(l)-yl qrou~ or a malonic ester-(l)-yl aroup).
The reaction is carried out by means of an oxidizing
agent in a solvent ~such as for example water, alacial acetic
acid, pyridine or carbon tetrachloride) at temperature between
0 and 100C, conveniently, however, at temperatures between
20 and 50C. The reaction is preferably carried out 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 or chromium trioxide/pyridine.
g) For the preparation of compounds of aeneral formula
I, wherein R3 represents a nitro aroup:
Reaction of a compound of general formula X
R




4 ~ W
3 ~ A - N - CO - B ~ ,(X)




(wherein R4, R5, A, B and W are as hereinbefore defined,
R3 represents a nitro qroup and Y represents a nucleophilically
exchanaeable radical such as a haloaen atom) with an amine
of general formula XI

H - ~ ,(XI)
--R2

- 19 ~ 762~

(wherein Rl and R2 are defined as mentioned before), and
optional subse~uent hydrolysis.
The term "a halogen atom" used in the definition
of the exchangeable radical Y particularly represents a
S fluorine, chlorine or a bromine atom, and preferably in the
o- or p-position relative to the nitro group.
The reaction is conveniently carried out in a
solvent such as for example, water, water/methanol, water/
ethanol, water/isopropanol, water/dioxan, methanol,
ethanol, dimethyl formamide, or in an excess of the amine
of general formula XI and/or the N-formyl derivate thereof
~optionally in the presence of an inorganic or tertiary
organic base), optionally in the presence of a reaction
accelerator such as copper or a copper salt and optionally
in a closed vessel at temperatures between 20 and 150C;
preferably, however at the boilin~ temperature of the
reaction mixture (e.g. at 100C~. The reaction may,
however, be carried out without a solvent.
The optional subsequent hydrolysis is conveniently
carried out in an aqueous solvent such as for example
methanol/water, ethanol/water or dioxan/water in the
presence o an acid (such as hydrochloric or sulfuric acid)
or a base such as sodium or potassium hydroxide at
temperatures ketween 50 and 100C.
h) For the preparation of compounds of general formula
I, wherein A represents a group of formula

6 / R7
CE~
I




- CH -

wherein R6 and R7 are as hereinbefore defined:
Reduction of an enamide of general formula XII

I 17&245


R R
6~ ~, 7
3~ ~Rl , (XII)


R




1' 2' R3, R4, R5, R6 ~ R7, B and W are as hereinbefore
defined.
The reduction is preferably carried out with hydrogen in
the presence of a hydrogenation catalyst such as palladium/charcoal
or platinum in a solvent such as for example methanol, ethanol,
isopropanol, ethanol/water glacial acetic acid, ethyl acetate,
dioxan, tetrahydrofuran, dimethyl formamide, benzene, or
benzene/ethanol at temperatures between 0 and 100C, preferably,
however at temperatures between 20 and 50C, and a hydrogen pressure
of 1 to 5 bar. When using a chiral hydrogenation catalyst such
as a transition metal 1T-complex, e.g. a complex made from
rhodium chloride and (+) or (-) 0,0-isopropylidene-2,3-dihydroxy-
1,4-bis-(diphenylphosphino)-butane (=DIOP), the hydrogenation is
effected enantioselectively. Moreover, other reduceable groups
may be reduced during the catalytic hydrogenation, e.g. a nitro
group to an amino group or a chlorine or a bromine atom to a

hydrogen atom.
i) For the preparation of compounds of general formula I,
wherein R4 represents a hydrogen atom and A represents a methylene
or ethylene group (optionally substituted by a methyl, ethyl or
isopropyl group), a methylene or ethylene group substituted by




--20--

1 ~7~245
two alkyl groups containing 1 to 3 carbon atoms each, a methylene
group (substituted by a cycloalkyl group containing 3 to 7 carbon
atoms, by a carboxyl, alkoxycarbonyl, or phenyl group, whereby
each of the aforementioned alkyl parts may contain from 1 to 3
carbon atoms), or a cycloalkylidene group 4 to 7 carbon atoms:
Reaction of a compound of general formula XIII


R3~ A' - OH

N.~Rl , (XIII)

\R2
[wherein ~1' R2 and R3 are as hereinbefore defined and A'
represents a methylene or ethylene group (optionally substituted
by a methyl, ethyl or isopropyl group), a methylene or ethylene
group substituted by two alkyl groups containing 1 to 3 carbon
atoms each, a methylene group (substituted by a cycloalkyl group
containing 3 to 7 carbon atoms, carboxyl, alkoxycarbonyl, or
phenyl group, whereby each of the above mentioned alkyl parts may
contain from 1 to 3 carbon atoms), or a cycloalkylidene group
containing ~ to 7 carbon atoms], with a compound of general
formula XIV


N:- C - B ~
R5 , (XIV)


wherein R5, s and W are as hereinbefore defined.

The reaction is carried out in the presence of a strong
acid, which simultaneously may serve as solvent, preferably in




~ -21-

l 17~24¢
concentrated sulfuric acid, at temperatures between 20 and 150C,
preferably at temperatures between 80 and 100C.
According to a further feature of the present invention,
a compound of general formula I thus obtained wherein W represents
the carboxy group, may if desired, subsequently be converted into
a corresponding compound of general formula I wherein W represents
an ester or amide




-21a-

1 ~76246
- 22 -

group by esterification or amidation and/cr- a compound
of general formula I wherein R3 and/or W represent(s) a
nitro group, may subsequently be converted by reduction
into a corresponding compound of aeneral formula I wherein
R3 and/or W represent(s) an amino group; and/or
a compound of general formula I wherein R3 and/or W re-
present(s) amino group, may subsequently be converted via
a correspondina diazonium salt into a corresponding compound
of general formula I wherein R3 represents a hydrogen or a
halogen atom, a hydroxy, alkoxy, mercapto, alkylmercapto,
chlorosulfonyl, or cyano group and/or W represents a hydrogen
or a halogen atom or a cyano aroup. O?tionally a compound
of general formula I thus obtained, wherein R3 represents
a hydroxy group, may subsequently be converted by
alkylation into a corresponding compoun~ o~ ~eneral formula
I wherein R3 represents an alkoxy aroup, or a compound of
formula I thus obtained, wherein R3 represents a chlorosulfonyl
group, may subsequently be converted by ammonia into a corresponding
compound of qeneral formula I wherein R3 represents an
aminosulfonyl group; and/or a compound of general formula
I wherein R3 represents an amino group may subsequently
be converted by means of acylation into a correspondina
compound of aeneral formula I wherein R3 represents an
alkanoylamino, aroylamino, alkoxycarbonylamino or an
alkylsulfonylamino group; and/or a compound of general
formula I wherein R3 represents an amino aroup may
subsequently be converted by means of alkylation into a
correspondina compound of general formula I wherein R3
represents an alkylamino or a dialkylamino group; and/or
a compound of general formula I wherein R3 represents a
chlorine or a bromine atom may subsequently converted
by means of dehalogenation into a correspondina compound
of general formula I wherein R3 represents a hydrogen
atom; and/or a compound of general formula I wherein R3
represents a nitrile group may subsequently be converted
by means of hydrolysis or alcoholysis into a correspondinq
compound of general formula I, wherein R3 represents an
aminocarbonyl, carboxy or an alkoxycarbonyl aroup;
and/or a compound of general formula I wherein R3

1 ~7624~
- 23 -

represents a carboxy or alkoxycarbonyl aroup and/or W
represents an(optionally esterifie~)carboxy aroup may
subsequently be converted by means of reduction into a
correspondina compound of cteneral formula I wherein R3
S and/or W represents a formyl or hydroxymethyl aroup;
and/or a compound of general formula I wherein W represents
an alkoxycarbonyl aroup (wherein the alkoxy aroup may
contain from 2 to 6 carbon atoms) substituted in any but
the ~-position by a hydroxy aroup may be converted into
a compound of general formula I wherein the said hvdroxy
group is replaced by an acyloxy group, by acylation;
and/or a compound of general formula I, wherein T^~ represents
a hydroxymethyl aroup may subsequently be converted (via
a correspondina halomethyl compound) by reaction with a
malonic acid diester, into a correspondina compound of
general formula I wherein W represents an ethvl group
substituted by two alkoxycarbonyl arours; and/or a
compound of general formula I wherein W represents a formyl
group 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 vinyl aroup substituted by a hydroxycarbonyl
or alkoxycarbonyl group; and/or a compound of general formula
I wherein W represents an ethyl group substituted by two
alkoxycarbonyl groups may subsequently be converted by
hydrolysis and decarboxylation into a correspondin~
compound of aeneral formula I wherein W represents an ethyl
group substituted by a carboxy group; and/or a compound
of general formula I wherein W represents a carboxy group.
may subsequently be converted via a sulfonic acid
hydrazide and subsequent disproportionation into a
correspondina compound of general formula I wherein W
represent a formyl aroup; and/or a compound of qeneral formula
I wherein Rl and R2 together with the ni.troaen ato~ to
which they are attached represent an aza-1,4-dioxa-spiro-alkyl
group containina 6 to 8 carbon atoms, may subsequently be
converted by means of hydrolysis in the presence of an
acid into a corresponding compound of aeneral formula I

l 1~624~
- 24 -
wherein ~l and ~2 toaether with the nitroaen atom to which
they are attached represent an unbranched alkyleneimino
group containing 4 to 6 carbon atoms wherein a methylene
group is replaced by a carbonyl qroup; and/or
a compound of aeneral formula I wherein Rl and R2 toaether
with the nitrogen atom to which they are attached represent
an unbranched alkyleneimino group containing 4 to 6 carbon
atoms, wherein a methylene group is replaced by a carbonyl
group, may subsequently be converted by means of reduction
into a corresponding hydroxy-alkyleneimino compound of
aeneral formula I; and /or a compound of general formula
I wherein W represents an aminocarbonyl group may subsequently
be converted by means of dehydratation into a corresponding
compound of general formula I wherein ~T represent a cyano
group.
The dehydratation is preferably carried
out with a dehydratina aqent such as for example phosphorus
pentoxide, sulfuric acid or p-toluene sulfonic acid
chloride optionally in a solven~ such as methylene chloride
or pyridine at temperatures between 0 and 100C, preferably,
at temperaturesbetween 20 and 80C.
The esterification is conveniently
carried out in a solvent, such as, for example, the
corresponding alcohol, pyridine, toluene, methylene chloride,
tetrahydrofuran or dioxan, in the presence of an acid-
activatina and/or dehydratina aaent such as thionyl chloride,
ethyl chloroformate, carbonyl diimidazole, N,N'-dicyclo-
hexylcarbodiimide or the isourea ether thereof, optionally
in the presence of a reaction accelerator such as
copper chloride or by transesterification, e.g. with
a corresponding carbonic acid diester, at temperatures
between 0 and 100C, preferably, however, at temperature
between 20C and the boilina temperature of the
corresponding solven~.
The amidation is conveniently carried
out in a solvent such as methylene chloride, chloroform,
carbon tetrachloride, ether, tetrahydrofuran, dioxan,
benzene, toluene, acetonitrilie or dimethyl formamide,

1 17~24~
- 25 -

optionally in the ~resence of an acid activatin~ agent
or a dehydratina agent, e.~. in the presence of ethyl
chloroformate, thionyl chloride, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexyl carbodiimide,
5 N,N'-dicyclohexyl carbodiimide/N-hydroxy succin-
imide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, or tri
phenyl phosphine/ carbon tetrachloride, or of an agent activa-
ting the amino group, e.g. phosphorus trichloride, and optio
nally in the presence of an i~organic base such as sodium
lO carbonate or a tertiary organic base such as triethylamine
or pyridine, which simultaneously may serve as solvent, at
temperatures between -25 and 250C, preferably, however, at
temperatures between -10C and the boiling temperature of
the used solvent. The reaction may also be carried out without
15 a solvent. ~oreover the water, which is formed during the
reaction, ma~,~ be removed by means of azeotropic distilla-
tion, e.g. by heating with toluene in a water separator funnel,
or by addition of a drying agent such as magnesium sulfate or
a molecular sieve~
( The reduction of the nitro compound is prefer-
ably carried out in a solven'c such as water, water/ethanol,
methanol, glacial acetic acid, ethyl acetate or dimethyl
formamide appropriately wit~ hydrogen in the presence of
a hydrogenation catalyst such as Raney-nickel, platinum
25 or palladium/charcoal, with metals such as iron, tin or
zinc in the presence of an acid, with metal salts such as
iron(II)sulfate, tin(II)ch]oride or sodium dithioniteJ or
with hydrazine in the pre~ence of Raney-nickel at tempera-
tures between 0 and 50C, preferably, however, at room
30 temperatures

The react~on of the diazonium salt, (e.g. the
fluoroborate J the hydrosulfate in sulfuric acid, the hydro-
chloride or the hydroiodide)is carried out9 if necessaryJ
in the presence of copper or a corresponding copper (I) 3alt
35 such as copper (I) chlor:ide/hydrochloric acidJ copper (I)

1 176246
- 26 -

bromide/hydrobromic acid, trisodium copper(l)tetracyanide
at pH 7, or an alkali metal xanthogenate, or copper (II)
chloride/sulfur dioxide in alacial acetic acid optionally
with the addition of magnesium chloride, at slightly
elevated temperatures, e.g. at temperatures between 15
and 100C. The subsequent reaction with hypophosphorous
acid is preferably carried out at -5 to 0C. The diazonium
salt is conveniently prepared in a solvent such as,
for example water/hydrochloric acid, methanol/hydrochloric
acid, ethanol/hydrochloric acid or dioxan/hydrochloric
acid, by means of diazotization of a correspondin~ amino
compound with a nitrite, e.a. sodium nitrite or an ester
of nitrous acid, at lower temperatures, e.g. at
temperatures between -10 and 5C.
The acylation is conveniently carried
out in a solvent such as methylene chloride, ether
tetrahydro'uran or in an excess o.f the used acylating agent
e.g. formic acid, acetic acid or propionic acid. or
their anhydrides, acid chlorides or esters, optionally
in the presence of an inorganic or a tertiary organic base,
which simultaneously may serve as solvent, and optionally
in the presence of an acid-activating agent or of a
dehydrating agent at temperatures between -25 and
150C, preferably, however, at temperatures between -10C
and the boiling temperature of the reaction mixture.
The N-alkylation is conveniently
carried out with a corresponding halide or sul~onic
acid ester, (e.a. methyl iodide, dimethyl sulfate, ethyl
bromide or p-toluenesulfonic acid ethyl ester), optionally
in the presence of a base such as sodium hydride, potassium
hydroxide or potassium tert.butylate and preferably
in a solvent such as for example, diethyl ether,
tetrahydrofuran, dioxan, ethanol, pyridine or dimethyl
formamide, at temperatures between 0 and 75C; preferably,
however, at room temperature. The methylation may, also
be carried out with formalclehyde/formic acid (appropriately
at the boiling temperature of the reaction mixture) and
the alkylation may be carried out with a corresponding

~ 27 ~ 624~

carbonyl compound in the presence of a hydride such as
sodium cyanoborohydride in a solvent such as acetonitrile
acetic acid or dimethyl formamide/acetic acid preferably
at pH 7 and at temperatures between 0 and 50C.
The dehaloaenation is conveniently
carried out in a solvent such as methanol, ethanol,
ethyl acetate, glacial acetic acid or dimethvl formamide
by means of catalytically activated hydrogen, e.~. with
hydrogen in the presence of platinum or palladium/charcoal,
at temperatures between 0 and 75C, preferably, however,
at room temperature, and at a hydrogen pressure of l -
5 bar.
The hydrolysis is conveniently carried
out either in the presence of an acid such as hydrochloric
sulfuric, phosphoric, polyphosphoric or trifluoroacetic
acid or in the presence of a base such as sodium hydroxide
or potassium hydroxide in a solvent such as for example,
water, ethanol, water/ethanol, water/isopropanol or water/
dioxan at elevated temperatures, e.g. at the boiling
temperature of the reaction mixture. The hydrolysis can
however, be also carried out with a nitrite, e.q.
sodium nitrite, in the presence of an acid such as sulfuric
acid, whereby this may conveniently serve simultaneously
as solvent, at temperatures between 0 and 50C. The
subsequent alcoholysis is conveniently carried out in the
presence of a hydrogen halide, e.a. hydrogen chloride,
at tmeperatures between 20C and the boilina temperaute
of the used alcohol.
The reduction is preferably carried
out with a metal hydride, e.a. with a complex metal
hydride such as lithium aluminium hydride, in a
solvent such as, for example, diethyl ether, tetrahydrofuran
or dioxan at temperatures between 0 and 100C, preferably
however, at temperature between 20 and 60C.
The 0-alkylation is conveniently
carried out with a corresponding halide, sulfonic acid
ester or diazoalkane, e.g. with methyl iodide, dimethyl
sulfate, ethyl bromide, p-toluene sulfonic acid ethyl
ester, methanesulfonic acid isopropyl ester or diazomethane

1 ~6246
- 28 -

optionally in the presence of a base such as sodium hydride,
potassium hydroxide or potassium-tert. butylate and
preferably in a solvent such as diethyl ether, tetrahydro-
furan, dioxan, methanol, ethanol, pyridine or dimethyl
formamide at temperatures between 0 and 75C, preferably,
however, at room temperature.
The conversion of a hvdroxymethyl group
into a halomethyl group is carried out with a haloaenating
agent such as for example, thionyl chloride, phosphorus
trichloride, phosphorus tribromide or phosphorus
pentachloride in a solvent such as methylene chloride,
carbon tetrachloride, benzene or nitrobenzene and
subsequent reaction with a malonic acid ester, e.g. with
an alkali salt cf the malonie acid diethyl ester, at
temperatures between 0 and 100C, preferably, however,
at temperatures between 20 and 50C.
The condensation of a formyl compound
is conveniently earried out in a solvent such as pyridine
or tetrahydrofuran with malonic acid, with a malonic
aeid ester, with a dialkylphosphonoacetic acid ester
or an alkoxycarbonylmethylene-triphenyl-phosphone,
optionally in the presence of a base as-a condensation agent,
e.g. in the presence of piperidine, potassium-tert.butylate
or sodium hydride, at temperatures between 0 and 100C-
Py subsequent acidification, (e.a. with hydrochloric orsulfuric acid) or by subsequent alkaline hydrolysis,
the desired acid is obtained.
~ he hydrolysis is decarboxylation is
conveniently carried out in the presence of an acid such
as hydrochloric,sulfuric, phosphoric, polyphosphoric or
trifluoroacetic acid in a solvent such as for example,
water, ethanol, water/ethanol, water/isopropanol or
water/dioxan at elevated temperatures, e.g. at the boiling
temperature of the reaction mixture.
The disproportionation of a sulfonic
acid hydrazide, which is obtained by reacting the correspond-
ing hydrazine with the corresponding reactive carboxylic
acid derivative, is carried out in the presence of a base

- 29 ~ 4~

such as sodium carbonate in a solvent such as eth~lene
glycol at temperatures between 100 and 200C, preferably,
however, at 160 - 170C.
The compounds of aeneral formula I obtained by
the above processes may if desired be converted into their
addition salts, especially into their physiologically
compatible salts with inoraanic or organic acids or
bases by conventional methods such as by reacting the
compounds as bases with a solution of the corresponding
acids in a suitable solvent, or by reactina the compounds
as acids with a solution of the corresponding bases in
a suitable solvent. Suitable acids include, for example,
hydrochloric acid, hydrochloric acid, hydrobromic acid
sulfuric acid, phosphoric acid, lactic acid, citric acid,
tartaric acid, succinic acid, maleic acid and fumaric
acid. Suitable bases include, for example, sodium or
potassium hydroxide and cyclohexylamine.
The compounds of general formula II to XIV used
as starting materials are known from the literature or
may be prepared according to known processes.
Thus, for example,a compound of general formula
II wherein A represents a bond can be obtained by
reduc~ion of the corresponding nitro compound, for
example by means of catalytically activated or nascent
hydroaen or by means of sodium dithionite or bv reaction
of the correspondinq com~ound hv a Hofmann, Curtius,
Lossen, or Schmidt reaction.
For example a compound of general formula II, wherein,
A represents a vinylidene aroup or the tautomeric
ketimine can be obtained by reaction of the corres~ondina
nitrile with the corresponding Grignard or lithium compound
and subsequent hydrolysis or by reaction of the corresponding
ketone with the corresponding amine in the presence of
titanium tetrachloride. ~or further reaction with a
compound of qeneral formula III or its reactive derivatices,
especially acid chlorides, an oraanometallic
complex can be used.

