AMIDINES, PROCESSES FOR THEIR MANUFACTURE, PHARMACEUTICAL PREPARATIONS CONTAINING THEM, AND THEIR USE

AMIDINES, PROCEDE DE PRODUCTION, PREPARATIONS PHARMACEUTIQUES LES CONTENANT ET UTILISATION

English Abstract

4-12736/+
Novel amidines, processes for their manufacture, pharma-
ceutical preparations containing them, and their use
Abstract
Novel amidines, especially N,N'-bridged carboxylic
acid amidine of the general formula
<IMG>
(I),
in which R1 represents an aromatic radical, R2 represent
optionally esterified or amidated l-carboxy-lower alkyl,
Ph represents optionally substituted 1,2-phenylene and
alk represents an aliphatic hydrocarbon radical separating
the imino group from the methine group by from 1 to 3
carbon atoms, and their salts, have, inter alia, anti-
inflammatory activity and can be used as active medica-
ment substances in pharmaceutical preparations. They
are produced according to methods known per se.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of N,N'-bridged carboxylic acid
amidines of the general formula
<IMG>
(I),
in which R1 represents phenyl optionally substituted by lower alkyl,
by lower alkoxy, by optionally halogen-containing lower alkylthio,
lower alkanesulphinyl or lower alkanesulphonyl, by sulphamoyl
optionally mono- or di-substituted by lower alkyl, and/or by
halogen, or represents 5- or membered monocyclic heteroaryl
optionally containing lower alkyl, lower alkoxy and/or halogen and
having as hetero atom nitrogen, oxygen or sulphur, or nitrogen and,
in addition, sulphur or oxygen, R2 represents l-carboxy-lower alkyl
of the formula -CH9R3)-R2 in which R2 represents carboxy, lower
alkoxycarbonyl optionally substituted by lower alkyl-, lower alkoxy-
or halogen-containing phenyl or pyridyl, by hydroxy or by lower
alkoxy, or represents carbamoyl optionally substituted once by
hydroxy or amino, once or twice by lower alkyl or hydroxy-lower
alkyl, or twice by 4- or 7-membered lower alkylene or 3-oxa-,
3-thia- or 3-aza-alkylene, R3 is hydrogen or lower alkyl, Ph is 1,2-
phenylene optionally substituted by lower alkyl, lower alkoxy,
halogen and/or trifluoromethyl, and alk is lower alkylene separat-
ing the methine group from the imino group by 2 carbon atoms or
54

vinylene, and their pharmaceutically acceptable salts, which
process comprises:
a) splitting off of H-Zl from compounds of general formula
<IMG> ( I I )
in which Zl represents optionally modified hydroxy or mercapto, or
from salts thereof, with the introduction of an additional bond, or
b) converting R2 by solvolysis into the group R2 in a compound
of the formula
(X),
in which R2 represents a group of the formula -CH(R3)-R2 and in
which R3 represents hydrogen or lower alkyl and R2 represents
functionally modified carboxy different from R2, or a group of the
formula -C(=O)-N2 + B , in which B is the anion of a mineral
acid, or
c) for the manufacture of compounds of the formula I in which
R2 represents l-carboxy-lower alkyl of the formula -CH(R3)-R'2 in
which R2 represents lower alkoxycarbonyl optionally substituted by
lower alkyl-, lower alkoxy- or halogen-containing phenyl or pyridyl,
by hydroxy or by lower alkoxy, or represents carbamoyl optionally

substituted once by hydroxy or amino, once or twice by lower alkyl
or hydroxy-lower alkyl, or twice by 4- or 7-membered lower alkylene
or 3-oxa-, 3-thia- or 3-aza-alkylene, R3 is hydrogen or lower alkyl,
alk represents vinylene and R1 and Ph have the above meanings, de-
hydrogenating compounds of the formula
<IMG>
(I l )
with the splitting off of hydrogen and simultaneously forming an
additional bond, and,
d)-(i) when a compound of the formula I wherein R2 denotes a group
of the formula -CH(R3)-R2 in which R2 represents carboxy is required,
hydrolysing in a resulting compound, wherein R2 represents lower
alkoxycarbonyl optionally substituted by lower alkyl-, lower
alkoxy- or halogen-containing phenyl or pyridyl, by hydroxy or by
lower alkoxy, or represents carbamoyl optionally substituted once
by hydroxy or amino, once or twice by lower alkyl or hydroxy-lower
alkyl, or twice by 4- or 7-membered lower alkylene or 3-oxa-, 3-
thia- or 3-azaalkylene, R2 to carboxy, or,
d)-(ii) when a compound of the formula I wherein R2 denotes a group
of the formula -CH(R3)-R2 in which R2 represents lower alkoxy-
carbonyl optionally substituted by lower alkyl-, lower alkoxy- or
halogen-containing phenyl or pyridyl, by hydroxy or by lower alkoxy
is required, esterifying the carboxy group in a resulting compound
wherein R2 represents carboxy to the group R2 as indicated above
in the process variant d)-(ii), or,
d)-(iii) when a compound of the formula I wherein R2 represents
56

a group of the formula -CH(R3)-R2 in which R2 represents carbamoyl
optionally substituted once by hydroxy or amino, once or twice by
lower alkyl or hydroxy-lower alkyl, or twice by 4- or 7-membered
lower alkylene or 3-oxa-, 3-thia- or 3-aza-alkylene is required,
amidating the carboxy group in a resulting compound wherein R'2
represents carboxy to the group R2 as indicated above in process
variant d)-(iii), or,
d)-(iv) when a compound of the formula I wherein R1 represents
phenyl substituted by lower alkanesulphinyl is required, oxidising
lower alkylthio in a compound of formula I wherein Rl represents
phenyl substituted by lower alkylthio to lower alkanesulphinyl, or,
d)-(v) when a compound of the formula I wherein R1 represents
phenyl substituted by lower alkylthio is required, reducing lower
alkanesulphinyl or lower alkanesulphonyl in a compound of formula I
wherein R1 represents phenyl substituted by lower alkanesulphinyl
or lower alkanesulphonyl to lower alkylthio, or,
d)-(vi) when a free compound of the formula I is required, convert-
ing a resulting salt into the free compound, or,
d)-(vii) when a pharmaceutically acceptable salt is required,
converting a resulting free compound into a pharmaceutically
acceptable salt.
2. Process according to claim 1, wherein process variant a) is
carried out using a compound of formula II in which Zl denotes
hydroxy.
3. Process according to claim 1, wherein process variant a) is
carried out using a compound of formula II which is formed under
the reaction conditions without isolating by cyclising, in the

presence of acidic catalysts, a compound of the formula
<IMG>
(IVa)
or salts thereof, in which Xl represents hydrogen and Yl represents
a group of the formula alk-NH-C(=Zi)(Rl) and Z1 represents oxo.
4. Process according to claim 1, wherein process variant b) is
carried out using a compound of formula X in which R2 denotes a
group of the formula -CH(R3)-R2, wherein R2 represents cyano, tri-
lower alkoxy-methyl, imino-halogeno-methyl or lower alkoxy-imino-
methyl.
5. Process according to claim 1, wherein process variant c) is
carried out with the use of an element of the sub-group VIII as
dehydrogenation catalyst.
6. Process according to claim 1, 2 or 3, wherein process variant
a) is carried out using a starting compound of formula II or IVa,
wherein Rl represents phenyl optionally substituted by lower alkyl,
lower alkoxy, lower alkylthio, halo-lower alkylthio, lower alkane-
sulphinyl, halo-lower alkanesulphinyl, lower alkanesulphonyl, halo-
lower alkanesulphonyl, sulphamoyl, N-mono- or N,N-di-lower alkyl-
sulphamoyl and/or halogen, or represents pyrrolyl, furyl, thienyl,
thiazolyl, pyridyl or pyrimidyl each optionally substituted by
lower alkyl, lower alkoxy and/or halogen, R2 represents a group of
the formula -CH(R3)-R2 in which R2 is carboxy, phenyl- or pyridyl-
lower alkoxycarbonyl optionally substituted by lower alkyl, lower
58

alkoxy or halogen, hydroxy- or lower alkoxy-lower alkoxycarbonyl,
lower alkoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, N-amino-
carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl or -hydroxy-lower
alkylcarbamoyl, or carbamoyl substituted by 4- or 7-membered lower
alkylene, or 3-oxa, 3-thia- or 3-aza-alkyleneaminocarbonyl, R3
represents hydrogen or lower alkyl, Ph represents 1,2-phenylene
optionally substituted by lower alkyl, lower alkoxy, halogen and/or
trifluoromethyl, and alk represents lower alkylene separating the
methine group from the imino group by 2 carbon atoms or vinylene
and Zl has the meaning given in claim 1 or 2, Xl, Yl and Z1 have
the meanings given in claim 3 or process variant b) is carried out
using a starting material of formula X wherein R2 and R2 have the
meanings given in claim 1 and R1 R3, Ph and alk are as defined
above, or process variant c) is carried out using a starting
material of formula I' wherein R1, R2 and Ph are as defined above,
so as to produce a compound of the formula I, wherein alk, Ph, R1,
R2 and R3 have the meanings given above, or a pharmaceutically
acceptable salt thereof.
7. Process according to claim 4 or 5, wherein process variant
c) is carried out using a compound of the formula I', wherein R
represents phenyl optionally substituted by lower alkyl, lower
alkoxy, lower alkylthio, halo-lower alkylthio, lower alkanesulphinyl,
halo-lower alkanesulphinyl, lower alkanesulphonyl, halo-lower
alkanesulphonyl, sulphamoyl, N-mono- or N,N-di-lower alkylsulphamoyl
and/or halogen, or represents pyrroly1, furyl, thienyl, thiazolyl,
pyridyl or pyrimidyl each optionally substituted by lower alkyl,
lower alkoxy and/or halogen, R2 represents a group of the formula

-CH(R3)-R? in which R? is carboxy, phenyl- or pyridyl-lower
alkoxycarbonyl optionally substituted by lower alkyl, lower alkoxy
or halogen, hydroxy- or lower alkoxy-lower alkoxycarbonyl, lower
alkoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, N-aminocarbamoyl,
N-mono- or N,N-di-lower alkylcarbamoyl or -hydroxy-lower alkyl-
carbamoyl, or carbamoyl substituted by 4- or 7-membered lower
alkylene, or 3-oxa, 3-thia- or 3-aza-alkyleneaminocarbonyl, R3
represents hydrogen or lower alkyl, Ph represents 1,2-phenylene
optionally substituted by lower alkyl, lower alkoxy, halogen and/or
trifluoromethyl or a salt thereof, or process variant b) is carried
out using a compound of formula X wherein R? and R? have the mean-
ings given in claim 4, alk represents lower alkylene separating
the methine group from the imino group by 2 carbon atoms or
vinylene, and R1 R3, Ph and alk are as defined above, so as to
produce a compound of the formula I, wherein alk, Ph, R1 R2 and
R3 have the meanings given above, or a salt thereof.
8. Process according to claim 1, 2 or 3, wherein process variant
a) is carried out using a compound of the formula II or IVa,
wherein R1 represents phenyl optionally substituted by lower alkyl
having up to and including 4 carbon atoms, by lower alkoxy having
up to and including 4 carbon atoms, by halo-lower alkylthio having
up to and including 4 carbon atoms, by lower alkylthio having up to
and including 4 carbon atoms, by halo -lower alkanesulphinyl having
up to and including 4 carbon atoms, by lower alkanesulphinyl having
up to and including 4 carbon atoms, by halo-lower alkanesulphonyl,
by lower alkanesulphonyl having up to and including 4 carbon atoms,
by sulphamoyl, by N-mono or N,N-di-lower alkanesulphamoyl each

having up to and including 4 carbon atoms in the alkyl radical,
and/or by halogen having an atomic number of up to and including
35, or represents pyridyl or the thienyl each optionally sub-
stituted by lower alkyl having up to and including 4 carbon atoms,
by lower alkoxy having up to and including 4 carbon atoms, and/or
by halogen having an atomic number of up to and including 35, R2
represents a group of the formula -CH(R3)-R? in which R? represents
carboxy, phenyl- or pyridyl-lower alkoxycarbonyl, optionally sub-
stituted by lower alkyl having up to and including 4 carbon atoms,
by lower alkoxy having up to and including 4 carbon atoms, and/or
by halogen, lower alkoxycarbonyl, mono- or dihydroxy-lower
alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, N-hydroxy- or
N-amino-carbamoyl, N-mono- or N,N-di-lower alkoxycarbamoyl, or
carbamoyl, R3 is hydrogen or lower alkyl having up to and including
4 carbon atoms, Ph is 1,2-phenylene optionally substituted by
lower alkyl having up to and including 4 carbon atoms, by lower
alkoxy having up to and including 4 carbon atoms, and/or by halogen
having up to and including an atomic number of 35, and alk is 1,2-
ethylene, and Z1 has the meaning given in claim 1 or 2, X1, Y1 and
Z? have the meanings given in claim 3 or a salt thereof, or process
variant b) is carried out using a starting material of formula X
wherein R? and R? have the meanings given in claim 1 and R1, R3, Ph
and alk are as defined above, or process variant c) is carried out
using a starting material of formula I' wherein R1, R2 and Ph are
as defined above so as to produce a compound of the formula I,
wherein alk, Ph, R1, R2 and R3 have the meanings given above, or
a pharmaceutically acceptable salt thereof.
61

