AU676775B2 - Substituted heterocyclic carboxamides, their preparation andtheir use as pharmaceuticals - Google Patents
Substituted heterocyclic carboxamides, their preparation andtheir use as pharmaceuticals Download PDFInfo
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- AU676775B2 AU676775B2 AU77564/94A AU7756494A AU676775B2 AU 676775 B2 AU676775 B2 AU 676775B2 AU 77564/94 A AU77564/94 A AU 77564/94A AU 7756494 A AU7756494 A AU 7756494A AU 676775 B2 AU676775 B2 AU 676775B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- Proteomics, Peptides & Aminoacids (AREA)
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- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
The invention relates to compounds of the formula I <IMAGE> a process for their preparation, and their use as medicaments. In particular, the compounds are employed for the inhibition of collagen biosynthesis, as inhibitors of proline hydroxylase and as fibrosuppressants.
Description
tVIU1 I2fi/naI Rogulatlon 3,2(2)
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT a Application Number: Lodged: Invention Title: SUBSTITUTED HETEROCYCLIC CARBOXAMIDES, THEIR PREPARATION AND THEIR USE AS PHARMACEUTICALS a a s The following statement is a full description of this invention, including the best method of performing it known to us HOECHST AKTIENGESELLSCHAFT HOE 93/F 349K Dr.Fl/we Description Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticals The invention relates to substituted heterocyclic carboxamides, to their preparation and to their use as inhibitors of prolyl-4-hydroxylase, and to their use as pharmaceuticals for treating fibrotic diseases.
Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase bring about a very selective inhibition of collagen biosynthesis by their influence on the collagen-specific hydroxylation reactions. In the course of these reactions, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase, respectively. If this reaction is prevented by inhibitors, there then arises a nonfunctional, subhydroxylated collagen molecule which can only be secreted by the cells into the extracellular space in small quantities. Furthermore, the subhydroxylated collagen cannot be incorporated into the collagen matrix and is very readily degraded proteolytically.
These effects result in a diminution of the overall quantity of collagen which is deposited extracellularly.
Inhibitors of prolyl hydroxylase are therefore suitable 25 substances for use in the therapy of diseases in which the deposition of collagens makes a substantial contribution to the clinical picture. These diseases include, inter alia, fibroses of the lung, liver and skin (scleroderma and cicatrizations following burns, injuries and surgical intervention) and also atherosclerosis.
It is known that the enzyme proline hydroxylase is efficiently inhibited by pyridine-2,4-dicarboxylic acid and pyridine-2,5-dicarboxylic acid Majamaa et al., 2 Eur. J. Biochem. 138 (1984) 239-245). However, these compounds are only active as inhibitors in cell culture at very high concentrations (Tschank, G. et al., Biochem.
J. 238 (1987) 625 to 633).
Prodrugs of pyridine-2,4(5)-dicarboxylates are also known. These are described in the relatively old German Applications P 42 33 124.2, P 42 38 506.7 and P 42 09 424.0.
N-Oxalylglycines which are inhibitors of prolyl-4hydroxylase are disclosed in J. Med. Chem. 1992, 35, 2652 to 2658 (Cunliffe et and EP-A-0 457 163 (Baader et al.).
Hydroxyisoquinolinecarboxylic acid glycylamides and hydroxycinnolinecarboxylic acid glycylamides are disclosed in Biochem. Soc. Trans. 1991, 19, 812 to 815 (Franklin et 3-Benzyloxypyridine-2-carboxylic acid (L-threonyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)-L-threonyl) amide hydrochloride are disclosed in Liebigs Ann. Chem. 1986, 1 to 20, Kessler et 20 al.
It has now been found, surprisingly, that heterocyclic carboxamides having an ether substituent, a thioether substituent or an amino substituent in the ortho position to the amide function have a strong inhibitory action on 25 prolyl-4-hydroxylase.
The compounds according to the invention conform to the formula I
SR'
e, d A B (0)m -3 in which Q is 0, S, NRW or a bond, x is 0or S, Y is C-R 3 or, if R 1 and R 2 form a cycle, Y is NorCR, la is 0 or 1, A is CO)-alkylene, which is optionally substituted by one or two substituents from the group halogen, cyano, nitro, trifl-uoromethyl, 6 )-alky1, (C 1 -hydroxyalkyl,
(C
1 -alkoxy, [CH 2 CfH( 2 flg,)Hal., preferably -fluoroalkoxy, (C 1 Ce) fluoroalkenyloxy, Ce) fluoroalkynyloxy,
-OCF
2 Cl or -0-CF 2 CHFCl, (C,-C 6 )-alkylmercapto, (Cl- C.)-alkylsulfinyl, (C 1
C
6 -alkylsulfonyl,
(C
1 -alkylcarbonyl, (C,-C 6 -alkoxycarbonyl, carbainoyl, N- (C.-C 4 -alkylcarbamoyl, N,N-di- (C3."C 4 alkylcarbamoyl, (Cl-C 6 -alkylcarbonyloxy, (C 3 -CS) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C 1
-C
4 I alkylsulfamoyl or N,N-di- (Cj-CA) -alkylsulfamoyl, or by a substituted (C 6
-C
12 )-aryloxy, (C 7
-C
1 )-aralkyloxy, (C 6
-C,
2 -aryl or (C7-C3 1 -aralkyl radical which carries in the aryl moiety 1, 2, 3, 4 or 5 identical or different substituents from the group halogen, cyano, nitro, trifluoromethyl, (Cl-C 6 )-alkyl, -alkoxy, ECH 2 JX-CfH(f+l-.,Halg, -OCF 2 Cl, -0-CF 2 CHFCl, (C,-C 6 -alkylmercapto, -alky1.sulfinyl, 30 (CI-C 6 )-alkylsulfonyl, (C 1 ,-C,)-alkylcarbonyl,
(C
1
-C
6 alkoxycarbonyl, carbanoyl, N- (C 1
C
4 -alkylcarbanoyl, N,N-di- (C 1
-C
4 -alkylcarbamoyl, (C 1
-C
6 -alkyl- 1 carbonyloxy, (C 3
-C
8 -cycloalkyl, sulfamoyl, N- (C 1
C
4 alkyl sul famoyl or N, N-di (C C 4 alkyl sul f amoyl, or by the substituents R 5 of the ay-carbon atom of an aramino acid, it being possible to use the natural -4 t.-amino acids and thei= D-isomers; B is an acid grouping from the group -CO 2
H,
-CONHCOR"', -CONHSOR'", CONESO 2 R" I -NIISO 2
CF
3 tetrazolyl, imidazolyl or 3-hydroxyisoxazolyl, where Rill is aryl, heteroaryl, (C 3
-C
7 -cycloalkyl or
(C
1
-C
4 -alkyl, optionally monosubsti.tuted by (C 6
C
1 2 -aryl, heteroaryl, OH, SHI (C 1
C
4 -alkyl,
(C
1
-C
4 )-oulfonyl, CF 3 Cl, Br, F, 1, NO 2
-COOH,
(C
2 -alk'3xycarbonyl, NH., mono- (C 1
,-C
4 -alkyl) -amino, di- (C 1
-C
4 -alkyl) -amino or (C 1 -perfluoroalkyl, R1, R 2 and R 3 are identical or different and are hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (Cl-C 2 -alkyl, (C 3 -CS) cycloalkyl (C 3
C,
8 -cycloalkyl- (C 1
-C
12 -alkyl, (C 3
-C
8 -cycloalkoxy,
(C
3
-C
8 -cycloalkyl- (Cl-C3.
2 -alkoxy, (C 3
-C
8 -cycloalkyloxy- (C, 1
-C
2 -alkyl, (C 3
-C
8 -cycloalkyloxy- (C 1
C
12 -alkoxy, (C 3
-C
8 -cycloalkyl- (C,-C 8 -alkyl- (Cl-
C
6 -alkoxy, (C 3 -cycloalkyl- (Cl-C 8 -alkoxy- (C 1
C
6 -alkyl, (C 3
-C
8 -cycloalkyloxy- (C 1 -alkoxy- (C 1 -alkyl, (C.-C 8 -cycloalkoxy- -alkoxy- (C 1 8 -alkoxy, (C 6
-C,
2 -aryl, (C 7
-C
16 -aralkyl, (C 7 aralkenyl, (C 7
-C
1 6 -aralkynyl, (C.-C 20 -alkenyl, (C 2
C
2 0 -a.Lkynyl, -alkoxy, (C 2
-C
2 0 -alkenyloxy,
(C
2
-C
2 0 -alkynyloxy, retinyloxy, (C,-C 2 -alkoxy-
C
1 2 -alkyl, (Cj-C3 11 -alkoxy- (CI-C 1 2 -alkoxy, alkoxy- -alkoxy- (C3 1 -alkyl, (C 6
_C
12 -aryloxy,
(C
7
-C,
6 -aralkyloxy, (C.-C 1 2 -aryloxy- (C.-c 6 -alkoxy, 7 -aralkoxy- -alkoxy, (C 1
-C
16 -hydroxyalkyl, -aryloxy- -alkyl, (7C6 aralkoxy- -alkyl, (C, 6 -C3.
2 -aryloxy- (C 1 oalkoxy- -alkyl, (C 7
-CI
2 -aralkyloxy- *alkoxy- (C 1
-C
6 -alkyl, (C 2
-C
20 -alkenyloxy- (Cl-C 6 alkyl, (C 2
-C
2 0 -alkynyloxy- -alkyl, retinyloxy-
(C
1
C,
6 -alkyl, [CH_JX-CrH( 2 f*l-g)Fgl _OCF 2 Cll 0OCF 2 CHFCl, (C3. .'C20) -alkylcarbonyl, (C 1
.C
20 -akylcrboyl, (C 3
-C
8 -cycloalkylcarbonyl,
(CI-C.
2 -arylcarbonyl, (C 7
-C
16 -aralkylcarbonyl, cinnamoyl, (C 2
-C
2 0 -alkenylcarbonyl, (C 2
-C
2 0 alkynylcarbonyl, (Cl-C 2 0 -alkoxycarbonyl, (C.-C 12 -alkozy- (Cl-C 1 2 S alkoxycarboxy1, (CO _C 12 -aryloxycarbonyl, (C 7
-C
16 aralkoxycai-bonyl,
(C
3
-C
8 -cycloalkoxycarbonyl,
(C
2
C
2 -alkenyloxycarbonyl, re tiny! oxyc arbonyl, (C 2
-C
2 alkynyloxycarbonyl, (C 6 -Cl 2 -ar-Yloxy- (CI-.C 6 -alkoxycarbonyl, (C 7 -Cl 6 -aralkoxy,- 6 alkoxycarbonyl,
(C
3
-C
8 -cycloalkyl- (C3 1 -alkoxycarbonyl, (C 3
-C
8 cycloalkoxy- -alkoxycarbonyl, 1 2 -alkylcarbonyloxy, (C 3
-C
8 cyc loalkyl carbon yloxy, (C 6 -Cl 2 -arylcarbonyloxy, (C7-C 16 -aralkylcarbonyloxy, cinnamoyloxy, (C 2
-C
1 2 -alkenylcarbonyloxy, (C 2 -C3.
2 -alkynylcarbonyloxy,
(C
1
-C
1 2 -alkoxycarbonyloxy, (Cl-C.
2 -alkox-y- (C,-C 12 alkoxycarbonyloxy, (C 6
-C,
2 -aryloxycarbonyloxy,
(C
7 Cl,) -aralkyloxycarbonyloxy, (C 3 -cycloalkoxycar- *bonyloxy,
(C
2
-C
12 -alkenyloxycarbonyloxy,
(C
2
-C
1 2 alkynyloxycarbonyloxy, carbamoyl, N- (C,-C 12 -alkylcarbamoyl, N,N-di- (Cl-
C.
2 -alkylcarbamoyl, N- (C 3 -cycloalkylcarbanwrl, N,N-dicyclo- (C 3
-C
8 -alkylcarbamoyl, N- (Cl-Cl 0 -alkyl- N- (C 3 CS) -cycloalkylcarbaioy1, N- (C 3
-C
8 -cycloalkyl-
(C
1
-C
6 -alkyl) carbamoyl, N- (C,-C 6 -alkyl 3 cycloalkyl- (Cl-C 6 -alkyl) carbamoyl, N- ()-dehydroabietylcarbanoyl, N- -alkyl-N- ()-dehydroabietylcarbanoyl, N- (C,-C 1 2 -arylcarbamoyl, N- (C 7 Cl.) -arcalkylcarbanoyl, N- (CI-Cl 0 -alkyl-N- (C 6
C
16 aryrlcarbamoyl, N- (Cl-Cl.) -alkyl-N- (C 7
-C
1 6 -aralkylcarbamoyl, N- (Cl-C 1 "alkoxy- (C 1
-C
10 -alkyl) carbamoyl, N- (C 6
_C
1 6 -aryloxy- 10 alkyl) carbamoyl, N- 1 6 aralkyloxy- (Cl-CI 0 -alkyl) carbamoyl, N- -alkyl-.N- ((Cl-.C 2 )-alkoxy- (cI-c 0 alkyl)carbamoyl, N- -alkyl-N- ((C 6
-C
1 2
I
-6 aryloxy (C 1
-C
10 )-alkyl) carbamoyl, N- (C,-C 1 0 -alkyl -N-
((C
7 -aralkyloxy- (C,-C 10 -alkyl) carbamoyl, or
CON'(CH
2 in which a CH 2 group can be replacad by 0, S, N- (Cl-C 8 -alkylimino, N- (C 3
-C
8 -cycloalkylimino, N- (C 3 -cycloalkyl- (C3.-C 4 -alkylimino, N- (C 6
-C
12 arylimino, N- (C 7 -aralkylimino or N C 4 alkoxy- -alkylimino, and h is from 3 to 7~, a carbamoy!. radical of the formiula II
H
0 -T (i) in which R' is the substituent of an ae-amino acid to which the L- and D-amino acids belong, s is 1, 2, 3, 4 or 5, and T is OR, OR or where R, and are identical or different and are hydrogen, (C.-C 1 2 -aryl, (C 7
-C.
1 -a..-alkyl, alkyl, (C 3
-C
8 )-.cycloalkyl, (+)-dehydroabietyl,
(C
1 -alkox-y- -alkyl, (C 7
-C
1 2 -aralkoxy- (C 1 -alkyl, (C,-C 1 2 -aryloxy- -alkyl, (C3 1 -C3 10 alkanoyl, optionally substituted (C 7
-C
16 -aralkanoyl or optionally substituted (C,-C 1 2 -aroyl, or R* and toget'her are -[ICH 2 h, in which a CH 2 group can be replaced by 0, S, So, S021 N-acylaznino, N-
(C
1 Cl) alkoxycarbonylimino, N- (C C 8 alkylimino, N- (C 3
-C
8 -cycloalkylimino, N- (C 3
-C
8 -cycloalkyl- 25 (C,-C 4 -alkylimino, N- (C 6
-C,
2 -arylimino, N- (C 7
C
1 6 aralkylimino or N- (C,-C 4 -alkoxy- -alkylimino, and h is from 3 to 7, carbamoyloxy, N- (C3 1
-C,
2 -alkylcarbaznoyloxy, N,N-di-
(CI-CL
2 -alkylcarbamoyloxy, N- (C 3
-C
8 -rycl,,alkylcarbamoyloxy, N_ (C,-C 1 2 -arylcarbamoyloxy, -7 N- (C 7
-C
1 6 -aralkylcarbamoyloxy, N- (C 1
C
10 -alkyl-N-
(C
6
-_C
1 2 -arylcarbamoyloxy, N- (C,-C 1 0 -alkyl-N- (C 7
-C
1 6 aralkylcarbamoyloxy, N- ((C3 1
-C
1 0 -alkyl) carbanioyloxy, N- (Cf,-C 12 aryloxy- (C 1 L- CIO) alkyl) carbamoyloxy, N-
(C
7
-C
1 6 aralkyloxy- (C CIO) alkyl) carbamoyloxy, N- (Cl-C 10 -alkyl-N- (CI-Cl.) -alkoxy- (C 1
-C
1 0 -z,.kyl) carbamoyloxy, N- (Cl-Cl 10 -alkyl-N- ((C 6
-C
1 2 -aryloxy- (C 1 CIO) alkyl) carbamoyloxy, F~ 'c CIO) alkyl (C 7 -C 6 aralkyloxy- (Cl-C 1 0 -alkyl) carbamoyloxy, anino, (C C.
2 -alkylamino, di- (C,-C3.
2 -alkylamino,
(C
3
-C
8 -cycloalkylaniino, (C3-CI 2 -alkenylaniino, (C 3
C
12 -alkynylamino, N- (C.-C 1 2 -arylaniino, N- (C 7
-C
11 aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C3.-C 12 -alkoxyamino, (C,-C 12 -alkoxy-N-
C
10 c) -alkylamino,
(C,-C
1 2 -alkanoylamino, (C 3
-C
8 -cycloalkanoylaniino,
(C.-C
1 2 aroylanmino, (C 7
-C
16 aralkanoyl amino, (C 1
C
12 -alkanoyl-N- (C 1 -Cl 10 -alkylamino, (C 3 -CB) -CYClo-
(C
1
-C
1 0 -alkylamino, (C 6
-C
1 2 aroyl -N- (Cl-Cl 0 -alkylamino, (C 7
-C
1 1 -aralkanoyl-N- (C,-C 10 alkylainino,
(C,-C
1 2 -alkanoylaniino- -alkyl, (C 3
-C
8 -cycloalkanoylaniino- -alkyl, (C.-C 1 2) aroylanino- (C 1 -alkyl, (C 7
-C
16 -aralkanoylamino- -alkyl, amino- (C,-C 10 -alkyl, N- (Cl-C 1 0 -alkylamino- (CI-C 10 alkyl, N, N-di (Cl- -alkylamino- (Cl-C 10 alkyl, (C 3 -cycloaJlkylamino- (Cl-C 1 0 -alkyl, (C 1
-C
2 0 -alkyl- ~mercapto, (C 1
-C
20 )-ak~ufn1 (Cl-C 20 )-lyufonyl, (C,-Cl 2 -arylmercapto, (C 6
-C,
2 -arylsulfinyl,
(C
6
-C
1 2 aryl sul fonyl, (C 7
-C
1 6 -aralkylmercapto,
*(C
7 -aralkylsulf inyl, (C 7
-C
16 aralkyl sul fonyl, (Cl-Cl.) -alkylmercapto- (C 1 -alkyl, (C C 1 2 alkyl sulfinyl- (C,-C 6 -alkyl, (Cl-C 1 2 -alkylsulfonyl- alkyl, (C 6 -Cl 2 -arylmercapto- (Cl-C 6 -alkyl, (C 6 -Cl 2 aryl sul finyl (C C 6 alkyl, (C C 12 aryl sul f onyl (C 1 -alkyl, (C7-C 16 -aralkylmercapto- -alkyl, 8-
(C
7 -aralkylsulf inyl- (Cl-C 6 -alkyl, (C 7
-C
1 6 aralkyl sul fonyl (Cl 1
C
6 alkyl, sul famoyl, N- (C C 10 alkyl sul famoyl, N, N- di- CIO) alkylsulfamoyl, (C 3 -cycloalkylsulfamoyl, N- (C.-C 12 -arylsulf amoyl, N- (C 7 -aralkylsulfamoyl, N- (CI C3 0 alkyl (C 6
-C
12 aryl mul f aoyl, N- C3.) alkyl (C 7 -C3.
6 aralkyl sul famoyl, (CI -C 1 -alkylsulfonamido, N- ((Cl-C3 1 0 -alkyl) (C3.-C 10 -alkylsulfonamido, (C 7
-C
1 6 aralkylsulfonamido or N- (C3.-C3 0 -alkyl- (C7-C 16 aralkyl sul fonamido, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by f rom 1 to 5 identical or dif ferent radicals f rom the group: hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C,-C 16 -alkyl, (C 3 -Cd)-cycloalkyl, (C 3
-C
8 cycloalkyl- (Cl-C.
2 -alkyl, (C 3 -cycloalkoxy, (C 3 -C 8 -c y c 1oa 1k y 1(C C 3 2 )-alk ox y
(C
3 -cycloalkyloxy- (C 1
C
12 -alkyl, (C-)-cco alkyoxy-(C 1 12 alkoy, 3
-C
8 -c clly-. (-C 8 alkylo- -alkoxy, (C 3 -cycloalkyl- alkoy- -alkoy, (C 3 -cycloalkyl- (Cl-Ca)- -alkyl, (C 3
-C
8 -cycloalkoxy- alkoxy- -alkoxy, (C,-C 12 -aryl, (C 7
-C
1 6 -aralkyl,
*(C
2 -alkenyl, (C 2 -C3 1 2 -alkynyl, -alkoxy,
(C
1
C
1 2 -alkoxy- (Cl-C 12 -alkoxy, (C3 1
-C
1 2 -alkoxy-
C
8 -alkoxy- (Cl-C 8 -alkyl, (C.-C 1 2 -aryloxy, (C 7
-C
16 aralkyloxy, (C.-C 12 -aryloxy- -alkoxy, (C 7
-C
1 6 aralkoxy- -alkoxy, -hydroxyalkyl, (C 6
C
16 -aryloxy- (Cj-C 8 -alkyl, (C 7
-C
1 6 -aralkoxy- (Cj-C 8 alkyl, (C.-C 1 2 -aryloxy- (C 1 -alkoxy.- (C: 1
-C
6 -alkyl,
(C
7
-C
2 -aralkyloxy- -alkoxy- (C 1 -alkyl,
[CH
2 ]x-CfH( 2 f+l-g)FgJ' -0CF 2 Cl, OCF 2 -CHFCl, -alkylcarbonyl, (C 112 )-alylcrboyl, (C 3
-C
8 -cycloalkylcarbonyl, 9- (CE -C 12 -arylcarbonyl, (C 7 -C3.
6 -aralkylcarbonyl,
(C
1
-C.
2 -alkoxycarbonyl, (C 1
C
1 2 -alkoxy- (C.-C 1 2 alkoxycarbonyl, (C 6 2 -aryloxycarbonyl, (C 7
-C
1 6 aralkoxycarbonyl, (C 3
-C
8 -cycloalkoxycarbonyl, (C 2
C.
2 -alkenyloxycarbonyl, (C2-C 12 -alkynyloxycarbonyl,
(C.-C
1 2 -aryloxy- -alkoxycarbonyl, (C 7
-C
1 6 aralkoxy- -alkoxycarbonyl, (C 3
-C
8 -cycloalkyl-
(C
1 -alkoxycarbonyl, (C 3
-C
8 -cycloalkoxy- alkoxycarbonyl, (C C 12 -alkylcarbonyloxy, (C 3 -cycloalkylcarbonyloxy, 2 -arylcarbonyloxy, (C 7
-C
1 5) aralkyl carbonyloxy, cinnanioyloxy, .(C 2
-C,
2 -alkenylcarbonyloxy, (C 2
-C
1 2 -alkynylcarbonyloxy,
(C
1
-C
12 -alkoxycarbonyloxy, (C 1
C
1 2 -alkoxy- 2 alkoxycarbonyloxy, (C 6 -C3 1 2 -aryloxycarbonyloxy, (C 7 Cl,) -aralkyloxycarbonyloxy, (C 3
-C
8 -cycloalkoxycarbonyloxy, (C 2
-C
1 2 -alkenyloxycarbonyloxy, (C 2
-C
1 2 alkynyloxycarbonyloxy, carbanioyl, N- (C -alkylcarbamoyl, N,N-di- (Cl-C 1 2 alkylcarbanoyl, N-(C 3 -C,)-cycloalkylcarbanoyl, N,Ndicyclo- (C 3
-C
8 -alkylcarbanoyl, N- (C 1
-C
10 -alkyl-N-
(C
3
-C
8 -cycloalkylcarbamoyl, N- ((C 3
-C
8 -cycloalkyl-
(C
1 -C,)-alkyl)carbamoyl, N- (Cl-C,)-alkyl-N-((C 3 cycloalkyl- -alkyl) carbamoyl, N- -dehydroabietylcarbanoyl, N- (C3 1
-C
6 -alkyl-N- -dehydroabietylcarbanoyl, N- (C 6
-C
12 -arylcarbaioyl, N- (C 7 Cl,) -aralkylcarbanioyl, N- -alkyl-N- 6 arylcarbanoyl, N- (C,-C3 10 -alkyl-N- (C 7 -Cl 6 -aralkylcarbamoyl, N- (C 1 -C3 16 -alkoxy- (C3 1
-C
10 -alkyl) 30 carbamoyl, N- ((C 6
-C,
6 -aryloxy- (Cl-Cl 0 alkyl) carbarnoyl, N- ((C 7 -aralkyloxy- (C3 1
-C
1 0 alkyl) carbanioyl, N- (C 1 -alkyl-N- ((C3 1 -Cl 0 -alkoxy- (Cl-Cl 0 -alkyl) carbanioyl, N- (Cl-Cl.) -alkyl-N- 1 2 -aryloxy- (C 1 Cl.) -alkyl) carbainoyl, N- (C 1 -Cl 0 -alkyl-N- (C7-C 16 10 aralkyloxy- (Cl-C 10 -alkyl) carbamoyl, CON (CH 2 h, in which CH 2 group can be replaced by 0, S, N- (Cl-Cs) alkylimino, N- (C 3
-C
8 -cycloalkylimino, N- (C 3
-C
8 cycloalkyl- (C,-C 4 -alkylimino, N- (C.-C 1 2 -arylimino, N- (C 7
-C
1 6 -aralkylimino or N- (Cl-C 4 -alkoxy- alkylimino, and h is from 3 to 7, carbanioyloxy, N- (CI-C 1 2 -alkylcarbamoyloxy, N,N-di- (Cl-C 12 -alkylcarbamoyloxy, N- (C 3
-C
8 -cycloalkylcarbamoyloxy, N- (Cr,-C3 1 6 -arylcarbamoyloxy, N- (C 7
C
16 -aralkylcarbamoylocy, N- (C 1
-CI
0 -alkyl-N-
C
12 -arylcarbamoyloxy, N- -alkyl-N- (C 7
-C
16 aralkylcarbamoyloxy, N- ((C3 1
-C
1 o) -alkyl) carbamoyloxy, N- (C 6
-C
12 aryloxry- (C CIO) alkyl) carb aoyloxy, N-
(C
7
-C
16 aralkyloxy- (Cl- CIO) alkyl) carbanioyloxy, N-
(CI-C
1 0 -alkyl-N- (Cl-Cl.) -alkoxy- (C 1
-C
1 0 alkyl)carbamoyloxy, N- -alkyl-N- ((C 6 -Cl 2 aryJloxy- (C 1 -Cj 0 -alkyl) carbamoyloxy, N- (C.
1 -CO) -alkyl- N- (C 7 -aralkyloxy- (Cl-Cl.) -alkyl) carbamoyloxy, amino, (C 1
-C
1 2 -alkylamino, di- (Cl-C.
2 -alkylaniino,
(C
3 -C)-cycloalkylamino, (C 3
-C
12 )-alkenylamino, (C 3
*:C
12 -alkynylamino, N- 2 -arylamino, N- (C 7
-C
11 aralkylamino, N-alkyl-aralkylamino, iq-alkyl-arylamino, (C,-C 1 2 -alkoxyamino, (CI- C 12 -alkoxy-N- (C 1 CIO) -alkylamino, 25 (CI-C 2 -alkanoylamino, (C 3 -cycl1oalkanoyl amino, 1C -C 12 -aroylamino, -aralkanoylamino, (C3 1
C.
2 -alkanoyl-N- (Cj-C 1 -alkylamino, (C 3
-C
8 -cycloalkanoyl-N- -alkylamino, (C.-C 1 2 -aroyl-N- (C 1
C
10 alkyl amino, (C7-C 1 l)-aralkanoyl-N- (Cl-Cl 0 -alkyl 30 amino, (Cl-C 1 2 -alkanoylamino- (C3 1
-C
8 -alkyl, (C 3
-C
8 cycl1oalkanoyl amino (C 1 -alkyl, (C 6
-C
12 -aroylamino- -alkyl, (C 7
-C
16 aralkanoyl amino -alkyl, amino- (C 1
-C
10 -alkyl, N- (Cj-C 10 -alkylamino- (Cl-C 10 alkyl, N,N-di- (Cl-C 10 -alkylamino- (C 1
-C
10 -alkyl, 11
(C
3
-C
8 -cycloalkylanino- (Cl 1
-C
1 c) -alkyl, (CI -C 12 -alkylmercapto, (Cl-Cl 2 -alkylsulfinyl, (Cl-
C
12 al1kyl sul fonyl, (C.-C 16 -arylmercapto, (C 6
-C
1 6 arylsulfinyl, (C 6
-C
16 aryl sul fonyl, (C 7
-C
1 6 aralkylmercapto, (C 7
-C
16 -aralkylsulf inyl or (C 7
-C
1 6 aralkylsulfonyl,
R
1 and R 2 or R 2 and R 3 form a chain [CH 2
J
0 in which one or two CH 2 groups of the chain, which is saturated or unsaturated by a C=C double bond, are optionally replaced by 0, S 1 So, SO 2 or NR', and o is 3, 4 or and R' is hydrogen, (C.-C 1 2 -aryl, (C 1
C
8 -alkyl, alkoxy- (C 1 -alkyl, (C 7
-C
1 2 -aralkoxy- (C 1
C
8 -alkyl, (C,-C3.
2 -aryloxy- (C.
1 -alkyl, (C3 1 -C2 1 0 -alkanoyl, optionally substituted (C 7
-C
1 -aralkanoyl or optionally substituted (C,-C 1 2 -aroyl, where the radicals R' and R 2 or R 2 and R 3 together with the pyridine or pyridazine carrying them, preferably form a 5, 6, 7, 8-tetrahydroisoquinoline ring, a 5, 6, 7, 8-tetrahydroquinoline ring or a 5, 6, 7, 8- :0 tetrahydrocinnoline ring, or R1 and R 2 or R 2 and R 3 form a carbocyclic or a **:.heterocyclic, 5- or 6-membered aromatic ring, where the radicals R' and R 2 or R 2 and R 3 together with the pyridine or pyridazine carrying them, preferably form the following optionally substituted heterocyclic ring systemA: Thienopyridines, Furanopyridines, Pyridopyridines, Pyrimidinopyridines, Imidazopyridines, 12 Thiazolopyridines, Oxazolopyridines, Quinoline, isoquinoline and Cinnoline, where quinoline, isoquinoline or c:-nnoline preferably satisfy the formulae la, lb and ic
R
1 6
R
1
RR
R
1
N,
R 1 4 ,2 1 OR 4 R 8' R 2 0 .R 1 9 Q
R
and the substituents R 11 to R 22 in each case independently of each other, have the meaning of R1, R 2 and R', R 4 is, if Q is a bond, halogen, nitrile or trifluoromethyl, or, if Q Is 0, S or NR', a branched or unbranched (Cl-C 2 0 )-alkyl radical, an unsubstituted, saturated fluoroalkyl radical of the formula [CH 21 CfH( 2 f+ 1 .g)Fg? a (C.-C 16 -aryl radical, a (CI-C 1 6 -aralkyl radical, a heteroaryl radical or a heteroaralkyl radical,
S
13 where these radicals are substituted by one or more radicals from the group hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (Cl-C 1 2 -alkyl, (C 3
-C
8 -cycloalkyl, (C 3
C
8 cycloalkyl- (C.-C 12 -alkyl, (C 3
-C
8 -cycloalkoxy, (C 3 CS) cycloalkyl- (C 1
C
1 2 -alkoxy, -cycloalkyloxy- (Cl-C.