1 17~24~
- 30 -

For example a compound of general formula II,
wherein A does no-t represent a bond or a vinylidene group,
can be obtained by reduction of the corresponding nitrile
with lithium aluminium hydride, by reaction o the
corresponding nitrile with the corresponding Grignard or
Lithium compound and optionally with subsequent lithium
aluminium hydride reduction or subsequent hydrolysis
to the ketimine, which subsequently is reduced with
catalytically activated hydrogen, with a complex metal
hydride or with nascent hydrogen, by hydrolysis or bv
hydrazinolysis of the corresponding phthalimido compound,
by reaction of the corresponding ketone with ammonium
formate and subsequent hydrolysis or with a ammonium salt
in the presence of sodium cyanoborohydride, by reduction
of the correspondina oxime with lithium aluminium hydride,
with catalytically activated or nascent hydrogen, by
reduction of the correspondina N-benzyl or N-l-phenylethyl
Schiff's base, e.g. with a complex metal hydride in ether
or tetrahydrofuran at temperatures between -78 and the
boiling temperature of the used solvent and subsequent
cleavage of the benzyl or l-phenylethyl aroup by means
of catalytic hydroaenation by Ritter reaction of a
correspondina alcohol and potassium cyanide in
sulfuric acid, or by a Hofmann, Curtius, Lossen
or Schmidt reaction. An amine o.f
general formula II thus obtained with a chiral center
can be resolved, e.q. by fractional crystallization of
the diastereoisomeric salts usina optionally active acids
and subsequent decomposition of the salts or by the
formation of diastereoisomeric compounds, their separation
and subsequent resolution into enantiomers. Furthermore,
an optionally active amine of general formula II can also
be prepared by enantioselective reduction of the
corresponding ketimine by means of complex boron or
aluminium hydrides, in which some of the hydride hydrogen
atoms are replaced by optically alctive alcoholate
radicals, or by means of hydroaen in the presence of a
suitable chiral hydrogenation catalyst, or in an analoaous

1 17624~
- 31 -

manner startina from an M~benzyl or optionally
optically active N~l-phenethyl Schiff's base and optionally
subsequent cleavaae of the benzyl or l-phenethyl radical.
A compound of general formula II wherein R4
represents a lower alkyl radical may be ohtained by
reduction of the correspondinq N-acyl compound, e. a .
by means of lithium aluminium hydride.
The compounds of aeneral formulae IV, V, and VII
to X used as starting materials may each be obtained
by reaction of an amine with a carboxylic acid or one of
its reactive derivatives and optional subsequent hydrolysis.
A compound of general formula VIII can be obtained by
Friedel-Crafts acetylation of the corresponding
acetyl-unsubstituted compound.
A compound of general formula XII used as a
starting material can be obtained preferably by acylation
of the corresponding ketimine or tautomeric forms with the
corresponding carboxylic acid or one of its reactive
derivatives.
A compound of aeneral formula XIII used as a start-
ing material can be obtained by reduction of the correspond-
ing carbonyl compound with the corresponding Grignard or
lithium reagent.
The compounds of general formula I posess5 valuable pharmacological properties, and in qeneral show
benefical effects on intermediary metabolism, and
especially, however, a blood-sugar lowering activity.
For example the following compounds have been
tested with regard to their biological properties:

~ ~7624~

- 32 -




A - 4- ~ 2-Pyrrolidino-benzyl)-aminocarbonylmethyl7bcnzoic acid,

B = 4- ~1-(2-Pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid,

C = 4- ~1-(5-Chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid,

D = 4- ~ 2-Piperidino-benzyl)-aminocarbonylmethyl7benzoic acid,

E = 4~ (2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7-
benzoic acid,

F = 4- ~1-(6-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbo-
nylmethyl7benzoic acid,

G = 4- ~1-(6-Methyl-2-piperidino-phenyl)-ethenyl)-aminocarbo-
nylmethyl7benzoic acid,

- ~i3 ~ 62~

H = 4- ~ 1-(2-Piperidino~phenyl)-ethyl)-aminocarbonylmethy~7-
benzoic acid,

I = Ethyl 4-~ 1-(2-Piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl~benzoate,

K = (+)Ethyl 4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl~ benzoate

L = 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
- benzoic acid-(2,2-dimethyl-dioxolane-4-yl)-methyl ester,

M e 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
toluene,

N = 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzyl alcohol,

O z 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzaldehyde,

P = 4- ~1-(2-Piperidino~phenyl)-ethyl)-aminocarbonylmethyl7-
phenyl acetic acid,

Q = 4- ~1-(4-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid,

R = 4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbo-
nyl-methyl7benzoic acid,

S = Ethyl 4-/(1-(6-Chloro-2-piperidino-phenyl)-ethyl)-amino-

carbonylmethylfbenzoate,

T = 4- ~1-(5-Fluoro-2-piperidino-phenyl)-ethyl)-amino-
carbonyl-methy ~benzoic acid,

1 176246
- 34 -

U - 4~ (4-Methyl-2 piperidino-phenyl)-ethyl)-amino-
carbonyl-methyl7benzoic acid,

V = 4- ~1-(5-Methyl-2-piperidino-phenyl)-ethyl)-amino-
carbonyl-methyl7benzoic acid,

W = 4- ~ 2-(2-Piperidino-phenyl)-Z~propyl)-aminocarbonyl-
methyl7benzoic acid,

X = 4- ~1-(2-Piperidino-phenyl)-2-methyl-propyl)-amino-
carbonyl-methy ~ benzoic acid,

Y - 4- ~ 2-Piperidino-benzhydryl)-aminocarbonylmethy ~benzoic
acid,

Z - 4- ~1-(2-(1,2,~,6-Tetrahydro-pyridino)-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid,

AA = 4- ~1-(2-(3-Methyl-piperidino)-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid,

15 AB = 4- ~1-(2-Hexahydroazepino-phenyl)Oethyl)-aminocarbonyl-
methyl7benzoic acid,

AC = 4- ~1-(2-Octahydroisoindolo-phenyl)-ethyl)-aminocarbo-
nyl-methy ~benzo~c acid,

AD = Ethyl 4~ -Methoxycarbonyl-2-piperidino-benzyl)-amino=
carbonylmethy~ benzoate and

AE = (+) 4- L( 1 (2-Piperidino-phenyl)-ethyl)-aminocarbonyl-
methyllbenzoic acid.
1. Blood-sugar lowering activity:

The blood-sugar lowering activity of the test compounds
was determined in home-bred female rats with a weight
of 180 - 220 g. 24 hours before starting the test the
animals were starved. Before the test the compounds were

~ ~62~
suspended in 1.5% methyl cellulose and administered to the animals by means of
an oesophageal tube.


Blood was taken before administering the test compounds as well as at 1J 2, 3 and
4 hours after administration from the retroorbital plexus vein. 50 ~g of each
sample were deproteinized with 0.5 ml of 0.33 N perchloric acid and centrifuged.
The glucose content in ~he supernatant was determined according to the Hexokinase
method by means of an analysis photometer. The statistical evaluation was per-
formed with the t-test according to Student with p = 0.05.


The following table contains the obtained values in percent compared with the
1 n controls:


Table 1:

F-- I _
Test 25 mg/kg 10 mg/kg 5 mg/kg
Com- _
pound 1 2 3 4 1 2 3 4 1 2 3 4
hours hours hours
__ ~ ~
A -36 -23 -14 n.s. -22 n.s. -10 n.s.
B -42 -35 -31 -13 -38 -18 n.s. n.s.
C -40 -30 -26 -22 -26 -17 n.s. n.s.
D -38 -36 -25 -14 -27 -16 -11 -13
E -42 -39 -34 -32 -45 -41 -36 -21
F -45 -42 -38 -32 -44 -39 -32 -24 -47 -33 -26 n.s.
G -31 -15 n.s. n.s.
H -40 -43 -45 -38 -45 -38 -35 -30 -45 -45 -36 -32
I -24 -27 -17 -13 -22 -22 n.s. n.s.
K -47 -42 -31 -22
L -39 -37 -32 -24 -43 -34 -29 -19
M -45 -44 -38 -32
N ! 40 -40 -30 -31 -35 -29 n.s. n.s
O 1_46 -47 -37 -36 -46 -41 -39 ~35 1 -43 -35 -26 -23




~r

~ 17~2~6
Continuation of Table 1:


I Test 25 mg/kg 10 mg/kg 5 mg/kg
com- ~ I . _
pound 1 2 3 4 1 2 3 4 1 2 3 4
hours hours hours
_ _ _, 1 .
P -41 -26 -19 n.s. -27 -18 n.s. n.s.
Q -35 -39 -33 -30
R -36 -36 -34 -28 -36 -34 -26 -20 -17 -18 -11 n.s.
S -44 -46 -39 -37
T -49 -47 -46 -46 -43 -36 -29 -29
U -37 -18 n.s. n.s. -42 -15 n.s. n.s.
V -28 -23 -25 -20
W -32 -34 -27 -20 -19 -24 -16 n.s.
X -46 -45 -43 -36 -43 -41 -36 -28 -36 -40 -32 -32
Y -44* -44* -41* -42* -44 -38 -41 -37
Z -45 -39 -35 -31
AA -46 -38 -44 -46 -42 -32 -26 -35 -48 -36 -33 -20
AB -45 -46 -39 -34 -41 -35 -24 -17 -29 -18 n.s. n.s.
AC -41 -44 -32 -26
AD -40 -32 -31 -17
AE** _ _ ~ -41 -34 -20 n.s.

* = dose: 20 mg/kg
** = dose: 1 mg/kg
n.s. = statistically not significant
2. Acute toxicity:
The acute toxicity was determined in home-bred female and male mice with
a body weight of 20 - 26 g after oral administration (suspension in 1%
methyl cellulose) of a single dose.
Observation time: 14 days


The following table contains the values obtained:




-36-

..:

- ~7 - 117624~

Test
com- orientating toxicity
pound
H ~2 00~ mg/kg p.o. (1 out of 10 animals died)
R > 2 000 mg/kg p.o. (0 out of 10 a~imals died)
Y ~ 2 000 mg/kg p.o. (0 out of 6 animals died)


The compounds of general formula I are suitable
for the treatment of diabetes mellitus due to their benefical
effects on intermediary metabolism and their blood-suaar
lowerina activity.
According to a yet further feature of the present
invention there are provided pharmaceutical compositions
comprising as active ingredient at least one compound of
aeneral formula I as hereinbefore defined or a physioloaically
compatible salt thereof, in association with one or
more ~harmaceutical carriers or excipients.
For pharmaceutical administration, the compounds
of general formula I or their physioloqically compatible
salts may be incorporated into conventional preparations
in either solid or liquid form, optionally in combination
with other active ingredients. The compositions may,
for example, be presented in a form suitable for oral
or parenteral administration. Preferred forms include,
for example, tablets, coated tablets, capsules, powders
or suspensions.
The active inaredient may be incorporated in
excipients customarily employed in pharmaceutical
compositions such as 'or example, corn starchl lactose,
magnesium stearate, aqueous or non-aaueous vehicles, fatty
substances of animal or vecetable oriain, paraffin
~5 derivatives, polyvinyl pyrrolidone, potato starch,
various wetting, dispersina or emulsifying agents and/or
preservatives.
Advantageously the compositions may be formulated
as dosage units, each dosaae unit being adapted to supnly
a fixed dose of active inaredient. Suitable sinale
dosage units for adults contain from 1 to 50 mq,

I 17~246

- 38 -

preferably 2.5 to 20 mq of active inqredient according
to the invention. Such dosage units may, for example,
be administered 1 or 2 times dailv~ The total
daily dosage may, however, be varied according to
the compound used, the sub~ect treated and the complaint
concerned.
Accordina to a yet further feature of the present
invention there is provided a method of treating a patient
suffering from, or susceptible to disorders of intermediary
metabolism and/or blood suaar w~ich comprises administerina
to the said patient an effective amount of a compound
of formula I, as hereinbefore defined, or a physioloqically
compatible salt thereof.
The following non-limiting examples serve to
illustrate the present invention:

- :39 -
Example 1 1176246

4- ~1-(5-Chloro-2-dimethylamino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid methyl ester

1.67 g (0~0103 mol) of carbonyl diimidazole were added with
stirring at 20C to a solution of 2.00 g (0.0103 mol) of
4-methoxycarbonyl-phenyl acetic acid in 13.5 ml of absolute
tetrahydrofuran. Subsequently the mixtur~ was heated to re-
flux temperature for 45 minutes excluding moisture. After
cooling to room temperature 2.05 g (0.0103 mol) of 1-(5-chloro-
2-dimethylamino-phenyl)-ethylamine irL 7 ml of absolute tetra-
hydrofuran were added and the reaction mixture was stirred over
night at 20C. After evaporating in vacuo the evaporation re-
sidue was purified by column chromatography on silica gel
(toluene/acetone = 10/1).
15Yield: 2.6 g (66.7 % of theory),
M.p.: 153 - 155C (from ether).
Calc.: C 64.08 H 6.18 Cl 9.46 N 7.47
Found: 64.30 6.04 9.70 7.39

Analogously to Example 1 the following compounds were prepared:

4- ~1-(5-Chloro-2-dipropylamino-phenyl)-ethyl)-aminocarbonyl-
m thyl7benzoic acid methvl ester

Yield: 42 % of theory,
M.p.: 135 - 137C (from ether/petroleum ether)
Calc.: C 66~83 H 7.25 Cl 8.23 N 6.50
Found: 66.95 7-35 8.35 6.05

4- ~1-(5-Chloro-2-dibutylamino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid methyl ester _ _

Yield: 64.8 % of theory,
M.p.: 110 - 112C.
Calc.: C 68.03 H 7.69 Cl 7.72 N 6.10
Found: 67.86 7.61 7.73 6.17

- ~o -
1 1~624~
4- ~1~(5-Chloro-2-N-cyclohexyl-N-methylamino-phenyl)-ethyl)-
aminocarbon~lmethyl7benzoic acid methyl ester

Yield: 63.9 % of theory,
M.p.: 152 - 153C (ether).
Calc.: C 67.78 H 7.05 C1 8.00 N 6.32
Found: 67.70 6.92 8.24 6.46

4- ~ 5-Chloro-2-pyrrolidino-benzyl)-aminocarbonylmethyl7-
benzoic acid methyl ester

Yield: 68.1 % of theory,
lO M.p.: 1~9 141C (methanol)
Calc.: C 65.19 H 5.99Cl 9.17 N 7.24
Found: 65.46 5.91 9.26 7.41

4- ~1-(5-Chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzolc acid methvl ester

15 Yield: 58.3 % of theory,
M p.: 133 - 135C (methanol)
Calc.: C 65.91 H 6.29 C1 8.84N 6.99
Fo~nd: 66.24 6.19 8.75 7.13

4- ~ 5-Chloro-2-piperidino-benzyl)-aminocarbonylmethy ~-
20 benzoic acid meth~1 ester

Yield: 75.1 % of theory,
M.p.: 123 - 125C (ether)
Calc.: C 65.91 H 6.29Cl 8.84N 6.99
Found: 66.05 6.13 8.86 7.21

4- ~1-(5-Chloro-2-piperidino-benzyl)-aminocarbonyl)-ethyl7-
benzoic acid methyl ester ___

Yield: 70.4 ~ of theory,
M.p.: 142 - 144C (ether).