9. Process according to claim 4 or 5, wherein process variant
c) is carried out using a compound of formula I', wherein R1
represents phenyl optionally substituted by lower alkyl having up
to and including 4 carbon atoms, by lower alkoxy having up to and
including 4 carbon atoms, by halo-lower alkylthio having up to and
including 4 carbon atoms, by lower alkylthio having up to and in-
cluding 4 carbon atoms, by halo -lower alkanesulphinyl having up to
and including 4 carbon atoms, by lower alkanesulphinyl having up to
and including 4 carbon atoms, by halo-lower alkanesulphonyl, by
lower alkanesulphonyl having up to and including 4 carbon atoms, by
sulphamoyl, by N-mono- or N,N-di-lower alkanesulphamoyl each having
up to and including 4 carbon atoms in the alkyl radical, and/or by
halogen having an atomic number of up to and including 35, or
represents pyridyl or the thienyl each optionally substituted by
lower alkyl having up to and including 4 carbon atoms, by lower
alkoxy having up to and including 4 carbon atoms, and/or by halogen
having an atomic number of up to and including 35, R2 represents a
group of the formula -CH(R3)-R2 in which R2 represents carboxy,
phenyl- or pyridyl-lower alkoxycarbonyl, optionally substituted by
lower alkyl having up to and including 4 carbon atoms, by lower
alkoxy having up to and including 4 carbon atoms, and/or by halogen,
lower alkoxycarbonyl, mono- or dihydroxy-lower alkoxycarbonyl,
lower alkoxy-lower alkoxycarbonyl, N-hydroxy- or N-amino-carbamoyl,
N-mono- or N,N-di-lower alkoxycarbamoyl, or carbamoyl, R3 is
hydrogen or lower alkyl having up to and including 4 carbon atoms,
Ph is 1,2-phenylene optionally substituted by lower alkyl having
up to and including 4 carbon atoms, by lower alkoxy having up to
and including 4 carbon atoms, and/or by halogen having up to and
62

including an atomic number of 35, or a salt thereof, or a process
variant b) is carried out using a compound of formula X wherein
R2 and R2 have the meanings given in claim 4 and R1 R3, Ph and
alk are as defined above, so as to produce a compound of the
formula I, wherein alk, Ph, R1 R2 and R3 have the meanings given
above, or a pharmaceutically acceptable salt thereof.
10. Process according to claim 1, 2 or 3, wherein process
variant a) is carried out using a compound of formula II or IVa,
wherein R1 represents phenyl optionally substituted by halogen,
lower alkylthio, lower alkanesulphinyl, lower alkanesulphonyl,
halo-lower alkylthio and/or sulphamoyl, or pyridyl or thienyl, R2
represents a group of the formula -CH2-R2 in which R2 represents
carboxy, lower alkoxycarbonyl or carbamoyl, Ph represents 1,2-
phenylene optionally substituted by lower alkoxy, lower alkyl. and/or
halogen, and alk is 1,2-ethylene or vinylene, and Zl has the
meaning given in claim 1 or 2, S1, Y1 and Z1 have the meanings
given in claim 3 or a salt thereof, or process variant b) is
carried out using a starting material of formula X wherein R2
represents the formula -CH2-R2 in which R2 is as defined in claim
1 and R1 Ph and alk are as defined above, or process variant c) is
carried out using a starting material of formula I' wherein R1 R2
and Ph are as defined above, so as to produce a compound of the
formula I, wherein alk, Ph, R1 R2 and R3 have the meanings given
above, or a pharmaceutically acceptable salt thereof.
11. Process according to claim 4 or 5, wherein process variaqnt
c) is carried out using a compound of formula I', wherein R1
represents phenyl optionally substituted by halogen, lower alkyl-
63

thio, lower alkanesulphinyl, lower alkanesulphonyl, halo-lower
alkylthio and/or sulphamoyl, or pyridyl or thienyl, R2 represents
a group of the formula -CH2-R2 in which R2 represents carboxy,
lower alkoxycarbonyl or carbamoyl, Ph represents 1,2-phenylene
optionally substituted by lower alkoxy, lower alkyl and/or halogen,
or a salt thereof, or a process variant b) is carried out using a
compound of formula X wherein R2 represents the formula CH2-R2 in
which R2 is as defined in claim 4, alk is 1,2-ethylene or vinylene,
and R1 and Ph are as defined above, so as to produce a compound of
the formula I, wherein alk, Ph, R1 and R2 have the meanings given
above, or a pharmaceutically acceptable salt thereof.

12. Process according to claim 1, 2 or 3, wherein process
variant a) is carried out using a compound of formula II or IVa,
wherein R1 represents phenyl optionally substituted by halogen
having an atomic number of up to and including 35, by lower alkyl-
thio having up to and including 4 carbon atoms, by lower alkane-
sulphinyl having up to and including 4 carbon atoms, by halo-lower
alkylthio having up to and including 4 carbon atoms, and/or by
sulphamoyl, or pyridyl or thienyl, R2 represents a group of the
formula -CH2-R2 in which R2 represents carboxy, lower alkoxycarbonyl
having up to and including 5 carbon atoms, or carbamoyl, Ph rep-
resents 1,2-phenylene optionally substituted by lower alkoxy having
up to and including 4 carbon atoms, by lower alkyl having up to
and including 4 carbon atoms, and/or by halogen having an atomic
number of up to and including 35, and alk is 1,2-ethylene or
vinylene, and Zl has the meaning given in claim 1 or 2, Xl, Yl
and Z1 have the meanings given in claim 3 or a salt thereof, or
process variant b) is carried out using a starting material of
formula X wherein R2 represents the formula -CH2-R2 in which R2
is as defined in claim 1 and R1 Ph and alk are as defined above,
or process variant c) is carried out using a starting material of
formula I' wherein R1 R2 and Ph are as defined above, so as to
produce a compound of the formula I, wherein alk, Ph, R1 and R2
having the meanings given above, or a pharmaceutically acceptable
salt thereof.
13. Process according to claim 4 or 5, wherein process variant
c) is carried out using a compound of formula I', wherein R1
represents phenyl optionally substituted by halogen having an

atomic number of up to and including 35 r by lower alkylthio having
up to and including 4 carbon atoms, by lower alkanesulphinyl having
up to and including 4 carbon atoms, by halo-lower alkylthio having
up to and including 4 carbon atoms, and/or by sulphamoyl, or
pyridyl, or thienyl, R2 represents a group of the formula -CH2-R2
in which R2 represents carboxy, lower alkoxycarbonyl having up to
and including 5 carbon atoms, or carbamoyl and Ph represents 1,2-
phenylene optionally substituted by lower alkoxy having up to and
including 4 carbon atoms, by lower alkyl having up to and including
4 carbon atoms, and/or by halogen having an atomic number of up to
and including 35 in which R2 has the meaning given in claim 4,
or process variant b) is carried out using a compound of formula
X wherein R2 represents the formula -CH2-R2 or a salt thereof, alk
is 1,2-ethylene or vinylene, and R1 and Ph are as defined above, so
as to produce A compound of the formula I, wherein alk, Ph, R1 and
R2 have the meanings given above, or a pharmaceutically acceptable
salt thereof.
14. Process according to claim 1, 2 or 3, wherein process variant
a) is carried out using formula II or IVa, wherein Rl represents
phenyl optionally substituted in the p-position by halo-lower
alkylthio having up to and including 4 carbon atoms, by lower
alkylthio having up to and including 4 carbon atoms, by lower
alkanesulphinyl having up to and including 4 carbon atoms, or by
halogen having an atomic number of up to and including 35, or in
the 3-position by sulphamoyl and, in addition, in the 4-position
by halogen having an atomic number of up to and includiding 35, or
pyridyl or thienyl, R2 represents a group of the formula -CH2-R2

in which R? represents carboxy, lower alkoxycarbonyl having up to
and including 5 carbon atoms, or carbamoyl, Ph represents 1,2-
phenylene optionally substituted in the 4-position in relation to
the bonded nitrogen atom by lower alkoxy having up to and including
4 carbon atoms, in the 3- and 5-position by lower alkyl having up
to and including 4 carbon atoms, or in the 4-position by halogen
having an atomic number of up to and including 35 and alk is 1,2-
ethylene or vinylene, and Z1 has the meanings given in claims 1
and 2, X1, Y1 and Z? have the meanings given in claim 3 or a salt
thereof, or process variant b) is carried out using a starting
material of formula X wherein R2 represents the formula -CH2-R?
in which R? is as defined in claim 1 and R1, Ph and alk are as
defined above, or process variant c) is carried out using a
starting material of formula I' wherein R1, R2 and Ph are as defined
above, so as to produce a compound of the formula I, wherein alk,
Ph, R1 and R2 have the meanings given above, or a pharmaceutically
acceptable salt thereof.
15. Process according to claim 4 or 5, wherein process variant
c) is carried out using a compound of formula I', wherein R1
represents phenyl optionally substituted in the p-position by
halo-lower alkylthio having up to and including 4 carbon atoms, by
lower alkylthio having up to and including 4 carbon atoms, by
lower alkanesulphinyl having up to and including 4 carbon atoms,
or by halogen having an atomic number of up to and including 35, or
in the 3-position by sulphamoyl and, in addition, in the 4-position
by halogen having an atomic number of up to and including 35, or
pyridyl or thienyl, R2 represents a group of the formula -CH2-R?
67

in which R2 represents carboxy, lower alkoxycarbonyl having up to
and including 5 carbon atoms, or carbamoyl and Ph represents 1,2-
phenylene optionally substituted in the 4-position in relation to
the bonded nitrogen atom by lower alkoxy having up to and including
4 carbon atoms, in the 3- and 5-position by lower alkyl having up
to and including 4 carbon atoms, or in the 4-position by halogen
having an atomic number of up to and including 35, in which R2 has
the meaning given in claim 4, or process variant b) IS carried out
using a compound of formula X wherein R2 represents the formula
-CH2-R2 or a salt thereof, alk is 1,2-ethylene or vinylene, and
R1 and Ph are as defined above, so as to produce a compound of the
formula I, wherein alk, Ph, R1 and R2 have the meanings given above,
or a pharmaceutically acceptable salt thereof.
16. Process according to claim 1, 2 or 3, wherein process
variant a) is carried out using a compound of formula II or IVa,
wherein R1 represents phenyl optionally substituted in the p-
position by lower alkylthio having up to and including 4 carbon
atoms, or by halogen having an atomic number of up to and including
35, R2 represents lower alkoxycarbonylmethyl, Ph represents 1,2-
phenylene optionally mono-substituted in the 4-position in relation
to the bonded nitrogen atom by lower alkoxy having up to and includ-
ing 4 carbon atoms, or in the 4-position by halogen having an
atomic number of up to and including 35, and alk is 1,2-ethylene
and Zl has the meaning given in claim 1 or 2, Xl, Yl and Zl have
the meanings given in claim 3 or a salt thereof, or process variant
b) is carried out using a starting material of formula X wherein
R2 represents the formula -CH2-R2 in which R2 is as defined in
claim 1 and R1 Ph and alk are as defined above, or process variant
68

c) is carried out using a starting material of formula I' wherein
R1 R2 and Ph are as defined above, so as to produce a compound of
the formula I, wherein alk, Ph, R1 and R2 have the meanings given
above, or a pharmaceutically acceptable salt thereof.
17. Process according to claim 4 or 5, wherein process variant
c) is carried out using a compound of formula I', wherein R1
represents phenyl optionally substituted in the p-position by
lower alkylthio having up to and including 4 carbon atoms, or by
halogen having an atomic number of up to and including 35, R2
represents lower alkoxycarbonylmethyl and Ph represents 1,2-
phenylene optionally mono-substituted in the 4-position in relation
to the bonded nitrogen atom by lower alkoxy having up to and
including 4 carbon atoms, or in the 4-position by halogen having
an atomic number of up to and including 35, or a salt thereof, or
process variant b) is carried out using a compound of formula X
wherein R2 represents -CH2-R2 in which R2 has the meanings given
in claim 4, alk is 1,2-ethylene and R1 and Ph are as defined above,
so as to produce a compound of the formula I, wherein alk, Ph, R
and R2 have the meanings given above, or a pharmaceutically
acceptable salt thereof.
18. Process according to claim 1, 2 or 3, wherein process variant
a) is carried out using a compound of formula II or IVa, wherein
R1 represents phenyl optionally substituted in the p-position by
lower alkylthio having up to and including 4 carbon atoms, by
lower alkanesulphinyl having up to and including 4 carbon atoms, or
by halogen having up to and including an atomic number of 35, R2
represents carboxymethyl, Ph represents 1,2-phenylene optionally

substituted in the p-position to the nitrogen atom by lower alkoxy
having up to and including 4 carbon atoms or by halogen having up
to and including an atomic number of 35, and alk represents 1,2-
ethylene, and Z1 has the meaning given in claim 1 or 2, X1, Y1 and
Z? have the meanings given in claim 3 or a salt thereof, or process
variant b) is carried out using a starting material of formula X
wherein R? represents the formula -CH2-R? in which R? is as defined
in claim 1 and R1, Ph and alk are as defined above, or process
variant c) is carried out using a starting material of formula I'
wherein R1, R2 and Ph are as defined above, so as to produce a
compound of the formula I, wherein alk, Ph, R1 and R2 have the
meanings given above or a pharmaceutically acceptable salt
thereof.
19. Process according to claim 4 or 5, wherein process variant
c) is carried out using a compound of formula I', wherein R1
represents phenyl optionally substituted in the p-position by
lower alkylthio having up to and including 4 carbon atoms, by
lower alkanesulphinyl having up to and including 4 carbon atoms,
or by halogen having up to and including an atomic number of 35,
R2 represents carboxymethyl, Ph represents 1,2-phenylene optionally
substituted in the p-position to the nitrogen atom by lower alkoxy
having up to and including 4 carbon atoms or by halogen having up
to and including an atomic number of 35, or a salt thereof, or
process variant b) is carried out using a compound of formula X
wherein R? represents -CH2-R? in which R? has the meanings given
in claim 4, alk is 1,2-ethylene and R1 and Ph are as defined above,
so as to produce a compound of the formula I, wherein alk, Ph,

R1 and R2 have the meanings given above, or a pharmaceutically
acceptable salt thereof.
20. Process according to claim 1, 2 or 3, wherein process
variant a) is carried out using a compound of formula II or IVa
wherein alk represents ethylene, Ph represents 4-methoxy-1,2-
phenylene, R1 represents p-chlorophenyl and R2 represents carboxy-
methyl or a lower alkoxycarbonylmethyl; and Z1 has the meaning
given in claim 1 or 2, X1 Y1 and Z1 have the meanings given in
claim 3 or a salt thereof, or process variant b) is carried out
using a starting material of formula X wherein R2 represents
-CH2-R2 in which R2 is as defined in claim 1, and R1 Ph and alk
are as defined above, and, when required, process variant d)-(i),
-(ii), -(vi) or -(vii) is carried out to produce 7-methoxy-1-
(p-chlorophenyl)-3,4-dihydro-pyrimidino[1,6-a]indole-5-acetic acid
or a pharmaceutically acceptable salt thereof or a lower alkyl ester
thereof.
21. Process according to claim 4, wherein a compound of the
formula X, wherein alk represents ethylene, Ph represents 4-methoxy-
1,2-phenylene, Rl represents p-chlorophenyl and R2 represents
-CH2-R" in which R2 has the meanings given in claim 4, or a salt
thereof, is selected as starting material, and when required,
process variant d)-(i) -(ii), -(vi) or -(vii) is carried out so as
to produce 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimidino
[1,6-a]indole-5-acetic acid or a pharmaceutically acceptable salt
thereof or a lower alkyl ester thereof.
22. Process according to claim 1, 2 or 3, wherein process
variant a) is carried out using a compound of formula II or IVa,

wherein alk represents ethylene, Ph represents 4-fluoro-1,2-
phenylene, R1 represents p-methylthiophenyl and R2 represents
carboxymethyl or a lower alkoxycarbonylmethyl; and Z1 has the
meaning given in claim 1 or 2, X1, Y1 and Z? have the meanings
given in claim 3 or a salt thereof, or process variant b) is
carried out using a starting material of formula X wherein R?
represents -CH2-R? in which R? is as defined in claim 1, and R1
Ph and alk are as defined above, and, when required, process
variant d)-(i), -(ii), -(vi) or -(vii) is carried out to produce
7-fluoro-1-(p-methylthiophenyl)-3,4-dihydropyrimidino[1,6-a]indole-
5-acetic acid or a pharmaceutically acceptable salt thereof or a
lower alkyl ester thereof.
23. Process according to claim 4, wherein a compound of the
formula X, wherein alk represents ethylene, Ph represents 4-fluoro-
1,2-phenylene, R1 represents p-methyl-thiophenyl and R? represents
-CH2-R? in which R? has the meanings given in claim 4, or a salt
thereof, is selected as starting material, and when required,
process variant d)-(i), -(ii), -(vi) or -(vii) is carried out so as
to produce 7-fluoro-1-(p-methylthiophenyl)-3,4-dihydropyrimido
[1,6-a]indole-5-acetic acid or a phamaceutically acceptable salt
thereof or a lower alkyl ester thereof.
24. Process according to any one of claims 1, 4 and 5, wherein
process variant b) is carried out using a compound of formula X and
I, wherein alk represents vinylene, Ph represents 4-fluoro-1,2-
phenylene, R1 represents p-methylthiophenyl and R? represents
-CH2-R? in which R? has the meanings given in claim 4, or process
variant c) is carried out using a compound of formula I' wherein
72