2 alkyl, (C 3
-C,
8 -cycloalkyloxy- (Cl-C 12 -alkoxy, (C 3 -CO) cycloalkyl- (C 1 -alkyl- -alkoxy, (C 3 -CB) -cycloalkyl- (C-C 8 -alkoxy- (C 1
C
6 -alkyl, (C 3 -cycloalkyloxy-
(C,-C
8 -alkoxy- -alkyl, (C 3
-C
8 -cycloalkoxy- (C3.-C 8 alkoxy- (C3 1 -alkoxy, (C.-C 1 2 -aryl, (C 7 -aralkyl,
(C
2 -C3.
2 -alkenyl, (C 2
-C,
2 -alkynyl, (C 1
C
1 2 -alkoxy, (C 1
C
1 2 -alkoxy- (C.-C 1 2 -alkyl, (Cl-C 12 -alkoxy- (C.-C 1 2 alkoxy, (C 1
-C
12 -alkoxy- -alkoxy- (Cl-C 8 -alkyl, (C 6
C
1 2 -aryloxy, (C 7 -aralkyloxy, (C,-C3.
2 -aryloxy- (Cl-
C
6 -alkoxy, (C 7 -Cj 6 -aralkoxy- (C 1 -alkoxy, (C 1
C
8 hydroxyalkyl, (C 6
-C
1 6 -aryloxy- -alkyl, (C 7
C
16 aralkoxy- (C 1 -alkyl, (C,-C 1 2 -aryloxy- (C 1 -alkoxy-
(C
1 -alkyl, (C 7
-C.
2 -aralkyloxy- (C 1 -alkoxy- (C 1 alkyl, [CH 2 x-CfH( 2 f+1-g) FgI -OCF 2 C1, -OCF 2 -CHFCl, (Cl-Cl 2 -alkylcarbonyl, (C 3
-C
8 -cycloalkylcarbonyl, (C 6
.*C
12 )-arylcarbornyl, (C- 1 )-aralkylcarbonyl, cinnamoyl, (C -C 12 -alkenylcarbonyl, (C- 1 )-aklynylcarbonyl,
(C
1
C
12 -alkoxycarbonyl, (C 1
C
12 -alkoxy- (CI-CI 2 -alkoxycarbonyl, (C.-C 12 -aryloxycarbonyl, (C 7 -aralkoxy- *carbonyl, (C 3
-C
8 -cycloallkoxycarbonyl, (C 2
-C
12 alkenyl oxycarbonyl, (C 2
-C
12 -alkyn'yloxycarbonyl, (C 6
-C
12 aryl oxy- -alkoxycarbonyl, (C 7
-C
16 -aralkoxy- (C3 1 alkoxycarbonyl, (C 3
-C
8 -cycloalkyl- (Cl-C 6 -alkoxycarbonyl,
(C
3
-C
8 cycloalkoxy- (C3 1 -alko.xycarbonyl,
(C
1
-C
12 -alkylcarbonyloxy, (C 3
-C
8 -cycloalkylcarbonylioxy,
(C,-C
12 -arylcarbonyloxy,
(C
7
-C
1 6 -aralkylcarbonyloxy, Ci-ctzMOYloxy, (C 2
-C
1 2 -alkenylcarbonyloxy, (C 2
-C
12 alkynylcarbonyloxy,
(C
1
-C
12 -alkoxycarbonyloxy, (C 1
C
12 -alkoxy- (CI-C 12 -alkoxy- 14 carbonyloxy, 1 2 -aryloxycarbonyloxy, (C 7 -aralkyloxycarbonyloxy, (C 3
-C
8 -cycloalkoxyca.2bonyloxy, (C 2
-C
12 alkea'yloxycarbonyloxy, (C 2
-C
1 2 -alkynyloxycarbonyloxy, carbanioyl, N- (CI_-C 12 -alkylcarbamoyl, N, N-di (C C 1 2 S alkylcarbamoyl, N- (C 3
-C
8 -cycloalkylcarbamoyl, N,N-dicyclo- (C 3 -CS) -alkylcarbamoyl, N- (C 1
C
10 -alkyl-N- (C 3
-C
0 cycloalkylcarbamoyl, N- ((C 3 -cycloalkyl- alkyl) carbarnoyl, N- -alkyl-N- ((C 3 -cycloalkyl-
(C
1 -alkyl) carbamoyl, N- -dehydroabietylcarbamoyl, N- (C 1 -alkyl-N- W+ -dehydroabietylcarbamoyl, N- (CS-C 1 2 arylcarbamoyl, N- 16 -aralkylcarbamoyl, N- (CI-C 1 0 alkyl-N- (C.-C 16 -arylcarbamoyl, N- (C 1
-C
10 -alkyl-N- (C 7
C
16 -aralkylcarbamoyl, N((C,-C 1 -alkoxy- (C3 1
-C
1 0 alkyl)carbamoyl, XN-( -aryloxy- (CI-C 1 0 alkyl)carbamoyl, N (C 7
-C
1 6 -aralkyloxy- (CI-C 0 alkyl) carbamoyl, N- (C3 1
-C
10 -alkyl (Cl-C: 10 -alkoxy- (C 1 CIO) -alkyl) carbainoyl, N- (CI-C 10 -aiiiyl-N- ((C,-Cl 2 -aryloxy- (Cl C7 0 alkyl) carbamoyl, N(C3.-C, 0 -alkyl-N- ((C 7
-C
16 ara2,kyloxy- (Cl-C 10 -alkyl) carbamoyl, CON(CH 2 in which a CH 2 group can be replacsd by 0, S, N- -alkylimino, N- (C 3 -cycloalkylimino, N- (C 3 -cycloalkyl- alkylimino, N- (C 6
-C
12 -arylimino, N- (C.
7
-C
16 -aralkylimino or N- (CI-C 4 -alkoxy- -alkylimino, and h is from 3 to 7, or by a carbamoyl radical of the formula Ii -Co0 N R -T (i in which Rx is the substituent of an a-amnino acid to which the L- and D-amino acids belong, s is 1, 2, 3, 4 or 5, and T is OH, OR or NRR*, where 15 R, R' and are identical or different and are hydrogen, 2 -ar-yl, (C 7
-C
11 l) -aralkyl, (C 1
-C
8 alkyl, (C 3 -cyclcoslkyl, -dehydroabietyl, (C 1
C
8 -alkoxy- (C 1
C
8 -alkyl, (C 7
-C
1 2 -aralkoxy- (C-L-CO) alkyl, (C.-C 1 2 -aryloxy- -alkyl, (C 1 -Clo) alkanoyl, optionally substituted (C 7
-C
1 6 -aralkanoyl or optionally substituted (C 6
-C,
2 -aroyl, or R* and together are ECH 2 Jh, in which a CH 2 group can be replaced by 0, S, SO, SO 2 N-acylaniino, N- (Cl-
C
10 -alkoxycarbonylimino, N- -alkylimino, N-
(C
3 -cycloalkylimino, N- (C 3
-C
8 -cycloalkyl- Cl C 4 -alkylimino, (C,-C 1 2 -arylimino, N- (C 7 -C16) aralkylimino or N- (Cl-C 4 -aikoxy- (C 1 alkylimino, and h is from 3 to 7, or by carbamoyloxy, N- (C 1
-C.
2 -alkylcarbaznoyloxy, N,N-di- (C3 1
C
12 -alkylcarbanmoyloxy, N- (C 3
-C
8 -cycloalkylcarbanoyloxy, N- 2 -arylcarbamoyloxy, N- (C 7
C
1 6 -aralkylcarbamoyloxy, N- (Cl-'Cl 0 -alkyl-N- (C.-C 12 -arylcarbaznoyloxy, N- (C3 1 -C3 1 -alkyl-N- 16 -aralkylcarbamoyloxy, N- ((C3 1 -Cl 0 alkyl)carbamoyloxy, 6
-C
1 2 -aryloxy- (Cl-Cl.) **-alkyl) carbamoyloxy, N- -aralkyloxy- (Cl-C 1 0 alkyl) carbamoyloxy, N- (Cl-Cl 0 -alkyl-N- ((C3 1
-C
10 -alkoxy- (C -alkyl) carbamoyloxy, N- (Cl-Cl.) -alkyl-N- 1 2 aryloxy- (CI-C.
10 -alkyl) carbamoyloxy, N- (C 1 -Cl 10 -alkyl-N- 16 -aralkyloxy- (Cl-Cl 0 -alkyl) carbanoyloxy, amino, (C 1
-C
1 2 -alkylainino, di- 2 -alkylamino, (C 3
C
8 cyc Ioalkyl amino, (C 3
-C
1 2 -alkenylamino, (C 3
-C
12 alkynylaxnino, N- (C,-Cl 2 -arylamino, N- 1 -aralkylamino, N- alkyl aralkyl amino, N- alky"i aryl amino, (Cl-Cl 2 :30 alkoxyainino, (Cl-C.
2 -alkoxy-N- (C 1
C
1 0 -alkylamino, (Cl-C 12 -alkanoylamino, (C 3
-C
8 -cycloalkanoylamino,
(C
6
C.
2 aroylamino, 16 aralkanoyl amino, (Cl-C.
2 -alkanoyl-N- (Cl-Cl.
0 -alkylamino, (C 3 -cycloalkanoyl-N- (C 1
C
10 -alkylamino, (C 6 -aroyl-N- -alkylamino, (C7,- -aralkanoyl-N- (Cl-C 1 0 -alkylamino, 16 (Cl-C 1 2 -alkanoylamino- -alkyl, (C 3 -cycloalkanoylamino- (C 1 -alkyl, (C.-C 1 2) -aroylamino- (Cl-C 8 alkyl, (C 7
-C
16 -aralkanoylamino- (C 1
-C
8 -alkyl, amino- (C 1 CIO) -alkyl, N- (C 1 -alkylamino- (C,-C3 10 -alkyl, N,N-di (C 1 CIO) -alkylamino- -alkyl, (C 3 -cycloalkylamino-
(C
1
-_C
1 2 -alkylmercapto, (C 1
C
12 -alkylsulf inyl, (C 1 -C 1 2 alkylsulfonyl, (C 6
-C
12 -arylmercapto, (CIS-C 2 -arylsulfinyl,
(C.-C
12 -arylsulfonyl, (C 7 -aralkylmercapto, (C 7
-C
1 6 aralkylsulfinyl, (C 7
-C,
6 -aralkylsulfonyl, sulfamoyl, N- (C CIO) alkyl sul famoyl, N,N-di- (C.-C 10 alkylsulfamoyl, (C 3 -cycloalkylsulfamoyl, N- (C 6
-C
1 2 aryl sul f amoy., N- (C 7 C3 6 aralkyl sul famoyl, N- (C 1 -alkyl 2 -arylsulfamoyl,. N- (C 1
C
10 alkyl-N- (C 7
-C
16 -aralkylsulfamoyl, (C CIO) alkyl sul fonamido, N- ((Cj-Cj 0 -alkyl) (Cj-Cj 0 -alkylsulfonamido, (C 7
"C
1 6 aralkylsulfonamido or N- ((Cl-C 10 -alkyl- (C 7
-C
16 -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, (CI-C 2 -alkyl, (C 3 -C-cycloalkyl, (C 3
-C
8 cycloalkyl- (C.-C 12 -alkyl, (C 3
-C
8 -cycloalkoxy, (C 3 -CO) eycloalkyl- (C 1
-C
12 -alkoxy, (C 3
-C
8 -cycloalkoyloxy- (C -C 12 alkyl, (C 3 -cycloalkyloxy- (CI-C 1 2 -alkoxy, (C 3
-C
8 cycloalkyl- -alkyl- (Cl-C, 6 -alkoxy, (C ce) cyclo alkyl- (C 1
-C
8 -alkoxy- -alkyl, (C 3 -Cd-cycloalkyloxy-
*(C
1
-C
8 -alkoxy- -zLkyl, (C 3
-C
8 -cycloalkoxy- (CI-Ce) alkoxy- (C 1
C
8 -alkoxy, 2 -aryl, (C 7
-C
1 6 -aralkyl,
(C
2
-C,
2 -alkenyl, (C 2
-C.
2 -alkynyl, (Cl-C 12 -alkoxy, (C 1 oC 1 2 -alkoxy- (Cl-C 1 -alkyl, (C.-C 1 2 -alkoxy- (CI-C 1 2 alkoxy, (Cl-C 12 -alkoxy- -alkoxy- -alkyl, (C 6
C
12 -aryloxy, (C 7
-C
1 -aralkyloxy, (C.-C 12 -aryloxy- (C 1 -alkoxy, (C 7 -aralkoxy- -alkoxy, 17
(C
1 -hydroxyaJlkyl, (C.-C 1 6 -aryloxy- -alkyl, (C7- Cl.) -aralkoxy- (C 1 -alkyl, (C.-C 12 -aryloxy- -alkoxy- -alkyl, (C7 -C 12 -aralkyloxy- (C 1 -alkoxy- (C 1 alkyl, [CE 2 ]xCfH( 2 f+l..g)FgI -OCF 2 C1,I -OCF 2 -CHFC1,
(C
1
C
1 2 -alkylcarbonyl, (C 3
-C
8 -cycloalkylcarbonyl,
(C
6 CIO) -arylcarbonyl, 16 -aralkylcarbonyl, (C C 1 2 -alkoxycarbonyl, (C.-C 1 2 -alkoxy- (C 1
-C
12 -alkoxycarbonyl, (C.-C 1 2 -aryloxycarbonyl, -aralkoxycarbonyl, (C 3
-C
8 -cycloalkoxycarbonyl, (C 2
-C
1 2 -alkenyJloxycarbonyl, (C 2
-C
12 -alkynyloxycarbonyl, (C 6 -aryloxy- -alkoxycarbonyl, -aralkoxy- -alkoxycarbonyl, (C 3
-C
8 -cycloalkyl- -alkoxycarbonyl,
(C
3 -cycloalkoxy- (C 1 -alkoxycarbonyl, (Cl-C 1 2 -alkylcarbonyloxy,
(C
3
-C
8 -cycloalkylcarbonyloxy,
(C
6
-C
1 2 -arylcarbonyloxy, -aralkylcarbonyloxy, cinnamoyloxy, (C 2
-C
12 -alkenylcarbonyloxy, (C 2
-C
12 alkynylcarbonyloxy, (Cl-C 1 2 -alkoxycarbonyloxy, (C.-C 1 2 -alkoxy- (C 1
C
1 2 alkoxycarbonylcxy, (C 6 -C3.2) aryloxycarbonyloxy, (C C 16 aralkyloxycarbonyloxy, (C 3 -cycloalkoxycerbonyloxy,
(C
2
-C.
2 -alkenyloxycarbonyloxy,
(C
2
-C,
2 -alkynyloxy- :carbonyloxy, .3.carbamoyl, N- 2 -alkylcarbamoyl, N,N-di- (CI-C 1 2 alkylcarbamoyl, N- (C 3
-C
8 -cycloalkylcarbanoyl, N,N-dicyclo- (C 3
-C
8 -alkylcarbamoyl, N- -alkyl-N- (C 3
-C
8 cycloalkylcarbamoyl, N- -cycloal.kyl- alky.) carbamoyl, N- -alkyl-N- ((C 3 -cycloalkyl-
(CI-C
6 -alkyl) carbamoyl, N- -dehydroabietylcarbamoyl, 3N- (C 1
C
6 -alkyl-N- -dehydroabietylcarbanoyl, N- (C,5-C.
2 arylcarbamoyl, N- (C7-Cl 6 -aralkylcarbamoyl, N- (Cl-C 10 :33~alkyl (C 6 6 -arylcarba-moyl, N- (C 1
-C
10 -alkyl-N- (C7-
C
16 -aralkylcarbamoyl, N- (C 1 0 -alkoxy- (Cl-C2 1 0 alkyl)carbamoyl, N- -aryloxy- alkyl) carbamoyl. N- (C7-C3 16 -aralkyloxy- (Cl-C 0 alkyl)carbamoyl, N- (C,-C 10 -alkyl-N- (C,-C3 0 -alkoxy- 18
(C,-C
1 0 -alkyl) rcarbanioyl, N- -alkyl-N- (C.-C 1 2 aryloxy- (Cl-C.
0 -alkyl) carbamoyl, N- (C 1
-C
10 -alkyl ((C 7
C
1 -aralkyloxy- (C 1
C
10 -alkyl) carbamoyl, CON (CH 2 h, in which a CH 2 group ca.n be replaced by 0, S, N- (Cl-C 8 alkylimino, N- (C 3
-C
8 -cycloalkylimino, N- (C 3
-C
8 -cycloalkyl- (C 1
-C
4 -alkylimino, N- (C 6
-C,
2 -arylimino, N- (C 7
-C
1 6 aralkyl1imino or N- (C 1
-C
4 -alkoxy- -alkylimino, and h is from 3 to 7, carbamoyloxy, N- (C 1
-C.
2 -alkylcarbanioyloxy, N,N-di- (Cl-
C
1 -alkylcarbaznoyloxy, N- (C 3
-C
8 -cycloalkylcarbamoyloxy, N- -arylcarbamoyloxy, N- (C 7
-C
16 -ar 1 alkylcarbamoyloxy, N- (C 1
C
10 -alkyl-N- 2 -arylcarbanioyloxy, N- (CI-
C
10 -alkyl-N- (C 7
-C
16 -aralkylcarbamoyloxy, N- ((CI -CIO) alkyl)carbamoyloxy, 6
-C
1 2 -aryloxy- (C-C 0 alkyl)carbamoyloxy, N- (C 7 -aralkyloxy- (C 1
-C
10 alkyl) carbamoyloxy, N- (Cl-Cl 0 -alkyl-N- ((C 1 Cl 0 -alkoxy- (C 1
CI
0 -alkyl) carbamoyloxy, N- (Cj-Cj 0 -alkyl-N- 1 2 aryloxy- (Cl-C3.
0 -alkyl) carbamoyloxy, N- (Cl-Cl.) -alkyl-N-
((C
7 -aralkyloxy- (C 1 -CO) -alkyl) carbamoyloxy, amino, (CI-C 12 -alkylamino, di- 2 -alkylamino, cycloalkylamino, (C 3
-C
1 2) -alkenylamino, (C 3
-C
12 -alkynylamino, N- (C 6
-C
12 -arylamino, N- (C 7
-C
11 -aralkylamino, :N-alkyl-aralkylamino, N-aikyl-arylamino, (C 1
-C
12 alkoxyamino, (Cl-C3.
2 -alkoxy-N- (Cl-C 10 -alkylamino, (CL-C1 2 -alkanoylamino, (C 3
-C
8 cyc loa lkanoyl amino, (C 6
C
12 aroy'Lamino, (C7-C 1 6 aralkanoyl amino, 2 -alka- *noyl-N- (C 1
-CI
0 -alkylainino, (C 3 -cycloalkanoyl-N- (Cl-
C
10 -alkylamino, (C 6
-C
12 -aroyl-N- (C 1
-C
10 -alkylamino, (C 7
C
11 -aralkanoyl-N- (CI-C 10 -alkylamino,
(C
1
-C
1 2 -alkanoylamino- -alkyl, (C 3
-C
8 -cyclo- **alkanoylamino- -alkyl, (C,-C 12 -aroylamino- alkyl, (C 7
-C
1 -aralkanoylamino- (Cl-'C 8 )-alkyl, amino- (C3-
C
10 -alkyl, N- (C 1 -Cl 0 -alkylamino- (C 1
-C
10 -alkyl, N,N-di-
(C.
1 -CIO) -alkylamino- (CI-CI 0 -alkyl, (C 3
-C
8 -cycloalkylamino- (Cj-Cj 0 -alkyl, 19
(C
1
-_C
12 -alkylmercapto, (C 1
C.
2 -alkylsulf inyl, (C 1 -Q1 2 alkylsulfonyl, (C, 6
-C
16 -arylmercapto, (C 6
"C
16 aryl sulfinyl, (C.-Cld)-arylsulfonyl, (C 7 -aralkylmercapto,
(C
7 -aralkylsulfinyl or (C.
7
-C
1 6 -aralkylsu!lfonyl, and
R
4 is provided that Q has the meaning of 1NR', where RI and R" are identical or different and are hydrogen, 2 -aryl, (C7-C 11 -aralkyl, -alkyl, -alkoxy- -alkyl, (C 7
-C
1 2 -aralkoxy-
C
5 -alkyl, -aryloxy- -alkyl, (C 1
-CI
0 alkanoyl, optionally substituted (C 7
-C
1 -aralkanoyl or optionally substituted (C.-C 1 -aroyl, or R' and R" together are -[rCH 2 J h, in which a CH 2 group can be replaced by 0, S, N-acylimino or N C.Co 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, 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.
in general, aryl 1,.s understood to mean carbocyclic and heterocyclic aromatic ring systems. In particular, it is understood to include phenyl-substituted, biphenylsubst.Ituted, naphthyl- substituted or unsubstituted 5- and 6-mexnbered heteroaromatic rings having 1, 2 or 3 nitrogen and/or oxygen aand/or sulfur c;.toms, such as derivatives of pyridyl, pyridazyl, pyrimidy:L, pyrazyl, imidazolyl, triazolyl, thienyl, oxazolyl and thiazolyl, and their benzo-fused derivatives.
The invention also embraces salts of the compounds of the formula I.
20 The formation of salts with baL.Ac reagents can take place once, twice or thi~, times on the acidic groups of the compounds of the ftcv. -4ula I radicals B, R 2
RI
and in particul,,r on the =adicals B, R 2 and/or R 4 Examples of reagents being used are alcoholates, hydroxides, carbonates, hydrogen carbonates, hydrogen phosphates, organometallic compounds of the alkali and alkaline Earth elements, the elements of the third and fourth main groups of the periodic system, and the elements of the transition metals, amines, optionally substituted 1 to 3 times by (C3,-CO) hydroxyalkyl, (C 1
-C
4 -alkoxy- (C 1 -alkyl, Ohenyl, benzyl or (C 1 -alkyl, which can be substitutea I to 3 times by hydroxyl or (C,-C 4 -alkoxy, for example tromethane (Tris buffer), 2-aminoethanol, 3-aminopropanol, hydroxylamine, dime thylhydroxylamine, 2 -methoxyethyl amine, 3-ethoxypropylamine, and basic amino acids and amino deriv-tives, such as amino acid esters, histidine, arginine and lysine, and their darivatives, and also .:..pharmaceuticals which contain a basic group, such as, for example, ®,~miloride, ®Verapamil and beta blockeris.
The invention also relates to the compounds according to formula 1, plus 3-benzyloxypyridine-2-carboxylic acid (Lthreonyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride for use as pharmaceuticals.
Compounds of the formula I are of great interest, in which Q is 0, S, NR' or a bond, *X i P, 0 Y is CR 3 or, if R 1 and R 2 form a cycle, Y is Nor CR 3 21 i is 0 or 1.
Compour 's of the formula I are very important, in which Q is 0, NR' or a bond, X is 0.
Compounds of the formula I are also very important in which Q is S and X is 0.
Compounds of the formula I are of particular importance in wxiich Q is 0, NR' or a bond, X is 0, Y is CR' or, if R' and R 2 form a cycle, N or CR, m is 0ori1, A is (C 1
-C
3 -alkylene which is optionally substituted once by halogen, cyano, trifluoromethyl, (C3 1
-C
6 alkyl, -hydroxyalkyl, (C 1 -alkoxy or -0-
[CH
2 -CfH( 2 f+l..g)FgI or A is where R' is one of the substituents of the ix-carbon atom of an ar-amino acid, in particular of a. natural L-ainino acid and of its D-isomer, B is C0 2
H,
*R
2 is~ hydrogen, (Cl-C 2 0 -alkyl, (C 2
-C
2 -alken-yl, (C 2
C
20 -alkynyl, (CI-C 20 -alkoxy, (C 2
-C
2 0 -alkenyloxy,
(C
2
-C
2 0 -alkynyloxy, retinyloxy, (C 1
-C
20 -alkoxy- (C 1 CO-alkyl, (C 2
-C
2 0 -alkenyloxy- C 3 -alkyl, retinyloxy- (C 1
-C
3 -alkyl, (C 2
-C
20 -alkynyloxy- (C 1 CO) -alkyl, halogen, cyano, trifluoromethyl, hydroxyalkyl, (C 1
C
20 alkanoyl, (C 7
C
1 araJ.kanoyl,
*(C
6
-C,
2 -aroyl, (C 6
-C,
2 -aryl, (C 7
-C
16 -Firalkyl,
ECH
2 Jx-CfH(2f+,g)FgI NRIRn, (Cl-C,)-alkylmercapto,
(C
1
C
1 -alkylsulfinyl, (Cl-C 10 ))-alkylsulfonyl, (C 6
C
1 2 -arylmercapto, (C.-C 1 2 -arylsulfinyl, (CG-C 1 2 arylsulfonyl, C 7 -C1 2 -aralkylmercapto, 22
(C
7
-C
12 aralkyl sul finyl, (C 7
-C
12 aral kylsul fonyl, 2 -aryloxy, (C 7
-C
16 -aralkyloxy, carboxyl, (C 1
C
2 -alkoxycarbonyl, (CI-CI 2 -alkoxy- (C.-C 12 -alkoxycarbonyl, (C 6
-C
1 2 -aryloxycarbonyl, (C 7
-C
1 6 aral koxycarbonyl, (C 3
-C
8 cycloalkoxycarbonyl, (C 2
C
2 -alkenyloxycarbonyl, retinyloxycarbonyl,
(C
2
-C
2 0 -alkynyloxycarbonyl, (C 3 -cycloalkyl- -alkoxycarbonyl, (C 3 -cycloalkoxy- (C 1
C
6 alkoxycarbonyl, (C 6
-C,
2 -aryloxy- -alkoxycarbonyl, (C 7
-C
16 -aralkoxy- -alkoxycarbonyl, carbanioyl, N- (C 1
-C
1 2 -alkylcarbamoyl, N, N-di- (CI-C 1 2 alkylcarbamoyl, N- (C 3 -cycloalkylcarbamoyl, N,Ndicyclo(C 3
-C
8 -alkylcarbantoyl,N- -alkyl-N- (C 3 -cycloalkylcarbamoyl, N- (C 3
-C
8 -cycloalkyl- (C 1 alkyl) carbamoyl, N- (C.-C 6 -alkyl-N- (C 3 -cycloalkyl- -alkyl) carbaioyl, N- -dehydroabietylcarbamoyl, N- -alkyl-N- W+ -dehydroabietylcarbainoyl, N- (C.-C 1 2 -arylcarbamoyl, N- (C 7
-C
1 6 aralkylcarbamoyl, N- (C 1
-CI
0 -alkyl (C.-C3 16 -arylcarbamoyl, N- -alkyl-N- (C 7
-C
16 -aralkylcarbamnoyl, N- (C 1
-C
12 -alkoxy- CI) -alkyl) carbamoyl, N- (C 6 -C3 1 6 aryloxy- (Cl- CIO) -alkyl) carbamoyl, N- ((C 7
C
1 -aralkyloxy- (Cl-C 10 -alkyl) carbax.o, N- (Cl-CI 0 alkyl-N- ((Cl-C.
0 -alkoxy- (Cl-Cl 0 -alkyl) carbamoyl, N- (Cl-C 1 0 -alkyl-N- (C.-C 1 2 -aryloxy- (Cj-C 10 O) alkyl)carbamoyl, N- (Cl-C 10 -alkyl-N- ((C 7 aralkyloxy- (Cl-Cl.) -alkyl) carbamoyl, CON (CH 2 )hI in which a Cl! 2 group can be replaced by 0, S, N- (C 1
-C
8 :alkylimino, N- (c 3 -cycloalkylimino, N- (C 3 CS) cycloalkyl- (Cl-C 4 -alkylimino, N- 1 2 -arylimino, N- (C 7
-C~
6 -aralkylimino or N- (Cl-C 4 -alkoxy- alkylimino, and h is from 3 to 7, where aryl is substituted in the manner as defined for R 1 and R 3 R1 and R 3 are identical or different and are hydrogen, halogen, (Cl-C.
2 -alkyl, (C.-C 12 -alkoxy, CHAJ.-Cf- 23
H(
2 f+l-)Halg, (C 1
C,
2 -alkoxy- (Cl-C.
2 alkyl, (C 1
-C
8 alkoxy- 2 -alkoxy, (Cl-C 1 2 -alkoxy- (C 1
-C
8 alkoxy- (C 2 -alkyl, (C 7
-C.
1 -aralkyloxy, (C 3 -CS) cycloalkyl, (C 3
-C
8 -cycloalkyl- -alkyl, (C 3 -cycloalkyloxy, (C 3
-C
8 -cycloalkyl- -alkoxy,
(C
3
-C
8 -cycloalkyloxy- -alkyl, (C 3 -CO) -cycloalkyloxy- (Cl-C 8 -alkoxy, (C 3 -cycloalkyl- alkyl- -alkoxy, (C 3 -cycloalkyl- (C 1 alkoxy- -alkyl, (C 3
-C
8 -cycloalkoxy- (C 1 alkoxy- (Cl-C 6 -alkyl, N]RYRz, (C 1 -alkylmercapto,
(C
1 -alkylsulf inyl or (C 1 -alkylsulfonyl, (Cs-
C.
2 -arylmercapto, (C 6 -C3.
2 aryl sul finyl, (C 6
-C
12 arylsulfonyl, (C 7
-C.