~ 41 ~ 6 2 4 ~
Calc.: C 66 57 H 6.56 Cl 8.55 N 6.75
Found: 66.50 6.49 8.44 6.86

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid methyl ester

5 Yield: 69.5 % o~ theory,
M.p.: 147 - 149C (ether).
Calc.: C 66.57 H 6.56 Cl 8.55 N 6.75
Found: 66.33 6.54 8.67 6.85

4-1T1-(5~Chloro-2-(3-methyl-piperidino)_phenyl)_ethyl)_
C~ 10 aminocarbonylmethY17benzoic acid methyl ester

Yield: 54.~ % of theory,
M.p.: 160 - 162C (methanol).
Calc.: C 67.20 N 6.81 Cl 8.27 N 6.53
Found: 67.27 6.81 8.13 6.45

4- ~1-(5-Chloro-2-(3,5-cis-dimethyl-piperidino)-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid methyl ester_

Yield: 44 % of theory,
M.p.: 190 - 193C (methanol)
Calc.: C 67.78 H 7.05 Cl 8.00 ` N 6.32
~J 20 Found: 67.50 7.05 8.25 6.48

4-L~1-(5-Chloro-2-piperidino-phenyl)-propyl)-aminocarbonyl-
methyl7benzoic acid methyl ester

Yield: 65.9 % of theory,
M.p.: 142 - 144C (ether).
25 Calc.: C 67.20 H 6.81 Cl 8.26 N 6.53
~ound: 67.45 6.63 8.38 6.63

- ~i2 ~ 2 4 ~

4- ~1-(5-Chloro-2-piperidino-phenyl)-2-methyl-propyl)-amino-
carbonvlmethyl7benzoic acid methyl ester

Yield: 61.4 ~ of theory,
M~p.: 156 - 158C (ether).
Calc.: C 67.78 H 7.05 Cl 8.00N 6.32
Found: 67.80 7.17 7.89 6.28

4-L~1-(5-Chloro-2-morpholino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid methyl ester

Yield: 69.8 % of theory,
M.p.: 156 - 158C (ether).
Calc.: C 63.38 H 6.04 Cl 8.50N 6.72
Found: 63.24 6.12 8.70 6.85

4- ~1-(5-Chloro-2-thiomorpholino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid methyl ester

15 Yield: 68.2 % of theory,
M.p.: 167 - 169C (ether).
Calc.: C 61.03 H 5.82 Cl 8.19N 6.47 S 7.41
Found: 60.83 5.77 8.33 6.49 7.39

4- ~1-(5-Chloro-2-(hexahydro-1H-azepino)-phenyl)-ethyl)-
aminocarbonvlmethYl7benzoic acid methyl ester

Yield: 41.7 % of theory,
M.p.: 146 - 147C (methylene chloride/petroleum ether).
Calc.: C 67.19 H 6.81 Cl 8.27 N 6.53
Found: 66.90 6.66 8.30 6.39

4- ~1-(5-Chloro-2-octahydroazocino-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid_methyl ester

Yield: 30 % of theory,
M.p.: 154 - 156C

_ ~3
1 ~7624~
Calc.: mol peak m/e = 442/444 (1 chlorine)
Found: m/e = 442/444 (1 chlorine)

4- ~1-(5-Chloro-2-(octahydro-1H-azonino)-phenyl)-ethyl)-
aminocarbon~lmethyl7benzoic acid methyl ester

Yield: 38 % of theory~
M.p.: 184 - 185C (chloroform/toluene)
Calc.: C 68.32 H 7.28 N 6.13
Found: 68.10 7.30 6.28

4- ~ 2-(5-Chloro-2-piperidino-phenyl)-2-propyl)-aminocarbonyl-
methyl7benzoic acid methyl ester

Yield: 84.4 % of theory,
M.p.: 162 - 164C
Calc.: mol peak m/e = 428/4~0 (1 chlorine)
Found: m/e = 428/430 (1 chlorine)

4- ~1-(5-Nitro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid meth~l ester

Yield: 68.3 % of theory,
M.p.: 178 - 180C (toluene)
Calc.: C 64.93 H 6.40 N 9.88
Found 65.05 6.43 9.87

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic
acid methyl ester

Yield: 59.1 % of theory,
M.p.: 145 - 147C
Calc.: C 72.61 H 7.42 N 7.36
Found: 72.35 7.39 7.40

- 44 -
1 17~24~
4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7-
benzoic acid methyl ester _ _

Yield: 32.9 ~ o~ theory,
M.p.: 124 - 126C (pe-troleum ether/acetone)
5 Calc.: mol peak m/e = 380
Found: m/e = 380

N-(4-Nitro-phenacetyl)-N-/1-(2-piperidino-phenyl)-ethvl7amine

Yield: 62.4 % of theory,
M.p.: 165 - 167C (ether)
Calc.: C 68.64 H 6.86 N 11.44
Found: 68.73 6.88 11.63

N-(4-Acetyl-phenacetyl~-N- ~-(2-piperidino-phenyl)-ethyl7amine

Yield: 32.4 % of theory,
M.p.: 162 - 164C (ether)
Calc.: C 75.79 H 7.74 N 7.69
Found: 75.51 7.86 7.38

N-(4-Acetyl-phenacetyl)-N- ~ -(5-chloro-2-piperidino-phenyl)-
ethyl7amine _ _ _

Yield: 50.3 % of theory,
M.p.: 162 - 163C (ether)
Calc.: C 69.24 H 6.82 N 7.02
Found: 68.88 6.63 6.70

2- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic
acid methYl ester

25 Yield: 82 % of theory,
M.p.: 107 - 108C
Calc.: C 72.60 H 7.42N 7.36
Found: 72.79 7.38 7.53

_ 45 - 11762~6

3~ (2-Plperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid ethyl ester

Yield: 47 % of theory,
M.p.: 155C
5 Calc.: C 73.07 H 7.67N 7.10
Found: 73,30 7.58 7.17

3-Chloro-4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid ethyl ester

Yield: 63 % of theory,
lO M.p.: 123 - 124C
Calc.: C 67.20 H 6.81Cl 8.27 N 6.53
Found: 67.28 6.84 8.36 6~50

4- ~1-(2-(1,2,3,4-Tetrahydro-isoquinoline-2-yl)-phenyl)-ethyl)-
aminocarbon,vlmethyl7benzoic acid ethyl ester

15 Yield: 43 ~ of theory,
M.p.: 142 - 144C
Calc.: C 75.99 H 6.83 N 6.33
Found: 75.64 6.75 6.~5

4-~r1-(2-Piperidino-phenyl)-ethvl)-aminocarbonylmethyl7toluene

20 Yield: 59 % of theory,
M.p.: 136 - 138C
Calc.: C 78.53 H 8.39 N 8.33
Found: 78.58 8.16 8.26

4- ~ 5-Chloro-2-piperidino-anilino)-carbonylmethyl7benzoic acid
25 ~ethyl ester

Yield: 40.3 % of theory,
M.p.: 156 - 158C (methanol/toluene)
Calc.: C 65.19 H 5.99 Cl 9.16
Found: 65.20 6.15 9.40

- 15 ~ I l~B24~
4- ~ -(2-Piperidino-anilino-carbonyl)-ethy_7benzoic acid-
methyl ester _ _ _ _

Yield: 26.9 % of theory,
M.p.: 71- 73C (petroleum ether)
Calc.: C 72.10 ~ 7.15 N 7.65
Found: 72.00 7.09 7.94

4- ~1-(2-(1,2,3,6-Tetrahydro-pyridino)-phenyl)-ethyl)-
amino-carbonylmethyl7benzoic acid ethyl ester

Yield: 63.4 % of theory,
M.p.: 125 - 127C (ether)
Calc.: C 73.44 H 7.19 N 7.14
Found: 73.38 7.13 7.13

4- ~ 2-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

15 Yield: 68 % o~ theory,
M.p.: 95 - 97C (ethanol)
Calc.: C 67.20 H 6.81 Cl 8.27 N 6.53
Found: 67.75 6.76 8.22 6.24

4~ (5-Fluoro-2-piperidino-phenyl)-ethyl)-ami~ocarbonyl-
methvllbenzoic acid ethvl ester

Yield: 47.3 % of theory,
M.p.: 138 - 140C (ether)
Calc.: C 69.88 H 7.99 N 6.79
Found: 70.10 7.10 6.87

_ 47 -- tl762~
4~ (5-Nitro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 56.5 % of theory,
M.p.: 144 - 147C (ethanol)
5 Calc.: C 65.59 H 6.65 N 9.56
Found: 65.78 6.56 9.73

4- ~ 2-(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonyl)-ethyl7-
benzoic_acid methyl ester

Yield: 90 % of theory,
.~ 10 M.p.: 129 - 131C
Calc .: C 73.06 H 7.67 N 7.10
Found: 72.61 7.77 7.52

4- ~ 2-Hydroxy-1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid ethyl ester

15 Yield: 44.4 % of theory,
M.p.: 132 - 135C (petroleum ether/acet~ne)
Calc.: C 70.22 H 7.37 N 6.82 m/e = 410
Found: 70.02 7.25 6.77 m/e = 410

4- ~1-(5-Hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
20 methyl7benzoic acid ethyl ester

Yield: 64.2 % of theory,
M~po 150 - 151C (ether)
Calc.: C 70.22 H 7.37 N 6.82 m/e = 410
Found: 70.37 7.17 6.81 m/e = 410

25 4- ~ ~ -Methoxycarbonyl-2-piperidino-ben~yl)-aminocarbonyl-
methyl7benzoic acid_ethyl ester

Yield: 59 % of theory,
M.p.: 110 - 112C (petroleum ether/acetone)
Calc.: C 68.47 H 6.90 ~ 6.39 m/e = 438
3Q Found: 68.57 6.64 6.46 m/e = 438

- 48 ~ 6 2 ~ `~

4~ (5-Chloro-2-(2-methyl-piperidino)-phenyl)-ethyl)-
aminocarbonvlmethyl7benzoic acid ethyl ester

Yield: 71.3 % of theory,
M.p.: ~ 20C
Calc.: m/e = 442/444 (1 chlorine)
Found: m/e = 4421444 (1 chloriné)

4- ~1-(2-Hexahydroazepino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl_ester

Yield: 68 % of theory,
M.p.: 145 - 148C (toluene)
Calo.: C 73.50 H 7.90 N 6.86
Found: 73.35 8.04 6.89

4- ~1-(2- ~ ,4-Dioxa-8-azaspiro ~ , ~ decyl-(8~7phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid ethyl ester

Yield: 64.3 % of theory,
M.p.: 143 - 145C (petroleum ether/acetone)
Calc.: C 69.01 H 7.13 N 6.19
Found: 69.30 7.38 6.21

4- ~1-(2-~2-Methyl-pyrrolidino)-phenyl)-ethyl)-aminocarbonyl-
methY17benzoic acid ethyl ester

Yield: 72 % of theory,
M.p.: 94 - 97C
Calc.~ C 73.07 H 7.66 N 7.10
Found: 72,25 7.67 7.11

L 176246
- 49 -
4-L~1-(3-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester _ _
I




Yield: 39,5 % of theory, M.p.: 178 - 179C
Calc.: m/e = 408
5 ~ound: m/e = 408

4- ~1-(3-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic ac d ethvl ester

Yield: 52,6 /0 of theory,
Calc.: m/e = 428/430 (1 chlorine)
Found: m/e = 428/430 (1 chlorine)


Example 2

(~) 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy17- 1
benzoic acid ethyl ester _ _

231,4 mg (1,43 m mol) of carbonyl diimidazole were added to
a solution of 290,9 mg (1.40 m mol) of 4-ethoxycarbonyl-
phenyl acetic acid in 6 ml of tetrahydrofuran, Subsequently
the mixture was heated to reflux temperature for 1,5 hours
excluding moisture. After cooling to room temperature 0,~85 ml
(-2.78 m mol) of triethylamine (dried over potassium hydroxide)
and 360 mg (1.30 m mol) of (~ (2-piperidino-phenyl)-ethyl-
amine dihydrochloride ~ ,p, 242C (decomp,); L~C720 = + 14.8
(c = 1; methanol )7 together with 2 ml of tetrahydrofuran were
added and the mixture was stirred for 4 hours at 50 C in ~n
oil bath. After evaporating in vacuo the evaporation residue
was distributed between chloroform and water. The chloroform
extract was dried over sodium sulfate, filtered through a
G3-glas frit and evaporated in vacuo to dryness. The obtained
residue was purified by column chromatography on silica gel
(chloroform/methanol = 6:1),

- 50 - l 17~246

Yield: 229 mg (44.7 % of theory),
M.p.: 89 - 90C (ether)
~7D0 = 8.2 ( G = 1; methanol)
Calc.: C 73.07 H 7.66 N 7.10 m/e = 394
5 Found: 73.20 7.68 7.14 m/e = 394

Analogously to Example 2 was prepared:

(-) 4- ~1-(2-Piperidino-phenyl)~ethyl)-aminocarbonylmethyl7-
benzoic acid ethyl ester

from (-) 1~(2-piperidino-phenyl)-ethylamino ~ihydrochloride
10 t~.p.: 239 - 242C (decomp.); /~ 20: -19.6 (c = 1; methanoll7.
Yield: 41.1 % of theory,
M.p.: 77 - 79C (ether/cyclohexane)
r~ 720 = -6.2 (c _ 1; methanol)
Calc.: C 73.07 H 7.66 N 7.10 m/e = 394
15 Fourd: 72.67 7.75 6.82 m/e = 394

Exam~le 3

4- ~1-(4-Chloro-2-piperidino-phenyl)-ethyl)~aminocarbonyl~
meth~l7benzoic acid ethvl ester

2.3 ml (0.023 mol) of carbon tetrachloride were added to a
20 solution of 5.5 g (0.023 mol) of 1-(4-chloro~2-piperidino-
phenyl)~ethylamine, 4.8 g (0.023 mol) of 4-ethoxycarbonyl-
phenyl acetic acid, 7.3 g (0.028 mol) of triphenyl phosphine
and 3.2 ml (0.023 mol) of triethylamine in 50 ml of aceto-
nitrile and the mixture was stirred for 24 hours at room
25 temperature After evaporating in vacuo the evaporation re~
sidue was distributed between 100 ml of water and ethyl ace-
tate. The combined organic extracts, which were dried over
sodium sulfate, were filtered, evaporated in vacuo and the
evaporation residue was purified by column chromatography
30 on silica gel (toluene/ ethyl acetate = 4:1).
Yield: 6.1 g (62 % of theory),
M.p.: 126 - 128C
Calc.: C 67.20 H 6.81 Cl 8.27 N 6.53
Found: 67.43 6.97 8.16 6.40

- 51 - 1~7624~

Analogously to Example 3 the following compounds were prepared:

4~ (4-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 48.2 ~ of theory,
M.p.: 120 - 122C
Calc.: C 73.50 H 7.89 N 6.86
Found: 73.61 7.95 6.73

4- ~1-(2-(4-Methyl-piperidino)~phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 55.8 % of theory,
M.p.: 125 - 128C (ether)
Calc.: C 73.50 H 7.90 N 6.86
Found: 73.30 7.99 7.20

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -
15 benzoic acid ethyl ester _

Yield: 71 % of theory,
M.p.: 147 - 148C
Calc.: C 73.06 H 7.67N 7.10
Found: 73.54 8.04 6.95

4- ~1-(2-Piperidîno-phenyl)-ethyl)-aminocarbonylmethyl7-
phenyl acetic acid

Prepared from 1-(2-piperidino-phenyl)-ethylamine and
p-phenylene diacetic acid.
Yield: 27 % of theory,
M.p.: 186 - 189C
Calc.: C 72.60 H 7.42N 7.36
~ound: 72.75 7.65 7.11

624 ~
4- ~ 2-Piperidino-benzhydryl)-aminocarbonylmethyl7benzoic
acid ethyl ester

Yield: 87.4 % of theory,
M.p.: 160 - 162C
5 Calc.: C 76.29 H 7.06N 6.14
Found: 76.44 7.08 6.17

4- ~ 5-Chloro-2-piperidino-benzhydryl)-aminocarborylmethyl7-
benzoic acid ethyl ester

Yield: 78 % of theory,
10 M.p.: 202 - 204C
Calc.: C 70,93 H 6.36Cl 7.22 N 5.71
Found: 70.85 6.40 7.11 5~45

4- ~1-(4-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid ethyl ester

15 Yield: 39 % of theory,
M.p.: 118 - 120C
Calc.: C 73.07 H 7.67N 7.10
Found: 73.20 7.78 7.11

4- ~1-(2-(4-Methyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethYl ester

Yield: 53 % of theory,
M.p.: 130 - 132C
Calc.: C 70.38 H 7.63 N 10.26
Found: 70.41 7.53 10.13

4-LI1-(2~(4-Benzyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester __ _

Yield: 75 ~ of theory
M.p.: 135 - 136C
Calc.: C 74020 H 7.26 N 8.66
Found: 74.45 7.34 8.54

- 53 - Il7~24~

4- ~1-(2-(4-p-chlorophenyl-piperazino)-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid eth~l ester _ _ _ __

Yield: 48.5 % of theory,
M.p.: 178 - 180C
Calc.: C 68.83 H 6.37 N 8.30Cl 7~01
Found: 68.71 6.22 8.41 6.82

4- ~ ~ -Cyclohexyl-2-piperidino-benzyl)-aminocarbonylmethyl7
benzoic acid ethvl ester
~. .. .. ~
Yield: 75 % of theory,
lO M.p.: 135C
Calc.: C 75.29 H 8.28N 6.06
Found: 75.11 8,13 5,99

N-(4-Chloro-phenacetyl)-N~ (2-piperidino-phen~l)-ethyl7amine

Yield: 79 % of theory,
15 M.p.: 150 - 152C
Calc.: C 70.67 H 7.06 Cl 9.93 N 7.85
Found: 70.94 7.84 10.09 7.90

4- ~ 2-Pyrrolidino-benzhydryl)-aminocarbonylmethy_7benzoic
acid ethvl ester
_.