R1 and Ph are as defined above, and R2 is carboxymethyl or a lower
alkoxycarbonylmethyl, and when required process variant d)-(i),
-(ii), -(vi) or -(vii) is carried out so as to produce 7-fluoro-
(p-methylthiophenyl)-pyrimido[1,6-a]indole-5-acetic acid, or a
pharmaceutically acceptable salt or a lower alkyl ester thereof.
25. Process according to claim 1, 2 or 3, wherein a compound of
formula II or IVa, wherein alk represents ethylene, Ph represents
1,2-phenylene, R1 represents phenyl and R2 represents carboxymethyl
or a lower alkoxycarbonylmethyl; and Zl has the meaning given in
claim 1 or 2, X1, Y1 and Z1 have the meanings given in claim 3
or a salt thereof, or process variant b) is carried out using a
starting material of formula X wherein R2 represents -CH2-R2 in
which R2 is as defined in claim 1, and R1 Ph and alk are as
defined above, and, when required, process variant d)-(i), -(ii),
-(vi) or -(vii) is carried out so as to produce l-phenyl-3,4-
dihydro-pyrimido[1,6-a]indole-5-acetic acid or a pharmaceutically
acceptable salt thereof or a lower alkyl. ester thereof.
26. Process according to claim 4, wherein a compound of the
formula X, wherein alk represents ethylene, Ph represents 1,2-
phenylene, R1 represents phenyl and R2 represents -CH2-R2 in which
R2 has the meanings given in claim 4, or a salt thereof, is
selected as starting material, and when required, process variant
d)-(i), -(ii), -(vi) or -(vii) is carried out so as to produce
l-phenyl-3,4-dihydro-pyrimido-[1,6-a]indole-5-acetic acid or a
pharmaceutically acceptable salt thereof or a lower alkyl ester
thereof.
73

27. A compound of the general formula
<IMG> ( I ),
in which R1 represents phenyl optionally substituted by lower
alkyl, by lower alkoxy, by optionally halogen-containing lower
alkylthio, lower alkanesulphinyl or lower alkanesulphonyl, by
sulphamoyl optionally mono- or di-substituted by lower alkyl, and/o
by halogen, or represents 5- or 6-membered monocyclic heteroaryl
optionally containing lower alkyl, lower alkoxy and/or halogen
and having as hetero atom nitrogen, oxygen or sulphur, or nitrogen
and, in addition, sulphur or oxygen, R2 represents l-carboxy-lower
alkyl of the formula -CH(R3)-R2 in which R2 represents carboxy,
lower alkoxycarbonyl optionally substituted by lower alkyl-, lower
alkoxy- or halogen-containing phenyl or pyridyl, by hydroxy or by
lower alkoxy, or represents carbamoyl optionally substituted once
by hydroxy or amino, once or twice by lower alkyl or hydroxy-lower
alkyl, or twice by 4- or 7 membered lower alkylene or 3-oxa-,
3-thia- or 3-azaalkylene, R3 is hydrogen or lower alkyl, Ph is
1,2-phenylene optionally substituted by lower alkyl, lower alkoxy,
halogen and/or trifluoromethyl, and alk is lower alkylene
separating the methine group from the imino group by 2 carbon
atoms or vinylene, or a salt thereof, whenever prepared by the
process claimed in any one of claims 1, 2 and 3 or by any process
which is an obvious chemical equivalent thereof.
74

28. A compound of the general formula
<IMG>
(I),
in which R1 represents phenyl optionally substituted by lower alkyl,
by lower alkoxy, by optionally halogen-containing lower alkylthio,
lower alkanesulphinyl or lower alkanesulphonyl, by sulphamoyl
optionally mono- or di-substituted by lower alkyl, and/or by
halogen, or represents 5- or 6-membered monocyclic heteroaryl
optionally containing lower alkyl, lower alkoxy and/or halogen and
having as hetero atom nitrogen, oxygen or sulphur, or nitrogen and,
in addition, sulphur or oxygen, R2 represents l-carboxy-lower alkyl
of the formula -CH(R3)-R2 in which R2 represents carboxy, lower
alkoxycarbonyl optionally substituted by lower alkyl-, lower alkoxy-
or halogen-containing phenyl or pyridyl, by hydroxy or by lower
alkoxy, or represents carbamoyl optionally substituted once by
hydroxy or amino, once or twice by lower alkyl or hydroxy-lower
alkyl, or twice by 4- or 7-membered lower alkylene or 3-oxa, 3-thia-
or 3-aza-alkylene, R3 is hydrogen or lower alkyl, Ph is 1,2-
phenylene optionally substituted by lower alkyl, lower alkoxy, halo-
gen and/or trifluoromethyl, and alk is lower alkylene separating
the methine group from the imino group by 2 carbon atoms or
vinylene, or salt thereof, whenever prepared by the process claimed
in any one of claims 4 and 5 or by any process which is an obvious
chemical equivalent thereof.

Description

The invention relates to novel N,N'-bridged carboxylic acid
amidines, and to processes for the manufacture thereof, of the
general formula
~ R2
Ph \ 17
N alk (I),
Rl / ~ N
in which Rl represents phenyl optionally substituted by lower alkyl,
by lower alkoxy, by optionally halogen-containing lower alkylthio,
lower alkanesulphinyl or loweralkanesulphonyl by sulphamoyl
optionally mono- or di-substituted by lower alkyl, and/or by
halogen, or represents 5- or 6-membered monocyclic heteroaryl
optionally containing lower alkyl, lower alkoxy and/or halogen
and having as hetero atom nitrogen, oxygen or sulphur, or nitrogen
and, in addition, sulphur or oxygen, R2 represents l-carboxy-lower
alkyl of the formula -CH(R3)-R2 in which R2 represents carboxy,
lower alkoxycarbonyl optionally substituted by lower alkyl~, lower
alkoxy- or halogen-containing phenyl or pyridyl, by hydroxy or by
lower alkoxy, or represents carbamoyl optionally substituted once
by hydroxy or amino, once or twice by lower alkyl or hydroxy-lower
alkyl, or twice by 4- or 7-membered lower alkylene or 3-oxa-, 3-thia-
or 3-aza-alkylene, R3 is hydrogen or lower alkyl, Ph is l,2-
phenylene optionally substituted by lower alkyl, lower alkoxy,halogen and/or trifluoromethyl, and alk is lower alkylene separat-
ing the methine group from the imino group by 2 carbon atoms or
vinylene, and their pharmaceutically acceptable salts.
f~

-- 2 --
Monocyclic 5-membered heteroaryl containing as hetero atom
nitrogen, oxygen or sulphur, or nitrogen and, in addition,
sulphur or oxygen is, for example, pyrrolyl, such as 2-
pyrrolyl, furyl, such as 2-furyl, thienyl, such as 2- or
3-thienyl, or thiazolyl, such as 2-thiazolyl .Corresponding
6-membered heteroaryl contains at least one nitrogen atom
and is, for example, pyridyl, such as 2-, 3- or 4-pyridyl,
or pyrimidyl, such as 2-pyrimidyl.
Esterified l-carboxy-lower alkyl contains as
esterified carboxy group, for example lower alkoxycarbonyl,
which may also be substituted once by optionally sub-
stituted aryl, such as phenyl or pyridyl, or one or more
times by hydroxy, halogen or lower alkoxy, such as lower
alkoxycarbonyl optionally substituted by hydroxy, lower
alkoxy and/or halogen, for example mono- or di-hydroxy-
lower alkoxy-, halogen- or lower alkoxy-lower alkoxycarbonyl,
or phenyl-lower alkoxycarbonyl substituted by lower alkyl,
lower alkoxy and/or halogen.
Amidated l-carboxy-lower alkyl contains as amidated
carboxy group, for example carbamoyl, which may optionally
be substituted once by hydroxy or amino, once or twice
by lower alkyl or hydroxy~lower alkyl, or twice by 4- to

7-membered lower alkylene or 3-oxa, 3-thia- or 3-aza-alkylene.
The following may be mentioned as examples: N-hydroxy-, N-amino-,
N-mono- or N,N-di-lower alkyl-, or N-mono- or N,N-di-hydroxyalkyl-
carbamoyl. Carbamoyl N-substituted twice by 4- to 7-membered lower
alkylene is, for example, pyrrolidino- or piperidino-carbonyl, or
morpholino-, thiomorpholino-, piperazino- or N-lower alkylpiper-
azino-, such as N-methylpiperazino, carbonyl.
1,2-phenylene is optionally additionally substituted one or
more times, for example by lower alkyl, lower alkoxy, halogen or
trifluoromethyl.
The radical alk is a lower alkylene radical separating the
methine group from the imino group by 2 carbon atoms, such as
ethylene or 1,2-propylene, or is a vinylene radical.
In the present description, by organic radicals and compounds
referred to as "lower" there are preferably to be understood those
having up to and including 7, especially up to and including 4,
carbon atoms.
The general definitions used hereinbefore and hereinafter
have, within the scope of the present description, especially the
following meanings:
Lower alkyl is, for example, methyl, ethyl, n-propyl, iso-
propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, and also a
pentyl, hexyl or heptyl radical.
Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
Lower alkylthio is, for example, methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec.-
-- 3

33
butylthio, tert.-butylthio, n-pentylthio, n-hexylthio or n-heptyl-
thio, and lower alkanesulphinyl or -sulphonyl is, for example,
methane-, ethane- or n-propane-sulphinyl or -sulphonyl.
- 3a -

~lt~L4~33
-- 4 --
N-lower alkylsulphamoyl, is, for example, N-methyl-
sulphamoyl, N-ethylsulphamoyl or N-propylsulphamoyl, and
N,N-di-lower alXylsulphamoyl i~, ~or example, ~,N-
dimethylsulphamoyl, ~,N-diethyl~ulphamoyl, N,~-methyl-
ethylsulphamoyl or N,~-dipropylsulphamoyl.
Halogen is, for example, halogen having up to and
including an atomic num~er of 35, such a~ fluorine,
chlorine or bromineO
~ alo-lower alkylthio is, for example, chloromethyl-
thio, chloroethylthio or chloropropylthio or one of the
corresponding fluoro- or bromo-lower alkylthio groups.
Halo-lower alXanesulphinyl or -sulphonyl is, for
example, chloromethane-, chloroethane- or chloropropane-
sulphinyl or -3ulphonyl and the corresponding fluoro-
or bromo-lower alkanesulphinyl or -lower alkane~ulphonyl
group~.
Lower alkoxycarbonyl is, for example, methoxycarbonyl,
ethoxycarbonyl, n-pro~oxycarbonyl, butoxycarbonyl, or a pentyl-
oxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl radical.
Phenyl- and pyridyl-lower alkoxycarbonyl are, for
example, phenylmethoxycarbonyl, phenylethoxycarbonyl and
2-, 3- or 4-pyridylmethoxycarbonyl respectively.
~ ydroxy-lower alkoxycarbonyl i9, for example,
1- or 2-hydroxyethylcarbonyl, 1- or 3-hydroxypropylcarbonyl
or ~- or 4-hydroxybutylcarbonyl and dihydroxy-lower
alkoxycarbonyl is, for example, 2,3-dihydroxypropoxy-
carbonyl, 2,3-, 2,4- or 3,4-dihydroxybutoxycarbonyl.
Lower alkoxy-lower alkoxycarbonyl is, for example,
2-methoxyethoxycarbonyl, 1- or 2-ethoxyethoxycarbonyl,
2- or 3-methoxypropoxycarbonyl or 2-, 3- or 4-methoxy-
butoxycarbonyl.
Hydroxyalkyl is, for example, hydroxymethyl or
hydroxyethyl, but also hydroxypropyl or hydroxybutyl.
N-lower alkylcarbamoyl is, for example, N-methyl-
carbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-
isopropylcarbamoyl or N-butylcarbamoyl and N,N-di-lower

33
alkylcarbamoyl is, for example, N,N-dLmethylcarbamoyl,
N,N-diethylcarbamoyl or ~,~-methylethylcar~amoyl.
~ -~ydroxy-lower alkylcarbamoyl iq, for example,
~-hydroxymethylcarbamoyl or N-2-hydroxyethylcar~amoyl
and, ~,N-dihydroxy-lower alkylcarbamoyl is, for example,
~,N-2,3-dihydroxypropylcar~amoyl.
Salts of compounds of the formula I according to
the inventio~ are pharmaceutically acceptable
aalt~, such a~ corresponding acid addition salts and/or,
when R2 is 1-car~oxy-lower alXyl, internal salt~ or ~alts
with bases. Suitable acid addition salts are, for example,
salts with inorganic acida, such as mineral acid9, or
organic acids, such as sulphamic acids, for example
cyclohexylsulphamic acid, optionally unsaturated
dicarboxylic acids, or carboxylic acids optionally addition-
ally substituted by hydroxy or additionally containing oxo
and/or carboxy, or qulphonic acidq. Mineral acidY are,
~or example, sulphuric acid or hydrohalic acids, such as
hydrobromic or hydrochloric acid. ThQre come into
consideration as optionally unsaturated dicarboxylic acids,
for example oxalic acid, malonic acid, fumaric acid or
maleic acid, and there are used as carboxylic acids
optionally additionally substituted by hydroxy or
additionally containing oxo and/or carboxy, for example
tartaric acid, malic acid, pyruvic acid or citric acid.
Sulphonic acids are, for example, benzenesulphonic,
p-toluenesulphonic or methanesulphonic acid.
Suitable salts with bases are, for example, metal,
such aa alkali metal or alkaline earth metal, salts,
for example sodium, potassium or magnesium salta, tranaition
metal saltq, such aa zinc or copper salts, or salta with
ammonia or aalts of substituted organic amines such as
morpholine, thiomorpholine, piperidine and pyrrolidine,
such as mono-, di- or tri-lower alkylamine-q or mono-,
di- or tri-hydroxy-lower alkylamines, for example mono-,
di- or tri-ethanolamine. Mono-lower alkylaminea are,
for example, ethylamine or tert.-butylamine. Di-lower
~ r~

-- 6 --
alkylamine~ are, for example, diethylamine or dipropyl-
amine, and there come into con~ideration as tri-lower
alkylamines, for example, triethylamine, tributylamine or
dimethylpropylamine.
The compounda of the formula I have valuable
phar,ma~ological properties. In particular they exhibit
a pronounced antinociceptive (analgesic) activity, which
may be demonstrated, for example, by the acetic acid-
wri~ng ~yndrome in rats in a dosage range of from
approximately 1 to approximately 30 mg/Xg p.o. and by
the phenyl-p-benzoquinone-writhing test in mice in a
dosage range of from approx~mately 1 to approximately
30 mg/kg p.o..
In addition, they have a marked anti-inflammatory
and anti-arthritic activity, which may be demon~trated
by suppre~sion of kaolin paw oedema in the normal rat
in a dosage range of from approximately 10 to 100 mg~Xg p.o.,
and which, in addition, may be demon~trated by the
suppresaion of carragee~n paw oedema in the rat, analogously
to the method described by Pasquale _ al., Agents and
Action~, 5, 256 (1976), in do~e~ of approximately 3 to
approximately 300 mg/Xg p.o..
Furthermore, in curative administration with
administration, four times, of approximately 10 to 100 mg/kg
p.o., the compounds of the formula I suppress Xaolin
paw oedema of the adjuvant-arthritis rat.
The compounda of the formula I are therefore
excellently suitable as medicamenta for the treatment of
inflammatory disorders, especially those in the rheumatic
and arthritic field, a~ antiphlogistic~ and/or a~
peripheral analgesics.