2 -aralkylmercapto, (C 7
-C
11 aralkylsulfinyl, (C 7 -CIO) aralkyl sul fonyl, substituted (C.-C 12 -aryloxy- -alkyl, (C7-C 11 aralkoxy- (C 1
C
6 -alkyl, (C.-C 12 -aryloxy- (C 1
-C
6 alkoxy- (C 1
C
6 -alkyl, (C 7
-C
11 -aralkyloxy- (CI-C 6 alkoxy- (C 1 -alkyl, 2 -aryloxy, (C 7
-C
1 1 aralkyloxy, (C,-C3.
2 -aryloxy- (Cl-C 6 -alkoxy or (C7,-
C,.
1 -aralkoxy- (C.-C 6 -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, (C3 1
-C,
6 alkyl, (Cl-C 16 -alkenyl, (C 1 -hydroxyalkyl, (C 1
C
1 -alkoxy, (C 1
-C
1 6 -alkenyloxy, [CH 2 Jx-CfH( 2 f+l..g)FgI
-OCF
2 Cl, -0-CF 2 -CHFCl, (C 1 -alkylmercapto, (Cl-C 6 alkylsulfinyl, (C3 1 -alkylsulfonyl, (C3 1 -alkylcarbonyl, -alkoxycarbonyl, carbamoyl, N-
(C.-C
4 -alkylcarbamoyl, N,N-di- (C 1
-C
4 -alkyl- 30 carbamoyl, -alkylcarbonyloxy, (C 3 -CI) -cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NRYRz, phenylmercapto, phenylsulfonyl, phenylsul finyl, sul f amoyl, N- (C C 4 alkylsul famoyl or N, Ndi-(CI-C 4 )-alkylsulfamoyl, or optionally carries up 35 to 3 of the abovementioned identical or different substituents, and two adjacent carbon atoms of the aralkyloxy radical together carry a chain- [CH 2 and/or -CH=CH-CH=CH-, where a CH. group of the chain is optionally replaced by 0, S 1 So, S02 or NR', 24 R' and R 2 or R 2 and R 3 form a chain [CH 2 0 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, R 4 is, if Qis a bond, fluorine, chlorine or bromine, or, if Qis 0 or NR', a branched or unbranched (C 1
C
2 0 )-alkyl radical, which can contain up to 3 c-c multiple bonds, an unsu~bstituted saturated fluoroalkyl radical of the formula CH 2 ]xCfH( 2 f+l,)F.I a
(C
6
-C
1 6 -aryl radical or a (C 7
-C
1 6 -aralkyl radical, which can cc'ntain up to 2 C-C multiple bonds in the alkyl chain, or an heteroaryl radical or an heteroaryl alkyl radical, where these radicals are substituted by one or more radicals from the group hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, carboxyl, (C 1
-C
1 2 -alkyl, (C 3
-C
8 -cycloalkyl,
(C
3
-C
5 -cycloalkyl- (Cl-C 1 2 -alkyl, (c 3 -CS) -cycloalkoxy, (C 3
-C
8 -cycloalkyl- (Cl-C.2) -alkoxy, (C 3 -CS) cycloalkyloxy- (C3 1
-C
1 2 -alkyl, (C 3
-C
8 -cycloalkyloxy-
(C
1
-C
12 -alkoxy, (C.-C 8 -cycloalkyl- -alkyl- (C3 1 -alkoxy, 3 c)-cycloalkoxy- (c3 1
-C
8 -alkoxy- -alkoxy, (C 6
-C
12 -aryl, (C7, 1 -aralkyl, (c 2
-C
12 alkenyl, (C 2 -C3.
2 -alkynyl, (Cl-C 12 -alkoxy, (C3 1
-C
12 alkoxy- (C,-C 12 -alkoxy, (C -alkoxy- (c 1 alkoxy- (C 1 -alkyl, 2 -aryloxy, (C7-C 1 6 aralkyloxy, VC,-C 1 2 -aryloxy- (cl-C 6 -alkoxy, (C7- Cl'1) aralkoxy- -alkoxy, (C 1
-C
8 -hydroxyalkyl,
[CH
2 _iI xCfH2f+l-,qFgI ~30 (C 1
-C
1 2 -alkylcarbonyl, (C 3 -cycloalkylcarbonyl,
(C
6
-C
1 2 -arylcarbonyl, (C.
7
-C
16 -aralkylcarbonyl, *(Cl-C 1 2 -alkoxycarbonyl, (C.-C 1 2 -alkoxy- (c.-C 12 alkoxycarbonyl, (C 6
-C
12 -aryloxycarbonyl, (C7 C 16 aralkoxycarbonyl, (C 3
-C
8 -cycloalkoxycarbonyl, (C 2
C.
2 -alkenyloxycarbonyl, (C 2
-C
1 2 -alkynyloxycarbonyl, 25
(C
3
-C
8 -cycloalkyl- (C 1
C
6 -alkoxycarbonyl, (CI -C.
2 -alkylcarbonyloxy, (C 3
-C
8 -cycloalkylcarbonyloxy, (C.-C 1 2 -arylcarbonyloxy, (C 7
-C
1 6 aralkylcarbonyloxy, carbaznoyl, N- (C 1
-C
1 2 -alkylcarbamoyl, N,N-di- (C 1 -Cl 2 -alkyllcarbamoyl, N- (C 3 -Ca) cycloalkylcarbamoyl, N,N-dicyclo- (C 3
-C
8 -alkylcarbamoyl, N- (Cl-C3 10 -alkyl-N- (C 3
-C
8 -cycloalkylcarbamoyl, N- ((C 3 -Cd)-cycloalkyl- alkyl) carbamoyl, N- (Cl-C, 6 -alkyl-N- ((C 3 -CS) -cycloalkyl- -alkyl) carbamoyl, N- ()-dehydroabietylcarbamoyl, N- (C 1 -alkyl-N- ()-dehydroabietylcarbamoyl, N- (C,-C 12 -arylcarbamoyl, N- (C 7
-C
16 aralkylcarbamoyl, N- 10 -alkyl-N- (C.-C3 16 -arylcarbamoyl, N- (C 1 Cl.) -alkyl-N- (C 7 -C3 16 -aralkylcarbamoy., N- ((C 1 Cl 0 -alkoxy- (C 1 -Cl 0 -alkyl) carbamoyl, N-
(C
6
-C
16 aryloxy- (Cl- alkyl) carbamoyl, N- (C 7 C3 16 aralkyloxy (C 1
C-
1 alkyl) carbamoyl, CON (CH 2 in which a CH 2 group can be replaced by 0, N- (Cl- -alkylimino, (C 3
-C
8 -cycloalkylimino, N C- 8 cycloalkyl- (C,-C 4 -alkylimino, N- (C.-C 12 -arylimino or N- (C 7 -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, trifluoromethyl, carboxyl, (C- 1 )-alkyl, 3 C)-cycloalkyl, -alkoxy, (C 3 -Cd)-cycloalkoxy, (Cl-C, 2 -alkoxy- ::::*carbonyl, N- -alkylcarbamoyl, N,N-di- -alkyicarbamoyl or N- (C 3 -Cd)-cycloalkylcarbamoyl, and R4 is provided Q has the meaning of NRW, where R' and R* are identical or different and are hydrogen, (C3 1 -alkyl, or (C 7
-C
11 -aralkyl which is optionally 26 substituted once by fluorine, chlorine or (C,-C 4 alkoxy, R' and R' are identical or different and are hydrogen, (C3 1 -Ca) -alkoxy- -alkyl, (C 7
-C
1 2 -aralkoxy- (C 1 -alkyl, 1 2 -aryloxy- (C 1 -alkyl, (C 1
-C
10 alkanoyl, optionally substituted (C 7
-C
1 -aralkanoyl or optionally substituted (C 6
-C
1 2 -aroyl, or RY and Rz together are ECH 2 1 in which a CH 2 group can be replaced by 0, S, N- (C,-C 4 -alkanoylimino or N-
-C
4 alkoxycarbonyl imino, and f is 1 to 8, g is 0or Ito (2 f h is 3 to 6, x is 0 to 3, and n is 3or 4.
Compounds of the formula I are preferred in which Q is 0, NR' or a bond, X is 0, Y is CR 3 or, if R' and R 2 f orm a cycle, N or CR, m isO0, A is (Cl-C 3 )-alkylene which is optionally substituted once by halogen, cyano, trifluoromethyl, alkyl, -hydroxyalkyl, (C 1 -alkoxy or 25 [CH 2 or A is -CHR 5 where R 5 is one of the substituents of the a-carbon atom of an ar-amino acid, in particular of a natural L-amino acid and of its D-isomer, B is C0 2
H
R 2 is hydrogen, (C 1
-C
20 -alkyl, (C 2 -alkenyl, (C 2
C
2 0 -alkenyloxy, (C 2
-C
2 0 -alkynyloxy, retinyloxy, .27 (C3.-C 20 -alkoxy- (C 1
-C
3 -alkyl, (C 1
I-C
2 -alkoxy- (Cl-
C
3 -alkyl, (C 2
-C
2 -alkenyloxy- (C,-C 3 -alkyl, retinyoxy- (C3 1
-C
3 -alkyl, (C 2
-C
2 -alkynyloxy- (Cl-
C
3 -alkyl, (Cl-C 2 -alkoxy, halogen, cyano, trifluoromethyl, (C,-C 16 -hydroxyalkyl, (CI-C 2 0 alkanoyl, (C 7
-C.
2 -aralkanoyl, 2 -aroyl,
(CH
2 J x-CfH( 2 f..g)FgI NR' (C 1
-C
1 0 -alkylmercapto,
C
12 -arylmercapto, (C 6
-C
12 aryl sul finyl, (CS-C 1 2 arylsulfonyl, (C 7
C
2 aral kylmercap to, (C 7
-C
12 aralkylsulfinyl, (C 7
-C
1 2 -aralkylsulfonyl, (C 6 -C3.
2 aryloxy, (C7-C 16 -aralkyloxy, carboxyl, (C 1
-C
2 0 alkoxycarbonyl, (C-C 2 -alkoxy- 2 alkoxycarbonyl, (C,-C 1 2 -aryloxycarbonyl, (C 7
-C
1 6 aralkoxycarbonyl, (C 3
-C
8 -cycloalkoxycarbonyl, (C 2
C
20 -alkenyloxycarbonyl, retinyloxycarbonyl, (C 2
-C
2 U alkynyloxycarbonyl, (C 3 -cycloalkyl- alkoxycarbonyl, (C 3
-C
8 -cycloalkoxy- (C 1
C
6 alkoxycarbonyl, (C,-C 12 -aryloxy- -alkoxycarbonyl, (C 7
-C
1 -aralkoxy- -alkoxycarbonyl, carbamoyl, N- (C.-C 1 2 -alkylcarbamoyl, N,N-*di- (Cl-C 12 alkylcarbamoyl, N- (C 3 -cycloalkylcarbaioyl, N,Ndicyclo(C 3
-C
8 -alkylcarbainoyl,N- (C 1 -Cl 0 -alkyl-N- (C 3 -cycloalkylcarbanoyl, N- (C 3
-C
8 -cycloalkyl- (Cl-C 6 alkyl)carbamoyl, -alkyl-N- ((C 3 -Cd)-CyCloalkyl (Cl 1
-C
6 alkyl) carbaioyl, N- dehydroabietyl carbamoyl, N- (C 1
-C
6 -alkyl -dehydroabietylcarbamoyl, N- (C 6 -C3.
2 arylcarbanoyl, N- (C 7
C
16 aralkylcarbamoyl, N- -alkyl-N- (C 6 -rl 30 carbamoyl, N- (Cl-C 10 -alkyl-N- (C 7
-C,
2 -aralkylcarbaMoyl, N- 2 -alkoxy- (C 1
C
10 -alkyl) carbamoyl, N-
((C
6
-C
1 6 -aryloxy- (Cl-C 10 -alkyl) carbaxnoyl, N- ((C 7
C
1 6) -aralkyloxy- (CI-Cl.) -alkyl) carbainoyl, N- (C 1
-C
10 alkyl-N- ((C 1
-C
1 0 -alkoxy- (Cl-Cl 0 -alkyl) carbamoyl, N- 35 (Cl-C 0 -alkyl-N- 1 2 -aryloxy- (C-C 1 0 alkyl)carbamoyl, N- (CI-C 10 )-akl--(C 7 -C3.
6 aralkyloxy- -alkyl) carbanioyl, or CON (CH 2 in which a CH 2 group uan be replaced by 0, S, N- (C 1 CI) alkylimino, N- (C 3
C
8 )-ccolyiio 28 N- (C 3
-C
8 -cycloalkyl- (C 1
-C
4 -alkylimino, N- (C 6 -Cl 2 arylimino, N.-(C 7 -aralkylimino or N C_4 alkcoxy- -alkylimino, and h is from 3 to 6, where aryl is substituted in the manner as defined for Rl and R 3 R' and R 3 _r identical or different and are hydrogen, halogen, (C,-Cl 2 -alkyl, (Cl-C 1 2) -alkoxy, -alkoxy- (Cl-C 12 -alkoxy, (Cl-C.
2 -alkoxy- (Cl- -alkoxy- (C 2
-C
6 -alkyl, (C 7 -Cl 1 -aralkyloxy, (C 3 -cycloalkyl, (C 3
-C
8 -cycloalkyl- (C 1 -alkyl,
(C
3
-C
8 -cycloalkyloxy,
(C
3
-C
8 -cycloalkyl- alkoxy, (C 3
-C
8 -cycloalkyloxy- (C.-C 8 -alkyl, (C 3 -C3) cycloalkyloxy- -alkoxy, (C 3
-C
8 -cycloalkyl- (Cl- C,)-alkyl- (C 1 -cd)-alkoxy, (C 3
-C
8 -cycloalkyl- alkoxy- -alkyl, (C 3 -cycloalkoxy- alkoxy- (C,-C 6 -alkyl, NRYRz, (C 1 -alkylmercapto,
(C
1
-C
8 -alkylsulf inyl or (C 1 L-Ce) -alkylsulfonyl, (C 6
C.
2 -arylmercapto, (C 6
C
1 2 aryl sul finyl, (CG-Cl 2 arylsulfonyl, (C 7 -aralkylmercapto, (C 7
-CIO)
aralkylsulfinyl, (C 7 Cl) aralkyl sul fonyl, **substituted (C, 6
-C
1 2 -arylox-y- (C 1 -alkyl, (C 7 -Cll) *aralkoxy- (C 1 -alkyl, (C,-C 1 2 -aryloxy- (C 1
-C
6 alkoxy- -alkyl, (C 7 -Cll) -aralkyloxy- 25 alkoxy- (C3.-C 6 -alkyl, (C.-C 12 -aryloxy, (C 7 -CIO) aralkyloxy, (C, 6 -Cl 2 -aryloxy- (C 1 -alkoxy or
(C
7 -Cll) -aralkoxy- -alkoxy, where an aromatic radical carries by 1, 2, 3, 4 or 5 identical or different substituents from the group hydrogen, 30 halogen, cyano, nitro, trifluoromethyl, (Cl-C 1 2 alkyl, (Cl-C 1 2 -alkenryl, (Cl-C 6 -hydroxyalkyl, C I- C 2 )-a1k o xy (Cl-C 1 2 -alkenyloxy, 0 [CH 2 x-CfH 2 f+lg)Fgf -OCF 2 Cl, -0-CF 2 -CHFCl, (C 1
C
6 alkylmercapto, -alkylsulfinyl, (Cl-C 6 -alkylsulfonyl, (Cl-C 6 -alkylcarbonyl, (Cl-C 6 -alkoxiycmrbo7nyl, carbamoyl, N- (C,-C 4 -alkylcarbaioyl, N,Ndi- (Cl-C 4 -alkylcarbanoyl, (C,-C 6 -alkylcarbonyloxy, 29
(C
3 -cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NRYRz, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulf anoyl, N- (C,-C 4 -alkylsulfanioyl or N,N-di- (C 1
,-C
4 -alkylsulfeAmoyl, 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 and/or -CH=CH-CH=CH-, where a CK 2 group of the chain is optionally replaced by 0, S, SO, S02 or NY R' and R 2 or R 2 and R' can form a chain [CH 2 where o is 3, 4 or 5, and R4 ,provided Q is a bond, is chlorine or, if Q is 0 or NR', is a branched or unbranched (C 1
-C
10 -alkyl radical, which can contain one or two C-C multiple bonds, or an unsubstituted fluoroalkyl radical of the formula [CH 2 1._CfH( 2 or (C 1
C
8 -alkoxy- (C 1
C
6 -alkyl, (C 1 -alkoxy- (Cl-C 4 -alkoxy- (C 1
C
4 -alky*" or a radical of the formula Z, ~:where E is a substituted phenyl radical of the formula F *R R R 1 0
R
or a (C 3 -cycloalkyl radical, where Goo*.:v is 0, 1, 2, 3, 4, 5 or 6, w is 0 or 1, and t is 0, 25 1, 2 or 3, with the restriction that v is not equal to 0 if w is 1, and R 6 R 7
R
9 and R' 0 are identical. or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, -alkyl, 30
(C
3
-C
8 ,)-cycloalkyl, (C3 1
-C
6 )-alkoxy, -O-[CH 2 i -_CfEH 2f+I g~pfg -OCF 2 C1, -0CFaCEFCli -alicylmercapto,
(C
1
-C
6 s) -hydroxyalkyl, -alkoxy- (C 1 -alkoxy, -alkoxy- -alkyl, -alkylsulf inyl, -alkylsulfonyl, (C, 1
-C
6 -alkylcarbonyl, (C 1 -Cs) alkoxycarbonyl, carbamoyl, N- -alkylcarbamoyl, N.,N-di- (C 1 -alkylcarbamoyl, (C 7
-C
11 -aralkylcarbamoyl which is optionally substituted by fluorine, chlorine, bromine, trif luoromethyl or (C 1
C,
6 -alkoxy, N- (C 3
-C
8 -cycloalkylcarbamoyl, N- (C 3
-C
8 -cycloalkyl-
(C
1
-C
4 -alkylcarbamoyl, (C.
1
-C
6 -alkylcarbonyloxy, phenyl, benzyl, phenoxy, benzyloxy, NkRRz, such a' amino, anilino, N-methylanilino, phenylmercapto, phenyl sul fonyl, phenyl sul finyl, sul famoyl, N- (CI -Ca) alkylsulfamoyl or N,N-di-(Cl-C,)-alkyjlsulfamoyl, or two adjacent substituents together are a ehain
-[ICH
2 j-I.CH=CH-CH=CH-,I where a CH 2 group of the chain is optionally replaced by 0, S, So, S02 or WR, and where a heteroaryl radical can carry 1, 2 or 3 substituents, and a cycloalkyl radical one substituent, from the above group, and R is pz vided Q has the meaning of NR', where R' is hydrogen or methyl, and is benzyl, and if R 1 and/or R' have the meaning of (C, 6
-C
1 2 ,)-aryloxy, (C 7
C
11 -aralkyloxy, (C 6
-C.
2 -aryloxy- (C.-C 6 -alkoxy, (C 7 -C3 1 1 aralkoxy-(C 1
-C,
6 )-alkoxy or a corresponding radical con- *~**taining terminal cycloalkyl groups, this radical is preferably then a radical of the formula D OZ or if R3- and/or R 3 have the meaning of (C 7
-C
1 1 -aralkyl, 0(C.-C.
2 -aryloxy- (Cl-C 6 -alkyl, (C 7
-C
11 -aralkoxy- (C 1
-C
6 alkyl or a corresponding radical containing terminal cycloalkyl groups, this radical is preferably then a radical of the formula Z, 31 A' and R' are identical or dif ferent and are hydrogen,
(C,-C
1 2 -aryl, (Cl-C 10 -alkyl, (C 3 -cycloalkyl, -alkoxy- (Cl-C 8 -alkyl, (C 7
-C.
2 -aralkoxy- (C 1
C
6 -alkyl, 2 -aryloxy- -alkyl, (CI-C1 0 alkanoyl, optionally substituted (C 7
-C
1 -aralkanoyl or optionally substituted (C,-C 1 2 -aroyl, or RY and Rz are together [CH 2 in which a CH 2 group can be replaced by 0, S 1 N- (C 1
-C
4 -alkanoylimino or N- (C C 4 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 3or 4.
Compounds of the formula I are particularly preferred in which Q is 0, X is 0, oY is CR 3 and, additionally, N if R' and R 2 form a cycle, *M is 0, *A is -CHR 5 where R 5 is the substituent of the acarbon atom of an a-amino acid, in particular of a natural L-amino acid or its D-isomer, B is C0 2
H,
R R 2 is hydrogen, bromine, chlorine, cyano, (C 1
-_C
1 8 alkyl, -alkoxy, (C 1
C
1 -alkoxymethy,.l, (C 2
-C
16 :0..alkenyloxymethyl, (C 2 -ialkynyloxymethyl, carbamoyl, 1
-C
10 aLlkylc arbamoyl, N- (C 1
-C
1 2 alkoxy- (C 1
-C
4 -alkyl) carbamoyl, N,N-di- (C 1 alkylcarbanioyl, N(C 3 -cycloalkylcarbanoyl, N- (C 6
C
12 -phenylcarbamoyl, N- 2 -phenylalkylcarbamoyl, N- (Cl-C 6 -alkyl (C 6
-C.
2 pheny] carbamoyl, N- 6 -alkyl-N- (C 7 -C3 1 2 -phenylalkylcarbamoyl, 32 N- (C.-C 6 -alkoxy- (Cl-C 6 -alkyl) carbamoyl, carboxyl,
(CI-C
2 0 -alkoxycarbonyl,
(C
2
-C
2 0 -alkenyloxycarbonyl, retinyloxycarbonyl, (C 3 -cycloalkoxycarbonyl,
(C
3 -cycloalkyl- (C 1 -alkoxycarbonyl, (C 3 -CS) cycloalkoxy- (C 1 -alkoxycarbonyl, phenyl- (C 1 alkoxycarbonyl, phenoxy- (C 1 -alkoxycarbonyl or benzyloxy- -alkoxycarbonyl, where a phenyl radical is substituted in the manner as defined for
R
1 and R and one of the radicals
R
1 or R 3 is hydrogen and the other a radical from the group hydrogen, fluorine, chlorine, (C 1 ,-C,)-alkyl,
(C
1
-C
10 -alkoxy, -cycloalkyl, (CS -C 6 -cycloalkyl- (C 1 -alkyl, -cycloalkyloxy, cycloalkyl- -alkoxy, -cycloalkyloxy- (Cl- -alkyl, -cycloalkyloxy- -alkoxy, -cycloalkyl- (C CO) -alkyl- (Cl-C 4 -alkoxy, cycloalkyl- (Cl'-C 4 -alkoxy- (C 1
C
2 -alkyl, (C, 5
-C
6 cycloalkoxy- (C 1 -C4 -alkoxy- (C 1 -C 2 )-alkyl, 0 (CH 2 %-CfH( 2 f+1lg)F9I (Cj-C 6 -alkoxy- -alkyl,
C
6 -alkoxy- -alkoxy, (C 1 -alkoxy- (C 1
C
4 alkoxy- (C 1
C
2 -alkyl, substituted (C 6
-C
12 -phenoxy,
:(C
7 -phenylalkyloxy, (C 6
-C.
2 -phenoxy- (Cl-C 6 **alkoxy or (C 7
-C
11 -phenylalkoxy- (C,-C 6 -alkoxy, phenoxy- C 4 -alkyl, (C 7
-C
1 1 -phenylalkyloxy-
(C,-C
4 -alkyl, phenoxy- (C,-C 4 -alkoxy- (C 1
C
2 -alkyL or (C 7 -Cl 11 -phenylalkyloxy- (Cl-C 4 -alkoxy- (C 1
,-C
2 alkyl, where an aromatic radical is substituted by 1, 2 or 3 identical or different substituents from the group fluorine, chlorine, cyano, trifluoromethyl, (C 1
-C
1 2 -alkyl, 1 2 -alkenyl, (C 2
-C
12 alkenyloxy or (CI 2 -alkoxy, *R1 and R 2 with the pyridine carrying them, form a 5, 6, 7, 8-tetrahydroisoquinoline ring, R 4 is a branched or unbranched (Cl-C 0 -alkyl radical, 4 -alkoxy- (Cl-C 4 -alkyl or a radical of the formula Z, 33 where E is a substituted phenyl radical of the f ormula F R7 R F or a (C 3 -cycloalkyl radical, where v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R6, R 7 Re, R9 and R 10 are identical or dif ferent and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, -alkyl, -alkoxy, 0 ICH 2 x-CfH (2f+l.g)FI N- (C 1
-C
8 -alkylcarbamoyl, N,Ndi- (C 1
C
6 -alkylcarbamoyl, N- (C 3
-C
6 -cycloalkylcarbamoyl, N- -dehydroabietylaminocarbonyl, or (C 7
-C
11 l) phenylalkylcarbamoyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl or -alkoxy, or whe-'e R 6 and R 7 or. and Re, together with the phenyl ring carying them, form naphthalene derivatives.
I If R3, or R 3 has the meaning of (C.-C 12 -phenoxy, (C 7
-C
11 phenylalkyloxy, (C.-C 1 2 -phenoxy- -alkoxy, (C 7
-C
11 phenylalkoxy- -alkoxy, -cycloalkyloxy- (C 1
C
6 alkoxy, (C.-C 6 -cycloalkoxy- (C,-C 6 -alkoxy or (C.
5
-C
6 cyc.oakl C- -alkyl- (C,-C 4 -alko,,cy, this radical is then, especially, a radical of the formula D OZ or if R 1 or R 3 has the meaning of phenyl, pheno:icy-(C 1
C
6 alkyl, (C 7
-C
1 l) -phenylalkyl (C 7
-CQ
1 -phenylalkyloxy- (Cl-C 4 alkyl, -cycloalkyl, -cycloalkyl- alkyl, (C.-C 6 -cycloalkoxy- (C:L-C 4 -alkyl, (C 5 -cycloalkyl- (CI-C 4 -alkoxyr- (C 1
-C
2 -alkyl or (C 5 -cycloalkoxy- 34
(C
1
-C
4 -alkoxy- (C 1
-C
2 -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 is1, and f i.s 1 to 4, g is 0orlIto (2f+l), x is 0orl1.
Compounds of the formula I are very par, .icularly preferred in which Q is 0, X is 0, Y is CR, m is 0, A is a -CH 2 group which can be substituted by a methyl group, B is -CO 2
H,
R 2 is hydrogen, -alkoxy, (Cl-C 1 6 -alkoxymethyl,
(C
2
-C
16 -alkenylo~cymethyl, retinyloxymethyl, N- (Cl- 10 -alkylcarbamoyl, N- ((C 1
C
1 2 -alkoxy- (C 1
-C
3 alkyl) carbamnoyl, N,N-di- (Cj-CB) -alkylcarbamoyl, N- (C.-C)-cycioalkylcarbamoyl, N-phenylcarbamoyl, Nphenyl- (Cl-C 4 11 1kylcarbamoyl, carboxyl, (C 1
-C
1 6 alkoxycarbonyl, -alkenyloxycarbonyl, retinyloxycarbonyl, -cycloalkoxycarbonyl, (Cs- -cycloalkyl- (C 1 -alkoxycarbony. or phenyl- (C3 1 Cd)-alkoxycarbonyl, where a phenyl radical is substituted in the manner as defined l.or R' and R 3 and one of the radicals R1 or R 3 is hydrogen and the other radical is a radical from the group hydrogen, (C 1 -Cl)-alkoxy, (Cs-C 6 cycloalkyloxy, -cycloalkyl- (C,-C 2 -alkoxy,
[CH
2 ].xCfH( 2 f.~l.g)Fgf (C 1
C
4 -alkoxy- (C 1
C
4 -alkoxy, substituted (C.-C 1 2 -phenoxy, (C 7 -C3.
1 -phenylalkyloxy,
(C
6
-C
1 2 -phenoxy- (C 1 CO) -alkoxy or (C 7 -CIO) -phenyl- 35 alkoxy- C 1 -CO)-alkoxy, where an aromatic radical is substituted by 1, 2 or 3 identical or different substituents from the group fluorine, chlorine, cyano, trifluoromethyl, (C 1
-C
10 -alkyl, (C 1
-C
10 alkoxy or (C 1
-C
10 -alkenyloxy, and R 4 is a branched or unbranched (C 1 -alkyl radical or a radical of the formula Z,
H
2 Hjt-E (Z) where E is a substituted phenyl radical of the formula F R ~R7 R (F) or a (C 3 -cycloalkyl radical, where ~v vis 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R R 9 and R 10 are identicail or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, -alkyl, (C 1
-C
6 a..alkoxy, O4- CH 2 -JX.CfH( 2 F~j N- -alkylcarbamoyl, N,N-di- -alkylcarbanoyl, N- (C 3
-C
6 cycloalkylcarbanoyl, N- -dehydroabietylaminocatrbonyl substituted benzyl radical, and f is 1 to 4, g is 0 or 1 to (2f+1) and x is 0 or 1.
Compounds of the formula I are particularly preferred in which Q is 0, X is 0, Y is CR, m is 0, B is -CO 2
HI
A is a -CH 2 -group, 36 R1is hydrogen, (Cl-C 6 -alkoxy or [CH 2 ]xCJHC 2 f+l..g)FgI R 2 is hydrogen, N- (C3-C 1 -alkylcarbamoyl, N- ((C 1
-C
1 2 alkoxy- (C3 1
-C
3 -alkyl) carbanoyl, N,N-di- -alkylcarbanioyl, N- "C 5 -cycloalkylcarbamioyl, N-phenylcarbamoyl, N-phenyl- (C 1 -alkylcarbamoyl, carboxyl, (Cl-C 16 -alkoxycarbonyl, (C 2
-C
16 -alkenyloxycarbonyl, retinyloxycarbonyl, (C 5
,-C
6 -cycloalkoxycarbonyl, (C 5 -cycloalkyl- -alkoxycarbonyl or phenyl- -alkoxycarbonyl, where a phenyl radical is substituited by 1 or 2 identical or different substituents from the group fluorine, chlorine, cyano, trifluoromethyl, (C 1
-C
10 -alkyl, (C 1
-C
1 D) alkenyloxy or (C,-C 1 -alkoxy, and R 3 is hydrogen, -alkoxy or -cycloalkyl-
C
2 -alkoxy, where one of the substituents R3, and R 3 is hydrogen, R 4 is a branched or unbranched (C 1 -alkyl radical, or a 2-phenylethyl radical, or a benzyl radical substituted by 1 or 2 radicals from the group flu- 20 orine, chlorine, cyano, trifluoromethyl, (C 1
C
6 alkyl, (C, 1 -alko.-0- CH.]CH fgFgI N- (C 1
-C
8 O***alkylcarbamoyl, N,N-di- (C 1
C
6 -alkylcarbamoyl, N- (C 3 -cycloalkylcarbamoyl or N- -dehydroabietylaminocarbonyl, and f is 1 to 4, g is 0 or 1 to (2f+l) and x is 1.