20 Yield: 57 % of theory,
M.p.: 163 - 165C
Calc.: C 75.99 H 6.83N 6.33
Found: 75.45 6.52 6.10

-- 54 - I 17524~

4-~2-Hexamethyleneimino-benzhydryl)-aminocarbonylmethyl7-
benzoic acid ethyl ester

Yield: 68 % of theory,
M.p.: 151 - 154C
Calc.: C 76. 56 H 7.28 N 5.95
Found: 76. 43 7.19 6.01

Example 4

4-LT1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid ethyl ester ~

lO 11.2 g (0.0539 mol) of 4-ethoxycarbonyl-phenylacetic acid,
17 g (0.0647 mol) of triphenyl phosphine, 22.6 ml (0.162 mol)
of` triethylamine and 5.2 ml (0.0539 mol) of carbon tetrachlo-
ride were successively added with stirring to a solution of
10.9 g (0.0539 mol) of freshly prepàred (2-piperidinophenyl)-
15 methyl-ketimine in 100 ml of acetonitrile. The solution, which
was clear after a short time, was stirred for 20 hours at 20C.
The resultant precipitate (triethylamine hydrochloride) was
filtered off and the filtrate was evaporated i~n vacuo. The
evaporation residue was purified by column chromatography
20 on silica gel (toluene/acetone = 10:1).
Yield: 15 g (70.1 % of theory),
M.p.: 112 - 115C (ether)
Calc.: C 73.44 H 7.19 N 7.14
Found: 73.28 7. 32 6.96

25 Analogously to Example 4 the following compounds were prepared:

4-LTbC -Cyclohexylidene-2-piperidino-benzyl)-aminocarbonyl-
methyl7benzoic acid et~ ter_ _ -

Yield: 24 % of theory,
M.p.: 131 - 133C
Calc.: C 75.62 H 7. 8~ N6. o~
Found: 75.59 7-47 6.01

_ 55 - 11~ 6 24 6
4- ~1-(2-Piperidino-phenyl)-propenyl)-aminocarbonylmethyl7-
benzoic acid ethYl ester

Yield: 65,0 % of theory (E- and Z-isomeric mixture)
M.p.: of the polar isomer: 82-84C
Calc.: C 73.86 H 7.44 N 6,89
Found: 73.73 7.57 7.01

Example 5

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic
acid ethyl ester

10 ~ solution of 50.6 g (0.267 mol) of 4-ethoxycarbonyl-phen-
acetyl chloride in 120 ml of methylene chloride was dropped
with slight ice cooling to a stirred solution of 49.6 g
(0.243 mol) of 1-(2-piperidinophenyl)-ethylamine ~ P- o 6:
100 - 107C; m.p. of the dihydrochloride: 23~ - 237C (decomp. ~7
- 15 and 37.3 ml (0.267 mol) of triethylamine in 245 ml of methylene
chloride at an internal temperature of 20 - 30C. After stirring
for 2 hours at room temperature, the resultant precipitate was
filtered off~ washed once with methylene chloride, and the
combined methylene chloride phases were extracted successive-
ly twice with water, once with 10 % aqueous ammonia, twicewith water, once~; with 100 ml of 3 % hydrochloric acid and
twice with water. The methylene chloride phase was dried over
sodium sulfate and evaporated in vacuo. The evaporation re-
sidue was crystallized from ether.
Yield: 88.8 g (92.7 ~ of theory),
M.p.: 148 - 150C

~ ~7624&
- 56 ~

Analogously to Example 5 the following compounds were prepared:

4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7benzoic
acid ethvl ester

Yield: 22.5 % of theory,
M.p.: 116.5 - 117C (ethanol/petroleum ether)
Calc.: C 73.07 H 7.66 N 7.10
Found: 73.48 7.62 7.15

4- ~1-(5-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

a Yield: 20.2 % of theory,
M. p.: 132 - 132.5C (ethanol)
Calc.: C 73.50 H 7.90 N 6.86
Found: 73.49 7.74 6.94

4- ~1-(5-Methoxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
15 methyl7benzoic_a i~ er _ _ _ __

Yield: 35.8 % of theory,
M.p.: 131 - 132C (ethanol)
Calc.: C 70.73 H 7.60 N 6.60
Found: 70.98 7.59 6.38
~ .
4- ~1-(2-Piperidino-phenyl)-ethyl)-N-methylamino-carbonyl-
methyl7benzoic acid ethvl ester

Yield: 65.2 % of theory,
M.p.: C 20C
Calc.: C 73.50 H 7.90 N 6.86
25 Found: 72.99 7.60 6.87

~ 176246
- 57 -
4- ~1-(2-Decahydro-isoquinoline-2-yl)-phenyl)-ethyl)-amino-
carbonylmethylZbenzoic acid ethyl ester

Yield: 44 % of theory,
M.p.: 159C
Calc.: C 74.95 H 8.08 N 6.24
Found: 75.09 8.01 6.01

4- ~1-(2-(1,2,3,4,5,6,7,8-Octahydro-isoquinoline-2-yl)-phenyl)-
ethyl~-aminocarbonylmethyl7benzoic_ cid ethyl ester

Yield: 35 % of theory,
W lO M.p.: 115 - 117C
Calc.: C 75.30 H 7.67 N 6.27
Found: 75.18 7.37 5.89

4- ~1-(2-Octahydro-isoindole-2-yl)-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid ethyl ester

Yield: 36 % of theory,
M.p.: 141C
Calc.: C 74.62 H 7.88 N 6.44
Found: 74.70 7.97 6.42

4- ~1-(3-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -
v 20 benzoic acid ethyl ester

Yîeld: 24 % of theory,
M.p.: 164C
Calc.: C 73.07 H 7.66N 7.10
Found: 72.80 7.48 7.13

2s 4-/¦1-(6-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 17 % of theory,
M.p.: ~ 20C
Calc.: C 67.20 H 6.81 Cl 8.26 N 6.53 m/e = 423/30
30 Found: 67.96 6.56 8.80 6.67 m/e = 423/30

- 58 - ~ 2 ~ ~
4~ (6-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 3.5 % of theory,
M.p.: C 20C
Calc.: C 73.49 H 7.89 N 6.85m/e = 408
Found: 73.80 7.61 7.01m/e = 408

4-L~1-(2-(3-Aza-bicyclo ~ .2._7nonane-3-yl)-phenyl)-ethyl)-
aminocarbonYlmethYl7benzoic acid ethYl ester

Yield: 0.5 % of theory,
M.p.: ~ 20 C
Calc.: m/e = 434
Found: m/e = 434

N~ (5-Chloro-2-piperidino-phenyl)-ethyl7-N-phenacetYlamine

Yield: 53.5 % of theory,
lS M.p.: 134 - 136 C (ethanol)
Calc.: C 70.67 H 7.06Cl 9.94N 7.85
Found: 70.40 7.32 9.77 7.68

Example 6

4- ~1-(2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7-
benzoic acid ethyl ester

A solution of 2.49 g (0.011 mol) of 4-ethoxycarbonylphen-
acetyl chloride in 10 ml of methylene chloride was adde~
with ice cooling over 15 minutes to a stirred solution of
2.02 g (0.010 mol) of freshly prepared methyl-(2-piperidino-
phenyl)-ketimine and 1.53 ml of (0.011 mol) of triethylamine
in 10 ml of methylene chloride at an internal temperature o~

~ '9 ~ 1 1~624~
1 to 6C. The reaction mixture was stirred for 20 minutes
at 20C and poured into cold sodium hydroa~n car~onate solution.
After extracting several times the organic extract was washed
~nce with water, dried over sodium sulfate, filtered, and
5 evaporated in vacuo. The evaporation residue was purified by
column chromatography on silica gel (toluene/acetone = 50:1).
Yield: 1.86 g (47.7 % of theory),
M.p.: 113 - 116C (ethanol)
Calc.: C 73.44 H 7.19 N 7.14 m/e = 392
lO Found: 72.95 6.98 7.22 m/e = 392

Analogously to Example 6 the following compounds were prepared:

4- ~1-(6-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 37 % of theory,
15 M.p.: 102 - 105C
Calc.: C 67.51 H 6.37 Cl 8.30 N 6.56 m/e = 426/28
Found: 67.86 6.39 8.58 6.23 m/e = 426/28

4- ~1-~6-Methyl-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-
methyl7benzoic acid ethYl ester

20 Yield: 41 % of theory,
M.p.: 116 - 118C
Calc.: C 73.86 H 7.43 N 6.89
Found: 73.75 7.43 6.77

- 60 - 1176246

Exam~le 7

4-L~1-(2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethy ~ -
benzoic acid ethyl ester

A solution of 1.55 g (6.86 m mol) of 4-ethoxycarbonyl-
phenacetyl chloride in 5 ml of methylene chloride was
~dded with stirring to a suspension o~ 2.20 g (6.Z4 m mol)
of magnesium iodide- ~ ethyl-(2-piperidino-phenyl)-ketimino7-
complex in 15 ml of methylene chloride, whereby the internal
temperature rose ~rom 20 to 30C. After stirring for 2 hours
at room temperature, the reaction mixture was mixed with wa-
V ter whilst stirring and extracted several times with methylenechloride. The methylene chloride solution was washed thrice
with water, dried over sodium sulfate, filtered and evapora-
ted in vacuo. The evaporation residue was purified by column
chromatography on silica gel (toluene/acetone = 50:2).
Yield: 1.1 g (45.8 % of theory),
M.p.: 115 - 118C (ethanol)
Calc.: C 73.44 H 7.19 N 7.14
Found: 73.30 7~06 7.16

20 Analogously to Example 7 the following compound was prepared:

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-
~ methyl7benzoic acid ethYl ester

Yield: 39.5 % of theory,
M.p.: 142 - 145C (ethanol)
25 Calc.: C 67.51 ~ 6.37 C1 8.30 N 6.56
Found: 67.51 6.37 8.36 6.49

- 6l - ~76~45

Example 8

4- ~1-(5-Chloro-2-dimethylamino-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid

A ~olution of 2.0 g (0.00534 mol) of 4- ~1-(5-chloro-2-di
methylamino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid-
methyl ester and 0.32 g (0.00801 mol) of sodium hydroxide in
23 ml of ethanol and 7 ml of water was stirred for 2 hours
at 50C. After evaporating in v_cuo, water was added and the
reaction mixture was ad~usted to pH 6 by means of 2 N-hydro-
chloric acid and extracted with ethyl acetate. The organic
,~ phase was extracted with water, dried over sodium sulfate,
filtered and e~aporated in vacuo. The evaporation residue
was recrystallized from ether.
Yield: 1.7 g (88 % of theory),
M.p.: 190 - 192C
Calc.: C 63.24 H 5.87Cl 9.83 N 7.76
Found: 62.90 5.81 10.02 7.90

Analogously to Example 8 the following compounds were prepared:

4-~ 1-(5-Chloro-2-dipropylamino-phenyl)-ethyl)-aminocarbonyl-
20 methvl7benzoic acid

~' Yield: 87.6 % of theory,
M.p.: 203 - 205C
Calc.: C 66.25 H 7.01Cl 8.50 N 6.72
Found: 65,97 6.96 8.52 6.55

4- ~1-(5-Chloro-2-dibutylamino-phenyl)-ethyl)-aminocarbonyl-
methYl7benzoic acid
.

Yield: 77.3 % of theory,
M.p.: 200 - 2~2C
Calc.: C 67.47 H 7.48Cl 7.97 N 6.30
30 Found: 67.45 7.60 8.28 6.44

- 62 ~ 6~5

4- ~1-(5~Chloro-2-N-cyclohexyl-N-methylamino-phenyl)-ethyl)-

Yield: 88.2 % of theory,
M.p.: 198 - 200C (ether).
Calc.: C 67.20 H 6.81 Cl 8.27 N 6.53
Found: 67.10 6.73 8.16 6.47

4- ~5 Chloro-2-pyrrolidino-benzyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 84.2 % of theory,
lO M.p.: 208 - 210C (ethyl acetate)
Calc.: C 64.42 H 5.68 Cl 9.51N 7.51
Found: 64.70 5.68 9.58 7.60

4- ~1-(5-Chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid _ __ _ -

Yield: 81.1 % of theory,
M.p.: 202 - 204C (ethyl acetate)
Calc.: C 65.20 H 5.99 Cl 9.17 N 7.24
Found: 65.02 6,12 9.32 7.10

4- ~ 5-Chloro-2-piperidino-benzyl)-aminocaroonylmethyl7-
20 benzoic acid __

Yield: 78 % of theory,
M.p.: 164 - 166C
Calc.: C 65.19 H 5.99Cl 9.17N 7.24
Found: 65.50 5.76 9.24 7.36

4- ~1-(5-Chloro-2-piperidino-benzyl)-aminocarbonyl)-ethyl7-
benzoic acid _ __ __ _

Yield: 81.1 % of theory,
M.p.: 213 - 216C (acetone/ether)

- 63 - t ~7624~

Calc.: C 65.90 H 6.29 C1 8.84 N 6.99
Found: 66.30 6.40 9.00 7.04

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

5 Yield: 84.9 % of theory,
M.p.: 213 - 215C (ether)
Calc.: C 65.91 H 6.29Cl 8.85 N 6.99
Found: 66.18 6.19 8.88 7.12

4- ~1-(5-Chloro-2-(3-methyl-piperidino)-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid _ _

Yield: 69.2 % of theory,
M.p.: 208 - 210C (ethyl acetate)
Calc.: C 66.57 H 6.56 Cl 8.55N 6.75
Found: 66.36 6.77 8.58 6.80

4- ~1-(5-Chloro-2-(3,5-cis-dimethyl-piperidino)-phenyl)-
ethyl)-aminocarbon~lmethyl7benzoic acid _

Yield: 82.2 % of theory,
M.p.: 212 - 214C (ether)
Calc.: C 67.20 H 6.81 Cl 8.26 N 6.53
~J 20 Found: 66.95 6.69 8.43 6.68

4- ~1-(5-Chloro-2-piperidino-phenyl)-propyl)-aminocarbonyl-
methyl7benzoic acid_ _ _

Yield: 81.5 % of theory,
M.p.: 200 - 203C (ether)
25 Calc.: C 66.57 H 6.56Cl 8.55N 6.75
Found: 66.74 6.35 8.59 6.45

- 64 - ~17~2~6

4- ~1-(5-Chloro-2-piperidino-phenyl)-2-methyl-propyl)-
aminocarbonylmethyl7benzoic acid

Yield: 82.7 % of theory,
M.p.: 236 - 240C (ethyl acetate)
5 Calc.: C 67.20 H 6.81 C1 8.27N 6.53
Found: 67.19 6.56 8.14 6.39

4- ~1-(5-Chloro-2-morpholino-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid _ _

Yield: 85.6 % of theory,
C~ 10 M.p.: 201 - 203C (ether)
Calc.: C 62.60 H 5.75Cl 8.80N 6.95
Found: 62.30 5,82 8.83 6.85

4~ (5-Chloro-2-thiomorpholino-phenyl)-ethyl)-aminocar-
bonvlmethyl7benzoic acid _ _

15 Yield: 87.6 % of theory,
M.p.: 216 - 217C (ether)
Calc.: C 60.20 H 5.53C1 8.4~N 6.69
Found: 59.90 5.51 8.61 6.53

4- ~1-(5-Chloro-2-(hexahydro-1H-azepino)-phenyl)-ethyi)-
20 aminocarbonylmethyl7benzoic acid

Yield: 81.2 % of theory,
M.p.: 202 - 204C (chloroform/toluene)
Calc.: C 66.58 H 6.56 Cl 8,55N 6.75
Found: 66.60 6.~7 8.50 6.59

- 6s ~

4~ (5-Chloro-2-octahydroazocino-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid

Yield: 44.4 % of theory,
M.p~: 196 - 197C (chloroform/petroleum ether)
Calc.: C 67.19 H 6.81 N 6.53
Found: 67.10 6.97 6.37

4- ~1-(5-Chloro-2-(octahydro-1H-azonino)-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid

Yield: 74.7 % of theory,
M.p.: 204 - 206C (ethyl acetate/petroleum ether)
Calc.: C 67.78 H 7.05 N 6.~2
Found: 67.50 7.03 6.04

4- ~ 2-(5-Chloro-2-piperidino-phenyl)-2-propyl)-amino-
carbonylmethyl7benzoic acid

15 Yield: 82.9 % of theory,
M.p.: 227 - 229C (acetone)
Calc.: C 66.57 H 6.56Cl 8.55N 6.75
Found: 66.03 6.66 8.67 6.59

4- ~1-(5-Nitro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
20 methyl7benzoic acid

Yield: 95.6 % of theory,
M.p.: 252 - 254C (ether)
Calc.: C 64.22 H 6.12N 10.21
Found: 64.20 6.17 10.12

-- 66 ~ 624~

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 85 % of theory,
M.p.: 170 - 172C
Calc.: C 72.11 H 7.15N 7.64
Found: 71.94 7.03 7.72

4- ~ 2-(2-Piperidino-phenyl)-2-propyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 72.7 % of theory,
M.p.: 213 - 215C
Calc.: C 72.61 H 7.42N 7.36
Found: 72.52 7.31 7.45

4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7-
benzoic acid

15 Yield: 64.6 % of theory,
M.p.: 120 - 122C
Calc.: C 72.11 H 7.15N 7.64 m/e = 366
Found: 72.42 7.38 7.45 m/e = 366
M.p. of the hydrochloride: 266C (decomp.)
Calc.: C 65.58 6.76 8.80 N 6.95
Found: 65.00 6.62 9.40 7.00

4- ~2-Piperidino-anilino)-carbonylmethyl7benzoic acid x 0.25 HCl

Yield: 72.5 % of theory,
M.p.: 216 - 217C
Calc.: (x 0.25 HCl) C 69.11 H 6.45 Cl 2.55 N 8.06
Found: 69.40 6.32 3.08 8.37


- 67 -

4- ~ 5-Chloro~2-piperidino-anilino)-carbonylmethyl7benzoic
acid h~drochloride

Yield: 51.3 % of theory,
M.p.: 232C (decomp.)
5 Calc.: C 58.68 H 5.42Cl 17.32N 6.84
Found: 58.26 5.44 17.97 6.74

4- ~ -(2-Piperidino-anilino-carbonyl)-ethyl7benzoic acid
semihydrate

Yield: 69.9 ~ of theory,
lO M.p.: 151 - 153C (petroleum ether/acetone)
Calc.: (x 0.5 H20) C 69.78 H 6.97 N 7.75
Found: 69.30 6.82 7.46

4- ~ -(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonyl)-ethyl7-
benzoic acid x 0.2 H20 _ _

15 Yield: 71.4 % of theory,
M.p.: 171 - 172C (acetone/petroleum ether)
Calc.: (x 0.2 H20) C 71.91 H 7.45 N 7.29
Found: 71.90 7.30 7.03

Example 9

20 4- ~1-(5-Benzyloxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

244 mg (0.487 m mol) of 4-L~1-(5-benzyloxy-2-piperidino-phenyl)-
ethyl)-aminocarbonylmethy ~ benzoic acid ethyl ester in 2.5 ml
of ethanol were heated with stirring with 0.73 ml of 1N sodium
25 hydroxide solution in a bath of 50C, until (after 3 hours)
no ester could be detected in the thinlayer chromatogram.
After addition of 0.7~ ml of 1N hydrochloric acid, the reac-
tion mixture was evaporated in vacuo and distributed between
ethyl acetate and water. The organic extract was dried over

- 68 - I 176246

sodium sulfate, filtered and evaporated in vacuo.
The evaporation residue was recrystallized from methanol.
Yield: 191 mg (8~ % of theory),
M.p.: 220 - 222C
Calc.: C 73.71 H 6.83 N 5.93
Found: 73.21 6.67 5.80

Analogously to Example 9 the following compounds were prepared:

4- ~1-(2-Hexahydroazepino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid
_

10 Yield: 68.5 % of theory,
M.p.: 174 - 176C (ethyl acetate)
Calc.: C 72.61 H 7.42 N 7.36
Found: 72.36 7.34 7.38

4- ~1-(2-(1,2,3,6-Tetrahydro-pyridino)-phenyl)-ethyl)-amino-
15 carbonylmethyl7benzoic acid

Yield: 68.2 % of theory,
M.p.: 158 - 160C (ethyl acetate)
Calc.: C 72.51 H 6.64 N 7.69
Found: 72.20 6.66 7.74

~J 20 4- ~ 2-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 75 % of theory,
M.p.: 192 - 195C (ethyl acetate)
Calc.: C 65.91 H 6.29 Cl 8.84 N 6.99
25 Found: 66.39 6.17 8.45 6.78

69 t ~6~4~

4~ (5-Fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7ben~oic acid

Yield: 52.9 % of theory,
M.p.: 174 - 176C (ethyl acetate)
Calc.: C 68.73 H 6.55 N 7.29
Found: 68.30 6.48 7.45

4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 53.9 % of theory,
10 M.p.: 120 - 122C (ethanol)
Calc.: C 72.11 H 7.15N 7.64 m/e - 366
Found: 72.45 7.04 7.64 mf e = 366

4- ~1-(5-Cyano-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid
.