4~33
Amony the above there are included, for example, compounds
of the formula I in which Rl represents phenyl optionally sub-
stituted by lower alkyl, lower alkoxy, lower alkylthio, halo-lower
alkylthio, lower alkanesulphinyl, halo-lower alkanesulphinyl, lower
alkanesulphonyl, halo-lower alkanesulphonyl, sulphamoyl, N-mono-
or N,N-di-lower alkylsulphamoyl and/or halogen, or represents
pyrrolyl, furyl, thienyl, thiazolyl, pyridyl or pyrimidyl each
optionally substituted by lower alkyl, lower alkoxy and/or
halogen, R2 represents a group of the formula -CH(R3)-R2 in which
R2 is carboxy, phenyl- or pyridyl-lower alkoxycarbonyl optionally
substituted by lower alkyl, lower alkoxy or halogen, hydroxy- or
lower alkoxy-lower alkoxycarbonyl, lower alkoxycarbonyl, carbamoyl,
N-hydroxycarbamoyl, N-aminocarbamoyl, N-mono-
`:
-- 7 --

or N,N-di-lower alkylcarbamoyl or -hydroxy-lower alkylcarbamoyl, or
carbamoyl substituted by 4- to 7-membered lower alkylene, or 3-oxa-,
3-thia- or 3-aza-alkyleneaminocarbonyl, R3 represents hydrogen or
lower alkyl, Ph represents 1,2-phenylene optionally substituted by
lower alkyl, lower alkoxy, halogen and/or trifluoromethyl and alk
represents lower alkylene separating the methine group from the
imino group by 2 carbon atoms or vinylene and their pharmaceutically
acceptable salts.
The invention relates especially to compounds of the formula
I in which Rl represents phenyl optionally substituted by lower
alkyl having up to and including 4 carbon atoms, such as methyl, by
lower alkoxy having up to and including 4 carbon atoms, such as
methoxy, by halo-lower alkylthio having up to and including 4 carbon
atoms, such as chloromethylthio, by lower alkylthio having up to and
including 4 carbon atoms, such as methylthio, by halo-lower alkane-
sulphinyl having up to and including 4 carbon atoms, such as chloro-
methanesulphinyl, by lower alkanesulphinyl having up to and
including 4 carbon atoms, such as methanesulphinyl, by halo-lower
alkanesulphonyl, such as chloromethanesulphonyl, by lower alkane-
sulphonyl having up to and including 4 carbon atoms, such as methane-
sulphonyl, by sulphamoyl, by N-mono- or N,N-di-lower alkanesulphamoyl
each having up to and including 4 carbon atoms in the alkyl radical,
such as N-methanesulphamoyl or N,N-diethylsulphamoyl, and/or by
halogen having an atomic number of up to and including 35, such as
chlorine, or represents pyridyl, such as 2-, 3- or 4-pyridyl, or
thienyl, such as 2-thienyl, each optionally substituted by lower
alkyl having up to and including 4 carbon atoms, such as methyl, by
lower alkoxy having up to and including 4 carbon atoms, such as
methoxy, and/or by halogen having

g
an atomic number of up to and including 35, such as
chlorine, R2 repre~ents a group of the formula -CX~R3)-R2
in which R2 represents car~oxy, phenyl- or pyridyl lower
alkoxycar~onyl, such as 2-, 3- or 4-pyridyl-lower alkoxy-
carbonyl, optionally ~ubstituted by lower alkyl having
up to and including 4 carbon atom~, such as methyl, by
lower alkoxy having up to and including 4 carbon atoms,
such as methoxy, and/or by halogen, such as chlorine, lower
alkoxycarbonyl, such a~ methoxycarbonyl, mono- or di-hydroxy-
lower alkoxycarbonyl, ~uch as 2-hydroxyethoxy- or 2,3-
dihydroxypropoxycarbonyl, lower al~oxy-lower alkoxycarbonyl
such a~ 2-methoxyethoxycarbonyl, ~-hydroxy- or N-amino-
carbamoyl, N-mono- or ~,~-di-lower alkoxycarbamoyl, such as
~-methyl- or N,~-diethylcarbamoyl, or carbamoyl, R3 i~
hydrogen or lower alkyl having up to and including 4 carbon
atoms, such as methyl, Ph is 1,2-phenylene optionally
sub~tituted by lower alkyl having up to and including 4
carbon atoms, such as methyl, by lower alkoxy having up to
and including 4 carbon atoms, such as methoxy, and/or by
halogen having up to and including an atomic number of 35,
~uch as fluorine and alk is 1,2-ethylene, and their
pharmaceutically acceptable ~alts.
The invention includes those ~referred compeunds
of the formula I in which R1 represents phenyl, optionally
~ub~tituted by halogen, lower alkylthio, lower alXane-
sulphinyl, lower alkane-~ulphonyl, halo-lower alkylthio
and~or ~ulphamoyl, or pyridyl or thienyl, ~2 repre~ents
a group of the formula -CH2-R2 in which R2 repre~ents
carkoxy, lower alkoxycarbonyl or carbamoyl, Ph repre~ents
1,2-phenylene optionally substituted by lower al~oxy,
lower alkyl and/or halogen, and alk i3 1, 2-ethylene
or vinylene, and their ~harmaceutically
acceptable salts.
The invention relates preferably to compounds of
the formula I in which R1 represents phenyl, optionally
substituted by halogen having an atomic num~er of up to

433
- 10 -
and including 35, such as chlorine, by lower alkylthio
having up to and including 4 carbon atoms, such as
methylthio, by lower al~anesulphinyl having up to and
including 4 carbon atoms, such as methanesulphinyl, by
halo-lower alkylthio having up to and including 4 carbon
atoms, such as chloromethylthio and/or by sulph~moyl,
pyridyl, e3pecially 2-pyridyl, or thienyl, especially
2-thienyl, R2 repreRentS a group of the formula -CH2-R2
in which R2 represents carboxy, lower alkoxycarbonyl
having up to and including 5 carbon atoms, such as
ethoxycarbonyl, or carbamoyl, Ph represent~ 1,2-phenylene
optionally substituted by lower alkoxy having up to
and including 4 carbon atom~. such a~ methoxy, by lower
alkyl having up to and including 4 carbon atomq, such a~
methyl, and/or by halogen having an atomic number of up
to and including 35, such a~ fluorine, and alk i9 1, 2-
ethylene or vinylene, and their salts, especially
pharmaceutically acceptable salts.
The invention relate~ in an especially preferred
manner to compounds of the formula I in which R1 repre-
sentQ phenyl optionally substituted in the p-position by
halo-lower alkylthio having up to and including 4 carbon
atoms, such a~ chloromethylthio, by lower alXylthio
having up to and including 4 carbon atoms, such as methyl-
thio, by lower alkanesulphinyl having up to and including
4 carbon atoms, such as methanesulphinyl, or by halogen
having an atomic number of up to and including 35, ~uch
as chlorine, or in the 3-position by sulphamoyl and, in
addition, in the 4-poqition by halogen having an atomic
number of up to and including 35, such a~ chlorine,
or pyridyl, especially 2-pyridyl, or thienyl, especially
2-thienyl, R2 representQ a group of the formula -CH2-R2
in which R2 represents carboxy, lower alkoxycarbonyl
having up to and including 5 carbon atoms, such as
ethoxycarbonyl, or carbamoyl, Ph represents 1,2-phenylene
optionally substituted in the 4-position in relation to
, .

33
the bonded nitrogen atom by lower alkoxy having up to
and including 4 carbon atoma, such as methoxy, in the 3-
and 5-po3ition by lower alkyl having up to and includinq
4 car~on atom~, such a~ methyl, or in the 4~position by
halogen having an atomic number of up to and including
35, ~uch a~ fluorine, and alk i3 1,2-ethylene or vinylene,
and their salts, e~pecially pharmaceutically acceptable
~alts.
The invention relate~ especially preferably to
compounds of the formula I in which Rl represents
phenyl optionally Aubstituted in the p-position by
lower alkylthio having up to and including 4 carbon atoms,
such as methylthio, by lower alkanesulphinyl having
up to and including 4 carbon atoms, such as methane-
sulphinyl, or by halogen having an atomic number of
up to and including 35, such as chlorine, R2 represents
lower alkoxycarbonylmethyl, such as ethoxycarbonylmethyl,
Ph represents 1,2-phenylene optionally mono-substituted
in the 4-position in relation to the bonded nitrogen atom
by lower alkoxy having up to and including 4 carbon
atoms, such as methoxy, or in the 4-position by
halogen having an atomic number of up to and in-
cluding 35, such as fluorine, and alk is 1,2-ethylene,
and their salts, especially pharmaceutically acceptable
salts.
The invention relates more especially to compounds
of the formula I in which R1 represent~ phenyl optionally
substituted in the p-po~ition by lower alkylthio having
up to and including 4 carbon atoms, such as methylthio, by

lower alkanesulphinyl having up to and including 4 carbon atoms,
such as methanesulphinyl, or by halogen having up to and including
an atomic number of 35, such as chlorine, R2 represents carboxy-
methyl, Ph represents 1,2-phenylene optionally substituted in the
p-position to the nitrogen atom by lower alkoxy having up to and
including 4 carbon atoms, such as methoxy, or by halogen having up
to and including an atomic number of 35, such as fluorine, and
alk represents 1,2-ethylene, and their salts, especially their
pharmaceutically acceptable salts.
The invention relates namely to the compounds of the formula
I and their pharmaceutically acceptable salts, mentioned in the
Examples.
The compounds of the formula I and their salts can be pro-
duced according to methods known per se, for example by splitting
off H-Zl from compounds of the general formula
R2
Ph
\ / \ alk (II)
Zl N
H
in which Zl represents optionally functionally modified hydroxy or
mercapto, or from salts thereof, with the introduction of an
additional bond.
- 12 -

33
_ 13 -
Functionally modified hydroxy or mercapto is, for
example, hydroxy or mercapto etherified by a lower
alkanol, such as methanol or ethanol, or by an optionally
sub~tituted aromatic alcshol, such as phenol, or hydroxy
e3terified by an inorganic acid, such a~ a mineral acid,
for example a hydrohalic acid, ~uch as hydrochloric acid,
and represents, for example, lower alkoxy, such a~
methoxy, or optionally ~ubstituted aryloxy, 3uch as
phenoxy, lower alkylthio, such as methylthio, or halogen,
such as chlorine or bromine.
~ -Z1 is split off in customary manner, for example
spontaneously, by thermal mean~, i.e. by heating, and/or
in the presence of a catalytic agent. The thermal
~plitting reaction is u~ually carried out in a temperature
range of from approximately 50 to approximately 200C.
The catalytic agents u~ed are, for example, basic or
acidic catalysts, there being used as bases, for example
alkali metal hydroxides, amides or hydrides, such as
pota~3ium hydroxide, sodium amide or sodium hydride,
metal oxides, ~uch as aluminium oxide, or especially
organic nitrogen bases, ~uch as tertiary amines, for
example pyridine, quinoline or N,N-dimethylaniline, and
as acidic catalysts, for example mineral acids or acidic
galts or anhydrides thereof, such as sulphuric acid or
phosphoric acids, hydrogen ~ulphates, such as alkali metal
hydrogen sulphates, for example potassium hydrogen
sulphate, pho~phorus pentoxide, or mineral acid halides,
such as sulphuric acid halides, for example 3ulphuryl chlor-
ide. The process i~, if necessary, carried out in the
presence of an inert solvent or diluent, in a closed
vessel and/or under an inert ga~, for example nitrogen.
Inert solvents and diluents are optionally
~ub~tituted hydrocarbons, ~uch as optionally halogenated
aliphatic or aromatic hydrocarbon~, for example chloro-
form or chlorobenzene, ethers, ~uch a~ aliphatic,
cycloaliphatic or aromatic ethers, for example diethyl
, l .
..