Compounds of the formula I are preferred to the highest *degree in which Q is 0, is 0, Y is CR, m is 0, A is a -CH 2 -group, B is -CO 2
H,
R
1 is hydrogen, 37 R 2 is hydrogen, N- (Cj-C: 0 -alkylcarbamoyl, N (C3 1
-C.
2 alkoxy- (C 1
C
3 -alkyl) carbamoyl, N-cyclohexylcarbainoyl, N-phenylcarbanoyl, N- (phenyl- (C 1
-C
2 -al~kyl) carbamoyl, where, in the last two cases, the phenyl radical can carry a fluorine substituent, (C 1
-C
1 alkyl substituent or (C:L-CO) -alkoxy substituent, carboxyl, -alkoxycarbonyl, (C 2
-C:
1 6 -alkenyloxycarbonyl, retinyloxycarbonyl, (C 5 -Cr) -cycloalkoxycarbonyl or benzyloxycarbonyl, R 3 is hydrogen, (Cl-C,)-alkoxy or 2-(cyclohexyl)ethyloxy, where one of the substituents R 2 and R 3 is hydrogen R 4 is a branched or unbranched (C 1
C
4 -alkyl radical or a benzyl radical which is substituted once by fluorine, chlorine, trifluoromethyl, (C 1
-C
4 -alkyl or
(C
1
-C
3 -alkoxy.
Compounds of the formula I are also preferred to the highest degree in which Q is S, 20 X is 0, Y is CR, m is 0, A is a -CH 2 group, B is CO 2
H,
R
1 is hydrogen, R 2 is hydrogen, N-(Cl-Cl 0 )-alkylcarbamoyl, N-((C 1
C
1 2 alkoxy- (C 1
,-C
3 -alkyl) carbamoyl, N-cyclohexylcarba- .~:moyl, N-phenylcarbanoyl, N- (phenyl- (C 1
-C
2 alkyl) carbaxaoyl, where, in the last two cases, the phenyl radical can carry a fluorine substituent, (C.-C 10 alkyl substituent or (C 1 -Cl)-alkoxy substituent, carboxyl, (C,-C 16 -alkoxyc&rbonyl, (C 2 -alkenyl oxycarbonyl, retinyloxycarbonyl, (C 5 -cycloalkoxycarbonyl or benzyloxycarbonyl, 38
R
3 is hydrogen, (Cl-C,)-alkoxy or 2-(cyclohexyl)ethyloxy, where one of the substituents R 2 and R 3 is hydrogen, and
R
4 is a branched or unbranched (C 1
-C
4 )-alkyl radical or a benzyl radical which is substituted once by fluorine, chlorine, trifluoromethyl, (C 1
-C
4 )-alkyl or
(C
1
-C
3 -alkoxy.
The compounds of the formula I are also preferred to the highest degree in which Q is S, X is O, Y is CR m is 0, A is a -CH,-group, B is -COH,
R
1 is hydrogen,
R
2 is carboxyl or (Ci-C 1 -alkoxycarbonyl,
R
3 is hydrogen, and
R
4 is a branched or unbranched (C-C 4 )-alkyl radical.
The compound of the formula I is also preferred to the highest degree in which Q is O, X is O, Y is CR 3 where R 3 is hydrogen, m is 0, A is a -CH 2 -group, B is -CO 2
H-,
R
1 and R 2 together with the pyridine carrying them, form an isoquinoline ring having an unsubstituted benzo moiety, and
R
4 is methyl.
The compound of the formula I is also preferred to the highest degree in which Q is O, 39 X is O, Y is CR 3 m is 0, A is a -CH,-group, B is -COH,
R
I is hydrogen,
R
2 and R 3 together with the pyridine carrying them, form a quinoline ring having an unsubstituted benzo moiety, and
R
4 is methyl.
The invention also embraces prodrugs for the compounds of the formula which prodrugs bring about an inhibition of collagen biosynthesis in vivo by liberating compounds of the formula I or their salts.
Finally, the invention also embraces prodrugs which, by liberating compounds of the formula I or their salts, bring about an inhibitory effect in vivo on prolyl-4hydroxylase.
Prodrug groupings are chemical groups which, in vivo, 20 are converted into the carboxylate group of the compounds of the formula I, and/or can be cleaved from the amide N atom, and/or can be converted into a pyridine ring.
Those prodrug groups which are suitable are known to the 25 person skilled in the art.
The following prodrug groupings receive particular mention: for the carboxylate group, ester groups, amide groups, hydroxymethyl groups and aldehyde groups, and their derivatives; for the pyridine N atom, N-oxides and Nalkyl derivatives; and for the pyridine ring, 1,4dihydropyridine derivatives or tetrahydropyridine derivatives.
I -I 40 The invention relates to the use of compounds of the formula I, and also the physiologically tolerated salts, for inhibiting collagen biosynthesis.
The invention relates to the use of compounds of the formula I, and also the physiologically tolerated salts, for inhibiting prolyl-4-hydroxylase.
The invention also relates to the use of compounds of the formula I, and also the physiologically tolerated salts, for producing a pharmaceutical against fibrotic diseases.
The invention also relates to the use of compounds of the formula I, and also 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 pharmaceuticals.
The invention relates, in particular, to the compounds of the formula I for use as fibrosuppressive agents.
The invention also relates to a process for preparing compounds of the formula I.
S 20 The compounds of the formula I, in which A is a Ssubstituted alkylene moiety, B is COH, Y is CR 3 and m is 0 or 1, are prepared by il.) Reacting pyridine-2-carboxylic acids of the formula II (R 23 is H) with the amino esters of the formula 25 III to form the amide esters of the formula IV, or i2.) Reacting pyridine-2-carboxylic esters of the formula II (R 23 is lower alkyl) under the conditions of aminolysis, to form the compounds o the formula IV; and I 41 ii) liberating the compounds of the formula I from their esters of the formula IV; with, where appropriate, iii) the compounds of the f ormula IV being prepared by alkylation of compounds of the formula, V with R 4
X,
and, where appropriate, iv) the compounds of the Formula IV being converted, provided Q is 0 or NR', into their pyridine N-oxides IV' (R 2 4 is (Cl-C 16 )-alkyl or benzyl) and the latter being hydrolyzed to form the pyridine N-oxides of the formula I' (R 24 is H).
Scheme 1
R
2 OR 4 R 3 CO 2 R 23
H
2 N-A-C0 2 -R 2 4 12.
R
2 0
R
3 0 NH-A-C0 2 R 2 4 lii) R
I
R
3
N
NH-A-COZ2 R2 4 R 2 q R'4 N -A-C0 2 14 R
N
0 NH-A-C0 2
R
2 4 0 I R24 C (C 1 alkyl benzy] I R 24
*N
R 23 is H or -alkyl, 42
R
24 is H, (CI-C 1 ,)-alkyl or benzyl, X is a leaving group, in particular halogen, OSOMe or OSOphenyl The methods of carboxyl activation and the condensation reactions known from peptide chemistry are suitable processes for the amide formation (reaction il).
The substances which are known to the person skilled in the art, such as thionyl chloride, oxalyl chloride, pivaloyl chloride, chloroformate derivatives, or N,N'carbonyldiimidazole, can be used as reagents for the carboxylic acid activation. The activated derivatives of the compounds of the formula II are prepared in situ and then reacted with the amide derivatives of the formula
III.
An example of a suitable condensing agent is the combination of N,N'-dicyclohexylcarbodiimide/N-hydroxy- 1H-benzotriazole and N-ethylmorpholine.
Suitable solvents are dichloromethane, tetrachloromethane, butyl acetate, ethyl acetate, toluene, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitromethane and/or pyridine.
SThe compounds of the formula I, in which R 1 and R 3 are hydrogen and R 2 is a carboxyl substituent, a carbamoyl 25 substituent or an ester substituent, were prepared as outlined in schemes 1, 2 and 3.
Scheme 2 illustrates the preparation of the compounds of the formula II in which R 2 is a carboxylic acid substituent, or its derivative, and R 1 and R 3 are hydrogen.
The 3-substituted 5-carboxypyridine-2-carboxylic esters of the formula XI and their isomers of the formula XII 43 are prepared from the pyridine-2,5-dicarboxylic diesters cf the formula VII.
The oxidation of the pyridine-2,5-dicarboxylates of the formula VII is described in J. Chem. Soc. Perkin Trans.
2, 1978, 34-38 and in J. Org. Chem. 25 (1960) 565 to 568 Peterson).
The halogenation (chlorination) of the pyridine N-oxides of the formula VIII with thionyl chloride and the reaction of the 3-chloropyridine-2,5-dicarboxylic diester (Formula IX) with alcoholates (Q is O or S) can be carried out in analogy w 4 .th the process described in the patent specification CH 658 651 (LONZA), where M is a singly charged or doubly charged metal ion, preferably from the first or second main group of the periodic system.
In analogy with the known literature (CA: vol. 68, 1968, 68 840 the monoesters of the formula XII are prepared, under hydrolysis conditions, from the substituted a pyridine-2,5-dicarboxylic diesters of the formula Xb.
20 Selective hydrolysis using Cu(II) salts, J. Delarge in Pharmaceutica Acta Helvetiae 44, 637-643, 1969, represents another process for preparing the compounds of the formula XII from the diesters of the formula Xb.
o° The compounds of the formula XII thus obtained are 25 reacted with the amino esters of the formula III to form the compounds of the formula IV (Scheme 2).
The pyridine-2-carboxylic ester-5-carboxylates of the formula XI can be prepared, under esterification conditions, from substituted pyridine-2,5-dicarboxylic acids of the formula Xa (see CA: vol. 68, 1968, 68840 h).
Suitable conditions are, for example, esterification with methanol in the presence of sulfuric acid, it being necessary to choose the reaction time so that complete 44 esterification to form the diester product only takes place to a secondary extent, or so that the diester products can be separated off as by-products.
The compounds of the formula XI are converted with amnines or alcohols into the 5-carboxylic acid derivatives of the formula XIV (Scheme 3).
These are then hydrolysed to form the compounds of the f ormula II (R 23 is H) which compounds are subsequently reacted in analogy with Scheme 1.
Scheme 2 N C0 2
R
AcOH/H 2 0 2 VIII ~C0 2
R
0 VI I R H lower alkyl N C 0 2
R
MOR or halogenation N C0 2
R
I X L C CI, B r M metal ion, singly or doubly charged 0 S X II R- lower alkyl C. Ce o C X b R lower alkyl N C 0 2
R
X I R *lower alkyl H 2 N- A -C 0 1R 2 45 Scheme 3 ROH or HNRR H0 2 C 0OR X II I R 2 R 4 N ,CO0 loweralkl Ir.C 0 lower akyl X I X IV R' COOR CO-NRR The '3-hydroxymethylpyridines of the formula Vla, which are disclosed in EP-A-O 304 732, EP-A-O 321 385 and EP-A- 0 208 452, can be used as intermediates for preparing derivatives which are substituted in the 4 position.
Scheme 4
R
2 R OR' io R 2 RIQR4 R oxidaton R3 N C H 2 OH R L~N C0 2
H
Vi 1 1
H)
V Ia Ila OR' 0MOw (We -methyl) 4 V Ib lib OR 08n (On benzyl) The 3-O-benzyl derivativei of the formula VIb were also obtained in an analogous manner, as described in those documents.
10 The compounds of the formulae Vla and Vib were reacted with an oxidizing agent, preferably with KMnO 4 in aqueous alkaline medium, to form the pyridine-2-carboxylic acid derivatives of the formula II (cf. Scheme 4).
The preparation of substituted pyridine-2-carboxylic acids is, for example, disclosed In DE-A-353 046, and for 3- (3-chlorophenoxy)pyridine-2-carboxylic acid an-! 3- (3methylphenoxy)pyridi34-ne-2-carboxylic acid in LT. .4em.
1975, 18, PP. 1-8, Villani et av" for 46 3,5-diethoxypyridine-2-carboxylic acid in J. Med. Chem.
1974, 17, pp. 172-181, French et al.; and for 3-methylthiopyridine-2-carboxylic acid and 3-benzylthiopyridine- 2-carboxylic acid in J. Med. Chem. 1974, 17, pp. 1065- 1071, Blank et al.; and for 3-methoxypyridine-2,5-dicarboxylic acid in CH-PS 658 651.
The compounds of the formula I are inhibitors of prolyl- 4-hydroxylase. The inhibition of this enzyme was determined as described by Kaule and Giinzler in Annal.
Biochem. 184, 219 to 297 (1990).
The novel compounds of the formula I possess valuable pharmacological properties and exhibit, in particular, antifibrotic activity.
The antifibrotic effect can, for example, be determined using the model of carbon tetrachloride-induced hepatic fibrosis. For this, rats are treated twice a week with CC14 (1 ml/kg) dissolved in olive oil. The substance under test is administered daily, where appropriate even twice a day, per os, or intraperitoneally dissolved in 20 a suitable tolerated solvent. The extent of the hepatic fibrosis is determined by histology, and the proportion of collagen in the liver is analyzed by means of determining hydroxyproline as described in Kivirikko et al.
(Anal. Biochem. 19, 249 f. (1967)). The fibrogenic ac- S 25 tivity can be measured by the radioimmunological determination of collagen fragments and procollagen pptides in the serum. In this model, the novel compounds are active at a concentration of from 1 to 100 mg/kg.
The fibrogenic activity can be measured by radioimmunological determination of the N-terminal propeptide of collagen type III or of the N-terminal or C-terminal crosslinking domain of collagen type IV (7s collagen or type IV collagen NC 1 in the serum.
For this purpose, measurements were made of the 47 concentrations of hydroxyproline, procollagen III peptide, 7s collagcn and type IV collagen NC in the liver of a) untreated rats (control) r b) rats which were administered carbon tetrachloride (CC1 4 control) c) rats which were first administered CC1 4 and then a novel compound (this test method is described by Rouiller, Experimental toxic injury of the liver; in The Liver, C.
Rouiller, vol. 2, 5. 335 to 476, New York, Academic Press, 1964).
The novel compounds can also be demonstrated to be active in the following systems.
Inhibition of hepatic prolyl-4-hydroxylase in vivo: This model is used to demonstrate the acute inhibition of prolyl-4-hydroxylase in vivo. For this, rats of both sexes (healthy or with induced hepatic fibrosis) are administered (intraperitoneally, intravenously or per os) 20 the substance under test or the corresponding vehicle and, after this, are given 14 C-L-proline (250 ACi/hg of o bodyweight), which is administered intraperitoneally.
There then follows a second intraperitoneal administration of "C-L-proline (250 ACi/kg of bodyweight).
S 25 Finally, the animals are exsanguinated under pentobarbital anesthesia and the livers removed. The hepatic collagen was purified by digestion with pepsin and fractional ammonium sulfate precipitation in conformity with published protocols (Ref. 1 and The purified 30 liver collagen was hydrolyzed and the content of 14
C-
hydroxyproline and 14 C-proline was determined by means of amino acid analysis using ion exchange chromatography.
Inhibition of prolyl-4-hydroxylaga is shown by a decrease in the quotient "C-hydroxyproline/[' 4 C-hydroxyproline+ 1 4 C-proline] 2,2'-Dipyridyl is used as the reference substance. Chojkier, M. 1986, HFpatocyte 48 collagen production in vivo in normal rats, J. Clin.
Invest. 78: 333-339 and 2: Ogata et al. 1991, Minor contribution of hepatocytes to collagen production in normal and early fibrotic livers, Hepatology 14: 361-367).
Inhibition of prolyl-4-hydroxylase in cell cultures: The following cell types are used for testing inhibitors of prolyl-4-hydroxylase in cell cultures: Normal human skin fibroblasts, (NHDF), rat liver epithelial cells, (ref. 1) and primary fat storing cells from rat liver (ref. For this, the cells are cultivated in the presence of inhibitors. At the same time, the collagen which is newly synthesized during this period is metabolically labelled with 4- 3 H-L-proline and 1 C-proline. The influence of the test substances on the degree of hydroxylation of the collagen is then determined in accordance with the method of Chojkier et al (ref. 2,2'-Dipyridyl is employed as the reference substance. Schrode, Mecke, Gebhard, R. 1990, 20 Induction of glutamine synthetase in periportal hepatocytes by co-cultivation with a liver epithelial cll line, Eur. J. Cell. Biol. 53: 35-41; 2. Blomhoff, R., Berg T. 1990, Isolation and cultivation of rat liver stellate cells, Methods Enzymol. 190: 59-71; and 3.: Chojkier, M. Peterkofsky, B. Bateman, J. 1980, A new method for determining the extent of proline hydroxylation by measuring changes in the ration of [4- 3 H] proline in collagenase digests, Anal. Biochem. 108: 385- 393).
The compounds of the formula I may be used as medicaments in the form of pharmaceutical preparations, which contain the compounds, where appropriate together with tolerated pharmaceutical excipients. The compounds can be used as medicines, for example in the form of pharmaceutical preparations which contain these compounds in a mixture together with a pharmaceutical, organic or inorganic 49 excipient which is suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc.
For this purpose, they can be administered orally in doses of from 0.1 to 25 mg/kg/day, preferably of from 1 to 5 mg/kg/day, or parenterally in doses of from 0.01 to mg/kg/day, preferably of from 0.01 to 2.5 mg/kg/day, in particular of from 0.5 to 1.0 mg/kg/day. The dosage can also be increased in severe cases. In many cases, however, smaller doses are also sufficient. These data refer to an adult of about 75 kg in weight.
The novel compounds of the formula I are designated substituted heterocyclic carboxylic acid glycylamides, preferably pyridine-2-carboxylic acid glycylamides, in the examples described below.
This mode of designation is understood to mean substituted N-carboxymethylpyridine-2-carboxamides.
20 Another option is to classify them as substituted N- (pyridyl-2-carbonyl)glycines.
Example 1 3-Methoxy-4-(2,2,2-trifluoroethyloxy)pyridine-2carboxylic acid glycylamide 25 a) 2-Methyl-3-methoxy-4-chloropyridine N-oxide 11.2 g (80.5 mmol) of 3-methoxy-2-methyl-4(1H)-pyridone were heated under reflux for 10 hours in 100 ml of fo" phosphorus oxychloride. Subsequently, the mixture was concentrated and 30 ml of toluene were added to each 2 ml volume; concentration then took place once again and the residue was taken up in 150 ml of water, with the pH of the mixture then being adjusted to 11 with K 2 C0 3 this mixture was then extracted with dichloromethane and the organic phase was washed ith water, dried and freed from 50 solvent.
8 g of the product were obtained, under standard conditions, from the pale brown oil (9 g) using m-chloroperbenzoic acid in dichloromethane, m.p. 88 to 89 0 C (from petroleum ether).
b) 2-Methyl-3-methoxy-4- (2,2,2-trifluoroethoxy)pyridine N-oxide 6.7 g of potassium tert-butoxide were added in portions, at -20 0 C, while stirring and under a nitrogen atmosphere, to 20 ml of trifluoroethanol. After the mixture had been warmed to 0 C, 5.2 g (30 mmol) of 2-methyl-3-methoxy-4chloropyridine N-oxide were added in portions. Tha mixture was heated under reflux for 3 hours, and then cooled down to room temperature; a further 3.45 g of potassium tert-butoxide were then added and the mixture was heated under reflux for 2 hours. After it had cooled down, 40 ml of water were added to the reaction mixture, which was then extracted with dichloromethane; the extract was then dried over MgSO 4 and freed from solvent in vacuo. The resulting oily product was subjected to further reaction.
c) 3-Methoxy-4- (2,2,2-trifluoroethoxy) -2-hydroxymethylpyridine 8 g (33.8 mmol) of the above compound were dissolved in 25 16 ml of glacial acetic acid, and 24 ml of acetic anhydride were added, at 80°C and while stirring, to this mixture. The reaction mixture was heated at 110°C for 2 hours and then cooled down to 80°C; 40 ml of methanol were then added to it dropwise. Subsequently, the mixture was concentrated in vacuo, and the oily residue added to ml of 2T methanolic NaOH, with this mixture being stirred for 30 minutes. Following treatment with active charcoal, and filtration, the mixture was concentrated in vacuo and 50 ml of water were added to the residue, after 51 which extraction took place with dichloromethane; the extract was dried (MgSO 4 and concentrated, and the residue was treated with diisopropyl ether. 3.9 g of the product were obtained in the form of colorless crystals, m.p. 107 to 108 0
C.
d) 3-Methoxy-4-(2,2,2-trifluoroethyloxy)pyridine-2carboxylic acid 0.8 g (3.3 mmol) of the above alcohol was dissolved in a solution composed of 0.3 g of potassium hydroxide and 25 ml of water, and 1.6 g of potassium permanganate were added in portions at 100°C and while stirring. After decolorization, the manganese dioxide which had formed was filtered off with suction from the hot mixture and washed twice with hot water; the filtrate was concentrated in vaauo to 1/3 of the volume, adjusted to pH 1 with cone. aqueous hydrochloric acid, and concentrated in vacuo; the residue was treated with anhydrous ethanol and the undissolved material was filtered off. 0.73 g of product, m.p. 1570, was obtained from the filtrate.
20 e) 3-Methoxy-4-(2,2,2-trifluoroethyloxy)pyridine-2carboxylic acid (glycyl ethyl ester) amide 0.58 g (2.3 mmol) of the above carboxylic acid was suspended in 100 ml of- anhydrous tetrahydrofuran, after 5 which 322 mg (2.3 mmol) of glycine ethyl ester 25 hydrochloride, 0.64 ml (5 mmol) of N-ethylmorpholine, 350 mg (2.6 mmol) of 1-hydroxy-lH-benzotriazole and 537 mg (2.6 mmol) of N,N'-dicyclohexylcarbodiimide were added at 20 0 C and while stirring, and the mixture was then stirred at 20°C for 48 hours. Undissolved material was 30 then filtered off and the filtrate was concentrated in vacuo; the residue was taken up in ethyl acetate and undissolved material was filtered off; the filtrate was stirred together with 100 ml of a saturated, aqueous solution of Na bicarbonate, and the organic phase was dried and concentrated in vacuo; the residue was 52 crystallized using diisopropyl ether. 0.45 g of the colorless crystalline product were obtained, m.p. 80 to 82°C.
f) 0.4 g (1.2 mmol) of the above ester was added to 50 ml of a 1.5 N methanolic solution of sodium hydroxide, and this mixture was stirred at 20 0 C for 30 minutes. It was then concentrated in vacuo and the residue was taken up in 50 ml of water; this mixture was adjusted to pH 1 with comp. aqueous hydrochloric acid and the small amount of undissolved material was filtered off; the filtrate was concentrated in vacuo and the residue was treated with 50 ml of anhydrous ethanol; this mixture was filtered and the filtrate was concentrated and brought to crystallization using diethyl ether. 0.32 g of the title compound was obtained, m.p. 163 to 165 0 C (with gas evolution).
Example 2 4-Chloro-3-methoxypyridine-2-carboxylic acid glycylamide a) 4-Chloro-2-hydroxymethyl-3-methoxypyridine 20 30 g (173 nmol) of 4-chloro-3-methoxy-2-methylpyridine Noxide (cf. Example la) were dissolved in 100 ml of glacial acetic acid, after which 150 ml of acetic anhydride were added dropwise, at 80°C and while stirring, and the mixture was then stirred at 1100C for 2 hours. The mixture was then cooled down to 80°C and 200 ml of methanol were added dropwise; the mixture was then heated to boiling for 15 minutes and, after having been cooled down, concentrated in vacuo; the residue was taken up in methanol and this mixture was allowed to flow into 30 300 ml of a 1.5 N methanolic solution of sodium hydroxide, with this mixture then being stirred at for 30 minutes and concentrated in vacuo; the residue was taken up in water, and this mixture extracted three times with dichloromethane, with the organic phase being dried and concentrated; the residue was crystallized using 53 petroleum ether. 23 g of product were obtained, m.p. 64 to 66 0
C.
b) 4-Chloro-3-methoxypyridine-2-carboxylic acid 8.65 g (50 mmol) of the above alcohol were dissolved in a mixture composed of 0.8 g of potassium hydroxide and ml of water, after which potassium permanganate was added in portions, at 60 0 C and while stirring, until no more discoloraticn could be seen (12 g, 75 mmol). After 1 hour at G60C, the manganese dioxide was filtered off with suction and then washed with hot water; the filtrate was concentrated in vacuo to 200 ml and adjusted, while cooling, to pH 1 with aqueous cone. HC1. After grinding, the product crystallizes out in association with cooling.
Additional product can be obtained from the mother liquor by treatment with petroleum ether. Total quantity, 4.2 g, m.p. 116 to 117C (with gas evolution).
c) 4-Chloro-3-methoxypyridine-2-carboxylic acid (glycyl ethyl ester) amide 4.7 g (25 mmol) of the above carboxylic acid were 20 suspended in 200 ml of anhydrous dichloromethane, and after that 3.5 g (25 mmol) of glycine ethyl ester hydrochloride, 6.4 ml (50 mmol) of N-ethylmorpholine, 3.8 g (28 mmol) of l-hydroxy-1H-benzotriazole and 5.15 g (25 mmol) of N,N'-dicyclohexylcarbodiimide were added sequentially, at 20°C and while stirring, and the mixture was then stirred at 20°C for 20 hours. Undissolved •material was then filtered off and the organic phase was shaken with a saturated, aqueous solution of sodium carboinate, dried and concentrated in vacuo; the residue (6 g of oil) was chromatographed on silica gel using ethyl acetate and 5.4 g of oily product were obtained.
d) The title compound was obtained by hydrolyzing the above ethyl ester. For this, 0.7 g (2.6 mmol) of this 54 ester was dissolved in 50 ml of methanol/water and after that 170 mg (7 mmol) of lithium hydroxide were added at 20°C and while stirring. After 30 minutes, the mixture was concentrated in vacuo; the residue was brought to pH 1 with conc. aqueous hydrochloric acid and this mixture was concentrated in vacuo; the residue was treated twice with anhydrous ethanol and the ethanolic phase was concentrated; the residue was treated with hot ethyl acetatt and the amorphous residue was dried on an oil pump. 0.31 g of the title compound was obtained.
Example 3 4-Butyloxy-3-methoxypyridine-2-carboxylic acid glycylamide M.p. 137 to 139°C (with gas evolution, from tetrahydrofuran) Examples 4 to 16 were prepared in an analogous manner: Example 4 3,4-Dimethoxypyridine-2-carboxylic acid glycylamide Example 20 3-Ethyloxy-4-(3-methoxybenzyloxy)pyridine-2-carboxylic acid glycylamide Example 6 4-Hexyloxy-3-methoxypyridine-2-carboxylic acid glycylamide Example 7 3-Methoxy-4-(3-methyl-l-butyloxy)pyridine-2-carboxylic acid glycylamide Example 8 4-(4-Fluorobenzyloxy)-3-methc.xypyridine-2-carboxylic acid glycylamide 55 Example 9 3 -Methoxy-4 (4 -trif luoromvathylbenzyloxy) pyridine-2 carboxylic acid glycylamide Example 3 -Me thoxy- 4- 2, 3, 3, 3-pentaf luoropropyloxy) pyridine -2 carboxylic acid glycylamide Example 11 4 2, 3,3, 4,4, 4-Heptaf luorobutyloxy) 3-me thoxypyridine 2-carboxylic acid glycylamide Example 12 4 (3 -Me thoxybenzyloxy) 3-me thoxypyri dine- 2 -c arboxyl ic acid glycylaniide Example 13 3-Ethyloxy-4- 2,2-trifluoroethyloxy)pyridine-2-carboxylic acid glycylamide Example 14 4-Butyloxy-3-ethyloxypyridine-2-carboxylic acid glycylamide Example 3-Methoxy-4- ((phenoxyethyl) oxy)pyridine-2-carboxylic acid glycylamide Example 16 3-Ethyloxy-4-benzyloxypyridifle-2-carboxylic acid glycylamide Example 17 3, 6-Dimethoxypyridine-2-carboxylic acid glycylamide a) 3, 6-Dimethoxy-2-methylpyridile N-oxide 1.15 g (50 Mmol) of sodium were dissolved in 100 ml of anhydrous methanol, and after that 7.4 g (40 mmol) of 56 3-methoxy-2-methyl-6-nitropyridine N-oxide were added at and while stirzing. The mixture was then heated to reflux for 3 hours and, after having been cooled down concentrated in vacuo; the residue was taken up in water and this mixture was extracted with dichloromethane; the organic phase was dried and concentrated and the residue was crystallized using diisopropyl ether. 7 g of product were obtained, m.p. 63 to 65 0
C.
b) 3,6-Dimethoxy-2-hydroxymethylpyridine 7 g (41.4 mmol) of the above compound were reacted with glacial acetic acid/acetic anhydride in analogy with Example Ic) and th resulting acetate was hydrolyzed using 1.5 N methanolic sodium hydroxide solution. 5.6 g were obtained of oily product which was subjected to further reaction under c).
c) 3,6-Dimethoxypyridine-2-carboxylic acid 5.6 g (33 mmol) of the above compound and 2.4 g of potassium hydroxide were dissolved in 150 ml of water, and after that 15 g (100 mmol) of potassium permanganate 20 were added in portions at 60°C and while stirring. The manganese dioxide which had formed was then filtered off with suction and washed twice with hot water; the combined water phase was concentrated to 100 ml, adjusted to pH 1 with cone. aqueous hydrochloric acid while being 25 cooled with ice, and concentrated in vacuo; the residue was treated with ethyl acetate and ethanol, and undissolved material was filtered off from this mixture, with the filtrate being concentrated in vacuo. The residue was crystallized using diethyl ether. 4 g of product were S 30 obtained, m.p. 131-132°C (with gas evolution).
d) 3,6-Dimethoxypyridine-2-carboxylic acid (glycyl ethyl ester) amide 2.2 g (12 mmol) of the above carboxylic acid were 57 suspended in 300 ml of anhydrous dichioromethane, and after that 1.68 g (12 mmol) of glycine ethyl ester hydrochloride, 3.25 ml (25 mmol) of N-ethylmorpholine, 1.62 g (12 mmol) of l-,hydroxy 1H.-be.nzotriazole and 5.2 g (12 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulf'onate were added, while stirring, and the mixiture was then atirred at 20*C for hours. The small amount of undissolved material was then filterel off and the filtrate was shaken once with water and then with a saturated, aqueous solution of Na bicarbonate; the organic phase w;:s dried and concentrated in vacuo and the residue was crystallized using diisopropyl ether. 2 g of product were obtained, m.p. 93 to 0
C.
e) The title compound was obtained by hydrolyzing 0.6 g (2.24 inmol) of the above ethyl ester at 209C using 120 mg of lithium hydroxide in 60 ml of methanol/water After concentration had taken place in vacuo, the retidue was acidified and extracted, at 20 1 with tetrahydrofuran; the filtrate was concentrated in vaduo and the yellow, resinous residue was crystallized using diethyl ether. 0.4gwere obtained of the title compound, m.p.
1300 (dcomosiion, wichis Otrongly hygroscopic. The residue from the inspissated reaction mixture was then extracted three times with 50 ml of hot acet,'ne on each occasion and the inspissation residue was crstallized using diethyl ether. A further 0.3.5 g of the title compound was obtained, m.p. 155SIC (decomposition).
Example 18 3,5-Diethoxypyridine-2-carboxylic acid glycylamide Example 19 3-Methoxy-6- (3-methyl-l-butyloxy)pyridin5-2-carboxylic acid glycylamide 105 to 107'C (from aqueous hydrochloric acid, pH 3 to 4) 58 Example 3-Ber,: &loxy- 4- (3-ethyloxypropyloxy)pyridine-2-carboxylic acid iycylamide M.P. 118-1200C (from acetone) According to 1H1 NMR, the product contains approximately of the 3-hydroxy derivative.
Example 21 3-Benzyloxy-4-hexyloxypyridine-2-carboxylic acid glycylamide M.p. 130 to 1320C (from aqueous hydrochloric acid) Example 22 6- (2-Butoxyethyloxy) -3-methoxypyridine-2-carboxylic acid glycylamide Example 23 6- (2-Cyclohexyl) ethyl) oxy-3-methoxypyridine-2-carboxylic acid glycylamide M.P. from 70 0 C (sintering from 500W, from aqueous hydrochloric acid, PH 3) Example 24 20 3-Ethyloxy-6-methylpyridine-2-carboxylic acid glycylamide Example 6-Benzyloxy-3-methoxypyridine-2-carboxylic acid glycylaide Example 26 3 -Benzyloxypyridine-2 -carboxylic acid glycylamide M.p. 142-144 0
C
9 Example 27.1 3 -Methoxypyridine-2 -carboxylic acid glycylamide amorphous substance, prepared by hydrolyzing the 3methoxypyridine-2-carboxlic acid (glycyl ethyl ester) aide, m.p. 141 to 142WC (with gas evolution, from 59 diethyl ether).
This ethyl ester was obtained by catalytic hydrogenation of 4-chloro-3-methoxypyridine-2-carboxylic acid (glycyl ethyl ester) amide (see Example 2c), which was obtained from 4-chloro-3-methoxypyridine-2-carboxylic acid (m.p.
119 to 120°C, from 4-chloro-3-methoxy-2-methylpyridine Noxide by reaction with acetic anhydride/glacial acetic acid and subsequent oxidation ot the 2-hydroxymethylpyridine derivative) (see Example 2a, b) and glycine ethyl ester hydrochloride.
Example 27.2 1-Methoxypyridine-2-carboxylic acid glycylamide hydrochloride a) 4-Chloro-3-methoxypyridine-2-carboxylic acid (glycyl benzyl ester) amide The product was obtained, in analogy with Example from 4-chloro-3-methoxypyridine-2-carboxylic acid (cf.
Example 2b), glycine benzyl ester tosylate, N-ethylmorpholine, 1-hydroxy-lH-benzotriazole and CMC, m.p. 57- 20 58 0
C.
Sb) The title compound was obtained by hydrogenating the above product in methanol/tetrahydrofuran using Pd on charcoal (10 in a hydrogenation vessel. After removing the catalyst, and freeing from the solvent, the product was crystallized using acetone, m.p. 168 0 C (with foaming).
Example 28 3-Ethoxypyridine-2-carboxylic acid glycylamide Example 29 3-Propyloxypyridine-2-carboxylic acid glycylamide
I
60 Exaiple 3-Butyloxypyridine-2-carboxylic acid glycylamide a) 3-n-Butyloxypyridine-2-carboxylic acid 6 g (15' "nol) of NaH (60 in mineral oil) were added in portions, at 20°C and while stirring, to 9.8 g mmol) of 3-hydroxypyridine-2-carboxylic acid in 150 ml of N,N-C .,,ethylacetamide. After 30 minutes, 15 ml (140 mmol) of butyl bromide were added dropwise and the mixture was heated at between 95 0 C and 125°C for hours. After having been cooled down, the mixture was concentrated in vacuo, treated with an aqueous solution of Na bicarbonate and extracted with dichloromethane; after drying, the residue was purified by chromatography on silica gel using ethyl acetate.
The 13 g of oily product thus obtained were introduced into 250 ml of a 1.5 N methanolic solution of sodium hydroxide, and the mixture was then stirred at 20°C for minutes and concentrated in vacuo; the residue was taken up in 200 ml of water and this mixture was 20 extracted with dichloromethane and the aqueous phase was adjusted to pH 1 with cone. aqueous hydrochloric acid; concentration took place in vacuo and the residue was .treated with ethyl acetate and then with anhydrous ethanol. The resulting solutions were concentrated and the residue was crystallized using acetone. 9.3 g were obtained of product 93-95°C) which, according to 1H NMR, still contained approximately 20 of 3-hydroxypyridine-2-carboxylic acid.
b) 2.8 g (20 mmol) of glycine ethyl ester hydrochloride, 5.2 ml (40 mmol) of N-ethylmorpholine, S* 2.7 g (20 mmol) of 1-hydroxy-lH-benzotriazole and 3.0 ml S" (20 mmol) of N,N'-diisopropylcarbodiimide were added, at and while stirring, to 4 g (20 mmol) of the above product in 200 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous acetonitrile, and the mixture was then stirred at 20°C for 20 hours.
61 After working up (treatment with Na bicarbonate solution, removal of precipitated diisopropylurea), 3.5 g of oily product, which still contained N,N'-diisopropylurea, were obtained following chromatography on silica gel (ethyl acetate/n-heptane 1:1; then pure ethyl acetate).
This mixture was introduced, at 20 0 C and while stirring, into 150 ml of a 1.5 N methanolic solution of sodium hydroxide and the total mixture was stirred for minutes.
This latter mixture was then concentrated in vacuo and the residue was taken up in water; this mixture was in turn extracted with 200 ml of dichloromethane and the aqueous phase was brought to pH 1 uning cone. aqueous HC1 and concentrated in vacuo; the residue was treated with anhydrous ethanol and then with N,N-dimethylformamide, with each extract being filtered to remove undissolved material and then concentrated and each of tbh residues being crystallized using ethyl acetate. 1.65 g of the title compound were obtained from the ethanol phase (slightly contaminated according to 1 H NMR, m.p. 170 0
C
with gas evolution) and a further 0.63 g from the dimethylformamide phase 182 0 C, with gas evolution).
Example 31 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid glycyl- 25 amide a) 4-Chlorobenzyl 3-(4-chlorobenzyloxy)pyridine-2carboxylate 8.4 g (60 mmol) of 3-hydroxypyridine-2-carboxylic acid were alkylated (3 hours, 110°C) with 5.2 g (approximately 130 mmol, 60 of sodium hydride and 19.3 g (120 mmol) of 4-chlorobenzyl chloride in N,N-dimethylacetamide in analogy with Example 30a). After concentration in vacuo and extraction with Na bicarbonate solution, the residue was purified on silica gel using heptane/ethyl acetate and 14.8 g of the product were crystallized from appropriate fractions using diisopropyl ether, m.p. 92 to L~L' C PILI~ 62 94 0
C.
b) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid 9.7 g (25 mmol) of the above ester were hydrolyzed with 200 ml of a 1.5 N methanolic solution of sodium hydroxide (24 h, 20°C). After working up (concentration, taking up of the residue in water, extraction with dichloromethane and acidification), 6.5 g of product were obtained, m.p.
144°C (from water, decomposition).
c) 3- (4 Chlorobenzyloxy)pyridine- 2 caroxylic (glycyl ethyl ester) amide 3.2 g (12 mmol) of the above pyridine-2-carboxylic acid were reacted, in analogy with example 17d), with 1.7 g (12 mmol) of glycine ethyl ester hydrochloride, 1.62 g (12 mmol) of l-hydroxy-(1H)-benzotriazole, 3.3 ml mmol) of N-ethylmorpholine and 5.2 g (12 mmol) of Ncyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-ptoluenesulfonate. After working up, 3.0 g of the product were crystallized using diisopropyl ether, m.p. 106 to 108 0
C.
20 d) The title compound was obtained by hydrolyzing the i above ethyl ester. 120 mg (5 mmol) of lithium hydroxide were added to 0.9 g (2.5 mmol) of the ethyl ester in :60 ml of methanol/water and the mixture was stirred at 20 0 C for 1 hour. It was then concentrated in vacuo and the resulting aqueous phase was adjusted to pH 3; the resulting precipitate was filtered off with suction, washed with water and dried in vacuo. 0.52 g of the title compound was obtained, m.p. 155 to 157°C.
Example 32 3-(3-Methoxybenzyloxy)pyridine-2-carboxylic acid glycylamide 63 a) 3-MethoxybenZyl 3-(3-methoxybenzyloxy)pyridine-2carboxylate In analogy with Example 38a), 10 g of the product were obtained as a colorless oil, which was subjected to further reaction, from 8.4 g (60 mmol) of 3-hydroxypyridine-2-carboxylic acid and 3-methoxybenzyl chloride following chromatography on silica gel.
b) 3-(3-Methoxybenzyloxy)pyridine-2-carboxylic acid g of the above ester were hydrolyzed in 300 ml of a 1.5 N methanolic solution of sodium hydroxide. 7.5 g of product werr obtained, m.p. 147°C (decomposition, from aqueous hydrochloric acid) c) 3-(3-Methoxybenzyloxy)pyridine-2-carboxylic acid (glycyl ethyl ester) amide 3.2 g (12 mmol) of the above carboxylic acid were reacted in analogy with Example 31c). 3.6 g of oily crude product were isolated which, according to the 1H NMR spectrum, still contained N-ethylmorpholine. The pure substance, 99 m.p. 135 to 137*C (from diisopropyl ether/ethyl acetate) 20 was obtained from this crude product.
d) 2.1 g (6 mmol) of.the above product were hydrolyzed using 0.4 g of NaOH in 60 ml of methanol. Following acidification to pH 3, 1.6 g of the title compound were obtained as a colorless crystalline substance, m.p. 89 to 91°C (from aqueous hydrochloric acid).
Example 33 3-(2-Phenylethyloxy)pyridine-2-carboxylic acid glycyle e amide sodium salt a) 3-(2-Phenylethyloxy)pyridine-2-carboxylic acid In analogy with Example 30a), 8.4 g (60 mmol) of 64 3-hydroxypyridine-2-carboxylic acid were alkylated with NaH/2-phenylethyl bromide in N,N-dimethylacetamide. The g of oily product obtained after purification by column chromatography were hydrolyzed with methanolic sodium hydroxide solution in analogy with Example 3 g of product were obtained 145 0 C (with foaming, from acetone)) which, according to the 1 H NMR spectrum, contained approximately 25 of 3-hydroxypicolinic acid.
b) 3-((2-Phenylethyl)oxy)pyridine-2-carboxylic acid (glycyl ethyl ester) amide 2.9 g of the above compound were reacted, in analogy with Example 30b), with glycine ethyl ester hydrochloride, Nethylmorpholine, 1-hydroxy-lH-benzotriazole and N,Ndicyclohexylcarbodiimide. After working up, the crude product was chromatographed on silica gel using ethyl acetate. 3-Hydroxypyridine-2-carboxylic acid (glycyl ethyl ester) amide was initially eluted as a by-product and crystallized from appropriate fractions using petroleum ether; 1.1 g 86 to 88 0 C, strong fluorescence in UV light). The product was then crystallized from appropriate fractions using diisopropyl ether, and 1.7 g of the product were obtained, m.p. 73-75 0
C.
c) The title compound was obtained by hydrolyzing 0.99 g (3 mmol) of the above ethyl ester using 100 ml of a IN methanolic solution of sodium hydroxide. After the mixture had been stirred at 20 0 C for 1 hour, it was concentrated and the residue was dissolved in a little water; this latter mixture was extracted with dichloromethane and the aqueous phase was acidified, while being cooled with ice, to pH 1 using conc. aqueous hydrochloric acid and then concentrated in vacuo; the residue was extracted twice with tetrahydrofuran and the extracts were concentrated; the residue was dissolved in a little water/tetrahydrofuran and 252 mg (3 mmol) of sodium bicarbonate were added to this solution. This mixture was concentrated to dryness and the residue was 65 crystallized using anhydrous ethanol. 0.38 g of the title compound was obtained as sodium salt, m.p. 300WC.
Example 34 3- (4-Trifluoromethylbenzyloxy) pyridine-2 -carboxylic acid glycylamide M.P. 161 to 1J3*C (from aqueous hydrochloric acid, PH 3) Example 3- (2-Propyl)benzyloxy)pyridine-2-carboxylic acid glycylaniide sodium salt M.P. 108WC (with decomp., from diisopropyl ether) Example 36 3- (4-Fluorobenzyloxy)pyridine-2-carboxylic acid glycylamide 135 to 1381C (from aqueous hydrochloric acid, PH 3 to 4) Example 37 3- (4-Methoxyphenyl) ethylamino) carbonyl)benzyloxy) pyridine-2 -carboxylic acid glycylamide M.P. 168-170*C (from dichloromethane) The following example nos. 38-64 were prepared in an analogous manner: Example 38 3- (2,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid glycylamide Example 39 3- (3-Fluorobenzyloxy)pyri dine-2-carboxylic acid glycylamide Example 3- (3-Chlorobenzyloxy)py'ridine-2-carboxylic acid glycylamuide 66 Example 41 3- (3,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid glycylaxnide Example 42 3 (3 -Trif luoromethylbenzyloxy) pyridine-2 -carboxylic acid glycyl amide Example 43 3- (4-Trifluoromethoxybenzyloxy) pyridine-2-carboxylic acid glycylamide Example 44 3- (3-Ethoxybenzyloxy)pyridine-2-carboxylic acid glycyl- Example 3- (4-Cyanobenzyloxy)pyridine-2-carboxylic acid glycyl- 1s amide Example 46 3- ((2-Pyridylmethyl)oxy)pyridine-2-car-boxylic acid glycylamide hydrochloride Example 47 20 3- ((3-Pyridylmethyl)oxy)pyridine-2-carboxylic acid glycylamide hydrochloride Example 48 3- ((4-Pyridylmethyl)oxy)pyridine-2-carboxylic acid glycylamide hydrochloride Example 49 3- ((2-Thienylmethyl)oxy)pyridine-2-carboxylic acid glycylaniide Example 3- (31 5-Dimethoxybenzyloxy)pyridine-2-carboxylic acid glycylamide 67 Example 51 3 -Cyclohexyloxypyridine-2 -carboxylic acid glycylamide Example 52 3- (3 -Phenyipropyloxy) pyridine-2 -carboxylic acid glycylamide Example 53 3- (4-Phenylbutyloxy) pyridine-2 -carboxylic acid glycylaniide Example 54 3- (((4-Methoxy-2-pyridyl)methyl)oxy)pyridine-2-crrboxylic acid glycylamide Example 3- (((4-Ethoxy-2-pyridyl)methyl) oxy)pyridine-2-carboxylic acid glycylamide Example 56 3 -Methylthiopyridine-2-carboxylic acid glycylamide Example 57 3 -Benzylthiopyridine-2 -carboxylic acid glycylamide Example 58 3- (3-Chlorophenoxy)pyridine-2-carboxylic acid glycylamide Example 59 3- (3-Methoxyphenoxy)pyridine-2-carboxylic acid glycylamide Example 3 -Phenoxypyridine-2 -carboxylic acid glycylamide Example 61 3- Butyloxypyridine carboxylic acid L- alanylamide 68 Example 62 3 -Butyloxypyridine-2-carboxylic acid D-alanylamide Example 63 3-Benzyloxypyridine-2 -carboxylic acid A-alanylamide Example 64 3- (3-Methylbutyloxy)pyridine-2-carboxylic acid L-leucylamide Example 4 -Methoxyisoquinoline-3 -carboxylic acid glycylamide a) Methyl 1,2-dihydro-4-hydroxy-l-oxoisoquinolile-3carboxylate, was prepared as described Suzuki et al., Synthesis 1978, 461).
b) Methyl 1,2-dihydro-4-methoxy-l-oxoisoquiolile-3carboxylate, from a) using (trimethylsilyl)diazomethane in methanol /acetoni tri le, m.p. 177 to 179 0 C (ethyl acetate/heptane).
c) Methyl 1-chloro-4-methoxyisoquinoline-3 -carboxylate, ~*:from b) using phosphorus oxychloride, m.p. 108*C (ethyl acetate).
d) Methyl 4-methoxyisoqtiinoline-3-carboxylate, from c) using hydrogen/Pd/C, m.p. 129*C (from methyl tertbutyl ether).
4-Methoxyisoquinoline-3-carboxylic acid, from d) by hydrolysis, m.p. 185-189 0 C (from aqueous hydrochioric acid).
f 4-Methoxyisoquinoline-3-carboxylic acid (glycyl methyl ester) amide, from e) using glycine methyl ester hydrochloride, DCC, HOBT, THF and NEM., oily substanc6 (crude product).
69 g) The title compound was obtained by hydrolyzing the above methyl ester, m.p. 147 0 C (from aqueous hydrochloric acid) Examples 66 to 76 were obtained in an analogous manner from the corresponding isoquinoline-3-carboxylic acids or the 5,6,7, 8-tetrahydro derivatives, respectively: Example 66 4-Ethoxyisoquinoline-3 -carboxylic acid g'lycylamide Example 67 4-Propyloxyisoquinoline-3-carboxylic acid glycylamide Example 68 4- (3-Methylbutyloxy)isoquinoline-3-carboxYlic acid glycylaziide Example 69 4-Methoxy-5,6,7,8-tetrahydroisoquinoline-3-c3rboxylic acid glycylamide Example 4- (3-Methylbutyloxy) -5,6,7,8-tetrahydroisoquinoline-3carboxylic acid glycylamide Example 71 6,7, 8-tetrahydroisoquinoline-3-carboxylic acid glycylamide Example 72 4 Ben zyl1oxy -5 6, 7, 8 te trahydro is oquino, 1ine -3 -c arboxyl ic acid glycylainide Example 73 4 -Benzyloxyisoquinoline- 3-carboxylic acid glycylainide 70 Example 74 4- (3-methoxybenzyloxy) 8-tetrahydroisoquinoline-3carboxylic acid glycylamide Example .1 7-Bromo-4-methoxyisoquinoline-3-carboxylic acid glycylami de Example 76 7-Methoxy-4-methoxyisoquinoline-3-carboxylic acid glycylamide Example 77 3-Methoxy-6-((3-methylbutyloxy)methyl)pyridine-2carboxylic acid glycylamide Example 78 3-Methoxy-6- ((cyclohexyloxy)methyl)pyridine-2-carboxylic acid glycylamide Example 79 3-Methoxy-6-benzyloxymethylpyridine-2-carboxylic acid glycylamide Examples 80 to 91 were prepared in accordance with the processes described in Schemes 1, 2 and 3.
Example 9* 5-Carboxy-3-methoxypyridine-2-carboxylic acid glycylami de 0 270 mg of the title compound from Example 81 were hydrolyzed at 201C using 50 ml of 1N methanolic NaOH.
After 30 minutes, the mixture was concentrated in vacuo and the residue was dissolved in 50 ml of watex; this solution was extracted with diothyl ether and the aqueous phase was adjusted to pH 1 with conc. aqueous hydrochloric acid and then concentrated in vacuo; the water was removed azeotLropically from the residue using ethyl 71 acetate and the residue was then treated with ethanol and this mixture was concentrated; the residue was crystallized using diethyl ether. 230 mg were obtained of the title compound, m.p. 173 0 C (with gas evolution, sintering at 170°C), which, according to the 1H NMR spectrum, still contains approximately 20 of an impurity.
The title compound was also obtained by hydrolyzing 0.45 g of 5-((-1-butyloxy)carbonyl)-3-methoxypyridine-2carboxylic acid N-(((1-butyloxy)carbonyl)methyl)amide, m.p. 80-81°C (from petroleum ether), using 50 ml of 1.5 N methanolic NaOH. 0.23 g was obtained of the title compound, m.p. 198-2000C -(from an ethanolic phase whose residue, following concentration, was crystallized using diethyl ether). According to the 1 H NMR spectrum and MS, the substance contains approximately 5-10 of its ethyl ester.
The isomeric 2-carboxy-3-methoxypyridine-5-carboxylic acid glycylamide was obtained in an analogous manner, m.p. from 65°C (sintering from 45 0 C, with foaming, from 20 diethyl ether, hygroscopic).
Example 81 5-Methoxycarbonyl-3-methoxypyridine-2-carboxylic acid glycylamide a) 5-Methoxycarbonylpyridine-2-carboxylic acid 1-oxide
S
12 g (60 mmol) of dimethyl were suspended in 30 ml of glacial acetic acid, and after that 13 ml of hydrogen peroxide (35 were added at and while stirring. The mixture was then heated to 100°C (internal temperature), while stirring, with a clear 30 solution being formed at 50°C. After the mixture had been stirred at 100 0 C for 90 minutes, it was allowed to cool down to 20°C and the crystalline precipitate was filtered off with suction and washed with water; After drying, g of product were obtained, m.p. 1600C (decomp.).
72 b) Dimethyl 3-chloropyridine-2,5-dicarboxylate 17 ml of thionyl chloride, 35 ml of anhydrous chloroform and 1.5 ml of N,N-dimethylformamide were heated to while stirring, and 7.5 g of the above product were then added in portions at this temperature. The mixture was then stirred at 60 0 C for a further 60 minutes, and, after cooling, the solvent and excess reagent were distilled off in vacuo; dichloromethane was added to the residue, and the N,N-dimethylformamide x HC1 complex was filtered off with suction and washed with dichloromethane.
Approximately 15 ml of triethylamine and 10 ml of methanol were added, while cooling, to the mother liquor and the mixture was stirred for 30 minutes. After concentrating by evaporation in vacuo, the residue was dissolved in 50 ml of water and this mixture was then extracted 3 x with dichloromethane; the organic phase was dried and concentrated, and the residue was chromatographed on silica gel using n-heptane and n-heptane:ethyl acetate 5.3 g of product were crystallized, using petroleum ether, from appropriate fractions, m.p. 36 to 38 0
C.
c) 3-Methoxypyridine-2,5-dicarboxylic acid 53 g (0.231 mol) of the above diester were dissolved in 500 ml of methanol, and after that 150 ml (0.81 mol) of sodium methoxide solution (30 in methanol) were added, Sat 20°C and while stirring, whereupon the temperature rose to 30 0 C. The mixture was heated under reflux for hours, 300 ml of water were added at 20°C, and the mixture was then stirred at 35°C for 30 minutes. The excess methanol was distilled off in vacuo and the aqueous phase was adjusted to pH 2, while cooling, with half-concentrated aqueous hydrochloric acid; the colorless crystalline product was filtered off with suction and dried. 49 g were obtained, m.p. 185°C (gas evolution); 255 0 C (decomp.).
-a 73 d) Dimethyl 3-methoxypyridine-2,5-dicarboxylate, cf.
Example e) 5-Methoxycarbonyl-3-methoxypyridine-2-carboxylic acid The compound was obtained, as a mixture with the isomeric monomethyl est Eample 90a)), from 3.4 g (15 mmol) of the above qiOe'rs' y hydrolysis with a dilute solution of methanolic hydroxide (0.54 g of NaOH (13.5 mmol)). 1.8 g of monoester mixture, m.p. 152°C, were obtained in addition to 0.8 g of unreacted diester.
f) 5-Methoxycarbonyl-3-methoxypyridine-2-carboxylic acid (glycyl benzyl ester) amide 1.8 g of the above mixture were condensed, in analogy with Example 90b), with 2.9 g (8.6 mmol) of glycine benzyl ester tosylate in the presence of N-ethylmorpholine, 1-hydroxy-IH-benzotriazole and CMC. After working up, 2.3 g of oily mixture were chromatographed on silica gel using dichloromethane (in the presence of up to 2 methanol). 0.82 g of product was obtained, m.p.
20 108°C. 0.6 g of the oily isomer was also isolated.
g) The title compound was obtained by dissolving 650 mg of the above benzyl ester in 100 ml of tetrahydrofuran/ o.o" methanol and hydrogenating it using Pd/C in a hydrogenation vessel. Once the catalyst had been filtered off with suction, the filtrate was concentrated and the residue was crystallized using diethyl ether. 380 mg were obtained of a colorless crystalline product, m.p. 158 to 1600C.
.0.4* Example 82 5-(3-Pentyloxy)carbonyl-3-methoxypyridine-2-carboxylic acid glycylamide I 74 Example 83 Cyclohexyloxycarbonyl -3 -methoxypyridine carboxylic acid glycylamide Example 84 5- (n-Butylaminocarbonyl) -3-methoxypyridine-2-carboxylic acid glycyla-mide Example (2-Methyl-2-butylaminocarboflyl) -3-methoxypyridine-2carboxylic acid glycylamide Example 86 (Cyclohexylaminocarbonyl) -3-methoxypyridine-2-carboxylic acid glycylaxnide a) 5- (Cyclohexylaminocarbonyl) -3-methoxypyridine-2-carboxylic acid The product was obtained, in analogy with Example from 5-carboxy-3-methoxypyridifle-2-carboxylic acid and cyclohexylamine, m.p. 155 0 C (sintering at 80*C, from aqueous hydrochloric acid).
b) 5 -(Cyc 1ohexyl amino carbonyl) 3-me thoxypyri dine 2 carboxylic acid (glycyl ethyl ester) amide The product was obtained, in analogy with Example from the above compound, m.p. 187 to 188 0 C (from diethyl e. ether) 25 c) The colorless crystalline title compound was obtained by hydrolyzing the above compound in analogy with Example M.P. 110 0 C (with foaming, a deep-black coloration at 240 0
C).
Example 87 (Cyclohexylaminocarbolyl) -3 -ethyloxypyridine-2 -carboxylic acid glycylamide 75 Example 88 ((2-Phenylethyl) aminocarbonyl) -3 -me thoxypyridine-2carboxylic acid glycylamide Example 89 5- -Dehydroabietylaminocarbonyl) -3 -methoxypyridine-2 carboxylic -'cid glycylamide a) 5- -Dehydroabietylaminocarbonyl) -3-methoxypyridine-2 -carboxylic acid The resinous product was obtained, in analogy with Example 90a), from 5-carbox-y! ethoxypyridine-2 -carboxylic acid and -dehydroabietylamine.
b) 5- -Dehydroabietylaminocarbonyl) -3-methoxypyridine-2-carboxylic acid (glycyl ethyl ester) amide The product was obtained in analogy with Example from the above compound, m.p. from 1500C with foaming, sintering at 1200C, from diethyl ether).
Sc) The title compound was obtained by hydrolyzing the :above compound in analogy with Example 90 d), 2151C (sintering at 150*C, from aqueous hydrochloric acid).
Example (2 (4 -Fluorophenyl) ethyl) aminocarbonyl) 3 -methoxy o pyridine-2 -carboxylic acid glycylamide 25 a) Methyl 5-carboxy-3-methoxypyridine-2-carboxylate g (50.7 mmol) of the 3-methoxypyridine-2,5-dicarboxylic acid (Example 81c) were suspended in 150 ml of anhydrous methanol, and after that 2 ml of concentrated sulfuric acid were added and the mixture was heated under ref lu~x for 3 hnnurs. Half of the methanol was then distilled off in vacuo and the residue was introduced 76 into 400 ml of ice water; the crystalline residue was filtered off with suction and washed with water; the residue was dissolved in 150 ml of a saturated, aqueous solution of Na bicarbonate and this mixture was extracted twice with 80 ml of dichloromethane on each occasion; the bicarbonate phase was adjusted to pH 1, while cooling, with half-concentrated aqueous hydrochloric acid and the precipitated product was filtered off with suction and dried. 5 g of colorless, crystalline substance were obtained, m.p. 196 to 197 0 C. 1.7 g of dimethyl ester, m.p. 53 to 55°C (from petroleum ether), were obtained from the dichloromethane phase.
b) 5- (2-(4-Fluorophenyl)ethyl)amino)carbonyl)-3methoxypyridine-2-carboxylic acid 3.2 g of methyl 5-carboxy-3-methoxypyridine-2-carboxylate were suspended in 300 ml of anhydrous dichloromethane, and after that 2.0 ml (15 mmol) of 2-(4-fluorophenyl)ethylamine, 1.95 ml (15 mmol) of N-ethylmorpholine, 2.2 g (16.5 mmol) of 1-hydroxy-1H-benzotriazole and 6.35 g 20 (15 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC) were added sequentially, at 200C and w-ile stirring, and the mixture was stirred for 24 hours. The undissolved material was then filtered off and the organic phase was extracted, in each case 3 x, with an aqueous solution of Na bicarbonate, with 1N aqueous hydrochloric acid and with water, and the e* organic phase was dried and concentrated. 3.7 g were obtained of methyl ester, m.p. 168 to 169°C, which was introduced into 150 ml of 1.5N methanolic NaOH. After 30 minutes, the mixture was concentrated and dissolved in 100 ml of water, and this mixture was adjusted to pH 1 with cone. aqueous hydrochloric acid; the crystalline precipitate was filtered off with suction, washed with water and dried. 3.4 g of product were obtained, m.p.
110°C (with foaming, sintering at 75 0
C).
I,
77 c) 5- (4-Fluorophenyl)ethyl) amino) carbonyl) -3methoxypyri dine 2-carboxyl ic acid (glycyl ethyl ester) amide In analogy with Example 90a) 3.2 g (10 mmol) of the above compound were reacted with 1.4 g (10 mmol) of glycine ethyl ester hydrochloride, N-ethylmorpholine, ,-hydroxy-1H-benzotriazole and CMC. Following analogous working up, 2.8 g of the colorless crystalline product were crystallized using diisopropyl ether, m.p. 170 to 1710C.
d) The title compound was obtained by hydrolysing 1. 0 g of the above glycine ethyl ester, at 20 0 C, in methanolic NaOH. 0.95 g of product, m.p. 206*C (with foaming) crystallizes from aqueous medium at pH 3.
Example 91 (4-Methoxyphanyl) ethyl) aminocarbonyl) -3-ethyloxypyridine-2 -carboxylic acid glycylamide Examples 92 to 1L05 were obtained from the correspondingly substituted pyridine-2-carboxylic acid derivatives of the 20 formula II and glycine ethyl ester hydrochloride and with subsequent hydrolysis of the glycine ethyl ester: compounds.
Example 92 5-Chloro-3-ethyloxypyridine-2-carboxylic acid glycylamide Example 93 5-Chloro-3-methyloxypyridine-2-carboxylic acid glycylamide Example 94 5-Cyclohexyloxymethyl- 3-methoxypyridine-2-carboxylic acid glycylamide -78 Example (3 -Methylbutyl) oxymethyl-3-methoxypyridine-2-carboxylic acid glycylamide Example 96 5-Eenzyloxymethyl-3-ethyloxypyridine-2.-carboxylic acid glycylamide Example 97 3- ((Cyclohexyl)methyloxy)pyridine-2-carboxyJlic acid glycylaiide Example 98 3- ((2-Cyclohexyl) ethyloxy)pyridine-2-carboxylic acid glycylamide Example 99 3- ((3-Cyclohexyl)propyloxy)pyridine-2-carboxylic acid glycylamide Example 100 3- (3-Methylbutyloxy)pyridine-2-carboxylic acid glycylami de Example 101 3-Hexyloxypyridine-2-carboxylic acid glycylamide ~:.Example 102 3- (4-Ethylbenzyloxy)pyridine-2-carboxylic acid glycylazide 5 Example 103 25 3- (4-Propylbenzyloxy)pyridine-2-carboxylic acid glycyl- :amide Example 104 3- (4 -Butylbenzyloxy) pyri dine- 2 -carboxylic acid glycylamide
I
79 Example 105 3-(4-tert-Butylbenzyloxy)pyridine-2-carboxylic acid glycylamide Examples 106 to 188 were prepared in analogy with Examples 80 to 91.
Example 106 5-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridine-2carboxylic acid glycylamide a) 3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic acid In analogy with Example 81c), 3.5 g (146 mmol) of sodium were dissolved in 350 ml of 2-methyl-l-propanol (isobutyl alcohol) and after thait 13.7 g (55 mmol) of 3-chloropyridine-2-carboxylic acid ethyl ester ylic acid methyl ester (prepared in analogy with Example 81b)) were added at 20 0 C and while stirring. The mixture *0e.
was then stirred at 80 0 C for 90 minutes and, after cooling, concentrated in vacuo; the residue was taken up in 200 ml of 1 N methanolic NaOH and this mixture was 20 stirred at 20 0 C. After 15 minutes, the solution became cloudy. Water was added until a clear solution was obtained and this was stirred for 1 hour and then concentrated in vacuo; the aqueous solution was acidified with aqueous hydrochloric acid and the crystalline product was filtered off with suction, washed and dried, and 10.6 g of dicarboxylic acid were obtained, m.p. 192°C (decomp.).
b) Dimethyl 3-(2-methyl-1-propyloxy)pyridine-2,5-dicar- .o boxylate The oily product was obtained from the above dicarboxylic acid under esterification conditions (methanol/sulfuric acid) and after working up (washing with water and extracting with ethyl acetate).
-o c 80 c) 5-Methoxycarbonyl-3- (2-methyl-l-propyloxy)pyridine- 2-carboxylic acid (glycyl benzyl ester) amide 0.48 g (12 mmol) of NaOH, dissolved in 50 ml of methanol, was added to 3.2 g (12 mmol) of the above diester in 25 ml of methanol, and the mixture was stirred at 65 0
C
for 90 minutes. The mixture was then acidified, while being cooled, with dilute aqueous hydrochloric acid and freed from methanol in vacuo. 2.5 g (10 mmol) of the monoester mixture thus obtained were stirred, in analogy with Example 90b), in 250 ml of dichloromethane, at for 24 hours, together with 3.4 g (10 mmol) of glycine benzyl ester tosylate, 1.4 g (10 mmol) of l-hydroxy-(1H)benzotriazole, 2.6 ml (20 mmol) of N-ethylmorpholine and 4.3 g (10 mmol) of CMC.
The undissolved material was then filtered off with suction and the filtrate was extracted with an aqueous solution of Na bicarbonate, with dilute hydrochloric acid and with water; the organic phase was dried and concentrated and the residue was chromatographed on silica gel 20 using n-heptane/ethyl acetate 0.8 g of colorless product was obtained from appropriate fractions, m.p. 103 to 105°C. 1.1 g of the isomeric resinous product were also obtained.
d) The title compound was obtained by dissolving 0.7 g of the above compound in 100 ml of tetrahydrofuran/ methanol and hydrogenating it for 2 hours using Pd on charcoal (10 in a hydrogenation vessel. The catalyst was then filtered off with suction and the filtrate •was concentrated; the residue was crystallized using S 30 diisopropylether and 0.45 g was obtained of the title compound, m.p. approximately 70°C (with foaming).
The isomeric compound was obtained in an analogous manner, m.p. approximately 60 0 C (with foaming, from diisopropyl ether).
81 Example 107 5-Ethoxycarbonyl-3- (2-methyl-1-propyloxy)pyridine-2carboxylic acid glycylamide Example 108 5-Methoxycarbonyl-3- (3-methyl-1-butyloxy)pyridine-2carboxylic acid glycylamide Example 109 5-Ethoxycarbonyl-3-ethoxypyridine-2-carboxylic acid glycylamide Example 110 5-Ethoxycarbonyl-3- (I1-propyloxy) pyri dine 2-carboxylic acid glycylamide Example 111 5-Ethoxycarbonyl-3- (2-propyloxy)pyridine-2-carboxylic acid glycylamide :Example 112 3 -Benzyloxy- 5-ethoxycarbonylpyridine-2 -carboxylic acid glycylamide Example 113 o 20 3- (4-Chlorobenzyloxy) -5-ethoxycarbonylpyridine-2carboxylic acid glycylamide 0 Example 114 5-Ethoxycarbonyl-3- (4-f luorobenzyloxy)pyridine-2carboxylic acid glycylamide Example 115 5-Ethoxycarbonyl-3-(4-(trifluoromethyl)benzyloxy) pyridine-2 -carboxylic acid glycylamide Example 116 5-Ethoxycarbonyl-3- (trifluoromethoxy)benzyloxy) pyridine-2-carboxylic acid glycylamide 82 Example 117 5-Ethoxycarbonyl-3- (2-propyl)benzyloxy)pyridine-2carboxylic acid glycylamide Example 118 3 (4 -Ethoxybenzyloxy) 5 -ethoxyc arbonylpyri dine- 2 -car boxylic acid glycylamide Example 119 5-Ethoxycarbonyl-3- (3 ,4-dimethoxybenzyloxy)pyridine-2carboxylic acid glycylamide Example 120 -Ethoxycarbonyl -3 (2 (4 f luorophenyl) ethyloxy) pyridine 2-carboxylic acid glycylaniide Example 121 -E thoxycarbonyl 3- 2, 2 -tri fluoroethyloxy) pyridine -2 carboxylic acid glycvlamide Example 122 Cyc lohexyloxy- 5 -ethoxycarbonylpyri dine 2 -carboxylic acid glycylamide Example 123 5-Ethoxycarbonyl-3- (naphthyl-2-methyloxy)pyridine-2carboxylic acid glycylamide Example 124 5-Ethoxycarbonyl-3- (naphthyl-l-methyloxy)pyridiiie-2carboxylic acid glycylamide 25 Example 125 5-Carboxy-3 (2 -methyl-1-propyloxy)pyridine-2-carboxylic acid glycylaniide The title compound was obtained by hydrolyzing 0.3 g of thie title compound from Example 106, at 20 0 C, in 50 ml of a IN methanolic solution of sodium hydroxidle. After 1 hour, the mixture was concentrated in vacuo and 83 extracted with diethyl ether; the aqueous phase was~ acidified, while being cooled, with aqueous hydrochloric acid; the aqueous phase was concentrated and then freed from water azeotropically using ethyl acetate and the residue was treated with acetone; the solution was concentrated and the residue was crystallized using petroleum ether. 0.27 g of product was obtained, m.p.
0 C (with foaming).
Example 126 5-Carboxy-3- (3-methyl-l-boutyloxy)pyridine-2-carboxylic acid glycylamide Example 127 5-Carboxy-3-ethoxypyridine-2-carboxylic acid glycylamide Example 128 5-Carboxy-3-propyloxypyridine-2-carbzx-ylic acid glycylam id e :Example 129 5-Carboxy-3- (>p-,ropyloxy)pyridine-2-carboxylic acid glycylamide Example 130 o 3-Benzyloxy-5-carboxypyridine'-2--carboxtylic acid glycylamide Example 131 3- (4-chlorobenzyloxy) -2-carboxyli-*c acid glycyl- 25 amide Example 132 5-Carboxy-3 fluorobenzyloxy) pyridine-2 -carboxylic acid glycylamide Example 133 5-Carboxy-3- ((4-trifluoromethyl)benzyloxy)pyridine-2carboxylic acid glycylamide 84 Example 134 5-Carboxy-3- ((4-trifluoromethoxy)benzyloxy) pyridine-2carboxylic acid glycylamide Example 135 5-Carboxy-3- (2-propyl)benzyloxy)pyridine-2-carboxylic acid g'lycylamide Example 136 5-Carboxy-3 -(4-ethoxybenzyloxy) pyridine-2 -carboxylic acid glycylamide Example 137 -Carboxy-3- (3 ,4-dimethoxybenzyloxy) pyridine-2-carboxylic acid glycylamide Example 138 5-Carboxy-3- (4-fluorophenyl)ethyloxy)pyridine-2carboxylic acid glycylamide Example 139 5-Carboxy-3-(2,2,2-trifluoroethyloxy)pyridine-2carboxylic acid gy'Acylamide Example 140 5-Carboxy-3-cyclohexyloxypyridine-2-carboxylic acid ~000glycylamide Example 141 5-Carboxy-3- (naphthy1-2-methyloxy)pyridine-2-carboxylic acid glycyla:.nide Example 142 5-Carboxy-3 (naphthyl-1-methyloxy)pyridine-2-carboxylic acid glycylamide Example 143 (3 -Pentyloxy) carbonyl- 3- (2 -ms-.thy- 1-propyloxy) pyridine- 2-carboxylic acid glycylamide 85 Example 144 (3-Pentyloxy) carbonyl-3- (3-methyl-1-butyloxy)pyridinei- 2-carboxylic~ acid glycylamide Example 145 3-Eths:xypyridine-5- (3-pentyloxy) carbonyl-2-carboxylic acid glycyJlamide Example 146 (3-Pentyloxy) carbonyl-3-propyloxypyridine-2 -carboxylic acid glycylam-dde Example 147 (3-Pentyloxy) carbonyl-3- (2-propyloxy)pyridine-2carboxylic acid glycylamide Example 148 (3-pentyloxy) carbonylpyridizne-2-carboxylic acid glycylamide Example 149 3- (4-Chlorobenzyloxy) (3-pentyloxy) carbonylpyridine-2carboxylic acid glycylamide, Example 150 3 (4 -Fluorob enzyl oxy) 5- (3 -pen tyl oxy) c arbonylpyr idine -2 ::::*carboxylic acid glycylamide Example 151 (3 Pen tyl oxy) c arbonyl -3 (4 -tri fluorome thyl) benzyl oxy) pyridine-2-carboxylic acid glycylamide Example 152 (3-Pentyloxy) carbonyl-3- ((4-trifluoromethoxy)benzyloxy) pyridine-2-carboxylic acid glycylaniide Example 153 3 -P en ty 1oxy) car b onyl1- 3 r opyl1)b e nz yl1oxy) pyridine-2-carboxylic acid glycylamide 86 Example 154 3 (4 -Ethoxybenzyloxy) 5- (3 -pentyloiyr) carbonylpyridine-2 carboxyl.ic acid glycylamide Example 155 3- (3,4-Dimethoxybenzyloxy) (3-pentyloxy)carbonyl' pyridine-'2-carboxylic acid glycylamide Example 156 3- (4-Fluorophenyl) ethyloxy) (3-pentyloxy) carbonylpyridine-2 -carboxylic acid glycylamide Example 157 (3-Pentyloxy)carbonyl-3- (2,2,2-trifluroethyloxy) pyridine-2 -carboxylic acid glycylamide Example 158 (3-pentyloxy)carbonylpyridine-2carboxylic acid glycylamide Example 159 3- (Naphthyl- 2-methyloxy) (3-pen, -yloxy) carbonylpyridine- 2-carboxylic acid glycylamide Example 160 3 (Naph thyl -1 me thyl oxy) 5- (3 pentyl oxy) c arbonylpyridine 2-carboxylic acid glycylamide Example 161 C: 5- (4-Heptyloxyll carbonyl-3- (2-methyl-1-propyloxy)pyridine- 2-carboxylic acid glycylamide Example 162 (4-Herptyloxy) carbonyl-3-ethoxypyridine-2-carboxylic acid glycylaxnide Examplo 163 3-Benzyloxy- 5- (4-heptyloxy) carbonylpyridiLne- 2-carboxylic acid glycylamide 87 Example 164 3 (4 -Chlorobenzyloxy) 5- (4 -heptyloxy) c arbonylpyri dine -2 carboxylic acid glycylamide Example 165 3- (4-Fluorobenzyloxy) (4-heptylcixy)pyridine-2carboxylic acid glycylamide Example 166 (4-Heptyloxy)carbonyl-3-(4- (2-propyl)benzyloxy)pyridine-2 -carboxylic acid glycylamide Example 167 3- (2-Methyl-l-propyloxy) (5-nony) -xy) carbonylpyridine- 2-carboxylic acid glycylamide Example 168 (5-nonyloxy) carbonyl) pyridine-2-carboxylic acid glycylamide Example 169 3- (4-Fluorobenzyloxy) (5-nonyloxy) carbonylpyridine-2carboxylic acid glycylamide Example 170 5 (5 -Nonyl oxy) c arbonyl 3- (4 (2 -propyl) benzyl oxy) pyr idine 2-carboxylic acid glycylamide Example 171 5-Geranyloxycarbonyl-3-ethoxypyric~ine-2-carboxylic acid glycylamide Example 172 (gearanyloxycarbonyl) pyridine-2-carboxylic acid glycylamide Example 173 3- (4-Chlorobenzyloxy) (geranyloxycarbonyl)pyridine-2carboxylic acid glycylamide 88 Example 174 3- (4-Fluorobenzyloxy) (geranyloxycarbonyl)pyridine-2carboxylic acid glycylamide Example 175 5-Geranyloxycarbonyl-3 (2 -propyloxy) pyridine-2 -carboxylic acid glycylamide Example 176 5-Farnesyloxycarbonyl-3- (2-propyloxy)pyridine-2-carboxylic acid glycylaniide Example 177 (farnesyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 178 5-Farnesyloxycarbonyl-3- (4-f luorobenzyloxy)pyridine-2- 25 carboxylic acid glycylamide Example 179 5-Farnesyloxycarbonyl-3-ethoxypyridine-2-carboxylic acid glycylamide Example 180 20 3-Methc"--y-5- (retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 181 3 -Ethoxy-5- (retinyloxycarbonyl) pyridine-2 -carboxylic acid glycylamide Example 182 3- (2-Propyloxy) -5-(retinyloxycarbonyl)pyridine-2carboxylic acid glycylamide 89 Example 183 (retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 184 3- (4-Fluorobeanzyloxy') (retinyloxcycarbonyl)pyridine-2carboxylic acid glycylamide Example 185 3 (3 -Methoxybenzyloxy) 5- (retinyloxycarbonyl) pyridine- 2 carboxylic acid glycylamide Example 186 Benz)yloxycarbonyl -3 (4 (2 -propyloxy) benzyloxy) pyridine 2-carboxylic acid glycylamide Example 187 -Benzyloxyc arbonyl -3 (4 -f luorobenzyloxy) pyridine- 2 -car 15 boxylic acid glycylamide Example 188 5-Butyloxycarbonyl-3-benzyloxypyridine-2-carboxylic acid glycylamide Example 189 5- (((4-Ethoxyphenyl) amino) carbonyl) -3-methoxypyridine-?o carboxylic acid glycylamide, analogously, to Example 191 Example 190 (((4-Ethoxyphenyl) amino) carbonyl) -3-benzyloxy-pyridine- 2-carboxylic acid glycylamide Example 191 (l-Butyloxy)phenyl)amino)carbonyl) -3-methoxypyridine-2 -carboxylic acid glycylamide a) Methyl 5 (1l-butyloxy) phenyl) amino) carbonyl) -3 me thoxcypyra dine -2 -carboxylate 90 3.2 g (15 mmol) of methyl 5-carboxy-3-methoxypyridine-2carboxylate (cf. Example 90a)) were reacted, in analogy with Example 90b), with 2.5 g (15 mmol) of 4-n-butoxyaniline and the reagents described in that example. 3.9 g of product were crystallized using diethyl ether (m.p.
138 to 141°C.
S 5- (1-Butyloxy)phenyl)amino) carbonyl) -3-methoxypyridine-2-carboxylic acid 3.2 g of the above ester were hydrolyzed at 20°C using 100 ml of 15 N methanolic sodium hydroxide solution.
2.7 g of product were obtained from aqueous hydrochloric acid, m.p. 128 to 130 C, sintering from 1200C.
c) 5- (1-Butyloxy)phenyl) amino) carbonyl) -3-methozypyridine-2-carboxylic acid N-((ethoxycarbonyl)- 15 methyl) amide 2.7 g (7.8 mmol) of the above pyridine-2-carboxylic acid were stirred in 500 ml of anhydrous dichloromethane, at 20 0 C for 24 h, together with 1.1 g (7.8 mmol) of glycine ethyl ester hydrochloride, 3.0 ml (23.4 mmol) of N- 20 ethylmorpholine, 1.2 g (8.6 mmol) of l-hydroxy-lH-benzotriazole and 3.3 g (7.8 mmol) of CMC.
S. The undissolved material was then filtered off and the organic phase was extracted sequentially with 200 ml each of water, aqueous Na bicairbonate solution, IN aqueous 25 hydrochloric acid and water, dried over Mg sulfate and concentrated in vacuo; the residue was crystallized using diethyl ether. 2.4 g of p;:oduct were obtained, m.p. 193- 195 0
C.
d) The title compound was obtained by hydrolyzing 1.0 g of the above glycine ester, at 20°C, in 100 ml of a 1.5 N methanolic solution of sodium hydroxide. After 30 min, the mixture was 6oncentrated in vacuo and the residue was dissolved in water; this solution was extracted with
,I
91 diethyl ether and the aqueous solution adjusted to PH 3 using aqueous hydrochloric acid. When the solution was cooled with ice, 390 mg of the title compound crystallized, m.p. 230WC, sintering at 193*C.
Example 192 (1-Butyloxy)phenyl)amino)carbonyl) (4-fluorobenzyloxy) pyridine-2-carboxylic acid glycylamide Example 193 (l-Butyloxy)phenyl) amino) carbonyl) -3-benzyloxypyridine-3-carboxylic acid glycylamide Example 194 3- (2-Methyl-l-propyloxy)pyridine-2, 5-dicarboxylic acid diglycylamide M.P. 103-105WC (from ethyl acetate) Example 195 sees 5 (Di N- ethylaminocarbonyl) 3 -ethoxypyridine- 2 -car boxylic acid glycylanide, amorphous substance, prepared in analogy with Example 223 using N,N-diethylamine.
Example 196 5- (N-Benzyl-N-methylaminocarbonyl) -3-methoxypyridine-2carboxylic acid glycylamide a See 0:Example 197 5-Farnesyloxycarbonyl-3-methoxypyridine-2 -carboxylic acid *see.:glycylamide Example 198 5-Geranyloxycarbonyl-3-methoxypyridine-2-carboxylic acid glycylamide Example 199 (Farnesyloxymethyl) -3 -methoxypyridine-2 -carboxylic acid glycylamide 92 Example 200 (Geranyloxymethyl) -3-methoxypyridine-2-carboxylic acid glycylaniide Example 201 5-Retinyloxymethyl-3-methoxypyridine-2-carboxylic acid glycylamide Example 202 5-Retinyloxymethyl-3-ethyloxypyridine-2-carboxylic acid glycylamide Example 203 N- (C-rboxymethyl) -4-methoxycinnoline-3 -carboxamide Examples 204 to 209 were prepared in analogy with Example 191: Example 204 15 5- (l-Hexyloxy)phenyl) amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl)amide a) Methyl 5- (l-hexyloxy)phenyl) amino) carbonyl) -3methoxy-2-carboxylate was prepared from methyl carboxy 3-methoxypyridine -2 carboxylate and 4 -hexyl oxyaniline, m,p. 118-119 0 C (from diethyl ether).
-:goo: b) 5- (4 Hexyl1oxy) phenyl) ami no) carbonyl) 3-me thoxy pyridine-2-carboxylic acid, 160-162*C, sintering at *60:14 8 0 C (f rom aqueous hydrochloric acid! tetrahydrofuran) c) 5- (1-Hexyloxy)phenyl) amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N- ((ethoxycarbonyl) methyl)amide was obtained, in analogy with Example 191c), from 4.2 g of the above compound. 4.0 g of product were crystallized using ethyl acetate, m.p.
157-159 0
C.
93 d) The title compound was obtained by hydrolyzing 1.2 g of the above ester, at 20 0 C, using 100 ml of a methanolic solution of sodium hydroxide. Following concentration in vacuo, acidification to pH 1 took place in water/tetrahydrofuran using aqueous hydrochloric acid; the mixture was concentrated in vacuo and the residue was crystallized using acetone. 840 mg of product were obtained, m.p. 193-195 0
C.
Example 205 5-(((4-(1-Decyloxy)phenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Example 206 (1-Decy)pl)phenyl)amino)carbonyl) -3-methoxypyridine- 2-carboxylic acid N-(carboxymethyl)amide a) 5-(((4-(1-Decyl)phenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid N-((ethoxycarbonyl)methyl)amide was prepared from 5-(((4-n-decylphenyl) amino) carbonyl) -3-methoxypyridine-2carboxylic acid 160 0 C (decomp.); from aqueous hydrochloric acid/THF) and glycine ethyl ester hydrochloride, m.p. 155-157 0 C (from diisopropyl ether) b) The title compound was obtained by hydrolyzing 1.5 g of the above ester in 200 ml of a 1 N methanolic solution of sodium hydroxide. 1.4 g of product, m.p.
195 0 C (decomp.), were isolated from aqueous hydrochloric acid/tetrahydrofuran.
Example 207 (((4-Geranyloxyphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide 94 Example 208 (1-octyloxy)phenyl) amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl)amide Example 209 5- (1-Octyloxy)propyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid N- (carboxymethyl)amide Example 210 (1-Butoxy) methyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl) amicia Example 211 (1l-Hexyloxy) methyl) 3-me thoxypyri dine- 2 -carboxylic acid N- (carboxymethyl)amide Example 212 (1-Octyloxy)methyl) -3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Example 213 ((l-Hex-3-enyloxy)methyl)-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Example 214 20 5- ((l-Decyloxy)methyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl) amide Example 215 (1-Dodecyloxy)methyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl) amide Example 216 ((1-Hexadecyloxy) methyl) -3-methoxcypyridine-2-carboxylic acid N- (carboxymethyl) amide Example 217 3 (4 Dehydroabietylaxaino) carbonyl) benzyloxy) pyri dine-2-carboxylic acid N- (carboxymethyl) amide 95 a) 4 Dehydroab ie tyl amino) carbonyl) chioromethylbenzene was obtained from 4-chloromethylbenzoic acid and (+)-dehydroabietylamine, m.p. 170-172*C (from ethyl acetate/heptane b) 3 (4 -Dehydroabietylamino) carbonyl) benzylioxy) pyridine-2-carboxylic acid N- ((ethyloxycarbonyl) methyl)amide, m.p. approximately 800C (amorphous substance, from ethyl acetate).
c) The title compound was obtained by hydrolyzing the above ester, m.p. 125 0 C (with foaming, from diisopropyl ether).
Example 218 3-Methoxyquinoline-2-carboxylic acid N- (carboxymethyl) amide a) 2-Acetyl-3-hydroxyquinoline, known from D.W. Bayne et al., J. Chem. Soc. Chem. Comm. 1975, 782 (M.p.
1061~C from aqueous hydrochloric acid).
b) 2-Acetyl-3-xnethoxyquinoline, fromu a) using potassium carbonate/methyl iodide in acetone, oily crude product.
c) 3-Methoxyquinoline-2-carboxylic acid, from b) using potassium hypochlorite in water/dioxane, m.p. 123*C (from methyl tert-butyl ether).
d) 3-Methoxyquinoline-2-carboxylic acid N- ((methoxy- :25 carbonyl) methyl) amide, from c) using DCC, HOET, TEF, .~.NEM and glycine methyl ester hydrochloride.
e) The title compound was obtained by hydrolyzing the above ester, m.p. 106*C (from ethyl acetate).
M
96 Example 219 (1 -Butyloxy)phenyl) amino) carbonyl) -3-chioropyridine-2-carboxylic acid N- (carboxymethyl)amide a) Methyl 5-carboxy-3-chloropyridine-2-carboxylate was prepared in analogy with Example 90a), m.p. 182- 1840C (from aqueous hydrochloric acid).
b) Methyl 5-C( (1-butyloxy)phenyl) amino) carbonyl) -3chloropyridine-2-carboxylate was obtained from the above compound using oxalyl chloride and 4- (1-butyloxy)aniline, m.p. 121-123 0 C (from diethyl ether).
c) 5- (1-Butyloxy)phenyl) amino) carbonyl) -3-chioropyridine-2-carboxylic acid by hydrolyzing the product from b) m.p. 163-164 0 C (from aqueous hydrochloric acid).
d) 5- (1-Butyloxy)phenyl)amino) carbonyl) -3-chioropyridine-2-carboxylic acid N- ((ethyloxycarbonyl) methyl) amide was obtained, in analogy with Example from the above substance by condensation (Nethylmorpholine, l-hydroxy-lH-benzotriazole and CMC) with glycine ethyl ester hydrochloride, m.p. 177- 1790C (from ethanol).
The title compound was obtained by hydrolyzing the above ester, m.p. 1900C (with decomposition, from aqueous hydrochloric acid).
Example 220 3- (N-Benzyl-N-methylamino) (l-butyloxy)phenyl) amino) carbonyl)pyridine-2-carboxylic acid N-(carboxymethyl) amide g (1.23 mmol) of the title compound from Example 219 was stirred in 10 ml of N-benzyl-N-methylaraine, firstly at 100-110WC for 2 h and then at 130 0 C for a further 2 h.
After the mix.ture had been cooled down, it was introduced 97 into 100 ml of IN hydrochloric acid and the halfcrystalline precipitate was taken up in dichlorcmethane; the undissolved material was filtered off and the residue was crystallized; 0.2 g of the title compound, m.p. 155- 157°C.
Example 221 3-(N-Benzylamino)-5-(((4-(l-butyloxy)phenyl)amino)carbonyl)pyridine-2-carboxylic acid N-(carboxymethyl) amide g (1.23 mmol) of the title compound from Example 219 was stirred in 10 ml of benzylamine, firstly at 120°C for 2 h and then at 135°C for 1.5 h. After the mixture had been cooled down, it was acidified and the precipitated resin was dissolved in dichloromethane; this solution was dried and concentrated and the residue was chromatographed on silica gel using ethyl acetate (with the addition of up to 20 methanol). 0.1 g of the title compound was crystallized from appropriate fractions using diisopropyl ether, m.p. 185-190*C.
Example 222 20 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid N- (carboxymethyl)amide 1-oxide 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) was dissolved in dichloromethane and reacted with 1.41 g of 3-chloroperbenzoic acid. After the mixture had been stirred at 20°C for 1 h, ammonia was passed in until there was no further precipitation; the precipitate was filtered off and the filtrate was concentrated and the oily residue crystallized using diethyl ether, m.p. 70-72°C.
b) 0.18 g of the title compound, m.p. 206-208°C _ill 98 (sintering at 200°C, from aqueous hydrochloric acid) was obtained by hydrolyzing 0.3 g of the above compound.
Example 223 5- (1-Butyloxy)propyl)amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide a) Methyl 5-(((3-(l-butyloxy)propyl)amino)carbonyl)-3methoxypyridine-2-carboxylic acid 1.7 ml of oxalyl chloride (20 mmol), and also 2 drops of N,N-dimethylformamide, dissolved in tetrahydrofuran, were added dropwise, at 10 0 C and while stirring, to 2.1 g mmol) of methyl 5-carboxy-3-methoxypyridine-2-carboxylate in 100 ml of anhydrous tetrahydrofuran and the reaction mixture was stirred at 10°C for 30 min and at 20 0 C for 1 h. It was then concentrated and the residue was dissolved in dichloromethane; 6.8 ml (50 mmol) of triethylamine, and then 1.3 g (1.5 ml, 10 mmol) of 3butoxypropylamine, dissolved in dichloromethane, were added, at 0°C, to this solution.
20 After 30 min, the mixture was allowed to warm to room temperature and was extracted with water, a solution of Na bicarbonate and aqueous IN HC1; the organic phase was dried and concentrated and the residue was crystallized using diethylether/petroleum ether 2.3 g of product were obtained, m.p. 51-53 0
C.
b) 5-(((3-(l-Butyloxy)propyl)amino)carbonyl)-3-methoxy- •pyridine-2-carboxylic acid N-((benzyloxycarbonyl)- *methyl)amide The above substance was hydrolyzed by standard procedures, and 1.5 g (5 mmol) of the amorphous butyloxy) propyl)amino)carbonyl)-3-methoxypyridine-2carboxylic acid, which was dried on an oil pump, was reacted with glycine benzyl ester tosylate, I' 99 N-ethylmorpholine, 1-hydroxy-1H-benzotriazole and CMC (as described) 1.42 g of the product were crystallized using acetone, m.p. 97-990C.
C) 1.3 g of the above benzyl ester were hydrogenated in 100 ml of tetrahydrofuran/methanol using Pd/C in a hydrogenation vessel. 0.8 g of the title compound was crystallized using diethyl ether, m.p.
155-157 0
C.
Example 224 5- (l-Lauryloxy)propyl) amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl)amide a) 5- (((3-Lauryloxypropyl) amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N- ((benzyloxycarbonyl) methyl)amide was obtained, in analogy with Example 223, using 3-lauryloxypropylamine, m.p. from 109-111'C (from diisopropyl ether:).
b) 1.3 g of the above benzyl ester were hydrogenated as described under 223c). 0.9 g of the title compound were obtained from petroleum ether, m.p. from 120WC.
Example 225 -Methoxyethyl) amino) carbonyl) -3 ethoxypyridine-2 carboxylic acid N- (carboxymethyl)amide The title compound was prepared in analogy with Example 223 using 2-methoxyethylamine.
25 a) 5- (2 -Methoxyethyl) amino) carbonyl) -3 -methoxypyri 2dine- 2 -carboxylic acid, m.p. 160-161WC (with gas evolution, from ethyl acetate) b) 5- (((2-Methoxyethyl) amino) carbonyl) -3-methoxypyridine-2-carboxylic acid N- ((benzyloxycarbonyl) methyl)amide was crystallized using diisopropyl ether, m.p. 129-131*C.
100 c) The title compound was obtained, as above, from the benzyl ester, m.p. 186-1880C (from diethyl ether).
Example 226 N-(3-Benzyloxypyridyl-2-carbonyl)alanine racemate, M.p. 186-187 0 C (from pentane/ethyl acetate) Example 227 N-(3-Benzyloxypyridyl-2-carbonyl)-L-phenylalanine, M.p. 100-1010C (from pentane/ethyl acetate).
Example 228 5- ((1-Butyloxy) carbonyl) -3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide trifluoroacetate a) Di-(1-butyl) 3-methoxypyridine-2,5-dicarboxylate g of dimethyl 3-methoxypyridine-2,5-dicarboxylate (cf. Example 90a)) were dissolved in 100 ml of 1-butanol, 15 and after that 1.5 ml of cone. sulfuric were added and the mixture was heated to boiling for 2 h, with a part of S. the solvent being distilled off. After the mixture had been cooled, it was concentrated in vacuo and the residue was taken up in dichloromethane; this solution was extracted with a saturated, aqueous solution of Na bicarbonate and the organic phase was dried and concentrated. 6 g of oily crude product.
b) Bis[5-((l-butyloxy)carbonyl)-3-methoxypyridine-2carboxylic acid]-Cu(II) complex 25 6 g (20 mmol) of the above product were added, dissolved in 10 ml of methanol, to a solution of 4.8 g (20 mmol) of Cu(II) nitrate x 3 H20 in 100 ml of methanol, and the mixture was heated to boiling for 4 h. It was then cooled down to 0-5 0 C and the crystalline precipitate was filtered off with suction and washed with diethyl ether.
4.2 g of blue-green, crystalline product were obtained, m.p. 2670C (with decomposition).
101 c) 5-((1-Butyloxy)carbonyl)-3-methoxypyridine-2-carboxylic acid 4 g of the above Cu comp ex were suspended in 75 ml of 1,4-dioxane H 2 S gas was passed in, while the mixture was being stirred, for 30 min, and the sediment (CuS) which had precipitated out was filtered off with suction through kieselguhr and then washed with 1,4-dioxane (continued introduction of H 2 S did not lead to any further precipitation); the filtrate was concentrated in vacuo. The residue was crystallized using petroleum ether, m.p. 96-98 0
C.
d) 5- ((1-Butyloxy)carbonyl)-3-methoxypyridine-2carboxylic acid N-((tert-butyloxycarbonyl)methyl)amide 0.76 g (3 mmol) of the above pyridinecarboxylic acid was condensed with 0.52 g (3 mmol) of glycine tert-butyl ester hydrochloride, 1.2 ml (9 mmol) of N-ethylmorpholine, 0.45 g (3.3 rmol) of l-hydroxy-(1H)-benzotriazole 0* and 1.3 g (3 mmol) of CMC. 0.8 g of product was obtained, 20 m.p. 50-52°C (from petroleum ether).
*o e) The title compound was obtained by adding 2.7 ml of trifluoroacetic acid, at 20 0 C, to 0.4 g of the above tert-butyl ester in dichloromethane. After 20 h, the mixture was concentrated in vacuo and 0.2 g was obtained of the colorless, crystalline, strongly hygroscopic product, which, on being filtered off with suction, deliquesced on the suction filter.
Example 229 3 -methoxypyridine-2-carboxylic acid N- (carboxymethyl) amide Example 230 (1-propyloxy)carbonyl)pyridine-2-carboxylic acid N-(carboxymethyl)amide 102 Example 231 ((1-Hexyloxy) carbonyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl)amide Example 232 3-Methoxy-5- ((1-pentyloxy) carbonyl)pyridine-2-carboxylic acid N- (carboxymethyl) amide Example 233 ((1-Heptyloxy) carbonyl) -3-methoxypyridine-2-carboxylic acid N- (carboxymethyl)aniide Example 234 (1-octyloxy) carbonyl)pyridine-2-carboxyl3 acid N- (carboxymethyl)amide Examples 235-238 were prepared in an analogous manner to Example 228 proceeding from 3-(2-propyloxy)pyridine-2,5dicarboxylic acid or the corresponding dialkyl esters.
*O Example 235 :5-Ethyloxycarbonyl-3- (2-propyloypyridine-2-carboxLylic acid N-(carboxymethyl)amide Example 236 5- ((1-Butyloxy)carbonyl) (2-propyloxy)pyridine-2carboxylic acid N- (carboxymethyl) amide o Example 237 ((1-Hexyloxy) carbonyl) -3-'(2-propyloxy)pyridine-2carboxylic acid N- (carboxyxnethyi)amide O 25 Example 238 ((-1-octyloxy:) carbonyl) (2-propyloxy)pyridine-2carboxylic acid N- (carboxymethyl) amide Example 239 5-Carboxy-3- (methylthio)pyridine-2-carboxylic acid N- (carboxymethyl)amide disodium salt 103 a) 3-(Methylthio)pyridine-2,5-dicarboxylic acid 4.6 g (12 mmol) of dibenzyl 3-chloropyridine-2,5-dicarboxylate were dissolved, at 20°C and while stirring, in ml of dimethyl sulfoxide, and after that 5.0 g (70 mmol) of sodium thiomethoxide were added, in association with which the temperature rose to 80°C. The reaction mixture was heated at 140 0 C for 1 h and then cooled down; water was added and the oily layer was separated off; cone. hydrochloric acid 1) was added to the aqueot,, DMSO phase and the precipitated product was filtered off with suction. 2.8 g were obtained of a yellow crystalline product, m.p. 223°C (with decomposition).
b) Dimethyl 3-(methylthio)pyridine-2,5-dicarboxylate 50 ml of 1,4-dioxane, 40 ml of tetrahydrofuran and 0.5 ml of cone. sulfuric acid were added to 2.8 g of the above comr-'und in 150 ml of methanol, and the mixture was heated to reflux for 2 h, during which time a solution was formed. After the solution had been cooled down, it 20 was concentrated in vacuo and 100 ml of an aqueous solution of Na bicarbonate were added to the residue; the latter mixture was extracted with dichloromethane and the organic phase was dried and concentrated. 1.4 g were •obtained of the yellow, crystalline product, m.p. 103- 105 0
C.
'o c) 5-Methoxycarbonyl-3- (methylthio)pyridine-2carboxylic acid-Cu(II) complex 1.3 g of the above dimethyl 3-methylthiopyridine-2,5dicarboxylate were reacted in analogy with Example 228b).
1.3 g of greenish/crystalline product were obtained, m.p.
330 0
C.
d) 5-Methoxy-3-(methylthio)pyridine-2-carboxylic acid 104 1.3 g of the above compound were reacted in analogy with Example 228c), 0.72 g of product, m.p. 183-185°C.
e) 5-Methoxycarbonyl-3- (methylthio)pyridine-2carboxylic acidN- ((1-butyloxy) carbonyl) me yl) amide The compound was obtained by condensing 0.68 g (3 mmol) of the above pyridinecarboxylic acid with 0.91 g (3 mmol) of glycine 1-butyl ester tosylate (1-hydroxy-1H-benzotriazole, N-ethylmorpholine and CMC). 0.55 g of pale yellow product was obtained, m.p. 47-49°C (from petroleum ether).
f) The title compound was obtained by hydrolysing 0.45 g (1.3 mmol) of the above ester using 50 ml of 1 N methanolic NaOH. The clear yellow solution became cloudy after 30 min. After 2 h, the precipitate was filtered off with suction, washed twice with methanol and dried in vacuo. 0.32 g of the title compound was obtained, m.p.
345°C (decomp.).
O*
*a 00*0 a I- 9
Claims (13)
- 2. A compound as claimed in claim 1 wherein the substituent -O-[CH 2 ]x- CfH(2f+i-g)Halg of A when it is (C 1 -C4)-alkylene is selected from the group consisting of: (Ci -C8)-fluoroalkoxy, (Ci -C8)-fluo roalkenyloxy, (Ci -Ca)-fluo roalkenyloxy, -OCF 2 CI or -O-CF 2 CHFCI, (Ci -C 6 )-alkylmercapto, (Ci -C 6 )-alkylsulfinyl, (Ci -C 6 )-alkylsulfonyl, (Ci -C 6 )-alkylcarbonyl, (Cl-C 6 )-alkoxycarbonyl, :carbamoyl, N-(Cl-C4)-alkylcarbamoyl, N,N-di-(Cl-C4)-alkylcarbamoyl, (Ci -C 6 )-alkylcarbonyloxy, (C 1 -C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C 1 -C 4 )-alkylsulfamoyl or N,N-di-(Cl- C 4 )-alkylsulfamoyl.
- 3. A compound of the formula I as claimed in claim 1 or 2 in which Q is0, S, NR'or abond, X :isO0, Y is CR 3 or, if R 1 and R 2 form a cycle, Y is N or CR 3 m is 0ori1.
- 4. A compound of the formula I as claimed in any one of claims 1 to 3, in which o is 0, NR' or a bond, and X is 0. A compound of the formula I as claimed in any one of claims 1 to 3, in which I1 Qis S,and 123a X is 0, and misO or 1.
- 6. A compound of the formula I as claimed in any one of claims 1 to 3 and in which QisS, X is 0, and m is0.
- 7. A compound of the formula I as claimed in any one of claims 1 to 4, in which 'Q is O, NR' or a bond, Xis O, SY is CR 3 or, if R 1 and R 2 form a cycle, N or CR 3 m is 0 or 1, 124 A is (C 1 CO)-alkylene 'hich is optionally substi- tuted once by halog- cyano, trifluoromethyl, -alkyl, -iydroxyalkyl, (C 1 -alkoxy or ECH 2 xCH( 2 f+l-g)FgI or A is -CHRs-, where R 5 is one of the substituents of the ar-carbon atom of an a-amino acid, in particu- lar of a natural L-amino acid and. of its D- isomer, B is CO 2 H, R 2 is hydrogen, (C 1 -C 2 ,)-alkyl, (C 2 -C 20 -alkenyl, C 2 -alkynyl, (C 1 -C 2 0 -alkoxy, (C 2 -C 20 -alkenyloxy, (C 2 -C 2 -alkynyloxy, retinyloxy, (C 1 -C 2 -alkoxy- (C 1 -C 3 -alkyl, (C 2 -C 2 0 -alkenyloxy- (C,-C 3 -alkyl, retinyloxy- (C,-C 3 -alkyl, (C 2 -C 2 0 -alkynyloxy- CO)-alkyl, halogen, cyano, trifluoromethyl, (Cl- C 8 -hydroxyalkyl, (C 1 -C 20 -alkanoyl, (C 7 -C 1 6 aralkanoyl, (C,-C 12 -aroyl, (C.-C 12 -aryl, (C7 C 16 aralkyl, [CU 2 x-CfH( 2 f~l-g)Fgf NR' (C 1 -C 10 alkylmercapto, (C C3. 0 alkyl sul finyl, (C 1 -C 10 alkylsulfonyl, (C6 -C3. 2 -arylmercap to, (C 6 -C 1 2 arylsulfinyl, (C C 1 2 aryl sul fonyl, (C 7 -C3 1 2 aralkylmercapto, (C 7 12 aralkyl sul finyl, (C 7 SC 12 -aralkylsulfonyl, (C,-C 1 2 -aryloxy, (C 7 -C 1 6 aralkyloxy, carboxyl, (C 1 -C 20 -alkoxycarbonyl, (C 1 -C 1 2 -alkoxy- (C 1 -C 1 2 -alkoxycarbonyl, (C 6 -C 1 2 aryloxycarbonyl, (C7-C 16 -aralkoxycarbonyl, (C 3 C 8 ,)-cycloalkoxycarbonyl, (C 2 -C 2 -alkenyl- oxycarbonyl, retinyloxycarbonyl, (C 2 -C 2 0 -alkynyl- *oxycarbonyl, (C 3 -cycloalkyl- alkoxycarbonyl, (C 3 -C 8 -cycloalkoxy- (C3 1 alkoxycarbonyl, (C.-C 12 -aryloxy- (Cl-C 6 -alkoxy- carbonyl, (C 7 -C 1 6 -aralkoxy- (C 1 C 6 -alkoxycarbonyl, carbanioyl, N- (C 1 -C 12 -alkylcarbamoyl, N,N-di- (C 1 C, 2 -alkylcarbamoyl, N- (C 3 -cycloalkyl- cax,'bamoyl, N, N- dicyclo (C 3 -CS) alkylcarbamoyl, 125 N- (C3 1 -C: 10 -alkyl-N- (C 3 -C 8 .cycloalkylcarbanoyl, N- (C 3 -CS) cycloalkyl- (Cl- C.)-alkyl) carbamoyl, N- (C 1 6 -alkyl-N- (C 3 -cycloalkyl- (Cl-C 6 alkyl) carbamoyl, N- -dehyd;.-oabietylcarbamoyl, N- -alkyl-N- W+ -Idc'hydroabietylcarbamoyl, N- (C.-C 1 2 -arylcarbamoyl, N- (C 7 -aralky3l- carbamoyl, N- (C 1 -C 1 -alkyl-N- (C.-C 1 -aryl- carbamoyl, N- 10 -alkyl-N- (C 7 -C, 6 -aralkyl- carbamoyl, N- 1 2 -alkoxy- (C 1 -C 1 0 alkyl) carbamoyl, N- 1 6 -aryloxy- (Cl-C 10 alkyl) carbamoyl, N- ((C 7 -aralk.,loxy- (Cl-C 1 o) alkyl) carbamoyl, N- (Cl-C 1 0 -aJlkyl-N- (C, 1 -C 10 alkoxy- (C 1 -C 10 -a2.kyl) carbamoyl, N- (C 1 -C 1 -alkyl- N- 6 -C3 1 2 -aryloxy- (Cl-C3 1 0 -alkyl) carbamoyl, N- (C 1 -CI 0 -alkyl-N- ((C 7 -C 1 6 -aralkyloxy- (Cl-C 1 0 alkyl)carbamoyl, C>'Hhin which a CH2 group can be replaced by 0, S, N- (Cl-C) -alkylimino, N- (C 3 -C 8 -c-ycloalkylimino, N- (C 3 -cycloalkyl- (Cl-C 4 -alkylimino, N- (C, 6 -C 1 -arylimino, N- (C7- 20 Cl,)-aralkylimino or N- (C3 1 -C 4 -alkoxy- (C 1 Cd) ~:alkylimino, and h is from 3 to 7, where aryl is substituted in the manner as defined f or R1 and R, .R3 and R 3 are identical or different and are hydro- gen, halogen, (CL-Cld)-alkyl, (Cl-Cld)-alkoxy, -0- [CH 2 x-CfH'( 2 f+I-g)HalgI (C 1 Cl.) -alkoxy- (Cl-C 1 2 -alkyl, (Cl-C 8 -alkoxy- (CQ-CI 2 -alkoxy, (C3 1 -C 12 -alkoxy- C 8 ,)-alkoxy- (C 2 -alkyl, (C 7 -C 11 -aralkyloxy, (C 3 C 8 -cycJloalkyl, (C 3 -C 8 -cycloalkyl- (C, 1 -al~kyl, 30 (C 3 -Cd)-cycloalkyloxy, (C 3 -Cd)-cycloalkyl- (CI-C 8 alkoxy, (C 3 -C 8 -cycloalkyloxy- (Cl-C 8 -alkyl, (C 3 -cycloalkyloxy- (C3 1 -alkoxy, (C 3 -C 8 -cyclo- alkyl- (C3 1 -C 6 -alkyl- (C 1 C 6 -alkoxy, (C 3 -C 8 -cyclo- alkyl-~ 6 -alkoxy- -alkyl, (C 3 -CS) cycloalkoxy- 6 -alkoxy- -alkyl, NMR' (C,-C 8 -alkylmercapto, -alkylsulfinyl or (C alkyl sul fonyl, (C,-Cl 2 -arylmercapto, -126 (C.-C 12 -arylsulfinyl, (C.-C 12 -arylsulfonyl, (C 7 C. 2 -aralkylmercapto, (C 7 -C 1 1 -aralkylsulf inyl, (C 7 C 1 aralkyl sul fonyl, substituted (C 6 -C 1 2 aryloxy- (C 1 -alkyl, (C 7 -C 1 1 -aralkoxy- (C,-C 6 alkyl, (C,-C3. 2 -aryloxy- (C 1 -C 6 -alkoxy- alkyl, (C 7 -C: 11 -aralkyloxy- (C 1 -C 6 -alkoxy- alkyl, (C,-C 1 2 -aryloxy, (C 7 -C 1 1 -aralkyloxy, (C 6 C 1 2 -aryloxy- -alkoxy or (C 7 -C 1 1 -aralkoxy- (C 1 -_C 6 -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, (Cl-C 16 -alkyl, (C 1 -C 16 alkenyl, (C 1 -hydroxyalkyl, (C 1 -C 16 -alkoxy, (C 1 -C3. 6 -alkenyloxy, [CH 2 xCfH( 2 fl-g)FgI -OCF 2 Cl, -O-CF 2 -CHFCl, -alkylmercapto, (C 1 -alkyl- sulfinyl, C 6 alkyl sul fonyl, (C 1 -alkyl- carbonyl, (C 1 -C 6 -alkoxycarbonyl, carbaxnoyl, 1W- (C 1 -_C 4 -alkylcarbamoyl, N, N-di (C C 4 alkyl carbamoyl, (Cl-C 6 -alkylcarbonyloxy, (C 3 -C 8 cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NXYRz, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamnoyl, N- -C 4 -a).kylsul- famoyl or N,N-di-~ (Cl-C 4 -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 ECH 2 and/or -CH=CH- CH=CH-, where a CH 2 group of the chain is optionally replaced by 0, S, Sol S02 or NR', R' and R 2 or R 2 and R 3 form a chain [CH 2 J 0 where o is 4 or 5 or form, together with the pyridine or pyridazize carrying them, a cinnoline ring, a quinoline ring or an isoqu~inoline ring, R 4 is, if Q is a bond, fluorine, chlorine or bro- mine, or, if Q is 0 or NR', a branched or 127 unbranched (C 1 -_C 2 0 -alkyl radical, which can con- tain up to 3 c-c multiple bonds, an uxisubstituted saturated fluoroalkyl radical of the formula [CH 2 1 -CfH( 2 a (C, 6 -C 1 -aryl radical or a (C 7 -aralkyl r~adical, which can contain up to 2 C-C multiple bonds i the alkyl chain, or a heteroaryl radical or a heteroaryl alkyl radical, where these radicals are substituted by one or more radicals from the group hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, carboxyl, C. 2 -alkyl, (C 3 -C 8 -cycloalkyl, (C 3 -cycloalkyl- C3. 2 -alkyl, (C 3 -CO) -cycloalkocy, (C 3 -Cd)-cyclo- alkyl- (C 1 -C 1 2 -alkoxy, (C 3 -C 8 -cycloalkyloxy- (C 1 C 1 2 -alkyl, (C 3 -C 8 -cycloalkyloxy- (C 1 -C 1 2 -alkoxy, (C 3 -C 8 -cycloalkyl- (Cl-C 8 -alkyl- (C 1 -alkoxy, (C 3 -C 8 -cycloalkoxy- -alkoxy- -alkoxy, (C,-C 1 2 -aryl, 6 -aralkyl, (C2 -C 12 -alkenyl, (C 2 -C 1 2 -alkynyl, (C 1 2 -alkoxy, (C 1 -C 1 2 -alkoxy- (C C 12 -alkoxy, (C 1 -_C 12 -alkoxy- (C 1 ,-C 8 -alkoxy- (C 1 -alkyl, 2 -aryloxy, (C7., 1 -aralkyloxy, :(C 6 -C 12 -aryloxy- (C 1 -alkoxy, (C7 C 1 -aralcoxy- (C,-C,)-alkoxy, (CI- Ca) -hydroxyalkyl (C 1 C 12 alkylcarbonyl, (C 3 C 8 cyc loa'Lkylcarbonyl, (C 6 -C 1 2 -arylcarbonyl, 16 -aralkylcarbony.l, C 1 2 -alkoxycairbonyl, (C 1 -C3 1 2 -alkoxy- (Cl-C. 2 alkoxycarbonyl, (C 6 C 1 2 aryloxycarbonyl, C 16 -arbonyl, (C 3 -cycloalkoxycarbonyl, C 2 C 12 )-alkenyloxycarbonyl, C 2 -C 12 alky-nyloxycarbonyl, (C 3 -C 8 -cyclioalkyl- (C 1 alkoxycarbonyl, (C3 1 -C, 2 -alkylcarbonyloxy, (C 3 -cycloalkyl- carbonyloxy, (C 6 -C, 2 -arylcarbonyloxy, 16 aralkylc'j ionyloxy, carbamc.--. A- (C.-C 12 -alkylcarbamoyl, N,N-di- (C 1 C 1 2 -alh 1 .y cbamoyl, N- (C 3 -cycloalkyl- 128 carbamoyl, N,N-dicyclo- -alkyJlcarbamoyl, N- (C 1 -C3 1 0 -alkyl-N- (C 3 -C 8 -cycloalkylcarbamoyl, N- ((C 3 -C 8 -cycloalkyl- (C.-C 6 -alkyl)carbamoyl, N- (Cl 1 -alkyl-N- ((C 3 -C 8 -cycloalkyl- alkyl) carbamoyl, N- -dehydroabietylcarbamoyl, N-),C 1 -alkyl-N- -dehydroabietylcarbamoyl, N- C 6 _C. 1 2 -arylcarbamoyl, N-(C aralkylcarbamoyl, N- (Cl-CI 0 -alkyl (C.-C 16 -aryl carbamoyl, N- (Cl-Cl.) -alkyl-N- (C 7 -C 16 -aralkylcar- bamoyli N (C C 1 0 al1koxy (CI C: 1 alkyl)carbamoyl, N- 1 6 -aryloxy- (Cl-C 0 alkyl)carbamoyl, N- 6 -aralkyloxy- (C 1 -C 10 alkyl)carbamoyl, CON(CH 2 in which a CH 2 group can be replaced by 0, N- (C 1 -alkylimino, N- (C 3 -cycloalkylimino, N- (C 3 -C 8 -cycloalkyl- (C 1 -C 4 alkylimino, N- (C.-C 12 -arylimino or N- (C 7 -C 1 6 S) aralkylimino, and h is from 3 to 6, where the radicals which contain an aryl radical for their part, be substituted on the aryl 20 by from 1 to 5 identical or different radicals from the group: hydroxyl, f:Lqorine, chlorine, cyano, trifluoro- methyl, carbo; yl, (C,-C 12 -alkyl, (C 3 -C 8 -Cyclo- alkyl, (Cl-C 6 -alkoxy, (C 3 -cycloalkoxy, (C 1 C 12 -alkoxycarbonyl, N- (C 1 -alkylcarbamoyl, N,N-di- (C 1 -alkyl- carbamoyl or N- (C 3 -cycloalkylcarbamoyl, and R 4 is provided Q has the meaning of NR', where R' and R" are identical or different and are hydrogen, (Cl-C,)-alkyl, or (C 7 -C 1 1 l)-aralkyl which is optionally substituted once by fluorine, chlorine or (Cl-C 4 -alkoxy, R' and R' are identical or different and are hydro- gen, (C 6 -_C 1 -aryl, (Cl-CI 0 -alkyl, (C 3 -C 10 129 cycJloalkyl, (C 1 -a.Lkoxy- -alkyl, (C 7 -C 12 aralkoxy- (C 1 -alkyl 2 -aryloxy- alkyl, -CIO) -alkanoyl, optionally substituted (C 7 -C 1 d)-ar&,,1kanoyl or optionally substituted C 1 2 -aroyl, or RY and Rz together are [CH 2 J I- in which a CH 2 group can be replaced by 0, S 1 N-(Cl-C 4 )-alkanoylimino or N- (C,-C 4 -alkoxycarbonylimino, and f is 1 to 8, g is 0ori1to (2f 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. AI'. cmodof the formula I an claimed in Aclaims 1 Uin which Q is 0, NR' or a bond, X is 0, Y is CR 3 or, i f R1 and R 2 form a cycle, N or CR', m isO0, A is (C 1 C 3 -alkylene which is optionally substi- tuted once by halogen, cyano, trif luoromethyl, *(C 1 -alkyl, -hydroxyalkyl, (Cl-C) -alko- or [CH 2 ].-CfH( 2 f+l-g)Fg Or *A is -CHR 5 where R 5 is one of the substituents of the a-carbon atom of an cy-amino acid, in par- ticular of a natural L-amino acid and of its D -isomer, B is CO 2 H, R 2 is hydr-,,en, (C 1 -_C 2 -alkyl, 2 C 0 aknl (C2_C2.) -alkenyl, 130 (C 2 -C 2 -alkenyloxy, (C,-C 2 d)-alkynyioxy, retinyloxy, (Cl-C 2 -alkoxy- (C3 1 -alkyl, (C,-C 2 alkoxy- (Cl-C 3 -alkyl, (C 2 -C 2 0 -alkenyloxy- (Cl-C 3 alkyl, retinyloxy- (C: 1 -C 3 -alkyl, (C 2 -C 2 0 alkynyloxy- (C3.-C 3 -alkyl, (C3 1 -C 2 0 -alkoxy, halogen, cyano, trifluoromethyl, (C 1 C 16 -hydroxyalkyl, (C3 1 -C 2 -alkanoyl, (C 7 -C 1 2 -aralkanoyl, (C 6 -C 1 2 aroyl, (CH 2 J X-CtHc 2 f.l 8 g)Fg NR' (C 1 -C 10 alkylmercapto, (Cl C3 0 alkyl sul finyl, (C 1 -C 10 alkylsulfonyl, (C.-C 1 2 -arylmercapto, (C 6 -C 1 2 arylsulfinyl), (C 6 -C 1 2 aryl sul fonyl, (C7 C 12 -aralkylmercapto, (C 7 -C 1 2 aralkyl sul finyl, (C 7 -C 12 -aralkylsulfonyl, (C,-C 1 2 -aryloxy, C 1 -aralkyloxy, carboxyl, (CI-C 2 0 -alkoxycarbonyl, (C 1 -C 1 2 -alkoxy- (CI-C,. 2 -alkoxycarbonyl, (C 6 -C 1 2 aryloxycarbonyl, 1 6 -aralkoxycarbonyl, (C 3 -cycloalkroxycarbonyl, (C 2 -C 20 -alkenyloxy- carbonyl, retinyloxycarbonyl, (C 2 -C 20 -alkynyl- oxycarbonyl, (C 3 -cycloalkyl- (C, 1 -alkoxy- carbonyl, (C 3 -C 8 -cycloalkoxy- (C 1 -alkoxy- :carbonyl, (C.-C 1 2 -aryloxy- (Cl-C 6 -alkoxycarbonyl, -aralkoxy- (CI-C) -alkoxycarbonyl, carbaxnoyl, N- (C 1 C. 2 -alkylcarbamoyl, N,N-di- (C 1 C. 2 -alkylcarbamoyl, N- (C 3 -C 8 -cycloalkyl- carbamoyl, N,N-dicyclo- (C 3 -C 8 -alkylcarbanoyl, N- -alkyl-N- (C 3 -C 8 -cycloalkylcarbamoyl, N- (C 3 -C 8 -cycloalkyl- -alkyl) carbamoyl, N- (C 1 -alkyl-N- ((C 3 -cycloalkyl- alkyl) carbamoyl, N- -dehydroabietylcarbamoyl, N- (C 1 -alkyl-N- -dehydroa-bietylcarbanmoyl, N- *(C 6 -C 1 L 2 -arylcarbamoyl, N- 16 -aralkyl- carbamoyl, N- (C 1 -CI 0 -alkyl-N- (C.-C1 6 arylcarbamoyi,N- (C. 1 -C3 1 0 -alkyl-N- 12 -aralkyl- carbamoyl, N- -alkoxr- (Cl-Cl.) alkyl) carbamoy1, N- ((C 6 -C 1 6 -aryloxy- (C, 1 -C 10 alkyl) carbamoyl, N- ((C,-Cl 6 -aralkyloxy- (CI-C 1 alkyl) carbamoyl, N- (C3 1 -Cl 0 -alkyl-N- (C. 1 -C 10 alkoxy- (C: 1 -C 10 -alkyl) carbamoyl, N- (Cl-C, 0 -alkyl-N- (C.