15 Yield: 71.6 % of theory,
M.p.: 198 - 200C (ether)
Calc.: C 70.57 H 6.44N 10.73
Found: 70.17 6.38 11.00

4- ~1-(5-Carboxy-2-piperidino-phenyl)~ethyl)-aminocarbonyl-
'J 2 methyl7benzoic acid
o




Prepared from the corresponding diethyl ester by saponifi-
cation with 2.5 equi~alents of sodium hydroxide.
Yield: 73.5 % of theory,
M.p.: 260C (decomp.)
Calc-: C 67.30 H 6.38 N 6.82
Found: 67.76 6.62 6.85

- 70 ~ 2 4 6

4~ (2- ~ ,4-Dioxa-8-azaspiro ~ . ~ decane-8-yl7phenyl)-
ethyl~-aminocarbonylmeth~17benzoic acid semihydrate

Yield: 85.7 ~ of theory,
M.p.: 130 - 135C (petroleum ether/acetone)
Calc.: (x 0.5 H20) C 66.49 H 6.74 N 6.46
Found: 66.56 6.65 6.46

4- ~ -Hydroxy-1-(2-piperidino phenyl)-ethyl)-aminocarbonyl-
meth 17benzoic acid
Y,

Yield: 65 % of theory,
lQ M.p.: 155 - 157C tdecomp) (petroleum ether/+ acetone)
Calc.: m/e = 382
Found: m/e = 382

4- ~1-(5-Chloro-2-(2-methyl-piperidino)-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic_acid

15 Yield: 64.1 % of theory,
M.p.: 195 - 198C (ethyl acetate)
Calc.: C 66.57 H 6.56 Cl 8.54N 6.75
Found: 66.01 6.25 8.32 6.90

4- ~1-(5-Aminocarbonyl-2-piperidino-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid

Yield: 86 % of theory,
M.p.: 231 - 235C (ethyl acetate)
Calc.: C 67.46 H 6.65 N 10.26
Found: 67.96 6.68 10.11

- 71 - 1 17624~
4- ~1-(2-(4-Methyl-piperidino)-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 67.7 % of theory,
M.p. : 173 - 175C (chloroform)
Calc.: C 72.61 H 7.42 N 7.36
Found: 72.20 7.36 7.45

4- ~1-(2-Piperidino-phenyl)-ethyl)-N-methylaminocarbonyl-
methyl7benzoic acid hvdrochloride

Conversion of the viscous betain (72 % crude) into the hydro-
chloride by means of hydrochloric acid in isopropanolic solu-
tion.
Yield: 32 ~ of theory,
M.p.: 222 - 230C (decomp.) (ethanol)
Calc.: C 66.25 H 7.01 Cl 8.50 N 6.71
Found: 66.07 6.37 8.37 6.58

2- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -
benzoic acid

Yield: 7 % of theory,
M,p.: 135C (decomp.)
Calc.: C 72.10 H 7.15N 7.64
Found: 72.29 7.03 7.37

3- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid _ _ _ _

Yield: 86 ~ of theory,
M.p.: 205 - 207C
Calc.: C 72.11 H 7.15N 7.64
Found: 72.30 7.29 7.71

1 17~246
- 72-

3-Chloro-4- ~1~(2-piperidino-phenyl)-ethyl)-amino-carbonyl-
methyl7benzoic acid

Yield: 38 % of theory,
M.p.: from 175C sintering, from 190C clear melt
Calc.: C 65.91 H 6.29 Cl 8.84 N 6.99
Found: 65.42 6.32 9.05 6.77

4- ~1-(2-(1,2,3,4-Tetrahydro-isoquinoline-2-yl)-phenyl)-
ethyl~-aminocarbonylmethyl7benzoic acid

Yield: 59 % of theory,
M.p. 207 - 209C
Calc.: C 75.34 H 6.32 N 6.76
Found: 75.30 6.29 6.67

4~ (3-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic
acid _ _ _ _

15 Yield: 33 % of theory,
M.p.: 206 - 208C
Calc.: C 72.09 H 7.15 N 7.64
Found: 72.04 7.14 7.57

4- ~1-(6-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
20 methYl7benzoic acid

Yield: 35 % of theory,
M.p.: 148 - 150C
Calc.: C 65.91 H 6.28 Cl 8.84 N 6.98
Found: 65.45 6.36 9.63 6.84

~ 73 ~ 1 176246
4- ~1-(6-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 33 % of theory,
M.p.: 170C
5 Calc.: C 72.60 H 7.41N 7.36
Found: 72.45 7.34 7.32

4- ~1-(2-(Octahydro-isoindole-2-yl)-phenyl)-ethyl)-amino-
carbonyl7benzoic acid _ _

Yield: 64 % of theory,
M.p.: 130C
Calc.: C 73.86 H 7.43N 6.89
Found: 73.60 7.47 6.72

4- ~1-(2-Decahydro-isoquinoline-2-yl)-phenyl)-ethyl)-amino-
carbonvlmethvl7benzoic acid

Yield: 71 % of theory,
M.p.: 220 - 221C
Calc.: C 74.25 H 7.66N 6.66 m/e = 420
Found: 74.45 7.50 6.58 m/e = 420

4- ~1-(2-(1,2,3,4,5,6,7,8-Octahydro-isoquinoline-2-yl)-
v 20 phenvl)-ethyl)-aminocarbonylmethyl7benzoic acid

Yield: 99 % of theory,
M.p.: 70C (decomp.)
Calc.: (x 0,5 H20) C 73.05 H 7.30 N 6.54 m/e = 418
Found: 73.00 7.165.98 m/e = 418

_ 7~ - L176~46

4~ (4-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 82.1 % of theory,
M.p.: 200 - 202C
5 Calc.: C 65.91 H 6.29Cl 8.84N 6.99
Found: 66.06 6.40 9.01 6.93

4- ~1-(4-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 66.5 % of theory,
10 M.p.: 110 - 115C
Calc.: C 72.60 H 7.42N 7.36
Found: 72.50 7.52 7.46

2-Piperidino-benzhydrYl~=aminocarbonylmethyl7benzoic acid

Yield: 88 % of theory,
15 M.p.: 232 - 234C
Calc.: C 75.68 H 6.59 N 6.54
Found: 75.16 6.52 6.74

4- ~ 5-Chloro-2-piperidino-benzhydryl)-aminocarbonylmethyl7-
benzoic acid

20 Yield: 78.5 % of theory,
M.p.: 255 - 260C
Calc.: C 70.05 H 5.88Cl 7.66N 6.o5
Found: 70.50 5.76 7.36 6.06

- 75 - I 1 7624 6
4-/¦1-(4-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid_

Yield: 81 % of theory,
M.p.: 208 - 210C
5 Calc.: C 72.11 H 7.15 N 7.64
Found: 72.24 7.26 7.54

4- ~1-(2-(4-Methyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 65 % of theory,
M.p.: 150 - 153C
Calc.: C 69.27 H 7.13 N 11.02
Found: 69.62 7.65 10.64

4- ~1-(2-(4-Benzyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid hvdrochlor de

15 Yield: 32 % of theory,
M.p.: 180C
Calc.: C 68.07 H 6.53 Cl 7.18N 8.51
Found: 67.85 6.56 7.18 8.51

4- ~1-(2-(4-p-Chlorophenyl-piperazino)-phenyl)-ethyl)-amino-
'~ 20 carbon~lmethyl7benzoic acid
.
Yield: 75 % of theory,
M.p.: 212C (decomp.)
Calc.: C 67.84 H 5.90Cl 7.42N 8.79
Found: 67.74 6.22 7 59 8.82

- 76 ~ 4~
4- ~ ~ -Cyclohexyl-2-piperidino-benzyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 33 ~ of theory,
M.p.: 199 - 202C
5 Calc.: C 74.62 H 7.89N 6.45
Found: 74.60 7.54 6.66

~+~-4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid x 0 3 H 0
~ 2 -- _ _
Yield: 40 % of theory,
lO M.p.: 107C (decomp. (isopropanol/ether)
r~72 = + 7.3 (c = 1; methanol)
Calc.: (x 0.3 H20) C 71.02 H 7.25 N 7.52 m/e = 366
Found: 70.90 7.22 7.42 m/e = 366

(-)-4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
15 ben~olc acid sodium salt
.
Crude yield of betain: 77 % of theory,
Calc.: m/e = 366
Found: m/e = 366
Conversion into the sodium salt by means of 1 equivalent of
20 sodium hydroxide solution in ethanol.
M.p. of the sodium salt: 190C (decomp.)

4- ~1-(2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7-
benzoic acid
. . ~ .

Yield: 53.6 ~ of theory,
25 M.p.: 158 - 160C (ethanol)
Calc.: C 72.51 H 6.64N 7.69
Found: 72.40 6.34 7.51

1 1 7624fi

4-[~1-(5-Cllloro-2-piperidino-phenyl)-ethenyl)-am~nocarbonyl-methyl] benzoic acid
Yield: 78.7 ~ of theory,
M.p.: 198 - 200C (acetone)
Calc.: C 66.24 H 5.81 Cl 8.88 N 7.02
Found: 65.74 5.72 9.37 7.10
4-[(~-Cyclohexylidene-2-piperidino-benzyl)-aminocarbonyl-methyll benzoic acid
Yield: 21 % of theory,
M.p.: 213 - 216C
Calc.: C 74.97 H 7.46 N 6.48
Found: 74.3 7.52 6.48
4-[(1-(6-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-methyl] benzoic acidYield: 39 % of theory,
M.p.: 162C
Calc.: C 66.24 H 5.81 Cl 8.88 N 7.02 m/e = 398/400
Found: 66.48 5.84 8.88 6.85 m/e = 398/400
4-~(1-(6-Methyl-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-methyl] benzoic acidYield: 49 % of theory,
M.p.: 128 - 130C
Calc.: m/e - 378
Found: m/e = 378
4-[(1-(2-Piperidino-phenyl)-propenyl)-aminocarbonyl-methyl] benzoic acid
Yield: 65 % of theory,
M.p. (Z - form): 185 - 187C (ethyl acetate)
Calc.: C 72.99 1-l 6.92 N 7.40
Found (Z - form): 73.10 6~99 7.56
M.p. (E - form): 108 - 110C

- 78 ~ 2 ~ 6
4~ (5-Hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid semihy~ra-te

Saponification with 2.5 equivalents of sodium hydroxide.
Yield: 55.9 % of theory,
5 Foam (~rom ether)
Calc.: (x 0.5 H20) C 67.50 H 6.95 N 7.16
Found: 67.11 7.15 6.87

4- ~1-(2-(2-Methyl-pyrrolidino)-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid

lO Yield: 62 ~ of theory,
M.p.: 169 - 172C
Calc.: C 72.11 H 7.15N 7.64
Found: 71.96 6.82 7.51

4- ~1-(5-Aminosulfonyl-2-piperidino-phenyl)-ethyl)-amino-
15 carbonylmethyl7benzoic acid _ _ _

Yield: 19.2 % of theory,
M.p.: 210C (decomp.)
Calc.: C 59.30 H 6.11N 9.43 m/e = 445
Found: 58.80 5.87 9.06 m/e = 445

20 4- ~1-(2-Piperidino-phenyl)-prop~l)-aminocarbonylmethyl7-
benzoic acid

Yield: 71.4 ~ of theory,
M.p.: 208 - 210C (ethanol)
Calc.: C 72.61 H 7.42N 7.36
Found: 72.30 7.44 7.45

25 Example 10

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid_ _ _ _ _

A solution of 13.5 g (0.338 mol) of sodium hydroxide in 50 ml
of water was added to 88.8 g (0.225 mol) of 4-L~1-(2-piperi-
30 dino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester

- 79 - Ll7624~
in 8~0 ml of ethanol and the mixture was stirred at an internal
temp~rature of 60C until no starting product could be detected
in the thinlayer chromatogram (approx. 45 minutes). After adding
400 ml of water the reaction mi~ture was adjusted at 25C
5 to p~ = 5.8 lusin~ a pE~ meter) by means of semi-concen-trated
hydrochloric acid. After a short time crystallization began.
After standing over~night at 20C, the precipitate was fil-
tered off and the crystals obtained were washed several times
with water. Subsequently, the crystals were dissolved in
methylene ch~oride and washed with alittle water. After dry-
ing the organic phase over sodium sulfate, the solution was
filtered and the solvent was removed in vacuo, whereby a solid
evaporation ~esidue of 57.5 g was obtained.
The ethanolic hydrochloric filtrate (pH = 5.8) was adjusted
to pH = 5.0 by means of semi-concentrated hydrochloric acid, then
the ethanol was distilled of in vacuo and the evaporated so-
lution was cooled in ice. The resultant precipitate was fil-
tered off, dissolved in methylene chloride, separated from
the a~ueous phase, the methylene chloride solution was dried,
filtered and evaporated in vacuo. The solid evaporation re-
sidue obtained was 13;0 g. Both evaporation residues (together
70.5 g) were recrystallized from the 5- to 6-fold amount of
ethanol/water (80/20) under addition of activated charcoal.
Yield: 62 % of theory,
M.p.: 16~ - 164C
Calc.: C 72.11 H 7.15 N 7.64
Found: 72.13 7.25 7.75
If on completion of the saponification, af~er the
addition of water and coolina to 25C immedia~ely the
30 pH is ad~usted to 5.0, and then continued as ~escribed
above, 75.9~ of the dried evaporation residue may be
obtained without further processin~ the etharlolic
hydrochloric filtrate, which even before tlne final
recrystallization ~ave a correct elementar~ analysis.
35 M.p. 172 - 176C
Calc.: C72.ll H 7.15 N 7.6~
Found: 71.90 7.08 7.52

1 1762~
- 80 -
Analogously to Example 10 the following compounds were prepared:

4- ~1-(5-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Yield: 56.6 % of theory,
M.p.: 215 - 217C (ethanol)
Calc.: C 72.61 H 7.42N 7.36
Found: 72.71 7.49 7.25

4- ~ dc-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl7
benzoic acid x o.66 H20

~' 10 Prepared by saponification of the 4~ -methoxycarbonyl-
2-piperidino-benzyl)-aminocarbonylmethyl7benzoic acid
ethyl ester with 2.5 equivalents of sodium hydroxide.
Yield: 72.2 % of theoryJ
M.p.: 235 - 240C (decomp.) (methanol/chlQrQform)
Calc.: (x 0.66 H20) C 64.69 H 6.33 N 6.85
Found: 64.64 6.23 6.61

Exam~le 11

4- ~1-(2-Piperidino-phenyl) ethyl)-aminocarbonylmethyl7-
benzoic acid sodium salt monoh~drate
~ .
500 mg (1.26 m mo:L) of 4- ~ 2-piperidino-phenyl)-ethyl)-
aminocarbonylmethy_7benzoic acid ethyl ester ln 5 ml of
- ethanol were stirred together with 1.26 ml of 1N-sodium
hydroxide solution for 1 hour at 50C. After cooling to
0C, the precipitated crystals were filtered off and washed
25 with cold ethanol and with ether.
Yield: 238 mg (48.6 % of theory),
M.p.: 245 - 250C
Calc.: (x 1 H20) C 65.01 H 6.69 N 6.89
Found: 65.40 6.83 6.72

76~4 ~?s

Analogously to Example 11 the following compound was prepared:

4~ (5-Methoxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid sodium salt monoh~drate

Yield: 17.5 96 of theory,
M.p.: 212 - 215C
Calc.: (x 1 H20) C 63.28 ~I 6.70 N 6.42
Found: 63.20 6.82 6.51

From the sodium salt was obtained analogously to Example 9
the corresponding acid as monohydrate:
~lO M.p.: 187 - 189C (ethanol/water)
Calc.: (x 1 H20) C 66.40 H 7.29 N 6.76
Found: 66.87 6.97 6.80

Example 1 2

4-Lr1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
5 benzoic acid sodium salt x 0.6 H20

8.4 g (0.0229 mol) of 4-~1-(2-piperidino-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid were dissolved at 60 to 65C
in 80 ml of ethanol. To this solution 22.9 ml of 1N sodium
hydroxide solution were added with stirring and stirring was
~ continued for 30 minutes. After cooling to 20C, a
precipitate was obtained. After cooling to 0C, the precipitate
was filtered and washed with cold ethanol and ether, The
precipitate thus obtained,of m.p. 250 - 251C, was recrystalli-
zed from ethanol/water (7/3).
,~ Yield: 7.2 g (78.6 % of theory),
M.p.: 253 - 255C
Calc.: (x o . 6 H20): C 66.18 H 6.61 N 7.02
Found: 66.10 6.64 7.13

1 ~7~24~
Examl~le 13

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy~7-
benzoic acid
-

100 mg (0.237 m mol) of 4-L~1-(2-piperidino-phenyl)-ethyl)-
5 aminocarbonylmethyl7benzoic acid-tert.butyl ester in 5 ml
of benzene were heated together with some crystals of
p-toluene sulfonic acid hydrate to reflux temperature for
half a day. According to the thinlayer chromatogram then
no starting product could be detected, and according
10 to the Rf-value and mass spectrum the desired product was
formed.
M.p.: 163 - 165C
Calc.: m/e = 366
F'ound: m/e = 366

15 EYample 14

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarhonylmethyl7-
benzoic acid

o.46 g (1 m mol) of 4-~1-(2-piperidino-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid benzyl ester in 20 ml of
20 ethanol were hydrogenated at 0.25 g of palladium/charcoal
at 50C and a hydrogen pressure of 5 bar. After 5 hours
the catalyst was filtered off over celite and the filtrate
was evaporated in vacuo. The evaporation residue was re-
crystallized from ethanol/water (8/2).
25 Yield: O.Z6 g (71 % of theory),
M.p.: 163 - 165C
Calc.: C 72.11 H 7.15 N 7.64
Found: 72.30 7.25 7. a1

Example 15

30 4-~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid
2.54 g (0.02 mol) of oxalyl chloride were dropped at 0 to 5C

2 4 fi

to a stirred solution of 3.57 g (0.01 mol) of N~ (5-chloro~
2-piperidino-phenyl)-ethyl7-N~/~henacetyl7amine in 16 ml of
carbon disulfide and subsequently 2.67 g (0.02 mol) of alumi-
nium chloride were added. After one hour again the same amounts
5 of oxalyl chloride and aluminium chloride were added and the
mixture was heated subsequently for 3 hours up to 50C. After -
cooling, ice water and hydrochloric acid were added and the
reaction mixture was extracted with chloroform. The organic
extract was dried and filtered and evaporated in vacuo. The
10 evaporation residue was purified by column chromatography on
silica gel (chloroform/methanol = 10:1).
Yield: o.60 g (15 % of theory),
~;_ M.p.: 213 - 214C (ether)
Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99
Found: 66.13 6.05 8.97 7.25

Example 16

N-~-Acetyl-phenacetyl7-N-L~-(5-chloro-2-piperidino-phenyl)-
ethyl7amine

A solution of 0.6 ml (8.43 m mol) of acetyl chloride in
20 5 ml of methylene chloride was added at an internal tempera-
ture of 0 to 5C to 1.12 g (8.43 m mol) of aluminium chloride
~_,, in 10 ml of methylene chloride. Subsequently, at 0 to 5C, a
solution of 1 g (2.81 m mol) of N-~-(5-chloro-2-piperidino-
phenyl)-ethy~7-N-/phenacetyl7amine in 5 ml of methylene chlo-
25 ride was added with stirring. The reaction mixture was stirred
for 1 hour at 3C and for 2 days at 20C. After decomposing
under cooling with ice water and hydrochloric acid, the
methylene chloride phase was separated and the aqueo-ls phase
was extracted with chloroform. The comblned organic phases were
30 drled over sodium sulfate, filtered and evaporated in vacuo. The
evaporation residue was purified by column chromatography on
silica gel (toluene/acetone = 4:1).
~ield: 0.28 g (25 % of theory),
M.p.: 160 - 161C
Calc.: C 69.24 H 6. 82 Cl 8.89 N 7.02 m/e = ~98/400
Found: 69.55 6 ~ 99 9.45 6.85 m/e = 398/400

~4
1 17~246

Example 17

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

A solution of 1.23 g (0.0031 mol) of N- ~ -acetyl-phen-
acety ~ -N- ~ -(5-chloro-2-piperidino-phenyl)-ethyl7amine
in 12 ml of dioxan was a~ded over 15 minutes at
35 - 40C to a stirred sodium hypobromite solution /Pre-
pared from 1.84 g (0.046 mol) of sodium hydroxide, dis-
solved in 9 ml of water, and 0.72 ml (0.014 mol) of bromine
under ice coolin~7. After 40 minutes at 35 - 40C aqueous
sodium hydrogen sulfite solution and water was added and
the mixture was evaporated in ~acuo. The residue was dis-
solved with water, acidified under cooling with 2N~hydrochlo-
ric acid and extracted with ether/ethyl acetate. The organic
phase was dried and filtered, and evaporated in vacuo.
The evaporation residue was recrystallized from ether.
Yield: 0.14 g (11 % of theory),
M.p.: 213 - 215C
Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99
2Q Found: 65.78 5.98 8.95 7.17

Analogously to Example 17 the following compound was prepared:

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 15 % of theory,
M.p.: 170 - 171C
Calc.: C 72.11 H 7.15N 7.64
Found: 72.45 7.G1 7.48

Example 18

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzaldehyde

Prepared from 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbo-

~ ~7624~

nylmethyl7benzyl alcohol by oxidat:ion with active manga-
nese dioxide in absolute acetone and subsequent purifi~
cation by column chromatography on silica gel (chloroform/
acetone = 20:1).
5 Yield: 4 ~ of theory,
M.p.: 159C
Calc.: C 75.40 H 7.48 N 7.99
Found: 75.05 7.18 7.67

Example 19

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid

Prepared from 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbo-
nylmethyl7benzaldehyde by heating with silver oxide in the
presence of 1N sodium hydroxide solution for 20 minutes on
~ steam bath 9 subsequent acidification with 2N sulfuric
acid at pH = 5, extraction with ethyl acetate and purifi-
cation by column chromatog~aphy on silica gel (toluene/
acetone = 1:1).
Yield: 3 ~ of theory
20 M.p.: 168 - 170C
Calc.: m/e = 366
Found: m/e = 366

Example 20

4- ~1-(2-Piperidino-phenyl)_ethyl)-aminocarbonylmethyl7-
benzoic acid ethyI ester

5.5 g (0.014 mol) of 4- ~1-(2-piperidino-phenyl)-ethenyl)-
aminocarbonylme-thyl7benzoic acid ethyl ester in 110 ml of
ethanol were hydrogenated at 1.5 g of palladium/charcoal
(10 %) at 20C and a hydrogen pressure of 5 bar. After
- 30 30 minutes the catalyst was filtered off over celite and


.

-


~f l 176246

the filtrate was evaporated in vacuo to a volume of 20 ml.
100 ml of petroleum ether were adde and the mixture was
cooled to 0C.
Yield: 4.7 g (85.5 ~0 of theory),
5 M.p.: 152 - 154C
Calc.: C 73.0~ H 7.66 N 7.10
Found: 72.80 7.63 7.08

Analogously to Example 20 the following compound was prepared:

4-~-(2-Piperidino-phenyl)-propyl)-aminocarbonylmethy_7benzoic
lO acid ethYl ester
V




Yield: 70.8 % of theory,
M.p.: 132 - 134C
Calc.: C 73.00 H 7.90 N 6.86
Found: 73.71 7.88 6.77

15 Example 21

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid

100 mg (0.2744 m mol) of 4-f~1-(2-piperidino-phenyl)-ethenyl)-
aminocarbonylmethyl7benzoic acid in 5 ml of absolute ethanol
20 were hydrogenated at 50 mg of palladium/charcoal (10 %) at
20C and at a hydrogen pressure of 1 bar under sha~sing.
After 1.5 hours the catalyst was filtered off and the fil-
trate was evaporated in vacuo.
._
Yield: 91 % of theory,
25 M.p.: 170 - 171C
Calc.: m/e = 366
Found: m/e = 366

~7 1 17~24~;

Example 22

4-~1-(2-Piperidino-phenyl)-ethyl)-amlnocarbonylmethyl7-
benzoic acid semihydrate

200 mg (0.5014 m mol) of 4-L~1-(5-chloro-2-piperidino-
5 phenyl)-ethenyl)-aminocarbonylmethyl7benzoic acid in
10 ml of absolute ethanol were hydrogenated at 100 mg of
palladium/charcoal (10 %) at 50C and at hydrogen pressure
of 1 ,bar under shaking. After 1.5 hours the catalyst was
filtered off, 5 ml of water were added, adjusted to pH = 6
10 by means of 1N-sodium hydroxide solution and the ethanol
was evaporated in_. A colourless precipitate was ob-
tained, which was filtered after cooling~
Yield: 100 mg (53.1 % of theory),
M.p.: 135C
Calc.: (x 0.5 H20) C 70.36 H 7.24 N 7.46 m/e = 366
Found: 70.31 7.44 7.78 m/e = 366

Example 23

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7
benzoic acid ethvl ester

~, 20 1.6 ml of conc. sulfuric acid were added in little drops to
' a' mixture of 2 g (9.74 m mol) of 1-(2-piperidino-phenyl)-
ethanol and 4 g (21.1 m mol) of 4-cyanomethyl-benzoic acid
ethyl ester whilst stirring and cooling with ice by keeping
the internal temperature at 35 to 40C. Subsequently, the
25 mixture was heated for 2.5 hours in a bath of 80C, further
2 g (10.5 m mol) of ~-cyanomethyl benzoic acid ethyl ester
and 0.8 ml of conc. sulfuric acid were added and heating
was continued for 1 hour at 80C and for 3 hours at 100C.
After that time no starting alcohol could be detected in
30 the thinlayer chromatogram. After cooling to 20C the mix-
ture was extracted with ethyl acetate whilst stirring and

8~
24~

cooling ice water was added. After extracting several timeswith ethyl acetate, the organic extract was dried over sodium
sulfate, filtered and evaporated in vacuo. The evaporation
residue was purified by column chromatography on silica gel
(toluene/acetone = 10:1). From the pre-fractions 0.5 g of
2-piperidino-styrol were isolated.
Yield: 0.66 g (17.4 % of theory),
M.p.: 147 - 150C (ethanoI)
Calc.: C 73.07 H 7.66 N 7.10
Found: 73.26 7.55 6.90

Example 24

4- ~'1-(5-Chloro-2-piperidino-phenyl)-ethyl~-aminocarbonyl-
methyl7benzoic acid

0.4 ml (5.55 m mol) of thionyl chloride were added to a
stirred solution of 1 g (5.55 m mol) of 4-carboxy-phenyl-
acetic acid and of 1.32 g (5.55 m mol) of 1-(5-chloro-
2-piperidino-phenyl)-ethylamine in 10 ml of absolute py-
ridine, whereby the internal temperature rised from 20C
to 35C. The deep-brown reaction mixture was stirred for
3 hours at 20C and evaporated in vacuo. The evaporation
residue was distributed between water (at pH = 3 after
addition of 2N hydrochloric acid) and chloroform. The or-
ganic extract was dried and filtered and evaporated in vacuo.
The evaporation residue was purified by column chromatography
25 on silica gel (chloroform/methanol = 10
Yield: 1.06 g (48 % of theory),
M.p.: 212 - 214C (ether)
Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99
Found: 65.79 6.01 8.69 6.87

~9 ~ 176245

Analogously to Example 24 the following compounds were prep~red:

4- ~1-(2~Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid

Yield: 52 % of theory,
M.p.: 169 - 171C
Calc.: C 72.11 H 7.15N 7.64
Found: 71.84 6.87 7.72

4~ (2-(4-Oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic_acid _ _ _ _ _ _

lQ Yield: 32 % of theory,
M.p.: 177 - 130C (decomp.) (acetone/petroleum ether)
Calc.: C 69.46 H 6.36 N 7.36
Found: 69.62 6.41 7.50

4- ~1-(2-(4-Hydroxy-piperidino)-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid x 0.66 H20 _ _

Yield: 23.5 % of theory,
M.p.: 176 - 179C (decomp.) (acetone/petroleum ether)
Calc.: (x o.66 H20) C 66.97 H 6.81 N 7.10
Found: 67.12 6.78 7.26
V
4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzonitrile

Prepared from 4-cyano-phenyl acetic acid.
Yield: 51 ~ of theory,
M.p.: 155 - 157C (ethyl acetate)
Calc.: C 76.05 H 7.25 N 12.09
Found: 76.41 7.10 12.20

9') 117624~



ExamPle 25

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzyl
alcohol _ _ _

Prepared from 4-L~1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl-
5 methyl7benzoic acid ethyl ester by lithium aluminium hydride
reduction in tetrahydrofuran.
Yield: 39 ~ of theory,
M.p.: 104 - 106C
Calc.: C 74.96 H 8.00N 7.94
Found: 74.80 7.80 7.80

Example_26

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7
benzyl malonic acid diethyl ester_

A solution of 3.7 g (10 m mol) of 4- ~1-(2-piperidino-phenyl)-
ethyl)-aminocarbonylmethyl7benzyl chloride ~ .p.: 12~ - 125C;
prepared from the alcohol described in Example 25 by means of
thionyl chloride in chlorofor_ 7 in 35 ml of absolute ethanol
was added to a solution of sodium malonic acid diethyl ester
f~repared from 0.7 g (30 m mol) of sodium in 25 ml of absolute
ethanol and 4.8 g (30 m mol) of malonic acid diethyl este ~ .
A catalytic amound of potassium iodide was added and the

1 1 ~624fi

mixture was refluxed for 16 hours. After evaporating in
vacuo, the evaporation residue was adjustedlneutral by
means of hydrochloric acid and extracted with methylene
chloride. The organic extract was dried over sodium sul-
5 fate, filtered and and evaporated in vacuo. The evapora-
tion residue was purified by column chromatog-aphy on
silica gel (toluene/acetone = 6:1).
Yield: ~.0 g (60 ~0 of theory),
M.p.: <20 C
lO Calc.: m/e = 494
Found: m/e = 494

Example 27

3- ~ ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -
phenyl7prop onic_acid

15 5 ml of 1N-sodium hydroxide solution were added to a solution
of 0.85 g (1.7 m mol) of 4- ~1-(2-piperidino-phenyl)-ethyl)-
aminocarbonylmethyl7benzyl malonic acid diethyl ester in
18 ml of ethanol. After stirring for 2 hours at 50C, the
mixture was evaporated in vacuo, and water and 5 ml of 1N-
20 hydrochloric acid were added. The formed precipita-te was
filtered off, dried in vacuo and heated for 30 minutes up
to 120C, whereby carbon dioxide was liberated . The
product was purified by column chromatography on silica
gel (chloroform/methanol = 20:1).
25 Yield: 0.15 g (22.4 % of theory),
M.p.: 68 - 70C
Calc.: C 73.06 H 7.67 N 7.10 m/e = 394
Found: 72.64 7.42 6.81 m/e = 394

,3, 1176246


4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzaldehyde

Prepared by heating crude N1- ~ - ~1-(2-piperidino-
5 phenyl)-ethyl)-aminocarbonylmethyl7benzoyl7-N2-tosyl-
- hydra~ine in anhydrous sodium carbonate at 160 - 170C
in ethylene glycol ~ repared from 4-/¦1-(2-piperidino-phenyl)-
ethyl)-aminocarbonylmethyl7benzoic acid and tosyl-hydrazine
with carbonyl diimidazole in tetrahydrofuran7.
lO Yield: 10 % of theory,
M.p.: 159C
Calc.: C~75.40 H 7.48N 7,99
Found: 74.99 7.24 7.60

Example 29

15 4-/T1-(2-piperidino-phenyl)-ethyl)-aminocaIbonylmethyl7
- benzoic acid

0.50 g (1.247 m mol) of 4- ~1-(5-chloro-2-piperidino-phenyl)-
ethyl)-aminocarbonylmethyl7benzoic acid in 20 ml of absolute
ethanol were hydrogenated at 0.25 g of palladium/charcoal
; 20 (10 %) at 50C and a hydrogen pressure of 5 bar. After 2 hours
the catalyst was filtered off over celite and after evaporatlng
i vacuo the residue was distributed at pH = 6 be-
tween water and ethyl acetate. The organic extract was washed
with water, dried and filtered and evaporated ln vacuo.
25 Yield: 0.31 g (67 % of theory),
M.p.: 170 - 172C (ether)
Calc.: C 72.11 H 7.15 N 7.64
Found: 71.76 6.98 7.51

()3 Il76246

Analogously to Example 29 the following compounds were prepared:

4- ~ 2-(2-Piperidino-phenyl)-2-propyl)-aminocarbonylmethy ~ ~
benzoic acid _ _ _ _ _ _ _ _

Yield: 68.5 ~ of theory,
5 M.p.: 213 - 215C
Calc.: C 72.61 H 7.42N 7.36
Found: 72.43 7.25 7.40

4- ~1-(2-Dimethylamino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid
-
lO Yield: 53.3 ~ of theory,
M.p.: 165 - 168C (acetone/petroleum ether)
Calc.: C 69.92 H 6.79 N 8.59
Found: 69.88 6.83 8.49

4-/~2-PYrrolidino-benzyl)-aminocarbonYlmethyl7benzoic acid

Yield: 55 % of theory,
M.p.: 212 - 215C (methanol)
Calc.: C 70.99 H 6.55 N 8.28
Found: 70.97 6.91 8.15

4- ~1-(2-Pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl7-
20 benZoic acid
.

Yield: 25 % of theory,
M.p.: 155 - 157C (acetone/ether)
Calc.: C 71.57 H 6.86 N 7.95
Found: 71.22 6.75 8.42

117~2~6


4-/~2-PiPeridino-benzyl~-aminocarbonylmethyl7benzoic acid

Yield: 60.4 ~ of theory,
M.p.: 175 - 177C (acetone)
Calc~: C 71.57 H 6.86 N 7.95
Found: 71.48 7.00 8.09

4-L~2-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -
benzoic acid

Yield: 60.4 % of theory,
M.p.: 164 - 166C (ethyl acetate)
Calc.: C 72.11 H 7.15 N 7.64
Found: 72.35 7.18 7.76

4- ~1-(2-(2-Methyl-piperidino)-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid

Yield: 90.9 % of theory,
M.p.: 171 - 173C (petroleum ether/acetone)
Calc.: C 72.61 H 7.42 N 7.36
Found: 72.30 7.39 7.43

4- ~1-(2-(3-Methyl-piperidino)-phenyl)-ethyl)-aminocarbonyl-
methyl7b nzoic acid

Yield: 86.3 % of theory,
M.p.: 170 - 173C (petroleum ether/acetone)
Calc.: C 72.61 H 7.42 N 7.36
Found: 72.20 7.28 7.12

4- ~1-(2-Dipropylamino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid
. . . _ . . . _ . .

Yield: 51.1 % of theory,
M.p.: 175 - 178C (ethyl acetate)
Calc.: C 72.22 H 7.91 ~ 7.32
Found: 72.10 8.05 7.69

~)5 tl7~45

4~ (2-Piperidino-phenyl)-2-methyl-propyl)-aminocarbonyl-
methvl7benzoic acid _ _

Yield: 86 % of theory,
M.p.: 215 - 217C (acetone)
5 Calc.: C 73.06 H 7.67 N 7.10
Found: 73.10 7.55 6.99

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid methyl ester

Prepared from 4-/r1-(5-chloro-2-piperidino-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid methyl ester.
Yield: 37.2 % of theory,
M.p.: 145 - 147C
Calc.: C 72.61 H 7.42 N 7.36
Found: 72.47 7.30 7.56

4- ~ 2-piperidino-anilino)-carbonylmethyl7benzoic acid methyl
ester

Prepared from 4- ~ 5-chloro-2-piperidino-anilino)-carbonyl-
methyl7benzoic acid methyl ester.
Yield: 60 ~0 of theory,
M.p.: 85 - 86C (toluene/petroleum ether)
~ Calc.: C 71.57 H 6.86 N 7.96
Found: 71.48 6.92 8.39

'3~ 624~
N-Phenacetyl-N-l1-(2-piperidino-phenyl)-ethyl7amine

Prepared from N-L1-(5-chloro-2-piperidino-phenyl)-ethyl7-
N-phenacetyl-amine.
Yield: 54.6 % of theory,
M.p.: 120 - 121C (petroleum ether/acetone)
Calc.: C 78.22 H 8.13 N 8.69
Found~ 77.90 8.24 8.75

Example 30

4-L¦1-(5-Amino-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid methyl ester _ _

2.0 g (0.0047 mol) of 4- ~1-(5-nitro 2-piperidino-phenyl)-
ethyl)-aminocarbonylmethyl7benzoic acid methyl ester in
20 ml of dimethyl formamide were hydrogenated at 0.2 g of
palladium/charcoal (10 %) in a Parr apparatus at 20C and
a hydrogen pressure of 1 bar. When the hydrogen absorption
was finished (2 hours), the catalyst was filtered off over
celite and evaporated +o dryness in vacuo.
Yield: 1.8 g (95 % of theory),
M.p.: 140 - 142C (toluene).

Analogously to Example 30 the following compounds were prepared:

4- ~1-(5-Amino-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

Yield: 97.8 % of theory,
M.p.: 148 - 149.5C (cyclohexane)
Calc.: C 70.39 H 7.63 N 10.26
Found: 70.20 7.67 9~60

4-L~1~(5-Amino-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid _

Prepared from 4-L~1-(5-nitro-2-piperidino-phenyl)-ethyl3-
aminocarbonylmethyl7benzoic acid.

I 1 762~6


Y;eld: 85.7 % of theory,
M.~.: 223 - 225C (ether)
Calc.: C 69.27 H 7.13 11.02
Found: 69.18 7.04 11.35

N-[4-Amino-phenacetyl]-N-[1-(2-piperidino-phenyl)-ethyl]-amine dihydrochloride
_ _ _ semihydrate
Prepared from N-[4-nitro-phenacetyl]-N-[(1-(2-piperidino-phenyl)-ethyl]amine.
Conversion of the crude amino compound into the dihydrochloride in ethanol
was by means of ethereal hydrochloric acid.
Yield: 17.5 % of theory,
M.p.: 238C (decomp.)
Calc.: (x 2 HCl x 0.5 H20)C 60.12H 7.21 Cl 16.91
Found: 60.52 7.52 17.05

Example 31

4-[(1-(5-Bromo-2-piperidino-phenyl?-ethyl)-aminocarbonylmethyl]benzoic acid
A solution of 0.072 g (1.05 m mol) of sodium nitrite in 0.5 ml of water was
added at an internal temperature of 0 to 5C to 0.40 g (1.05 m mol) of
4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid
in 2 ml of semi-conc. aqueous hydrobromic acid. The resultant diazonium salt
solution was then added to 0.196 g of copper (I) bromide in 2 ml of 48 %
hydrobromic acid, whereby considerable formation of gas occurred. The reaction
mixture was stirred for 1.5 hours at an internal temperature of 45 - 50C,
cooled and adjusted to pH 4 by means of 4N sodium hydroxide solution. After
extraction with warm e-thyl acetate, the extract was washed with water, dried
and filtered. After evaporating in vacuo, the obtained residue was purified
by column chromatography on silica gel (chloroform/methanol = 7:1).




-97-

I t7~24 6

Yield: 0.08 g (17 % of theory),
M.p.: 212 - 213C (ethyl acetate/petroleum ether)
Calc.: C 59.32 H 5.66 Br 17.94 N 6.29
Found: 59.30 5.71 17.85 6.48

Analogously to Example 31 the i'ollowing compound was prepared:

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

Prepared by diazotization of 4- ~1-(5-amino-2-piperidino-
phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid in conc.
HCl and Sandmeyer reaction with copper (I) chloride.
Yield: 25.2 % Gf theory,
M.p.: 213 - 215C
Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99
Found: 66.20 6.~1 8.87 6.~2

If the reaction is carried out in hydrochloric acid without
copper (I) chloride, a yield of 19 % of theory is obtained.
Furthermore, 9 % of the corresponding 5-hydroxy compound is
obtained.

Example 32

~20 4- ~1-(5-Iodo-2-piperidino-phenyl) ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester

A solution of 0.17 g (2.44 m mol) of sodium nitrite in
0.52 ml of water was slowly added at 0 to 5C whilst
stirring to 1.0 g (2.44 m mol) of 4- ~1-(5-amino-2-piperi-
dino-phenyl)-ethyl)-aminocarbonylmethyl7benZoiC acid ethyl
ester in 1.9 ml of semi-conc. hydriodic acid and the solu-
tion was warmed to 20C over 1 hour. After heating for
2 hours at 100C, the reaction mixture was cooled and ex-
tracted with ethyl acetate. The organic phase was washed

~ 1~6246

with dilute sodium bicarbonate solution and with water,
dried over sodium sulfate, filtered, and evaporated in
vacuo. The evaporation residue was purified by column
chromatography on silica gel (toluene/acetone = 5:1).
5 Yield: 0.011 g (0.93 % of theory),
M.p.: 145 - 147C (ether)
Calc.: C 55.39 H 5.62 N 5.38 m/e = 520
Found: 55.95 5.53 5.05 m/e = 520

Example ~3

lO 4- ~1-(5-Cyano-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl_ester _ _

A solution of 0.34 g (4.88 m mol) of sodium nitrite in
2.3 ml of water was ~d~, with stirring at -5 to 0C,
to 2.0 g (4.88 m mol) of 4- ~1-(5-amino-2-piperidino-phenyl)-
15 ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester in 4.0 ml
of water and 3.5 ml of conc. hydrochloric acid. The mixture
- was stirred for 15 minutes and then neutralized with 1.1 g
of calcium carbonate. The suspension thus obtained was added
by means of 2xlSml portions of water into a 0C solution, which
20 was prepared from 0.568 g (6-.~4 m mol) of copper (I) cyanide,
1.24 g (19 m mol) of potassium cyanide and 5.8 ml of water,
whereby immediately a red-coloured precipitate was obtained.
The reaction mixture was heated whilst stirring for 30 minu-
tes at an internal temperature of 45C, then for 30 minutes
25 at 70C and for 60 minutes at 95C. The red-coloured spot was
now no lo~ger visible in the thinlayer chromatogram,
The reaction mixture was cooled to 20C and
extracted with ethyl acetate. The organic extract was dried
over sodium sulfate, filtered, and evaporated in vacuo. The
30 evaporation residue was purified by two column chromatogra-
phies on sllica gel ((a) toluene/acetone = 10:1, (b) methylene
chloride/acetonitril~glacial acetic acid =10:1:0.05). Besides
the corresponding 5-Cl- and 5~H-compourds, the desired
5-cyano compound was obtained.
35 Yield: 0.1~6 g (9 % of theory),
M.p.: 165 - 167C (ether)

~ 1 76246

Calc.: C 71.58 ~ 6.97 N 10.02 m/e = 419
Found: 71.64 6.94 9.72 m/e = 419

Example 34

4-L~1-(5-Aminosulfonyl-2-piperidino-phenyl)-ethyl)-amino-
carbonvlmethvl7benzoic acid ethvl ester

a) A solution of 0.37 g (5.36 m mol) of sodium nitrite in
0.7 ml of water was added with stirring at 4 to 6C
to a suspension of 2.0 g (4.88 m mol) of 4- ~1-(5-amino-
2-piperidino-phenyl)-aminocarbonylmethy ~ benzoic acid
ethyl ester in 2.02 ml of semi-conc. hydrochloric acid.
Subsequently, 0.37 g (3.89 m mol) of ma~nesium chloride
were added. The mixture thus obtained was dropped sub-
sequently at 30C to a solution, which w`as prepared from
4.9 ml of glacial acetic acid (saturated with sulfur di-
oxide) and 0.27 g of copper(II)chloride dihydrate. There-
b~ the internal temperature rose to 40C and nitrogen
was formed. After stirring for 15 minutes in a bath at
50C, 7.5 ml of water were added and the mixture was ex-
tracted with chloroform. The organic extract was dried
over sodium sulfate, filtered, and evaporated in vacuo.
The viscous, red-brown evaporation residue (2.7 g; still
chloroform-containing) contained besides the correspon-
ding 5-chloro-compound the desired 4- ~1-(5-chlorosulfonyl-
2-piperidino-phenyl)-ethyl)-aminocarbonylmethy_7benzoic
acid ethyl ester.

b) A solution of the evaporation residue obtained according
to Example a) in 10 ml of chloroform was added at 2C
whilst stirring to 50 ml of conc. ammonia. After 30 minu-
tes saturated sodium chloride solution was added to ob-
tain separation of the phases. After extractingwith chloroform, the organic extract was dried and fil-
tered and e~aporated in vacuo. The evaporation residue
was purified by column chromatography on silica gel

l o l
1 1~624~
(chloroform/methanol = 10:1). Besides 55 ~ of the corres-
ponding 5-chloro-compound the desired 5-aminosulfonyl
compound was obtained as foam.
Yield: 32 % of theory,
Calc.: m/e = 473
Fourd: m/e = 473

Example 35

4-~¦1-(5-Dimethylamino-2-piperidino-phenyl)-ethyl)-
aminocarbonvlmethyl7be~zoic acid

, 10 10 g (1.589 m mol) of sodium-cyanoboro - hydride and after
2 minutes 0.056 ml of glacial acetic acid were added at
20C to a stirred solution of 0.20 g (0.5242 m mol) of
4-/¦1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbo-
nylmethyl7benzoic acid and 0.45 ml of 40 % formalin in
2 ml of acetonitri~ and 1 ml of absolute dimethyl ~orm-
amide, After 1.5 hours the reaction mixture was evapora-
ted in vacuo. The evaporation residue was dissolved in
, .
water by addition of hydrochloric acid at pH 2 - 3.
After several ~ extrac-tior~ with chloroform the
aqueous phase was adjusted to pH 6 to 7 by means of
saturated sodium hydrogen carbonate solution an~lextracted
several times with chloroform. This organic extract was
dried and filtered. After evaporating in vacuo the evapora-
tion residue was recrystallized from isopropanol. The colour-
less crystals were washed with absolute ether.
Yield: 0.09 g (42.8 % of theory),
M.p.: 185C (decomp. from 175C)
Calc.: C 70.39 H 7.63 N 10.26
Found: 70.10 7.63 10.47

Example 36

4- ~1-(5-Acetylamino-2-piperidino-phenyl)-ethyl)-amino-
carbonylmethYl7benzoic acid

0.10 g (0.262 m mol) of 4- ~1-(5-amino-2-piperidino-phenyl)-
ethyl)-aminocarbonylmet~ly ~ benzoic acid in 1 ml of acetic an-


102
11~624~
hydride were stirred for 6 hours at 20C, then evaporatedin vacuo, distilled off several times with toluene, and
. . ~
the evaporation residue was recrystallized from ether.
Yield: 0.08 g (72.7 /0 of theory),
M.p.: 241 - 243C
Calc.: C 68.07 H 6.90 N 9.92
Found: 67.53 6.8~ 9.72

Example 37

4- ~1-(5-Benzoylamino-2-piperidino-phenyl)-ethyl)-amino-
carbon~lmethyl7benzoic acid _ _

0.30 ml (2.62 m mol) of benzoyl chloride were added to
a solution of 1 g (2.62 m mol) of 4- ~1-(5-amino-2-piperi-
dino-phenyl)-ethyl)-aminocarbonylmethy ~benzoic acid and
0.37 ml (~ 62 m mol) of triethylamine in 10 ml of anhy-
drous dimethyl formamide. After stirring for 2 hours at
20 - 30C, the reaction mixture was evaporated in vacuo
and distributed between water and ethyl acetate. The or-
ganic phase was dried and filtered and evaporated ~IL~
The evaporation residue (1.12 g) was recrystallized from
ethanol by addition of acti~ated charcoal.
Yield: 0.5 g (39.4 % of theory),
M.p.: 225 - 227C
Calc.: C 71.73 H 6.43 N 8.65
Found: 7i.70 6.50 8.66

Analogously to Example 37 the following compound was prepared:

4~ (5-Ethoxycarbonylamino-2-piperidino-phenyl)-ethyl)-
aminocarbonylmethvl7benzoic acid

Yield: 34.2 % o~ theory,
M.p.: 220C (decomp.)
Calc.: C 66.21 H 6.89 N 9.26
Found: 65.97 6.83 9.57

lO3 ~ 17624t3

Example 38

4~ (5-Methylsulfonylamino-2-piperidino-phenyl)ethyl)-
aminocarbo~Ylmethvl7benzoic acid

0.20 ml (0.262 m mol) of mesyl chloride were added to a
solution of 0.10 g (0.262 m mol) f 4-L~1-(5-amino-2-pi-
peridino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid
in 1 ml of anhydrous pyridine. After the exothermic reac-
tion was finished the mixture was allowed to stand for
4 hours at 20C. Subsequently the reaction mixture was
evaporated in vacuo and the evaporation residue was di-
~;~ stributed at pH 2 - 3 between water and chloroform. The
acidic aqueous phase was adjusted to pH 6 to 7 by means
of sodium hydrogen carbonate solution and extracted with
chloroform. This chloroform extract was dried and filtered.
The residue obtained after evaporating in vacuo was puri-
fied by column chromatography on silica gel (chloroform/
methanol = 4:1).
Yield: 0.03 g (25 %. of theory),
M.p.: 210 - 220C (decomp.) (ether)
Calc.: mol peak m/e = 459
Found: m/e = 459

Example 3g
V
4-LT1-(5-Acetoxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid

0.35 g (0.915 m mol) of 4-~1-(5-hydroxy-2-piperidinophenyl)-
ethyl)-aminocarbonylmethyl7benzoic acid were heated together
with 0.103 ml (1.098 m mol) of acetic a~hydride on the steam
bath and after standing for 4 days at 20C, the reaction
mixture was recrystallized from methanol.
Yield: 0.16 g (41.2 % of theory),
M. p.: 218 - 221C
Calc.: C 67.91 H 6.65 N 6.60
Found: 67.70 6.~5 6.55

1~4
1 ~76246
Example 40

4~ (5-Methoxy-2-piperidino-phenyl)-ethyl)-amino-
carbon~lmethyl7benzoic acid methyl ester

A solution of 60 mg (0,157 m mol) of 4- ~1-(5-hydroxy-
2-piperidino-phenyl)-ethylj-aminocarbonylmethyl7benzoic
acid in 1 ml of methanol (~ 1 drop of water) was add~
dropwise ~ an ethereal diazomethane solution, un-
til no formation of gas took place. To destroy excess
diazomethane 2N acetic acid was added. After evaporating
in vacuo, the evaporation residue was distributed be-
tween toluene/ether and dilute sodium hydroxide solution.
After drying, filtering and evaporating the organic phase
in vacuo, the evaporation residue was purified by column
chromatography on silica gel (chloroform/methanol = 5:1).
Yield: 27 % of theory,
M.p~: Foam
Calc.: mol Feak m/e = 410
Found: m/e = 410

Example 41

4- ~1-(5-Benzyloxy-2-piperidino-phenyl)-ethyl)-amino-
carbonvlmeth~l7benzoic acid ethYl ester

~ solution of 0.50 g (1.218 m mol) of 4- ~1-(5-hydroxy-
2-piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ benzoic
acid ethyl es-ter in 10 ml of anhydrous dimethyl formamide
was quickly ad~ed to a suspension of 1.353 m mol of
sodium hydride (32.5 mg of a 50 % suspension in oil) in
2 ml of anhydrous dimethyl formamide. ~fter stirring for
1.5 hours at 20C, 0.16 ml (1.353 m mol) of benzyl bromide,
dissolved in 2.3 ml of anhydrous dimethyl formamide, were
added and stirring was continued for 16 hours at 20C.
After evaporating in vacuo the residue was distributed
between water and ether. The organic extract was dried~

2 4 6
filtered and evaporated in vacuo. The evaporation residue
was purified by column chromatography on silica gel
(toluene/acetone = 10:1).
Yield: 0.34 g (55~7 % of theory),
M.p.: 155 - 157G (ether)
Calc.: C 74.37 H 7.25 N 5.60
Found: 74.11 7.41 5.39

Example 42

4- ~1-(5-Aminocarbonyl-2-piperidino-phenyl)-ethyl)-amino-
carbonylmethyl7benzoic acid ethyl ester

3.8 g (9.06 m mol) of 4- ~1-(5-cyano-2-piperidino-phenyl)-
ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester and
~8 g of polyphosphoric acid were stirred for 2.5 hours
at 80 - 90C. Under ice-cooling,water was added care-
fully and the reaction mixture was extra~ted with ethyl aceta-
te and adjustedlalkaline by means of conc. ammonia. The or-
ganic phase was washed with water, dried and evaporated in
vacuo. The evaporation residue was purified by column chro-
matography on silica gel (chloroform/methanol = 20/1).
Yield: 1 g (25.2 % of theory),
M.p.: 188 - 189C (ethanol)
Calc.: C 68.63 H 7.14 N 9.60
~J Found: 68.42 6.95 9.46

Example 43

4~ (5-Ethoxycarbonyl-2-piperidino-phenyl)-ethyl)-amino-
carbonvlmethvl7benzoic acid ethvl ester

U~r refluxr dried hydrog~n chloride was introduced into
a solution of 1.1 g (2.62 m mol) of
4- ~1-(5-cyano-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid ethyl ester in 22 ml of absolute etha-
nol until after 4 hours no nitri~ could be detected. The

~ 176246

reaction mixture was evaporated in vacuo, mixed with water and ether, and
adjusted to alkaline by means of sodium hydrogen carbonate solution. The
separated ether phase was extracted with water, dried and filtered, and
evaporated in vacuo. The evaporation residue was purfied by column chroma-
tography on silica gel (methylene chloride/acetonitrile/glacial acetic
acid = lO:l:O.n5).
Yield: 0.6 g (49.2 % of theory),
M.p.: 136 - 138C (ether)
Calc.: C 69.51 H 7.35 N 6.00
Found: 69.28 7.34 5.83


Example 44
4-[(1-(2-(4-Oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl~benzoic acid
A solution of 2.9 g (6.86 m mol) of 4-[(1-(2-[1,4-dioxa-8-aza-spiro[4.5]decane-
8-yl]phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid semihydrate in 40 ml of
acetone was adjusted to pH = 2 by the addition of 2N hydrochloric acid. After
stirring for 6 nours at 50C 5 drops of conc. hydrochloric acid were added
and the mixture was allowed to stand for 16 hours at 20C. The reaction
mixture was evaporated in vacuo, mixed with water and ethyl acetate and
adjusted to pH = 6 by means of 2N ammonia. After extracting several times
with ethyl acetate, the combined organic extracts were washed with water,
dried, filtered, and evaporated in vacuo. The evaporation residue was re-
crystallized from acetone/petroleum ether.
Yield: 1.9 g (73.1 ~ of theory),
M.p.: 177 - 180C (decomp.)
Calc.: C 69.46 H 6.36 ~ 7.36
Found: 69.75 6.33 7.29




-106-

, ~

~ 1 76~46

Example 45

4-[~1-(2-(4-Hydroxy-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid

x 0.66 H o
0.224 g (5.92 m mol) of sodium boro-hydride were added in portions with stirringto a solution of 1 g (2.63 m mol) of 4-[(1-(2-(4-oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]be~zoic acid in 20 ml of absolute ethanol. After stirring
for 1.5 hours at room temperature, the reaction mixture was adjusted to acidic
by means of 2N hydrochloric acid, evaporated in vacuo, mixed with ;;ater and
ethyl acetate, and adjusted to pH ~ 6 by means of 2N sodium hydroxide solution.
After extracting several times with ethyl acetate, the organic phase was dried,
filtered, and the extract was evaporated in vacuo. The evaporation residue
was recrystallized from petroleum ether.
Yield: 0.78 g (75 % of theory),
M.p.: 175 - 180C (decomp.)
Calc.: (x 0.66 H20) C 66.97H 6.81 N 7.10
Found: 66.72 6.62 6.98

Example 46

4-~(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl~-benzoic acid propyl ester
O.g4 g (5.80 m mol) of carbonyl diimidazole were added to a solution of 2 g
(5.46 m mol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]benzoic

acid in 20 ml of absolute tetrahydrofuran and the mixture was heated to reflux
temperature for 30 minutes excluding moisture. Subsequently, 1.64 ml (2.2 m mol)
of l-propanol were added, the reaction mixture was stirred for 18 hours at 20oc
and heated for 8 hours to reflux temperature. After evaporating in vacuo, the
evaporation residue was purified by column chromatography on silica gel
(toluene/acetone = 10:1).
Yield: 1.3 g (58.3 % of theory),
M.p.: 150 - 151C (ethyl acetate)
-107-
,~

l08
1 1~62~6
Calc.: C 73.51 H '7.90 N 6.86
Found: 73,70 7.78 6.92

Analogously to Example 46 the following compounds were
propared:

5 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid isopro~yl ester

Yield: 45 % of theory,
M.p.: 141 - 143C (ether)
Calc.: C 73.51 H 7.90 N 6.86
Found: 73.20 7.79 6.70

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid butvl ester

Yield: 49 96 of theory,
M.p.: 148C (ether/toluene)
Calc.: C 73.90 H 8.11 N 6.63
Found: 74.10 7.99 6.70

4-/¦1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methvl7benzoic acid ethyl ester

Yield: 41 % o:E theory,
20 M.p.: 130 - 133C (ether)
Calc.: C 67.21 H 6.81 Cl 8.26 N 6.53
Found: 66.90 6.65 8.32 6.67

4-L~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid bUtYl ester

25 Yield: 30.7 % of theory,
M.p.: 115 - 118C
Calc.: C 68.33 H 7.27 Cl 7.75 N 6.12
Found: 68.20 7.23 7.68 5.95

109 1 1 7624 6

4~ (5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoic acid tert.butyl es~er

Yield: 1 % of theory,
Calc.: mol peak m/e = 456/8
5 Found: m/e = 456/8

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid-(2-methoxyethyl ester)

Yield: 56 % of theory,
M.p.: 155 - 157C (ethyl acetate)
lO Calc.: C 70.74 H 7.60 N 6.60
Found: 70.55 7.38 6.47

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid7-(2,2-dimethyl-dioxolane-4-yl?-methyl7ester

Yield: 30.5 yO of theory,
15 M.p.: 110 - 112C (ether)
Calc.: C 69.98 H 7.55 N 5.83 m/e = 480
Found: 69.80 7.50 5.76 m/e = 480

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid benzyl ester _ _

~0 Yield: 73.7 % of theory,
M.p.: 126 - 128C (ethyl acetate)
Calc.: C 76.28 H 7.06 N 6.14
Found: 76.33 7.20 6.03

4-l¦1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -
25 benzoic acid-(2-hydroxy-ethyl)-ester

After addition of 10 equivalents of ethylene glycol the
reaction mixture was heated to reflux temperature for 17 hours.
Yield: 71.4 % of theory,
M.p.: 128 - 129 C (ethyl acetate/ether)

llo 1 1 7624~

Calc.: C 70.21 H 7.36 N 6.82 m/e = 410
Found: 70.14 7.42 6.70 m/e = 410

1,2-Bis ~ ~ (2-piperidino-phenyl)-ethyl)-aminocarbonyl-
methyl7benzoyloxy7ethane

After addition of 0.5 equivalents of ethylene glycol the
reaction mixture was heated to reflux temperature for 17 hours.
Yield: 43.5 % of theory,
M.p.: 188 -191C (toluene)
Calc.: C 72.80 H 7.17 N 7.38 m/e = 758
Found: 72.85 7.07 7.37 m/e = 758

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid-(2-diethvlamino-ethyl)-ester

Yield: 56.7 % of theory,
M.P.: 99 - 101C (petroleum ether)
Calc.: C 72.23 H 8.44 N 9.03
Found: 72.40 8.37 8.95

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid-2-(1,3-dimethvl-xanthine~7-vl)-ethyl ester

As solvent absolute pyridine was used. After addition of 1
equivalent of 7-(2-hydroxy-ethyl)-theophylline and after
addition of a little piece of metallic sodium the reaction
mixture was stirred for 4 hours in the bath of 130C.
Yield: 40.9 ~ of theory,
M.p.: 121 - 12~C (ether)
Calc.: C 65.01 H 6.34N 14.68 m/e = 572
Found: 64.78 6.38 14.90 m/e = 572

Example 47

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy,~ -
benzoic acid methyl ester_

~ mixture of 2 g (5.46 m mol) of 4- ~ 1-(2-piperidino-phenyl)-

Il] 1~ 24~

ethyl)-aminocarbonylmethy ~ benzoic acid, 0.53 g of methanol,
0.38 ml of conc. sulfuric acid, and 1.65 ~l of 1,2-dichloro-
ethane was refluxed for 24 hours, then evaporated in vacuo,
dissolved in chloroform, and extracted with diluted sodium
hydrogen carbonate solution. The organic phase was washed
with water, dried, filtered, and evaporated in vacuo. The
evaporation residue was purified by column chromatography
on silica gel (toluene/acetone = 5:1).
Yield: 0.93 g (44.8 % of theory),
M.p.: 146 - 147C
Calc.: C 72.60 H 7.42 N 7.36
Found: 72.19 7.33 7.01

Exam~le 48

4- ~ 2-(2-Piperidino-phenyl)-2-propyl)-aminocarbonylmethy ~ -
benzoic acid ethYl ester

0.20 g (0.526 m mol)~of 4- ~ 2-(2-piperidino-phenyl)-2-propyl)-
aminocarbonylmethyl7benzoic acid and 2 ml of 4N ethanolic
hydrochloric acid were stirred at 20C. After 36 hours, the
reaction mixture was evaporated in vacuo, and the evaporation
residue was distributed between wa-~er (at pH - 8 by addition
of ammonia (10 %~) and ethyl acetate. The organic phase was
washed with water, dried, filtered, and evaporated in vacuo.
The evaporation residue was purified by column chromatography
on silica gel (toluene/acetone = 10:1).
Yield: 0.079 g (36.7 % of theory),
M.p.: 151 - 153C (ether)
Calc.: C 73.50 H 7.90 N 6.86
Found: 73.40 7.95 6.96

I:12 1.~ 76246

Example 49

4~ (2-Piperidino-phenyl)-ethylj-aminocarbonylmethy~ 7-
benzoic acid tert.butyl ester

A mixture of 3.60 g (17.4 m mol) of N,N'-dicyclohexyl-
carbodiimide, 1.9 ml (20.4 m mol) of tert.butanol and
0.036 g (o.36 m mol) of copper(I)chloride was stirred
for 3 days at room temperature, then 12 ml of methylene
chloride were added, and the solution thus obtained was
added to a solution of 2 g (5.46 m mol) of 4-L~1-
(2-piperidino-phenyl)-ethyl)-aminocarbonylmethy~7benzoic
acid in 80 ml of methylene chloride. After stirring for
16 hours at 20C, the resultant precipitate was filtered
off, washed with methylene chloride, and the methylene chlori-
de solution was evaporated in vacuo. The evaporation residue
was purified by column chromatography on silica gel (toluene/
acetone = 15:1).
Yield: 0.45 g (19.7 % of theory),
M.p.: 125 - 127C (ether)
Calc.: C 73.90 H 8.11 N 6.63
Found: 74.20 8.09 6.77

Exam~le 50

- 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid 2-(nicotinoyloxy)-ethyl ester

A solution of 0.16 g (1.13 m mol) of nicotinic acid chlo-
ride in 5 ml of me-thylene chloride was quickly ~dded to a
solution of 0.45 g (1.10 m mol) of 4-L~1-(2-piperidino-phenyl)-
ethyl)-aminocarbonylmethy_7benzoic acid (2-hydroxy-ethyl)-
ester and 0.16 ml (1.16 m mol) of triethylamine in 10 ml of
methylene chloride. After stirrin~ for 4 hours at 20C, the
reaction mixture was extracted with water, dried, and the
methylene chloride solution was filtered and evaporated in
vacuo. The evaporation residue was purified by column chromato-
graphy on silica gel (chloroform/acetone = 3:1).

ll3 1.~ 7624~

Yield: 0.34 g (60 % of theory),
M.p.: 103 - 105C (ether)
Calc.: C 69.88 ~ 6.45 N 8.15
Found: 70.13 6.55 8.13

5 Example 51

4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmet;hyl7-
benzamide

2.3 g (0.0142 mol) of carbonyl diimidazole were given to
4.76 g (0.013 mol) of 4-~1-(2-piperidino-phenyl)-ethyl)-
lO aminocarbonylmethyl7benzoic acid in 60 ml of absolute
pyridine and the mixture was subsequently heated for 45
minutes to 50C. After cooling in a carbon dioxide/methanol
bath 7 ml of liquid ammonia were added and heated for 20 hours
to 80C in an autoclave. Subsequently the reaction mixture
15 was cooled and evaporated in vacuo. The residue was dissolved
in 50 ml of hot methanol, 200 ml of water were added and the
mixture was allowed to rest over-night. The crystalline pre-
cipitate was suction filtered and recrystallized from metha-
nol by addition of activated charcoal.
20 Yield: 3.5g (73.6 yO of theory),
M.p.: 197 - 199C
Calc.: C 72.30H 7.45 N 11.50
Found: 72.307.45 11.32

Example 52

25 4-~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
N-meth lbenzamide
Y _ _

2 g (5.46 m mol) of 4-L~1-(2-piperidino-phenyl)-ethyl)-
aminocarbonylmethy~7benzoic acid and 0.94 g (5.80 m mol)
of carbonyl diimidazole in 20 ml of absolute pyridine were
30 heated to reflux temperature for 1 hour. Subsequently, 0.41 g
(6.07 m mol) of methylamine hydrochloride were added and the
mixture was stirred for 1 hour at 20C and refluxed for
2 hours Af-ter evaporating in vacuo, the residue was distri-


11'1 1176246

buted between water and methylene chloride; the organic extractwas dried, filtered, and evaporated in vacuo. mhe evapora-
tion residue was purified by column chromatography on silica
gel (chloroform/methanol/conc. ammonia = 10:1:0.05).
Yield: 1.7 g (82 ~ of theory),
M.p.: 218 - 220C (isopropanol)
Calc.: C 72.77 H 7.70 N 11.07
Found: 72088 7.67 10.91

Analogously to Example 52 the following compound was prepared:

4- ~1-(2-Piperidino-phenyl) ethyl)-aminocarbonylmethyl7-
N,N dimethvl-benzamide _ _ -

Yield: 52.5 % of theory,
M.p.: 148 - 150C ~ethyl acetate)
Calc.: C 73.26 H 7.94 N 10.68
Found: 73.60 7.85 10.73

Example 53

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
N but l-benzamide
-- Y _ _.

0.94 g (5.80 m mol) of carbonyl diimidazole were added to the
solution of 2 g (5.46 m mol) of 4-/r1-(2-piperidino-phenyl)-
ethyl)-aminocarbonylmethyl7benzoic acid in 20 ml of absolute
tetrahydrofuran. The mixture was heated to reflux temperature
for 30 minutes, 0.44 g (6.1 m mol) of 1-butylamine were added,
and the reaction mixture was again refluxed for 2 hours. After
evaporating in vacuo, the evaporation residue was purified by
column chromatography on silica gel (chloroform/acetone = 6:1).
Yield: 1.65 g (71.7 % of theory),
M.p.: 178 - 181C (ethyl acetate)
Calc.: C 74.09 H 8.37 N 9.97
Found: 74.34 8.26 9.95

' I j 1 17624~

Analogously to Example 53 the following compounds were obtained:

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid piperidide

Yield: 73.8 % of theory,
M.p.: 131 - 133C (toluene)
Calc.: C 74 .79 H 8.14 N 9.69 m/e ~ 433
Found: 75.13 7.99 9.48 m/e = 433

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzoic acid morpholide _ _ _ _ _

lO Yield: 50.5 % of theory,
M.p.: 148 - 150C (ethyl acetate/ether)
Calc.: C 71.69 H 7.64 N 9.65
Found: 71.60 7.80 9.57

Example 54

]5 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-
benzonitrile

1.14 g (6 m mol) of p-toluene-sulfonic acid chloride were
added in two portions whilst stirring at room temperature
'J to a mixture of 2.19 g (6 m mol) of 4-L~1-(2-piperidino-
20 phenyl)-ethyl)-aminocarbonylmethyl7benzamide and 1.07 g
(13.5 m mol) of absolute pyridine. The reaction mixture
was stirred for 15 minutes at 20C and then for 2 hours
at 50C. After cooling, water was added, the mixture was
adjustedl~alkaline by means of conc. ammonia, and extracted
~'5 thrice with chloroform. The combined chloroform extracts
were washed with water, dried over sodium sulfate, filtered,
and evaporated in vacuo. The evaporation residue was purified
by column chromatography on silica gel (chloroform/ethyl
acetate = 4:1).

I 176~4~
Yield: 1.15 g (55.3 % of theory),
M p.: 155 - 157C (ethyl acetate)
Calc.: C 76.05 H 7.25 N 12.09
Found: 76.30 7.07 11.90

117 ~ 4~

Example A

Tablets containing 5 mg of 4~ (2-piperidino-phenyl)-ethyl)-
aminocarbonylmethyl7benzoic acid

Composition:
5 1 tablet contains:
Active ingredient (1)5 0 mg
Corn starch (2)62.0 mg
Lactose (3)48.0 mg
Polyvinyl pyrrolidone (4)4.0 mg
Magnesium stearate (5)1.0 mg
120.0 mg

Method of preparation:

1, 2, 3, and 4 were mixed and moistened with water. The moist
mixture was granulated through a screen of mesh size 1.5 mm
and dried at approx. 45C. The dry granulate was granulated
through a screen of 1.0 mm mesh size and mixed with 5. The
finished mixture was pressed to tablets on a tablets press
with punches of 7 mm diameter and an unilateral notch.
Weight of tablet: 120 mg

Example B

Coated tablets containing 2.5 mg of 4- ~1-(2-piperidino-phenyl)-
ethyl)-aminocarbonYlmethyl7benzoic acid

1 coated tablet core contains:
Active ingredient (1)2.5 mg
Potato starch (2) 44.0 mg
Lactose (3) 30.0 mg
Polyvinyl pyrrolidone (4)3.0 mg
Magnesium stearate (5)0.5 mg
80.0 mg

I l ~ 1 17 ~246

Method of preparation:

1, 2, 3, and 4 were mixed well and moistened with water.
The moist mass was granulated through a screen of mesh
size 1 mm, dried at approx. 45C and the granulate was
again granulated through the same screen. After adding of
5, curvatured coated tablet cores of a diameter of 6 mm
were pressed on a tablets pressing machine. The coated tab-
let cores thus prepared, were covered in conventional manner
with a coating, which essentially consists of sugar and tal-
cum. The finished coated tablets were polished with wax.
Weight of coated tablets: 120 mg.

Example C
.




Tablets containing 10 mg of 4- ~1 (2-piperidino-phenyl)-
ethvl)-aminocarbonylmeth~17benzoic acid

COmposition:
1 tablet contains:
Active ingredient 10.0 mg
Lactose pulverized 70.0 mg
Corn starch 31.0 mg
Polyvinyl pyrrolidone 8.0 mg
Magnesium stearate 1.0 mg
120.0 mg

119

Method of preparation: 1 17 6 2 ~ g

The mixture of active ingredient, lactose and corn starch
was moistened with a 20 % solution of polyvinyl pyrrolidone
in water. The moist mass was granulated through a screen with
a mesh size of 1.5 mm and dried at 45C. The dried granulate
was granulated through a screen of 1 mm mesh size and homo-
geneously mixed with magnesium stearate.
Weight of tablets: 120 mg
Punch: 7 mm ~ with a notch.

lO Example D
Coated tablets containing 5 mg of 4- ~1-(2-piperidino-phenyl)-
ethyl)-aminocarbonylmethvl7benzoic acid

1 coated tablet core contains:
Active ingredient 5.0 mg
15 Calcium phosphate secondary70.0 mg
Corn starch 50.0 mg
Polyvinyl pyrrolidone4.0 mg
Magnesium stearate 1.0 mg
130.0 mg

20 Method of preparation:

The mixture, consisting of the active ingredient, the cal-
cium phosphate and the corn starch, was moistened with a
15 % solution of poly~inyl pyrrolidone in water. The moist
mass was granulated through a screen of 1 mm mesh size,
25 dried at 45C and again passed through the same screen.
The granulate was mixed with the above mentioned amount of
magnesium stearate and the mixture thus obtained was pressed
into coated tablet cores.

1~0
Weight of core: 130 mg 117624~
Punch: 7 mm 0

The thus prepared coated tablet cores were covered according
to conventional manner with a layer consisting of sugar and
talcum. The finished coated tablets were polished with wax.
Weight of coated tablet: 180 mg.