33
- 14 -
ether, dioxan, tetrahydrofuran, dipheny~ ether or
anisole, ketone~, such as aliphatic ketone~, for example
acetone or methylethylketone, amides, uch as dialkyl-
amides, for example dimethylformamide, or sulphoxides,
such as di-lower alkyl~ulphoxides, for example dimethyl-
sulphoxide.
Starting material~ of the formula IIcan ke produced according to proce~seQ known per se, for
example by cycli~ing compounds of the formula
l;
X1 (IVa)
or salt~ thereof, in which X1 represents hydrogen and
Y1 represents a group of the formula -alk-NH-C(-Zj)(~1)
or X1 represents -C(-Z1)(R1) and Y1 repre~ents a group
of the formula -alk-N~2 and Z1 represents optionally
functionally modified oxo, and, if desired, converting
a so-obtainable free compound of the formula II into a
different free compound, or into a salt, or converting a
salt obtainable according to the process into the free
compound or into a different salt.
Functionally modified oxo is, for example, thioxo,
~etali~ed or thio-ketalised oxo, e~terified dioxy, or
imino. Ketalised oxo compound~ are, for example, ketals
with lower alkanol~, such as methanol or ethanol, or
lower alkanediols, such as ethylene glycol or propylene-
glycols, for example 1,3-dihydroxypropane, and thioketal~
are, for example, thioketal~ with lower alkanethiols,
for example methanethiol or ethanethiol, or lower

_ 15 -
alkanedithiols, ~uch a~ 1,2-ethanedithiol, or propane~i-
thiol~, for example p~opane-1,3-dithiol.
Imino is, for example, imino optionally -~ub~tituted
by lower alkyl or phenyl, such as ~I-lower alkylimino,
for example N-propylimino.
The cy~lisation i~ carried out in known manner,
for example in the presence of catalysts, such as acidic
catalysts. These are, for ~xample, mineral acid~, such
as qulphuric acid or polypho~phoric acid, mineral acid
halides, such as sulphuryl chloride, or phosphorus
halides, for example phosphorus pentachloride, or organic
sulphonic acids, such as benzenesulphonic, p-toluene-
sulphonic or methanesulphonic acid. The cyclisation is,
if necessary, carried out in one of the above-mentioned
inert solvents or diluents, preferably while heating,
for example in a temperature range of from approximately
20 to approximately 200C, in a closed vessel and/or
under inert gas, for example nitrogen.
In an advantageous embodiment of the afore-described
process, compounds of the formula IVa are used as starting
materials and cyclisation to compounds of the formula II
and splitting off H-Z1 from the compounds of the formula II
are carried out in situ without isolation of the inter-
mediates.
An especially advantageous embodiment of the
afore-described process carried out by way of the
compounds of the formula II consists, for example, in
quaternising, especially with benzyl bromide, compounds
of the formula
_ ./ \N-Bz (IVd) ,
\~-~,/-
H
.
.~

l4~3
- 16 -
in which Bz represent~ an optionally aubstituted ~-
phenyl-lower alkyl radical, preferably ~enzyl, 3plitting
the bond at the quaternary nitrogen atom by mean~ of
cyanide~, such as alkali metal cyanides, for example
30dium cyanide, and, in a re~ulting compound of the
formula IVe
Ph -il C~
~ ~! (IVe) ,
Bz ~ z
as desired solvoly~ing the cyano group, ~plitting off
the benzyl groups by hydrogenolysia in the presence of
a hydrogenation catalyat, for example palladium, and
reacting the then free amino compound with a compound
~ 1
of the formula R1-C in which Z1 represents
~ al
optionally functionally modified oxo and ~al representa
halogen, and finally reacting by means of a cyclLsing
agent, preferably a mineral acid halide, such as
phosphorus oxychloride or phoaphorus chloride, to form
a compound of the formula II.
,

33
- 17 -
The compounds of the general formula I or salts thereof can
~urthermore be produced, for example, from a compound of the
formula
Ph--11~ 2
~M~ alk
~1/ N
in which R2 represent~ a group of the formula -C~(R3)-R2
and in which R3 repreqents hydrogen or lower alkyl and
R2 represents functionally modified carboxy different from
R2, or a group of the formula
-C~=O)-N2 B , in which ~ i9 the anion of a mineral
acid, for example chloride, bromide or tetrafluoroborate,
or represents methyl optionally oxidised to the stage of
formyl, or salts thereof, by converting Q2 by solvolysis
or oxidation into the group R2 and, if de3ired, converting
a so-obtainable free compound of the formula I into a
different free compound or into a salt, or converting a
salt obtainable in accordance with the proce~s into the
free compo~nd or into a diferent salt. Functionally
modified carboxy compounds and functionally modif~ed
carboxy compoundq different from R2 are, for example
optionally functionally modified ortho-ester group-~, such
a9 trihalo-, halo-di-lower alkoxy- or tri-lower alkoxymethyl
groups, anhydridised carboxy, such a~ cyano, a group of
the for~ula =C=O, cyano-, azido- or halocarbonyl, acyloxy-
carbonyl, s-~ch as acetoxycarbonyl, or derivative~ of
carboxy of the formula R2 or ~2~ in which oxo i~ optionally
replaced by thio or optionally substituted imino, ~uch a~
optionally esterified thiocarboxy, such as lower alkylthio-
carboxy, for example ethylthiocarboxy, amidated thiocarboxyl,

l~tj~433
~ 18 ~
imino-ester~, such as imide- or amide-halide groupings,
for example iminochloromethyl or aminodichloromethyl,
imino ether groupings, ~uch as lower alkylLmino ether or
lower alkyleneimino ether groupings, for example methoxy-
iminomethylene or ethoxyiminomethylene, or amidino group~,
such as amidino or lower alXylamidino, for example methyl-
amidino.
Methyl oxidi~ed to the formyl stage, or functionally
modified groups thereof are, for example, optionally
reactively e~terified or etherified hydroxymethyl or
optionally functionally modified formyl, such as hydroxy-
methyl, mono- or di-halomethyl, lower alkoxymethyl, formyl
or formimino.
Functionally modified carboxy compounds, such as
optionally functionally modified ortho-esters, anhydridised
carboxy or acyloxycarbonyl can be solvolysed directly,
or in several solvolysis steps, to free, esterified or
amidated carboxy.
The 301volysis of R2 is carried out in known manner,
for example by hydrolysis with water, by ammonolysi~
with ammonia, by aminolysis with a desired primary or
secondary amine or by alcoholysis with a corresponding
alcohol. The process is carried out, if necessary, in the
presence of a catalyst, in a solvent or diluent, in a
closed vessel, in a temperature range of from approximately
0 to approximately 150C and/or under inert gas, for
example nitrogen.
Catalysts are, for example, basic condensing agents,
such as alkali metal or alkaLine earth metal hydroxides,
for example sodium, potassium or calcium hydroxide, or
tertiary organic amine~, such as pyridine, or trial~ylamines,
~or example triethylamine, or acidic hydrolysing agents,
~uch as mineral acids, for example hydrohalic acids, such
as hydrochloric acid, or organic carboxylic or sulphonic
acid~, such a~ lower alkanecarboxylic acids or optionally
substituted benzenesulphonic acids, for example acetic acid

31 4~33
-- 19 --
or p-toluenesulphonic acid.
Methyl op~ionally oxidised to the formyl stage,
~uch a~ methyl, hydroxymethyl or formyl, or functionally
modified derivatives thereof, such as halomethyl, for
example chloromethyl, mercaptomethyl, thioformyl or
optionally ~ub~tituted formimino, may be oxidi~ed directly
or by way of several oxidation step~, optionally by way
of hydroxymethyl or formyl, to car~oxy. Etherified
hydroxymethyl, preferably lower alkoxymethyl, for example
ethoxymethyl, is oxidi~ed, in the presence of an o~idising
agent, to form esterified carboxy, especially lower alkoxy-
carbonyl. The reaction of formyl to form carbamoyl is
carried out, for example by means of an amino compound
in the presence of an oxidising agent, ~uch as a tran~-
ition metal oxide, for example manganese dioxide, and, if
nQces~ary, in the pre~ence of a nucleophile, especially a
cyanide.
Oxidation of R2 is carried out ln customary manner,
for example using customary oxidising agents. These are,
for example, optionally catalytically acti~ated oxygen,
alkali metal ~alts of chromates or manganates, such as
~odium chromate or potassium permanganate, or transition
metal oxides, ~uch a~ manganese dioxide or chromium
trioxide. The oxidation i~ carried out, if necessary, in
an inert sol~ent, in a clo~ed vessel and/or while cooling
or heating, for example at approximately 0 to approximately
150C
The ~tartlng materials of the formula X can ~e
pro~duced according to analogou~ processes, for example
by reacting compounds of the formula
~ X1
Ph - ,
~ alk (VIa) ,
R1

llt~ 33
-- 20 ~
in which X1 represents oxo or thioxo, with compound9 of
the formula P(Z2)3-~2, whiCh may ke in the form either of
phosphonium ylide9 or of phosphoranes, or X1-P(Z3)2-R2,
and in which Z2 represent~ alkyl and/or phenyl and Z3
represents alkyl and/or phenyl, or represent~ alkoxy, such
a9 lower alkoxy, and/or phenoxy, and ~2 represent~ function-
ally modified carboxy dif~erent from R2~ or a group of the
formula -C(=O)N2B or methyl optionally oxldl~ed to the
formyl stage, splitting off from intermediate~ of the
formula
l; l4
(VIh) ,
~ alk
R~
optionally obtainable in thiq manner, in which X1 represents
-0~ or sQ and Z4 represents a radical of the formula
-P(Z2)3 or -P(X;)(Z3)2, re9pectively, a compound of the
la 1 P(Z2)3 or X1-P(X1)(Z3)2 respectively, and
isomerising a compound obtained in this manner to a
compound of the formula X.
The reaction is usually carried out in an inert
solvent, for example an optionally halogenated hydrocarbon,
~uch as an aromatic compound, for example benzene or
toluene, an ether, such as tetrahydrofuran or dioxan, or
an amide, for example dimethylformamide, in a temperature
range of from approximately 20 to approximately 150 C
and/or optionally in the presence of a catalyst, such as a

~1~1433
- 21 -
ba-qe, for example an alkali metal alcoholate, ~uch a3
potassium tert.-~utanolate.
In a preferred embodiment, the starting material~
of the formula X in which R2 i8 a radical that can be
converted by ~olvoly3i~ or oxidatio~ into R2 are obtained,
and qtarting, for example, from compounds of the formula
Ph ~ Bz t IVd )
H
in which Bz repre~entq an optionally substituted a-phenyl-
lower alkyl radical, preferably benzyl, the tertiary
nitrogen ato~ i~ quaternised, especially with benzyl
chlorid~, the bond at the quaternary nitrogen atom is
split by mean~ of a qtrong ba~e, such a~ by a cyanide,
for example ~odium cyanide, and in a resulting compound
of the formula
` Pl. i~ CN
\~f\.
~ ~! (IVe)
BzN~Bz
the cyano group i~ converted into R2, for example by
~olvoly~is to carboxy or lower alkoxycarbonyl and then
reduction to hydroxymethyl or lower alkoxymethyl
respectively, and the Bz groups are qplit off by hydro-
genoly3is in the preqence of a hydrogenation cataly~t.
The compound obtained in thi~ manner i~ then reacted with

4~33
a compound of the formula Rl-C Z~ , in which Zi represents
optionally functionally modified oxo and Hal represents halogen,
and cyclisation to corresponding compounds of the formula X is
carried out in the presence of a customary cyclising agent, such
as a mineral acid halide, for example phosphorus oxychloride.
Compounds of the formula I in which R2 represents
esterified or amidated l-carboxy-lower alkyl and alk represents
vinylene are produced, for example by dehydrogenating
: appropriate compounds of the formula
R2
Ph ~ /
\ I! (I')
I (CH2)2
R / ~ N /

433
with ~he splitting
off of hydrogen with qimultaneous formation of an addi-
tional bond, and, if desired, converting a compound
obtainable according to the invention into a different
compound of the formula I or converting a free compound
of the formula I obtainable according to the invention
into a salt, or converting a salt obtainable according
to the process into the free compound of the formula I
or into a different salt~
The dehydrogenation i~ carried out in a manner
known per se, especially at elevated temperature, for
example in a temperature range of from approximately
100 to approximately 300C, and with the use of a
dehydrogenating agent. Such agents are, for example,
dehydrogenation catalysts, for example sub-group ele-
ments, preferably of the sub-group VIII, such as palla-
dium or platinum, or salts thereof, quch aq ruthenium-
triphenyl-phosphide-chloride, the catalysts optionally
being supported on a suitable carrier, such as carbon,
aluminium oxide or silicon dioxide. Other dehydrogena-
ting agents are, for example, quinones, such as p-
benzoquinone, for example tetrachloro-p-benzoquinone
or 2,3-dichloro-5,6-dicyano-p-benzoquinone, or anthra-
quinones, for example phenanthrene-9,10-quinone. The
reaction is carried out in an inert, optionally high-
boiling, solvent, such as an ether, for example diphenyl
ether, if necessary under pressure, in a closed vessel
and/or under an inert gas, for example nitrogen.
The compounds of the formula I to be u~ed as
starting materials can be produced according to the
afore-described processe~.
A compound of the formula I obtainable according
to the invention can be converted into a different com-
pound of the formula I in a manner known per se.
If the group R2 contains free carboxy, this can
be converted according to esterification methods known

~ti 1433
- 24 -
E~ ~e into correspondingly esterified carboxy, for
example by reacting optionally xeactive modified carboxy
or a salt thereof by alcoholysis with a desired alcohol,
for example a reactive derivative thereof or an olefin
derived therefrom, or by alkylation with diazo-lower
alkane.
Suitable reactive functional carboxy derivatives
are, for example, anhydrides, there being used a~ anhyd-
rides especially mixed anhydrides, for example those
with inorganic acids, such as hydrohalic acids, for
example hydrochloric acid, or hydrazoic or hydrocyanic
acids, or with organic carboxylic acids, such as lower
alkanoic acids, for example acetic acid.
Reactive derivatives of an alcohol are, for example,
carboxylic, phosphor~us,sulphurous or carbonic acid
e~ters, for example lower alkanecarboxylic acid esters,
tri-lower alkylphosphite, di-lower alkylsulphite or
pyrocarbonate, or mineral or sulphonic acid e~ters, for
example chloride, bromide or sulphuric acid esters,
benzenesulphonic, toluenesulphonic or methanesulphonic
acid ester~, of the alcohol concerned.
~ he esterification of free carboxy is carried out
in the pre~ence of a condensing agent. There come into
con~ideration as agents that split off water by cat~lysi3
in the esterification with alcohols, for example acids,
for example protonic acids, such as hydrochloric, hydro-
bromic, sulphuric, pho~phoric, boric, benzene~ulphonic
and/or toluene~ulphonic acid or Lewis acids, such as
boron trifluoride etherate. Customary water-binding
condensing agents are, for example, carbodiimideq ~ub-
stituted by hydrocarbon radical~, for example NfN'-
diethylcarbodiimide, N,N-dicyclohexylcarbodiimide or
N-ethyl-N'-(3-dimethylaminopropyl~-carbodiimide. Con-
densing agents for the esterification with reactive
esters are, for example, basic condensing agents, such
as inorganic bases, for example alkali metal or alkaline

33
- 25 -
earth metal hydroxide~ or carbonate~, such as sodium,
potassium or calcium hydroxide or carbonate, or organic
nitrogen bases, for example tertiary organic amines,
such as triethylamine or pyridine. The esterification
is advantageously carried out with the alcohol in
excess. It is preferably carried out in an anhydrous
medium, if necessary in the presence of an inert solvent,
such as in halogenated hydrocarbons, for example chloro-
form or chlorobenzene, or in ethers, for example tetra-
hydrofuran or dioxan.
The reaction with an olefin can be carried out,
for example, in the presence of an acidic catalyst, fox
example a Lewi~ acid~ for example boron trifluoride, a
sulphonic acid, for example p-toluenesulphonic acid, or
especially a basic catalyst, for example sodium or
potassium hydroxide, advantageou~ly in an inert solvent,
such as an ether, for example diethyl ether or tetra-
hydrofuran.
Furthermore, free carboxy or reactive functional
carboxy derivative3 can be converted into a desired
amidated form by solvolysis with ammonia or a primary
or secondary amine, it being pos~ible also for hydroxyl-
amines or hydrazines to be used, the solvolysis being
carried out in customary manner with dehydration, option-
ally in the presence of a condensing agent. There are
used as condensing agents preferably bases, for example
inorganic bases, such as alkali metal hydroxides, for
example sodium or potassium hydroxide, organic nitrOgen
bases, such a~ tert.-amine,s, for example pyridine,
tributylamine or N-dimethylaniline, or tetrahalosilanes,
such as tetrachloro~ilane.
Further, ccmpounds of the formula I ob$ainable accor-
ding to the invention in which R2 contains esterified
carboxy a3 substituent, can be transesterified in custo-
mary manner, for example by reaction with a corresponding
alcohol or a metal salt thereof, quch a~ an alkali metal
salt, for example the sodium or potassiwm ~alt, if neces~ary

33
in the presence of a catalyst, for example a strong baqe,
~uch as an alkali metal hydroxide, amide or alcoholates,
for example pota~sium hydroxide, sodium amide or sodium
methanolate, or a strong acid, ~uch as a mineral acid,
for example sulphuric acid, phosphoric acid or hydro-
chloric acid, or such as an organic sulphonic acid, for
example an aromatic sulphonic acid, ~uch as p-toluene-
sulphonic acid.
Esterified carboxy can furthermore be converted
into the free carboxy group according to known processes,
for example by hydrolysis in the presence of a catalyst.
There come into consideration as catalysts preferably
bases, for example alXali metal hydroxides, such a~
sodium or potassium hydroxide. Esterified carboxy may
furthermore be converted into carboxy in customary manner,
for example by solvolysis, optionally in the presence of
a catalyst, for example an acidic or basic agent, or
into amidated carboxy by ammonolysis or aminoly~is with
ammonia or with a primary or secondary amine~ There
are used as bases, for example al~ali metal hydroxides,
such as sodium or potassium hydroxides, and as acids,
for example mineral acids, such as sulphuric acid,
phosphoric acid or hydrochloric acid. Li~ewise, com-
pounds of the formula I obtainable according to the
invention in which the group R2 contains an amidated
carboxy ~ubstituent can be transformed according to
methods known E~ se that split the amide bond and thu~
convert the carbamoyl into free carboxy. This operation
is carried out in the presence of a cataly~t, for example
a base, such as an alkali metal or alkaline earth metal
hydroxide or carbonate, for example sodium, potassium
or calcium hydroxide or carbonate, or an acid, such a_
a mineral acid, for example hydrochloric acid, sulphuric
acid or pho~phoric acid.
If the group R2 of the formula I contains an
esterified carboxy group, this can be converted into an

33
~ 27 -
amidated carboxy group, for example by customary sol-
voly3is, advantageously by an aXCe~Q of ammonia, or
an amine containing at least one hydrogen atom, option-
ally in the presence of a catalyst. There are used as
cataly~t~, for example acids, such as mineral acids,
for example hydrochloric, sulphuric or phosphoric acid,
or base~, such a~ alXali metal hydroxides, for example
sodium or potassium hydroxide.
If the group R2 of the formula I contains a~ sub-
stituent amidated carboxy, this can be converted into
esterified carboxy, for example by customary solvolysis
with an alcohol in the presence of a catalyst. The
catalysts used are, for example, acidic catalysts, such
as mineral acids, for example phosphoric acid, hydro-
chloric acid or sulphuric acid.
If the ~ubstituent R1 of the formula I is 9ub -
stituted by lower alkylthio, thia can be oxidised in
customary manner to corresponding lower alkanesulphinyl
or lower alXanesulphonyl. There come into consideration
as suitable oxidising agents for the oxidation to the
sulphoxide stage, for example, inorganic peracids, quch
as peracids of mineral acids, for example periodic acid
or persulphuric acid, organic peracids, such as suitable
percarboxylic or persulphonic acids, for example per-
formic, peracetic, trifluoroperacetic, perbenzoic or p-
toluenepersulphonic acid, or mixtures of hydrogen peroxide
and acids, for example a mixture of hydrogen peroxide
with acetic acid.
Fre~uently, the oxidation i~ carried out in the
presence of suitable catalysts, and there should be
mentioned as cataly3ts suitable acids, such a~ optionally
substituted carboxylic acids, for example acetic or tri-
fluoroacetic acid, or tranqition metal oxides, such as
oxides of elements of sub-group VII, for example vanadium,
molybdenum or tung~ten oxide. The oxidation is carried
out under mild conditionq, for example at temperatureq of
,.

~l~..,tl.433
- 28 -
approximately -50 to approximately l1G0C.
The oxidation ~ the sulphone stage can al30 be
carried out in corresponding manner with dinitrogen
tetroxide as catalyst in the presence of oxy~en at low
temperatures as can also the direct oxidation of the
lower alkylthio to lower alkanesulphonyl except that
usually the oxidising agent is used in excesq.
Compounds of the formula I in which R1 repreaenta
an aromatic radical ~ubstituted by lower alXylsulphinyl
or lower alkylsulphonyl can be reduced according to
methods known per se to the corre~ponding lower alkylthio
compounds and ~tarting from lower alkanesulphonyl
derivatives al.qo to lower alkanesulphinyl. A ~uitable
reducing agent is for example~ catalytically activated
hydrogen there being used noble metals or oxides such
aa palladium platinum or rhodium or their oxides
optionally supported on a suitable carrier such as
active carbon or barium sulphate. There also come into
consideration reducing metal cations ~uch as tin(II~
lead(II~ copper(I~ manganeae(II~ titanium(II~
vanadium(II~ molybdenum(III~ or tungaten(III~ compounda
hydrogen halides ~uch as hydrogen chloride hydrogen
bromide or hydrogen iodide hydrides auch aa complex
metal hydrides for example lithiumaluminium hydride
sodium borohydride and tributyltin hydride phosphorus
compounds such as phosphoru~ halides for example pho~-
phorus trichloride pho~phorus tribromide phosphorus
pentachloride or phosphorus oxychloride phosphinea
auch as triphenylpho~phine or phosphorua pentasulphide-
pyridine or sulphur compound3 such a~ mercaptans thio
acids such as thiophosphoric acid~ or dithiocarboxylic
acids dithionite or ~ulphur/oxygen complexes .~uch aq
an iodine/pyridine/sulphur dioxide complex.
Resulting qalts can be converted into free compounds
in a manner known per se for example by treating with an

- ~9 ~ 4;~
acidic reagent, such as a mineral acid, or a base, for
example an alkali hydroxide solution.
Depending on the choice of starting materials and
method~, the new compounds may be in the form of one
of the possible isomers or mixtures thereof, for example,
depending on the number of asymmetrical carbon atoms,
as pure optical isomer~, such as antipodes, or as mix-
tures of isomers, such as racemates, mixtures of dia-
stereoisomers or mixtures of racemates.
Resulting mixtures of diastereoisomers and mixtures
sf racemates can k~e separated on the basis of the physico-
chemical differences of the constituents, in known manner,
into the pure isomers, diastereoisomers or racemates,
for example by chromatography and/or fractional crystal-
lisation.
Resulting racemates can furthermore ~e resolved into
the optical antipodes by known methods, for example by
recrystallisation from an optically active solvent, by
means o~ microorganisms or by reacting an acidic end pro-
duct with an optically active base that forms salts with
the racemic acid, and separating the salts obtained in
this manner, for example on the basis of their different
solubilities, into the diastereoisomers, from which the
antipode3 can be liberated by the action of suitable
agent~. Advantageously, the more active of the two anti-
podes is isolated.
The compounds, including their salts, can also be
obtained in the form of their hydrates, or include other
solvents used for the crystallisation.
Owing to the close relationship between the new
compounds in free form and in the form of their salts,
there are herein to be understood by the free compounds
cr tAeir salts accordingly and appropriately optionally
also the corresponding salts or free compounds respectively.
The invention relates also to those embodiments of
the process according to which compound~ obtainable as
intermediates at any stage of the process are u~ed a~
starting material~ and the remaining steps are carried

11~14~33
~ 30
out, or a starting ma~erial is used in the form of a
salt or especially is formed under the reaction con-
dition~.
In the process of the present invention, there
are preferably used a3 ~tarting materials tho~e that
result in compounds described at the beginning as being
especially valuable. The invention relates also to
novel starting materials and processes for their manu-
~acture.
The phannaceutical preparations according to the
invention, which contain compounds of the formula I or
pharmaceutically acceptable salts thereof, are those
for enteral, such as oral or rectal, and parenteral,
administration as well as for topical administration
to warm-blooded animals,that contain the pharmacological
active substance alone or together with a pharmaceutically
acceptable carrier. The dosage of the active substance
depends on the species of warm-blooded animal, the age
and the individual condition, and on the method of
administration. Normally, where administration is oral
and the warm-blooded animal weighs approximately 75 kg,
an approximate daily dosage of 30 to 300 mg, advantage-
ously divided into several equal portions, is estimated.
The new pharmaceutical preparations contain, for
example, from approximately 10 % to approximately 80 ,',
preferably from approximately 20 % to approximately 60 %,
of the active substance. Pharmaceutical preparations
according to the invention for enteral or parenteral
administration are, for example, those in dosage unit
forms, such as dragées, tablets, capsules or suppositories,
or also ampoules. These are produced in a manner known
E~ se, for example by means of conventional mixing,
granulating, coating, dissolving or lyophilising processes.
Thus, pharmaceutical preparations for oral administration
can be obtained by combining the active substance with
solid carriers, optionally granulating a resulting mixture,
and proce~ing the mixture or granulate to form tablets

33
or dragée cores, if desired or necessary after the addi-
tion of suitable adjuncts.
Suitable carriers are especially fillers, such
as sugar, for example lactose, saccharose, mannitol or
sorbitol, cellulose preparations and/or calcium phos-
phates, for example tricalcium pho~phate or calcium
hydrogen pho~phate, also binders, such a~ starch pastes
using, for example, corn, wheat, rice or potato ~tarch,
gelatin, tragacanth, methylcellulose and/or polyvinyl-
pyrrolidone, and/or, if desired, disintegrators, such
as the above-mentioned starches, and also carboxymethyl
starch, cross-linked polyvinylpyrrolidone, agar, alginic
acid or a salt thereof, such a~ sodium alginate. Adjuncts
are especially flow-regulating agents and lubricants, for
example silica, talc, stearic acid or salts thereof, such
as magnesium or calcium stearate, and/or polyethylene-
glycol. Dragée cores are provided with suitable, option-
ally gastric juice-resistant, coating~, there being used,
inter alia, concentrated sugar solutions, which option-
ally contain gum arabic, talc, polyvinylpyrrolidone,
polyethyleneglycol and/or titanium dioxide, lacquer
solutions in suitable organic solvents or solvent mixtures,
or, to produce gastric juice-resistant coatings, solutions
o suitable cellulose preparations, such as acetylcellulose-
phthalate or hydroxypropylmethylcellulosephthalate.
Colouring matter or pigments may be added to the tablets
or dragée coatings, for example for identification pur-
poses or for indicating different doses of active substance.
Other pharmaceutical preparations for oral admini-
stration are dry-filled capsules made of gelatin, and soft
~ealed cap~ules con~isting of gelatin and a plastici~er,
such as glycerin or sorbitol. The dry-filled capsules may
contain the active substance in the form of a granulate,
for example in admixture with fillers, such as lactose,
binders, such as starches, and/or glidants, such as talc
or magnesium stearate, and optionally stabilisers. In

11~14~3
- 32 -
soft capsul~s the active ~ubstanc~ i~ preferably dis-
~olved or ~u~pended in suitable liquids, such aq fatty
o;ls, paraffin oil or liquid polyethyleneglycols, it
likewise being po~ible for stabilisers to be added.
There come into consideration as rectally admini-
~trable pharmaceutical preparations, ~or example suppo-
sitorie~ consisting of a combination of the active 9ub-
stance with a suppository ba~e. Suitable suppository
bases are, for example, natural or synthetic triglycerides,
paraffin hydrocarbons, polyethyleneglycols or higher
alkanols. It i~ also possible to use gelatin rectal
capsules that contain a combination of the active sub-
stance with a base, there coming into consideration as
base ~ubstances, for example liquid triglycerides, poly-
ethyleneglycols or paraffin hydrocarbons.
Especially suitable forms for parenteral admini-
stration are aqueous solutions of an active substance
in water-soluble form, for example a water-soluble salt,
or suspensions of the active substance, such as corres-
ponding oily injection suspensions, suitable lipophilic
solvents or vehicles, such as fatty oils, for example
sesame oil, or synthetic fatty acid esters, for example
ethyloleate or triglycerides, being used, or aqueous
iniection suspension~ that contain viscosity-increasing
substances, for example sodium carboxymethylcellulose,
~orbitol and/or dextran and optionally also stabilisers.
For topical administration, there come into con-
sideration especially creams, ointments, pastes, foams,
tincture~ and solutions that contain from approximately
0.5 to approximately 20 % of the active substance.
Cream~ are oil-in-water emulsions that consiqt of
more than 50 ,' of water. As oily base there are used
especially fatty alcohol~, for example lauryl, cetyl or
stearyl alcohol, fatty acids, for example palmitic or
stearic acid, liquid-to-solid waxes, for example iso-
propylmyristate, wool wax or beeswax, and~or hydrocarbons,
; ,.
.

433
_ 33 -
for example Vaseline (petrolatum) or paraffin oil. There
come into consideration as emulsifiers surface-active
subqtances with predominantly hydrophilic properties,
such as corresponding non-ionic emulsifiers, for example
fatty acid esters of polyalcohols or ethylene oxide
adducts thereof, such as polyglycerin fatty acid ester~
or polyoxyethylene-sorbitan-fatty acid esters (Tweens-trade
mark), also polyoxyethylene fatty alcohol ethers or fatty acid
esters, or corre~ponding ionic emulsifiers, such as
alkali metal salts of fatty alcohol sulphateq, for example
sodium lauryl sulphate, ~odium cetyl sulphate or sodium
stearyl sulphate, which are usually used in the presence
of fatty alcohols, for example cetyl alcohol or stearyl
alcohol. Additives to the aqueouq phase are, inte~ alia,
agent~ that reduce the drying-out of creams, for example
polyalcohols, cuch as glycerin, sorbitol, propyleneglycol
and/or polyethyleneglycol, and al30 preservatives,
odoriferous substar.ces, etc.
Ointments are water-in-oil emulsions that contain
up to 70 %, but preferably from approximately 20 % to
approximately 50 %, water or aqueous phases. There come
into consideration as fatty pha~e especially hydrocar~ons,
for example Vaseline, paraffin oil and/or hard paraffins,
which, to improve the water-binding capacity, preferably
contain suitable hydroxy compounds, such a~ fatty alcohols
or esters thereof, for exæmple cetyl alcohol or wool wax
alcohols, or wool wax. Emulsifiers are corresponding
lipophilic ~ubstances, such as qorbitan ~atty acid esters
(Spans-trade mark~,for example sorbitan oleate and~or sorbitan
isostearate. Additives to the aqueous phase are, inter
alia, moisture-retaining agents, such as polyalcohols,
for example glycerin, propyleneglycol, sorbitol and/or
polyethyleneglycol, and preservatives, odoriferous sub-
stances etc.

11~1433
- 34 -
Fatty ointments are anhydrous and contain as base
especially hydrocarbons, for example paraffin, Vaseline
and/or liquid paraffins, also natural or partially ~yn-
thetic fat, for example, coconut fatty acid triglyceride,
or preferably hardened oils ~ for example hydrogenated
peanut oil or castor oil, al~o fatty acid partial esters
of glycerin, for example glycerin mono- and di-stearates,
a~ well as, ~or example, the fatty alcohols that increase
the ability to absorb water, the emulsifiers and/or the
additives, mentioned in connection with the ointments.
Pastes are creams and ointments with secretion-
absorbing powder constituents, such as metal oxides, for
example titanium oxide or zinc oxide, and also talc and/or
aluminium silicates which serve to bind any moisture or
secretions present.
Foams are dispensed from pressure containers and
are liquid oil-in-water emulsions in aerosol form, halo-
genated hydrocarbons, such as chlorofluoro-lower alkanes,
for example dichlorodifluoromethane and dichlorotetra-
fluoroethane, ~eing used as propellanta. As oil phase
there are used, inter alia, hydrocarbons, for example
paraffin oil, fatty alcohols, for example cetyl alcohol,
fatty acid esters, for example isopropylmyristate, and/or
other waxes. As emulsifiers there are used, inter alia,
mixtures of emulsifiers with predominantly hydrophilic
properties, ~uch as polyoxyethylene-sorbitan-fatty acid
esters (Tweens~, and emulsifiers with predominantly lipo-
philic properties, such as sorbitan fatty acid esters
(Spans~. In addition there are the customary additives,
such as pre~ervatives etc.
Tinctures and solutions usually have an aqueou-
~ethanolic base, to which there are added, inter alia,
polyalcohols, for example glycerin, glycols and/or
polyethyleneglycol, a~ moisture-retaining agents for
reducing evaporation, and fat-restoring substances, such
as fatty acid ester~ with low polyethyleneglycols, that

3 4':~
- 35 -
is to say lipophilic substances soluble in aqueous mix-
ture as a replacement for the fatty substances removed
from the qkin by the ethanol, and, if necessary, other
adjunct~ and additives.
The manu~acture of the topically administrable
pharmaceutical preparationR is carried out in a manner
known Per se, for example by dissolving or suspending
the active sub~tance in the base material or in a portion
thereof, if necessary. When processing the active sub-
stance in the form of a solution~ this is usually dissolved
in one of the two phases before emulsification, when
processing in the form of a suspension, it is usually
mixed with a portion of the base after emulsificatio~
and then added to the rest of the formulation.
The present invention relate~ also to the use of
compounds of the formula I and the salts of such com-
pounds with salt-forming properties preferably for the
treatment of inflammations, especially inflammatory
disorders of the rheumatic type, especially chronic
arthritis.
The following examples illustrate the above-described
invention but are not intended in any way to limit the
scope thereof. Temperatures are in degrees Centigrade.
There is no consistent characterisation in the
litexature of the lin~ing point~ in the pyrimido-indole
ring system,
~ ~19a 1~ ~1
~ 6~- ~ 5 ~' ~ 4 ~'
;~'~
'~J~

11~14~3
- 36 -
forming the basis of the compounds of the formula I.
Thus, the older literature sources characterise
the linking points in the ring system by ~3,4-a],
wherea~ recently the characterisation r1,6-a] has been
used.
From con~iderations of principle, the following
nomenclature is used hereinafter for the above ring
structure: pyrimldor1,6-a1indole.

433
- ~7 -
Example 1: 7-(methoxy-1-(p-~hlorophenyl)-3,4-dihydro-
pyrimido[1,6-a]indole-5-acetic acid ethyl ester hydrochloride
165 g (0.4 mol) of 2-[(p-chloro~enzoyl-amino)-ethyl~-
5-methoxy-indole-3-acetic acid ethyl e~ter are boiled under
reflux for 3 hours in 825 ml of pho~phorus trichloride and
exces~ pho~phoru.~ trichloride is ~ubsequently di~tilled
off at a bath temperature of 60 under a slight vacuum.
The residue is dis~olved in 1500 ml of methylene chloride,
extracted by ~tirring with 2000 ml of ice-water and
rendered alkaline by adding 500 ml of concentrated ammonia
and, after brief stirring, the methylene chloride phase iq
separated off. The methylene chloride phase i~ washed
neutral with water, dried over ~a2S04 and the methylene
chloride i~ distilled off. The residue (136.7 g) is
di~solved in 120 ml of acetone and 500 ml of ether, and
100 ml of an approximately 4 normal hydrogen chloride
solution in ether ar~ added to the solution. While ~o
doing, the hydrochloride of 7-methoxy-1-(p-chlor~phenyl-
3,4-dihydro-pyrimido[1,6-a]indole-acetic acid ethyl ester
crystalli~es out.
C~30~ C~2-COOC2~S
il 11
~ /\N~ \
~ I . HCl
Cl~

i14;33
- 3~ -
The latter i3 filtored with 3uction and wa~hed
with acetone/ether 1: 10 yielding yellowi~h cry~tals having
a melting point of 204-208 and, after recry~talliaation
from methanol/acetone, a melting point of 205-208.
The ~tarting material can be manufactured aa
follow~:
a) 13t g (0.45 mol) of 3-~enzyl-6-m~thoxy-tetra-
hydro-y-carboli~e are di~olved at 40, while stirring, in
1300 ml of acetonitrile, and, in the course of 10 minutes,
94 g (0.55 mol) of benzyl brcmide are added. After a
~hort time, the benzyl ammoni~m deriYative begins to
cryatalli~e out~ Stirring i9 continued at room temp~rature
for approximatsly t5 hour~, the mixture i~ then cooled in
an ice bath, and the crystals are filtered with suction,
m.p. 150-151.
b) 464 g ~1 1) of the resulting ~,N-dibenzyl-6-
methoxy-tetrahydro-r-carboliminium bromidQ are di3~01ved,
while heating to 65, in 4250 ml of methanol, and, in
the cour~e of 5 minute~ and while stirring, a qolution of
196 g (4 1) of sodium cyanide in 500 ml of water i3
added. The soluti~n is boiled under reflux for 3 houra.
On cooling, 2-(dibenzylamino-ethyl)-3-cyano-methyl-5-
methoxy-indole crystallisQs, after aeeding, to yield
colourle~s crystals having a melting point of 102-104.
c) 220 g (0.537 mol) of the nitrile produced in
b) are dissolv~d in ~00 ml of absolutQ ethanol and the
801ution i-~ ~aturated, at -5, with dry hydrogen chloride.
The aolution ia then atirred for 5~ day~ at 20. The
aeparated crystals are allow~d to settle, th~ ~upernata~t
aolution ia d~canted, the aediment is di~aolved in 2000 ml
of ice-water and the ~olution ia Jtirr~d for approximRtQly
3 houra at 20. While cooling with ice, it is then
rendered alkaline with concentrated ammonia ~olution and
extracted by ~tirring with ~500 ml of toluene/ice-watQr.
The ~eparated toluene phase is wa~hed with water, dried
C 'i
I

1~tj1~33
- 39 -
over aodium ~ulphate and filtered over 1000 g of aluminium
oxidQ (Act. Grade 3) and ~ub3equ~ntly washed with toluene.
After di~tilling off the toluene, a light brown oil ~emain~
which is ~ubjected to hydrogenation a~ described in d)
without furth~r purifi~ation.
d) 181.3 g of the 2-dibe~zylamino~5-methoxy-indole-
3-acetic a~id ethyl ester obtain~d in c) are dissolved in
1500 ml of ab~olute alcohol and hydrogenated at 20-35
under normal pre~ure with the addition of 18 g of
palladium-on-carbon (5 %). When 12500 ml of ~2 have been
ab~orbed a further 18 g of cataly~t are added and
hydrogenation i~ continued until the ab~orption of ~2
cea~e3 at a total of 17300 ml. After filtering off the
catalyat and ~ubsequantly wa~hing with methylene chloride,
the ~olution i~ concentrated to dryne~ by evaporation
and the re~idue i~ dis~olved in 250 ml of ether. After
~eeding, 2-aminoethyl-5-methoxy-indole-3-acetic acid
ethyl e ter crystall~ses to form colourless crystals
having a melting point of 79-80.
e) 61.7 g ~0.223 mol) of the 2-aminoethyl-5-
methoxy-indole-3-acetic acid ethyl ester produced in d)
are di~olved in 600 ml of methylene chloride and the
solution i~ covered with a layer of 150 ml of 2N sodium
hydroxide ~olution. A ~olution of 43 g (0.245 mol) of
p-chlorobenzoyl chloride i9 added, at 0-5, in the coursQ
of 2~ hour~, while stirring vigorou~ly, and extraction
by ~tirring ia then carried out for a further hour. The
methylene chloridQ phase i~ then ~eparated off, ~ashed with
water, dried over MgS04 and concentrated to dryne~a by
evaporation. The re~idue cryatalliqea on being taken
up in ether, to form colourlel~ cryatal~ of 2-C(p-chloro-
benzoyl-amino)-ethyl3-S-methoxy-indole-3-acetic acid
ethyl e~ter having a melting point of 136-138.
~ '
~ 3
.~

33
-- 40 --
Example 2: 1-Phenyl-3,4-dihydro-pyrimido[1,6-a]indole-5-
acetic acid ethyl e~;ter.
54 g (0.154 mol) of 2-(benzoylamino-ethyl)-indole-
3-acetic acid ethyl ester are boiled under reflux for
3 hours in 250 ml of pho~phoru~ oxychloride. Exce~s
phosphoru3 oxychloride is then distilled off at 60
_ vacuo and the re~idue i~ stirred with 10()0 ml of
ice-water. The aqueous solution is clarified by filtration
over Hyflo, rendered alkaline with concentrated ammonia
and extracted with 500 ml of ether. The ether phase i9
dried over sodium sulphate and concentrated to dryne~.
l!he residue i~ dissolved in 200 ml of acetone, and 25 ml
of an approximately 4 normal hydrogen chloride ~olution
in ether are added. After seeding, the hydrochloride of
1-phenyl-3,4-dihydro-pyrimido~1,6-a]indole-5-acetic acid
ethyl ester crystallises to form yellowish cry~tal~ having
a melting point of 172-175, which can be recrystallised
from 1N hydrochloric acid (melting point 187-189). The
base liberated from the salt melts at 83-84 after
recrystallisation from ether.
The 2-(benzoylamino-ethyl)-indole-3-acetic acid
ethyl e~ter having a melting point of 162-163 which is
u~ed a~ starting material can be manufactured analogously
to Example 1 a) - e).
,
Example 3:
7-fluoro-1-(p-methylthio-pheny~,-3,4-dihydro-
pyrimido~1,6-a]indole-5-acetic acid ethyl ester having
a melting point of 119-120 is obtained, in a manner
analogous to that de~cribed in Example 2, from 2-[(p-methyl-
thio-benzoyl-amino)-ethyl]-5-fluoro-indole-acetic acid
ethyl ester having a melting point of 157-158.

- 41 -
Example 4:
. _
6,8-dLmethyl-1-phenyl-3,4-dihydro-pyrimido~1,6-a]-
indole-5-acetic acid ethyl e~ter having a melting point
o~ 142-143 is obtained, in an analogous manner, from
2-benzoyl-aminoethyl-4,5-dimethyl-indole-3-acetic acid
ethyl ester having a melting point of 183-184.
Example 5:
1-(3-~ulphamoyl-4-chloro-phenyl)-3,4 dihydro-
pyrimido[1,6-a]indole-5-acetic acid ethyl e~ter having a
melting point of 227-228 i~ obtained, in an analogo~
manner, from 2-[~3-~ulphamoyl-4-chlorobenzoyl-amino)-
ethyl]-indole-3-acetic acid ethyl ester having a melting
point of 212-213.
Example 6:
1-(2,6-dichlorophenyl)-3,4-dihydro-pyrimidoL1,6-a]-
indole-5-acetic acid ethyl eqter having a melting point
of 92-93 (hydrochloride m.p. 138-142) i~ obtained, in
an analogous manner, from 2-(2,6-dichlorobenzoyl-aminoethyl)-
indole-3-acetic acid ethyl e~ter having a melting point of
125-126.
Example 7:
_
1-(2-picolinyl)-3,4-dihydro-pyr~nido~1,6-a3indole-
5-acetic acid ethyl e~ter having a melting point of
113-114 (hydrochloride m.p. 192-204) i~ obtained, in
an analogous manner, from 2-(2-picolinoyl-aminoethyl)-
indole-3-acetic acid ethyl e~ter having a melting point
of 117-118 .

- 42 -
Example 8:
-
The hydrochloride of 1-(2-thienyl)-3,4-dihydro-
pyrImido{1,6-a~i~dole-5-acatic acid ethyl ester having
a melting point of 153-157 is obtained, in an analogou~
manner, from 2-(2-thienylamino-ethyl)-indole-3~acetic
acid ethyl ester having a melting point of 140-141.
Example 9: 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-
pyrimido[1 ! 6-a]indole-5-acetic acid
117.2 g (0.27 mol) of 7-methoxy-1-(p-chlorophenyl)-
3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl
ester hydrochloride are introduced, while stirring, into
a solution of 550 g of potassium hydroxide in 200 ml of
water and 1500 ml of methanol. The mixture i~ ~tirred for
10 hours at room temperature, the methanol is distilled
off in vacuo, the residue is diqsolved in 1500 ml of ice-
water, and 700 ml of concentrated hydrochloric acid are
added to the solution while cooling with ice. The
separated hydrochloride is filtered with suction and
recrystallised from 2300 ml of 50 % ethanol to yield
7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido~1,6-a]-
indole-5-acetic acid hydrochloride in the form of yellowish
crystals having a melting point of 225-228 (with
decomposition).
Example 10:
_
The hydrochloride of 1-phenyl-3,4-dihydro-pyrimido-
[1,6-a]indole-5-acetic acid having a melting point of
235-240 (with decomposition) is obtained in an analogous
manner from the corresponding ethyl eqter.

43 1~ 33
Example 11
The hydrochloride of 7-fluoro-1-(p-methylthio-
phenyl)-3,4--dihydro-pyrimido[1,6-a]indole-5-acetic acid
having a melting point of 220-222 (with decompositior~)
i~ obtained in an analogou~ manner from the corresponding
ethyl ester.
Example 12:
The hydrochloride of 7-fluoro-1-(p-methyl~ulphinyl-
phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid
having a melting point of 208-210 (with decompo~ition)
i~ obtained in an analogous manner from the corresponding
ethyl eqter.
Example 13:
The hydrochloride of 6,8-dimethyl-1-phenyl-3,4-
dihydro-pyrimido[1,6-a]indole-5-acetic acid having a
melting point of 212-220 (with decomposition) i9 obtained
in an analogous manner from the corresponding ethyl ester. l'he
corresponding hemihydrate ha~ a melting point of above 210.
Example 14:
The hydrochloride of 1-(3-sulphamoyl-4-chloro-
phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid
having a melting point of 216-220 (with decompo~ition)
i~ obtained in an analogous manner from the corre~ponding
ethyl ester.
.
Example 15:
_
The hydrochloride of 1-(2,6-dichlorophenyl)-3,4-
dihydro-pyrimido[1,6-a]indole-5-acetic acid having a
melting point of 270-277 (with decomposition) is obtained
in an analogous manner from the corre~ponding ethyl
e~ter.

_ 44 _ i~433
Example 16:
The hydrochloride of 1-(2-thienyl)-3,4-dihydro-
pyrimido~1,6-a]indole-5-acstic acid having a melting
point of 230-235 (with decompo~ition) i9 obtained in an
analogous manner from the correqponding ethyl ester~
1-(2-thienyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic
acid crystalli~e~ at pH 6-7 from the aqueous solution
of the hydrochloride, in the form of an internal salt
having a melting point of 187-189.
Example 17: 1-phenyl-3,4-dihydro-pyrimido~1,6-a~indole-
.
5-acetic acid amide
1 g ~0.003 mol) of 1-phenyl-3,4-dihydro-pyrimido-
[1,6-a]indole-5-acetonitrile i9 heated at 100 for 30
minutes in 10 g of polyphosphoric acid. The reaction
mixture is di solved in 100 ml of water, the ~olution is
rendered alkaline, while cooling with ice, by adding
concentrated ammonia and the reaction product is extracted
with methylene chloride. The methylene chloride phase i9
washed neutral with water, dried over Na2S04 and the
solution is concentrated to dryness. The solid 1-phenyl-
3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid amide
remaining as residue is recrystallised from methanol to
yield colourless cry~tals having a melting point of
239-240. The corresponding hydrochloride has a melting
point of 253-260 (with decomposition).
The starting material can be manufacturedaY
follows:
a) 38 g (0.1 mol) of 2-(dibenzylamino-ethyl)-indole-
3-acetonitrile are introduced into 300 g of polyphosphoric
acid and the mixture i9 heated at 100, while qtirring,
for approximately 60 minutes. The mixture i-~ poured onto
1 kg of ice, rendered alkaline by adding concentrated
~ '

- 45 -
ammonia and extracted with ether. After waqhing and
drying the ether pha~e and concentrating it by evaporation,
2-(dibenzylamino-ethyl)-indole-3-a~etamide i3 obtained
as a syrup which can be cry~talli-~ed from a little ether,
m.p. 135-136.
b) 120 g (0.3 mol) of 2-(dibenzylamino-ethyl)-
indole-3-acetamide are hydrogenated at 30-35 under normal
pres~ure, with the addition of 12 g of 5 % palladium-~n-
carbon, in 1.2 litres of methanol. When 14.4 litre~ of
hydrogen have been ab~orbed, hydrogenation is discontinued,
the catalyst i~ filtered off and the solution is concen-
trated to dryne~ in vacuo. The residue is recrystallised
from 100 ml of ethanol with the addition of 250 ml of
ethex. The resulting 2-aminoethyl-indole-3-acetamide ha3
a melting point of ~56-157.
c) 17.5 ml (0.15 mol) of benzoyl chloride are
added, while qtirring thoroughly and cooling to
approximately 5, to 21.7 g (0.1 mol) of 2-aminoethyl-
indole-3-acetamide in a mixture of 200 ml of ether and
100 ml of water, and 100 ml of 2N ~aOH are gradually
added dropwise. ~he reaction i3 complete after approximate-
ly 1 hour. Stirring i~ continued for 1 hour at 0-5 and
the ~eparated 2-(benzoylamino-ethyl)-indole-3-acetamide
having a melting point of 223-225 is filtered with
suction.
d) 1.6 g (0.005 mol) of 2-(benzoylamino-ethyl)-
indole-3-acetamide ia heated under reflux for 2 hours
in 16 ml of pho~phorus oxychloride. Exce-q~ phosphoru3
oxychloride i~ di3tilled off, the oily reqidue i3 taken
up in water and by-productq of the reaction are removed
by extracting with ether. Concentrated ammonia is added
to the aqueou3 phase, while cooling, and extraction with
ether iq carried out. After washing and drying the ether
phaqe and concentrating it by evaporation, 1-phenyl-3,4-
. .

33
-- 46 --
dihydro-pyr~mido[t,6-a]indole-5-acetonitrile is obtained
a~ a yellowish oil which,by dissolving in methanol and
adding ethereal hydrochloric acid, can be converted
irlto a crystalline hydrochloride having a melting point
of 195--205.
Example 18:
_ .
q~he hydrochloride of 1-(3-sulphamoyl-~chloro-
phenyl) 3, ~dihydro-pyrimidoC1,6-a]indole-5-acetamide
having a melting point of 249-257 (with decompo-~ition)
is obtained, in a manner analogou~ to that described in
Example 17, from ~-(3-sulphamoyl-4-chloro-phenyl)-3,4-
dihydro-pyrimido[1,6-a~indole-5-acetonitrile having a
melting point of 280-285.
Example 19:
12 g (0.03 mol) of 1-(p-methylthio-phenyl)-3,~
dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl ester
are di~solved in 120 ml of glacial acetic acid, and 4 ml
of 30 % hydrogen peroxide are added. The mixture i9 left
to stand for approximately 20 hour~ at room temperature,
is poured onto 1 litre of ice-water, rendered alXaline
with concentrated ammonia and extracted with ethyl acetate.
The ethyl acetate phase i9 washed, dried and concentrated
by evaporation. The re-~ulting 1-~p-methyl~ulphoxy-phenyl)-
3,4-dihydro-pyriJoido[1,6-a]indole-5-acetic acid ethyl ester
crystallise~ from ether to yield yellowish crystal~ having
a melting point of 150-151.
Example 20:
In a manner analogous to that described in Example 1
the hydrochloride of 7-fluoro-1-(p-methylthio-phenyl)-
3,4-dihydro-pyrimido[1,6-a]indole-3-acetic acid ethyl e~ter

43~
~ 47 -
having a melting point of 210 (with decomposition) i~
obtained startinq from 2-[(~-methylthio-phenyl-amino)-
ethyl]-5-fluoro-indole-5-acetic acid ethyl ester and,
starting from 2-[(p-chloromethylthio-phenyl-amino)-
ethyl]-5-fluoro-indole-3-acetic acid ethyl ester, there is
obtained the hydrochloride of 7-fluoro-1-(p-chloromethyl-
thio-phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic
acid ethyl e~ter having a melting point of 198-202.
Example 21:
The hydrochloride of 7-fluoro-1-(p-methylsulphoxy-
phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid
ethyl ester having a melting point of 261-264 i~
obtained, in a manner analogous to that described in
Example 19, qtarting from 7-fluoro-1-(p-methylthio-
phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid
ethyl ester hydrochloride.
Example 22:
7-fluoro-1-(p-methylthio-phenyl)-pyrimido[1,6-a]-
indole-S-acetic acid having a ~nelting point of 213-220
(with decomposition) is obtained, i~ a manner analogous
to that de~cribed in Example 9, by hydrolysing 7-fluoro-
1-(p-methylthio-phenyl)-pyrimido[1,.6-a]indole-5-acetic
acid ethyl eqter.
Example 23: 7-fluoro-1-(p-methylthio-phenyl)-pyrimido-
. ., ~ . . _ . _ _ .
[1,6-a]indole-5-acetic acid ethyl e~ter
2 g of 7-fluoro-1-(p-methylthio-phenyl~-3,4-
dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyL ester
are heated under reflux, while qtirring, in 20 ml of
diphenyl ether with O.S g of palladium-on-carbon (10 %).
After 2 hourq, a further 0.5 g of palladium-on-carbon

l~ 3
-- ~8 --
i9 added and the mixture i9 heated for a further 3 hour3.
After filtering off the cataly~t, the reaction mixture
is concentrated in vacuo, the residue is taken up in a
little ethyl acetate and chromatographed over silica gel.
Using hexane/ethyl acetate t9:1) fractions are obtained
which, after concentration by evaporation and recrystal-
li~ation from ether, yield 7-fluoro-1-(p-methylthio-phenyl)-
pyrimido~1,6-a]indole-5-acetic acid ethyl ester having a
melting point of 120-122.
.~ \, ~ ~/ 2 2 5
11 1~
`-/'~ b
il~ ~i' \~
~-X ~
The following are obtained in an analogous manner:
1-phenyl-pyrimido[1,6-a]indole-5-acetic acid ethyl ester
having a melting point of 59-62
and
7-methoxy-1-(p-chlorophenyl)-pyrimido[1,6-a]indole-
5-acetic acid ethyl e~ter having a melting point of
130-131.
Example 24:
1,O g (O.003 mol) of 1-phenyl-3,4-dihydro-
pyrimido[l,6-a]indole-5-ace_onitrile i~ stirred for
48 hour~ at 0 in 50 ml of absolute ethanol and 50 ml of
ethanol ~aturated with hydrogen chloride. The solvent is

~1~1433
- 49 -
then distilled off under reduced pressure. The remaining,
crude hydrochloride of 1-phenyl-3,4-dihydro-pyrimido-
[1,6-a]indole-5-acetiminoethyl e~ter iY quspended in 10 ml
of water and heated at 40 for 15 minute~ while stirring.
After cooling, 1-phenyl-3,4-dihydro-pyrimido~1,6-a]indole-
5-acetic acid ethyl ester hydrochloride crystalliQes and,
after recry~talli ation from 1~ hydrochloric acid, yields
cry~talQ having a melting point of 187-189.
Example 25:
3.84 g (0.01 mol~ of 7-fluoro-1-(p-methylsulphoxy-
phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid
ethyl e~ter are heated under reflux for 2 hour~, while
stirring, in 500 ml of ethyl acetate with 40 g of
deactivated Raney nickel. The catalyqt i~ then filtered
off and the filtrate i-Q ccncentrated by evaporation under
reduced pressure. The residue yields, after recrystal-
lisation from ether, 7-fluoro-1-(p-methylthio-phenyl)-3,4-
dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl eqter
having a melting point of 119-120.
Example 26:
Tablets each containing 25 mg of active substance,
for example 7-fluoro-1-(p-methylthio-phenyl)-3,4-dihydro-
pyrimido[1,6-a]indole-5-acetic acid or a salt thereof,
for example the hydrochloride, can be manufactured in the
following manner:
Conqtituents (for 1000 tablet~):
.
active substance 25.0 g
lacto~e 100.7 g
wheat qtarch 7.5 g
polyethylene glycol 6000 5.0 g
talc 5.0 g
magne~ium qtearate 1.8 g
deminerali-qed water q.s.
~,~

33
- 50 -
Manufacture:
All the ~olid ingredienta are fira~ forced through
a aieve having a me3h width of 0.6 mm. Then the active
substance, lacto~e, talc, magneaium atearate and half of
the 3tarch are mixed. The other half of the ~tarch i3
auspended in 40 ml of water and thi~ auspension is added
to a boiling ~olution of the polyethylene glycol in 100 ml
of water~ The resulting starch paste i~ added to the main
portion and the mixture i~ granulated, if necesYary with
the addition of water. The granulate ia dried overnight
at 35, forced through a aieve having a me~h width of 1.2 mm
and preaaed to form tableta of approximately 6 mm diameter
having concave facea on both aides.
In an analogoua manner, it is also poasible to
manufacture tableta each containing 25 mg of one of the
compounda of the formula I mentioned in Examples 1 to 19,
it being po~aible for the compounda to be also in the
form of acid addition aalta, such aa hydrochlorides,
and for compounds in which R2 is 1-carboxymethyl to be
alao in the form of aalta and bases, auch as sodium,
potaaaium or zinc aalta.
Example 27:
Tablet~ for chewing, each containing 30 mg of
active sub~tance, for example 7-fluoro-1-(p-methylthio-
phenyl)-3,4-dihydro-pyrimido~1,6-a]indole-5-acetic acid
or a salt thereof, for example the hydrochloride, can be
manufactured, for example in the following manner:

3~
- 51 -
Compo~ition (for 1000 tablets):
_;
active ~ubstance 30.0 g
mannitol 267.0 g
lacto~e 179.5 g
talc 20.0 g
glycine 12.5 g
~tearic acid 10.0 g
saccharine 1.0 g
5 % gelatine solution q.s.
Manufacture:
All the solid ingredients are first fnrced through
a sieve having a mesh width of 0.25 mm. The mannitol and
the lactose are mixed and granulated with the addition of
the gelatine solution, the mixture i9 forced through a
sieve having a me~h width of 2 mm, dried at 50 and again
forced through a sieve having a mesh width of 1.7 mm.
~he active ~ubstance, glycine and saccharine are carefully
mixed, the mannitol, the lactose granulate, the ~tearic
acid and the talc are added, and the whole i9 thoroughly
mixed and pre~sed to form tablets of approximately 100 mm
diameter having concave faces on both ~ides and a break
groove on the upper side.
In an analogous manner it is also possible to
manufacture tablets for chewing,each containing 30 mg
of one of the compounds of the formula I mentioned in
Examples 1 to 19, it being possible for the compound~ to
be also in the form of acid addition ~alts, such as
hydrochlorides, and for compounds in which R2 is 1-
carboxymethyl to be al~o in the form of salts with
bases, ~uch a~ sodium, pota~sium or zinc salts.

- 52 -
Example 28:
Tablets each containing 100 mg of active ~ubstance,
for example 7-fluoro-1-(p-methylthio phenyl)-3,4-dihydro-
pyrimido~1,6-a]indole-5-acetic acid or a ~alt thereof,
for example the hydrochloride, can be manufactured in the
following manner:
Composition (for 1000 tablets):
._~ .
active substance 100.0 g
lactose 248.5 g
corn ~tarch 17.5 g
polyethylene glycol 6000 5.0 g
talc 15.0 g
magnesium stearate 4.0 g
demineralised water q.q.
Manufacture:
The solid ingredients are fir~t forced through a
~ieve having a mesh width of 0.6 mm. Then the active
~ub-~tance, lactose, talc, magnesium stearate and half
of the starch are intimately mixed. The other hal f of the
qtarch is suspended in 65 ml of water and thi~ suspension
i9 added to a boiling solution of the polyethylene
glycol in 260 ml of water. The resulting paste is
added to the pulverulent subqtances, and the whole is
mixed and granulated, if necessary with the addition of
water. The granulate is dried overnight at 35 , forced
through a ieve having a mesh width of 1.2 mm and
pressed to form tablet~ of approximately 10 mm diameter
having concave face~ on both ~ides and a break groove
on the upper side.
In an analogous manner, it i~ also possible to
manufacture tabletq each containing ~00 mg of a compound
of the formula I according to Examples 1 to 25, it being
~1 .

14~3~
- 53 -
possible for compounds to ke also in the form of acid
addition 9alts, such as hydrochlorides, and for compound~
in which R2 is 1-~ar~oxymethyl tG be also in the form of
salts with ba~es, such as sodium, potassium or zinc 3alts.
;`. ~.,: