SUBSTITUTED HETEROCYCLIC CARBOXAMIDES, THEIR PREPARATION AND THEIR USE AS PHARMACEUTICALS

CARBOXAMIDES HETEROCYCLIQUES SUBSTITUES, LEUR PREPARATION ET LEUR UTILISATION COMME COMPOSES PHARMACEUTIQUES

English Abstract

Abstract of the disclosure

Substituted heterocyclic carboxamides, their preparation
and their use as pharmaceuticals
The invention relates to compounds of the formula I,
(I)
Image
to a process for their preparation and to their use as
pharmaceuticals. The compounds are employed, in particu-
lar, for inhibiting collagen biosynthesis and as
inhibitors of prolyl hydroxylase and as fibrosuppressive
agents.

Claims

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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula I
(I),
Image

in which
Q is O, S, NR' or a bond,
X is O or S,
Y is C-R3 or,
if R1 and R2 form a cycle,
Y is N or CR3,
m is 0 or 1,
A is (C1-C4)-alkylene, which is optionally substi-
tuted by one or two substituents from the group
halogen, cyano, nitro, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Halg, preferably (C1-C8)-fluoro-
alkoxy, (C1-C8)-fluoroalkenyloxy, (C1-C8)-fluoro-
alkynyloxy, -OCF2Cl or -O-CF2-CHFCl, (C1-C6)-
alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-
alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-
alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-
carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-
alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl,
benzyl, phenoxy, benzyloxy, anilino, N-methylani-
lino, phenylmercapto, phenylsulfonyl, phenylsul-
finyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or
N,N-di-(C1-C4)-alkylsulfamoyl, or
by a substituted (C1-C12)-aryloxy, (C7-C11)-aralk-
yloxy, (C6-C12)-aryl or (C7-C11)-aralkyl radical
which carries in the aryl moiety 1, 2, 3, 4 or 5
identical or different substituents from the

- 136 -
group halogen, cyano, nitro, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2]c-CfH(2f+1-
g)Halg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkyl-
mercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-
sulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-
carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl,
N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkyl-
carbonyloxy, (C3-C8) -cycloalkyl, sulfamoyl, N-(C1-
C4)-alkylaulfamoyl or N,N-di-(C1-C4)-alkyl-
sulfamoyl, or

by the substituents R3 of the a-carbon atom of an
a-amino acid, it being possible to use the
natural L-amino acids and their D-isomers;
B is an acid grouping from he group -CO2H,
-CONHCORn"', -CONHSOR'", CONHSO2Rn"', -NHSO2CF3,
tetrazolyl, imidazolyl or 3-hydroxyisoxazolyl,
where R"' is aryl, heteroaryl, (C3-C7)-cycloalkyl
or (C1-C4)-alkyl, optionally monosubstituted by
(C6-C12)-aryl, heteroaryl, OH, SH, (C1-C4)-alkyl,
(C1-C4)-alkoxy, (C1-C4)-thioalkyl, (C1-C4)-sul-
finyl, (C1-C4)-sulfonyl, CF3, Cl, Br, F, I, NO2,
-COOH, (C2-C5)-alkoxycarbonyl, NH2, mono-(C1-C4)-
alkyl)-amino, di-(C1-C4-alkyl)-amino or (C1-C4)-
perfluoroalkyl,
R1, R2 and R3 are identical or different and are
hydrogen, hydroxyl, halogen, cyano, trifluoro-
methyl, nitro, carboxyl, (C1-C20)-alkyl, (C3-C8)-
cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-
C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-
alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-
C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cyclo-
alkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyclo-
alkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cyclo-
alkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-
cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-
C12)-aryl, (C7-C16)-aralkyl, (C7-C16)-aralkenyl,
( C 7 - C 1 6 ) - a r a l k y n y l, ( C 2 - C 2 0 ) - a l k e n y l,

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(C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyl-
oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-
alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8-
alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-
C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-
C6)-alkoxy, (C1-C16)-hydroxyalkyl, (C6-C16)-
aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-
alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-
alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-
alkyl, (C2-C20)-alkonyloxy-(C1-C6)-alkyl, (C2-C20)-
alkynyloxy-(C1-C6)-alkyl, retinyloxy-(C1-C6)-
alkyl, -O-[CH2-]-xCfH(2f+1=g)Fg, -OCF2Cl, -OCF,-CHFCl,
(C1-C20)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C15)-aralkylcarbonyl,
cinnamoyl, (C2-C20)-alkenylcarbonyl, (C2-C20)-
alkynylcarbonyl,

(C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C20)-alkonyloxycarbonyl, retinyloxycarbonyl,
(C2-C20)-alkynyloxycarbonyl, (C6-C23)-aryloxy-(C1-
C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-
alkoxycarbonyl,(C3-C8)-cycloalkyl-(C1-C6)-alkoxy-
carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-
carbonyl,
(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-
bonyloxy, (C6 -C12)-arylcarbonyloxy, (C7-C26)-
aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-
alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy,

(C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-
C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyl-
oxy,(C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cyclo-
alkoxycarbonyloxy, (C2-C12) -alkenyloxycarbonyloxy,
(C2-C12)-alkynyloxycarbonyloxy,

- 108 -
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-
C12)-alkylcarbamoyl, N-(C3-C8)-Cycloalkyl-
carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-
(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-
((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-
C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-
(C6-C11)-arylcarbamoyl, N-(C7-C16)-aralkylcarb-
amoyl, N-(C1-C10)-alkyl-N-(C7-C16)-arylcarbamoyl,
N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl, N-
((C1-C18)-alkoxy-(C1-C10)alkyl)carbamoyl, N-((C6-
C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-
aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-
alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-
aralkyloxy-(C1-C10)-alkyl)carbamoyl, or CON(CCH2)h,
in which a CH2 group can be replaced by O, S, N-
(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-
(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-
arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-
alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7,
a carbamoyl radical of the formula II

Image (II),
in which
Rx is the substituent of an .alpha.-amino acid to
which the L- and D-amino acids belong,
s is 1, 2, 3, 4 or 5, and
T is OH, OR or NR*R**, where
R*, R** and R*** are identical or different and are
hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl,

- 109 -
(C1-C8)-alkyl, (C3-C8)-cycloalkyl,
(+)-dehydroabietyl, (C1-C8)-alkoxy-(C1-C8)-
alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-
C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl,
optionally substituted (C7-C16)-aralkanoyl or
optionally substituted (C6-C12)-aroyl, or

R* and R** together are -[CH2]h, in which a CH2
group can be replaced by O, S, SO, SO2, N-
acylamino, N-(C1-C10)-alkoxycarbonylimino, N-
(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino,
N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-
C12)-arylimino, N-(C7-C16)-aralkylimino or N-
(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is
from 3 to 7,
carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-
di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cyclo-
alkylcarbamoyloxy, N-(C1-C12)-arylcarbamoyloxy, N-
(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-
C16)-aralkylcarbamoyloxy, N-((C1-C10)-
alkyl) carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-
alkyl) carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-
C10)-alkyl) carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-
C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy,N-(C1-C10)-
alkyl-N-((C6-C12)-aryloxy-(C1-C10)-
alkyl) carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-
aralkyloxy-(C1-C10)-alkyl)carbamoyloxy,

amino, (C1-C12)-alkylamino, di-(C1-C11)-alkylamino,
(C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino,
(C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-
C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-
arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-
(C1-C10)-alkylamino,
(C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino,
(C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-

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C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-
a l k a n o y l - N - ( C1 - C10 ) - a l k y l a m i n o ,
(C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aral-
kanoyl-N-(C1-C10)-alkylamino,

(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-
cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroyl-
amino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-
C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkyl-
amino-(C1-C10)-alkyl, N,N-di(C1-C10)-alkylamino-
(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-
alkyl, (C1-C10)-alkylmorcapto, (C1-C20)-alkyls-
ulfinyl, (C1-C20)-alkylsulfonyl, (C6-C12)-aryl-
mercapto, (C6-C12)-arylsulflnyl, (C6-C12)-aryl-
sulfonyl, (C7-C16)-aralkylmorcapto, (C7-C16)-
aralkylsulfinyl, (C7-C16)-aralkylsulfonyl, (C1-
C12)-alkylmorcapto-(C1-C6)-alkyl, (C1-C12)-alkyl-
sulfinyl-(C1-C6)-alkyl,(C1-C12)-alkylsulfonyl-(C1-
C6)-alkyl, (C6-C12)-arylmercapto-(C1-C6)-alkyl,
(C6-C12)-arylsulfinyl-(C1-C6)-alkyl, (C6-C12)-aryl-
sulfonyl-(C1-C6)-alkyl, (C7-C16)-aralkylmercapto-
(C1-C6)-alkyl, (C7-C16)-aralkylsulfinyl-(C1-C6)-
alkyl, (C7-C16)-aralkylsulfonyl-(C1-C6)-alkyl,
sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-
C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl,
N-(C6-C12)-arylsulfamoyl,
N-(C7-C16)-aralkylsulfamoyl,
N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl,
N-(C1-C10)alkyl-N-(C7-C16)-aralkylsulfamoyl,
(C1-C10)-alkylsulfonamido,
N-((C1-C10)-alkyl)-(C1-C10)-alkylsulfonamido, (C7-
C16)-arnlkylsulfonamido or N-((C1-C10)-alkyl-(C7-
C16)-aralkylsulfonamido,
where the radicals which contain an aryl radical
can, for their part, be substituted on the aryl
by from 1 to 5 identical or different radicals
from the group:
hydroxyl, halogen, cyano, trifluoromethyl, nitro,


- 111 -
carboxyl, (C1-C16)-alkyl, (C3-C8)-cycloalkyl, (C3-
C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy,
(C3-C8)-cycloalkyl-(C1-C12)-alkoxy,
(C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-
cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-
(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyaloalkyl-
(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cyclo-
alkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-
cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-
C12)-aryl, (C7-C16)-aralkyl, (C2-C16)-alkonyl, (C2-
C12)-alkynyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy,
(C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-
C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-
alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-
C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-
C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C6-C16)-aryloxy-
(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-
C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-
aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl,
-O-[CH2]x-C-CfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl,

(C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,

(C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12) -
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C12)-alkenyloxycarbonyl, (C2-Cl2)-alkyny-
loxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-
carbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl,
(C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-
cycloalkoxy-(C1-C6)-alkoxycarbonyl,
(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-
bonyyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-
aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-
alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy,
(C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-


- 112 -
(C1-C12)-alkoxycarbonyloxy, (C6-C12)-
aryloxycarbonyloxy, (C7-C16)-aralkyloxy-
carbonyloxy, (C3-C8)-cycloalkoxycarbonyloxy, (C2-
C12)-alkonyloxycarbonyloxy, (C2-C12)-alkynyloxy-
carbonyloxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-
C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-
(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-
((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-
C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-
(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkyl-
carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-
carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-
carbamoyl, N-((C1-C16)-alkoxy-(C1-Cl0)-alkyl)-
carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-
N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-
(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, CON(CH2)h, in which a CH2 group
can be replaced by O, S, N-(C1-C8)-alkylimino, N-
(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-
C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-
aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkyl-
imino and h is from 3 to 7,

carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-
di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cyclo-
alkylcarbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-
(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7
C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl)-carba-
moyloxy,N-((C6-C12)-aryloxy-((C1-C10)-alkyl)-carba-
moyloxy, N-((C7-C12)-aralkyloxy-(C1-C10)-alkyl)-



- 113 -
carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-
(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-
((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-
(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyloxy,
amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino,
(C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino,
(C3-C12)-alkynylamino, N-(C3-C12)-arylamino, N-(C7-
C11)-aralkylamino, N-alkyl-aralkylamlno, N-alkyl-
arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-
(C1-C10)-alkylamino,

(C1-C2)-alkanoylamino, (C3-C8)-cycloalkanoylamino,
(C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-
C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-
alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-
(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-
alkylamino,

(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-
cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroyl-
amino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-
C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkyl-
amino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-
(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-
alkyl,
(C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl,
(C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-
C16)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-
aralkylmercapto, (C7-C16)-aralkylsulfinyl or (C7-
C16)-aralkyloulfonyl,

R1 and R2 or R2 and R3 form a chain [CH2]o in which
one or two CH, groups of the chain, which is
saturated or unsaturated by a C=C double bond,
are optionally replaced by O, S, SO, SO2 or
NR', and o is 3, 4 or 5, and


- 114 -
R' is hydrogen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8)-
alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C6)-
alkyl, (C6-C12)-aryloxy-(C3-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-aralk-
anoyl or optionally substituted (C6-C12)-aroyl,
where

the radicals R' and R2 or R2 and R3, together with
the pyridine or pyridazine carrying them,
preferably form a 5, 6, 7, 8-tetrahydroiso-
quinolins ring, a 5, 6, 7, 8-tetrahydroquinoline
ring or a 5, 6, 7, 8-tetrahydrocinnoline ring,
or
R1 and R2 or R2 and R3 form a carbocyclic or a
heterocyclic, 5- or 6-membered aromatic ring,
where

the radicals R1 and R2 or R2 and R3, together with
the pyridine or pyridazine carrying them,
preferably form the following optionally substi-
tuted heterocyclic ring systems:

Thienopyridines,
Furanopyridines,
Pyridopyridines,
Pyrimidinopyridines,
Imidazopyridines,
Thiazolopyridines,
Oxazolopyridines,
Quinoline, isoquinoline and
Cinnoline,
where quinoline, isoquinoline or cinnoline pre-
ferably satisfy the formulae 1a, 1b and 1c


- 115 -

Image
1a 1b

Image

1c

and the substituents R11 to R22, in each case inde-
pendently of each other, have the meaning of R1, R2
and R3,

R4 is if Q is a bond, halogen, nitrile or trifluoro-
methyl, or, if Q is O, S or NR', a branched or
unbranched (C1-C10-alkyl radical, an unsubstituted,
saturated fluoroalkyl radical of the formula [CH2]x-
CfH(2f+1-g)Fg, a (C6-C16)-aryl radical, a (C7-C16)-aralkyl
radical, a heteroaryl radical or R heteroaralkyl
radical,

where these radicals are substituted by one or more
radicals from the group
hydroxyl, halogen, cyano, trifluoromethyl, nitro,
carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl,


- 116 -
(C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy,
(C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8) -cyclo-
alkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-
C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-
alkoxy, (C3-C8) -cycloalkyl-(C1-C8)-alkoxy-(C1-C6)-
alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-(C1-C6)-
alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-
alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-
alkenyl, (C2-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-
alkoxy-(C1-C12)-alkyl,(C1-C12)-alkoxy-(C1-C12)-alkoxy,
(C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-
aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-
alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-
hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-
aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-
alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-
alkoxy-(C1-C6)-alkyl, -O-[CH2]x-CH2(2f+1-g)Fg, -OCF2Cl,
-OCF,-CHFCl,
(C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,
cinnamoyl, (C2-C12)-alkonylcarbonyl, (C2-C12)-
alkynylcarbonyl,

(C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-
C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl,
(C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-
aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-
(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-
alkoxycarbonyl,

(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-
bonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkyl-
carbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcar-
bonyloxy, (C2-C12)-alkynylcarbonyloxy,

(C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-

- 117 -
alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-
C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxycar-
bonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12-
alkynyloxycarbonyloxy,

carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-
alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-
dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-
(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-
(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-
cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydro-
abietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydro-
abietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-
C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-
arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-
carbamoyl,N((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl,
N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-
C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-
alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-
aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in
which a CH2 group can be replaced by O, S, N-(C1-C8)-
alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-
cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino,
N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-
alkylimino, and h is from 3 to 7, or by

a carbamoyl radical of the formula II


Image (II),

in which
Rx is the substituent of an .alpha.-amino acid to which
the L- and D-amino acids belong,

- 118 -
s is 1, 2, 3, 4 or 5, and
T is OH, OR or NR*R**, where

R*, R**, and R*** are identical or different and are
hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-
alkyl, (C3-C8)-cycloalkyl, (+)-dehydroabietyl,
(C1-C8)-alkoxy-(C1-C8)-alkyl,(C7-C12)-aralkoxy-(C1-
C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-
aralkanoyl or optionally substituted (C6-C12)-
aroyl, or

R* and R** together are -[CH2]h, in which a CH2 group
can be replaced by O, S, SO, SO2, N-acylamino, N-
(C1-C10)-alkoxycarbonylimino, N-(C1-C8)-alkylimino,
N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-
(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-
C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-
alkylimino, and h is from 3 to 7, or by

carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-
(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-
carbamoyloxy, N-(C6-C12)-arylcarbamoyloxy, N-(C7-C16)-
aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-
arylcarbamoyloxy,N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-
carbamoyloxy, N-((C1-C10)-alkyl)carbamoyloxy, N-((C6-
C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-((C7-C16)-
aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-
alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy,
N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-
alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-
aralkyloxy-(C1-C10)-alkyl)carbamoyloxy,

amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino,
(C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-
C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7,-C11)-
aralkylamino, N-alkyl-aralkylamino, N-alkyl-aryl-
amino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-
C10)-alkylamino,

- 119 -
(C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino,
(C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-
C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-
alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-
C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkyl
amino,

(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-
alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-(C1-
C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl,
amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-
alkyl, N,N-di(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-
C8)-cycloalkylamino-(C1-C10)-alkyl,

(C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-
C12)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C2)-
arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C16)-
aralkylmercapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-
aralkylsulfonyl,

sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-C10)-
alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl,
N-(C6-C12)-arylsulfamoyl,
N-(C7-C16)-aralkylsulfamoyl,
N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl, N-(C1-C10)-
alkyl-N-(C7-C16)-aralkylsulfamoyl,
(C1-C10)-alkylsulfonamido,
N-((C1-C10)-alkyl) (C1-C10)-alkylsulfonamido,(C7-C16)-
aralkylsulfonamido or N-(C1-C10)-alkyl-(C7-C16)-
aralkylsulfonamido, where the radicals which contain
an aryl radical can, for their part, be substituted
on the aryl by from 1 to 5 identical or different
radicals from the group:
hydroxyl, halogen, cyano, trifluoromethyl, nitro,
carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-
cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-
C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cyclo-
alkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-
C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-

- 120 -
alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-(C1-C6)-
alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-(C1-C6)-
alkyl, (C3-C8) -cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-
alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-
alkenyl, (C1-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-
alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy,
(C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-
aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-
alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-
hydroxyalkyl, (C7-C16)-aryloxy-(C1-C6)-alkyl, (C7-C16)-
aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C8)-
alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-
alkoxy-(C1-C6)-alkyl, -O-[CH2-]x-CfH(2f+1-g)Fg, -OCF2Cl,
-OCF2-CHFCl,
(C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,
(C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-
C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl,
(C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-
aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-
(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-
alkoxycarbonyl,
(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-
carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralk-
ylcarbonyloxy, cinnamoyloxy, (C2-C12)-
alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy,

(C1-C12) -alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-
C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-
carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12)-
alkynyloxycarbonyloxy,

carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-
alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-

- 121 -
dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-
(C3-C8) -cycloalkylcarbamoyl, N-((C3-C8) -cycloalkyl-
(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-
cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydro-
abietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydro-
abietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-
C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-
arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-
carbamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-
carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)-
carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-
(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-
aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl,
CON(CH2)h, in which a CH2 group can be replaced by O,
S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino,
N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-
arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-
alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7,

carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-
(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-
carbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-(C7-C16)-
aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-
arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-C16)-
aralkylcarbamoyloxy, N-((C1-C10)-alkyl)carbamoyloxy,
N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-
((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-
(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-
carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-
C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-
aralkyloxy-(C2-C10)-alkyl)carbamoyloxy,
amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino,
(C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-
C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-
aralkylamino, N-alkyl-aralkylamino, N-alkyl-aryl-
amino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-

- 122 -
(C10)-alkylamino,

(C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino,
(C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-
C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-
alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-
C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-
alkylamino,

(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-
alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-(C1-
C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl,
amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-
alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-
C8)-cycloalkylamino-(C1-C10)-alkyl,

(C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-
C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-
arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aral-
kylmercapto, (C7-C16)-aralkylsulfinyl or (C7-C16)-
aralkylsulfonyl, and

R4 is R", provided that Q has ths meaning of NR', where
R' and R" are identical or different and are hydro-
gen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl,
(C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12(-aralkoxy-(C1-
C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-aralkanoyl
or optionally substituted (C6-C12)-aroyl, or

R' and R" together are -[CH2]h, in which a CH2 group
can be replaced by O, S, N-acylimino or N-(C1-
C10)-alkoxycarbonylimino, and

f is 1 to 8,
g is 0 or 1 to (2f+1),
x is 0 to 3,
h is 3 to 7,


- 123 -
including the physiologically active salts,
with 3-benzyloxypyridine-2-carboxylic acid (L-
threonyl)amide and 3-benzyloxypyridine-2-carboxylic
acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being
excepted.
2. A compound of the formula I as claimed in claim 1,
in which
Q is O, S, NR' or a bond,
X is O,
Y is CR3, or,
if R1 and R2 form a cycle,
Y is N or CR3,
m is 0 or 1.
3. A compound of the formula I as claimed in claims 1
and 2,
in which
Q is O, NR' or a bond, and
X is O.
4. A compound of the formula I as claimed in claims 1
and 2, in which
Q is S, and
X is O, and
m is 0 or 1.
5. A compound of the formula I as claimed in claims 1,
2 and 4, in which
Q is S,
X is O, and
m is 0.
6. A compound of the formula I as claimed in claims 1
to 3, in which
Q is O, NR' or a bond,
X is O,
Y is CR3 or, if R1 and R2 form a cycle, N or CR3,
m is 0 or 1,

- 124 -
A is (C1-C3)-alkylene which is optionally substi-
tuted once by halogen, cyano, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy
or -O-[CH2]x-CfH(2f+1-g)Fg, or
A is -CHR5-, where R5 is one of the substitutents of
the .alpha.-carbon atom of an .alpha.-amino acid, in particu-
lar of a natural L-amino acid and of its
D-isomer,
B is CO2H,
R2 is hydrogen, (C1-C20)-alkyl (C2-C20)-alkenyl, (C2-
C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyloxy,
(C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-alkoxy-
(C1-C3)-alkyl, (C2-C20)-alkenyloxy-(C1-C3)-alkyl,
retinyloxy-(C1-C3)-alkyl, (C2-C20)-alkynyloxy-(C1-
C3)-alkyl, halogen, cyano, trifluoromethyl, (C10
C8)-hydroxyalkyl, (C1-C20)-alkanoyl, (C7-C16)-
aralkanoyl, (C6-C12)-aroyl, (C6-C12)-aryl, (C7-C16)-
aralkyl, -O-[CH2]x-CfH(2f+1-g)Fg, NR'R", (C1-C10)-
alkylmercapto, (C1-C10)-alkylsulfinyl, (C1-C10)-
alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C12)-
arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C12)-
aralkylmercapto, (C7-C12)-aralkylsulfinyl, (C7-
C12)-aralkylsulfonyl, (C6-C12)-aryloxy, (C7-C16)-
aralkyloxy, carboxyl, (C1-C20)-alkoxycarbonyl,
(C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-
aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-
C8)-cycloalkoxycarbonyl, (C2-C20)-alkenyl-
oxycarbonyl, retinyloxycarbonyl, (C2-C20)-alkynyl-
oxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-
alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-
alkoxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-
carbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-
C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo(C3-C8)-alkylcarbamoyl,


- 125 -
N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-
(C3-C8) cycloalkyl-(C1-C6)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-
(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkyl-
carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-
carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-
carbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-
N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, CON(CH2)h, in which a CH2 group
can be replaced by O, S, N-(C1-C8)-alkylimino, N-
(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-
(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-
C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-
alkylimino, and h is from 3 to 7,

where aryl is substituted in the manner as defined
for R1 and R3,

R1 and R3 are identical or different and are hydro-
gen, halogen, (C1-C12)-alkyl, (C1-C12)-alkoxy, -O-
[CH2]x-CfH(2f+1-g)Halg, (C1-C12)-alkoxy-(C1-C12)-alkyl,
(C1-C8)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-
C8)-alkoxy-(C2-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-
C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl,
(C3-C8)-cycloalkyloxy, (C3-C8)-cycloalkyl-(C1-C8)-
alkoxy, (C3-C8)-cycloalkyloxy-(C1-C8)-alkyl, (C3-
C8)-cycloalkyloxy-(C1-C8)-alkoxy, (C3-C8)-cyclo-
alkyl-(C1-C6)-alkyl-(C1-C8)-alkoxy, (C3-C8)-cyclo-
alkyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C8)-
cycloalkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, NRYRZ,
(C1-C8)-alkylmercapto, (C1-C8)-alkylsulfinyl or
(C1-C8)-alkylsulfonyl, (C6-C12)-arylmercapto,

- 126 -
(C6-C12)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-
C12)-aralkylmercapto, (C7-C11)-aralkylsulfinyl,
(C7-C11)-aralkylsulfonyl, substituted (C6-C12)-
aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-
alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-(C1-C6)-
alkyl, (C7-C11)-aralkyloxy-(C1-C6)-alkoxy-(C1-C6)-
alkyl, (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-
C12)-aryloxy-(C1-C6)-alkoxy or (C7-C11)-aralkoxy-
(C1-C6)-alkoxy, where an aromatic radical carries
1, 2, 3, 4 or 5 identical or different substi-
tuents from the group hydrogen, halogen, cyano,
nitro, trifluoromethyl, (C1-C16)-alkyl, (C1-C16)-
alkenyl, (C1-C6)-hydroxyalkyl, (C1-C16)-alkoxy,
(C1-C16)-alkenyloxy, -O-[CH2]x-CfH(2f+1-g)Fg, -OCF2Cl,
-O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkyl-
sulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkyl-
carbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-
(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-
carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-
cycloalkylcarbamoyl, phenyl, benzyl, phenoxy,
benzyloxy, NRYRZ, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsul-
famoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or
optionally carries up to 3 of the abovementioned
identical or different substituents, and two
adjacent carbon atoms of the aralkyloxy radical
together carry a chain -[CH2-] and/or -CH=CH-
CH=CH-, where a CH2 group of the chain is
optionally replaced by O, S, SO, SO2 or NR'.
R1 and R2 or R2 and R3 form a chain [CH2]o, where o is
3, 4 or 5, or
form together with the pyridine or pyridazine
carrying them, a cinnoline ring, a quinoline ring
or an isoquinoline ring,
R4 is, if Q is a bond, fluorine, chlorine or bro-
mine, or, if Q is O or NR', a branched or


- 127 -
unbranched (C1-C20)-alkyl radical, which can con-
tain up to 3 C-C multiple bonds, an unsubstituted
saturated fluoroalkyl radical of the formula
[CH2]x-CfH(2f+1-g)Fg, a (C6-C16)-aryl radical or a (C7-
C16)-aralkyl radical, which can contain up to 2
C-C multiple bonds in the alkyl chain, or
heteroaryl radical or a heteroaryl alkyl radical,
where these radicals are substitued by one or
more radicals from the group hydroxyl, fluorine,
chlorine, cyano, trifluoromethyl, carboxyl, (C1-
C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-
(C1-C12)-alkyl, (C3-C8)-cycloalkocy, (C3-C8)-cyclo-
alkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-
C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy,
(C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy,
(C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl,
(C2-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-
(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-
C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy,
(C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-
(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl,
-O-[CH2-]x-CfH(2f+1-g)Fg,

(C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,

(C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C12)-alkenyloxycarbonyl, (C2-C12)-
alkynyloxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-
alkoxycarbonyl,

(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-
carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-
aralkylcarbonyloxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-
C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-

- 128 -
carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-
(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-
((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-
C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-
(C6-C12) -arylcarbamoyl, N-(C7-C16)-
aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-
carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcar-
bamoyl, N-((C1-C10)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, CON(CH2)h in which a CH2 group
can be replaced by O, N-(C1-C8)-alkylimino, N-(C3-
C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-
alkylimino, N-(C6-C12)-arylimino or N-(C7-C16)-
aralkylimino, and h is from 3 to 6,

where the radicals which contain an aryl radical
can, for their part, be substituted on the aryl
by from 1 to 5 identical or different radicals
from the group:

hydroxyl, fluorine, chlorine, cyano, trifluoro-
methyl, carboxyl, (C1-C12)-alkyl, (C3-C8)-cyclo-
alkyl, (C1-C8)-alkoxy, (C3-C8)-cycloalkoxy, (C1-
C12)-alkoxycarbonyl,

N-(C1-C6)-alkylcarbamoyl, N,N-di-(C1-C6)-alkyl-
carbamoyl or N-(C3-C8)-cycloalkylcarbamoyl, and

R4 is R", provided Q has the meaning of NR', where
R' and R" are identical or different and are
hydrogen, (C1-C8)-alkyl, or (C7-C11)-aralkyl which
is optionally substituted once by fluorine,
chlorine or (C1-C4)-alkoxy,

RY and RZ are identical or different and are hydro-
gen, (C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-

- 129 -

cycloalkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-
aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-
alkyl, (C1-C10)-alkanoyl, optionally substituted
(C7-C16)-aralkanoyl or optionally substituted (C6-
C12)-aroyl, or
RY and RZ together are -[CH2]h-, in which a CH2 group
can be replaced by O, S, N-(C1-C4)-alkanoylimino
or N-(C1-C4)-alkoxycarbonylimino, and

f is 1 to 8,
g is 0 or 1 to (2f + 1),
h is 3 to 6,
x is 0 to 3, and
n is 3 or 4, including the physiologically active
salts, with 3-benzyloxypyridine-2-carboxylic acid
(L-threonyl)amide and 3-benzyloxypyridine-2-
carboxylic acid ((Fmoc-Phg)L-threonyl)amide
hydrochloride being excepted.

7. A compound of the formula I as claimed in claims 1
to 3 and 6, in which
Q is O, NR' or a bond,
X is O,
Y is CR3 or, if R1 and R2 form a cycle, N or CR3,
m is 0,
A is (C1-C3)-alkylene which is optionally substi-
tuted once by halogen, cyano, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy
or -O-[CH2]x-CfH(2f+1-g)Fg or

A is -CHR5-, where R5 is one of the substituents of
the .alpha.-carbon atom of an .alpha.-amino acid, in par-
ticular of a natural L-amino acid and of its
D-isomer,

B is CO2H,

R2 is hydrogen, (C1-C20)-alkyl, (C2-C20)-alkenyl,

- 130 -
(C2-C20)-alkenyloxy, (C2-C20)-alkynyloxy,
retinyloxy, (C1-C20)-alkoxy-(C1-C3)-alkyl, (C1-C20)-
alkoxy-(C1-C3)-alkyl, (C2-C20)-alkenyloxy-(C1-C3)-
alkyl, retinyloxy-(C1-C3)-alkyl, (C2-C20)-
alkynyloxy-(C1-C3)-alkyl, (C1-C20)-alkoxy, halogen,
cyano, trifluoromethyl, (C1-C16)-hydroxyalkyl,
(C1-C20)-alkanoyl, (C7-C12)-aralkanoyl, (C6-C12)-
aroyl, -O-[CH2]x-CfH(2f+1-g)Fg, NR'R", (C1-C10)-
alkylmercapto, (C1-C10)-alkylsulfinyl, (C1-C10)-
alkylsulfonyl, (C1-C10)-arylmercapto, (C6-C12)-
arylsulfinyl), (C7-C12)-arylsulfonyl, (C7-
C12)-aralkylmercapto, (C7-C12)-aralkylsulfinyl,
(C7-C12)-aralkylsulfonyl, (C6-C12)-aryloxy, (C7-
C16)-aralkyloxy, carboxyl, (C1-C20)-alkoxycarbonyl,
(C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-
aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-
C8)-cycloalkoxycarbonyl, (C2-C20)-alkenyloxy-
carbonyl, retinyloxycarbonyl, (C2-C20)-alkynyl-
oxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxy-
carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-
carbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl,
(C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-
C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-
(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-
(C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-
C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-
(C6-C12)-arylcarbamoyl, N-(C1-C10)-aralkyl-
carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-
arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C12)-aralkyl-
carbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-

- 131 -
alkyl)carbamoyl ,N-(C1-C10)-alkyl-N-((C7-C16-aral-
kyloxy-(C1-C10)-alkyl)carbamoyl, or CON(CH2)h, in
which a CH2 group can be replaced by O, S, N-(C1-
C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-
C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-
arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-
alkoxy-(C1-C6)-alkylimino, and h is from 3 to 6,

where aryl is substituted in the manner as defined
for R1 and R3,

R1 and R3 are identical or different and are hydro-
gen, halogen, (C1-C12)-alkyl, (C1-C12)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Halg, (C1-C12)-alkoxy-(C1-C12)-
alkyl, (C1-C8)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-
alkoxy-(C1-C8)-alkoxy-(C2-C6)-alkyl, (C7-C11)-
aralkyloxy, (C3-C8)-cycloalkyl, (C3-C8)-cyclo-
alkyl-(C1-C8)-alkyl, (C3-C8)-cycloalkyloxy, (C3-
C8)-cycloalkyl-(C1-C8)-alkoxy, (C3-C8)-cycloalkyl-
oxy-(C1-C8)-alkyl, (C3-C8)-cycloalkyloxy-(C1,-C8)-
alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-alkyl-(C1-C6)-
alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-alkoxy-(C1-C6)-
alkyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-(C1-C6)-
alkyl, NRYRZ, (C1-C8)-alkylmercapto, (C1-C8)-
alkylsulfinyl or (C1-C8)-alkylsulfonyl, (C6-C12)-
arylmercapto, (C6-Cl2)-arylsulfinyl, (C6-C12)-
arylsulfonyl, (C7-C12)-aralkylmercapto, (C7-C11)-
aralkylsulfinyl, (C7-C11)-aralkylsulfonyl,
substituted (C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-
C11)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-
C6)-alkoxy-(C1-C6)-alkyl, (C7-C11)-aralkyloxy-(C1-
C6)-alkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy, (C7-
C11)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy or
(C7-C11)-aralkoxy-(C1-C5)-alkoxy, where an aromatic
radical carries by 1, 2, 3, 4 or 5 identical or
different substituents from the group hydrogen,
halogen, cyano, nitro, trifluoromethyl, (C1-C12)-
alkyl, (C1-C12)-alkenyl, (C1-C6)-hydroxyalkyl, (C1-
C 1 2 ) - a l k o x y , ( C 1 - C 1 2 ) - a l k e n y l o x y,


- 132 -
-O-[CH2]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-
alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-
alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-
alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-
carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-
alkylcarbonyloxy, (C3-C8)-cycloalkylcarbamoyl,
phenyl, benzyl, phenoxy, benzyloxy, NRYRZ,
phenylmercapto, phenylsulfonyl, phenylsulfinyl,
sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-
(C1-C4)-alkylsulfamoyl, or optionally carries up
to 3 of the abovementioned identical or different
substituents, and two adjacent carbon atoms of
the aralkyloxy radical together carry a chain
-[CH2-] and/or -CH=CH-CH=CH-, where a CH2 group
of the chain is optionally replaced by O, S, SO,
SO2 or NRY,
R1 and R2 or R2 and R3 can form a chain [CH2]o, where
o is 3, 4 or 5, and
R4 is, provided Q is a bond, chlorine or, if Q is O
or NR', is a branched or unbranched (C1-C10)-alkyl
radical, which can contain one or two C-C
multiple bonds, or an unsubstituted fluoroalkyl
radical of the formula -[CH2]x-CfH(2f+1-g)Fg or (C1-
C8)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C4)-
alkoxy-(C1-C4)-alkyl or a radical of the formula
Z,
-[CH2]v-[O]w-[CH2]t-E (Z)
where E is a substituted phenyl radical of the
formula F
Image (F),

- 133 -
or a (C3-C8)-cycloalkyl radical, where
v is 0, 1, 2, 3, 4, 5 or 6, w is 0 or 1, and t is
0, 1, 2 or 3, with the restriction that v is not
equal to 0 if w is 1, and R6, R7, R8, R8 and R10
are identical or different and are hydrogen,
halogen, cyano, nitro, trifluoromethyl, (C1-C6)-
alkyl, (C3-C8)-cycloalkyl, (C1-C6)-alkoxy,
-O-[CH2-]x-CfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-
C6)-alkylmercapto, (C1-C6)-hydroxyalkyl, (C1-C6)-
alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-
alkyl, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsul-
fonyl, (C1-C6)-alkylcarbonyl, (C1-C8)-alkoxy-
carbonyl, carbamoyl, N-(C1-C8)-alkylcarbamoyl,
N,N-di-(C1-C8)-alkylcarbamoyl, (C7-C11)-aralkyl-
carbamoyl which is optionally substituted by
fluorine, chlorine, bromine, trifluoromethyl or
(C1-C6)-alkoxy, N-(C3-C8)-cycloalkylcarbamoyl, N-
(C3-C8)-cycloalkyl-(C1-C4)-alkylcarbamoyl, (C1-C6)-
alkylcarbonyloxy, phenyl, benzyl, phenoxy,
benzyloxy, NRYXZ, such as amino, anilino, N-
methylanilino, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkyl-
sulfamoyl or N,N-di-(C1-C8)-alkylsulfamoyl, or
two adjacent substituents together are a chain
-[CH2-]n or -CH=CH-CH=CH-, where a CH2 group of
the chain is optionally replaced by O, S, SO, SO2
or NRY, and where a heteroaryl radical can carry
1, 2 or 3 substituents, and a cycloalkyl radical
one substituent, from the above group, and

R4 is R", provided Q has the meaning of NR', where
R' is hydrogen or methyl, and
R" is benzyl, and

if R1 and/or R3 have the meaning of (C6-C12)-aryloxy,
(C7-C11)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy,
(C7-C11)-aralkoxy-(C1-C6)-alkoxy or a corresponding
radical containing terminal cycloalkyl groups, this

- 134 -
radical is preferably then a radical of the formula
D
OZ (D), or

if R1 and/or R3 have the meaning of (C7-C11)-aralkyl,
(C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-
C6)-alkyl or a corresponding radical containing
terminal cycloalkyl groups, this radical is pre-
ferably then a radical of the formula Z,

RY and RZ are identical or different and are hydro-
gen, (C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-
cycloalkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-
C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-
C8)-alkyl, (C1-C10)-alkanoyl, optionally substi-
tuted (C7-C16)-aralkanoyl or optionally substi-
tuted (C6-C12)-aroyl, or

RY and RZ are together -[CH2]h-, in which a CH2 group
can be replaced by O, S, N-(C1-C4)-alkanoylimino
or N-(C1-C4)-alkoxycarbonylimino, and

f is 1 to 8,
g is 0 or 1 to (2f+1),
h 3 to 6,
x is 0 to 3, and
n is 3 or 4,
including the physiologically active salts, with
3-benzyloxypyridine-2-carboxylic acid (L-thre-
onyl)amide and 3-benzyloxypyridine-2-carboxylic
acid ((Fmoc-Phg)L-threonyl)amide hydrochloride
being excepted.

8. A compound of the formula I as claimed in claims 1
to 5, in which
Q is O,
X is O,
Y is CR3 and, additionally, N if R1 and R2 form a


- 135 -
cycle,
m is 0,
A is -CHR5-, where R5 is the substituent of the
.alpha.-carbon atom of an .alpha.-amino acid, in particular
of a natural L-amino acid or its D-isomer,
B is CO2H,
R2 is hydrogen, bromine, chlorine, cyano, (C1-C18)-
alkyl, (C1-C8)-alkoxy, (C1-C18)-alkoxymethyl, (C2-
C18)-alkenyloxymethyl, (C2-C18)-alkynyloxymethyl,
carbamoyl, N-(C1-C10)-alkylcarbamoyl, N-((C1-C12)-
alkoxy-(C1-C4)-alkyl)carbamoyl, N,N-di-(C1-C8)-
alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl,
N-(C6-C12)-phenylcarbamoyl, N-(C7-C12)-phenylalkyl-
carbamoyl, N-(C1-C6)-alkyl-N-(C6-C12)phenyl-
carbamoyl, N-(C1-C6)-alkyl-N-(C7-C12)-phenylalkyl-
carbamoyl, N-((C1-C6)-alkoxy-(C1-C6)-
alkyl)carbamoyl, carboxyl, (C1-C20)-alkoxy-
carbonyl, (C2-C20)-alkenyloxycarbonyl, retinyl-
oxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C3-C8)-
cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cyclo-
alkoxy-(C1-C6)-alkoxycarbonyl, phenyl-(C1-C6)-
alkoxycarbonyl, phenoxy-(C1-C6)-alkoxycarbonyl or
benzyloxy-(C1-C6)-alkoxycarbonyl, where a phenyl
radical is substituted in the manner as defined
for R1 and R3, and one of the radicals
R1 or R3 is hydrogen and the other a radical from
the group hydrogen, fluorine, chlorine, (C1-C8)-
alkyl, (C1-C10)-alkoxy, (C5-C6)-cycloalkyl, (C5-
C6)-cycloalkyl-(C1-C6)-alkyl, (C5-C6)-cycloalkyl-
oxy, (C5-C6)-cycloalkyl-(C1-C6)-alkoxy, (C5-C6)-
cycloalkyloxy-(C1-C6)-alkyl, (C5-C6)-cycloalkyl-
oxy-(C1-C6)-alkoxy, (C5-C6)-cycloalkyl-(C1-C4)-
alkyl-(C1-C4)-alkoxy, (C5-C6)-cycloalkyl-(C1-C4)-
alkoxy-(C1-C2)-alkyl, (C5-C6)-cycloalkoxy-(C1-C4)-
alkoxy-(C1-C2)-alkyl, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C6)-
alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-
alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C2)-

- 136 -
alkyl, substituted (C6-C12)-phenoxy, (C7-C11)-
phenylalkyloxy, (C6-C12)-phenoxy-(C1-C6)-alkoxy or
(C7-C11)-phenylalkoxy-(C1-C6)-alkoxy, phenoxy-
(C1-C4)-alkyl, (C7-C11)-phenylalkyloxy-(C1-C4)-
alkyl, phenoxy-(C1-C4)-alkoxy-(C1-C2)-alkyl or (C7-
C11)-phenylalkyloxy-(C1-C4)-alkoxy-(C1-C2)-alkyl,
where an aromatic radical is substituted by 1, 2
or 3 identical or different substitutents from
the group fluorine, chlorine, cyano, trifluoro-
methyl, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-
alkenyloxy or (C1-C12)-alkoxy,

R1 and R2, with the pyridine carrying them, form a
5, 6, 7, 8-tetrahydroisoquinoline ring,

R4 is a branched or unbranched (C1-C10)-alkyl
radical, (C1-C4)-alkoxy-(C1-C4)-alkyl or a radical
of the formula Z,

-[CH2]v-[O]w-[CH2]t-E (Z)

where E is a substituted phenyl radical of the
formula F

(F) ,
Image

or a (C3-C8)-cycloalkyl radical, whero v is 0, 1,
2 or 3, w is 0, and t can be 0 or 1, and in which
R6, R7, R8, R9 and R10 are identical or different
and are hydrogen, fluorine, chlorine, cyano,
trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,
-O-[CH2-]x-CfH(2f+1-g)Fg, N-(C1-C8)-alkylcarbamoyl,
N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C6)-cyclo-
alkylcarbamoyl, N-(+)-dehydroabietylamino-
carbonyl, or (C7-C11)-phenylalkylcarbamoyl, which

- 137 -
is optionally substituted by fluorine, chlorine,
trifluoromethyl and (C1-C6)-alkoxy, or where R6
and R7 or R7 and R8, together with the phenyl ring
carrying them, form naphthalene derivatives, or

if R1 or R3 has the meaning of (C6-C12)-phenoxy,
(C7-C11)-phenylalkyloxy, (C6-C12)-phenoxy-(C1-C6)-
alkoxy, (C7-C11)-phenylalkoxy-(C1-C6-alkoxy,
(C5-C6)-cycloalkyloxy, (C5-C6) cycloalkyl-(C1-C6)-
alkoxy, (C5-C6)-cycloalkoxy-(C1-C6)-alkoxy or (C5-
C6)-cycloalkyl-(C1-C4)-alkyl-(C1-C4)-alkoxy, this
radical is then, especially, a radical of the
formula D

OZ (D), or

if R1 or R3 has the meaning of phenyl, phenoxy-
(C1-C6)-alkyl, (C7-C11)-phenylalkyl, (C7-C11)-
phenylalkyloxy-(C1-C4)-alkyl, (C5-C6)-cycloalkyl,
(C5-C6)-cycloalkyl-(C5-C6)-alkyl, (C5-C6)-cyclo-
alkoxy-(C1-C4)-alkyl, (C5-C6)-cycloalkyl-(C1-C4)-
alkoxy-(C1-C2)-alkyl or (C5-C6)-cycloalkoxy-
(C1-C4)-alkoxy-(C1-C2)-alkyl, this radical is
then, especially, a radical of the formula Z in
which, in both cases,

v is 1, 2, 3 or 4, w is 0 and t is 0, or
v is 1, 2, 3 or 4, w is 1 and t is 0, or
v is 1, 2, 3 or 4, w is 1, t is 1, and
f is 1 to 4,
g is 0 or 1 to (2f+1),
x is 0 or 1
including the physiologically active salts, with
3-benzyloxypyridine-2-carboxylic acid (L-thre-
onyl)amide and 3-benzyloxypyridine-2-carboxylic
acid ((Fmoc-Phg)L-threonyl)amide hydrochloride
being excepted.

9. A compound of the formula I ae claimed in claims 1

- 138 -
to 6, in which
Q is O,
X is O,
Y is CR3,
m is 0,
A is a -CH2- group which can be substituted by a
methyl group,
B is CO2H,
R2 is hydrogen, (C1-C8)-alkoxy, (C1-C16)-alkoxymethyl,
(C2-C16)-alkenyloxymethyl, retinyloxymethyl, N-
(C1-C10)-alkylcarbamoyl,N-((C1-C12)-alkoxy-(C1-C3)-
alkyl)carbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl,
N-(C5-C6)-cycloalkylcarbamoyl, N-phenylcarbamoyl,
N-phenyl-(C1-C4)-alkylcarbamoyl, carboxy, (C1-C16)-
alkoxycarbonyl, (C2-C16)-alkenyloxycarbonyl,
retinyloxycarbonyl, (C5-C6)-cycloalkoxycarbonyl,
(C5-C6)-cycloalkyl-(C1-C6)-alkoxycarbonyl or
phenyl-(C1-C6)-alkoxycarbonyl, where a phenyl
radical is substituted in a manner as defined for
R1 and R3, and one of the radicals

R1 or R3 is hydrogen and the other radical is a
radical from the group hydrogen, (C1-C10)-alkoxy,
(C5-C6)-cycloalkyloxy, (C5-C6)-cycloalkyl-(C1-C2)-
alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C4)-alkoxy-
(C1-C4)-alkoxy, substituted (C6-C12)-phenoxy, (C7-
C11)-phenylalkyloxy, (C6-C12)-phenoxy-(C1-C4)-
alkoxy or (C7-C11)-phenylalkoxy-(C1-C4)-alkoxy,
where an aromatic radical is substituted by 1, 2
or 3 identical or different substituents from the
group fluorine, chlorine, cyano, trifluoromethyl,
(C1-C10)-alkyl, (C1-C10)-alkoxy or (C1-C10)-
alkenyloxy, and

R4 is a branched or unbranched (C1-C8)-alkyl radical
or a radical of the formula Z,

-[CH2]v-[O]w-[CH2]t-E (Z).

- 139 -
where E is a substituted phenyl radical of the
formula F


Image (F) ,

or a (C3-C8)-cycloalkyl radical, where
v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1,
and in which R6, R7, R8, R9 and R10 are identical
or different and are hydrogen, fluorine,
chlorine, cyano, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, N-(Cl-C8)-
alkylcarbamoyl, N,N-di-(C1-C6)-alkylcarbamoyl,
N-(C3-C6)-cycloalkylcarbamoyl, N-(+)-dehydro-
abietylaminocarbonyl substituted benzyl radical,
and f is 1 to 4, g is 0 or 1 to (2f+1) and x is
0 or 1 including the physiologically active
salts.

10. A compound of the formula I as claimed in claims 1
to 3 and 6 to 9, in which
Q is O,
X is O,
Y is CR3,
m is 0,
A is a -CH2 group,
B is CO2H,

R1 is hydrogen, (C1-C6)-alkoxy or -O-[CH2]x-CfH(2f+1-
g)Fg,
R2 is hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((C1-
C12)-alkoxy-(C1-C3)-alkyl)carbamoyl, N,N-di-(C1-
C8)-alkylcarbamoyl,N-(C5-C6)-cycloalkylcarbamoyl,
N-phenylcarbamoyl, N-phenyl-(C1-C2)-alkyl-
carbamoyl, carboxyl, (C1-C16)-alkoxycarbonyl,

- 140 -
(C2-C16)-alkenyloxycarbonyl, retinyloxycarbonyl,
(C5-C6)-cycloalkoxycarbonyl, (C5-C6)-cycloalkyl-
(C1-C6)-alkoxycarbonyl or phenyl-(C1-C6)-alkoxy-
carbonyl, where a phenyl radical is substituted
by 1 or 2 identical or different substituents
from the group fluorine, chlorine, cyano, triflu-
oromethyl, (C1-C10)-alkyl, (C1-C10)-alkoxy or
(C1-C10)-alkenyloxy, and

R3 is hydrogen, (C1-C5)-alkoxy or (C5-C6)-cycloalkyl-
(C1-C2)-alkoxy, where one of the substituents R1
and R3 is hydrogen,

R4 is a branched or unbranched (C1-C6) alkyl
radical, or a 2-phenylethyl radical, or a benzyl
radical substituted by 1 or 2 radicals from the
group fluorine, chlorine, cyano, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-
g)Fg, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C6)-
alkylcarbamoyl, N-(C3-C6)-cycloalkylcarbamoyl or
N-(+)-dehydroabietylaminocarbonyl, and f is 1 to
4, g is 0 or 1 to (2f+1) and x is 1, including
the physiologically active salts.

11. Compounds of the formula I as claimed in claims 1 to
3 and 6 to 10, in which
Q is O,
X is O,
Y is CR3,
m is 0,
A is a -CH2-group,
B is CO2H,
R1 is hydrogen,
R2 is hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((C1-
C12)-alkoxy-(C1-C3)-alkyl)carbamoyl, N-cyclo-

- 141 -
hexylcarbamoyl, N-phenylcarbamoyl, N-(phenyl-(C1-
C2)-alkyl)carbamoyl, where, in the last two
cases, the phenyl radical can carry a fluorine
substituent, a (C1-C1o)-alkyl substituent or
(C1-C10)-alkoxy substituent, carboxyl, (C1-C16)-
alkoxycarbonyl, (C2-C16)-alknyloxycarbonyl,
retinyloxycarbonyl, (C5-C6)-cycloalkoxycarbonyl
or benzyloxycarbonyl,

R3 is hydrogen, (C1-C6)-alkoxy or 2-(cyolohexyl)-
ethyloxy, where one of the substituents R2 and R3
is hydrogen,

R4 is a branched or unbranched (C1-C4)-alkyl radical
or a benzyl radical which is substituted once by
fluorine, chlorine, trifluoromethyl, (C1-C4)-
alkyl or (C1-C3)-alkoxy, including the physio-
logically active salts.

12. A compound of the formula I as claimed in claims 1
to 3 and 6, in which
Q is O
X is O,
Y is CR3,
where R3 is hydrogen,
m is 0,

A is a -CH2 group,
B is -CO2H, and
R1 and R2, together with the pyridine carrying them,
form an isoquinoline ring having an unsubstituted
benzo moiety, and
R4 is methyl.

13. A compound of formula I as claimed in claims 1 to 3
and 6, in which
Q is O,
X is O
Y is CR3,

- 142 -
m is 0,
A is a -CH2 group,
B is -CO2H,
R1 is hydrogen, and
R2 and R3, together with the pyridine carrying them,
form a quinoline ring having an unsubstituted
benzo moiety, and
R4 is methyl.

14. A compound of the formula I as claimed in claims 1,
2, 4 and 5, in which
Q is S,
X is O,
Y is CR3,
m is 0,

A is a -CH2 group,
B is -CO2H,
R1 is hydrogen,

R2 is hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((C1-
C12)-alkoxy-(C1-C3)alkyl)carbamoyl, N-cyclohexyl-
carbamoyl, N-phenylcarbamoyl, N-(phenyl-(C1-
C2)alkyl)carbamoyl, where, in the last two cases,
the phenyl radical can carry a fluorine
substituent, (C1-C10)-alkyl substituent or (C1-
C10)-alkoxy substituent, carboxyl, (C1-C16)-
alkoxycarbonyl, (C2-C16)-alkenyloxycarbonyl,
retinyloxycarbonyl, (C5-C5)-cycloalkoxycarbonyl
or benzyloxycarbonyl,

R3 is hydrogen, (C1-C6)-alkoxy or 2-(cyclohexyl)-
ethyloxy, where one of the substituents R2 and R3
is hydrogen, and

R4 is a branched or unbranched (C1-C4)-alkyl radical
or a benzyl radical which is substituted once by
fluorine, chlorine, trifluoromethyl, (C1-C4)-
alkyl or (C1-C3)-alkoxy.

- 143 -
15. A compound of the formula I as claimed in claims 1,
2, 4, 5 and 14, in which
Q is S,
X is O,
Y is CR3,
m is 0,
A is a -CH, group,
B is -CO2H,
R1 is hydrogen,
R2 is carboxyl or (C1-C16)-alkoxycarbonyl,
R3 is hydrogen, and
R4 is an unbranched or branched (C1-C4)-alkyl
radical.

16. A compound of the formula I as claimed in claims 1
to 15, plus 3-benzyloxypyridine-2-carboxylic acid
L-threonylamide and 3-benzyloxypyridine-2-carboxylic
acid ((Fmoc-Phg)-L-threonyl)amide for use as pharma-
ceuticals.

17. A compound as claimed in claims 1 to 16 to be used
for inhibiting collagen biosynthesis.

18. A compound as claimed in claims 1 to 16 as an
inhibitor of prolyl hydroxylase.

19. A compound as claimed in claims 1 to 16 for use as
a fibrosuppressive agent.

20. A compound as claimed in claims 1 to 16 for pre-
paring a pharmaceutical against fibrotic diseases.

21. A compound as claimed in claims 1 to 16 for pre-
paring a pharmaceutical against fibrotic diseases of
the liver.

22. A compound as claimed in claims 1 to 16 for pre-
paring a pharmaceutical against fibrotic diseases of
the lung.

- 144 -
23. A compound as claimed in claims 1 to 16 for pre-
paring a pharmaceutical against fibrotic diseases of
the skin.

24. A process for preparing compounds according to
formula I as claimed in claims 1 to 15, in which
formula A is a substituted alkylene moiety, B is
CO2H, Y is CR3 and m is 0 or 1, by

i1.) reacting pyridine-2-carboxylic acids of the
formula II (R23 is H) with the amino esters of
the formula III (R2) is (C1-C16)-alkyl or benzyl)
to form the amide esters of the formula IV, or

i2.) reacting pyridine-2-carboxylic esters of the
formula II (R2) is lower alkyl), under the
conditions of aminolysis, to form the compounds
of the formula IV;
and
III

Image

II IV

ii) liberating the compounds of the formula I from
their esters of the formula IV;
with, where appropriate,

iii) the compounds of the formula IV (R4 is alkyl)
being prepared by alkylation of compounds of
the formula V (R4 is H) with R4X,

- 145 -

Image ,
IV I
Image ,

V IV

where X is a leaving group, in particular
halogen, OSO2Me or OSO2 phenyl, and, where
appropriate,

iv) the compounds of the formula IV, provided Q is
O, S or NR', being converted into their
pyridine N-oxides (IV')

Image

IV'

and, where appropriate, the latter being
hydrolysed to form the compounds of the formula
I' (R24 is H).

Description

` 213Q86~

HOECHST A~TIENG~S~LSC~AFT HOE 93/F 349~ Dr.Fl/ws

Deecription

Substituted hetorocyclic carboxamidee, thoir preparation
and thoir use as pharmaceuticals

The invention relates to ~ubstituted hotorocyclic carbox~
amidee, to their pr-paration and to thoir u~o aB inh~-
bitors of prolyl-4-~ydroxyla~o, and to their use as
pharmaceuticals for treating fibrotic diseaee~.

Compounds which inhibit tho onzymo~ prolino hydroxylase
and lyeine hydroxyla~e bring about a vory soloctiva
inhibltion of collagon bio~ynthesis by thoir influenco on
the collagon-specific hydroxylation roaction~. In the
course of theso roactions, protein-bound prolino or
lysine is hydroxylatod by the enzymes proline hydroxylaso
or lyeino hydroxyla~o, resp~ctively. If thie reaction i~
prevented by inhibitors, there then arises a non-
functional, ~ubhydroxylated collagen ~olecule which can
only be eecreted by the cells into tho oxtrace~lular
space in small quantitios. Furthormor-, the eubhydroxy-
lated collagen cannot be incorporated into the collagenmatrix and i~ very readily degradod protoolytically.
The~- offect~ re~ult in a diminution of the overall quan-
tity of collagen which is doposited oxtracellularly.

Inhibitors of prolyl hydroxylase are thoreforo suitable
substances for use in~tho therapy of disoa~os in which
tho deposition of collagen~ makos a substantial contri-
bution to the clinical picture. Th-se d~soases includo,
inter alia, fibroses of the lung, liver and skin
(scloroderma and cLcatrizations following burns, in~urios
and surgical intor~ention) and also athorosclorosis.

It is known that the enzyme proline hydroxylase is
efficiently inhibited by pyridine-2,4-dicarboxylio acid
and pyridine-2,5-dicarboxylic ?cid (~. Ma~amaa et al.,
- :.,:..-

213486~
- 2 -
Eur. J. Biochem. 138 (1984) 239-245). ~owever, tho~e
compound~ are only active as inhibitor~ in cell culture
at vsry high concentrations (Tschan~, G. et al., Blocham. ~ ~ ~
J. 238 (1987) 625 to 633). ~;
Prodrugs of pyridino-2,4(5)-dicarboxylates are also
known. Those are describod in the relatively old German
Applicatlons P 42 33 124.2, P 42 38 506.7 and P 42 09
424Ø

N-Oxalylglyc~nes which are inhibitors of prolyl-4-
hydroxylase are dioclosod in J. Med. Chem. 1992, 35, 2652
to 2658 (Cunliffo et al.), and ~P-A-0 457 163 (Baader ot
al.).

Hydroxyisoquinolinecarboxylic acid glycyl~mldes and
hydroxycinnolinecarboxylic acid glycylamlde~ aro
disclosed in Biochem. Soc. Trans. 1991, 19, 812 to 815
(Franklin st al.). 3-~anzyloxypyrid$n--2-c~rboxylic ~cid
(L-threonyl)amide and 3-ben~yloxypyridine-2-carboxylic `~
acid ((Fmoc-Phg)-L-threonyl)amido hydrochlorid- are
disclosed in Liebigs Ann. Chem. 1986, 1 to 20, Ro~sler et
al.

It has now bqen found, ~urprisingly, that heterocyclic
carboxamides having an ether sub~tituent, a thioether ~;
substituont or an amino substituent in the ortho po~itlon
to the amide function have a strong inhibitory actlon on
prolyl-4-hydroxyla~e.

The compounds according to the invent~on conform to the
formula I ; '~
R 1 ~: : .`

R2~,N H-A- B ( I )

X , , .. :~ . ",,;
( )m

... .:, ~ ~.
' ' ' ,~: ~ ' .''


-`` 2134866
- 3
in which
Q i8 O, 8, NR' or a bond,
X i~ O or S,
Y 18 C-R3 or,
if Rl and R2 form a cyel-,
Y is N or CR3,
m i8 0 or 1,
A ~8 (Cl-C~)-alkylen~, whieh is optionally ~ub~titutod
by one or two ~ubstitu~t~ from the group halogen,
eyano, nitro, trifluoro~othyl, (Cl-C,)-alkyl, (Cl-
C~)-hydroxyalkyl, (Cl-C~)-alkoxy, -O-~CH,]~
C~H~ al~, proferably (C1-C,)-fluoroal~oxy, (C~
C~)-fluoroalkenyloxy, (Cl-C~)-fluoroalkynyloxy,
-OCF~C1 or -O-CF~-CHFC1, (C1-C6)-alkylmereapto, (C~
C~)-alkylsulflnyl, (Cl-C~)-alkyloulfonyl,
(Cl-C6)-allcylcarbonyl, (Cl-C6)-alkoxycarbonyl,
carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl-C~
alkylcarbamoyl, (Cl-C~)-alkylcarbonyloxy, (C3-C,)-
eycloalkyl, ph-nyl, b-nzyl, ph-noxy, benzyloxy,
anilino, N-methylanilino, phonylmereapto, ph nyl-
sulfonyl, phanyl~ulf~nyl, sulfamoyl, N-(Cl-C~
alkylsulfamoyl or N,N-di-(Cl-C~)-alkyl~ulfamoyl, or

by a ~ub~tituted (C~-Cll)-aryloxy, (C7-C1l)-aralkyl-
oxy, (Cc-Cll)-aryl or (C7-Cl,)-aralkyl radical whieh
earri-s in th- aryl i~ty 1, 2, 3, 4 or 5 id~ntieal
or difft~rent ~ub~tituent~ from the group halog-n,
eyano, nitro, trifluoromethyl, (Cl-C6)-alkyl, (Cl-
C~)-alkoxy, -O-[CH~ C~Ht~ al~, OCFsCl, -O-CF~
CHFCl, (Cl-C~)-alkylmeroapto, (Cl-C~)-alkylsulfinyl,
(Cl-C~)-alkylsulfonyl, (Cl-C,)-alkylearbonyl, (C1-C~
alkoxyearbonyl, earbamoyl, N-~Cl-C~)-alkylearbamoyl,
N,N-di-(C1-C~)-alkylearbamoyl, (C1-C~)-alkyl-
earbonyloxy, (C3-C~) -eycloalkyl, sulfamoyl, N-(C
C~)-alkyl~ul~amoyl or N,N-di-(C1-C~)-alkyl~ulfamoyl,
or ~` I:'~'`i!,'';'' `,'':

by the ~ub~tituent~ Rs of the a-carbon atom of an a-
amino acid, lt b-1ng po~lbl- to u~- th- natur~

- 2134866
- 4 -
L-a~ino acide and thoir D-lso~ores
B i~ an acid grouping from t~e group -CO~,
-CON~COR~', -CONHSOR'~, CONHSOlR~', -NHSO,CF"
tetrazolyl, imidazolyl or 3-hydroxyl~oxazolyl, whore
Rn' is aryl, h-teroaryl, (C3-C7)-cycloalkyl or
(C,-C~)-alkyl, optionally noeubstitutod by (C~-
C,l)-aryl, heteroaryl, OH, SH, (C,-C~)-alkyl,
(C1-C~)-alkoxy, (C~-C~)-thioalkyl, (C,-C~ ulfinyl, ;~
(C~-C~)-sulfo~yl, CF3, Cl, Br, F, I, NO" -COOH,
0 (C,-C5) -alkoxycarbonyl,NE~,mono-(C~-C~-alkyl)-amlno,
di-(Cl-C~-alkyl)-amino or (C~-C~)-perfluoroalkyl,

Rl, R~ and R3 aro identical or difforont and ar~ ~ydrogon,
hydroxyl, halogen, cyano, tri~luoromethyl, nitro,
carboxyl, (C,-C20)-alkyl, (C,-C,)-cycloalkyl, (C3-
C,)-cycloalkyl-(C~-C")-alkyl, (C3-C,)-cycloalkoxy,
(C3-C,)-cycloalkyl-(C,-Cl,)-alkoxy, (C3-C,)-cyclo- ~;~
alkyloxy-(C1-C~)-alkyl, (Cl-C~)-cycloalkyloxy-(C~
C")-alkoxy, (C3-C,) -cycloalkyl-(C,-C,)-alkyl-(C,-
C~)-alkoxy, (C3-C,) -cycloalkyl-(C,-C,)-alkoxy-(C,-
C6)-alkyl, (C3-C,) -cycloalkyloxy-(C,-C~)-alkoxy-(C~
C6)-alkyl, (C3-C,)-cyGloalkoxy-(C~-C~)-alkoxy-(C~ "'~
C,)-alkoxy, (C~-C,2)-aryl, (C7-C")-aralkyl, (C7-C") - .`; :~`f :`;
aralkenyl, (C7-C,c)-aralkynyl, (Cs-C,0)-alkonyl, (Cl- ~ t
Cl0)-alkynyl, (C,-C~0)-alkoxy, (C~-C~0)-alkenyloxy,
(Cl-Cl0)-alkynyloxy, retlnyloxy, (C1-Cl0)-alkoxy-(C,- .
C,l)-alkyl, (C,-C,l)-alkoxy-(C,-C,l)-alkoxy, (C,-C,l)-
alkoxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C~-C")-aryloxy,
(C7-ClC) -aralkyloxy, (Cc-C")-aryloxy-(Cl-Cc)-alkoxy, . ~'!.. ',,~,~",'.'`.
(C~-C~)-aralkoxy-(C~-Cc)-alkoxy, (C~-C~)-hydroxy-' '; '~' ';'` ,`,.!, '~'', ','
alkyl, (C~-C~)-aryloxy-(C~-C~)-alkyl, (C7-Cl,)-
aralkoxy-(C,-C,)-alkyl, (C~-C")-aryloxy-(C,-C,)~
alkoxy-(CI-C~)-alkyl, (C7-C") -aralkyloxy-(C,-C,)-
alkoxy-(C,-C~)-alkyl, (C,-C,0)-alk~nyloxy-(C,-C~
alkyl, (C~-C,0)-alkynyloxy-(C~-C,)-alkyl, r-tinyloxy-
(C,-C~)-alkyl, -O-tC~ -C~H~ )F~, -OCF,Cl, -OCF,-
CHFCl, . .~
'~: ,: ." ' . . ~ .
(Cl-Cl0)-alkylcarbonyl, (C3-C,)-cycloalkylcarbonyl, .;~
.: ., .::

" , .:, ,.;, .

- 2134866
-- 5 --
(C,-Cl2)-arylcarbonyl, (C7-C~,)-arallcylcarbonyl,
s:~nnamoyl, (C2-C,0)-alk~slylcarbonyl, (C,-C20)-
alkynylcarbonyl,

(C,-C20)-alkoxycarbonyl, (c1-c12)-alkoxY-(c~-cl2)
alkoxycarbonyl, (C6-C12)-aryloxy¢arbonyl, (C7-C1~
aralkoxycarbonyl, (C3-C,) -cycloalkoxycarbonyl, (C2-
C20)-alkenyloxycarbonyl, rotinyloxycarbonyl, (C,-C,0)-
alkynyloxycarbonyl, (C,-C1~)-aryloxy-(C1-Cc)-alkoxy-
carbonyl, (C7-Cl~)-aralkoxy-(Cl-C~)-alkoxycarbollyl,
(C3-C,)-cycloallcyl-(C1-C~)-alkoxycarbonyl, (C3-C,,)-
cycloalkoxy-(C,-C~)-alkoxycarbonyl,

(C~-C~2)-alkylcarbonyloxy, (C3-C:~)-cycloalkylcarbon-
yloxy, (C6-C,2)-arylcarbonyloxy, (C7-C1,)-aralkyl-
carbonyloxy, cinnamoyloxy, (C2-C12)-alkonylcarbonyl-
oxy, (C2-C12)-alkynylcarbonyloxy,

~C,-C,2)-alkoxycarbonyloxy, (C,-C,2)-alkoxy-(C,-C,2)-
alkoxycarbonyloxy, (C,-C,2)-aryloxycarbonyloxy, (C7-
C,6)-aralkyloxycarbonyloxy, (C3-C,)-cycloalkoxycar-
bs~nyloxy, (C2-C~2)-alkcnyloxycarbonyloxy, (C,-Cls)-
alkynyloxycarbonyloxy,
.':. ~'.';''"'~:
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-
Cl2)-alkylcarbamoyl, N-(C3-C~)-cycloalkylcarbamoyl,
N,N-dicyclo- (C3 - C,) -alkylcarbamoyl, N-(C1-C10)-alkyl-
N- (C3-C,) -cycloalkylcarbamoyl, N-((C3-C~) -cycloalkyl-
(C~-C6)-alkyl)carbamoyl, N-(cl-c~)-alkyl-N-((c3-c~
cycloalkyl (C~-C6?,-alkyl)carbamoyl, N-(l)-dehydro-
abietyl¢arbamoyl, N-(C1-C,)-alkyl-N-(+)-dchydro-
abietylcarbamoyl, N-(C,-C12)-arylcarbamoyl, N- (C7-
C16)-aralkylcarbamoyl, N-(C1-Clo)-alkyl-N-(cc-c~
arylcarbamoyl, N-(C,-C~0)-alkyl-N-(C,-Cl~)-aralkyl-
carbamoyl, N-((C1-C1,)-alkoxy-(C1-C,0)-alkyl)car!~a-
moyl, N-((C,-C,6)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-((C7-Cl6)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-
(C1-C10) -alkyl-N- ( (C1-C10) -alkoxy- (C,-C,0) -
alkyl) carbamoyl, N-(C1-C1o) -alkyl-N-((C,-C,2)-
.. ........

213~866
- 6 -
aryloxy(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-C~O)-al~cyl-N-
((C7-Cl6)-aralkyloxy-(C,-C10)-allcyl)carbamoyl, or ~ ~ :
CON(C}I,)h, in which a C}12 group can be r~plac~d by O,
S, N-(Cl-C~)-allcylimino, N- (C3-C,) -cycloallcylimino,
N- (C3-C,) -cycloalkyl-(Cl-C~)-alkyl~ino, N-(C,-Cl,)-
arylimino, N- (C7-Cl~) -arallcyli~no or N-(C1-C~)-
alkoxy-(Cl-C,)-alkylimino, and h ic from 3 to 7,
a aarbamoyl radical of tho fonhula II
- 1 , " ~
R' H
--CO~ I NR ~~~--T ( I I ), ~ ~;
L 5
in which
R~ ie the subetituent of an a-amis~o acid to wh~oh
the L- and D-amino acidc belong,
e ie 1, 2, 3, 4 or 5, and
T ie OH, OR or NR-R--, whore

R-, R^- and R--- are ~dentical or diffsront and are
hydrogen, (C6-Cl2)-aryl, (C7-Cll)-arallcyl, (Cl-C,)-
alkyl, (C3-C,)-cycloalkyl, (~)-dehydroabiotyl,
(Cl-C~ lkoxy-(Cl-C~)-alkyl,(C7-Cl,)-aralkoxy-(Cl-
C,)-alkyl, (C~-Cl~)-aryloxy-(Cl-C~)-alkyl, (Cl-Cl0)-
alkanoyl, optionally eubetituted (C7-Cl~)-aralk-
anoyl or optionally eubetituted (C~-Cl,)-aroyl, or

R~ and R-- togothor are -lCE~,]b, in which a C~, group
oan be roplac~d by O, S, SO, SO" N-acylamlno, N-
(Cl-C~0)~allcoxy~arbonyl~n~no, N-(Cl~C~)-alkylimino,
N- (C3-C,) -cycloallcylimino, N-(C~-C~)-cycloallcyl-
(Cl-C~)-alkylimino, N-(C~-Cl~)-arylimino, N-(C7Cl~
aralkylimino or N-(Cl-C~)-alkoxy-(Cl-C~)-alkyl-
imino, and h ie from 3 to 7,

carbamoyloxy, N-(C,-C")-alkylcarbamoyloxy, N,N-dl-
(Cl-Cl2)-alkylcarbamoyloxy, N- (C3-C,) -cycloalkylcarb-
amoyloxy, N- (C~-C,;,)-arylcarbamoyloxy,
' ' .'' '' .: "" '
",.,


`` 213~866 : ~ ~
_
N-(C7-C~-aralkylcarbamoyloxy, N-(Cl-C10)-al ~l-N-
(C6-Cl2)-arylci~rbamoyloxy,N-(C~-ClO)-alkyl-N-(C7-C~
aralkylcarbamoyloxy, N-((Cl-C~0)-al ~l)carbamoyloxy,
N-((C,-C,2)-aryloxy-(C,-C10)-al~yl)car~ ~ ylo ~, N-
((C7-C") -aralkyloxy-(C~-C,0)-al ~l)carbamoyloxy, N-
(cl-clo)-al~yl-N-((cl-clo)-alkoxy-(cl-clo)-al~yl)-
carbAmnyloxy, N-(C,-C10)-al~l-N-(~C~-C~2)-arylo~-(C,-
C10)-alkyl)carbamoylo~, N-(C~-C,0)-alkyl-N-((C7-C~
aralkyloxy-(C,-C,0)-alkyl)carbamoyloxy,

amino, (Cl-C,2)-alkylamino, di-(C,-Clj)-al ~1 ~ no,
(C,-C,)-cycloal~ylamino, (C3-C~2)-alk~nyl ~ no, (C3-
Cl2)-alkynylamino, N-(C,-C,2)-aryl~no, N-(C7-C1~
aralkylamino, N-alkyl-aralkylamino, N-al ~l-aryl-
amino, (C,-Cl2)-alkoxyA~no, (C,-C12)-alkoxy-N-(C,-
C~0)-alkyl ~ino,

(C,-C,3) -alk~oylamino, (C3-C~)-cycloalkanoylamino,
(C~-C~2)-aroyl ~ino, (C7-Cl6)-aral~anoyl~no, (C~
C,2)-alkanoyl-N-(C,-C,0)-alkylamino, (C3-C,)-cyclo-
alkanoyl-N-(C~-C10)-alkylamino, (C~-C~2)-aroyl-N-
(C,-C,0)-alkyl ~ no, (c7-cll)-aralkanoyl-N-(cl-clo)
alkylamino,

~C,-C,2)-alkanoylamino-(C,-C,)-alkyl, (C3-C,)-cyclo-
alkanoylamino-(C,-C~)-alkyl, (C~-C12)-aroylamlno-(C,-
C,)-alkyl, (C7-C,6)-aralkanoyl ~ no-(C,-C~)-alkyl,
2i amlno-(C,-C,0)-alkyl, N-(Cl-C,0)-alkylamlno-(C,-i~O)~
alkyl, N,N-dl(C,-C,o)-alkylamino-(C~-C~0)-alkyl, (C~
C,?-cycloalkylamino-(C,-C10)-alkyl, (C~-C20)-al~yl-
mercapto, (C1-C20)-alkyloulfinyl, (C1-C20)-alkyloul-
fonyl, (C~-C~2)-arylm-rcapto, (C~-C~2)-arylculfinyl,
(C~-C~2)-aryloulfonyl, (C7-C~)-aralkylmorcapto,
(C7-C~6)-aralkylculfinyl, (C7-C,6)-aralkyl~ulfonyl,
(Cl-C12)-alkylmercapto-(C~-C~)-alkyl, (C,-C,j)-alkyl~
culf$nyl-(C~-C~)-alkyl, (C~-C~2)-alkylsulfonyl-(C~-C~)-
alkyl, ~C~-Cl2)-arylmerc~pto-(C,-C~)-alkyl, (C~-C,2)-
arylsulfinyl-(Cl-C,)-alkyl,(C~-Cl2)-aryloulfonyl-(Cl-
C6)-alkyl, (C7-C,~)-aral ~lmorcapto-(C,-C~)-alkyl,
::~:: ::. .:

2134866
-- 8 --
(C7-C16) -aralkylsulfinyl-(Cl-C~)-alkyl, (C7-c~
aralkylsulforyl-(C1-C~)-alkyl, : ~ ;

~ulfamoyl, N-(Cl-Cl0)-alkyl~ulfamoyl, N,N-di-(Cl-Clo)- ~ :
alkylsulfamoyl, (C,-C,)-cyeloalkyl~ulfamoyl, : ~
N-(C,-C,2)-aryleulfamoyl, - .~-
N-(C7-Cl~)-aralkylsulfamoyl, : , .;
N-(C~-C,O)-alkyl-N-(C~-C~l)-arylsulfamoyl, ~ .
N-(C~-C,O)-alkyl-N- (C7-C") -aralkylsulfamoyl,
(C1-C,0)-alkyl~ulfona~ido,
N-((C,-C,0)-alkyl)-(C~-C,0)-alkylsulfonam~do,~C7-C
aralkyl~ùlfona~ldo or N-((C~-C~O)-alkyl- (C7-C~
aralkylsulfonamido,
where the radlcals whieh conta~n an aryl radleal
can, for the~r part, bs ~ubstltuted on the aryl by
from 1 to 5 idontical or dlfforant radlcal~ from the

hydroxyl, halogon, cyano, trifluoromethyl, nltro,
carboxyl, (C,-C~)-alkyl, (C3-C,)-cyclo-lkyl, (C3-C~ ".,~
cycloalkyl-(Cl-Cl,)-alkyl, (C3-C,) -cycloalkoxy,
(C 3-C~) -C y C 1 0 a 1 k y 1 - (Cl- Cl,) - a 1 k o x y, :~
(C3-C,) -cycloalkyloxy-(Cl-Cl,)-alkyl, (C,-C,)-cyclo-
alkyloxy-(Cl-Cl,)-alkoxy, (C3-C,) -cycloalkyl-(Cl-C~
alkyl-(Cl-C,)-alkoxy, (C3-C,) -cycloalkyl-(Cl-C,)-
alkoxy-(Cl-C,)-al~yl, (C3-C,) -cycloalkyloxy-(Cl-C~
alkoxy-(Cl-C~)-alkyl, (C3-C,) -cycloalkoxy-(Cl-C,)- .
alkoxy-(Cl-C,)-alkoxy, (C,-Cl,)-aryl, (C7-C,~) -aralkyl,
(C~-Cl~)-allcenyl, (C,-Cl,)-alkynyl, (Cl-Cl~)-alkoxy, ... ;''.~', ,',:`:.
(Cl-Cl,)-alkanyloxy, (Cl-Cl,)-alkoxy-(Cl-Cl,)-alkyl, ~` `' .; .;~
(Cl-Cl~)-alkoxy- (Cl-C12) -alkoxy, (Cl-Cl,)-alkoxy-(Cl- .. .
C,)-alkoxy-(Cl-C~)-alkyl, (C~-Cl,)-aryloxy, (C7-C
aralkyloxy, (C~-Cl2)-aryloxy-(Cl-C~)-alkoxy, (C7-C
aralkoxy-(Cl-C,)-alkoxy, (Cl-C,)-hydroxyalkyl, (C~
Cl~)-aryloxy-(Cl-C,)-alkyl, (C7-Cl~)-aralkoxy-(Cl-C~)- :~-: : ;
alkyl, (C~-Cl,)-aryloxy-(Cl-C,)-alkoxy-(Cl-C,)-alkyl, `.. ~.
( C7-Cl~) - aralkyloxy-(Cl-C,)-alkoxy-(Cl-C,)-alkyl, ~ ~ :
-O-tCH,.]~-C~H(,~ )F~, -OCF,Cl, OCF2-CHFCl,

(Cl-C12)-alkylcarbonyl, (C3-C,)-cyeloalkylcarbonyl,

:: . : ~'

2131866
.
g
(C6-Cl2)-arylcarbonyl, (C,-Cl,~-arallcylcarbonyl,

(C,-Cl2)-alkoxycarbonyl, (el-e12)-alkoxY-(cl-cl2)
alkoxycarbonyl, (C,-Cl2)-aryloxycarbonyl, (C,-Cl,)-
aralkoxycarbonyl, (C,-C,)-cycloalkoxycarbonyl, (C2-
Cl2)-allcenyloxycarbonyl, (C2-Cl2)-allcynyloxyearbonyl,
(C~-C~2)-aryloxy-(Cl-C~)-alkoxycarbonyl, (C7-cl~
aralkoxy-(Cl-C,)-alkoxycarbonyl, (C,-C,)-cycloalkyl-
(C1-C~)-allcoxycarbonyl, (C,-C")-eyeloalkoxy-(Cl-C~
al;coxyc:arbonyl,

(Cl-Cl2)-allcylearbonyloxy, (C,-C,)-eyeloallcylearbo-
nyloxy, (Cc-C12)-arylearbonyloxy, (C7-Cl~)-arallcyl-
carbonyloxy, cinna~oyloxy, (C2-Cl2)-alkenyl¢arbonyl-
oxy, (C2-Cl2)-alkynylcarbonyloxy,

(Cl-Cl2)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(Cl-Cl2)-
alkoxycarbonyloxy, (C,-Cl2)-aryloxycarbonyloxy, (C7-
Cl6)-aralkyloxycarbonyloxy, (C~-C~)-cycloalkoxycar-
bonyloxy, (C2-Cl2)-alkenyloxycarbonyloxy, (C2-Cl2)-
alkynyloxycarbonyloxy,

carbamoyl, N-(Cl-Cl2)-alkylcarbamoyl, N,N-dl-(Cl-C12)-
alkylcarbamoyl, N- (C3-C,) -cyeloalkylcarbamoyl, N,N-
d~cyelo- (C3-C,) -alkylcarbamoyl, N-(C1-C10)-alkyl-N-
(C3-C,) -cy¢loalkyl¢arbamoyl, N-( (C3-C,) -eycloallcyl-
(Cl-C~)-alkyl)carbamoyl, N-(Cl-C~)-alkyl-N-( (C3-C,) -
cycloalkyl- (Cl-C6) -alkyl)earbamoyli N-(l)-dehydro-
abietylcarb~oyl, N-(C1-C~)-alkyl-N-(I)-dohydro-
abiotyl¢a*am!oyl~ N-(C~-Cl~)-aryl¢arb~oyl, N- (C7-
Cl~)-aralkyl¢arbamoyl, N-(Cl-c30)-alkyl-N-(cc-clc)-
aryl¢arbamoyl, N-(C1-C10~-alkyl-N-(C7-Cl~)-arallcyl-
carbamoyl, N- ((Cl-Cl,) -alkoxy- (Cl-C10) -alkyl) -
carbamoyl, N- ( (C,-Cl6) -aryloxy- (C1-C10) -
alkyl)carbu~oyl, N-((c7-cl~)-aralkyloxy-(cl-clo)-
alkyl)carbamoyl,
N-(Cl-C"0)-alkyl-N-((Cl-C1O)-alkoxy-(Cl-C1O)-alkyl)-
¢arbamoyl, N-(Cl-C10)-alkyl-N-((Cc-Cll)-aryloxy-(Cl-
C10)-alkyl)¢arb~noyl, N-(cl-c~o)-alkyl-N-((c7-cl6)-
-,.
" ,
,, ~ .

213~866
.
- 10 - ,,
aralkyloxy-(Cl-C10)-allcyl)carbamoyl, CON(C~)h, $n
which a C}Iil group can b~ roplaced by O, S, N-(Cl-C,)~
alkyl~m~no, N- (C3-C,) -cycloalkyl~m~no, N-(C,-C~
cycloalkyl-(Cl-C~)-alkyl~m~no, N-(C~-Cl2)-aryl~m~no,
N-(C7-Cl6)-aralkyl~m~no or N-(Cl-C")-alkoxy-(Cl-Cs)-
alkylimino, and h ic from 3 to 7,

carbamoyloxy, N-(C1-C~j,)-alkylcarbamoyloxy, N,N-d~
(Cl-Cl~)-alkylcarbamoyloxy, N-(C~-C~)-cycloallcyl~
carbamoyloxy, N-(C~-Cl~)-arylcarbamoyloxy, N-(C,- `: -~ : j
Cl~)-aralkylcarbamoyloxy, N-(Cl-C10)-allcyl-N-(C~
Cll)-arylcarbamoyloxy, N-(cl-clo)-allcyl-N-(c7-cl~
arallcylcarbamoyloxy, N-((Cl-C10)-alkyl)carl:~amoyloxy,
N-~(C6-Clj~)-aryloxy-(Cl-C10)-alkyl)carbamoyloxy, N-
((C7-Cl6)-aralkyloxy-(Cl-C10)-allcyl)carbamoyloxy, N-
(Cl-C10) -alkyl-N- ( (Cl-C10) -alkoxy- (Cl-C~O) -
alkyl)carbamoyloxy, N-(cl-clo)-allcyl-N-((
aryloxy-(C,-C10)-allcyl)carbamoyloxy,N-(C1-C10)-allcyl~
N-((C7-Cl6)-arallcyloxy-(C1-C10)-alkyl)carb~oyloxy,
: , ; ~ .
amino, (Cl-Cl2) -alkylamino, di-(C1-C1,)-alkylamino,
(C3-C,) -cycloalkylamino, (C~-Cl~)-allcenyl~m~no, (C3- ~:~' ,,.. :, .
Cl~)-alkynylamino, N-(C6-Cl~)-arylamino, N-(C7-Cl~
aralkylamino, N-alkyl-arallcylamlno, N-alkyl-aryl- j :; .r: ",'
amino, (C1-C1~)-alkoxyamino, (C1-C1~)-alkoxy-N-(C1- :~
C10)-alkylamino, ; ~ . A'.`'

(C1-C1,)-alkanoylamlno, (C3-C,) -cycloalkanoylamino, ;.
(C6-C1,)-nroylamlno, (C7-C16)-aralkanoylamino, (C1- ::
C~-alkanoyl-N-(Cl-C10)-alkylamino, (C3-C,) -cyclo- .
alkanoyl-N-(C1-C10)-alkylamino, (C~-C1,)-aroyl-N-(C1- ~
C~0)-alkylamino, (C7-Cll)-aralkanoyl-N-(C1-C10)-alkyl- `
amino, . ~

(Cl-Cl~) -alkanoylamino-(Cl-C~) -alkyl, (C3-C,) _ ` ~ `
cycloalkanoyl~n~no-(Cl-C~)-alkyl, (C6-Cl,)-aroylamino-
(C,-C~)-a;Lkyl, (C7-C16)-aralkanoylamino-(C1-C,)-allcyl,
amino-(Cl-C10)-allcyl, N-(Cl-C10)-alkylamino-(Cl-C,O)-
alkyl, N,N-di-(Cl-C10)-alkylamino-(Cl-ClO)-allcyl, ~. : ~ ~:.. ; .

:.~ ,:. ..
'" "' ' ': ~'~

213~86~
11 .
(C~-C~)-cycloal~ylamino-(Cl-Cl0)-alkyl,

(Cl-Cl2)-allcylmercapto, (Cl-Cl2)-allcyl~ulfinyl, (Cl-
C~2)-alkylsulfonyl, (C~-Clc)-arylmorcapto, (C~-Cl,)~
aryleulfinyl, (C6-Cl~)-arylsulfonyl, (C7 -Cl~
aralkylmercapto, (C~-Cl~)-aral~yl~ulfinyl or (C7-C16)-
aral~ylsulfonyl,

Rl and R2 or R2 and R3 form a chain tCH2]o ~n which ono or
two CH2 groups of ths chnin, which is ~aturat~d or
unuaturated by a C-C doublo bond, are optionally
replaced by 0, S, S0, S02 or NR', and o 1~ 3, 4 or
5, and

R' i~ hydrogen, (C6-Cl~)-aryl, (Cl-C~)-alkyl, (Cl-C,)-
alkoxy-(Cl-C~)-al~yl, (C7-C~ aral~oxy-(Cl-C,)-alkyl,
(c6-cl2)-aryloxy-(cl-c~)-al~yl~ (Cl-C10)-al~anoyl,
optionally sub~tituted (C7-C~ aral~anoyl or
optionally ~ub~titutod (C6-Cl2)-aroyl, whore

the radical~ Rl and R2 or R2 and R3, togother with
the pyrldine or pyrldazlne carrylng th~m, preferably
form a 5, 6, 7, 8-tetrahydrolsoqulnollne rlng, a
5, 6, 7, 8-tetrahydrogulnollne rlng or a 5, 6, 7, 8-
tetrahydrocinnoline rlng,
or
Rl and R2 or Rs and R3 form a carbocycllc or a
h-terocycllc, 5- or 6-membered aromatic rlng, where

the radlcals Rl and R2 or R2 and R3, together w~th
the pyrldlne or pyridazine carrylng them, preferabiy
form the followlng optlonally ~ub~tltuted
h-terocyclic ring sy~temss

Thlenopyrldlne~
Furanopyrldines,
Pyridopyrldln-s,
Pyrlmidinopyridlne~,
Imidazopyridinos,

.
i~ :' ~',' '"''

2 1 3 4 8 6 6
- 12
Thiazolopyridinoe,
Oxazolopyridinee,
Quinolino, ~oguinolino and ;~
Cinnolina,
whoro quinolino, ieoquinoline or cinnollno pre~
forably eatiefy the formulae la, lb and lc


R~2 ~ ~R~ ~ OR~



1~ 1 b ; : . :. .`

, ,~: ., :: ., :.........
R 2 o

~ Q R~
R22~q~ : ~ :
`N~

1 C , ; ~ .

and the eubstituent~ R~l to Rss, in oach caeo independontly
of each othor, have the meaning of Rl, R2 and R3, :
., : ~ I I ' , .,: . : :: . '
R~ ie, if Q iB a bond, halogon, nitrilo or trifluoro-
mothyl, or, if Q ie O, S or NR', a braDch-d or
unbranched (Cl-CsO)-alkyl radical, an uneub~titutod, :~
~aturatod fluoroalkyl radical of the formula lC~]~
C~H~s~ )F~, a (C~-C1c)-aryl radical, a (Cj-C1,)-aralkyl
radical, a heteroaryl radical or a hetoroaralkyl : . .;
radical, . .:
.;'.;,,'.'"'",.:~

,~ ,, ."~
.

213~866

- 13 -
whore the~ rad~cals are s~bstituted by one or more
radical~ from th~ group
hydroxyl, halogen, cyano, tr~fluoromothyl, n~tro,
carboxyl, (C1-C,2)-alkyl, (C3-C,) -cycloalkyl, (C3-C,)-
cycloalkyl-(C,-Cl2)-alkyl, (C3-C,) -cycloalkoxy, (C3-C,) -
cycloalkyl-(C~-C~)-alkoxy, (C3-c~) -cycloal~yloxy-(C~-C~2)-
alkyl, (C3-C,) -cycloalkyloxy- (C,-C,2) -al~oxy, (C3-C,) -
cycloalkyl-(C~-C~)-al~yl-(C~-C~)-alkoxy, (C3-C,) -GyC10-
alkyl-(C,-C,)-alkoxy-(C,-C,)-alkyl, (C,-C,)-cycloalkyloxy-
(C~-C~)-alkoxy-(C~-C~)-alkyl, (C3-C,) -cycloalkoxy-(C~-C~
alkoxy-(C,-C,)-alkoxy, (C~-C")-aryl, (C7-C") -aral~yl,
(C~-Cl2)-alkonyl, (C2-C~)-alkynyl, (Cl-C~2)-al~coxy, (C,-
C")-alkoxy-(C1-C~)-alkyl, (c~-c~2)-alkoxY-(c~-c~2)-
alkoxy, (C,-C,2)-alkoxy-(C,-C,)-alkoxy-(C,-C,)-alkyl, (C,-
Cl,)-aryloxy, (C7-C~c)-aralkyloxy, (C,-C")-aryloxy-(C~
C6)-alkoxy, ~C7-C~)-aralkoxy-(C~-C~)-alkoxy, (C,-C,)-
hydroxyalkyl, (Cc-C~)-aryloxy-(C,-C,)-alkyl, (C7-C")-
aralkoxy-(C1-C~)-alkyl, (C~-C")-aryloxy-(C~-C~)-alkoxy-
(C~-C~)-alkyl, (C7-C")-aralkyloxy-(C,-C~)-alkoxy-(C~-C~
alkyl, ~O~lC~,]~~C~ lg~F~, -OCF2Cl, -OCF,-CHFCl,
..: :: ,:
(C~-C")-alkylcarbonyl, (C3-C~) -cycloalkylcarbonyl, (C,-
C~2)-arylcarbonyl, (C7-C")-aralkylcarbonyl, c~nnamoyl,
(C2-C")-alkenylcarbonyl, (C,-C,2)-aklynylcarbonyl,

(C~-C~2)-alkoxycarbonyl, (C~-C")-alkoxy-(C~-C")-alkoxy-
carbonyl, (C~-C,2)-aryloxycarbonyl, (C7-C~)-aralkoxy-
carbonyl, (C3-C,)-cycloalkoxycarbonyl, (C~-C")-alko~yl-
oxycarbonyl, (C2-C~2)-~lkynyloxyoarbonyl, (C~-C")-aryl-
oxy-(C,-C~)-alkoxycarbonyl, (C7-C")-aralkoxy-(C,-C,)-
alkoxycarbonyl~(c3-C~) -cycloalkyl-(C~-C~)-alkoxycarbonyl,
(C3-C,) cycloalkoxy-(C~-C~)-alkoxycarbonyl,

(C~-C~2)-alkylcaxbonyloxy, (C3-C,) -cycloalkylcarbonyloxy,
(C~-C")-arylcarbonyloxy, (C7-C") -aralkylcarbonyloxy,
clnnamoyloxy, (C,-C")-alk~nylcarbonyloxy, (C,-C~
alkynylcarbonyloxy,
. - :;::: ..,, :.. ., :.,
(C~-C1,)-alkoxycarbonyloxy,(C~-C~2)-alkoxy-(C,-C,2)-alkoxy-
: ::.:; . . ~

213~866 ~ :
- 14 - ~-
carbonyloxy, (C,-Cl,)-aryloxycarbonyloxy, (C,-Cl,)-aralkyl-
oxycarbonyloxy, (C3-C,)-cycloalkoxycarbonyloxy, (C,-Cl,)-
alkenyloxycarbonyloxy, (C,-Cl,)-al~ynyloxycarbonyloxy,

carbamoyl, N-(C~-Cs,)-al~ylcarbamoyl, N,N-di-(Cl-C~
alkylcarbamoyl, N- (C3-C,) -cycloalkylcarba~oyl, N,N-dl-
cyclo- (C3-C~) -alkylcarbamoyl, N-(Cl-C10~-alkyl-N- (C3 C,)
cycloalkylcarbamoyl, N-((C3-C~)-cycloalkyl-(C~-C~
alkyl)carbamoyl, N-(cl-c~)-alkyl-N-((c3-c~) -cycloalkyl-
(Cl-C~)-alkyl)carbamoyl, N-(~)-dehydroabi-tylcarbamoyl, ; '~
N-(Cl-C,)-alkyl-N-(~)-dehydroab~etylcarbamoyl, N-(C,-Cl2)-
arylcarbamoyl, N- (C7-C") -aralkylcarbamo~l, N-(Cl-C1o)-
alkyl-N-(C~-Cl~)-arylcarbamoyl, N-(Cl-Cl0)-al~yl-N- (C7-
Cl6)-aralkylcarbamoyl, N((cl-clo)-alkoxy-(cl-clo)- -'
alkyl)carbamoyl, N-((C~-Cl~)-aryloxy-(Cl-Cl~)- ; -
alkyl)carbamoyl, N-((C7-Cl,)-aralkyloxy-(Cl-Cl0)-
alkyl)carbamoyl, N-(Cl-Cl0)-alkyl-N-((Cl-C10)-alkoxy-(Cl-
Cl0)-alkyl)carbamoyl, N-(Cl-ClD)-alkyl-N-((C~-Cl~)-aryloxy- ~;
(Cl-Cl0)-alkyl)carbamoyl, N(cl-clo)-alkyl-N-((c7-cl~
aralkyloxy-(C1-Cl0)-alkyl)carbamoyl, CON(CH~)h, in which
20 a CH, group can be replaced by O, S, N-(Cl-C,)-alkyllmino, ;~
N- (C3-C,) -cycloalkyllmlno, N-(C3-C,)-cycloalkyl-(Cl-C~
alkyllmino, N-(C,-Cl,)-aryllmlno, N-(C7-Cl~)-aralkyllmino
or N-(Cl-C~)-alkoxy-(Cl-C~)-alkyl~mlno, ~nd h ~e from 3 to
7, or by

a carbamoyl radlcal of the formula II
. :' ~ .~ ', ,~'~' ':' ":'
R X H ~ :
C O - - N R l ~ `r ( I I ) . ~ :
S ::.. '; ::;':.. -,
ln whlch ~ ;~
RY le the eubstituent of an a-amino acld to which the
L- and D-amlno acids belong,
e le 1, 2, 3, 4 or 5, and
T is OH, OR or NR-R--, where
. ,,. ~",,.


2134~66
- 15 ~
R-, R--, and R--- are ident~cal or dlfforont and aro
hydrogon, (C~-C,2)-aryl, (C7-Cll)-aral~yl, (Cl-C~
alkyl, (C3-C,)-cycloalkyl, (I)-do~ydroabietyl, (C
C,)-allcoxy-(Cl-C~)-alkyl, (C7-Cl~) -aralkoxy-(Cl-C~
alkyl, (C~-Cl~)-aryloxy-(Cl-C~)-alkyl, (Cl-C10)-
alkanoyl, optlonally cubctitutod (C~-C16) -aralkanoyl
or optionally ~ub~tituted (C,-Cl2)-aroyl, or

R and R togother aro -~ ]h~ in w~ch a CEI~ group can
be replaced by O, S, SO, SO~, N-aeyla3~no, N-(Cl-
C,0)-alkoxycarbonyl~m~no, N-(C1-C,)-~lkylimino, N-
(C~-Ca) -cycloallcylimino, N- (C3-C,) -cycloalkyl-
(C~-C~)-alkylimino, N- (C6-C~2) -arylimino, N- (C,-C,6)~
aralkylimino or N-(C~-C,)-alkoxy-(C~-C,)-alkyllmino,
and h i~ from 3 to 7, or by

carbamoyloxy, N- (Cl-C~2) -alkylcarbamoyloxy, N,N-di-(C~
Cl2)-alkylcarbamoyloxy, N-(C3-C~)-cycloalkylcarbamoyloxy,
N-(Cc-C,2)-arylcarbamoyloxy, N-(C,-Cl~)-aralkyl-
carbamoyloxy,N-(Cl-C10)-alkyl-N- (CC-C12) -arylcarbamoyloxy,
N-(Cl-C10)-alkyl-N-(C7-Clc)-aralkylcarbamoyloxy, N-((Cl-C~O)-
alkyl)carbamoyloxy, N-((c~-cl2)-aryloxy-(cl-clo)
-alkyl)carbamoyloxy, N-((C7-Clc)-aralkyloxy-(Cl-ClO)-
alkyl)carba~oyloxy, N-(Cl-C10)-alkyl-N-((Cl-C10)-alkoxy-
(C,-C1~)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((C~-Cl2)-
aryloxy-(Cl-C,0)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-
((C7-Cl6)-aralkyloxy-(Cl-C~0)-alkyl)carbamoyloxy,

amlno, (Cl-cl2) -alkylamlno, di- (Cl-cl2) -alkylamlno, (C3-
C~)-cycloalkylamlno, ~C3-C12) -allcenylamino, (C3-C12)-
alkynylamlno, N-(C~-C,2)-arylamino, N-(C,-Cll)-aral~yl-
amino, N-alkyl-aralkylamlno, N-alkyl-arylamlno, (Cl-Cl2)-
alkoxyamino, (C~-C12) -alkoxy-N-(C,-C,0)-allcyl~ no,

(Cl-C,2)-alkanoylamlno, (C3-C,)-cycloalkanoylamlno, (C,-
C,2)-aroylamlno, (C,-C,c)-aralkanoylamlno, (Cl-Cl2)-alka-
noyl-N-(Cl-C10)-alkylamino, (C3-C,) -cycloallcanoyl-N-(Cl-
C10)-alkylamlno, (Cc-Cl2)-aroyl-N-(Cl-ClO)-alkylamlno, (C,-
C"~-aralkanoyl-N-(C,-C,0)-alkylamlno,

213~866
- 16 -
(C1-C")-alkanoylamino-(C1-C~)-alkyl, (C3-C,) -eyelo-
alkanoylamino-(Cl-C,)-alkyl, (C~-C12) -aroylamino-(Cl-C~)-
alkyl, (C7- C16) - aral~anoylamino-(C1-C~)-alkyl, amino-(Cl-

C10)-alkyl, N-(C1-C1O)-alkylamlno-(C1-C1O)-alkyl~ N,N-di~C1-
C1o)-alkYlamino-(C1-C1O)-alkyl, (C~-C,)-eyeloalkylamlno-
(C1-C10)-alkyl,

(C1-C12)-alkylmercapto, (C1-C12)-alkylsulfi~yl, (C1-Cl2)-
alkylsulfonyl, (C6-C12) -arylmereapto,(C,-C,)-aryl~ulfinyl,
(Cc-Cl2)-arylsulfonyl, (C7-Cl~)-aralkylmorcapto, (C7-Cl6)-
aralkylsulfinyl, (C7-C1~)-aralkyl~ulfonyl,

sulfamoyl, N-(Cl-C10)-alkyl~ulfamoyl, N,N-di-(Cl-C1o)-
alkylsulfamoyl, (C3-Ca)-eyeloalkylsulfamoyl,
N-(C~-C12)-aryleulfamoyl,
N-(C7-C1c)-aralkylsulfamoyl,
N-(C~-C10)-alkyl-N-(C~-Cl2)-arylsulfamoyl, N-(Cl-clo)
alkyl-N-(C7-C1~)-aralkylsulfamoyl,
(C1-C10)-alkylsulfonamldo,
N-((C1-C10)-alkyl)-(Cl-ClO)-alkylsulfonamido, (C7-C~
aralkyl~ulfonamido or N-((C~-C10)-alkyl-(C7-Cl,)-aralkyl-
~ulfonamido, where the radleals whieh ¢ontain an aryl
radieal ean, for their part, bo sub~tituted on tho aryl
by from 1 to 5 ldentieal or differont radioal~ from the
group:
hydroxyl, halogon, eyano, trifluoromethyl, nit~o,
carboxyl, (C1-C12)-alkyl, (C3-C,) -eyeloalkyl, (C3-C,)-
cycloalkyl-(C1-C~2)-alkyl, (C3-C,) -eyeloalkoxy, (C3-C,) -
eycloalkyl- (Cl-C12) -alkoxy, (C3-C,) -eycloalkoyloxy-(C1-C1~
alkyl, (C3-C,) ~-eyeloalkyloxy- (C~-C12) -alkoxy, (C,-c~? -
cycloalkyl-(Cl-C~)-alkyl-(C1-C~)-alkoxy, (C3-C,) -eyelo-
alkyl-(Cl-C,)-alkoxy-(Cl-C~)-alkyl, (C,-C,)-eyeloalkyloxy-
(C1-C,)-alkoxy-(C1-C,)-alkyl, (C3-C~) -eyeloalkoxy-(C1-C,)-
alkoxy-(Cl-C~)-alkoxy, (C~-C12)-aryl, (C7-C1c~-aralkyl,
(C2-C12) -alkenyl, (C2-cl2) -alkynyl, (Cl-cl2) -alkoxy, (C1-
Cl2)-alkoxy-(C1-Cl2)-alkyl, (el-C1~)-alkoXy-(cl-cl2)-
alkoxy, (Cl-C,2)-alkoxy-(C1-C,)-alkoxy-(C1-C,)-alkyl, (C,-
C12)-aryloxy, (C7-C1c)-aral~yloxy, (Cc-Cl2)-aryloxy-(Cl-
C,)-alkoxy, (C7-C1,)-aralkoxy-(C1-Cc)-alkoxy,
.: . .: : ~:,.' ~:
' .:: .. " :::':i:
. . ~ : . , . :~ ~
,; :

213~866
- 17 - -
(Cl-C,)-hydroxyalkyl, (C,-Cl~)-aryloxy-(Cl-C,)-al~yl, (C7-
Cl~)-aralkoxy-(C,-C,)-alkyl, (C~-Cl2~-aryloxy-(Cl-C~)-alkoxy-
(Cl-C6) -alkyl, (C,-Cl,)-aralkyloxy-(Cl-C~)-alkoxy-(~l-C~
alkyl, -O-[CH~]~-CrH~ )F~, -OCF,Cl~ -OCF,-CHFCl, -~
:: .
(Cl-Cl~)-alkylcarbonyl, (C3-C,)-cycloal~ylcarbonyl, (C,-
Cl,)-arylcarbonyl, (C7-Cl~)-arallcylcarbonyl, ;

(Cl-Cl~)-alkoxycarbonyl, (Cl-Cl,)-alkoxy-(Cl-Cl2)-alkoxy-
carbonyl, (C~-Cl~)-aryloxycarbonyl, (C7-C~ ralkoxycarb-
o~yl, (C3-C~)-cycloalkoxycarbonyl, (C,-C1,)-alkonyloxy-
10 carbonyl, (C,-C12) -alkynyloxycarbonyl, (C~-C12) -aryloxy-
(Cl-C~)-alkoxycarbonyl, (C7-Cl~)-aralkoxy-(Cl-C~)-alkoxy-
carbonyl, (C3-C,)-cycloalkyl-(Cl-C,)-alkoxycarbonyl,
(C3-C~)-cycloalkoxy-(Cl-C~)-alkoxycarbonyl,
(Cl-Cl,)-alkylcarbonyloxy, (C3-C,)-cycloal~ylcarbonyloxy, ~;~ s
15 (C~-Cl,)-arylcarbonyloxy, (C7-C1~)-aral~ylcarbonyloxy, :~
cinnamoyloxy, (C,-Cl,)-alkonylcarbonyloxy, (C~-Cl,)~
alkynylcarbonyloxy,
. ~ !
(Cl-Cl~)-alkoxycarbonyloxy, (Cl-Cl~)-alkOxy- (Cl~Cla) ~
alkoxycarbonylcxy, (C~-Cl~)-aryloxycarbonyloxy, (C7-C
20 aralkyloxycarbonyloxy, (C3-C~)-cycloalkoxycarbonyloxy, :~
(C,-Cl,)-alkonyloxycarbonyloxy, (C,-Cl2)-allcynyloxy~
carbonyloxy, :~

carbamoyl, N-(Cl-Cl~)-alkylcarbamoyl, N,N-dl-(Cl-C1,)- ... :. ~
alkylcarbamoyl, N-(C3-C,)-cycloalkylcarbamoyl, N,N-di- : ;;
cyclo-(C3-C,)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C,)-
cycloalkylcarbamoyl, N-((c3-c!)-cycloalkyl-(cl-c~
alkyl)carbamoyl, N-(Cl-C~)-alkyl-N-((C3-C,)-cycloalkyl-
(Cl-C~)-alkyl)carbamoyl, N-(l)-dehydroabietylcarbamoyl, : ,
N-(Cl-C~)-alkyl-N-(~)-dehydroabletylcarb~moyl, N-(C~-C1,~
30 arylcarbamoyl, N-(C7-C1~)-aralkylcarbamoyl, N-(Cl-Clo)- ; ;:~ ::
alkyl-N-(C~-Cl~)-arylcarbamoyl, N-(Cl-Cl0)-al~yl-N-(C7-
Cl~)-aralkylcarbamoyl, N-((cl-clo)-alkoxy-(cl-clo)
alkyl)carbamoyl, N-((c~-cl~)-aryloxy-(cl-clo)-
alkyl)carbamoyl, N-((C7-C1~)-aral~yloxy-(C1-C10)-
alkyl)oarbamoyl, N-(Cl-C~0)-alkyl-N-((C1-C10)-alkoxy~

': ~ '
:

- 213~866 ` ~:
- 18 -
(C1-C10)-alkyl)carbamoyl, N-(cl-clo)-al~yl-N-((cc-cl2) -
aryloxy-(C,-C10)-al~yl)carbamoyl, N-(C,-C10)-al~yl-N-((C,- .
Cl6)-aralkyloxy-(Cl-C10)-al~yl)carbamoyl, CON(CH2)~, ln . :
which a CH2 group can be replac~d by O, ~, N-(C1-C,)-
alkylimino, N-(C,-C,)-cycloalkylimino, N- (C3-C,) -cyclo-
alkyl-(C,-C~)-alkylimino, N-(C~-C12)-aryl~m~no, N-(C~-C1~)-
aralkylimino or N-(C1-C~)-alkoxy-(C1-C~)-al~ylimi~o, and h
i8 from 3 to 7,

carbamoyloxy, N-(C1-C")-alkylcarbamoyloxy, N,N-di-(C1-
C1~)-alkylcarbamoyloxy, N- (C3-C,) -cycloal~ylcarbamoyloxy,
N- (C6-cl6) -arylcarbamoyloxy, N-(C,-Cl~)-aralkyloarbamoyl-
oxy, N-(Cl-C10)-alkyl-N- (C6-C12) -aryl~arba~oyloxy, N-(C~
C~0)-alkyl-N- (C7-ClC) -aralkylcarbamoyloxy, N-((Cl-clo)
alkyl)carbamoyloxy, N-((C,-Cl~)-arYlXY-(cl-clo)- :; :~
alkyl)carbamoyloxy, N-((C,-Cl,)-aralkyloxy-(C1-C10)-
alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((Cl-ClO)-alkoxy-(Cl- ::~
C10)-alkyl)carbamoyloxy, N-(cl-clo)-alkyl-N-((cc-cL~) - : .
aryloxy-(Cl-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-
((C7-C1~)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, . - .

20 amlno, (Cl-C1,)-alkylamino, d~-(C1-C1~)-alkylamino, (C3-C,) -:~
cycloalkylamino, (C3-Cl,) -al~onylamino, (C3-C~) -alkynyl-
amino, N-(C,-C1,)-arylamino, N-(C7-C11)-aralkylamlno,
N-alkyl-aralkylamino, N-alkyl-arylamino, (Cl-C1,)-
alkoxyamlno, (C1-C1,)-alkoxy-N-(C1-C10)-alkyl~no,

(C1-C")-alkanoylamino, (C3-C,) -cycloalkanoylamino, (C~
Cl~)-aroylamino, (C,-Cl,)-arallcanoylamino, (Cl-Cl~)-alka- .,'. ::~
noyl-N-(C1-C10~-alkylamino, (C3-C,) -cycloalkanoyl-N-(cl-
C10)-alkylamino, (C,-C1,)-aroyl-N-(C1-C10)-alkylamino, (C,-
C11)-aralkanoyl-N-(Cl-C10)-alkylam~no, i; ~ ;

(C1-C1,)-alkanoylamino-(C1-C,)-alkyl, (C,-C~)-cyclo-
alkanoylamino-(C1-C~)-alkyl, (Cc-C1,)-aroylamino-(C1-C~)- : .- .::.:i::.. :
alkyl, (C,-C1c)-aralkanoylumino-(Cl-C,)-alkyl, amino-(C1-
C10)-alkyl, N-(C1-C10)-alkylamino-(Cl-ClO)-alkyl, N,N-di-
(cl-clo)-alkylamino-(cl-clo)-alkyl~ ( C3 - C,) - cycloalkyl-
35 ~mino-(C1-C10)-alkyl, ~ :
- ~', :~'' ~:., '

! ',, "' ., .. ' ', ~: '

213~866
- 19 -
(Cl-C12)-alkylmercapto, (Cl-C~ alkylsulfinyl, (C~-C~
al~ylsulfonyl, (C6-Clc)-arylmercapto, (C~-C1,)-aryl-
sulfi~yl, (C~-C")-arylsul~onyl, (C7-C")-aralkylmercapto,
(C7-C1~)-aralkyleulfinyl or (C7-C~)-aralkyl~ulfonyl, and

R~ i~ R", providod that Q ha~ the m~aning of NR', where
R~ and R" aro identical or difforent and ar~ hydro-
gon, (C,-Cl,)-aryl, (C7-Cl)-aral~yl, (C1-C~)-alkyl,
(~1~C~)-alkoxy-(Cl-c~)-alkyl~ (C7-Cl~)-aral~oxy-(C,- ~ 8
C~)-alkyl, (C~-C,2)-aryloxy-(C1-C~)-al~yl, (Cl-C~0)-
alkanoyl, optionally ~ubstitut-d (~7-C1,)-aralkanoyl
or optionally sub~titut-d (C~-C12) -aroyl, or

R' and R" togothor are -~CH,lh, in which a CH~ group
can be roplacsd by 0, S, N-acylimino or N-(C1-C~o)~
alkoxycarbonylimino, and ~`;

f i3 l to 8,
g is 0 or 1 to (2f~
x i~ 0 to 3,
h i8 3 to 7,

lncludlng tho physiologically act$ve ~alts, ~ ;
with 3-bonzyloxypyridine-2-carboxyllc acid (L-throonyl)-
amido and 3-benzyloxypyrldine-2-carboxylic aoid ((Fmoc-
Phg)L-threonyl)amlde hydrochlorlde being xcept-d.

In general, aryl is understood to mean carbocyclic and
hoterocycllc aromatlc ring ~ystems. In partlcular, it ~8 ;
under~tood to lnclude phenyl-substituted, blphonyl-
~ubstltuted, naphthyl-~ubstltut~d or un~ubstituted 5- and
6-membered heteroaromatlc rlngs havlng 1, 2 or 3 nltrog-n
and/or oxygen and/or ~ulfur atoms, 8uch as dQrlvatlv~ of
pyrldyl, pyrldazyl, pyrimldyl, pyrazyl, imldazolyl, ; ~ -
triazolyl, thlenyl, oxazolyl and thiazolyl, and their
benzo-fu~od derivative~

The inv~ntion also mbraces salts of the compounds of th~
formula I.

:: .

213~866
- 20 -
The formation of ~alt~ w~th ba~io reagento can take place
once, twice or three times on th~ acidio groups of tho
compounds of the formula I (i - radicals B, Rl, R~, R3
and R~), in particular on tho radicals B, R' and/or R~

Examples of reagonts boing usod are nlcoholat~, hy-
droxides, carbo~ates, hydrog n carbonatos! hydrogon
phosphates, organometallic compounds of tho alkali and
alkaline earth element~, the elements of the third and
fourth main group~ of tho period~c systom, and tho
elements of the transition met~l~

amines, optionally substituted 1 to 3 times by (C,-C,)-
hydroxyalkyl, (C,-C~)-alkoxy-(C,-C,)-alkyl, phenyl, benzyl
or (C,-C,)-alkyl, which oan be substituted 1 to 3 t~mes
by hydroxyl or (Cl-C~)-alkoxy, for example tromethane
(Tri~ buffer), 2-aminoethanol, 3-aminopropanol,
hydroxylamine, dimothylhydroxylamin-, 2-methoxy~thyl-
amine, 3-ethoxypropylamine, and
ba~ic amino ac~d~ and amlno dorlvative~, ~uoh a~ amino
acid ester~, hl~tidlne, arginine and lysi~e, and their
derivatives, and also
"" '.: '"' ' ;'~'
pharmaceuticals which contain a baslc group, such as, for
xample, ~Amiloride, ~Verapamil and beta blocker~
~ - ,. ::: ;j ,- ..~:,
The lnventlon al~o r~lates to the compounds according to
formula I, plus 3-b-nzyloxypyrldlne-2-carboxyllc acld (L-
threonyl)amld~3 and 3-bsnzyloxypyridine-2-carboxylic aoid
((Fmoc-Phg)L-thr~olnyl)~mido hydrochlorldo for uco as
pharmaceutlcal~
..` ,~ :
Compound~ of the formula I are of great int-r-~t, ln
whlch
30 Q ~ 0, ~, NR' or a bond,
X 18 0, ~
Y 1~ CR3 or, ;
lf R~ and Rl form a cycle,
Y 1~ N or CR3,

,
:: .

213~866
- 21 -
m i8 0 or 1

Compounds of tho formula I are vory lmportant, in whieh
Q is 0, NR' or a bond,
X is 0

5 Compound~ of the formula I aro al~o very lmportant in
which Q is 8 and X i~ 0 ~ ~ ;

Compounds of tho formula I aro of particular importa~ee
in whieh
Q i~ 0, NR' or a bond, ;;, ~ `
1 0 X i 8 0,
Y is CR3 or, if R' and R' form a eyelo, N or CR3,
m is 0 or 1,

A i~ (Cl-C3) -allcyleno whieh is opt~ onally substitutod
once by halogon, eyano, trifluoromethyl, (Cl-C,)~
alkyl, (Cl-C6)-hydroxyallcyl, (Cl-C,)-alkoxy or -0-
[C}~2~"--Cf~It,f,l ~F~" or

A is -CHR5-, whero R5 18 onts of the ~ub~tituents of
the a-ear}~on atom of an a-amino aeld, in partieular ~ ;
of a natural L-amino acid and of its D-isom r,

B i8 C0~%,
:.
R2 is hydrogon, (Cl-C,0)-alkyl, (C,-C,0)-alkonyl, (C,-
C,0)-alkynyl, (Cl-C~O)-alkoxy, (C,-C,0)-allcenyloxy,
(C2-C,O) -alkynyloxy, r-tinyloxy, (Cl-C~0) -alkoxy- (Cl-
C3) -alkyl, (C,-C,0~ -allc-nyloxy- (C1-C~) -alkyl,
retinyloxy- (Cl-C~) -alkyl, (C,-C,0) -alkynyloxy- (Cl-
C~)-alkyl, halogen, eyano, trifluoromethyl, (Cl-C~
hydroxyalkyl, (Cl-C,0)-alkanoyl, (C7-Cl~)-aralkanoyl,
(C~-Cl~) -aroyl, (C~-Cl2) -aryl, (C7-Cl~) -arallcyl,
~O~ ~CH2~"-CrH~t.~l s"F", N}~'Rn, (Cl-C1O) -alkylm-rcapto,
(Cl-C10)-alkyl~ulfiDyl, (Cl-C10)-alkylsul~onyl, (C~
Cl,)-arylm~rcapto, (C~-Cl,)-arylsulflnyl~ (C,-Cl,)-
arylsulfonyl, (C7-Cl,)-arallcyl~oreapto,
'.,''' ~'''',''~'''.,''

:: :: :;: :.::, . . :,:

2l3~s6e
- 22 -
(C7-Cl~)-aralkylsulfinyl, (C7-C~2)-aralkylsulfonyl,
(Cc-cl2)-aryloxy~ (C7-CI6)-aralkyloxy, earboxyl, (Cl-
C20)-alkoxycarbonyl, (Cl-Cl2)-alkoxy- (Cl-Cla) -alkoxy-
carbonyl, (C,-Cl2)-aryloxycarbo~yl, (C7-Cl~ ral-
koxycarbonyl, (C,-C,)-eycloalkoxyearbonyl, (C,-
C20)-alkonyloxycarbonyl, r~tinyloxycarbonyl,
(C2-C20)-alkynyloxycarbonyl, (C3-C,) -cyeloalkyl-(Cl-
Cc)-alkoxycarbonyl, (C,-C~)-eyeloal~oxy-(Cl-C~
alkoxyearbonyl, (C~-C32)-aryloxy-(Cl-C~)-alkoxy~
carbonyl, (C,-C16) -aralkoxy-(C1-C~)-alkoxyearbonyl,

earbamoyl, N-(C1-Cl2)-alkylearbumoyl, N,N-di-(C,-Cl2)~
alkylearbamoyl, N- (C3-C,) -eyeloalkylearbam~yl, N,N-
dieyelo (C3-C,) -alkylearbamoyl,N-(Cl-Cl0)-al~yl-N- (C3-
C,)-eyeloal~ylearbamoyl, N- (C3-C,) -eyeloalkyl-(C -C~
alkyl)earbamoyl, N-(cl-c~)-alkyl-N-((c3-c~) -eyelo-
alkyl-(Cl-C~)-alkyl)earbamoyl, N-(l)-dehydroabietyl-
carbamoyl, N-(Cl-C~)-alkyl-N-(~)-dehydroab~otyl~
earbamoyl, N-(C~-C1,)-arylcarbamoyl, N-(C,-C")-
aralkylcarbamoyl, N-(Cl-Cl0)-alkyl-N-(C~-Cl~)-aryl-
carbamoyl, N-(Cl-Cl0)-alkyl-N-(C7-Cl~)-aralkylcar-
bamoyl, N-((Cl-Cl2)-alkoxy-(C -Cl0)-alkyl)earba_oyl,
N-((C~-C1~)-aryloxy-(Cl-Cl0)-alkyl)earbamoyl, N-~(C,-
Cl~)-aralkyloxy-(C1-Cl0)-alkyl)earbamoyl, N-(Cl-C1o)~
alkyl-N-((Cl-Cl0)-alkoxy-(Cl-C10)-alkyl)earbamoyl, N-
(Cl-Cl0)-alkyl-N-((C,-C1,)-aryloxy-(Cl-Cl0)-
alkyl)earbamoyl, N-(cl-clo)-alkyl-N-((c7-cl~)
aralkyloxy-(C1-C10)-al~yl)earbamoyl, CON(CE~)~, in
whieh a C~2 group ean be replaeed by O, S, N-(C1-C,)-
alkylimlno, j N! ~C3-C,) -eyeloalkylimino, N- (C3-C,) -
eyeloalkyl-(C1-C~)-alkylimino, N-(C~-C1~)-aryllmlno,
N- (C7-C~) -aralkyllmlno or N-(C1-C~)-alkoxy-(C1-C,)-
alkyllmino, and h i~ from 3 to 7,
.
, .., ~ .
where aryl i~ ~ub~tltut-d in tho manner a- defined for
and R',
5 R1 and R3 are idontleal or difforont and are hydrogen,
halogen, (C1-C1,)-alkyl, (C1-C~2)-alkoxy, -O-[C~ -C~

213~66
- 23 -
~, (c~-cl2)-alkoxy-(cl-cl2)-al~yl, (~-C~
alkoxy- (C~-C12) -alkoxy, (C,-C,2) -alkoxy-(C~-C~
alkoxy-(C2-C~)-alkyl, (C7-C~) -aralkyloxy, (C3-C,) -
cycloalkyl, (C3-C,) -cycloalkyl-(C,-C,)-alkyl, (C3-
C~)-cycloalkyloxy, (C3-C,) -cycloal~yl-(C~-C~)-alkoxy,
(C3-C,) -cycloalkyloxy-(C,-C,)-~l~yl, (C~-C,)-cyclo-
alkyloxy-(C,-C~)-alkoxy, (C,-C,)-cycloal~yl-(C~-C,)-
alkyl-(C,-Cc)-alkoxy, (C3-C,) -cycloalkyl-(C~-C~
alkoxy-(C,-C~)-alkyl, (C3-C,) -cycloalkoxy-(C~-C~
alkoxy-(C,-C,)-alkyl, NRYRZ, (C,-C,)-alkylm rcapto,
(C,-C,)-alkyl~ulf~nyl or (C~-C,)-alkyl~ulfonyl, (C,-
Cl~)-arylmercapto, (C,-C")-aryl~ulfinyl, (C~-C
arylsulfonyl, SCj-C")-aralkylmercapto, (C7-C
aralkyl~ulflnyl, (C7-C,l)-aralkyl~ulfonyl,
oubstituted (C~-Cl2)-aryloxy-(C,-C~)-alkyl, (C7-C
aralkoxy-(C1-C6)-alkyl, (C~-Cl~)-aryloxy-(C~-C~
alkoxy-(C,-Cc)-al~yl, (C7-Cl~)-aralkyloxy-(C,-Cs)-
alkoxy-(C,-C~)-alkyl, (C,-C1,)-aryloxy, (C7-C,1)~
aralkyloxy, (C6-C12)-aryloxy-(C1-C~)-alkoxy or (C7-
C~)-Aralkoxy-(C~-Cc)-alkoxy, wh-ro an aromatic
radical carrie~ by 1, 2, 3, 4 or 5 idontical or
difforont sub~tituont~ from tho group hydrogen,
halogon, cyano, nitro, trlfluoromothyl, (C,-C
alkyl, (C,-C,6) -alkonyl, (C,-C6) -hydroxyalkyl, (C
C16) -alkoxy, (C,-C,6) -alkonyloxy, -O-[CH~]~-C~H~ F~
-OCF~Cl, -O-CF~-CHFCl, (C,-C,)-alkylmorcapto, (C~-C6)-
alkylsulfinyl, (C~-C6) -alkyl~ulfonyl, (C,-C~)-al~yl-
carbonyl, (C,-C6)-alkoxycarbonyl, carbamoyl, N-
(C,-C~)-alkylcarbamoyl, N,N-di-(C~-C~)-alkyl-
carbamoyl, (Ç~-C~)-alkylcarbonyloxy, (C,-C~)-cyclo-
alkylcarbamoyl, ph-nyl, bonzyl, phenoxy, benzyloxy,
NRYRZ, phonylmorcapto, phonylculfonyl, ph~nyl-
~ulfinyl, ~ulfamoyl, N-(C,-C~)-alkyloulfamoyl or N,N-
di-(C,-C~)-alkylsulfamoyl, or optionally carrie~ up
to 3 of tho abovomontloned ldontlcal or diffor-nt
~ub~titu~nt~, and two ad~acont carbon atom~ of th~
aralkyloxy radical togethsr carry a chaln-tCH~
and/or -CH=C~-CH3C~-, whero a C~ group of tho chaln
1~ optionally roplaced by O, S, SO, SO, or NR',

213~86B
- 24 -
R~ and R2 or Rl and R3 form a chain [CH~o~ where o is 3,
4 or 5, or

form, together wlth the pyridine or pyridazine
carryi~g thQm, a einnollns ring, a quinollno ring or
an lsoquinoline ring,

R~ i~, if Q is a bond, fluorine, chlorine or bro~ino,
or, if Q is 0 or NR', a branehod or unbranehod (C~
C20) -alkyl radieal, wh~eh can eontain up to 3 C-C
multiple bonds, u~ uneubetitutod ~aturatod fluoro-
alkyl rndical of the formula tC~2]~-Ct~(2~ F~, a
(C6-Cl,)-aryl radieal or a (C7-Cl,)-aralkyl radieal,
which can contain up to 2 C-C multiple bonds $n tho
alkyl chain, or an h~toroaryl rad$cal or an het~ro-
aryl alkyl radical, whero these radieals are ~ubsti-
tutod by one or ro radicals from the group
~ydroxyl, fluorine, ehlorine, eyano, tri~luoro-
methyl, earboxyl, (Cl-Cl,)-alkyl, (C3-C,) -cyeloalkyl,
(C3-C,) -cyeloalkyl-(Cl-Cl~)-alkyl, (C3-C,) -eyelo-
alkoxy, (C3-C,) -cyeloalkyl-(Cl-Cl2)-alkoxy, (C3-C,) -
cycloalkyloxy-(Cl-Cl,)-alkyl, (C3-C,) -eyeloalkyloxy-
(C,-C12)-alkoxy, (C3-C,) -eyeloalkyl-(Cl-C,)-alkyl-(Cl-
C6)-alkoxy, (C~-C,)-eyaloalkoxy-(Cl-C,)-alkoxy-(Cl-
C,)-alkoxy, (C~-Cl2)-aryl, (C7-Cl~)-aralkyl, (C~-Cl,)-
alkenyl, (C2-Cl2)-alkynyl, (Cl-C")-alkoxy, (Cl-Cl2)-
alkoxy-(C,-Cl2)-alkoxy, (Cl-Cl,)-alkoxy-(Cl-C~
alkoxy-(Cl-C,)-alkyl, (C~-C12) -aryloxy, (C,-C
aralkyloxy, (C~-C12) -aryloxy-(Cl-C~)-alkoxy, lC7-
C16) -aralkoxy-(Cl-C~)-alkoxy, (Cl-C,)-hydroxyalkyl,
-0-lCH2.~-c~H~2~ )F~

(Cl-C12) -alkylearbonyl, (C,-C,)-eyeloalkylearbonyl,
(C6-C12) -aryloarbonyl, (C7-Clc)-aralkylearbonyl,

(Cl-C12) -alkoxyearbonyl, (Cl-cl2) -alkoxy- (Cl-c12) -
alkoxyearbonyl, (C6-C~2)-aryloxyearbonyl, (C7-Cl,)-
aralkoxycarbonyl, (C~-C~)-¢yeloalkoxyearbo~yl, (C2-
Cl2)-alkonyloxyearbonyl, (C2-Cl2)-alkynyloxyearbonyl,

213~86G
- 25 -
(C3-C,) -cycloalkyl-(Cl-C~)-alkoxycarbonyl,

(Cl-Cl,)-allcylcarbonyloxy, (C~-C,)-cycloalkyl-
carbonyloxy, (C~-C12) -arylcarbonyloxy, (C,-C~
aralkylcarbonyloxy, carbamoyl, N-(Cl-Cl2)-allcylcar- ~ -
bamoyl, N,N-d~-(Cl-Cl2)-alkylcarbamoyl, N- (C3-C,) -
cycloalkylcarbamoyl, N,N-dicyclo- (C3-C,) -alkyl-
carbamoyl, N-(Cl-Cl0)-alkyl-N-(C,-C,)-cyoloallcylcar-
b a m o y l, N - ( ( C 3 - C, ) - c y c l o a l k y l - ( Cl- C~
allcyl)carbamoyl, N-(Cl-C,)-alkyl-N-( (C3-C,) -cyelo-
alkyl-(C1-Cc)-alkyl)carbamoyl, N-(l)-dehydroabiotyl-
carbamoyl, N-(Cl-C~)-allcyl-N-(I)-dohydroabietyl-
carbamoyl, N-(C~-Cl,)-arylcarbamoyl, N- (C7-Cl~) -
aralkylcarb~moyl, N-(Cl-Cl0)-alkyl-N-(C~-Cl~)-aryl-
carbamoyl, N-(Cl-ClO)-alkyl-N-(C,-Cl,)-aralkylcarba-
moyl, N-((Cl-Cl0)-alkoxy-(Cl-Cl0)-alkyl)carbamoyl, N-
((C~-Cl~)-aryloxy-(Cl-Cl0)-alkyl)carbamoyl, N-((C,-
Cl~)-aralkyloxy-(Cl-C,0)-alkyl)carbamoyl, CON(CHl)~ ln
whlch a CH2 group can be replaced by O, N-(Cl-
C~)-alkyllmino, N-(C3-C8)-cycloalkylimino, N- (C3-C,) -
cycloalkyl-(Cl-C~)-alkylim~no, N-(C~-Cl,)-arylimino
or N- (C7-Cl~) -aralkylimino, and h 18 from 3 to 6,

where the radlcals which contain an aryl radlcal
aan, for th-lr part, be ~ub~ltutesd on tho aryl by
from 1 to 5 ldontlcal or dlfferent radlcal~ from tho ;~ r "~ ''''~'
groups

hydroxyl, fluorine, chlor~ne, cyano, trlfluoro-
methyl, carboxyl, (Cl-Cl~)-alkyl, (C3-C,) -cyeloalkyl,
(Cl-C~)-alkoxy, (C3-C~)-'cycloalkoxy, (C~-Cl2)-alkoxy- ,.
earbonyl, ~ ~

N-(Cl-C~)-alkylcarbamoyl, N,N-d~-(C1-C~)-alkyl- ~ ~ ~'',' ';''''~J'','
carbamoyl or N- (C3-C,) -cycloalkylcarbamoyl, and

R~ 1~ R, provided Q ha~ tho m-aning o~ NR', whoro R'
and R~ aro id-ntlcal or difforent and are hydrog-n, ;
(Cl-C,)-alkyl, or (C,-Cll)-arallcyl which i~ optlonally

213~866
- 26 -
substituted onco by fluor~ne, chlorine or (C,-C,)- . ;~ ~ ~
alkoxy, ~ ~ .

RY and R~ are identical or difforent and are hydrogon,
(C~-C~ aryl, (Cl-C~0)-alkyl, (C~-C10)-cycloal~yl,
(C,-C,)-alkoxy-(C,-C~)-alkyl, (C7-cl2) -aralkoxy-(Cl- ~;~
C,)-alkyl, (C,-Cl,)-aryloxy-(Cl-C,)-alkyl, (Cl-C10)-
alkanoyl, optionally substituted (C,-Cl,)-aral~anoyl
or optionally sub~tituted (C,-Cl,)-aroyl, or

RY and R~ together are -[CH,~, in which a CH, group can
be replaced by O, S, N-(Cl-C~)-alka~oylimlno or N-
(Cl-C~)-alkoxycarbonylimlno, and ~ -

f is l to 8, ~ ~
g is 0 or 1 to (2f ~ 1), -:; ;~:.::;.. ~-.. ~.
h is 3 to 6,
15 x is 0 to 3, and
n is 3 or 4.

Compound~ of the formula I are preferred in whlch
Q i~ O, NR' or a bond,
X is O,
20 Y is CR3 or, if Rl and R' form a cycle, N or CR',: ; -
m io 0, ~ :

A i~ (Cl-C3)-alkylene which i~ optionally ~ubstituted
once by halogen, cyano, trlfluoromethyl, (Cl-C6)-
alkyl, (C,-C6~-hydroxyalkyl, (Cl-C6)-alkoxy or
-O-lC~,]X-Ct~ F~ or : ::
: I ' ` ~ ! ' ~ .
A i~ -C~R5-, where R5 is one of the substituent~ of th-
a-carbon atom of an a-amino acid, ln partioular of
a natural ~-amino aoid and of it~ D-lsomor,
: :-

. ~, ":.. ,:
B is CO,H
:. . :,: ,. : ~, ~:
30 R' is hydrogen,.(Cl-C20)-alkyl, (Cl-C,0)-alkonyl, (C,- ::
C20)-alkenyloxy, (C2-C20)-nlkynyloxy, retinyloxy,
'''' "'''.'~"'"

213~866 ~ ~ ~
- 27 -
(Cl-Cl0)-alkoxy-(C,-C,)-alkyl, (C,-C,0)-alkoxy-(C,-
C3) -alkyl, (C~-C20)-al~enyloxy-(C~-C~)-alkyl,
retinyloxy-(C~-C~-alkyl, (C2-C~o) -alkynyloxy-(C~
C,)-alkyl, (C1-C,0)-alkoxy, haloge~, eyano,
trlfluoromethyl, (C~-C")-hydroxyalkyl, (C~-C~0)-
alkanoyl, (C7-C~2)-aralkanoyl, (C~-C~)-aroyl,
-O-tCH~-C~(s~ F~, Na~a~ (cl-clo) -al~ylmor¢apto,
(C~-C~0)-al~yleulf~nyl, (C~-C~)-al~ylsulfonyl, (C~
C~2)-arylmercapto, (Cc-C~)-arylsul~y}, (C~-C~2)-
aryl~ulfonyl, (C~-C~aralkylmoseapto, (C7-C")-
aralkyleulfinyl, (C7-C,2)-aralkyl~ulfonyl, (C,-C~
aryloxy, (C,-C~)-aral~yloxy, earboxyl, (C,-C,0)-
alkoxyearbonyl, (C,-C~2)-alkoxy-(C,-C~
alkoxyearbonyl, (C~-Cl,)-aryloxyearbo~yl, (C,-C")-
aralkoxycarbonyl, (C3-C,) -cycloalkoxycarbonyl, (C2-
C,0)-alkenyloxycarbonyl,retinyloxycarbonyl, (C~-C20)-
alkynyloxyearbonyl, (C3-C~) -cyeloalkyl-(C~-C~
alkoxycarbonyl, (C3-C,)-~ycloalkoxy-(C~-Cc)-
alkoxycarbonyl, (C,-C1,)-aryloxy-(C,-C~)-alkoxy-
carbonyl, (C7-C,c)-aralkoxy-(C,-C,)-alkoxycarbonyl,
carbamoyl, N-(Cl-C")-alkylearbamoyl, N,N-di-(C,-CL,)-
alkylcarbamoyl, N-(C3-C~)-cycloalkylearbamoyl, N,N-
dicyclo(C3-C~)-alkylearbamoyl,N-(C~-C~0)-alkyl-N-(C3-
C~)-cycloalkyl¢arbamoyl, N-(C3-C~)-cyeloalkyl-(C,-Cc)-
alkyl)carbamoyl, N-(C,-C,)-alkyl-N-((C3-C,)-cyclo-
alkyl-(C~-C~)-alkyl)carbamoyl, N-(~)-dohydroabiotyl-
carbamoyl, N-(C,-C,)-alkyl-N-(I)-dehydroabiotyl-
carbamoyl, N-(C~-C~ arylcarbamoyl, N-(C,-C~
aralkylcarbamoyl, N-(Cl-C,0)-alkyl-N-(C,-C~,)-aryl-
carbamoyl! N-lC1-C~0)-alkyl-N-(C,-C~2)-aralkylcarb-
amoyl, N-((C,-C")-alkoxy-(C,-C,0)-alkyi)carbamoyl, N-
((C~-C~,)-aryloxy-(C,-C~0)-alkyl)carbamoyl, N-((C7-
C~)-aralkyloxy-(C,-C,0)-alkyl)carbamoyl, N-(C1-C~o)~
alkyl-N-((C~-C,0)-alkoxy-(C~-C~O)-alkyl)earbamoyl, N-
(C,-C,0)-alkyl-N-((C,-C")--ryloxy-(C,-C~O)-
alkyl) carbamoyl, N- (C,-C,0) -alkyl-N- ( (C,-C~
- aralkyloxy- (C,-C,O) -alkyl) carbamoyl, or CON(Cl!I,)h, ln
whlch a CH~ group can be replaced by 0, S, N- (Cl-C,) -
alkylimino, N- (C3-C,) -cycloalkyllmlno,

213~66
- 28 -
N-(C3-C~)-cycloallcyl-(C1-C4)-allcyl~m~no, N- (C6-C~
aryl~mino, N- (C,-C16) -aralJcyl~m~no or N-(C1-C4)-
alkoxy-(Cl-Cc)-alkyl~m~no, and h i~ from 3 to 6,

wherQ aryl ls ~ubstituted Jn tho mannQr aEI dof~ned for
and R3,

Rl and R3 are ident~cal or diff~r-nt and are hydrogen,
halogen, (Cl-Cl,)-alkyl, (C1-C~)-alkoxy,
-O- lCEI~]J-C~ al~l~ (cl-cl~) -alkoxy-(C1-Cl,)-allcyl,
(Cl-C,)-alkoxy-(Cl-Cl,)-alkoxy, (Cl-Cl,)-alkoxy-(C,~
C~)-alkoxy-(C~-C6)-alkyl, (C7-C 1) -~ralkyloxy, (C3-
C~)-cycloalkyl, (C3-C~)-cycloalkyl-(C1-C~)-al~cyl,
(C3-C,) -cycloallcyloxy, (C3-C,)-cycloalkyl-(Cl-C,)-
alkoxy, (C3-C~)-cycloalkyloxy-(Cl-C~)-alkyl, (C3-C,)-
cycloalkyloxy-(Cl-C,)-allcoxy, (C3-C,)-cycloallcyl-(Cl-
C6) -alkyl-(Cl-C~)-alkoxy, (C3-C,)-cycloalkyl-(Cl-Cc)-
alkoxy- (C,,-C6) -allcyl, (C3-C,)-cycloallcoxy-(Cl-cc)-
alkoxy-(Cl-C~)-alkyl, NRYRZ, (Cl-C,)-alkylmercapto,
(C,-C,)-allcyl~ulfinyl or (Cl-C,)-alkylsulfonyl, (C,-
Cl,)-arylmercapto, (C,-Cl,)-aryl~ulfinyl, (C,-Cl2)-
aryl~ulfonyl, (C,-Cl,)-aralkylmercapto, (C,-Cl,)-
aralkylsulfinyl, (C,-Cll)-aralkylsulfonyl,
sub~t~tutod (C6-Cl,)-aryloxy-(Cl-C,)-alkyl, (C,-Cll)-
aralkoxy-(Cl-C~)-alkyl, (C~-C1~)-aryloxy-(Cl-C~
alkoxy-(C1-C~)-alkyl, (C7-C~l) -aralkyloxy-(C1-C~
alkoxy-(Cl-C,)-alkyl, (C,-Cl2)-aryloxy, (C7-C~
aralkyloxy, (C,-Cl,)-aryloxy-(Cl-C,)-alkoxy or
(C,-Cll)-aralkoxy- (Cl-C6) -alkoxy, where an aromatic
radical carri~ by 1, 2, 3, 4 or 5 identlcal or
different sub~tituQnt~ from the group hydrogen,
halogen, cyano, nitro, trifluoromothyl, (Cl-Cl~
alkyl, (Cl-Cl,)-alkonyl, (Cl-C,)-hydroxyalkyl,
(Cl-Cl,) -alkoxy, (Cl-Cl,) -allc-nyloxy,
--[CH~]x~CtH(~ F~ -OCF,Cl, -O-CF,-CHFCl, (C1-C,)-
alkylmercapto, (Cl-C6)-alkyl~ulfinyl, (Cl-C~)-alkyl-
~ulfonyl, (Cl-C,)-alkylcar}~onyl, (Cl-C,)-alkoxy-
carbonyl, carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,N-
di-(Cl-C~)-alkylcarba~oyl, (Cl-C,)-alkylcarbonyloxy,

., .,, .: .,

213~86G

- 29 -
(C~-C~)-cycloalkylcarbamioyl, phenyl, b~zyl, phonoxy,
benzyloxy, NRYR~i, phenylmercapto, phonylsulfonyl,
phenylsulfinyl, sulfamoyl, N- (C1-C,) -alkylsulfamoyl
or N,N-di- (Cl-C~) -all~ylsulfamoyl, or optlonally
carries up to 3 of tho abovementloned ide~lt~ cal or
difforent eubstituents, and two ad~acsnt carbon
atoms of the aralkyloxy radlcal togeth~r carry a
chain -tCH,-~ and/or -C~l.CEI-CE~.C~I-, whero a C~l~ group
of the chain ~8 optionally roplacod by 0, S, SO, SO, : ~ -
or NRY,

Rl and R' or R2 and R3 can form a chain tC~,] O~ whore o i8 :
3, 4 or 5, and :
",
R4 , provided Q is a bond, is chlorine os, if Q i~3 0 or
NR~, is a branched or u~branchsd (Cl-C10)-allcyl
radical, which can contain one or two C-C multlple ~ ~
bonds, or an unsubstituted fluoroalkyl radical of - :::
the formula - LcH2]~,-c~ 2~ y~F~ or (Cl-C,) -alkoxy- (C~
Cc) -alkyl, (Cl-C,) -alkoxy- (C1-C~) -alkoxy- (Cl-C~) -alkyl ~ ~;
or a radical of the f ormula Z, . .
~: : ::.
-[C H2lV-1O]w-[CHJ, E (Z) ~ : ~; s

whero E i~ a oubstitutod phenyl radlcal of the
f orsnula F
R~ R~
~ R ~ ( F )

R l C R ; .~. . .
or a (C3-C,)-cycloalkyl radical, whoro

v i0 O, 1, 2, 3, 40 5 or 6, w 18 O or 1, and t ~8 O, . ::
1, 2 or 3, with the re~trictlon that v is not egual :~;
to O if w is 1, and R', R7, R~, R9 and R10 are iden- -;
tical or d~fferent and are hydrogen, halogen, cyano,
nitro, trifluoromethyl, (C,-C~)-alkyl, ;~
,. ,.":

:' :,"' '.:;':'

'~';'''',,.,,,'', `.`'''''~'''. "'' ', j

2134866

- 30 -
(C~-C~)-cycloalkyl, (Cl-C~)-alkoxy, -O-~CH,]~-C~H~
F~, -O~F~Cl, -O-CF, CHFCl, (Cl-Cc)-al~yl~ercapto,
(Cl-C~)-hydroxyalkyl, (C1-C~)-alkoxy-(Cl-Cc)-alkoxy,
(Cl-C~)-alkoxy-(Cl-C~)-alkyl, (Cl-C~)-alkylsulfinyl,
(Cl-C~)-alkylsulfonyl, (C,-C,)-alkylcarbonyl, (Cl-C,)-
alkoxycarbonyl, carbamoyl, N-(C~-C,)-alkylcarbu~oyl,
N!N-di-(Cl-C,)-alkylcarba yl, (C7-Cll)-aralkylcarba- `
moyl which i~ optionally ~ubetituted by fluorine, ~-
chlorine, bromine, trifluorom~thyl or (C~-C~)-alkoxy,
N- (C3-C,) -cycloal~ylcarbamoyl, N-(C~-C,)-~ycloal~yl-
(Cl-C~)-alkylcarbamoyl, (C1-C,)-alkylcarbonyloxy,
phenyl, b~nzyl, phonoxy, b~nzyloxy, NRYR~, ~u¢h a~
amino, nnilino, N-m thylan~lino, ph-nylmercapto,
phenyleulfonyl, phonyl~ulflnyl, ~ulfamoyl, N-(Cl-C,)-
alkylsulfamoyl or N,N-dil-(Cl-C~)-alkylsulfamoyl, or
~wo ad~acent ~ubetltuents togeth-r ars a chain
-~C~ -C~.C~-C~.C~-, where a CH, group of th- cha~n
iB optionally r~placed by O, S, SO, SO, or NRY, and
where a heteroaryl radical can carry 1, 2 or 3
sub~tituents, and a cycloalkyl radical one ~ ;
sub~tituent, from the above group, and

R~ ie R~, providod Q hac the meaning of NR', where ~ ;
R' ~ hydrog~3n or methyl, and ;~ ;
R i~ benzyl, and

if Rl and/or R3 have the meaning of (C~-Cl~)-aryloxy, (C7-
Cll)-aralkyloxy, (C~-Cl,)-aryloxy-(Cl-C~)-alkoxy, (C7-Cll)-
aralkoxy-(Cl-C~)-alkoxy or a corre~ponding radical con-
taining terminal cycloalkyl group~, this radical lc ; ; ~ i;
preferably then a radical of tho formula D ~ ~

OZ (D), or ,~ ~

if ~1 and/or R3 havo the moaning of (C7-Cll)-aralkyl, ~ ,`
~C,-Cll)-aryloxy-(Cl-C~)-alkyl, (C7-Cll)-aralkoxy-(Cl-C,)-
alkyl or a corro~ponding radical containing torminal ; ```
cycloal~yl groups, thi~ radical i~ pr~forably then a ;~
radical of the formula Z,

:: . . : ..

2134865
- 31 -
RY and RZ aro ldent~ c81 or difforent and aro hydrogon, : ~:
(C6-Cl2)-aryl, (Cl-ClO)-allcyl, (C3-C10)-cycloallcyl, ~,
(Cl-C,)-alkoxy-(Cl-C,)-alkyl, (C7-Cl,)-aral~oxy-(C,-
C~)-alkyl, (C~-C,s)-aryloxy-(Cl-C~)-al~yl, (Cl-C10)-
alkanoyl, optionally cubstituted (C7-Cl6~-aralkanoyl
or optlonally ~ubstitutod (C~-Cl2)-~royl, or

RY and RZ aro togothor -tC~2~, in which a CE~ group ca~ ,t.''
be replaced by 0, S, N-(Cl-C~)-alka~oylimino or N- -~
(Cl-C~)-alkoxycarbonylimlno, and ;~

f ~ 1 to 8,
. .
g ie 0 or 1 to (2f
h i~ 3 to 6,
x is 0 to 3, and
n is 3 or 4. ; :-~
~ . ~ .. -.~-.... .
lS Co~pound~ o~ tho formula I ar~ particularly pr~ferred in ..
which ;~

X is 0, :; ~ ' ~'J '. ,1.~'~''~''`
Y i~ CR3 and, additionally, N lf Rl and R2 form a
cyclo,
m i8 0~ '''J''',"'",''~ ,''
A 1~ -CHR~-, whor- R' i~ the ~ubstituont of th- a-
carbon atom of an a-amino acid, in partlcular of a :~
natural L-amlno acid or lt~ D-lsomer,

B is C02H,
.. -
R' is hydrogen, bromino, chlorino, cyano, (Cl-C~
alkyl, (C~-C,)-alkoxy, (Cl-Cl,)-alkoxymothyl, (C~-C~
alkonyloxymothyl, (C~-C~)-alkynyloxymothyl, :.:~
carbamoyl, N-(Cl-C10)-al~ylcarbamoyl, N-((Cl-C~2)- .. -
alkoxy-(Cl-C~)-alkyl)carbamoyl, N,N-di-(Cl-C,)-
alkylcarbamoyl, N(C~-C,)-cycloalkylcarbamoyl, N-(C,- .
- Cl2)-phenylcarbamoyl, N-(C7-Cl2)-phonylalkylcarba- ; `
moyl, N-(Cl-Cc)-alkyl-N-(C,-Cl2)phenylcarbamoyl, N- j : -
(Cl-C6)-alkyl-N-(C7-Cl,)-phonylalkylcarbamoyl, :~
,., ,,. .~ ~
'' :' ~`

2 1 3 ~ 8 6 6
- 32 -
N-((C,-C~)-alkoxy-(Cl-C~)-alkyl)earbamoyl, oarboxyl,
(Cl-C~O)-allcoxycarbonyl, (C3-C20)-alkenyloxycarbo~yl,
ret~nyloxyearbonyl, (C3-C,)-eyoloalkoxyearbonyl,
(C3-C~)-eyeloalkyl-(Cl-C~)-al~oxyearbo~yl, (C3-C,)-
eyeloalkoxy-(Cl-C,)-alkoxyearbonyl, phenyl-(C~-C~)-
alkoxyearbonyl, phonoxy-(Cl-C,)-alkoxyearbonyl or
benzyloxy-(Cl-C,)-al~oxyearbonyl, wher- a ph~nyl
radleal 1~ su~etituted ln the mann-r ae defined $or
Rl and R3, and one of the radieale

Rl or R3 ~e hydrogen and the other a radieal from the
group hydrogen, fluorln~, ehlorln~, (Cl-C,)-alkyl,
(Cl-C1O)-alkoxy, (Cs-C~)-cycloalkyl, (Cs-C~)-cyclo-
alkyl-(Cl-C6)-alkyl, (C5-C,) -eyeloalkyloxy, (C5-C,)
cycloalkyl-(Cl-C~)-al~oxy, (Cs-C,)-cycloalkyloxy-(C
C~)-alkyl, (C5-C,) -cycloalkyloxy-(C1-C~)-al~oxy, (C5-
C,)-eyeloalkyl-(Cl-C~)-alkyl-(Cl-C~)-al~oxy, (Cs-C,)~
cycloalkyl-(Cl-C~)-alkoxy-(Cl-C~)-alkyl, (C5-c~
cycloalkoxy-(Cl-C~)-alkoxy-(Cl-C2)-alkyl,
-O-[CH2]~-C~K(2f~l~,F~,(Cl-C,)-alkoxy-(Cl-C~)-alkyl,(Cl-
C,)-alkoxy-(Cl-C,)-alkoxy, (Cl-C,)-alkoxy-(Cl-C~
alkoxy-(Cl-C2)-alkyl, eubet~tut~d (C,-Cl2)-ph-noxy,
(C7-Cll)-phonylalkyloxy, (C~-Cl2)-phenoxy-(Cl-C~
alkoxy or (C7-cll) -ph-nylalkoxy-(Cl-C~)-alkoxy,
phenoxy-(Cl-C~)-alkyl, (C7-Cll)-phenylalkyloxy-
(Cl-C~)-alkyl, phenoxy-(Cl-C~)-alkoxy-(Cl-C~-alkyl
or (C7-C~l)-phenylalkyloxy-(Cl-C~)-alkoxy-(Cl-C2)-
alkyl, whor- an aromatlc radleal le ~ubetltut-d by
1, 2 or 3 ldentlcal or dlfferent subetituents from
the group 1uor,1ne, chlorlne, eyano, trifluoro-
methyl, (Cl-Cl2)-alkyl, (C2-Cl2)-alkenyl, (C2-Cls)-
alkenyloxy or (Cl-Cl~)-alkoxy,

Rl and R2, wlth the pyrldlne earrylng them, form a 5, 6,
7, 8-tetrahydrolsoqulnoline rlng,

R~ le a branehed or unbraneh~d (Cl-C10)-alkyl rad1eal,
(Cl-C~)-alkoxy-(Cl-C~)-alkyl or a radleal of th~
formula Z,
', ~ ~' ;`'' ,''~'''. '


---`` 213~8~6
- 33 -
,~CH2lV-1Olw-~cH2J~-E (Z) '' '

whero E i8 a ~ub~t~ tutod phenyl radlcal of tho
f onnula F
R ~ R
_~_ RS ( ~

R 1 0 R9 ~ ~ -

or a (C3-C,)-eyeloallcyl radleal, wh-r~ v 1EI 0, l, 2 -;
or 3, w i8 O, and t ean b- 0 or 1, and ln wh~ eh R',
R7, R', R9 and Rl ~r~ ~dent~cal or differ-nt ~d are
hydrogen, fluorine, chlortno~ cyano, trlfluoro-
m o t hy l , ( C , - C ~ ) - a l ky l , ( C l - C , ) - a l k oxy ,
~O~ ~CH~;]~~C~H~ )Fg~ N- (Cl-C~) -alkylear~amoyl, N,N-
di- (C,-C6) -alkylcarbamoyl, N- (C,-C,) -cyeloalkylearba-
moyl, N-(~)-dehydroab~otylaminocarbonyl, or (C7-Cll)-
phenylalkylcarbamoyl, which ~ s optionally
tituted by fluorinn, ehlorine, trlfluoromethyl
or (C,-C~)-alkoxy, or whoro RC and R' or R7 and R', ~ a
togother w$th the phonyl ring carying th-m, form
naphthalono dorivatives ~;
: . . ~ , : , .,
If Rl or R' ha~ th- moaning of (C~-Cl2)-phenoxy, (C7-Cll)- ~ ~
~ ,....... .
ph-nylalkyloxy, (C~-Cl,) -phenoxy- (Cl-C~) -alkoxy, (C,-Cl,) -
phonylalkoxy- (C,-C,) -alkoxy, (C,-C,) -cycloalkyloxy- (C~-C,) - ~ ~ `
alkoxy, (C,-C~) -eycloalkoxy- (Cl-C,) -alkoxy or (C5-C,) - ~ .~ . ..... ... /
cyeloalkyl- (Cl-C~) -alkyl- (Cl-C~) -alkoxy, thi~ radical i8
th-n, o~pecially, a radical of tho formula D

OZ (D), or
- . .:: ~. ::; .
. :,, :. .. ,:,,
if Rl or R3 has tho mo~ing of phenyl, phonoxy-(C,-C,)-
25 alkyl, (C7-Cll) -ph-nylalkyl (C7-Cll) -phenylalkyloxy- (Cl-C") -
alkyl, (C~-C~) -cycloalkyl, (C~-C~) -cycloalkyl- (Cl-C~
allcyl, (C~-C~) -cycloalkoxy- (Cl-C~) -alkyl, (Cs-C~) -eyclo- ~ -
alkyl- (Cl-C~) -alkoxy- (Cl-C,) -alkyl or (C,-C~) -cycloalkoxy-

'~.',,,,..~

- 213~866
- 34 -
(C,-C~)-alkoxy-(Cl-C,)-alkyl, th~ radlcal i8 thon,
e~pocially, a radical of tho formula Z in which, ln both
ca~es,

v is 1, 2, 3 or 4, w is 0 and t is 0, or
v is 1, 2, 3 or 4, w i~ 1 and t is 0, or
v is 1, 2, 3 or 4, w ~8 1, t 1~ 1, and
f is 1 to 4, .
g i~ 0 or 1 to (2f~
x i~ 0 or 1. ::~

Compounds of the formula I ar~ very particularly pre-
f~rred in which -~
Q i8 O, . `
X i~ o,
Y i~ CR3, -
m is 0,
A i~ a -CH2- group which can b~ ~ub~tituted by a ~ - m
methyl group, ~ ,":,a
8 is -CO2H,
R2 is hydrogen, (Cl-C,)-alkoxy, (Cl-Cl~)-alkoxymothyl,
(Cl-Cl~)-alk~nyloxymethyl, retlnyloxymethyl, N-(C1- .
C~0)-alkylcarbamoyl, N-((Cl-Cl,)-alkoxy-(Cl-C3)-
alkyl)carbamoyl, N,N-di-(Cl-C~)-alkylcarbamoyl, N~
(C5-C~)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-
phenyl-(Cl-C~)-alkylcarbamoyl, carboxyl, (C~-Cl~ . P
alkoxycarbonyl, (C2-Cl~)-alk~nyloxycarbonyl, . . ~
ret~nyloxycarbonyl, (C~-C~)-cyclonlkoxycarbonyl, (C5- ~ ,.. ."~,.` ;,;
C,)-cycloalkyl-(Cl-C,)-alkoxycarbonyl or phenyl-(C
C~)-alkoxycarbonyl, where a phonyl radical i~
sub~t~tutod in the manner a~ defined for Rl and R3,
and one of th~ radicals

R1 or R3 1~ hydrogen and the other radical i~ a radical ;~
from the group hydrog-n, (C,-C~0)-alkoxy, (C,-C,)-
cycloalkylo.~y, (C,-C,)-cycloalkyl-(Cl-C,)-alkoxy,
~O~~CH~l~~CtH~s~ g~Fy~ (Cl-C~)-alkoxy-(Cl-C~)-alkoxy,
cubstituted (C6-Cl,)-ph~noxy, (C7-C11)-phenylalkyloxy,
(C~-C12) -phenoxy-(Cl-C~)-alkoxy or (C7-Cll)-phsnyl-

~;, ,

213~866
- 35 -
alkoxy-(C~-C,)-al~oxy, wh~r- an aromatic rad~c~l le
substitutcd by 1, 2 or 3 ldentical or dlffor-nt
eubst~tuente from the group fluorine, chlor~n~s,
cyano, trlfluoromothyl, (C1-C10)-alkyl, (Cl-C10)-
alkoxy or (Cl-C10)-alkenyloxy, and
: ~ " ., ' ~
R~ is a branchod or unbranchod (Cl-C~)-alkyl rad~cal or .. :.. .. `
a r~dlcal of tho formula Z,

-lCH~lv-lOlw-lCHalt-E (Z)

where B ia a eubstitutod ph~anyl radical o tho
lC formula F
R~ R7
~ R~ ( F ) , ~ ` ~

t o
R . .~
.-. :,.`:.
or a (C3-C,)-cycloalkyl radical, whero .
v 1~ O, 1, 2 or 3, w is 0, and t can b- 0 or 1, and ~. -;:: .;;
in which R6, R', R', R9 and Rl aro ~dent~cal or
different and aro hydrogen, fluorino, chlorlne, ~ . . .
cyano, trifluoromethyl, (Cl-C~)-alkyl, (C~-C6)- . .:
alkoxy, -O-lCH,~X-CtH~lt~l9)F9, N-(Cl-C,)-alkylcarba-
moyl, N,N-dl-(Cl-C~)-alkylcarb~moyl, N-(C,-C,)-
cycloalkylcarbamoyl, N-(I)-dohydroabietylamlnocar-
bonyl substituted benzyl radlcal, and f i8 1 to 4, ; . :
g l~ 0 or 1 to (2f~ and x 1~ 0 or 1.

Compound~ of the formula I aro partlcularly preferr-d ln ..
whlch . ~:
Q 18 O,
X 18 O, .; .
25 Y is CR3, ~:~
m 1~ 0,
B 18 -CO2H,
A 1~ a -CH~-group,

,. ., ~ .

213~g66
- 36 -
Rl $~ hydrogen, (Cl-C~)-alkoxy or ~O~tC~,]~~C~HO~.lg,Fg,

R2 is hydrogen, N-(C~-C,0)-alkylcarbamoyl, N-((Cl-C~
alkoxy-(C,-C,)-alkyl)carbamoyl,N,N-di-(C~-C,)-alkyl-
carbamoyl, N-(Cs-Cc)-cycloalkylcarb~moyl, N-phonyl-
carbamoyl,N-phenyl-(C~-C~)-alkylcarbamoyl,carboxyl,
(C~-C~)-alkoxycarbonyl, (C2-C~)-alkenyloxycarbonyl,
rotinyloxycarbonyl, (C~-C,)-cycloalkoxycarbonyl, (C5-
C6)-cycloalkyl-(C~-C~)-alkoxycarbonyl or phenyl-(C
C~)-alkoxycarbonyl, whero a phonyl radical 1~
sub~tituted by 1 or 2 ld-ntloal or difforont
sub~tituente from the group fluorine, chlorine,
cyano, trifluoromethyl, (Cl-C,0)-alkyl, (C,-C,0)-
alkenyloxy or (C,-C~0)-alkoxy, and

R3 i~ hydrogen, (C,-C5) -alkoxy or (C5-C,) -cycloalkyl-~C,-
C2)-alkoxy, wher~ one of the ~ubstltuent~ R1 and R3
i~ hydrogen, ~ 6 i

R~ i~ a branched or unbranched (C,-C,)-al~yl radical, or
a 2-phonylethyl radlcal, or a bonzyl radical
~ub~tituted by 1 or 2 radlcal~ from tho group flu-
orlne, chlorlne, cyano, trlfluoromethyl, (Cl-C,)-
alkyl, (C,-C,)-alkoxy, -O-~CX2]~-C~H~ )F~, N-(Cl-C,)-
alkylcarba~oyl, N,N-di-(C,-C,)-alkylcarbamoyl,N-(C,-
C,)-cycloalkylcarbamoyl or N-(~)-dehydroabletyl-
aminocarbonyl, and f 1~ 1 to 4, g 1~ 0 or 1 to
(2f~1) and x 1
: : :
Compound~ of the formula I are preferred to the hlghe~t
degree ln whlch
Q 1~ O,
X 1~ O,
Y i8 CR3,
m i~ 0,

A 1~ a -CH,-group,
B 18 -CO
R~ 18 hydrogen,

213~866

- 37
R~ i~ hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((Cl-C~
al~oxy-(Cl-C,)-alkyl)carbamoyl, N-~yclohexylcar~
bamoyl, N-phenylcarbamoyl, N-(phenyl-(Cl-Cs)-al~yl)-
carbamoyl, whero, in the last two caco~, the phenyl
radlcal can carry a fluorins subotituent, (Cl-Clo3-
alkyl oub~tituent or (Cl-ClO)-alkoxy cub~tituent,
carboxyl, (Cl-Cl,)-alkoxycarbonyl, (Cs-Clc)-alkenyl~
oxycarbonyl, retinyloxycarbonyl, (C5-C~) -cyclo-
al~oxycarbonyl or bonzyloxycarbonyl,

R3 i8 hydrogan, (Cl-C~)-alkoxy or 2-(cyclohexyl)ethyl-
oxy, whore one of tho ~ubet~tuento Rs and R~ io
hydrogon, ; ~

R~ i~ a branchod or uDbranched (Cl-C~)-alkyl radical or ~ . .:;
a benzyl radical which ic ~ubotitutod once by flu-
orine, chlorino, trifluoromethyl, (Cl-C~)-al~yl or .
( Cl - C3 ) -alkoxy~

Compounds of the formula I are aloo preferred to the ;.
highe3t degree in which
Q i~ 8, ;. ;
20 X i8 O, ,.
Y i8 CR3,
m io 0,

A io a -CHs- group,
i l~ - COsH,
Rl io hydrogen,

Rl io hydrogen, N-(Cl-C10)-al~ylcarbamoyl, N-((Cl-Cl,)-
alkoxy- (Cl-C3) -al~yl)carbamoyl, N-cyclohexylcarha-
moyl, N-phenylcarbamoyl, N-(phenyl-(Cl-Cs)al~yl)-
carb~moyl, wherQ, in the laot two ca~e~, the phenyl
radical can carry a fluorin~ ~ubotituent, (Cl-C10)-:.; ::;: :~:
alkyl oubotituent or (Cl-C10)-alkoxy ~ubctituent, ::
carboxyl, (Cl-Cl,)-alkoxycarbonyl, (C~-Cl~)-alkenyl- :.
oxycarbonyl, retinyloxycarbo~yl, (C5-C,)-cycloalk-
oxy~arbonyl or benzyloxycarbonyl,
,, ~ ", ,,; "
~' ' ".:. ' `.:

2134866
- 38 -
R3 is hydrogen, (Cl-C,)-~lkoxy or 2-(cyclohexyl)-
ethyloxy, whore one of tho substituont~ R' and R' ~o
hydrogen, and

R~ 18 a branched or unbranch-d (~,-C~)-alkyl radical or
a benzyl radical which lc substltut-d onco by flu-
orine, ohlorln-, trifluoromothyl, (Cl-C~)-alkyl or
(Cl-C3)-alkoxy

The compound~ of the formula I aro al~o profqrr-d to the
highe~t degree ~n wh~ch

10 Q i~ S, ~-

Y i8 CR3
m is 0,
A is a -CH2-group, -
15 B i8 -CO~H, ' ~' ~,,, ~'~ ,'''~'"'',~`'~','~''!'~
Rl iB hydrogen, ~ >-
R2 is carboxyl or (Cl-Cl,)-alkoxycarbonyl,
R3 is hydrogen, and ;
R~ is a branch-d or unbranch~d (Cl-C~)-alkyl radlcal

Tho compound of tho formula I i~ al~o pr-forred to the
hlgh-~t dogreo in which
Q i~ 0,
X ia 0,
Y i~ CR3, whor~ R3 i~ hydrogon, ~ -
m i~ 0,
A 18 a -CH2-group,
B is -C02H-,
Rl and R2, togethor with th- pyridin- carrying them, form
an i~oqulnollno ring havlng an unsubstltut-d b~nzo
moloty, and
R~ 1~ methyl
" ;'~ . ' : ^~;: ,
,, ~, ,.., ~
Tho compound of tho formula I 1~ also pref-rr-d to tho
highe~t degr-- in which -~
Q ;8 0,

t . ''~
'':': ' " ',', "' .', ' " ' '~;

21~866
- 39 - ;
X is 0,
Y ie CR3, -~
m ie 0,
A ie a -C~-group,
5 B i~ -C0~
Rl is hydrogon,
R' and R3, togother with the pyridine carrying them, form
a quinolino ring having an unsubstituted benzo ~;
moioty, and
R4 is mothyl.
, .
Tho invention al80 ~mbracee prodrugs for tho compound~ o~ :
tho formula (I), which prodrugs bring about an i~hl~it~on -~
of collagon blosynthosie in vivo by liborating compounds ~ i~
of tho formula I or thoir ealte.
,~
"
Finally, the invontion also ~mbracoe prodruga which, by
liberating compounide of the formula I or their ealta,
bring about i~n lnhlbitory effect in vivo on prolyl-4-
hydroxylaee.
.
Prodrug groupinge aro chomical groupe whlch, ln vlvo, -
,
0 - aro convortod ~nto the carboxylato group of the
compounde of th~ formula I, and/or
- can bo cleav~d from the amldo N atom, and/or
- can bo converted into a pyrldlno ring. ~ ;~
., -: .~
-, . . ::.::
Thoee prodrug groupe which aro ouitable are known to tho
porson skllled in the~art.
:,. :::
~he followlng prodrug grouplngs receive partlcular
montlons ;
for the carboxylate group, ester groupe, amlde group~
hydroxymothyl groups and aldehydo group~, and tholr
derlvatlvess for the pyrldino N atom, N-oxide~ and N-
alky~ deriratlvoe; and fox the pyrldlne rlng, 1,4-
dihydropyridine derivatives or tetrahydropyridino
derivativee. ~ i
'.." ~:
,: ~.,,,i:

213~866
- 40 -
The invention relatos to tho u~e of c Q ounds of tho
formula I, and also the phy~iologically tolarated ~alt~
for inhibiting collagon biosynthesis.

The inventlon relatos to the use of compounds of the
formula I, and also tho physiologically tolerat~d ~alts,
for inhibiting prolyl-4-hydroxylase. ~ -~

The inve~tion also relate~ to the use o~ compou~ds of the ~ ;~
formula I, and al80 the physiologically toleratod salt~
for producing a pharmaceutical against fibrotic disease~

The invention also relates to the use of compound~ of the
formula I, and al~o the physiologically tolerated salts,
for producing a pharmaceutical against fibrotic diseases
of the liver, the lung and the skin.
::
Finally, the invention relates to the compounds of the ~ ;
formula I for use as pharmaceutical~

The invention relate~, in particular, to the compounds of -
the formula I for use as fibrosuppressive ag-nte.

The invention al~o relate~ to a procese for pr-paring
compounds of the formula I.

20 The oompound~ of the formula I, in whi¢h A i~ a ~
~ubstituted alkylene moiety, B i~ C02~, Y is CR' and m is ;;~ ;
0 or 1, are prepared by ;~
,, ~ j , , , , :
11.) Rea¢ting pyridine-2-carboxylic acids of th- formula
II (R~3 is H) with the amino esters of th- formula
III to form tho amid- e~ters of the formula IV, or i-

i2.) Reacting pyridins-2-carboxylic estere of the for~ula; ; -~
II (R~3 is lower al~yl), under the conditions of
aminolysis, to form the compounds of the formula IV;
and

2131866
,--
- 41 -
ii) liberating the compound~ of the formula I from th~ir
eeters of the formula IVs with, whero appropriate,

iii) the oompounde of the formula IV boing prepared by
alkylation of compounds of the for~ula V with R~
iand, where appropriate, : ; :
: .. . ~
i~) the compounds o~ th~ Formula IV being convert~d, :
pro~ided Q is 0 or NR', into thoir pyridine N-oxidee :-:
IV' (R'~ iB (C3-C3,)-alkyl or benzyl) and the l~Att~r :~:
being hydrolyzod to form the pyridino N-oxid~s of
tho formula I' (R2~ ie H). :

Scheme 1 . :

~C22~2~ -c~2l~2~
l V
~ - ~
~ X t ~ ~ ~
", , ... . .. ~.
R

J R2~NH-~-CO2R2~ ~
R~ . ;
O ' . ' ,' " ,.,
V .-: - .::`.
:, ' ' ', ' ~'',

O R ' ~ N - A - t O, 2
A - C O, ~ , "'~ : ; . .
o O : ~ . .','"'.''' :'''::'
v~ c,-e")-~ . ~n~
I ~ 12~ N . . ~ ~
' ~ .,; ',;: .
;, . ~ ' ' . ,:
' ,,:,~. ;:.',:",'
:''; ~',.'.'' i
R~3 ie H or (C,-C16)-alkyl, .

;: :.;. .: ,.

.,, : .:

'".;' .~ ' '" ' ''','', ' ' ~ '


6", ' ' ;; ~

213~866

- 42 -
R~ i B X, (Cl-Cl,)-alkyl or bonzyl,
X ie a leaving group, ln particular halogen, OSO~Me or
OSO~phenyl

The methods of carboxyl actlvation and the condensatlon
reactions known from peptide ch d ~try are sultable
procosse~ for the amide formation (reactlon il)

The eub~tance~ which are known to the per~on skllled ln
the art, such as thlonyl chloride, oxalyl chloride,
pivaloyl chloride, chloroformate derivativo~, or N,N'-
carbonyldiimidazolo, can b- u~ed a~ roag-nt~ for tho
carboxylic acid activatlon The aotlvated dorlvAtive~ of
the compounds of the formula II aro prepared ln situ and
then rsacted with tho amide derivativee of tho ~ormula
III

A~ exa~ple of a euitable conden~ing agent ie the
combination of N,N~-dicyclohexylcarbodllmldo/N-hydroxy-
lH-benzotriazolo and N-ethylmorphollne

Sultablo aolvents aro dichlorom thane, t-trachloro-
methane, butyl acotato, othyl acotnt-, tolu-n-, totra-
hydrofuran, dlmethoxy-tha~e, 1,4-dloxano, ac-tonltrlle,
N,N-dlmethylformamld-, N,N-dim-thylacotam$do, dimothyl
~ulfoxldo, nltromethano and/or pyrldlne

The compoundo of the formula I, ln whlch R~ and R3 aro
hydrogen and R~ 18 a carboxyl eubstltuent, a carbamoyl
~ub~3titu-nt or an ! est~r ~ub~tltuont, wero proparod a~
outllned ln schomes 1, 2 and 3
,, , . " . :,. .:
8cheme 2 lllu~trat-r3 th- preparatlon of tho compound~ of
the formula TI ln whlch Rl lo a c~rboxyllc acid
~ubstltuont, or lts derlvatlve, and Rl and R' aro hydro-
gen
:, '. . ,: '" ' ~'
Th- 3-~3ubstituted 5-carboxypyridlne-2-carboxyllc e~3ter~
of the formula XI and thelr isomer~ of the for~ula XII
'

2134866

- 43 -
are prepared from the pyrldlno-2,5-dicarboxyllc die~ti~rs
of tho formula VII.

The oxidation of the pyridine-2,5-dicarboxylatos of tho
formula VII is d~scribed in J. Chem. Soc. Per~in Tra~.
2, 1978, 34-38 and in J. Org. Chem. 25 (1960) 565 to 568
(M.L. Peterson).

The halogenation (chlorination) of the pyrid~no N-ox~d,~,s
of the formula VIII with thionyl chloride and the reac-
tion of the 3-chloropyridine-2,5-dicarboxyllc diostor
(Formula IX) with alcoholat~s (Q i,s o or 8) can be
carried out in analogy with tho proco,~ do,scrlbed in the
patent specification 7~H 658 651 (LONZA), where M 18 a
singly charged or doubly chargod metal ion, preferably
from the first or second mai~ group of the periodic
syetem.

In analogy with the known literaturo (7-A: vol. 68, 1968,
68 840 h), the monoesters of tho formula XII are pre~
pared, under hydrolysis condltions, from the substituted
pyridine-2,5-dicarboxylic dio~ters of the formula Xb.

Seloctive hydrolysis using ~u(II) salts, J. Delarge in
Pharmaceutica Acta Holvetiao 44, 637-643, 1969, repre-
,s,-nt~ anothar procos~ for preparing the compounds of the
formula XII from tho diesters of the formula Xb. 1~ ;
,:-, . :,.: ,,,
. : ;
The compounds of the formula XII thus obtained are
reaoted with the,amino estor~ of the formula III to form
the compounds of tho formula IV (SchQme 2).
,:~
Ths pyridine-2-carboxylic ester-5-carboxylates of the
formula XI can be prepared, under eeiterification condi-
tlons, from substituted pyridino-2,5-dicarboxylic acids
of tho formula Xa (see CA: vol. 68, 1968, 68840 h).
~ultable conditions are, for examplo, eE,terification with
mothanol in the presence of sulfuric acid, it being
necessary to choose the reaction time 80 that complete
' " ::' "
"....



II:A . i; i ~ .
' ; . ~;

213~866
- . .
- 44 -
esterification to form tho d~e~ter product only ta~o~
placo to a ~ocondary oxtent, or ~o that tho diostor ~ -
products can bo ~oparatsd off a~ by-product~.

Tho compounds of tho formula XI aro convsrtod w~th amlnoo
or alcohole $nto ths 5-carboxylic acid doriv~tl~o of the
formula XIV (Scheme 3).

These are then hydrolysod to form tho ~iompounds of th~
formula II (R23 i~ ~), which compou~d~ aro sub~oqu-ntly
reacted in analogy with Scheme 1.

Scheme 2

RO2C~ 2 ~ ~`CO2R
V l I I
V I I
h~logen~tion
( R ~ H, lower ~Ikyl ) ~

:` ,' '~ ''''".: ' .",'


UOR~ e r
R O ~ C~O R U ( ~ ) O R ~ R O 2 C~¢~L
~C O 2 R C O 2 R
I X
X a : R H L C I, a ~
X b : R lower ~Ikyl 1~ metd ion, :
~ingly or doubly
\ ch rged
\ O O . 5 ,
: '~ '' :`"'"'
U 2 C~O R ~C O H
X I R Iower dkylX I I R Iow ~Ikyl
H, \l - A - C O 2 R ~
I V ' .,

213~866
,
- 45 -
Scheme 3
ROIl o r HNRR
~02C ~R~ X I I I ' R2 QR~
~C 2 low ~1 ~C 2 lower~l
X I X I V R2 . COOR, CO-NR R

The 2-hydroxymethylpyridlnes of the ~or~ula VI-, which
are dir~clo~ed in ~P-A-O 304 732, EP-A-O 321 385 a~d EP-A-
0 208 452, can bo used a~ ~ntermodiatee for preparing ~ -
5 derlvativo~ (Rl) which are eubstitut-d in th- 4 posltlon ~ -

. .
Scheme 4 ~ -

R2 ~ QR Id 1i ~2

R~ CH20H R C02~
V I I I ( R 1 ~ H )
v I o ~ ~ I c : o R 4 O ~ me~yl)
V l ~ ~ l l b : O R ~ O i~ n ( ~ n benzyl ) ; ~ -

',
Th- 3-0-benzyl derlvative~ of the formula VIb were al~o
obtained in an analogous manner, a~ de~cribod ln thoso
documents
.. : ,:
The compounds of the~ formulas VIa and VIb wor- react-d
wlth an oxldlzlng agent, preforably wlth RMnO~ ln agueous
alkalino msdlum, to form th- pyridino-2-carboxylic acid
dorivatlv-s of tho formula TI (of Schemo 4)

Th- proparation of sub~tltuted pyridine-2-carboxylic ~ ;
acids 18, for example, dlsclo~od ln DE-A-353 046, and for ~; ,;
3-(3-chlorophonoxy)pyridine-2-carboxylic acld and 3-(3- ~ `
methylphonoxy)pyridlno-2-carboxylic ncid in J Med Chem
1975, 18, pp 1-8, Vlllani ot al ; ~or
' ~
: , . .

213~8S6
-


- 46 -
3,5-diethoxypyridine-2-carboxylic acld ln J. Med. Chem.
1974, 17, pp. 172-181, French et al.; and for 3-mothyl-
thiopyridine-2-carboxylic acid and 3-benzylthlopyridine-
2-carboxylic acid in J. Med. Chem. 1974, 17, pp. 1065-
1071, Blank et al.; and for 3-methoxypyridine-2,5-d~car-
boxylic acid in CH-PS 658 651.

The compounds of the formula I are iDhlbltors of prolyl-
4-hydroxyla~e. Tho lnhibition of thls onzyme w~e
determined a~ described by ~aulo und G~nzler in Annal.
Biochem. 184, 219 to 297 (1990).

TAe novel compounda of the formula I pos~ece valuablo
pharmacological propertios and exh~bit, in particular,
antifibrotic acti~ity.

T~e antifibrotic effect can, for example, be determined
u~ing the model of carbon tetrachloride-induced hopatic
fibro~is. For this, rats aro troated twic- a waek with
CCl~ (1 ml/kg) - dls~olved in olivo oil. Tho oubstanco
under te~t is administered daily, whero appropriate oven
twice a day, por 08, or intrnperitonoally - dle~olvod in
a ~uitable toleratod solvont. Tho extent of tho hopatic
fibro~i~ is detormined by hi~tology, and the proportion
of collagon in tho llvor 1~ analyzod by means of deter-
mining hydroxyproline - a~ describod in Rivirikko t al.
(Anal. Biochem. 19, 249 f. (1967)). The fibrogenic ac-
tivity can be meaeur-d by the radioimmunologlcal detor-
mination of collagen fragments and procollagon peptidos
in the ~erum. Injthis model, the novol,compounds !aro
active at a concontration of from 1 to 100 mg/~g.
~ :..-. .
The fibrogenic activlty can be moasured by radiolmmuno-
logi¢al determination of the N-terminal propsptido of
¢ollagen type III or of the N-torminal or C-terminal
cro~slinking domain of collagen type IV (79 collage~ or
type IV collagen NCl) in the serum. - ~ ~;
~ ~ '
For this purposo, mea~urement~ wero made of the ~?~:

213~866

- 47 -
concentrations of hydroxyproline, procollagen III
peptide, 78 collagen and type IV collagen NC in the llver
of
a) untreated rat~ (control)
b) rats which wero adminlster-d carbon tetrachlorido
(CCl" control)
c) rat~ which were first administered CCl" and tho,n a
novel compound
(this te~t method 1D described by Rouillor, C., ~xpcri-
mental toxlc ln~ury of the llv~r; in Tho Llver, C.
Rouillor, vol. 2, 5. 335 to 476, New York, Acade~ic
Press, 1964).

The novel compounds cu~ al~o b- demon~trated to b~ active
ln the following ~ystem~

Inhibition of hepatic prolyl-4-biydroxylase ln vlvo~

Thi~ model i~ used to demonstrate the acute inhlbition of
prolyl-4-hydroxyla~e in vlvo. For thi~, r~ts of both
~exe~ (healthy or with induced hepat$c flbrosi~) are
administered (intraporitoneally, intravonously or per 08)
the substance under tast or th- corrosponding ~ohicle
and, after thio, aro giv-n 1~C-L-proline (250 ~Ci/kg of
bodyweight), which is administerod intraperiton-ally.
There then follows a socond lntraperltoneal admiini~
tration of l"C-L-prolino (250 ~C~/kg of bodywelght).
Finally, the animals are exsang~inat-d under pento-
barbital ane~thesla and the liver~ removed. The hepatic
collagen was purifiod ~by dlgo~tlon with popsln and
fractlonal ammonium eulfate precipitation in conformity
with published protocol~ (Ref. 1 and 2). The purifiod
liver collagen was hydrolyzed and the content of 1'~C-
hydroxyprolino and 1~C-proline wa~ determirod by mean~ of
amino acid analy~ls u~ing lon exchange chromatography.
Inhibitlon of prolyl-4-hydroxylaso is s,hown by a d-croase
in the quotient 1'~-hydroxyprollne/[1~C-hydroxy~
proline~1"C-proline]. 2,2'-Dipyridyl i~ u~ed as the
reference substanco. (1: Cho~kier, M. 1986, Hepatocyte

:
21348~6
- 48 -
collagen production $n vivo in normal rat~, J. Clin.
Invest. 78: 333-339 and 2: Oga~a I., qt al. 1991, M~nor
contribut$on of hopatocytos to collagen productlon in
normal and oarly f$brotic livors, ~opatology 14:
361-367).

Inhibition of prolyl-4-hydroxyla~e in cell cultur-s:
~: , .,; ,;:
The following cell types are us-d for t~sting inhibitor~
of prolyl-4-hydroxyla~o in coll cultur~c: `
Normal _uman skin fibroblasts, (N~DF), rat liver
opithelial cells, (ref. 1) and primary fat storing c-lls
from rat liver (ref. 2). For thi~, the coll~ ar- oult~
. , ,
vated in the pro~ence of inhibitors. At the ~amo time,
the collagen which iB nowly ~ynthesized during thi~
period ~8 metabolically labelled with 4-3H-L-proline and ;~
~C-prol$ne. The iafluonce of the test cubst~ncee on tho
: .~
degree of hydroxylation of the collagen is then deter-
mined in iaccordance with the method of Cho~kier et al
(ref. 3). 2,2~-Dipyridyl i8 ~mployod as tho r~feronce
sub~tance. (1.: Schrode, W., Mecke, D., G-bhard, R. 1990,
Induction of glutamine synthqtase in periportal hepato-
cyte~ by co-cultivation with a liver pithelial cell
line, Eur. ~. Coll. Biol. 53: 35-41; 2. Blomhoff, R.,
Borg T. 1990, I~olation and cultivation of rat liv-r
~tellate cell~, Mothods Enzymol. 190: 59-71s and 3.:
Cho~kier, M. Peterkofsky, B. Batema~, J. 1980, A new
m-thod for dot-rmlning the xtent of prolino hydroxy-
lation by m-a~uring changes in the ration of [4-'X]:t~C~
proline in collagenase,dig-sts, Anal. Biochom. 108: 385-
393).

Tho compound~ of the formula I may be used as medicament~
in the form of pharmaceutical pr-paration~, which contain
tho compound~, whoro appropriat- together with toleratod
pharmac-utical oxcipient~. The compounds can bo u~od a~
medicines, for example ln tho form of pharmaceutical ~`
preparation~ which contain the~e compound~ in a mixture
together with a pharmaceutical, organic or inorganic ; ;;
':'.: :.. ~ '~
. - .: ,::
::' , :" ' :,; : `~

213~866
- 49 -
excipient which i8 suitablo for ~nteral, percutaneoua or
parenteral adm~nietration, such aA, for sxampl~, water,
gum arabic, gelat~n, lactoeQ, starch, magneeium stearate,
talc, vogetable oilB, polyalkylene glycol~, vaeelino,
etc.

Por this purposs, they can be adminietor-d orally ~n
doses of from 0.1 to 25 mg/kg/day, proferAbly of fro~
to 5 mg/kg/day, or parenterally ln doeoe of from 0.01 to
5 mg/kg/day, proferably of from 0.01 to 2.5 mg/kg/day, ln
particular of from 0.5 to 1.0 mg/kg/d~y. Tho doeage can
aleo be increased ln sovere ca~e~. In many casee, how-
evor, emaller doeo~ aro al~o sufflcient. Thsee data rofor
to an adult of about 75 kg ln weight.

The novel conyounds of tho formula I are doeignatod
eubetltutod hoterocyclic carboxyllc acld glycylamidee,
prefsrably pyrldlne-2-carboxyllc acld glycylamide~, ln
the examplos doecrlbod bolow.
This mode o~ deelgnatlon le underetood to moan
subetltutod N-carboxymothylpyridine-2-carboxamldoe.
20 Anothor optlon ie to claseify th~m ae eubetitut-d N- ; ~
(pyridyl-2-carbonyl)glycinee. ,;

Examplo 1 ~ ~ `
3-Mothoxy-4-(2,2,2-trifluoroothyloxy)pyridlns-2-
carboxyllc acid glycylamide

a) 2-Mothyl-3-methoxy-4-chloropyridine N-oxide

11.2 g (80.5 mmol) of 3-mothoxy-2-mothyl-4(1~)-pyrldone -
were heatod under reflux for 10 houro ln 100 ml of -~
phoephorus oxychloride. Subeogu-ntly, th~ mixturo wae
conc-ntxated and 30 ml of toluen- were add~d to each 2 ml
volume5 concentration thon took placo onco agaln and the
r-eldue wa~ takon up ln 150 ml of water, wlth the pH of
the mixture then belng adjuetod to 11 wlth ~,CO3; thle
mixturo was thon extractod with dichloromethano and tho
organic phaee was waehod with wator, dr~ed and freed from

." '; ;~'~'~: ,';;

2134866

~ 50
solvent

8 g of ths product were obtained, under ~tandard con-
d~tlons, from the pale brown oil (9 g) using m-chloropor-
benzoic acid in d~chloromothano, m p 88 to 8gC (fro~
5 petroleum other) ; ;

b) 2-Methyl-3-methoxy-4-(2,2,2-trifluoroethoxy)pyrldino
N-oxide

6 7 g of potas~ium tert-butoxide were added ln portions,
at -20C, while otirring and undor a nitrogon atmosph-ro,
to 20 ml of trifluoroethanol Ater tho mixture had beon
warmed to 0C, 5 2 g (30 mmol) of 2-methyl-3-methoxy-4-
chloropyridlne N-oxide wero added in portlon~ The
mixturo was heated under reflux for 3 hours, ~nd then
coolod down to room temperatureS a further 3 45 g of
potassium tert-butoxide w~ro then add~d and the mixture
was heatod under roflux for 2 hours After it had coolod
down, 40 ml of water wore addod to the r~act~on m~xture, ~-
which was thon extractod with dichloromethane; the
extract was then dried over MgSO~ and freed from ~olvont
ln vacuo Tho rosulting oily product wa~ ~ub~-cted to
furthor roaction

c) 3-Methoxy-4-(2,2,2-trifluoroethoxy)-2-hydroxymethyl-
pyr~dlne
. ~ .
8 g (33 8 mmol) of tho a~ovo compound wer- dis~olv-d in ~ ~ ;
25 16 ml of glacial acotic acid, and 24 ml of acotic ~ ~;
anhydrid- wore addod, at 80C and while stlrring, to this
mixturo The reaction mixturo was hoated at 110C for 2
houra and thon coolod down to 80C; 40 ml of methanol ;-~
wer- th-n addod to it dropwlse Sub~equontly, th~ mixture
30 wa~ conc-ntrated ln vacuo, and tho oily residue addod to ;
75 ml of 2N m thanolic NaOH, with thi~ mixturo boing
etirred for 30 minutes Following treatment with active -~
charcoal, and filtration, the mixture was conc~ntrated in ~ .',,',.'.,'t
vacuo and 50 ml of water wero addod to tho rosidue, after -~`
~,' ~, "'' ',

213~866
. .
- 51 -
which extract~on took placo w~th dichloromethan~; the
extract was dried (NgS0~) and conc~ntratod, and the
residue was treatod with dii60propyl othar 3 9 g of the
product wero obtained ~n th- form of eolorloss erystal~
m p 107 to 108C

d) 3-Methoxy-4-(2,2,2-trifluoroothyloxy)pyridino-2-
earboxylic acid

0 8 g (3 3 mmol) of the abovo alcohol was dis~olv-d in a
solution composed of 0 3 g of potao~ium hydroxide and
25 ml of water, and 1 6 g of pota~ium p-rmanganate were
addod in portions at 100C and whil- otirring Aft-r
decolorlzation, the manganese dioxide which had formed
was filtered off with ~uction fro~ the hot m~xture and
waehed twice with hot waters ~he filtrat~ wae concen-
trated in va~uo to 1/3 of the volume, ad~u~ted to p~with conc agueous hydrochlorlc acid, und eoncentrat~d in
vacuo; the rosldue was treatod w~th ~ydrous thanol and
tho undis~olved matorial was filtored off 0 73 g of
product, m p 157, was obtainod frc~ t~o filtrate
~ . ,
o) 3-Mothoxy-4-(2,2,2-trifluoroothyloxy)pyridine-2-
carboxylic acid (glycyl thyl oster) umlde

0 58 g (2 3 mmol) of tho above carboxyllc acid wae
~u~pendod in 100 ml of anhydrou~ t-trahydrofuran, aft-r
whlch 322 mg (2 3 mmol) of glycin- thyl e~ter
hydrochlorlde, 0 64 ml (5 mmol) of N--thylmorpholino,
350 mg (2 6 mmol) of l-hydroxy-l~-b-nzotriazole and 53j7
mg (2 6 mmol) of N,N'-dlcyclohexylcarbodilmlde were add-d
at 20C and while etlrrlng, and tho mixture was th~n
stirred at 20C ~or 48 hours Undls~olvod matorial wa~
th-n f~ltsred off and th~ flltrat- wae eonc-ntrated ln
vacuot the residue wa~ tak-n up ln ~thyl acetate ancl
undl~eolved materlal wa~ filterod off; th- filtrate wae
~tirred together with 100 ml of a ~aturated, aqueous
~olution of Na bicarbonate, and th- organic phase waB
dried and concontratod in vacuo; the r-eidue wae

:, ~:,,;: ..
:, . ,: :,

`
213~866
.
- 52 -
cryetallized using diisopropyl othor 0 45 g of tho
colorlese cryetalline product wero obtained, m p 80 to
82C

f) 0 4 g (1 2 mmol) of tho above oet-r wa~ added to
50 ml of a 1 5 N mothanolic solution of sodium hydroxid~,
and this mixturo wa~ ~tirrod at 20C for 30 mi~utes It
wae then concantrated in vacuo and tho ros$duo was taken
up in 50 ml of wator; this mixtur~ wa~ ad~u~ted to pH 1
with comp aqu00us hydrochlortc acid and tho small amount
of undissolved material was flltor~d of~; th- filtrate
was concentrated in vacuo and the residue wae treated
wlth 50 ml of anhydroue othanol; thi~ mlxturo WaB
filtered and tho filtrate wa~ concentratod and brought to
crystallizatlon using diothyl eth-r 0 32 g of the title
15 compound wae obtained, m p 163 to 165C (with gae
evolution)

Example 2
4-Chloro-3-methoxypyridino-2-carboxylic acid glycylamide
a) 4-Chloro-2-hydroxymethyl-3-methoxypyridin-

20 30 g (173 mmol~ of 4-chloro-3-methoxy-2-methylpyridine N-
oxide (cf Example la) w-r- di~olv~d in 100 ml of
glaclal acetic acid, after which 150 ml o~ acetic
anhydride w-re added dropwis-, at 80C and while ~tir~
rlng, and th- mixtur~ was then stirred at 110C for 2
25 hours The mixture was thon cooled down to 80C ~nd 200
ml of methanol were added dropwi~e; the mixturo was then
heated to boiling for 15 minutes and, aft~r having beon
cooled down, concentrated in vacuo; the residue was taken
up in methanol and thi~ mixture was allowed to flow into
30 300 ml of a 1 5 N methanolic solution of ~odium
hydroxide, with this mixture then boing stlrred at 20C
for 30 minutes and concentrated in vacuo; th- residue wa~
takon up in wator, and this mixture extract~ad three timos
with dichloromethane, with the organic phase boing driod
and concentratod; tho residuo was crystallizod using

.' ',~ ~;

213~866
- 53 -
potroleum athor. 23 g of product were obtainod, m.p. 64
to 6SC.
: -:
b) 4-Chloro-3-methoxypyridino-2-carboxylic acid

8.65 g (50 mmol) of tho above alcohol were di~sol~ed ln
a mixturo comFosed of 0.8 g of potasslum hydroxide and
60 ml of wator, after which potas-ium pesm~ganat~ was
addod in portions, at 60C and while ~tirring, until no
moro discoloration could bo soen (12 g, 75 mmol). Aft-r
1 hous at 60C, the ma3ganeso dioxide was filtered off
wlth suction and then washed wlth hot waterS the flltrate
was concontrated ln vacuo to 200 ml and ad~ustod, while
cooling, to pH 1 with aguoou~ conc. ~Cl. After grindlng,
tho product csystallizss out in a~sociation with cooling.
Additional product can be obtalnod from tho mother liguor
by troatment with potroleum other. Total guantity, 4.2 g,
m.p. 116 to 117C (with ga~ evolution).
,
c) 4-Chloro-3-mothoxypyridino-2-carboxyl~cacid(glycyl
othyl ester) umide

4.7 g (25 mmol) of ~he above carboxyllc acld were
~uspended ln 200 ml of anhydrou~ dichloromethans, and
after that 3.5 g (25 mmol) of glyclne ethyl estor
hydrochlorldo, 6.4 ml (50 mmol) of N-ethylmorpholino,
3.8 g (28 mmol) of l-hydroxy-lH-bonzotriazolo and 5.15 g
(25 mmol) of N,N'-dicyclohoxylcarbodilmido were added
~eguentially, at 2qC a,nd while tirring, and the mixture
was th-n stirred at 20C for 20 hours. ~ndis~olved
mat-rial wa~ then ~$1t-rod off and the organic phase was
~haken with a saturated, aguoous solution of odium
carbonate, driod and ooncentrated in vacuoS th~ rosiduo
(6 g of oil) wa~ chromatographod on ~ilica g~l u-ing
~thyl acetato and 5.4 g of oily product wero obtained.

d) The t$tlo compound wa~ obtain-d by hydrolyz$ng tho
abovs othyl ester. For th$~, 0.7 g (2.6 ~mol) of th$~

213~866
- 54 -
est-r wa~ dlssolved in 50 ml of methisnol/water (3 1), and
after that 170 mg (7 ~mol) of lithium hydroxldo wero
added at 20C and while stirring Aft~r 30 minut~, the
mixture wa8 concentrated $n vacuo; tho resldue w
brought to p~ 1 with conc aquoous hydrochloric a¢ld and
thl~ mlxture was concentrated ln vacuo; the r~slduo was
troatod twlce with i~n~ydrous thanol and the ethi~nollc
phaso was concentrated; the re~ldue wa~ treated with hot
ethyl acetate and the amorphous re~ldu- was drlod on an
oil pump 0 31 g of the tltle compound was obtalned

Example 3
4-Butyloxy-3-mothoxypyrldine-2-carboxylic acld glycyl-
amide
M p 137 to 139C (with gas evolutlon, from tetrahydro-
furan)
..
-. : . :-.
: . .. ~ . . .,:
ExampleEi 4 to 16 were prepar~d in an analogou~ mannors

Example 4
3,4-Dlmethoxypyr$dine-2-carboxylic acld glycylam~d~

Example 5
3-Ethyloxy-4-(3-mothoxybenzyloxy)pyrldlne-2-carboxylic
acid glycylamlde

Exampl- 6
4-~exyloxy-3-mothoxypyrldine-2-carboxylic acld glycyl~
amlde - ~-
.., ~ . .. .
25 Examplo 7 ~ ,",;
3-Mothoxy-4-(3-methyl-1-butyloxy)pyrldlne-2-carboxylic ~ ~-
acld glycylamide

Example 8 ; ~`~
4-(4-Fluorobenzyloxy)-3-msthoxypyrldlno-2-carboxyllc acid
30 glycylamlde -

: :''::''' .":'.
. ~
",, ',,.~ ,: ';
, i ~ . ~ .:: .
:: .
.: : :. ,: .::

2~3~866

- 55 -
Examplo 9
3-Methoxy-4-(4-trifluoromothylbonzyloxy)pyrldlno-2-
carboxyllc acid glycyl ~ido

Bxamplo 10
3-Mothoxy-4-(2,2,3,3,3-pentafluoropropyloxy)pyridlne-2-
carboxylic ac$d glyeylamido :~

Examplo 11
4-(2,2,3,3,4,4,4-~optafluorobutyloxy)-3-methoxypyrldln~
2-carboxylic acid glycylamide
.
Example 12
4-(3-Mothoxybenzyloxy)-3-mothoxypyridlno-2-carboxylic
acid glycylamido ~;
:
Example 13
3-Ethyloxy-4-(2,2,2-trifluoroothyloxy)pyrldlne-2-carboxy- : .
lic acid glycylamide
~ '
Example 14
4-Butyloxy-3-ethyloxypyrldine-2-carboxyllc acld glycyl-
amlde
~. . -
::, :~: . ~ . .: . .
Example 15
3-Mothoxy-4-((phenoxyothyl)oxy)pyrldine-2-carboxyllc acid
glycylamide :`
: ,,:
Examplo 16 ;~ .; n-
3-Ethyloxy-4-bonzyaoxypyridino-2-carboxylie aeld glyeyl- ~ ~.
amide

25 Example 17 :~
3,6-Dimethoxypyridlno-2-carboxylic acid glyeylamide ~ jÇ;~`~

a1 3,6-Dlmethoxy-2-methylpyridino N-oxido .~ -

1.15 g (50 mmol) of ~odlum were dis~olvod ln 100 ml of
anhydrou~ methanol, and aftor that 7.4 g (40 mmol) of
, "".,",",,",,,,,,,~

: . ' ; , .

213~8~6
- 56 -
3-methoxy-2-methyl-6-nitropyridine N-oxide woro added at
20C and while ~tirring The mixture was th~n heatad to
reflux for 3 hours and, aft~r having boen cooled down,
concentrated in vacuo; tho re~iduo was ta~en up in wat-r
And this mixturo was oxtractod with d$chloromethane; the
organlc pha~e was dri-d and concentrated and the r~ldue
wa~ cry~tallized using diisopropyl ether 7 g of product
wore obtained, m p 63 to 65C
.~
b) 3,6-Dimethoxy-2-hydroxymethylpyridine

7 g (41 4 mmol) of the abov~ compound were react-d with
glacial acet$c acid/acetic anhydride in analogy with
Examplo lc) and the rosulting acetate was hydrolyzed
using 1 5 N methanolic sodium hydrox$de solution 5 6 g
were obtainod of oily product which wa~ sub~octed to
further reaction under c)
c) 3,6-Dimethoxypyridine-2-carboxylic acid

5 6 g (33 mmol) of the abovo compound and 2 4 g of
potas~ium hydroxide wer- di~solv-d in 150 ml of wat-r,
and after that 15 g (100 mmol) of potasslum p-rmanganate
w-re addod in portion~ at 60C and whilo ~tirring Th-
mangano~- dloxide which had formed wa~ thon filt-r-d off
with ~uction and wa~h-d twico with hot wator; the com-
bined wator pha~e was concentrated to 100 ml, ad~u~ted to
pH 1 with conc agu~ou~ hydrochloric acid while being
cool-d with ice, and concentrated in vacuo; the r-~idu~
was treat-d with othyl acetat- and othanol, and undi~
solv-d materlal wa~ filterod off from this mixturo, with
th- filtrate being concentrat-d in vacuo The r-sidu- wa~
cry~tallized u~ing di-thyl th-r 4 g of product were
obtained, m p 131-132C (with gas volution)

d) 3,6-Dimethoxypyridine-2-carboxylic acid (glycyl
ethyl oster) amid-
2 2 g (12 m~ol) of the abov~ carboxylic acid wero
~'' ' ''''" ''"'

~ ,::; ::':':
,

2~34866 ~:-
.
- 57 -
suspended in 300 ml of anhydrous dichloromothano, ~nd
after that 1.68 g (12 mmol) of glycine thyl ostor
hydrochloride, 3.25 ml (25 mmol) of N-~thylmorpholine,
1.62 g (12 mmol) of l-hydroxy-l~-benzotriazole and 5.2 g
(12 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbo-
diimide mothyl-p-toluen~ulfonato wero add~d, w~ilo
~tirring, and tho mixtur~ was then ~tirr~d at 20C for
20 hour~. Tho ~mall amount Oe undio~olved mat~rial wa~
then filtered off ~nd the filtr~te wa~ cha~-n once with
wator ~d ~hen with a ~aturatod, aquoou~ solution of Nn
bicarbonate; the organic pha~e was dr~od and concentrated
in vacuo and tho re~idue was crystallizod using diloo-
propyl ethor. 2 g of product wore obtainod, m.p. 93 to
95C.

e) The title compound wa~ obtalned by hydrolyzing 0.6 g
(2.24 mmol) of the above ethyl oster at 20C u~lng 120 mg
of lithium hydroxide in 60 ml of methucol/wator (3
After concentration had taken place in ~acuo, the re~idue
was acidified and extracted, at 20C, with tetrahydro-
furan; the filtrate wa~ concentrated in vacuo and the
yellow, re~inous re~idue wa~ cry~tallized u~ing diethyl ~ -
other. 0.14 g wero obtalned of the title compound, m.p.
130C (decomposition), which i~ ~trongly hygroccopic. The
re~idue from the in~pis~ated reaction mixturo wae then
extracted three tim-~ with 50 ml of hot aceton~ on each
occa~ion and the in~pis~ation re~idue wac cryctalllzcd
u~lng dlethyl ethor. A further 0.35 g of tho title
compound wa~ obtainod, m.p. 155C (decomposition).

Example 18
3,5-Diethoxypyridine-2-carboxylic ac$d ylycylamide

~Sxample 19
3-Methoxy-6-(3-methyl-1-butyloxy)pyridine-2-carboxylic ~ ;
acid glycylamide ~ ;
M.p.: 105 to 107C (from aqueou~ hydrochloric acid, p~ 3
to 4)

":~

213~86~

- 58 -
Exsmple 20
3-Benzyloxy-4-(3-ethyloxypropyloxy)pyridine-2-oarboxyllc
scid glycylamide
M.p. 118-120C (from acetone)
According to lH NMR, tho product contains ~pproximatsly
15 % of the 3-hydroxy dorivativo.

Example 21
3-Benzyloxy-4-hexyloxypyridi~o-2-csrboxylic acid glycyl-

M.p. i30 to 132C (from agueou~ hydrochloric acid)

Example 22 ~ ,j?~
6-(2-Butoxyethyloxy)-3-mothoxypyridlne-2-carboxyllc ac~d
glycylamide
: ,,., ~.... ~
Example 23
6-(2-Cyclohexyl)ethyl)oxy-3-methoxypyridine-2-carboxylic
acid glycylam~do ~-
M.p. from 70C (~intering from 50C, from aqueou~ hydro-
chloric ac~d, p~ 3)

Examplo 24
20 3-Ethyloxy-6-~ethylpyridino-2-carboxylic acid glycyl- ````~
amid~
: ', , .: ,', . . .
Example 25
6-Bonzyloxy-3-methoxypyr;d~ne-2-carboxylic acid glycyl-
amide
"' . ,. ~
25 Example 26 '! ' ;,.. ',.'
3-Benzyloxypyr$dine-2-carboxylic acid glycylam~do
M.p. 142-144C

Examplo 27.1
3-Methoxypyrldine-2-carboxyli¢ acid glycylamlde
amorphous ~ub~tanco, pr-pared by hydrolyzing tho 3-
methoxypyridine-2-carboXlic acid (glycyl othyl ost-r)
amlde, m.p. 141 to 142C (with ga~ ovolutlon, from

2~ 3~866

- 59 -
diothyl other).

This ethyl ester was obtalned by catalytic hydrogenation
of 4-chloro-3-methoxypyridine-2-carboxylic acid (glycyl
othyl estor~ ~mido (ooo ~x~mple 2c), whlch wa~ obtainod
from 4-chloro-3-mothoxypyrldine-2-carboxylic acid (m.p.
119 to 120C, from 4-chloro-3-mothoxy-2-mothylpyridine N-
oxide by reaction with acotic anhydride/glacial acotic
acid and subseguont oxidation of tho 2-hydroxy~ethyl-
pyridino dorivativo) (~oe Examplo 2a, b3 ~nd glyclno
othyl ootor hydrochlorido.

Example 27.2
3-Methoxypyridino-2-carboxylic acid glycylamlde
hydrochloride

a) 4-Chloro-3-methoxypyridine-2-carboxylicacid(glycyl
benzyl e~ter) ~do ~ ~-

The product was obtained, in analogy with Examplo 90a), ~ ~', ,'`''''',J~
from 4-chloro-3-methoxypyridino-2-carboxyllc acid (cf.
Example 2b), glycine benzyl ostor tosylate, N-ethylmor-
pholine, l-hydroxy-lH-benzotriazole and CMC, m.p. 57-
20 58C. ~ ~
..: , ,., , :'
b) The title compound wao obtained by hydrog-nating the
above product in mothanol/tetrahydrofuran (1:1) uoing Pd ;~
on charcoal (10 %) in a hydrogenatlon v-~el. After
removing the catalyot, and freeing from the oolv-nt, the
product was crystallized using acetone, m.p. 168C (with
foaming). ;~
' ~: ~ ' '.:,
Examplo 28
3~Ethoxypyridins-2-carboxylic acid glycylamide ~ - ~
: ' ' '
, :, .
Examplo 29 ;
3-Propyloxypyridine-2-carboxylic acid glycylamide

.

213~866
- 60 -
Example 30
3-Butyloxypyr~d~ne-2-carboxyl~c acid glycylam~de
a) 3-n-Butyloxypyr~dine-2-carboxyl~c ac~d
:"-,
6 g ~150 mmol) of N~H (60 %, in minoral oil) were added
in portions, at 20C and whll- stirrlng, to 9 8 g
(70 mmol) of 3-hydroxypyridino-2-carboxyli~ acld ln
150 ml of N,N-dimothylac-tamide Aftor 30 m~nut-s, 15 ml
(140 mmol) of butyl bromide wero added dropwiso and the
mixture was hoatod at between 95C and 125C for 2 5
hour~ After havlng boen cooled down, ~he mixture wa~
concentrated ~n vacuo, treatod w~th an aqu-ou~ solution
of Ni~ blcarbonato and oxtractod wlth dichloromethanes
aftor drying, tho residuo was puri~ied by chromatography
on sllica gel uolng ethyl acetate
The 13 g of oily product thus obtained were lntroducod
into 250 ml of a 1 5 N mothanollc ~olutlon of sodlum
hydroxide, and the m~xturo wa~ then ~tlrrod at 20C for
30 minutes and concentrated ln vacuo; the residue was
ta~en up in 200 ml of water and thi~ mixturo wae
extracted with dichloromethano and the ~quoouo phas- was
ad~u~t-d to pH 1 with conc aquoou~ hydrochlorlc acld~
conc-ntration took place ln vacuo and tho re~ldue wao
troatod wlth othyl acetato and thon wlth anhydrous
ethanol Tho r-~ultlng ~olutions wore conc~ntr~tod and
the reoidue wa~ crystallized using acetono 9 3 g were
obtained of product (m p 93-95C) which, accordlng to lH
NMR, otlll contalnod approxlmately 20 % of 3-hydroxy-
pyrldino-2-carboxylic acld

b) 2 8 g (20 mmol) of glyclne ethyl ster
hydrochlorld-, 5 2 ml (40 mmol) of N-ethylmorphollno,
2 7 g (20 mmol) of l-hydro~y-lH-benzotrlazole and 3 0 ml
(20 mmol) of N,N'-dllsopropylcarbodilmid- were added, at
20C and whlle stirrlng, to 4 g (20 mmol) of th- above
product in 200 ml of anhydrous tetrahydrofuran and 100 ml
of anhydrous acetonltrile, and the m~xture wa~ then
otlrred at 20C for 20 hours

, ,''': .

2134866
- 61 -
Aftor wor~ing up ~treatmont with Na bicarbonate oolution,
removal of precipitated diisopropyluroa), 3 5 g of oily -
product, which ~till contained N,N'-diisopropyluroa, w~ro ~ -
obtained following chromatography on oilica gol (ethyl
ac-tato/n-hoptane 1 1; then puro othyl acotato)
Thi~ mixture was introduced, at 20C and whllo ~tirring, ~ ;
into 150 ml of a l S N methanolic ~olution of sodlum
hydroxide and the total mixtur- wa~ stirred for 30 ~ ;s-
minutes
Thi~ latter mixtur- wa~ th n conoontrat-d in vacuo and
the re~idue wao ta~en up in waterS thi~ mixtur- wac ~n
turn oxtractod with 200 ml of dlchlorom than- and the
agueou~ pha~e wa~ brought to pH 1 u~ing conc aqueouc 8Cl
and concentrated in vacuo; th- residuo wao tr-at-d with
anhydrous ethanol and thon with N,N-dim thylfo-m~mide,
wlth ach extract boing f~lt-r-d to romove undis~olved
mat~rial and th-n con¢entrat-d and each of the r-oiduoo ~- m;-
being cry~talliz-d u~ing thyl acetat- 1 65 g of th~
title compound w re obtained from the ethanol phaoe ~
20 (~lightly contaminat-d according to '8 NMR, m p 170C ~ ~"X,
with gac evolution) and a furth-r 0 63 g from the
dimethylformamide phaoo (m p 182C, with ga~ ovolution)

~xa~plo 31 ~ -
3-~4-Chlorob-nzyloxy)pyridino-2-carboxylic acid glycyl-
amld-

a) 4-Chlorob-nzyl 3-(4-chlorob-nzyloxy)pyrldine-2-
carboxylate

8 4 g (60 mmol) of 3-hydroxypyridine-2-carboxyllc acid
w-r- alkylated (3 houro, 110C) with 5 2 g (approximatoly
130 Iol~ 60 ~) of ~odium hydride and 19 3 g (120 mmDl)
of 4-chlorobonzyl chlorld- ln N,N-dlm-thylacotamido in
analogy with ~xampl- 30a) Aft-r concontration in ~acuo
and xtraction wlth Na bicarbonate solution, th- r-cidu-
wao purifi-d on oillca gol u~lng h-ptano/ethyl aoetat-
(lsl), and 14 8 g of th- product were cry~tallizod from
appropriate fractiono u~ing diioopropyl eth-r, m p 92 to

213~866
.
- 62 -
94C.
b) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid

9.7 g (25 mmol) of the above e~ter were hydrolyzed w$th
200 ml of a 1.5 N mothanolic ~olution of eodlum hydroxide
(24 h, 20C). After working up (concontratlon, taking up
of the reslduo in wator, extraction w~th dlchlorometh~ne
and acidificatlon), 6.5 g of product were obtainod, ~.p.
144C (from water, decompo~ition).

c) 3-(4-Chlorobenzyloxy)pyrldine-2-car~oxyllc (glycyl
othyl ostor~ amide

3.2 g (12 mmol) of the above pyridine-2-carboxylic acid
were reactod, in analogy with example 17d), with 1.7 g
(12 mmol) of glycine ethyl ~ster hydrochlorido, 1.62 g
(12 mmol) of l-hydroxy-(lH)-benzotriazolo, 3.3 ml (25
mmol) of N-ethylmorpholine and 5.2 g (12 mmol) of N-
cyclohexyl-N'-(2-morpholinoethyl)carbodiimlde ~othyl-p-
toluene~ulfonat~. After working up, 3.0 g of tho product
were cry~tallized u~ing dii~opropyl ether, m.p. 106 to
108C.
.
d) Th~ title ¢ompound wa~ obtnined by hydrolyzi~g the
abov- ethyl e~t-r. 120 mg (5 mmol) of lithium hydroxide
w-re added to 0.9 g (2.5 ",ol) of the ethyl e~ter in
60 ml of methanol/wator (3:1), and the mlxtur~ wae
~tirrod at 20C for l hour. It wa~ then concentratod in
vacuo and the re~ulting agueou~ pha~- was ad~u~tod to
pH 3; the ro~ulting precipitate wa~ filtored off with
~uction, wa~hed with water and dried in vacuo. 0.52 g of
tho title compound wa~ obtained, m.p. 155 to 157C. ~-

Examplo 32
3-(3-Nethoxybenzyloxy)pyridine-2-carboxylic acid glycyl-
amlde

' ,: '', '~`;'
.,, "
~ ":,''' "

213 ~866

- 63 -
a) 3-Methoxybenzyl 3-(3-mothoxybenzyloxy)pyrldlno-2-
carboxylate

In analogy with Examplo 38a), 10 g of ths product woro
obtalned as a colorles~ oil, which was sub~octed to
further reactlon, from 8.4 g (60 mmol) of 3-hydroxy~
pyrid~na-2-carboxylic acid and 3-methoxybenzyl chlorlde
following chromatography on ~ilica gol.
i ~ . ~",
b) 3-(3-Methoxybenzyloxy)pyr$dlne-2-carboxyllc acid

10 g of the above e~tsr were hydrolyz-d in 300 ml of a ;~
1.5 N methanolic eolutlon of eodlum hydroxide. 7.5 g of
product were obtained, m.p. 147C (docomposltion, from
agueou~ hydrochlorlc acld)

c) 3-(3-Me~hoxybenzyloxy)pyrldlne-2-carboxyllc acid ;
(glycyl ethyI ester) amlde

3.2 g (12 mmol) of th~ above car~oxyllc ncid were reacted
in analogy wlth Example 31c). 3.6 g of olly crudo product
wero i~olated which, accordlng to the H NMR opectrum,
etill contalned N-ethylmorphollne. The pure cub~tanc-,
m.p. 135 to 137C (from dlleopropyl ether/ethyl acetate)
wa~ obtalned from thl~ crude product.

d) 2.1 g (6 mmol) of the above product wor~ hydrolyzed
u~lng O.4 g of NaO~ ln 60 ml of methanol. Followlng
acldlflcatlon to p~ 3, 1.6 g of th~ title compound wore
obtained aa a colorle~s cry~talline ~ub~tanco, m.p. 89 to
91C (from aguoou~ hydrochlorlc acid).

Ex~mplo 33
3-(2-Phonylethyloxy)pyridlne-2-carboxyllc acld glyayl-
amld- ~odlum salt
~,
a) 3-(2-Phenylethyloxy)pyrldine-2-carboxyllc acld
In analogy with Example 30a), 8.4 g (60 mmol) of

213~866
- 64 -
3-hydroxypyrid$ne-2-carboxylic acid w~re al~ylatad with
Na~/2-phenylethyl bromide in N,N-dim~thylacetamide. The
10 g of oily product obtained after purification by
column chromatography were hydrolyzod w~th methanoliG
eod~um hydroxide solution in analogy with Examplo 30a).
3 g of product were obtained (m.p. 145C (with fo~ming~
from acetono)) which, according to the 1~ NMR spectrum,
contained approximately 25 % of 3-hydroxypicolinic acid.
:-, :, :.- ,.
b) 3-((2-Phenylothyl)oxy)pyridin--2-carboxylic acld
(glycyl ethyl ester) ~do
, -: " ~
2.9 g of the abo~e compound wer~ roacted, ln ~nalogy w~th
Example 30b), w~th glycino ethyl estor hydrochloride, N-
ethylmorpholine, 1-hydroxy-lH-benzotriazole and N,N-
dicyclohexylcarbodiimide. After working up, the crude
product wa~ chromatographed on ailica g-1 using ethyl
acetate. 3-Hydroxypyridine-2-carboxylic acid (glyoyl
ethyl e~ter) amide was initlally eluted ao a by-product
and cry~tallized fro~ appropriate fraction~ using petro-
leum other; 1.1 g (m.p. 86 to 88C, strong fluore~conce
in W light). The product was then crystallized from
appropriate fractions using diisopropyl ethor, and 1.7 g
of the product wero obtained, m.p. 73-75C.

c) The titl- compound wa~ obtained by hydrolyzing
0.99 g (3 mmol) of the above ethyl e~ter using 100 ml of
a lN methanolic solution of sodium hydroxide. After the
mixture had been stirred at 20C for 1 hour, it wa~
conc-ntrated and the rosldue was dissolved ln a little
water~ this latter mixture was extracted wlth dichloro-
methano and the agueous pha~e was acidified, while being
cooled with i¢e, to p~ 1 using conc. agusou~ hydrochloric
a~id and then concontrated in vacuo; the residuo was
oxtracted twico with totrahydrofuran and the extracts
were concentrated~ the r-sidue was di~solvod in a little
water/tstrahydrofuran (lsl), and 252 mg (3 mmol) of
~odium bicarbonate wore added to thls ~olution. This
mlxture was concentrat-d to dryne~ and th- r-~idue was

,

213~866

- 65 -
crystallizsd using anhydrous ~thanol. 0.38 g of the title
compound was obtained as sodium ~alt, m.p. ~ 300C. ~ ~ -

Exismple 34 ~ -~
3-(4-Trifluoromethylbonzyloxy)pyridiae-2-carboxyllc acid
glycylamide
M.p. 161 to 163C (from aquoous hydrochloric acid, pH 3)
, ~ .; :.. :,-
Example 35
3-(4-(2-Propyl)benzyloxy)pyridine-2-carboxylic acid ` j ;
glycylamide ~odium ~alt
10 M.p.-108C (with decomp., from d~l~opsopyl other)

Example 36 ~;
3-(4-Fluorobenzyloxy)pyridino-2-carboxylic acid glycyl-
amide
M.p.: 135 to 138C (from agueous hydrochloric acid, pH 3
to 4)

Example 37
3-(4-(2-(4-Msthoxyphenyl)ethylamino)carbonyl)b nzyloxy)-
pyridine-2-carboxylic acid glycylamid-
M.p. 168-170C (from dichloromothan-) -

Tho following xample no~. 38-64 w-re preparod in an
analogous manner:

Exi~mple 38
3-(2,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid
glycylamido , ;~

25 Examplo 39 ,
3-(3-Fluorobonzyloxy)pyridine-2-carboxylic acid glycyl- ~;~
amido
~:.... ,:; .
Exunplo 40
- 3-(3-Chlorobenzyloxy)pyridine-2-carboxyllc acid glycyl-
30 i3mide ;~
, ,, ., :: ::
, ~'' ' ~`', "' '''",

: ' ' ~ ,', ` ':

213~866
. ,
- 66 -
Example 41 .
3-(3,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid
glycylamide -- .

Example 42
5 3-(3-Trifluoromotkylbenzyloxy)pyridine-2-carboxylic acid ; :::
glycylamido

Examplo 43 . ~
3-(4-Trifluoromethoxybonzyloxy)pyridine-2-carboxylic acld ::
glycylamide

Example 44
3-(3-Ethoxybenzyloxy)pyridino-2-carboxylic acid glycyl-
amido .

Example 45
3-(4-Cyanobenzyloxy)pyridino-2-carboxylic acid glycyl-
amide

Exa~plo ~6
3-((2-Pyridylmethyl)oxy)pyridine-2-carboxylic acid : :
glycylamido hydrochloride
:'.' . '..'.
Exampl- 47 ~ .
3-((3-Pyrldylmothyl)oxy)pyridine-2-carboxylic acid
glycylamido hydrochloride .. :

Examplo 48 .~:
3-((4-Pyrldylmethyl)oxy)pyridino-2-carboxylic acid ~ ~:
glycylamido hydrochlorido ~:

Examplo 49
3-((2-Thionylmethyl)oxy)pyridino-2-oarboxylic acid
glycylamldo

Exampl- 50 ~.;
3-(3,5-Dim~thoxybenzyloxy)pyridino-2-carboxylic acid
30 glycylamide -~
:. ~, ": :,
: ~ . ., :. .
... ,-
.. .
,,: , :

213~866
- 67 - ;~
,
Example 51
3-Cyclohoxyloxypyridine-2-carboxyllc acid glyeyla~ido

Example 52 ~ ~ :
3-(3-Phenylpropyloxy)pyridine-2-carboxylic acid glycyl- . -
amide
. :~
Examplo 53 .
3-(4-Phenylbutyloxy)pyridino-2-carboxylic aeid glycyl-
amide :

Examplo 54
3-(((4-Nethoxy-2-pyridyl)methyl)oxy)pyridino-2^earboxylic
acid glyeylamide :

Example 55
3-(((4-Ethoxy-2-pyridyl)mothyl)oxy)pyr~dino-2-carboxylic -
acid glyeylamide
-: -
Example 56
3-Methylthiopyridine-2-earboxylic acid glycylamide ~
~ .
Example 57
3-Ben~ylthiopyridino-2-earboxylic aeid glyeylamide : ~:;

Examplo 58 ~ .
3-(3-Chloroph-noxy)pyridine-2-earboxylie aeid glyeyl~
amide

Ex~mple 59 :~
3-~3-Methoxyphonoxy)pyridino-2-earboxylie aeld glyeyl-
amido
. ,.:.. :: .. : ::
~: . :..;.:: ~ ,:
25 Example 60 :~
3-Phenoxypyridine-2-earboxylie acid glyeylamide
:::, : .,
Example 61
3-~utyloxypyridine-2-earboxylie aeid ~-alanylamide

2134866
~ .. ..
..:..:.
- 68 -
Example 62
3-Butyloxypyridino-2-cnrboxylic acid D-alanylamido
'
Example 63
3-Benzyloxypyridine-2-carboxylic acid ~-alanyl~nide

Example 64
3-(3-Methylbutyloxy)pyridino-2-carboxyllc ac~d ~-leucyl-
amide

Example 65
4-Methoxyi~oquinoline-3-carboxylic acid glycylamide

a) Methyl 1,2-dihydro-4-hydroxy-1-oxoi~oqulnoline-3-
carboxylato, wa~ propared a~ de~cribed (~. Suzuki et ;~
al., Synthe~ie 1978, 461). -

b) Mothyl 1,2-dihydro-4-methoxy-1-oxoisoguinoline-3-
carboxylato, from a) u~i~g (trimethyl~ilyl)-
diazomethano in methanol/ac-tonitrile, m.p. 177 to ;
179C (ethyl acetate/hoptano).

c) Mothyl 1-chloro-4-mothoxyi~oquinolin--3-carboxylate,
from b) using pho~phoru~ oxychlorido, m.p. 108C
(othyl ac-tate).
~' .~ .. ,', ' ., .:
20 d) Mothyl 4-mothoxyisoguinolino-3-carboxylate, from c) ;
uoi~g hydrogon/Pd/C, m.p. 129C (from mothyl tert- ~ ~`
butyl other).
',":':,':
o) 4-Methoxyi~oguinolino-3-carboxylic acid, from d) by ~ -
hydroly~i~, m.p. 185-189C (from aguoouc hydro-
chloric acid). ``

f) 4-Mothoxyi~oquinolino-3-¢arboxylic ~cid (glycyl ~ ~;
mothyl o~tor) amido, from e) u~ing glycine mothyl
e~tor hydrochlorido, DCC, HOBT, THF and NEM, oily
~ubstance (crude product).

,:., ''.'"'",,;' ''''


213~866
- 69 -
g) The titlo compound wae obtained by hydrolyzing the
abovs ~ethyl eetor, m.p. 147C (fram agueoue hydro-
chloric acid)

Examplss 66 to 76 were obtained in an analogou~ mannsr
from ths correeponding ieoguinoline-3-carboxylia acid~ or
the 5,6,7,8-tetrahydro derivativos, reepecti~sly~

Exampls 66
4-Ethoxyisoquinoline-3-carboxylic acid glycylumlde

Examplo 67
10 4-Propyloxyieoguinoline-3-carboxylic acid glycylamido .

~xampls 68
4-(3-Nethylbutyloxy)ieoguinolin~-3-carboxylic acid
glycylamide
.,:. :,,
Example 69 - ~
4-Methoxy-5,6,7,8-tetrAhydroieoquinoline-3-carboxylic ~ :
acid glycylamide
. I ~, ~ .
Examplo 70
4-(3-Mothylbutyloxy)-5,6,7,8-tetrahydroieoguinoline-3-
carboxylic acid glycylamido
: :. . .,:. ~";.
20 Examplo 71 . ::~
4-Ethoxy-5,6,7,8-tstrahydroieoguinollno-3-carboxylic acid
01ycylamide ~,~ ;,:':,.'~.;~::'
, ~ ~, ,, . .:
Examplo 72
4-Bsnzyloxy-5,6,7,8-t~trahydroieoguinolino-3-carboxylic
25 acid glycylamide -
.
Examplo 73
4-Benzyloxyi~oguinoline-3-carboxylic acid glycylamids : ~: '~A .


''~ ~''~`"''''''.

213~866
- 70 -
Example 74
4-(3-Methoxybenzyloxy)-5,6,7,8-tetrahydroisoguinoline-3-
carboxylic acid glycylamide

Example 75
7-Bromo-4-methoxyisoguinollno-3-carboxylic acid glycyl-
amide

Example 76
7-Methoxy-4-methoxyisoguinolin~-3-carboxyllc acid
glycylamide

Example 77
3-Mothoxy-6-((3-methylbutyloxy)methyl)pyridlne-2-
carboxylic acid glycylamlde ~
.,~ ; : ~ :,,
Example 78
3-Methoxy-6-((cyclohexyloxy)methyl)pyrldln--2-carboxylic
15 acld glycylamide ;

Ex~mplo 79 ,
3-Methoxy-6-benzyloxymothylpyridine-2-carboxylic acld
glycylamide

Exampl~ 80 to 91 were propared ln accordanco wlth the
procesc-s de~crib~d in Schemes 1, 2 and 3

Example 80
5-Carboxy-3-methoxypyridlne-2-carboxyllc acld glycyl-
amlde

270 mg of tho tltle compound ~rom Example 81 wer-
hydrolyzod at 20C uslng 50 ml of lN methanollo NaO~
After 30 minute~, the mlxture was concentrated ln vacuo
and tho resldue wae dl~solved in 50 ml of water; thl~
~olutlon was oxtracted with dlethyl ethor and tho aguoous ;
phase wa~ ad~u~ted to p~ 1 wlth conc~ agueou~ hydro- ;~
chloric acid and thon concentrated ln vacuo; tho wator
was removed azeotropioally from the resldue u~lng ethyl

213~866
- 71 -
acetate and the ros~due wa~ then troated with othanol and
thi~ mixture wa~ concentrated; the r~iduo was cry~tal-
lized u~ing d~ethyl othor. 230 mg ware obtainod of the
titlo compound, m.p. 173C (with gas evolution, sintering
at 170C), whlch, according to the lH NMR sp-ctrum, ~till
contain~ approximatoly 20 ~ of an impurity.
.
The title compound wa~ al~o obtained by hydrolyzing
0.45 g of 5-((-1-butyloxy)carbonyl)-3-methoxypyridin--2-
carboxylic acid N-(((1-butyloxy)carbonyl)me~hyl)amido,
m.p. 80-81C (from petroloum ether~, using 50 ml of 1.5 N ~;~
methanolic NaO~. 0.23 g was obtainod of tho titlo com-
pound, m.p. 198-200~ (from an othanolic pha~o w~o~o
re~idue, following concontration, wa~ crystallizod ucing
diethyl ethor). According to tho '~ NMR ~poctrum and MS,
the aub~tance contain~ approximately 5-10 % of it~ othyl
e~tor.

The isomeric 2-carboxy-3-methoxypyridine-5-carboxylic
acid glycylamido wa~ obtalned in an nnalogou~ mann-r,
m.p. from 65C (~intering from 45C, with foaming, from
20 diethyl othor, ~ygroscopic). -
'' ; ': ~ :: :
Examplo 81 ~ ~ `
5-M-thoxycarbonyl-3-methoxypyridine-2-carboxylic acid ;~
glycylamid~
a) 5-Nethoxycarbonylpyridine-2-cnrboxylic acld l-ox~de

12 g (60 mmol) of dimothyl pyridine-2,5-dicarboxylato
woro ~uspsnded in 30 ml of glacial acotic acid, and aft-r -~ ;
that 13 ml of hydrogen peroxid- ~35 %) wer- added at 20C
and whil- ctirring. Tho mixture wa~ than hoat-d to 100C
(intornal temp-rature), whilo ~tirring, with a clear
solution boing for~od at 50C. Aftor the mixturo had b-en
~tirred at 100C for g0 minut-s, it wae allowed to cool
down to 20C and the cry~talline precipitate was filt~r-d
off w$th ~uction and wa~hed with wator; After drying,
7.5 g of product wero obtained, m.p. 160C (decomp.).

. .
, . ,::

213~866
- 72 -
b) Dimethyl 3-chloropyridin~-2,5-dicarboxylate

17 ml of thionyl chlorido, 35 ~1 of anhydrous chloroform
and 1 5 ml of N,N-dim-thylformamide wore hoated to 60C,
whilo stirring, and 7 5 g of tho above product w~ro then
added in portions at thi~ tomperatur~ The mixturo was
thon stirred at 60C for a further 60 minuto~, and, after
cooling, tho solvent and exeo88 rsagsnt were di~tllled
off in vacuo; dichloromethano wa~ added to the re~ldue,
and the N,N-dimethylform~m~de x ~Cl complex wns filtor-d
off with ~uetion and wa~hed w$th dichloromethuno
Approximately 15 ml of triethylamin- and 10 ml of
methanol wore addod, whil- ¢ooling, to the mothor liguor
and the mixturo was stirrod for 30 minute~ After eoneon-
trating by evaporation in vacuo, tho residuo was dia-
solvod ~n 50 ml of wator and this mixture wAs thenextracted 3 x with dichloromethane; th- organie phase was
dried and concentr~tod, and tho rssidue wa~ chr o to-
graphed on silica g-l u~ing n-heptano and n-heptane ethyl
acetate ~3 1) 5 3 g of product were crystallizsd, using
potroleum ether, from appropriato fractlon~, m~p 36 to
38C

c) 3-Mothoxypyridln--2,5-dlcarboxylic acid

53 g (0 231 mol) of tho abovo dloster wore di~solved in
500 ml of metha~ol, and after that 150 ml (0 81 1) of
eodlum methoxide solutlon (30 % ln mothanol) were added,
at 20C and whilo ~tirring, whereupon tho temporaturo
roeo to 30C The mixturo was heatod undor r-flux for
4 5 houre, 300 ml of wator wer~ add-d at 20C, and tho
mlxturo was thon ~tirrod at 35C for 30 minutes The
oxces~ mothanol w~s distillod off ln vacuo and the
aquoous phase was ad~u~ted to p~ 2, while eooling, with
half-concentrated aqueous hydrochloric ac~ds the color-
le88 crystalline product wa~ filtered off with euctlon
and dried 49 g were obtalned, m p 185C (gas vo-
lution); 2S5C (decomp )
~ .




',,.,,, , ., ,/" ,,",."~.. ... ..... .... ...

213~866
.
- 73 -
d~ Dimothyl 3-methoxypyr~dino-2,5-dicarboxylato, cf.
Exa~ple 90a)

o) S-Mothoxycarbonyl-3-msthoxypyrldin--2-carboxylic
~cid -.

The compound was obtain-d, as a mixture with tho ~someric
monomethyl sster (Gf. Examplo 90a)), fro~ 3.4 g (15 ol)
of the above dia~ter by hydroly~i~ with a d~lute olutio~
of methanolic sodium hydroxide (0.54 g of NaOH (13.5
mmol)). 1.8 g of monoo~ter m~xture, m.p. 152C, w~r-
obtatned in addltion to 0.8 g of unreaoted die~t-r.
::, .~, ;.:~..,
f) 5-Methoxycarbonyl-3-methoxypyridlne-2-carboxylic
acid (glycyl benzyl ester) amido ;~

1.8 g of tho above mixturo wore cond~nsod, in analogy
with Examplo 90b), wlth 2.9 g (8.6 mmol) of glyclne
benzyl eeter tosylat- in tho pre~once of N--thylmor-
pholine, l-hydroxy-l~-bonzotriazole and CMC. A~tor
working up, 2.3 g of oily mixture wore chromatogra~hed on
~ilica gel u~ing dichloromothane ~in the pres-nco of ~p
to 2 % methanol). 0.82 g of product wa~ obt~lnod, m.p.
108C. 0.6 g of th- olly l~omor was al~o lsolatod.

g) The tltle compound wa~ obtained by di~solvlng 65Q mg
of tho above benzyl ~ster ln 100 ml of totrahydrofuran/
methanol (1:1) and hydrogenatlng it u~ing Pd/C ~n a
hydrogenation vessel. Onco the cataly~t had b~en filtorod
off wlth ~uctlo~, the filtrato was concontrated and tho
reslduo was cry~tallizod u~lng diothyl othor. 380 mg woro
obtal~ed of a colorles~ crystalllne product, m.p. 158 to
160C. ;;

Ex~mple 82
5-(3-Pentyloxy)carbonyl-3-methoxypyrldine-2-carboxyllc
acld glycylamlde ;~;

.~ . ., ~.Z~,`.
, . . ,:.,,: ,
.. . .... .

2134 86G
- 74 -
Example 83
5-Cyclohexyloxycarbonyl-3-methoxypyridino-2-carboxyllc
acid glycyl~mide

Examplo 84
5-(n-Butylam$nocarbonyl)-3-methoxypyridino-2-carboxylic
acid glycylamide

Example 85 -
5-(2-Msthyl-2-butylaminocarbonyl)-3-methoxypyrid~ne-2-
carboxylic acid glycylamide

10 Example 86 - ;~
5-(Cyclohexylaminocarbonyl)-3-methoxypyridine-2-car- , -~
boxylic acid glycylamide

a) 5-(Cyclohexylaminocarbonyl)-3-methoxypyridine-2-car-
boxylic acid
Tho product was obtained, ln analogy with Ex mple 90b),
from 5-carboxy-3-m-thoxypyridin--2-carboxylic acid and
cyclohexylamine,
m.p. 155C (sintering at 80C, from aqu-ouc hydrochloric
acid).
:..~ . :: .. :..0 b) 5-~Cyclohexylaminocarbonyl)-3-methoxypyrldino-2-
carboxyllc acld ~glycyl ethyl e~ter) amlde
The product wa~ obtaln-d, ln analogy with Example 90c),
from th- above compound, m.p. 187 to 188C (from dl-thyl
eth~r)

c) The colorle~ crystalllne title compound wa~
obtalned by hydrolyzlng the abovo compound ln analogy
wlth Example 90c),
m.p. 110C (wlth foamlng, a desp-blac~ coloratlon at
240C).

Examplo 87
5-(Cyclohexylaminocarbonyl)-3-ethyloxypyridin--2-car-
boxylic acid glycylamido
- :,
.,~; ,
' . . ~: ~ ..,

213~866
- 75 -
Exampl~ 88
5-((2-Phonylothyl)aminocarbonyl)-3-mothoxypyridine-2~
carboxylic acid glycylamido --
Examplo 89
5~ )-Dehydroabietylaminoearbonyl)-3-methoxypyrldine-2-
carboxylic acid glycyl~mide

a) 5-(~)-Dohydroabi~tylamlnocarbonyl)-3-methoxy- ;- ~;
pyridine-2-carboxyllc acid

The resinou~ product wa~ obta~nod, in analogy with
Examplo 90n), fro~ 5-carboxy-3-mothoxypyridin--2-oar-
boxylic ~cid and ~I)-dehydroabiotyl~mine.

b) 5-((+)-Dehydroabi-tylaminocarbonyl)-3-mothoxy-
pyridino-2-carboxyllc acld (glycyl thyl e~ter)
amide

The product WaB obtained in analogy with Exa~ple 90c),
from the above compound, m.p. from 150C with foaming,
~intering at 120C, from di-thyl ethor).

c) Tho tltlo compound wa~ obtalnod by h~drolyzin~ th-
above compound ln analogy wlth ~xampl- 90 d),
m.p. 215C (sintoring at 150C, from aquoous hydrochloric
acld).
" ~"r~
Example 90
5-((2-(4-Fluoroph-nyl)othyl)aminocarbonyl)-3-methoxy- ; ~ ;~
pyrldine-2-carboxylic acid glycyl~mid-

a) Mothyl 5-carboxy-3-mothoxypyridin--2-carboxylate

10 g (50.7 ~mol) of the 3-mothoxypyridine-2,5-dicar-
boxyllc acid (Example 81c) were ~uspended ln 150 ml of ;
anhydrou~ m-thanol, and after that 2 ml of concentrat-d
~ulfurlc acid wer- add-d and the mlxture was heatod under
reflux for 3 hour~. Half of tho methanol was then
di~tilled off in vacuo and the residue was lntroduced ~;


, ~ , . .;: ,:

213486~
- 76 -
into 400 ml of ic8 water; the cry~talline re~idue wa~
filtered off with suction and wa~hed w~th water; the
residue wao dissolvod in 150 ml of a ~aturatod, aqueous
~olution of Na bicarbonate and this mixtur~ was extracted
twice with 80 ml of dichloromethane on each occa~ion; the
bicarbonate phaso was adju~ted to p~ 1, while cooling,
with half-concentrated aqueous hydrochloric acid and the
precipitat0d product was flltered o~f with ouction and
driod. 5 g of colorl-ss, crystalline ~ub~tance wore
obtained, m.p. 196 to 197C. 1.7 g of dimethyl e~ter,
m.p. 53 to 55C (from petrol-um sther), wero obtainod
from the dichloromethane phaoo.

b) 5-(((2-(4-Fluorophonyl)othyl)amino)carbonyl)-3-
methoxypyridine-2-carboxylic ~cid

3.2 g of methyl 5-carboxy-3-methoxypyridine-2-oarboxylate
were eu~pend~d in 300 ml of anhydrous dichloromethano,
and after that 2.0 ml (15 ~mol) of 2-(4-fluorophenyl)-
ethylamine, 1.95 ml (15 mmol) of N-ethylmorphollne, 2.2 g
(16.5 m~ol) of 1-hydroxy-1~-benzotriazole and 6.35 g
(15 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodi-
imide methyl-p-tolueneoulfonato (CMC) were added sequen-
tially, at 20C and whilo otirring, and the mixture wao
otlrrod for 24 hours. Ths undis~olvod matorial wa~ then
filterod off and tho organic pha~e was extracted, in each
ca~e 3 x, with an aqueou~ solution of Na ~icarbonate,
with lN aqueous hydrochloric acid and w$th water, and the
organic pha~e was dried and concentrated. 3.7 g were
obtainod of methyl oster, m.p. 168 to 169C, which was
introduoed into 150 ml of 1.5N methanolic NaO~. After
30 minuteo, tho mlxture was concontratod and d~ssolved in
100 ml of wator, and this mlxture wa~ adjustod to p~ 1
with ~onc. aqueouo hydrochloric acid; the crystalline
precipitato was filterod off with suction, washed with
water and dried. 3.4 g of product wero obtained, m.p.
110C (with foaming, ~intering at 75~

213~86~
- 77 -
c) 5-(((2-(4-Fluorophenyl)othyl)amino)carbonyl)-3-
mothoxypyridine-2-carboxylic ncid (glycyl ~thyl
eeter) amide

In analogy with Exa~ple 90a), 3.2 g (10 mmol) of the
above compound wero reactod with 1.4 g (10 m~ol) of
glycine othyl eeter hydrochloride, N-othylmorpholine,
1-hydroxy-lH-benzotrlAzole and CMC. Following analogous
working up, 2.8 g of the colorless cryetallin~ product
were cryatallized using diisopropyl othsr, m.p. 170 to
171C.

d) The titlo compound wae obtained by hydrolyeing 1.0 g
of the above glycine othyl estor, at 20C, ln 1.5N
methanolic NaOH. 0.95 g of product, m.p. 206C (with
foaming) crystallizoe from aqueoue medium at p~ 3.

Example 91
5-((2-(4-Methoxyphenyl)othyl)aminocarbonyl)-3-ethyloxy-
pyridine-2-carboxylic acid glycylamide
.
Examples 92 to 105 were obtained from the corre~pondingly
eubst~tuted pyridine-2-carboxylic acid derivativee of the
formula II and glycine ethyl e~tor hydrochloride and with
~ubeequent hydrolyeis of the glycine othyl ester com-
pound-.

Example 92
5-Chloro-3-othyloxypyridine-2-carboxyl~c acid glycyl-
25 amldo ~;
.: .: . ;: ' ~`Example 93
5-Chloro-3-mothyloxypyridino-2-carboxylic acid glycyl-
amido

Example 94
30 5-Cyclohoxyloxymothyl-3-methoxypyridine-2-carboxylic acid -~
glycylamide
' ' ' '

213~86~
- 78 -
Example 95
5-(3-Methylbutyl)oxymothyl-3-m~thoxypyridlno-2-carboxyllc
acid glycylamido

Example 96
5-Benzyloxymethyl-3-ethyloxypyrtd$ne-2-carboxylic aoid
glycylamide

Example 97 .
3-((Cyclohoxyl)mothyloxy)pyrid~ne-2-carboxylic acid
glycylamido ~ :. ;.
:
Example 98
3-((2-Cyclohexyl)othyloxy)pyridine-2-carboxylic acid
glycylamide ~-~

Example 99
3-((3-Cyclohexyl)propyloxy)pyridino-2-cnrboxylic acid
glycylamide

Example 100
3-(3-Methylbutyloxy)pyridino-2-carboxylic ac~d glycyl-
amido

Example 101
3-~exyloxypyrldine-2-carboxylic acid glycylamide

Example 102
3-(4-Ethylbonzyloxy)pyridine-2-carboxylic acid glycyl- . :
amid~
,:
Example 103
3-(4-Propylbonzyloxy~pyridine-2-ca~boxylic acid glycyl-
amide
~, '' ',

Example 104
3-(4-~utylbenzyloxy)pyridine-2-carboxylic acid glycyl-
amide
; ..

213~866
- 79 -
Example 105
3-(4-tert-Butylbonzyloxy)pyridine-2-carboxyl~c ac~d
glycylamide

Examplee 106 to 188 wore prepared in ~alogy with
Examplee 80 to 91.

Example 106
5-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridine-2-
carboxylic acid glycyl~mide

a) 3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic
acid

In analogy with Example 81c), 3.5 g (146 mmol) of sodium
wero di~solved in 350 ml of 2-methyl-1-propanol (i80-
butyl alcohol), and a~ter that 13.7 g (55 mmol) of
3-chloropyridine-2-carboxylic acid ~thyl eet~r 5-carbox-
ylic acid methyl ostor (pr~pared in analogy with kxample81b)) wore addod at 20C and while stirsing. The mixturo
was thon etirred at 80C for 90 minute~ and, aft~r
cooling, concentrat~d in ~acuo; tho reeiduo wae takon up
in 200 ml of 1 N methanolic NaOH and this mixturo wae
stirred at 20C. Aftor 15 minutes, tho eolution bocamo
cloudy. Water wae added untll a clear solution wae
obtainod and thie wae etirrod for 1 hour and thon concen-
trated in vacuo; the aqueoue eolution wae acldifiod with
agueous hydrochloric acid and tho cry~tallino product was
$iltered off with euction, waahed and dri~d, and 10.6 g
,
of dicarboxylic acid were obtained, m.p. 192C (decomp.).

b) Dimethyl 3-(2-met~yl-1-propylo~y)pyrld~n~-2,5-dicar-
boxylate

The oily product wae obtained from the abovo dicarboxylic
acid undor eeterification conditions (methanol/sulfuric
acid) and after working up (washing w~th water and
extracting with ethyl acetate). ~; -

. , ,, :

~,""i,.. '~,fi ,~ "", ,,,,,"

213~66
- 80 -
c) S-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridino-
2-carboxylic acid (glycyl banzyl oeter) anido

0.48 g (12 mmol) of NaO~, diseol~od in 50 ml of methanol,
wae added to 3.2 g (12 mmol) of the abovo dioeter ~n
25 ml of mothanol, and tho mixturo wae etirred at 65C
for 90 minutee. The mixture was thon acldifi-d, whilo
being coolod, with diluto agueoue hydrochloric acid and
froed from methanol in vacuo. 2.5 g (10 mmol) of tho
monoester mixture thus obtainod woro ~tirrod, ln analogy
with Examplo 90b), in 250 ~1 of dlchloro~e~hano, ~t 20C
for 24 hour~, together with 3.4 g (10 ~m~l) of glyc~ne
benzyl e~ter toeylate, 1.4 g (lO ,,ol) of l-hydroxy-(l~)-
benzotriazole, 2.6 ml ~20 mmol) of N-sthylmorpholine and
4.3 g (10 mmol) of CMC.
The undieeol~ed materlal was thon iltered off with
euction and tho filtrate was extracted with an agueous
solution of Na bicarbonate, with diluto hydroahloric acid
and with water; the organic phaee was drlod and concen-
tratsd and tho residue was chromatographod on eilica gal
uslng n-heptane/ethyl acetate (1:1). 0.8 g of aolorlese
product wae obtained from appropriate fra¢tiono, m.p. 103
to 105C. 1.1 g of the ieomeric roeinoue product were
al~o obtained.

d) Tho titlo compound wae obtained by dieeolving 0.7 g
of the above compound in 100 ml of totrahydrofuran/
mothanol (lsl) and hydrogenating it for 2 hour~ ueing Pd
on charcoal (10 %) in a hydrogenation ~oeeol. Tho cata-
lyet wae then filtor~d off with euction and the flltrate
: : . .
wae concentrated; tho reeidue wae cryetallized using
diieopropylether and 0.45 g wae obtainod of the titlo
compound, j~
m.p. approximatoly 70C (with foaming).

Tho isomeric compound wae obtainod in an analogoue ;~
manner, m.p. approximately 60C (with foaming, from
diieopropyl ether).
'., '':" -,,'' ~-
~ ''' `'`''

2131866
- 81 -
Example 107
5-Ethoxycarbonyl-3-(2-mothyl-1-propyloxy)pyrid~ 2-
carboxylic acid glycylamido

Examplo 108
5 5-Mothoxycarbonyl-3-(3-mothyl-1-butyloxy)pyridino-2-
carboxylic acid glycylamido

Examplo 109
5-Ethoxycarbonyl-3-ethoxypyridine-2-carboxyllc ~eid
glycylamide

10 Example 110
5-Ethoxycarbonyl-3-(1-propyloxy)pyridino-2-carboxyl~c
acid glyeylamido : ~:

Examplo 111 -
5-Ethoxycarbollyl-3-(2-propyloxy)pyridlne-2-carboxyl$c :~
15 acid glycylamido

Example 112 ~.:
3-Benzyloxy-5-othoxycarbonylpyridine-2-carboxylle acid ~ ~ :
glycylamido

Example 113
20 3- (4-Chlorob~nzyloxy) -5-ethoxycarbonylpyridine-2-
earboxylie aeid glycylamido

Examplo 114
5-E thoxyearbonyl-3- (4-fluorobenzyloxy) pyridine-2- -: :
earboxylie acid glycylamido .

25 Examplo 115
5-Ethoxyearbonyl-3- (4- (tr~ fluoromethyl) - :~
benzyloxy)pyridino-2-carboxylic aeid glycylamldo ;

Examplo 116 . .
5-Ethoxyearbonyl-3- (4- (trifluoromethoxy)be~zyloxy) - -~: :
pyridino-2-carboxylic acid glycyl~ide ~-
''''"

2131866

- 82 -
Example 117
5-Ethoxycarbonyl-3-(4-(2-propyl~benzyloxy)pyridino-2-
carboxylic acid glycylamide
Example 118
3-(4-Ethoxybenzyloxy)-5-ethoxycarbonylpyridine-2-car-
boxylic acid glycyla~ide

Example 119
5-~thoxycarbonyl-3-(3,4-dimethoxybenzyloxy)pyridi~-2-
carboxylic ac$d glycylamide

Exa~ple 120
5-Ethoxycarbonyl-3-(2-(4-fluorophenyl)ethyloxy)pyridine-
2-carboxylic acid glycyl~mide

Example 121 ~ ~;
5-Ethoxycarbonyl-3-(2,2,2-trifluoroothyloxy)pyridine-2-
carboxylic acid glycylamide

Example 122 -
3-Cyclohexyloxy-5-ethoxycarbonylpyridine-2-carboxylic
acid glycylamide ::

Example 123
5-Ethoxycarbonyl-3-(naphthyl-2-methyloxy)pyridine-2-
carboxylic ~cid glycylamido

Exampls 124 .;
5-Ethoxycarbonyl-3-(naphthyl-1-mothyloxy)pyridine-2-
carboxylic acid glycylamide

Example 125
5-Carboxy-3-(2-methyl-1-propyloxy)pyridine-2-carboxylic
acid glycylamide

The title compound wa~ obtained by hydrolyzing 0.3 g of -:
th~ title compound from Example 106, at 20~, in 50 ml of
a lN methanolic solution of ~odium hydroxide. After
1 hour, the ~ixture was concentrated in ~acuo and ~ -~

:
2131~66
"
- 83 -
extracted with diethyl other; the agueous pha~o wae
acidified, while bei~g coolod, with agueous hydroohlorlc
acid; the aqueou~ phass was concentrated and then fre~d
from water azeotropically using ethyl acetato and the
residuo was treatod with acetone; the solution W~8
concentrated and the residue was ery~talliz~d uoing
petroleum ethsr. 0.27 g of product was obtained, m.p.
80C (with foaming).

Exampla 126
5-Carboxy-3-(3-methyl-1-butyloxy)pyridine-2-earboxylic
acid glycylamide

Example 127
5-Carboxy-3-ethoxypyridine-2-carboxylic aeid glycylamide ~ -

Example 128 ;;~
5-Carboxy-3-propyloxypyridine-2-earboxylic acid glyeyl-
amide `~

Example 129 ; -
5-Carboxy-3-(2-propyloxy)pyridine-2-earboxylie acid
glycylamide

Examplo 130
3-Bonzyloxy-5-carboxypyridine-2-carboxylie aeid glyeyl-
amide
. :.~ '.
Example 131 ; -
5-Carboxy-3-(4-ehlorobenzyloxy)-2-carboxylicacidglycyl-
25 amide ;

Example 132
5-Car~oxy-3-(4-fluorobenzyloxy)pyridine-2-carboxylie ac~d
glyeylamide

Example 133
5-Carboxy-3-((4-trifluoromethyl)benzyloxy)pyridino-2-
carboxylie acid glyeylamide

213~8~6
:

' Bxample 134
:-~ 5^Carboxy-3-((4-trifluoromethoxy)banzyloxy)pyrldlne-2-
' carboxylic acid glycylamide
,~i
1 Examplq 135 -
1 5 5-Carbo~y-3-(4-(2-propyl)benzy~loxy)pyridi~-2-carboxylic
;~ acid glycylamide
~xample 136 :-
5-Car~oxy-3-(4-ethoxybenzyloxy)pyridine-2-carboxyllc acid `~
glycylamids :~
:: :
Example 137
5-Carboxy-3-(3,4-dimethoxybanzyloxy)pyridine-2-carboxylic E ;~
acid glycylamide

Example 138 ~`
~ . 5-Carboxy-3-(2-(4-fluorophe~yl)sthyloxy) pyr~dine-2- :~
: 15 carboxylic acid glycylamide ~. -
~ ' '. ~ ' '~,
~xample 139
5-Carboxy-3-(2,2,2-trifluoroethyloxy)pysidi~e-2-: ~'
carboxylic acid gylcylamlde
: ' '~
Example 140
20 5-Carboxy-3-cyclohexyloxypyridine-2-carboxylic a~ld ~` ;
glycylamide
~, . .
~x~mple 141
5-Carboxy-3-(naphthyll2-~ethyloxy)pyridine-2-carboxylic
acid glycylamide

Example 142
S-Carboxy-3-(naphthyl-~-methyloxy)pyridin2-2-carboxylic
acid glycyl~mide

Example 143
5-(3-Pentyloxy)carbonyl-3-(2-m~thyl-1-propyloxy)pyridine~
2-carboxylic acid glycylamid~
. :
;~ .

21~866
- 85 -
Example 144
5-(3-Pentyloxy)carbonyl-3-(3-me~hyl-1-butyloxy)pyridlne-
2-carboxylic aeid glycylamide

Example 145
3-Ethoxypyridine-5-(3-pentyloxy)earbonyl-2-e~rboxylic
acid glyeylamide --

Example 146
5-(3-Psntyloxy)earbonyl-3-propyloxypyridine-2-earboxylie
acid glyeylamide

Example 147
5-(3-Pentyloxy)carbonyl-3-(2-propyloxy)pyridine-2- :
carboxylie acid glycylamide

Example 148
3-~enzyloxy-5-(3-pentyloxy)earbonylpyridino-2-carboxylie
acid glyeylamide

Example 149
3-(4-Chlorobenzyloxy)-5-(3-pentyloxy)earbonylpyridine-2- -
carboxylie acid glycylamide
, ~
Example 150 :
3-(4-Fluorobenzyloxy)-5-(3-pentyloxy)carbonylpyridine-2-
earboxylie acid glycylamlde

Example 151
5-(3-Pentyloxy)earbonyl-3-((4-trifluorclmethyl)benzyloxy)-
pyridine-2-earboxylic acid glycylamide

Example 152
5-(3-Pentyloxy)carbonyl-3-((4-trifluoromethoxy)benzyl-
oxy)pyridine-2-earboxylie aeicl glyeylamid~

Example 153
5-(3-Pentyloxy)earbonyl-3-(4-(2-propyl)benzyloxy)-
pyridine-2-earboxylic aeid glycylamide

~; ~

213~866
- 86 -
Example 154
3-(4-Ethoxybsnzyloxy)-5-(3-pontyloxy)earbo~ylpyridino-2- ~ -
carboxylie acid glyeylamido

Examplo lS5
S 3-(3,4-Dimethoxybenzyloxy)-5-(3-pentyloxy)carbonyl-
pyridino-2-carboxylic acid glycyla~ido

Example 156
3-(2-(4-Fluorophenyl)-thyloxy)-5-(3-p~ntyloxy)carbo~yl-
pyrldine-2-carboxylic aeid glyeylamide

Exæmplo 157
5-(3-Pentyloxy)earbonyl-3-(2,2,2-trifluoroothyloxy)-
pyrldino-2-earboxylle aeld glyeylamido ~ -

Examplo 158
3-Cyelohoxyloxy-5-(3-pentyloxy)earbonylpyridine-2-
15 earboxylie aeid glyeylamide ;~

Exa~ple 159
3-(Naphthyl-2-m-thyloxy)-5-(3-pontyloxy)earbonylpyr~dino-
2-earboxylle aeid glyeylamido

Exampl- 160
3-(Naphthyl-1-m-thyloxy)-5-(3-pentyloxy)carbonylpyrldine-
2-earboxylie aeid glycylamido

Example 161
5-(4-~optyloxy)earbonyl-3-(2-methyl-1-propyloxy)pyridino-
,
2-earboxyllc aeld glycylfimldo

Examplo 162
5-(4-Hoptyloxy)carbonyl-3-othoxypyridine-2-earboxylic `~
acid glycyla~ide

Example 163
3-Benzyloxy-5-(4-heptyloxy)carbonylpyridino-2-carboxylie
30 aeid glyoylamido ;-

~, ..
.

2134~66
- 87 -
Example 164
3-(4-Chlorobenzyloxy)-5-(4-heptyloxy)carbonylpyridi~-2-
carboxylic ac~d glycylamide

Examplo 165
3-(4-Fluorobenzyloxy)-5-(4-heptyloxy)pyrid~ne-2-
carboxylic acid glycylamide

Example 166
5-(4-Heptyloxy)carbonyl-3-(4-(2-propyl)be~zyloxy)-
pyridine-2-carboxyliG acid glycylamido

Examplo 167
3-(2-Methyl-1-propyloxy)-5-(5-nonyloxy)carbonylpyridine- - -
2-carboxylic acid glycyl~m$de
. .
Example 168 ~ ,
3-Benzyloxy-5-(5-nonyloxy)carbonyl)pyridino-2-carboxylic
ac~d glycylamide
:,
Example 169
3-(4-Fluorobenzyloxy)-5-(5-nonyloxy)carbonylpyr~dine-2- . ~:
carboxylic acid glycylamide

Example 170
5-(5-Nonyloxy)carbonyl-3-(4-(2-propyl)benzyloxy)pyridi~e-
2-carboxylic acid glycylamide

Example 171
5-Geranyloxycarbonyl-3-othoxypyridine-2-aarboxylic acid
glycylamido

25 Ex~mplo 172 -
3-Benzyloxy-5-(geranyloxycarbonyl)pyridin~-2-carboxylic : ;~:
acid glycylamide ~: :

Examplo 173
3-(4-Chlorobenzyloxy)-5-(geranyloxycarbonyl)pyridi~e-2-
carboxylic acid glycylamide
. ' ~' .
,: '''

~`~ <:

21~866
- 88 -
Example 174
3-(4-Fluorobenzyloxy)-5-(goranyloxyc~rbonyl)pyrid$ne-2-
carboxylic acid glycylamide

Example 175
5-Geranyloxycarbonyl-3-(2-propyloxy)pyrid$ne-2-carboxylic
acid glycylamlde

Example 176
5-Farnosyloxycarbonyl-3-(2-propyloxy)pyr$din~-2-car-
boxylic acid glycylamide

10 Example 177 -~
3-Bonzyloxy-5-(farne~yloxycarbonyl)pyridine-2-carboxylic
acld glycylamlde ~ :~

Example 178 ::

5-Farnesyloxycarbonyl-3-(4-fluorobenzyloxy)pyr$dlno-2- ~;
carboxylic acid glycylamide

Example 179 . ~ :
5-Farn-~yloxycarbonyl-3-othoxypyridine-2-carboxylic acid
glycylamide

Examplo 180
3-Methoxy-5-(retinyloxycarbonyl)pyridine-2-carboxylic
acid glycylamide
~., .
Example 181
3-Ethoxy-5-(rotinyloxycarbonyl)pyridine-2-carboxylic acid
glycylamlde

Example 182
3-(2-Propyloxy)-5-(ret~nyloxycarbonyl)pyrldine-2-
carboxylic acid glycylamide


. . ~

213~86G
- 8~ -
Example 183
3-Benzyloxy-5-(retinyloxycarbonyl)pyridine-2-carboxylic
acid glycylamide

Example 184
3-(4-Fluorobenzyloxy)-5-(retinyloxycarbonyl)pyridine-2-
carboxylic acid glycylamide

Example 185
3-(3-Methoxybenzyloxy)-5-(ret~nyloxycarbonyl)pyridine-2-
carboxylic acid glycylamide

Example 186
5-Benzyloxycarbonyl-3-(4-(2-propyloxy)benzyloxy)pyridine-
2-carboxyllc acid glycylamide .

Example 187 -: ;
5-Benzyloxycarbonyl-3-(4-fluorobenzyloxy)pyridine-2-car-
boxylic acid glycylamide

Example 188
5-Butyloxycarbonyl-3-benzyloxypyridine-2-carboxyllc acid
glycylamide

Example 189
5-(((4-Ethoxyphenyl)amino)carbonyl)-3-methoxypyridine-2-
carboxylic acid glycylamid~, analogouely to Exa~ple 191

Example 190
5-(((4-Ethoxyphenyl)amino)carbonyl)-3-benzyloxypyridine-
2-carboxylic acid glycylamide

~xamplo 191
5-(((4-(1-Butyloxy)phonyl)amino)carbonyl)-3-methoxy-
pyridine-2-carboxylic acid glycylamide ~ :

a) Methyl 5-(((4-(1-butyloxy)phenyl)amino)carbonyl)-3- . .
methoxypyridine-2-carboxylat~
' : '

213486~
- so -
3.2 g (15 mmol) of methyl S-carboxy-3-methoxypyrid~ne-2-
carboxylate (cf. Example 90a)) were reacted, ln nnalogy
with Example 90b), with 2.5 g (15 mmol) of 4-n-butoxy-
anillne and the reagents do~cribed in that example. 3.9 g
of product were crystallized using diethyl ~th~r (m.p.
138 to 141C.
~ .
b) 5-(((4-(1-Butyloxy)phenyl)amino)car~o~yl)-3-methoxy-
pyridino-2-carboxylic ac$d ~-~

3.2 g of the above e~ter were hydrolyzed at 20C ucing
100 ml of 1.5 N mathanolic aodium hydroxide oolution.
2.7 g of product were obta~ned from agueous hydrochloric
acid, m.p. 128 to 130C, sintering from 120C.

c) 5-(((4-(1-Butyloxy)phenyl)amino)c rbonyl)-3-~othoxy-
pyridine-2-carboxylic acid N-~(ethoxyc~rbonyl)-
methyl) am~de

2.7 g (7.8 mmol) of the a~ovo pyridine-2-carboxylic acid
were stirred in 500 ml of anhydroue dichloromethano, at
20C for 24 h, togather with 1.1 g (7.8 mmol) of glycine
ethyl oster hydrochlorido, 3.0 ml (23.4 ~^1) of N-
ethylmorpholine, 1.2 g (8.6 m~ol) of 1-hydroxy-1~-bonzo-
trlazolQ and 3.3 g (7.8 mmol) of CMC.

Tho undissolved material was then filtored off and tho
organic pha~e was extracted ~equentially with 200 ml each
of water, aquoous Na bicarbonato ~olution, lN aqueous
hydrochloric acid and water, dried over Mg sulfate and
concentrated in vacuo; the residue wa~ cry~tallized ueing
diethyl ethor. 2.4 g of product were obtained, m.p. 193-
195C.

d) The titlo compound was obtained by hydrolyzing 1.0 g
of the above glycine oster, at 20C, in 100 ml of a 1.5 N
methanolic solution of sodium hydroxide. After 30 m~n,
the mixturo wa~ concontrate~ in vacuo ~nd the roEidue wa~
diesolved i~ water; this solution was oxtracted with

2~3~86~
:'``
- 91 -

diethyl ether and the aqueous solut~on ad~u~tod to p~ 3
u~ing agueous hydrochloric ~cid. When tke ~olution wa~
cooled with ice, 390 mg of the title compound crystal-
lized, m.p. 230C, sinterlng at 193C.

5 Example 192 .
5-(((4-(1-Butyloxy)phenyl)amino)carbonyl)-3-(4-fluoro-
benzyloxy)pyridine-2-c~rboxyllc acid glycylamide

Example 193
5-(((4-(1-Butyloxy)ph~nyl)amlno)carbonyl)-3-b~nzyloxy-
pyridine-3-carboxylic acid glycylamide

Example 194
3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic acid
diglycylæmide
N.p. 103-105C (from 0thyl acetate)

Example 195
5-(Di-N,N-ethylaminocarbonyl)-3-~thoxypyridin~-2-car-
boxylic acid glycylamide, amorphou3 ~ub~tance, prepared-~ ~ :
in analogy with Ex~ple 223 u~ing N,N-di~thylamino.

Example 196
5-(N-Bonzyl-N-methylamlnocarbonyl)-3-methoxypyridine-2-
carboxylic acld glycylamlde

Ex~mple 197
5-Farne~yloxyc~rbo~yl-3-mothoxypyridine-2-carboxylic acid -:
glycylamide

Example 198
5-Geranyloxycarbonyl-3-methoxypyrldin~-2-carboxylic acid ::
glycylamide -~
.
Example 199
5-(Farnesyloxymethyl)-3-methoxypyridins-2-cArboxylic acid
glycylamide

213 ~866

- 92 -
Example 200
5-(Geranyloxymethyl)-3-methoxypyridille-2-carboxyl~c acid
glycylamide

Example 201
5 5-Retinyloxymethyl-3-methoxypyridine-2-carboxylic acid
glycylamide

Example 202
5-Retinyloxymethyl-3-ethyloxypyridi~e-2-carboxylic ac:id
glycylamide

10 Example 203
N-(Carboxymethyl)-4-methoxycinnoline-3-carboxamide

Examples 204 to 209 were prepared in ~nalogy with Example
191: ~ -

Example 204
15 5- (((4-(1-Hexyloxy)phenyl)amino)carbonyl)-3-methoxy-
pyridine-2-carboxylic acid N-(carboxy~ethyl)am$de

a) Methyl 5-(((4-(1-hexyloxy)phenyl)amino)car}~onyl)-3-
methoxy-2-carboxylate was E~repared from methyl 5-
carboxy-3-mqthoxypyridine-2-carboxylate and 4-hexyl-
oxyaniline, m.p. 118-119C (from diethyl ether). ;~-

b) 5-(((4-(1-Hexyloxy)phenyl)~mino)carbonyl)-3-methoxy- ;
pyridine-2-carboxylic acid, 160-162C, ~intering at
148C (from aqueouc hydrochloric
acid/tetrahydrofuran)

c) 5-(((4-(l Hexyloxy)phenyl)amino)carbonyl)-3-methoxy-
pyridin0-2-carboxylic acid N-((ethoxycarbonyl)-
me~thyl)amide was obtain~d, in analogy with Example
l91c), from 4.2 g of the above compound. 4.0 g of
product were crystallized u~ing ethyl acetate, m.p.
157-159C.

213 186~
:`.
_ 93 _
d) The title compound wa~ obtainsd by hydrolyzing 1.2 g
of tho above oster, at 20C, ueing 100 ml of a 1.5N
methanolic solution of codium ~ydroxide. Following
concentration ln vacuo, acidi~icatio~ to p~ 1 took
place in water/totrahydrofuran u~ing aquoou~ hydro-
chloric acid; tho mlxturo was concontrated in v~cuo
and the reeidue wa~ cry~tallized ufling acetone. 840
mg of product were obtained, m.p. 193-195C.

Example 205

5-(((4-(1-Decyloxy)phenyl)amino)carbonyl)-3-methoxy-
pyridine-2-carboxylic acid N-(carboxy~ethyl)amide

Example 206 -

5-(((4-(1-Decyl)phenyl)~;no)carbonyl)-3-methoxypyridine-
2-carboxylic acid N-(carboxymethyl)amide
-'- .
a) 5-(((4-(1-Decyl)phenyl)amino)carbonyl)-3-mothoxy-
pyridine-2-carboxylic acid N-((othoxycarbonyl)-
methyl)amide was prepared from 5-(((4-n-decyl-
phenyl)amino)carbonyl)-3-methoxypyridin~-2-
carboxylic acid (m.p. 160C (decomp.); from aqueou~
hydrochlorlc acid/THF) and glycin~ othyl ~ter
hydrochloride, m.p. 155-157C (fron dii~opropyl
othsr).
~ -: . .
b) The title compound wa~ obtained by hydrolyzing 1.5 g
of tho abovo eeter in 200 ml of a 1 N methanolic
~olution of ~odium hydroxido. 1.4 g of product, m.p.
195C ~decomp.), were isolated from aqu~ou~ hydro-
chloric acid/t~trahydrofura~.

Examplo 207
5-(((4-~eranyloxyphenyl)amino)carbonyl)-3-mothoxy-
pyrldine-2-carboxylic acid N-(carboxymethyl)amide

21318~6

- 94 -
Example 208
5-(((4-(1-Octyloxy)phenyl)am~no~carbonyl)-3-~ethoxy-
pyridine-2-carboxylic acid N-(carboxymethyl)a~lde

Example 209
5-(((3-(1-Octyloxy)propyl)amino)carbonyl)-3-methoxy-
pyridine-2-carboxylic acid N-~car~oxymethyl)umide

Example 210
5-((1-Butoxy)mothyl)-3-mothoxypyridi~e-2-carboxylic ac~d
N-(carboxymethyl)am~do

Example 211
5-((1-Hoxyloxy)methyl)-3-mothoxypyridine-2-Carboxylic
acid N-(carboxymethyl)amido

Example 212 ~ :
5-((1-Octyloxy)methyl)-3-mothoxypyridine-2-carboxylic
15 acid N-(carboxymethyl)amide ~ ~ :

Examplo 213 -
5-((1-~ex-3-onyloxy)methyl)-3-methoxypyridine-2-car-
boxylic acid N-(carboxymothyl)amide :p

Exa~ple 214
20 5-((1-Docyloxy)methyl)-3-m~thoxypyridine-2-carboxylic : . :
acid N-(carboxymethyl~amide

Examplo 215
5-((l-Dodecyloxy)methyl)-3-methoxypyrldine-2-carboxylic :~
acid N-(carboxymothyl)amide -~

25 Example 216 ~:
5-((1-~exadecyloxy)methyl)-3-methoxypyridlne-2-carboxyllc
acid N-(carboxymethyl)amide

Examplo 217
3-S4-(((+)-Dohydroabietylamino)carbonyl)benzyloxy)pyri-
30 di~e-2-carboxylic acid N-(carboxymethyl)amido : :

213~866
;
- 95 -
a) 4-(((~)-Dehydroabietylamino)oarbonyl)chloromethyl-
benzeno was obtained from 4-chloromethylbonzoic acid
and (~)-dehydroabiotyl~mine, ~.p. 170-172C (from
othyl acetate/hoptano (1:1)).

b) 3-(4-(((~)-Dehydroabiotylamino)carbonyl)benzyloxy)-
pyridino-2-carboxylic acid N-((~thyloxycarbonyl)-
mothyl)amido, m.p. approximat~ly 80C (a~orphou~
substance, from ethyl aootato).

c) Tho titlo compound was obtained by hydrolyzing the
above es10r, m.p. 125C (w~th ~oaming, ~rom dii~o-
propyl ether).

Example 218
3-Mothoxyguinoline-2-carboxylic acid N-(oarboxymothyl)-
amido

a) 2-Acetyl-3-hydroxyquinoline, ~nown from D.W. Bayne
et al., J. Chem. Soc. Chem. Comm. 1975, 782 (M.p.
106C from agueouR hydrochloric acid).
.: ',' .
b) 2-Acetyl-3-mothoxyquinolino, from a) ucing pota~sium
carbonate/methyl lodido in acotone, oily crude ;~
product.

c) 3-Methoxyguinoline-2-carboxylic acid, from b) u~ing
potaa~ium hypochlorite in water/dioxane, m.p. 123C
(from methyl tort-butyl ether).
.
d) 3-Methoxyguinoline-2-carboxylic acid N-((methoxy-
carbonyl)methyl)amido, from c) u~ing DCC~ ~OBT, THP,
NEM and glyc$ne mothyl o~tor hydrochlorido.

o) Tho title co~pound wa~ obtained by hydrolyzing the
above ester, m.p. 106C (from othyl ac~tate).

'' ~' ''

':

213~866
- 96 -
Example 219
5-(((4-(1-Butyloxy)phenyl)amino)carbonyl)-3-chloropyri-
dine-2-carboxylic acid N-(carboxyme~hyl)amid~

a) Methyl 5-carboxy-3-chloropyridine-2-csr~oxylate w~s
prepared in analogy with Example 90a), m.p. 182-
184C (from aqueou~ hydrochloric acid).
.




b) Methyl 5-(((1-butyloxy)phenyl)amino)carbonyl)-3-
chloropyridine-2-carboxylate wa~ obtalned from the
above ~ompound us~ng oxalyl chloride and 4-(1-butyl-
oxy)aniline, m.p. 121-123C (from di~thyl other).

c) 5-(((4-(1-Butyloxy)phenyl)smino)carbonyl)-3-~hloro-
pyrldine-2-carboxylic acid by hydrolyzing the
product from b), m.p. 163-164C (from agueou~ hydro-
chloric acid).

d) 5-(((4-(1-Butyloxy)phenyl)æmino~carbonyl~-3-~hloro-
pyridine-2-carboxyli~ acid N-((ethyloxycarbonyl)-
methyl)amide waa obtained, in ~nalogy with ~xample
90b), from tho abo~e ~u~tsnce by conden~ation (N-
ethylmorpholine, l-hydroxy-lH-benzotrlszole and CMC)
with glyclne ethyl ostor hydrochloride, m.p. 177-
179C (from othanol).

e) ~he titlo compound was obtainad by hydrolyzi~g the
above o~tor, M.p. 190C (with docompo~ition, from
aqueou~ hydrochlorlc acid).

Example 220
3-(N-Benzyl-N-methylamino)-5-(((4-(1-butyloxy)phe~yl)-
smlno)carbonyl)pyr~dine-2-carboxylic Acid N-(carboxy-
methyl)amide

0.5 g (1.23 mmol) of the title compound from Exampl~ 219
wa~ stirred ln 10 ml of N-be~zyl-N-methylamino, firstly
at 100-110C for 2 h and then at 130C for a further 2 h.
After the mixture had been cooled down, it was introduced
. ~. ...

2~34866


~nto 100 ml of lN hydrochloric acid ~nd th~ h~lf-
crystalline precipitate wa~ taken up in dichloromethane;
the undiseolved mat~rial was filtersd off and the residue
was crystallized; 0.2 g of the title compound, m.p. 155-
5 157 C .

~xample 221
3-(N-Benzylamino)-5-(((4-(1-butyloxy)phenyl)amino)car-
bonyl)pyridine-2-carboxylic acid N-(carboxy~ethyl)A~de -~

0.5 g (1.23 mmol) of the title compound from Example 219
wa~ ~tirred in 10 ml of bon~ylamine, fir~tly at 120C for
2 h and then at 135C for 1.5 h. After the mixture hnd
been cooled down, it was acidifiod and the precipitat~d
re~in wae dissolved in dichloromethane; thi~ ~olution wa~
dried and conaentrated and the re~idue wa8 chromato-
graphed on ~ilica gel us$ng ethyl ac~tate (with the
addition o~ up to 20 % methanol). 0.1 g of th~ titl~
compound wa~ cry~tallized from appropriate f~action~
u~ing dii~opropyl other, m.p. 185-190C.

Example 222
:
3-(4-Chlorobenzyloxy)pyridine-2-carboxyllc acid N-
(carboxymethyl)amide 1-oxido

a) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid N-
((ethyloxy)methyl)amide 1-oxide

0.7 g (2 mmol) of the compound from Example 31c) wa~
di~olved in dichloromethane and roacted with 1.41 ~
g of 3-chloroperbenzoic acid. After the mixtura had ~;
been ~tirrod at 20C for 1 h, ammonia wa~ pa~ed in ;
until thero wac no further pr~cipitation; tho
procipitats wa~ filtered off and the filtrate waa ~-
concontratod and the oily residuo cryctallized ucing
diethyl ether, m.p. 70-72C.
b) 0.18 g of the title compound, m.p. 206-208C

213~866

- 98 -
(sintering at 200C, fro~ aqueous hydrochloric acid)
was obtained by hydrolyzing 0.3 g of tke above
compound.
Example 223

5-(((3-(1-Butyloxy)propyl)P~no)carbonyl)-3-methoxypyri-
dine-2-c~rboxylic acid N-(carboxymethyl)amido

a) Methyl 5-(((3-(l-butyloxy)propyl) a~ no)carbonyl)-3-
methoxypyridine-2-carboxylic acid

1.7 ml of oxalyl chloride (20 mmol), and al80 2 drops of
N,N-dimethylformamide, dissolved in tctrahydrofuran, were
added dropwiEie, at 10C and whlle itirr~ng, to 2.1 g
(10 mmol) of methyl 5-carboxy-3-methoxypyridine-2-car-
boxylate in 100 ml of i~nhydrouEi totrahydrofurian and the
reaction mixture wa~i ~itirred at 10C for 30 min and at
20C for 1 h. It was then concentrated and the residue
was dis~iolved in dichloromethane; 6.8 ~l (50 mmol) of
triethyla~ine, and then 1.3 g (1.5 ml, 10 mmol) of 3-
butoxypropylamine, diseolved i~ dichloromsthanei, wore
added, at 0C, to thi~i siolution.
Aftor 30 min, the mlxture was allowed to warm to room
tomperature and waE extracted with water, a Eiolution of
Na bicarbonate and aqueouE lN ~Cl; the organic phas~ waEi
dried and concentrated and the residue wa~i crystallized
u~ing diethyleth~r/petroleium ether (3:1). 2.3 g of
product were obtained, m.p. 51-53C.

b) 5-(((3-(1-Butyloxy)propyl)amino)carbonyl)-3-methoxy-
pyridine-2-carboxylic acid N-((benzyloxycarbonyl)-
methyl)a~ide
~ . . .
The above subEitance was hydrolyz0d by Eitandard pro-
c0dures, and 1.5 g (5 mmol) of the amorphous 5-(((3-(1-
butyloxy)propyl)amino)carbonyl)-3-methoxypyridine-2-
carboxylic acid, which wa~i dried on an o~l pump, was
reacted with glycine benzyl oster toEiylate, ;
.

213~866

- 99
N-ethylmorpholine, l-hydroxy-l~-benzotriazole and ~MC (a8
de~cribed). 1.42 g of the product were cry~tallized using
acetone, m.p. 97-99C. -

c) 1.3 g of the above benzyl e~ter were hydrogenatod in
100 ml of tetrahydro~uran/methanol (1:1) u~$ng Pd/C
(10 %) in a hydrogenation ves~el. 0.8 g of the title
compound wae crystallized u~ing diethyl othor, m.p.
155-157C.

Example 224
5-(((3-(1-Lauryloxy)propyl)amino)carbonyl)-3-methoxy-
pyridine-2-carboxyllc acid N-(carboxym~thyl)amide

a) 5-(((3-Lauryloxypropyl)am$no)c~rbonyl)-3-methoxy- -
pyridine-2-carboxyl~c acid N-((benzyloxycarbonyl)-
methyl) mide was obtained, i~ analogy with Example 223,
u~ing 3-lauryloxypropylamine, m.p. from 109-111C (from
diisopropyl ether).

b) 1.3 g of the above benzyl e~ter were hydrogenated aa
dQscribed under 223c). 0.9 g of the titlo compound wero
obtained from petroloum ether, m.p. from 120C.

20 Example 225 -;
5-(((2-Methoxyethyl)amino)carbonyl)-3-methoxypyridine-2- ~ - -
carboxylic acid N-(carboxymethyl)amide ~ i

The title compound wa~ prepared in analogy with Example
223 u~ing 2-methoxyethylamine.

a) 5-(~(2-Methoxyethyl)amino)carbonyl)-3-~ethoxypyri-
dine-2-sarboxyllc acid, m.p. 160-161C (wlth ga~
evolution, from ethyl acetate)

b) 5-(((2-Methoxyethyl)amino)carbo~yl)-3-methoxypyri-
dine-2-carboxylic acid N-((benzyloxycarbonyl)-
methyl)amide wa~ ~ry~tallized u~ing dii~opropyl
ether, m.p. 129-131C.

:

213~366
- 100 -
c) The title compound was obtained, aa above, from the
benzyl ester, m.p. 186-188C (from diethyl ether).

Example 226
N-(3-Benzyloxypyridyl-2-carbonyl)alanine racemate,
M.p. 186-187C (from pentane/ethyl acetate)

Example 227
N-(3-Benzyloxypyr~dyl-2-carbonyl)-L-phenylalanine,
M.p. 100-101C (from pentane/ethyl acetate).

Example 228
5-((1-Butyloxy)carbonyl)-3-methoxypyridin~-2-carboxylic
acid N-(carboxymethyl)amide trifluoroacetate

a) Di-(1-butyl) 3-methoxypyr~dine-~,5-dicarboxylate

5.0 g of dimethyl 3-methoxypyridine-2,5-dicarboxylate
(cf. Example 90a)) were dissolvod in 100 ml of 1-butanol,
and after that 1.5 ml of conc. ~ulfuric were added and
the mixture wa~ hoated to boiling for 2 h, with a part of
the solvent bsing distilled off. After the mixture had
been cooled, it was concentrated in vacuo and the rosidue
was taken up ~n dichloro~ethane; this solution wa~
oxtr~ct-d with a oaturated, aqueou~ ~olution of Na
bicarbonato and the organic phase was dried and concen-

trated. 6 g of o$1y crude product.
., .
b) ~is[5-((1-butyloxy)carbonyl)-3-methoxypyridine-2-
carboxylic acid]-Cu(II) complex
.
6 g (20 mmol) of the above product were addod, disaolved
in 10 ml of mothanol, to a solution of 4.8 g (20 mmol) of
Cu(II) nitrate x 3 ~,0 in 100 ml of methanol, and t:he
mixture was heated to boiling for 4 h. It wa~ then cooled
down to 0-5C and the cry~talline precipitate was fil-
terod off with suction and washed with diethyl ether.
4.2 g of bluo-groen, cry~talline product were obtained,
.p. 267C (wlth decomposition).
'' ;' `' '' ~' '

.: ~

2i31866

- 101 -
c) 5-((1-Butyloxy)carbonyl)-3-mothoxypyridine-2-car-
boxylic acid

4 g of the above Cu complex were suisipended in 75 ~1 of
1,4-dioxane. ~2S gaisi w~,~i pai~ised in, while the mixture was
being stirred, for 30 min, ~nd the eedlment ~CuS) wh~ich
had precipitated out wai~i filtered off with i~iuction
through kie3elguhr and then washed with 1,4-dioxane
(continued introduct~on Or H,S did not l~ad to any
further precipitation); the filtrate w~i6i concentratod in
vacuo. The residue wae crystii~llized uciiny potroleum
ether, m.p. 96-9SC.

d3 5-((1-Butyloxy)carbo~yl)-3-methoxypyridino-2-
carboxylic acid N-((tert-butyloxyc~rbonyl)-
methyl)amide

0.76 g (3 mmol) of the a~ovo pyridinecarboxylic acid wa,~
condensed with 0.52 g (3 mmol) of glycine tert-butyl
ester hydrochloride, 1.2 ~1 (9 ol) of N-~thylmorpho-
line, 0.45 g (3.3 ~mol) of 1-hydroxy~ )-benzotriazole
and 1.3 g (3 mmol) of CMC. 0.8 g of product wa~c obtained,
m.p. 50-52C (from peitroleum ther).

ei) The title compound wac obtain~d by ~dding 2.7 ml of
trlfluoroacetic acid, at 20C, to 0.4 g of the above
tert-butyl ei~iteir in dichloromethane. Aftsr 20 h, the
mixture was concentrated in vacuo and 0.2 g W~8 obtained
of the colorleei~i, cryi~tall$ne, strongly hygroi~icop~c
product, which, on being filtered off with ,aiuction,
deliquesced on the suction filteir.

Example 22g
5-Ethyloxycarbonyl-3-methoxypyridine-2-carboxylic acid
N-(carboxymethyl)amide

Example 230
3-Methoxy-5-((1-propyloxy)carbonyl)pyridine-2-carboxyl~c
acid N-(carboxymethyl)amide

213~866
- 102 -
Example 231
5-(~ exyloxy)carbonyl)-3-mathoxypyridine-2-carboxylic
acid N-(carboxymethyl)amide

Exa~ple 232 ~-
3-Methoxy-5-((1-pentyloxy)carbonyl)pyr$dino-2-carboxylic
acid N-(carboxymethyl)amido

Example 233
5-((1-Heptyloxy)carbo~yl)-3-methoxypyridino-2-carboxyl~c
acid N-(carboxymethyl)amlde

Example 234
3-Methoxy-5-((1-octyloxy)carbonyl)pyridine-2-carboxylic
acid N-~carboxymethyl)amide

~xamples 235-238 were prepared in an analogous manner to
Example 228 proceeding from 3-(2-propyloxy)pyridine-2,5-
dicarboxylic acid or the corre~ponding dial~yl esters.

Examplo 235
5-Ethyloxycarbonyl-3-(2-propyloxy)pyridine-2-carboxylic
acid N-(carboxymethyl)amide ~`
~ ..
Examplo 236
5-((1-Butyloxy)carbonyl)-3-(2-propyloxy)pyridine-2-
carboxylic acid N-(carboxymethyl)amide

Example 237 . .
5-((1-Hexyloxy)carbonyl)-3-(2-propyloxy)pyridino-2- :
carboxylic acid N-(carboxymethyl)amide
",
25 Example 238 - --.;
5-((-1-Octyloxy)carbonyl)-3-(2-propylc-xy)pyridine 2-
carboxylic acid N-(c~rboxymethyl)amide

Example 239
5-Carboxy-3-(methylthio)pyridine-2-carboxylic ~cid
N-(carboxymethyl)amide di~odium salt
' ' ~

2134~66
- 103 -
a) 3-(Methylthio)pyridino-2,5-dicarboxyllc acid

4.6 g (12 mmol) of dibenzyl 3-c~loropyridine-2,5-dicar-
boxylate were dissolvod, at 20C ~nd while ~tirring, in
30 ml of dimethyl sulfoxido, and aftor that 5.0 g
(70 mmol) of sodium thiomethoxido wore ~ddod, in as~oci-
ation with which the temperaturo roce to 80C. The
reaction mixture was he~tod ~t 140C for 1 h and then
cooled down; water wa~ added ~nd tho oily layor w~
~eparatod off; conc. hydrochloric acid (p~ 1) was ~dded
to the aqueouo DMS0 pha~e and the preciplt~tod product
waQ filter0d off with suction. 2.8 g wsro obtained of a
yellow cry~talline product, m.p. 223C (with decom-
position).
b) Dimethyl 3-(methylthio)pyridine-2,5-dicarboxylate

50 ml of 1,4-dioxane, 40 ml of tetrahydrofuran and 0.5 ml
of conc. ~ulfuric aoid were added to 2.8 g of the above
compound in 150 ml of mothanol, ~nd tho mixture w2s
heated ~o reflux for 2 h, during which tim0 a eolution
wa~ formed. After tho ~olution had been cooled down, it
was concentrated in vacuo and 100 ml of an aqueou~
solution of Na bicarbonato were addod to the rosidue; the
latter mixture wae oxtracted with dichloro~ethane and the
organic phase was dried a~d concentrated. 1.4 g were
obtained of tho yellow, crystallino product, ~.p. 103-
105C.

c) 5-Methoxycarbonyl-3-(methylthio)pyridine-2
carboxylic acid-Cu(II) complex

1.3 g of the ~bova dimethyl 3-msthylthiopyridine-2,5-
dicarboxylate were reacted in analogy with Example 228~
1.3 g of grsenish/cry~talline product were obtained, m.p.
~ 330C.
d) 5-Methoxy-3-(methylthio)pyridine-2-carboxylic acid

- ::

213~866
- 104 -
1.3 g of the above compound were ro~cted in analogy with
Example 228c), 0.72 g of product, m.p. 183-185C.

e) 5-Methoxycarbonyl-3-(methylthio)pyr~din~-2-
carboxylicac$dN-((1-butyloxy)carbonyl)methyl)amldo

S ~he compound was obtained by condensing O.68 g (3 mmol)
of the above pyridinecarboxylic acid wit~ 0.91 g (3 ol)
of glycine 1-butyl e~ter tosylata (1-hydroxy-1~-benzotri-
azole, N-ethylmorpholine ~nd CMC). 0.55 g of pale yellow
product was obtained, m.p. 47-49C (frcm potroleum
10 ether) .

f) The title compound wa~ obtained by hydroly~ing
O.45 g (1.3 mmol) of the above e~ter u~ing 50 ml of 1 N
methanolic NaO~. The clear yollow ~olution hecamo cloudy
after 30 min. Aftor 2 h, the precipitate was filtered off
with ~uction, washed twice w~th ~ethanol and dried in
vacuo. 0.32 g of the title compound wa~ obtained, m.p.
345C (decomp.).
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Representative Drawing