-C 1 2 -aryloxy- (C,-Q 10 131 alkyl)carbanioyl,N- (Cl-Cl.) -alkyl-N- (C 7 -aral- kyloxy- (Cl-C 10 -alkyl)carbamoyl, or CON(CH 2 in which a CH 2 group can be replaced by 0, S, N- C 1 -alkylimino, N- (C 3 -C 8 -cycloalkylimino, N- (C 3 -cycloalkyl- (C 1 -C 4 -alkylimino, N- (C 6 -C 1 2 arylimino, N- (C 7 -C 16 -aralkylimino or N- (C 1 -C 4 alkoxy- -alkylimino, and h is from 3 to 6, where aryl is substituted in the manner as def ined f or R' and R 3 R 1 and R 3 are identical or different and are hydro- gen, halogen, (CI-C 12 -alkyl, 2 -alkoxy, [CH 2 1 CfH( 2 f+j,)Hal.1 (C 1 -C 12 -alkoxy- (Cj-C 12 alkyl, (C 1 -alkoxy- (C 1 -C 1 2 -alkoxy, (CC-C 1 2 alkoxy- -alkoxy- (C 2 -C 6 -alkyl, (C 7 -C 1 1 (C 3 -C 8 -cycloalkyl, (C 3 -CO) -CYClo- alklrl- (CI-C 8 -alkyl, (C 3 -C 8 -cycloalkyloxy, (C 3 C 8 -cycloalkyl- (C 1 -C 8 -alkoxy, (C 3 -C 8 -cycloalkyl- oxy- (C3 1 -alkyl, (C 3 -C 8 -cycloalkyloxy- (C 1 :alkoxy, (C 3 -C 8 -cycloalkyl- 6 -alkyl- (C 1 -C 6 alkoxy, (C 3 -C-cycloalkyl- (C 1 -alkoxy- (C 1 C 6 alkyl, (C 3 -C 8 -cycloalkoxy- (C,-C 6 -alkoxy- alkyl, NYRz, (CI-C) -alkylmercapto, (C 1 C) alkylsulfinyl or (C 1 -C 8 -alkylsulfonyl, (C 6 -C 12 arylmercapto, (C 6 -C 1 2 aryl sul finyl, (C 6 -C 12 arylsulfonyl, (C 7 -Cl 2 -aralkylmercapto, (C7 -C 1 1 aralkyleulfinyl, (C 7 -C 11 -aralkylsulfonyl, substituted (C 6 -C 12 -aryloxy- (Cl-C 6 -alkyl, (C 7 C 11 -aralkcxy- (C 1 -alkyl, (C,-C2, 2 -aryloxy- (Cl- C 6 -alko~cy- (Cl-C 6 -alkyl, (C 7 -C 11 -aralkyloxy- C 6 -alkoxy- (C,-C 6 -alkyl, (C,-C 12 -aryloxy, (C 7 C 11 -aralkyloxy, (C 6 -aryloxy- -alkoxy or (C 7 -C 11 l) -aralkoxy- (C,-C 6 -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, (C 1 -C 1 2 alkyl, (CI-C 12 -alkenyl, -hydroxyalkyl, (C 1 C 1 2 a 1koxy C 1 -C 1 alk enyl oxy 132 ECH 2 ]xCfH( 2 f+l..g)F9' -OCF 2 Cl, -0-CF 2 -CHFCl, (Cl-C 6 alkylmercapto, -alkylsulf inyl, (C 1 -C 6 alkylsulfonyl, (C 1 -alkylcarbonyl, (C 1 -C 6 alkoxycarbonyl, carbamoyl, N- (Cl-C 4 -alkyl- carbamoyl1, N,N-di- (Cl-C 4 -alkylcarbamoyl, (C 1 C 6 alkylca-Lonyloxy, -cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NRYRz, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfanioyl, N-(Cl-C 4 )-alkylsulfaloyl or N,N-di- (C 1 C 4 )-alkylaulfamoyl, or optionally carries up to 3 of the abovementioned identical or different sibstituents, and two adjacent carbon atoms of the aralkyloxy radical together carry a chain -[CH 2 -J and/or -CH=CH-CH=CH-, where a CH,, group of the chain is optionally replaced by 0, S, SO, S02 or NRY, R 1 and R 2 or R 2 and R 3 can form a chain [CH;1 0 1 where o is 3, 4 or 5, and R 4 is, provided Q is a bond, chlorine or, if Q is 0 V 20 or NR'1, is a branched or unbranched -alkyl radical, which can contain one or two C-C multiple bonds, or an unsubstituted fluoroalkyl radical of the formula [CHa1x-CfH( 2 fl.g)Fg Or C 8 -alkoxy- (C 1 -alkyl, (C 1 -alkoxy- alkoxy-(C 1 -C,)-alkyl or a radical of the formula o -[CH 2 ]v-[O]w-[CH 2 Jt-E (Z) where E is a substituted phenyl radical of the formula F R 6 R 133 or a (C 3 -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 R 7 Re, R 9 and R 10 are identical or different and are hydrogen, halogen, cyano, nitro, trif luoromethyl, (Cl-C 6 alkyl, (C 3 -CIS) cyc loalkyl, -alkoxy, 0 ECH 2 J x-CfHC 2 f..g9)FgI -OCF 2 Cl, -0-CF 2 -CHFCl, (Cl- C 6 -alkylmercapto, -hydroxyalkyl, alkoxy- (C 1 -C 6 -alkoxy, (C: 1 -C 6 -alkoxy- (C 1 -C 6 alkyl, (C 1 C 6 -alkylsulf inyl, (C 1 C 6 -alkylsul- fonyl, (Cl-C, 6 -alkylcarbonyl, -alkoxy- carbonyl, carbamoyl, N- (C 1 L-Ca) -alkylcarbaioyl, N,N-di- -alkylcarbamoyl, (C 7 -CIO) aralkyl carbamoyl wh~ich is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl or (Cl-C 6 -alkoxy, N- (C 3 -C 8 -cycloalkylcarbamoyl, N- (C 3 -C 8 -cycloalkyl- (C 1 -C 4 -alkylcarbamoyl, alkylcarbonyloxy, phenyl, benzyl, phenoxy, benzyloxy, NRYRz, such as amino, anilino, N- methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C 1 -alkyl- sulfamoyl or N,N-di-(C,-C,)-alkylsulfamfoyl, or two adjacent substituents together are a chain or -CH=CH-CH=CH-, where a CH. group of the chain is optionally replaced by 0, S' S0, S02 or NA, and where a heteroaryl radical can carry 1, 2 or 3 substituents, and a cycloalkyl radical one substituent, from the above group, and R 4 is provided Q has the meaning of NRW, where RI is hydrogen or methyl, and R is benzyl, and if R' and/or R 3 have the meaning of 2 -aryloxy, (C 7 -C 1 -aralkyloxy, (C 6 -_C 12 -aryloxy- (C 1 -alkoxy, (C 7 -C 11 -aralkoxy- -alkoxy or a corresponding radical containing terminal cycloalkyl groups, this 134 radical is preferably then a radical of the formula D OZ or if R1 and/or R 3 have the meaning of (C 7 -C 1 ,-aralkyl, (C,-C 1 2 -ar-yloxy- -alkyl, (C 7 -C, 1 -aralkoxy- (C 1 C 6 -alkyl or a corresponding radical containing terminal cycloalkyl groups, this radical is pre- ferably then a radical of the formula Z, R' and Rz are identical or different and are hydro- gen, (C,-C 12 -aryl, (Cl-Cl.) -alkyl, (C 3 CIO) cycloalkyl, (C 1 -alkoxy- -alkyl, (C 7 C 12 -aralkoxy- -alkyl, (C,-C 12 -aryloxy- (Cl- -alkyl, (CI-Cl.) -alkanoyl, optionally substi- tuted (C 7 -C 1 6 -aralkanoyl or optionally substi- tuted (C,-C 1 2 -aroyl, or Ry and Rz are together -[1CH 2 J in which a CH 2 group can be replaced by 0, S, N-(Cl-C 4 )-alkanoylimino or N- (C 1 -C 4 -alkoxycarbonylimino, and f is I to 8, g is 0Oorl1 to (2f+1), h 3 to 6, x is 0 to 3, and n is 3 or 4, in-,luding the physiologically active salts, with 25 3-benzyloxypyridine-2-carboxylic acid (L-thre- 0. too onyl) amide and 3 -benzyloxypyridine-2 -carboxylic acid ((Fmoc-Phg) L-threonyl) amide hydrochloride being excepted. ary on~ec A compound of the formula I as claimed in claims 1 to L, in which Qis 0, S X is 0, K Y is CR 3 and, additionally, N if R 1 and R 2 form a Yr 0' 135 cycle, m is 0, A is -CHR 5 where R 5 is the substituent of the a-carbon atom of an~ a-amnino acid, in particular of a natural L-eimino acid or its D-isomer, B is CO 2 H, R 2 is hydrogen, bromine, chlorine, cyano, (C 1 alkyl, -alkoxy, (C 1 ,-C 1 5 -alkoxymethyl, (C 2 C, 8 -alkenyloxymethyl, (C 2 -C 18 -alkynyloxymethyl, carbamoyl, N- -alkylcarbamoyl, N- (C3,-C 12 alkoxy- (Cl-C 4 -alkyl) carbamoyl, N,N-di- (Cl-CO) alkylcarbanioyl, N- (C 3 -cycloalkylcarbamoyl, N- (C 6 -C 1 2 -phenylcarbaznoyl,N- (C 7 -C 1 2 -phenylalkyl- carbamoyl, N- -alkyl-N- C 2 )phenyl- carbamoyl, N- -alkyl-N- (C 7 -C, 2 -phenylalkyl- carbamoyl, N- ((C 1 -alkoxy- (C 1 alkyl) carbamoyl, carboxyl, (C,-C 2 -alkox-y- carbonyl, (C 2 -C 20 -alkenyloxycarbonyl, retinyl- oxycarbonyl, (C 3 -C 8 -cycloalkoxycarbonyl, (C 3 -C 8 cycloalkyl- (C.-C 6 -alkoxycarbonyl, (C 3 -CS) -cyclo- alkoxy- (C 1 ,-C 6 -alkoxycarbonyl, phenyl- (CI-C 6 alkoxycarbonyl, phenoxy- (C C 6 alkoxycarbonyl or benzyloxy- -alkoxycarbonyl, where a phenyl radical is substituted in the manner as defined for R1 and R 3 and one of the radicals Ror R 3 is hydrogen and the other a radical f rom the group hydrogen, fluorine, chlorine, (C 1 alkyl, (Cl-C. 0 -alkoxy, -cycloalkyl, *C 6 -cycloalkyl- (Cl-C,)-alkyl, (C_ 5 -cycloalkyl- oxy, -cycloalkyl- (C,-C 6 -alkoxy, (C 5 -C 6 cycloalkyloxy- (C3 1 -alkyl, -cycloalkyl- oxy- -alkoxy, (C,-C 6 -cycloalkyl- (Cl-C 4 alkyl- (C 1 -C 4 -alkoxy, (C 5 -cycloalkyl- (Cl-C 4 alkoxy- -alkyl, (C.-C 6 -cycloalkoxy- (Cl-C 4 alkoxy- (C 1 -C 2 -alkyl, ECH 2 J .xCiH 2 f+1-g)FgI (C 1 -_C 6 alkoxy- (C 1 -C 6 -alkyl, (C 1 -alkoxy- alkoxy, (C 1 -C 6 -alkoxy- (Cl-C 4 -alkoxy- (C 1 C 2 136 alkyl, substituted 2 -phenoxy, (C 7 -C 1 1 phenylalkyloxy, (C 6 -C 12 -phenoxy- -alkoxy or (C 7 -Cj 1 -phenylalkoxy- (C 1 -alkoxy, phenoxy- (C 1 -C.).-alkyl, (C 7 -C 1 1 -phenylalkyloxy- alkyl, phenoxy- -alkoxy- (C 1 -C 2 -alkyl or (C 7 C 1 1) -phenylalkyloxy- (C 1 -C 4 -alkoxy- (C3 1 -C 2 -alkyl, where an aromatic radical is substituted by 1, 2 or 3 identical or dilferent subs ti tutents from the group fluorine, chlorine, cyano, trifluoro- methyl, (Cl-C. 2 -alkyl, (C2-C 1 2 -alkenyl, (C 2 -C3. 2 alkenyloxy or 2 -alkoxy, R" and R 2 with the pyridine carrying them, form a 6, 7, 8-tetrahydroisoquinoline ring, R 4 is a branched or unbranched (Cl-C 10 -alkyl radical, (C 1 -C 4 -alkoxy- (Cl-C 4 -alkyl or a radical of the formula Z, where E is a substituted phenyl radical of the formula F 6 7 R R 1 R or a (C 3 -C,)-cycloalkyl radical, where v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R 7 R' and R" 0 are identical or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, -alkyl, 6 -alkoxy, Ot- CH 2 XCfH( 2 f+l.g) gf N- -alkylcarbamoyl, N,N-di- (C 1 -C 6 -alkylcarbanoyl, N- (C 3 -C 6 -CYClo- alkylcarbamoyl, N- -dehydroabietylamino- carbonyl, or (C 7 -phenylalkylcarbamoyl, which 137 is optionally substituted by fluorine, chlorine, trifluoromethyl and (Cl-C,)-alkoxy, or where R' and R 7 or R 7 and Re, together with the phenyl ring carrying them, form naphthalene derivatives, or if R3- or R 3 has the meaning of (C 6 -C 12 -phenoxy, (C 7 -C 11 -phenylalkyloxy, (C.-C 1 2 -phenoxy- (C 1 C 6 alkoxy, 1 -phenylalkoxy- (C,-C 6 -alkoxy, (CS-C) -cycloalkyloxy, -cycloalkyl. (C 1 alkoxy, -cycloalkoxy- (Cl-C 6 -alkoxy or C 6 -cycloalkyl- (Cl-C 4 -alkyl- (C 1 C 4 -alkoxy, this radical is then, especially, a radical of the formula D OZ or if R 1 or R 3 has the meaning of phenyl, phenoxy- (Cl-C 6 -alkyl, (C 7 -Cj 1 -phenylalkyl, (C 7 -C 1 1 phenylalkyloxy- (CI-CO)-alkyl, -cycloaikyl, -cycloalkyl- (Cl-C 6 -alkyl, (CS-C 6 -cyclo- alkoxy- (C 1 C 4 -alkyl, (C 5 -C 6 -cycloalkyl- (C 1 C 4 alkoxy- (Cl-C 2 -alkyl or -cycloalkoxy- (Cl-C 4 -alkoxy- (C3.-C 2 -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+l), x is 0 or 1 including the physiologically active salts, with 330 3-benzyloxypyridine-2-carboxylic acid (L-thre- onyl) aiide and 3 -benzyloxypyridine.- 2-carboxylic acid ((Fzoc-Phg)L-threonyl)anide hydrochloride being excepted. Oar\ one (O9'.A compound of the formula I as claimed in claims 1 138 to 7, in which Q is 0, x is 0, Y is CR 3 m is 0, A is a -CH 2 group which can be substituted by a methyl group, B is CO 2 H, R 2 is hydrogen, (C -alkoxy, -alkoxymethyl, (C 2 -C 1 6 -alkenyloxymethyl, retinyloxymethyl, N- (CI-Cl.) -alkylcarbanioyl,N- ((C3 -C: 12 -a'Lkoxy- (CI-C 3 alkyl) carbamoyl, N,N-di- (C3 1 -alkylcarbamoyl, N- -cycloalkylcarbaioyl, N-phenylcarbamoyl, N-phenyl- (C3 1 -C 4 -alkylcarbamoyl, carboxy, (C 1 alkoxycarbonyl, (C 2 -C3.6) -alkenyloxycarbonyl, retinyloxycarbonyl, (C 5 -cycloalkoxycarbonyl, -cycloalkyl- -alkoxycarbonyl or phenyl C 6 -alkoxycarbonyl, where a phenyl radical is substituted in a manner as defined for 20 R 1 and R1, and one of the radicals Ror R 3 is hydrogen and the other radical is a radical from the group hydrogen, (C 1 -C 10 -alkoxy, (C.-C 6 )-cycloalkyloxy, (C,,-C,)-cycloalkyl- alkoxy, [CH 2 1 x-CfH1 2 f+I.g)FgI (C 1 -C 4 -alkoxy- (C,-C 4 -alkoxy, substitu~ted (C C. 2 -phenoxy, *C 11 -phexnylalkyloxy, (C.-C 1 2 (Cl-C 4 alkoxy or 11 -phevylalkoxy- (C3-C 4 -alkoxy, where an aromatic radical is substituted by 1, 2 or 3 identical or different substituents from the 30 group fluorine, chlorine, cyano, trifluoromethyl, (Cl-C 10 -alkyl, (C 1 -C 10 -alkoxy or C 1 0 alkenyloxy, and R' is a branched or unbranched (Cl-CB,) -alkyl radical or a radical of the formula Z, 139 where E is a substituted phenyl radical of the formula F F),0 1 a or a (C 3 -C,)-cycloalkyi radical, where v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R5, R7 Ra, R' and R 10 are identical or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, -alkyl, (C 1 -Cs) -alkoxy, [C *CR2+-)9 14 (Ci-Ce) alkylcarbanoyl, N,N-di- (C 1 -alkyloarbamoyl, (C 3 -cycloalkylcarbamoy-, N- -dehydr- akietylaminocarbonyl substituted benzyl radical, and f is 1 to 4, g is 0 or 1 to (2f+l) and x is o or 1 including the physiologically active salts. A compound of the formula I as claimied ih~cam 1 to q- and 1to lo, in which Q is 0, X is 0, Y is CR 3 m is 0, A is a -CH 2 group, B is C02H, is hydrogen, -alkox~r or iLZWl 2 ]X-CfH( 2 f+l. R' is bydrogen, N- (C3-C 10 -alkylcarbamoyl, N- ((C 1 -alkoxy- (C,-C 3 -alkyl) carbamoyl, N,N-di- (Cl- -alkylcarbamoyl,N- (C,-C 6 -cycloalkylcarbamoyl, N-phanylcatbamoyl, N-phenyl- (C 1 -alkyl- carbagwoyl, carboxyl, (c 1 -alkoxycarbonyl, 140 (C 2 -C 16 -alkenyloxycarbonyl, retinyloxycarbonyl, -cycloalkoxycarbonyl, -cycloalkyl- (C 1 -alkoxycarbonyl or phenyl- (Cl-C 6 -alkoxy- carbonyl, where a phenyl radical is substituted by 1 or 2 identical or different substituents f rom the group f luorine, chlorine, cyano, trif lu- oromethyl, (C 1 -CI 0 -alkyl, (C 1 -C 10 -alkoxy or (Cl-C 1 -alkenyloxy, and R' is hydrogen, (C 1 C)-alkoxy or (C-C)-cycloalkyl- (Cl-C 2 )-alkoxy, where one of the substituents R1 and R 3 is hydrogen, R 4 is a branched or unbranched -alkyl radical, or a 2-phenylethyl radical, or a benzyl radical substituted by 1, or 2 radicals from the group fluorine, chlorine, cyano, trifluoromethyl, -alkyl, (Cl-C 6 -alkoxy, ECH 2 iX,-CfH(,f+ 1 og)Fgl N- (C.-C 8 -alkylcarbamoyl, N, N-di- (CI-C 6 alkylcarbainoyl, N- (C 3 -C 6 -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. QkA> onle o 122 .Compounds of the formula I as claimed in claims 1 to ~and -1 to jin which ~Q is 0, X is 0, Y is CR, *m is 0, A is a -CH 2 -group, B is C0 2 H, R' is hydrogen, RtZ, is hydrogen, N- (Cl-C 10 -alkylcarbamoyl, N- ((C 1 SC 12 -alkoxy- (C 1 -C 3 -alkyl) carbamoyl, N-cyc).o- 141 hexylcarbamoyl, N-phenylcarbamoyl, N- (phenyl- (Ci- C 2 )-alkyl) carbamoyl, where, in the last two cases, the phenyl radical can carry a fluorine substituent, a (Ci-C 10 )-alkyl substituent or a (C 1 -C 1 0 -alkoxy substituent, carboxyl, (Ci-C 1 6 alkoxycarbonyl, (C 2 -C 16 -alkenyloxycarbonyl, retinyloxycarbonyl, (C 5 -cycloalkoxycarbonyl or benzyloxycarbonyl, R 3 is hydrogen, (CI-C -alkoxy or 2-(cyclohexyl)- ethyloxy, where one of the substituents R 2 and R 3 is hydrogen, R 4 is a branched or unbranched (C 1 -C 4 )-alkyl radical or a benzyl radical which is substituted once by fluorine, chlorine, trifluoromethyl, (C 1 alkyl or (C-C 3 )-alkoxy, including the physio- logically active salts. c w~ oyie oT VgyZZ. A compound of the formula I as claimed inAclaims 1 \O0 q and 1, in which Q is O X is 0, Y is CR 3 where R 3 is hydrogen, m is 0, A is a -CH 2 group, B is -COH, and S" R 1 and R 2 together with the pyridine carrying them, form an isoquinoline ring having an unsubstituted benzo moiety, and R' is methyl. -23. A compound of formula I as claimed in claims 1 to 3 and 6, in which Q is 0, X is CRO Y is CR 3 I I--I 142 m is 0, A is a -CH. group, B is -CO 2 HI R 1 is hydrogen, and R 2 and R together with the pyridine carrying them, form a quinoline ring having an unsubstituted benzo moiety, and R 4 is methyl, i(4CA compound of the formula I as cJ'ximed in claims 1, 3,5 and 6~in which Qis S, x is 0, Y is CR, m is 0, A is a -CH 2 group, B is -CO 2 H, R 1 is hydrogen, i s hydrogen, N- (C3 1 -C 1 0 -alkylcarbanoyl, N- ((Cl- C 12 -alkoxy- (C 1 -C 3 )alkyl)carbamoyl, N-cyclohexyl- carbamoyl, N-phenylcarbamoyl, N-(phenyl-(Cl- C 2 alkyl) carbanoyl, where, in the last two cases, the phenyl radical can carry a fluorine substituent, (C 1 -alkyl substituent or (Cl- C 10 -alkoxy substituent, carboxyl, (C 1 -Ci 6 alkoxycarbonyl, (C 2 -C 16 -alkenyloxycarbonyl, retinyloxycarbonyl, -cycloalkoxycarbonyl or benzyloxycarbonyl, R 3 is hydrogen, (Cl-C 6 )-alkoxy or 2-(cyclohexyl)- ethyloxy, where one of the substituents R 2 and R 3 is hydrogen, and R" is a branched or unbranched (C,-C 4 -alkyl radical or a benzyl radical which is substituted once by fluorine, chlorine, tvifluoromethyl, (C 1 -C 4 ~alkyl or (C 1 -C 3 -al1;toy. 143
- 16. A compound of the formula I as claimed in any one of claims 1, 3, 5, 6 and 15, in which Qis S, X is O, Y CR 3 mis 0, A is a -CH 2 group, B is -C0 2 H, R 1 is hydrogen, R 2 is carboxyl or (C 1 -C 16 )-alkoxycarbonyl, R 3 is hydrogen, and R 4 is an unbranched or branched (C1-C 4 )-alkyl radical.
- 17. A compound of the formula I as claimed in any one of claims 1 to 16, plus 3-benzyloxypyridine-2-carboxylic acid L-threonylamide and 3- benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)-L-threonyl) amide for use as pharmaceuticals.
- 18. A method of inhibiting collagen biosynthesis comprising administering to Or c comf:SlotOoA. a patient r6quiring such treatment an effective amount of a compound as claimed in any one of claims 1 to 17.
- 19. A method of inhibition of prolyl hydroxylase comprising administering to a Or COmp.OOstQ patient requiring such treatment an effective amount of a compound as claimed in any one of claims 1 to 17. A method of fibrosuppression comprising administering to a patient or :2 Cmd430Soa\. requiring such treatment an effective amount of a compound as claimed in any one of claims 1 to 17.
- 21. A method of treatment of fibrotic disease comprising administering to a O c M OSiltoAm patient requiring such treatment an effective amount of a compoundtas claimed S in any one of claims 1 to 17. -r o 143a
- 22. The method according to claim 21 wherein the fibrotic diseases are diseases of the liver.
- 23. The method according to claim 21 wherein the fibrotic diseases are diseases of the lung.
- 24. The method according to claim 21 wherein the fibrotic diseases are diseases of the skin. i oo«* *e 144 23.-kA compound an-claimed in claims 1 te fo-r pre--- -paring a ph.rmaccutial against fbrotia diseaes cf the skin. 2 4- 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 COH, Y is CR 3 and m is 0 or 1, by ii.) reacting pyridine-2-carboxylic acids of the formula II (R 23 is H) with the amino esters of the formula III (R 24 is (C 1 -C 16 -alkyl or benzyl) to form the amide esters of the formula IV, or i2.) reacting pyridine-2-carboxylic esters of the formula II (R 23 is lower alkyl) under the conditions of aminolysis, to form the compounds 15 of the formula IV; and 1 i) liberating the compounds of the formula I from COR2 12 0 II IV 0 *000** 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 (R 4 is alkyl) being prepared by alkylation of compounds of the formula V (R 4 is H) with R 4 X, 145 NH-A-CO 2R2 i i) H-A-CO 2 H 1NH-A-CO 2R 2 4 RL ~NH-A-CO 2 R 2 4 V 0 where X is halogen, OS! appropriate, a 0 2 me leaving group, in particular or 0S0 2 phenyl, and, where 00*t iv) the compounds of the formula IV, provided Q is 0, S or NR', being ccnverted into their pyridine N-oxides (IV,) SR 4 -NH-A-CO 2R 2 4 S S *S S* S S S and, where appropriate, the latter being hydrolysed to form the compounds of the formula I' (R 2 4 is H). DATED this 31st day of October 1994. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BIJRW(YJD ROAD HAWTHORN. VIC. 3122. 1 HOE 93/F 349K Abstract of the disclosure Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticals The invention relates to compounds of the formula I, NH-A-B I) 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. 9
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4337271A DE4337271A1 (en) | 1993-11-02 | 1993-11-02 | ubstd. heterocyclic carboxylic acid amides and their prepn. |
| DE4337271 | 1993-11-02 | ||
| DE4410881 | 1994-03-29 | ||
| DE19944410881 DE4410881A1 (en) | 1994-03-29 | 1994-03-29 | Substd. heterocyclic carboxylic acid amides and their prepn. |
| DE19944433928 DE4433928A1 (en) | 1994-09-23 | 1994-09-23 | Substd. heterocyclic carboxylic acid amides and their prepn. |
| DE4433928 | 1994-09-23 |
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| AU7756494A AU7756494A (en) | 1995-05-18 |
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| CN106146395B (en) * | 2015-03-27 | 2019-01-01 | 沈阳三生制药有限责任公司 | 3- hydroxypyridine compound, preparation method and its pharmaceutical applications |
| KR102647879B1 (en) | 2015-04-01 | 2024-03-15 | 아케비아 테라퓨틱스 인코포레이티드 | Compositions and methods for treating anemia |
| CN112088155A (en) | 2018-05-09 | 2020-12-15 | 阿克比治疗有限公司 | Process for the preparation of 2- [ [5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl ] amino ] acetic acid |
| JP7458987B2 (en) * | 2018-09-13 | 2024-04-01 | キッセイ薬品工業株式会社 | imidazopyridinone compounds |
| US11524939B2 (en) | 2019-11-13 | 2022-12-13 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018006A1 (en) * | 1992-03-11 | 1993-09-16 | Narhex Limited | Amine derivatives of oxo- and hydroxy-substitued hydrocarbons |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4015255A1 (en) | 1990-05-12 | 1991-11-14 | Hoechst Ag | OXALYL-AMINOSA-E-LEED DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT FOR INHIBITING THE PROLYL HYDROXYLASE |
| EP0541042A1 (en) * | 1991-11-05 | 1993-05-12 | Hoechst Aktiengesellschaft | 2,4- and 2,5-pyridine-dicarboxylic acid derivatives, process for their preparation and their use |
| TW352384B (en) * | 1992-03-24 | 1999-02-11 | Hoechst Ag | Sulfonamido- or sulfonamidocarbonylpyridine-2-carboxamides, process for their preparation and their use as pharmaceuticals |
-
1994
- 1994-10-27 DE DE59401924T patent/DE59401924D1/en not_active Expired - Fee Related
- 1994-10-27 AT AT94117018T patent/ATE149486T1/en not_active IP Right Cessation
- 1994-10-27 EP EP94117018A patent/EP0650961B1/en not_active Expired - Lifetime
- 1994-10-27 DK DK94117018.5T patent/DK0650961T3/en active
- 1994-10-27 ES ES94117018T patent/ES2101421T3/en not_active Expired - Lifetime
- 1994-10-28 PL PL94305646A patent/PL179794B1/en unknown
- 1994-10-30 IL IL11145494A patent/IL111454A/en not_active IP Right Cessation
- 1994-10-31 AU AU77564/94A patent/AU676775B2/en not_active Ceased
- 1994-10-31 MY MYPI94002894A patent/MY112413A/en unknown
- 1994-10-31 NZ NZ264821A patent/NZ264821A/en unknown
- 1994-11-01 CZ CZ19942683A patent/CZ289356B6/en not_active IP Right Cessation
- 1994-11-01 NO NO944162A patent/NO301880B1/en not_active IP Right Cessation
- 1994-11-01 CA CA002134866A patent/CA2134866A1/en not_active Abandoned
- 1994-11-02 CN CN94117623A patent/CN1107145A/en active Pending
- 1994-11-02 JP JP6292032A patent/JPH07228571A/en not_active Abandoned
- 1994-11-02 KR KR1019940028871A patent/KR950014072A/en not_active Application Discontinuation
- 1994-12-05 TW TW083111257A patent/TW399046B/en not_active IP Right Cessation
-
1997
- 1997-04-18 GR GR970400831T patent/GR3023174T3/en unknown
-
1998
- 1998-06-22 HK HK98105872A patent/HK1006711A1/en not_active IP Right Cessation
- 1998-09-29 CY CY9800039A patent/CY2120B1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018006A1 (en) * | 1992-03-11 | 1993-09-16 | Narhex Limited | Amine derivatives of oxo- and hydroxy-substitued hydrocarbons |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2101421T3 (en) | 1997-07-01 |
| NZ264821A (en) | 1997-02-24 |
| TW399046B (en) | 2000-07-21 |
| GR3023174T3 (en) | 1997-07-30 |
| NO944162L (en) | 1995-05-03 |
| KR950014072A (en) | 1995-06-15 |
| CZ289356B6 (en) | 2002-01-16 |
| CN1107145A (en) | 1995-08-23 |
| EP0650961A1 (en) | 1995-05-03 |
| HK1006711A1 (en) | 1999-03-12 |
| MY112413A (en) | 2001-06-30 |
| DK0650961T3 (en) | 1997-09-15 |
| EP0650961B1 (en) | 1997-03-05 |
| AU7756494A (en) | 1995-05-18 |
| CY2120B1 (en) | 2002-04-26 |
| CA2134866A1 (en) | 1995-05-03 |
| DE59401924D1 (en) | 1997-04-10 |
| NO944162D0 (en) | 1994-11-01 |
| ATE149486T1 (en) | 1997-03-15 |
| IL111454A0 (en) | 1994-12-29 |
| JPH07228571A (en) | 1995-08-29 |
| PL305646A1 (en) | 1995-05-15 |
| IL111454A (en) | 2001-08-08 |
| CZ268394A3 (en) | 1995-05-17 |
| NO301880B1 (en) | 1997-12-22 |
| PL179794B1 (en) | 2000-10-31 |
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| Date | Code | Title | Description |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |