CA2134866A1 - Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticals - Google Patents
Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticalsInfo
- Publication number
- CA2134866A1 CA2134866A1 CA002134866A CA2134866A CA2134866A1 CA 2134866 A1 CA2134866 A1 CA 2134866A1 CA 002134866 A CA002134866 A CA 002134866A CA 2134866 A CA2134866 A CA 2134866A CA 2134866 A1 CA2134866 A1 CA 2134866A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkoxy
- carbamoyl
- cycloalkyl
- aryloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
Abstract
Abstract of the disclosure Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticals The invention relates to compounds of the formula I, (I)
Description
` 213Q86~
HOECHST A~TIENG~S~LSC~AFT HOE 93/F 349~ Dr.Fl/ws Deecription Substituted hetorocyclic carboxamidee, thoir preparation and thoir use as pharmaceuticals The invention relates to ~ubstituted hotorocyclic carbox~
amidee, to their pr-paration and to thoir u~o aB inh~-bitors of prolyl-4-~ydroxyla~o, and to their use as pharmaceuticals for treating fibrotic diseaee~.
Compounds which inhibit tho onzymo~ prolino hydroxylase and lyeine hydroxyla~e bring about a vory soloctiva inhibltion of collagon bio~ynthesis by thoir influenco on the collagon-specific hydroxylation roaction~. In the course of theso roactions, protein-bound prolino or lysine is hydroxylatod by the enzymes proline hydroxylaso or lyeino hydroxyla~o, resp~ctively. If thie reaction i~
prevented by inhibitors, there then arises a non-functional, ~ubhydroxylated collagen ~olecule which can only be eecreted by the cells into tho oxtrace~lular space in small quantitios. Furthormor-, the eubhydroxy-lated collagen cannot be incorporated into the collagenmatrix and i~ very readily degradod protoolytically.
The~- offect~ re~ult in a diminution of the overall quan-tity of collagen which is doposited oxtracellularly.
Inhibitors of prolyl hydroxylase are thoreforo suitable substances for use in~tho therapy of disoa~os in which tho deposition of collagen~ makos a substantial contri-bution to the clinical picture. Th-se d~soases includo, inter alia, fibroses of the lung, liver and skin (scloroderma and cLcatrizations following burns, in~urios and surgical intor~ention) and also athorosclorosis.
It is known that the enzyme proline hydroxylase is efficiently inhibited by pyridine-2,4-dicarboxylio acid and pyridine-2,5-dicarboxylic ?cid (~. Ma~amaa et al., - :.,:..-213486~
HOECHST A~TIENG~S~LSC~AFT HOE 93/F 349~ Dr.Fl/ws Deecription Substituted hetorocyclic carboxamidee, thoir preparation and thoir use as pharmaceuticals The invention relates to ~ubstituted hotorocyclic carbox~
amidee, to their pr-paration and to thoir u~o aB inh~-bitors of prolyl-4-~ydroxyla~o, and to their use as pharmaceuticals for treating fibrotic diseaee~.
Compounds which inhibit tho onzymo~ prolino hydroxylase and lyeine hydroxyla~e bring about a vory soloctiva inhibltion of collagon bio~ynthesis by thoir influenco on the collagon-specific hydroxylation roaction~. In the course of theso roactions, protein-bound prolino or lysine is hydroxylatod by the enzymes proline hydroxylaso or lyeino hydroxyla~o, resp~ctively. If thie reaction i~
prevented by inhibitors, there then arises a non-functional, ~ubhydroxylated collagen ~olecule which can only be eecreted by the cells into tho oxtrace~lular space in small quantitios. Furthormor-, the eubhydroxy-lated collagen cannot be incorporated into the collagenmatrix and i~ very readily degradod protoolytically.
The~- offect~ re~ult in a diminution of the overall quan-tity of collagen which is doposited oxtracellularly.
Inhibitors of prolyl hydroxylase are thoreforo suitable substances for use in~tho therapy of disoa~os in which tho deposition of collagen~ makos a substantial contri-bution to the clinical picture. Th-se d~soases includo, inter alia, fibroses of the lung, liver and skin (scloroderma and cLcatrizations following burns, in~urios and surgical intor~ention) and also athorosclorosis.
It is known that the enzyme proline hydroxylase is efficiently inhibited by pyridine-2,4-dicarboxylio acid and pyridine-2,5-dicarboxylic ?cid (~. Ma~amaa et al., - :.,:..-213486~
Eur. J. Biochem. 138 (1984) 239-245). ~owever, tho~e compound~ are only active as inhibitor~ in cell culture at vsry high concentrations (Tschan~, G. et al., Blocham. ~ ~ ~
J. 238 (1987) 625 to 633). ~;
Prodrugs of pyridino-2,4(5)-dicarboxylates are also known. Those are describod in the relatively old German Applicatlons P 42 33 124.2, P 42 38 506.7 and P 42 09 424Ø
N-Oxalylglyc~nes which are inhibitors of prolyl-4-hydroxylase are dioclosod in J. Med. Chem. 1992, 35, 2652 to 2658 (Cunliffo et al.), and ~P-A-0 457 163 (Baader ot al.).
Hydroxyisoquinolinecarboxylic acid glycyl~mldes and hydroxycinnolinecarboxylic acid glycylamlde~ aro disclosed in Biochem. Soc. Trans. 1991, 19, 812 to 815 (Franklin st al.). 3-~anzyloxypyrid$n--2-c~rboxylic ~cid (L-threonyl)amide and 3-ben~yloxypyridine-2-carboxylic `~
acid ((Fmoc-Phg)-L-threonyl)amido hydrochlorid- are disclosed in Liebigs Ann. Chem. 1986, 1 to 20, Ro~sler et al.
It has now bqen found, ~urprisingly, that heterocyclic carboxamides having an ether sub~tituent, a thioether ~;
substituont or an amino substituent in the ortho po~itlon to the amide function have a strong inhibitory actlon on prolyl-4-hydroxyla~e.
The compounds according to the invent~on conform to the formula I ; '~
R 1 ~: : .`
R2~,N H-A- B ( I ) X , , .. :~ . ",,;
( )m ... .:, ~ ~.
' ' ' ,~: ~ ' .'' -`` 2134866 in which Q i8 O, 8, NR' or a bond, X i~ O or S, Y 18 C-R3 or, if Rl and R2 form a cyel-, Y is N or CR3, m i8 0 or 1, A ~8 (Cl-C~)-alkylen~, whieh is optionally ~ub~titutod by one or two ~ubstitu~t~ from the group halogen, eyano, nitro, trifluoro~othyl, (Cl-C,)-alkyl, (Cl-C~)-hydroxyalkyl, (Cl-C~)-alkoxy, -O-~CH,]~
C~H~ al~, proferably (C1-C,)-fluoroal~oxy, (C~
C~)-fluoroalkenyloxy, (Cl-C~)-fluoroalkynyloxy, -OCF~C1 or -O-CF~-CHFC1, (C1-C6)-alkylmereapto, (C~
C~)-alkylsulflnyl, (Cl-C~)-alkyloulfonyl, (Cl-C6)-allcylcarbonyl, (Cl-C6)-alkoxycarbonyl, carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl-C~
alkylcarbamoyl, (Cl-C~)-alkylcarbonyloxy, (C3-C,)-eycloalkyl, ph-nyl, b-nzyl, ph-noxy, benzyloxy, anilino, N-methylanilino, phonylmereapto, ph nyl-sulfonyl, phanyl~ulf~nyl, sulfamoyl, N-(Cl-C~
alkylsulfamoyl or N,N-di-(Cl-C~)-alkyl~ulfamoyl, or by a ~ub~tituted (C~-Cll)-aryloxy, (C7-C1l)-aralkyl-oxy, (Cc-Cll)-aryl or (C7-Cl,)-aralkyl radical whieh earri-s in th- aryl i~ty 1, 2, 3, 4 or 5 id~ntieal or difft~rent ~ub~tituent~ from the group halog-n, eyano, nitro, trifluoromethyl, (Cl-C6)-alkyl, (Cl-C~)-alkoxy, -O-[CH~ C~Ht~ al~, OCFsCl, -O-CF~
CHFCl, (Cl-C~)-alkylmeroapto, (Cl-C~)-alkylsulfinyl, (Cl-C~)-alkylsulfonyl, (Cl-C,)-alkylearbonyl, (C1-C~
alkoxyearbonyl, earbamoyl, N-~Cl-C~)-alkylearbamoyl, N,N-di-(C1-C~)-alkylearbamoyl, (C1-C~)-alkyl-earbonyloxy, (C3-C~) -eycloalkyl, sulfamoyl, N-(C
C~)-alkyl~ul~amoyl or N,N-di-(C1-C~)-alkyl~ulfamoyl, or ~` I:'~'`i!,'';'' `,'':
by the ~ub~tituent~ Rs of the a-carbon atom of an a-amino acid, lt b-1ng po~lbl- to u~- th- natur~
J. 238 (1987) 625 to 633). ~;
Prodrugs of pyridino-2,4(5)-dicarboxylates are also known. Those are describod in the relatively old German Applicatlons P 42 33 124.2, P 42 38 506.7 and P 42 09 424Ø
N-Oxalylglyc~nes which are inhibitors of prolyl-4-hydroxylase are dioclosod in J. Med. Chem. 1992, 35, 2652 to 2658 (Cunliffo et al.), and ~P-A-0 457 163 (Baader ot al.).
Hydroxyisoquinolinecarboxylic acid glycyl~mldes and hydroxycinnolinecarboxylic acid glycylamlde~ aro disclosed in Biochem. Soc. Trans. 1991, 19, 812 to 815 (Franklin st al.). 3-~anzyloxypyrid$n--2-c~rboxylic ~cid (L-threonyl)amide and 3-ben~yloxypyridine-2-carboxylic `~
acid ((Fmoc-Phg)-L-threonyl)amido hydrochlorid- are disclosed in Liebigs Ann. Chem. 1986, 1 to 20, Ro~sler et al.
It has now bqen found, ~urprisingly, that heterocyclic carboxamides having an ether sub~tituent, a thioether ~;
substituont or an amino substituent in the ortho po~itlon to the amide function have a strong inhibitory actlon on prolyl-4-hydroxyla~e.
The compounds according to the invent~on conform to the formula I ; '~
R 1 ~: : .`
R2~,N H-A- B ( I ) X , , .. :~ . ",,;
( )m ... .:, ~ ~.
' ' ' ,~: ~ ' .'' -`` 2134866 in which Q i8 O, 8, NR' or a bond, X i~ O or S, Y 18 C-R3 or, if Rl and R2 form a cyel-, Y is N or CR3, m i8 0 or 1, A ~8 (Cl-C~)-alkylen~, whieh is optionally ~ub~titutod by one or two ~ubstitu~t~ from the group halogen, eyano, nitro, trifluoro~othyl, (Cl-C,)-alkyl, (Cl-C~)-hydroxyalkyl, (Cl-C~)-alkoxy, -O-~CH,]~
C~H~ al~, proferably (C1-C,)-fluoroal~oxy, (C~
C~)-fluoroalkenyloxy, (Cl-C~)-fluoroalkynyloxy, -OCF~C1 or -O-CF~-CHFC1, (C1-C6)-alkylmereapto, (C~
C~)-alkylsulflnyl, (Cl-C~)-alkyloulfonyl, (Cl-C6)-allcylcarbonyl, (Cl-C6)-alkoxycarbonyl, carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl-C~
alkylcarbamoyl, (Cl-C~)-alkylcarbonyloxy, (C3-C,)-eycloalkyl, ph-nyl, b-nzyl, ph-noxy, benzyloxy, anilino, N-methylanilino, phonylmereapto, ph nyl-sulfonyl, phanyl~ulf~nyl, sulfamoyl, N-(Cl-C~
alkylsulfamoyl or N,N-di-(Cl-C~)-alkyl~ulfamoyl, or by a ~ub~tituted (C~-Cll)-aryloxy, (C7-C1l)-aralkyl-oxy, (Cc-Cll)-aryl or (C7-Cl,)-aralkyl radical whieh earri-s in th- aryl i~ty 1, 2, 3, 4 or 5 id~ntieal or difft~rent ~ub~tituent~ from the group halog-n, eyano, nitro, trifluoromethyl, (Cl-C6)-alkyl, (Cl-C~)-alkoxy, -O-[CH~ C~Ht~ al~, OCFsCl, -O-CF~
CHFCl, (Cl-C~)-alkylmeroapto, (Cl-C~)-alkylsulfinyl, (Cl-C~)-alkylsulfonyl, (Cl-C,)-alkylearbonyl, (C1-C~
alkoxyearbonyl, earbamoyl, N-~Cl-C~)-alkylearbamoyl, N,N-di-(C1-C~)-alkylearbamoyl, (C1-C~)-alkyl-earbonyloxy, (C3-C~) -eycloalkyl, sulfamoyl, N-(C
C~)-alkyl~ul~amoyl or N,N-di-(C1-C~)-alkyl~ulfamoyl, or ~` I:'~'`i!,'';'' `,'':
by the ~ub~tituent~ Rs of the a-carbon atom of an a-amino acid, lt b-1ng po~lbl- to u~- th- natur~
L-a~ino acide and thoir D-lso~ores B i~ an acid grouping from t~e group -CO~, -CON~COR~', -CONHSOR'~, CONHSOlR~', -NHSO,CF"
tetrazolyl, imidazolyl or 3-hydroxyl~oxazolyl, whore Rn' is aryl, h-teroaryl, (C3-C7)-cycloalkyl or (C,-C~)-alkyl, optionally noeubstitutod by (C~-C,l)-aryl, heteroaryl, OH, SH, (C,-C~)-alkyl, (C1-C~)-alkoxy, (C~-C~)-thioalkyl, (C,-C~ ulfinyl, ;~
(C~-C~)-sulfo~yl, CF3, Cl, Br, F, I, NO" -COOH, 0 (C,-C5) -alkoxycarbonyl,NE~,mono-(C~-C~-alkyl)-amlno, di-(Cl-C~-alkyl)-amino or (C~-C~)-perfluoroalkyl, Rl, R~ and R3 aro identical or difforont and ar~ ~ydrogon, hydroxyl, halogen, cyano, tri~luoromethyl, nitro, carboxyl, (C,-C20)-alkyl, (C,-C,)-cycloalkyl, (C3-C,)-cycloalkyl-(C~-C")-alkyl, (C3-C,)-cycloalkoxy, (C3-C,)-cycloalkyl-(C,-Cl,)-alkoxy, (C3-C,)-cyclo- ~;~
alkyloxy-(C1-C~)-alkyl, (Cl-C~)-cycloalkyloxy-(C~
C")-alkoxy, (C3-C,) -cycloalkyl-(C,-C,)-alkyl-(C,-C~)-alkoxy, (C3-C,) -cycloalkyl-(C,-C,)-alkoxy-(C,-C6)-alkyl, (C3-C,) -cycloalkyloxy-(C,-C~)-alkoxy-(C~
C6)-alkyl, (C3-C,)-cyGloalkoxy-(C~-C~)-alkoxy-(C~ "'~
C,)-alkoxy, (C~-C,2)-aryl, (C7-C")-aralkyl, (C7-C") - .`; :~`f :`;
aralkenyl, (C7-C,c)-aralkynyl, (Cs-C,0)-alkonyl, (Cl- ~ t Cl0)-alkynyl, (C,-C~0)-alkoxy, (C~-C~0)-alkenyloxy, (Cl-Cl0)-alkynyloxy, retlnyloxy, (C1-Cl0)-alkoxy-(C,- .
C,l)-alkyl, (C,-C,l)-alkoxy-(C,-C,l)-alkoxy, (C,-C,l)-alkoxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C~-C")-aryloxy, (C7-ClC) -aralkyloxy, (Cc-C")-aryloxy-(Cl-Cc)-alkoxy, . ~'!.. ',,~,~",'.'`.
(C~-C~)-aralkoxy-(C~-Cc)-alkoxy, (C~-C~)-hydroxy-' '; '~' ';'` ,`,.!, '~'', ',' alkyl, (C~-C~)-aryloxy-(C~-C~)-alkyl, (C7-Cl,)-aralkoxy-(C,-C,)-alkyl, (C~-C")-aryloxy-(C,-C,)~
alkoxy-(CI-C~)-alkyl, (C7-C") -aralkyloxy-(C,-C,)-alkoxy-(C,-C~)-alkyl, (C,-C,0)-alk~nyloxy-(C,-C~
alkyl, (C~-C,0)-alkynyloxy-(C~-C,)-alkyl, r-tinyloxy-(C,-C~)-alkyl, -O-tC~ -C~H~ )F~, -OCF,Cl, -OCF,-CHFCl, . .~
'~: ,: ." ' . . ~ .
(Cl-Cl0)-alkylcarbonyl, (C3-C,)-cycloalkylcarbonyl, .;~
.: ., .::
" , .:, ,.;, .
(C,-Cl2)-arylcarbonyl, (C7-C~,)-arallcylcarbonyl, s:~nnamoyl, (C2-C,0)-alk~slylcarbonyl, (C,-C20)-alkynylcarbonyl, (C,-C20)-alkoxycarbonyl, (c1-c12)-alkoxY-(c~-cl2) alkoxycarbonyl, (C6-C12)-aryloxy¢arbonyl, (C7-C1~
aralkoxycarbonyl, (C3-C,) -cycloalkoxycarbonyl, (C2-C20)-alkenyloxycarbonyl, rotinyloxycarbonyl, (C,-C,0)-alkynyloxycarbonyl, (C,-C1~)-aryloxy-(C1-Cc)-alkoxy-carbonyl, (C7-Cl~)-aralkoxy-(Cl-C~)-alkoxycarbollyl, (C3-C,)-cycloallcyl-(C1-C~)-alkoxycarbonyl, (C3-C,,)-cycloalkoxy-(C,-C~)-alkoxycarbonyl, (C~-C~2)-alkylcarbonyloxy, (C3-C:~)-cycloalkylcarbon-yloxy, (C6-C,2)-arylcarbonyloxy, (C7-C1,)-aralkyl-carbonyloxy, cinnamoyloxy, (C2-C12)-alkonylcarbonyl-oxy, (C2-C12)-alkynylcarbonyloxy, ~C,-C,2)-alkoxycarbonyloxy, (C,-C,2)-alkoxy-(C,-C,2)-alkoxycarbonyloxy, (C,-C,2)-aryloxycarbonyloxy, (C7-C,6)-aralkyloxycarbonyloxy, (C3-C,)-cycloalkoxycar-bs~nyloxy, (C2-C~2)-alkcnyloxycarbonyloxy, (C,-Cls)-alkynyloxycarbonyloxy, .':. ~'.';''"'~:
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-Cl2)-alkylcarbamoyl, N-(C3-C~)-cycloalkylcarbamoyl, N,N-dicyclo- (C3 - C,) -alkylcarbamoyl, N-(C1-C10)-alkyl-N- (C3-C,) -cycloalkylcarbamoyl, N-((C3-C~) -cycloalkyl-(C~-C6)-alkyl)carbamoyl, N-(cl-c~)-alkyl-N-((c3-c~
cycloalkyl (C~-C6?,-alkyl)carbamoyl, N-(l)-dehydro-abietyl¢arbamoyl, N-(C1-C,)-alkyl-N-(+)-dchydro-abietylcarbamoyl, N-(C,-C12)-arylcarbamoyl, N- (C7-C16)-aralkylcarbamoyl, N-(C1-Clo)-alkyl-N-(cc-c~
arylcarbamoyl, N-(C,-C~0)-alkyl-N-(C,-Cl~)-aralkyl-carbamoyl, N-((C1-C1,)-alkoxy-(C1-C,0)-alkyl)car!~a-moyl, N-((C,-C,6)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-Cl6)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10) -alkyl-N- ( (C1-C10) -alkoxy- (C,-C,0) -alkyl) carbamoyl, N-(C1-C1o) -alkyl-N-((C,-C,2)-.. ........
213~866 aryloxy(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-C~O)-al~cyl-N-((C7-Cl6)-aralkyloxy-(C,-C10)-allcyl)carbamoyl, or ~ ~ :
CON(C}I,)h, in which a C}12 group can be r~plac~d by O, S, N-(Cl-C~)-allcylimino, N- (C3-C,) -cycloallcylimino, N- (C3-C,) -cycloalkyl-(Cl-C~)-alkyl~ino, N-(C,-Cl,)-arylimino, N- (C7-Cl~) -arallcyli~no or N-(C1-C~)-alkoxy-(Cl-C,)-alkylimino, and h ic from 3 to 7, a aarbamoyl radical of tho fonhula II
- 1 , " ~
R' H
--CO~ I NR ~~~--T ( I I ), ~ ~;
in which R~ ie the subetituent of an a-amis~o acid to wh~oh the L- and D-amino acidc belong, e ie 1, 2, 3, 4 or 5, and T ie OH, OR or NR-R--, whore R-, R^- and R--- are ~dentical or diffsront and are hydrogen, (C6-Cl2)-aryl, (C7-Cll)-arallcyl, (Cl-C,)-alkyl, (C3-C,)-cycloalkyl, (~)-dehydroabiotyl, (Cl-C~ lkoxy-(Cl-C~)-alkyl,(C7-Cl,)-aralkoxy-(Cl-C,)-alkyl, (C~-Cl~)-aryloxy-(Cl-C~)-alkyl, (Cl-Cl0)-alkanoyl, optionally eubetituted (C7-Cl~)-aralk-anoyl or optionally eubetituted (C~-Cl,)-aroyl, or R~ and R-- togothor are -lCE~,]b, in which a C~, group oan be roplac~d by O, S, SO, SO" N-acylamlno, N-(Cl-C~0)~allcoxy~arbonyl~n~no, N-(Cl~C~)-alkylimino, N- (C3-C,) -cycloallcylimino, N-(C~-C~)-cycloallcyl-(Cl-C~)-alkylimino, N-(C~-Cl~)-arylimino, N-(C7Cl~
aralkylimino or N-(Cl-C~)-alkoxy-(Cl-C~)-alkyl-imino, and h ie from 3 to 7, carbamoyloxy, N-(C,-C")-alkylcarbamoyloxy, N,N-dl-(Cl-Cl2)-alkylcarbamoyloxy, N- (C3-C,) -cycloalkylcarb-amoyloxy, N- (C~-C,;,)-arylcarbamoyloxy, ' ' .'' '' .: "" ' ",., `` 213~866 : ~ ~
_ N-(C7-C~-aralkylcarbamoyloxy, N-(Cl-C10)-al ~l-N-(C6-Cl2)-arylci~rbamoyloxy,N-(C~-ClO)-alkyl-N-(C7-C~
aralkylcarbamoyloxy, N-((Cl-C~0)-al ~l)carbamoyloxy, N-((C,-C,2)-aryloxy-(C,-C10)-al~yl)car~ ~ ylo ~, N-((C7-C") -aralkyloxy-(C~-C,0)-al ~l)carbamoyloxy, N-(cl-clo)-al~yl-N-((cl-clo)-alkoxy-(cl-clo)-al~yl)-carbAmnyloxy, N-(C,-C10)-al~l-N-(~C~-C~2)-arylo~-(C,-C10)-alkyl)carbamoylo~, N-(C~-C,0)-alkyl-N-((C7-C~
aralkyloxy-(C,-C,0)-alkyl)carbamoyloxy, amino, (Cl-C,2)-alkylamino, di-(C,-Clj)-al ~1 ~ no, (C,-C,)-cycloal~ylamino, (C3-C~2)-alk~nyl ~ no, (C3-Cl2)-alkynylamino, N-(C,-C,2)-aryl~no, N-(C7-C1~
aralkylamino, N-alkyl-aralkylamino, N-al ~l-aryl-amino, (C,-Cl2)-alkoxyA~no, (C,-C12)-alkoxy-N-(C,-C~0)-alkyl ~ino, (C,-C,3) -alk~oylamino, (C3-C~)-cycloalkanoylamino, (C~-C~2)-aroyl ~ino, (C7-Cl6)-aral~anoyl~no, (C~
C,2)-alkanoyl-N-(C,-C,0)-alkylamino, (C3-C,)-cyclo-alkanoyl-N-(C~-C10)-alkylamino, (C~-C~2)-aroyl-N-(C,-C,0)-alkyl ~ no, (c7-cll)-aralkanoyl-N-(cl-clo) alkylamino, ~C,-C,2)-alkanoylamino-(C,-C,)-alkyl, (C3-C,)-cyclo-alkanoylamino-(C,-C~)-alkyl, (C~-C12)-aroylamlno-(C,-C,)-alkyl, (C7-C,6)-aralkanoyl ~ no-(C,-C~)-alkyl, 2i amlno-(C,-C,0)-alkyl, N-(Cl-C,0)-alkylamlno-(C,-i~O)~
alkyl, N,N-dl(C,-C,o)-alkylamino-(C~-C~0)-alkyl, (C~
C,?-cycloalkylamino-(C,-C10)-alkyl, (C~-C20)-al~yl-mercapto, (C1-C20)-alkyloulfinyl, (C1-C20)-alkyloul-fonyl, (C~-C~2)-arylm-rcapto, (C~-C~2)-arylculfinyl, (C~-C~2)-aryloulfonyl, (C7-C~)-aralkylmorcapto, (C7-C~6)-aralkylculfinyl, (C7-C,6)-aralkyl~ulfonyl, (Cl-C12)-alkylmercapto-(C~-C~)-alkyl, (C,-C,j)-alkyl~
culf$nyl-(C~-C~)-alkyl, (C~-C~2)-alkylsulfonyl-(C~-C~)-alkyl, ~C~-Cl2)-arylmerc~pto-(C,-C~)-alkyl, (C~-C,2)-arylsulfinyl-(Cl-C,)-alkyl,(C~-Cl2)-aryloulfonyl-(Cl-C6)-alkyl, (C7-C,~)-aral ~lmorcapto-(C,-C~)-alkyl, ::~:: ::. .:
(C7-C16) -aralkylsulfinyl-(Cl-C~)-alkyl, (C7-c~
aralkylsulforyl-(C1-C~)-alkyl, : ~ ;
~ulfamoyl, N-(Cl-Cl0)-alkyl~ulfamoyl, N,N-di-(Cl-Clo)- ~ :
alkylsulfamoyl, (C,-C,)-cyeloalkyl~ulfamoyl, : ~
N-(C,-C,2)-aryleulfamoyl, - .~-N-(C7-Cl~)-aralkylsulfamoyl, : , .;
N-(C~-C,O)-alkyl-N-(C~-C~l)-arylsulfamoyl, ~ .
N-(C~-C,O)-alkyl-N- (C7-C") -aralkylsulfamoyl, (C1-C,0)-alkyl~ulfona~ido, N-((C,-C,0)-alkyl)-(C~-C,0)-alkylsulfonam~do,~C7-C
aralkyl~ùlfona~ldo or N-((C~-C~O)-alkyl- (C7-C~
aralkylsulfonamido, where the radlcals whieh conta~n an aryl radleal can, for the~r part, bs ~ubstltuted on the aryl by from 1 to 5 idontical or dlfforant radlcal~ from the hydroxyl, halogon, cyano, trifluoromethyl, nltro, carboxyl, (C,-C~)-alkyl, (C3-C,)-cyclo-lkyl, (C3-C~ ".,~
cycloalkyl-(Cl-Cl,)-alkyl, (C3-C,) -cycloalkoxy, (C 3-C~) -C y C 1 0 a 1 k y 1 - (Cl- Cl,) - a 1 k o x y, :~
(C3-C,) -cycloalkyloxy-(Cl-Cl,)-alkyl, (C,-C,)-cyclo-alkyloxy-(Cl-Cl,)-alkoxy, (C3-C,) -cycloalkyl-(Cl-C~
alkyl-(Cl-C,)-alkoxy, (C3-C,) -cycloalkyl-(Cl-C,)-alkoxy-(Cl-C,)-al~yl, (C3-C,) -cycloalkyloxy-(Cl-C~
alkoxy-(Cl-C~)-alkyl, (C3-C,) -cycloalkoxy-(Cl-C,)- .
alkoxy-(Cl-C,)-alkoxy, (C,-Cl,)-aryl, (C7-C,~) -aralkyl, (C~-Cl~)-allcenyl, (C,-Cl,)-alkynyl, (Cl-Cl~)-alkoxy, ... ;''.~', ,',:`:.
(Cl-Cl,)-alkanyloxy, (Cl-Cl,)-alkoxy-(Cl-Cl,)-alkyl, ~` `' .; .;~
(Cl-Cl~)-alkoxy- (Cl-C12) -alkoxy, (Cl-Cl,)-alkoxy-(Cl- .. .
C,)-alkoxy-(Cl-C~)-alkyl, (C~-Cl,)-aryloxy, (C7-C
aralkyloxy, (C~-Cl2)-aryloxy-(Cl-C~)-alkoxy, (C7-C
aralkoxy-(Cl-C,)-alkoxy, (Cl-C,)-hydroxyalkyl, (C~
Cl~)-aryloxy-(Cl-C,)-alkyl, (C7-Cl~)-aralkoxy-(Cl-C~)- :~-: : ;
alkyl, (C~-Cl,)-aryloxy-(Cl-C,)-alkoxy-(Cl-C,)-alkyl, `.. ~.
( C7-Cl~) - aralkyloxy-(Cl-C,)-alkoxy-(Cl-C,)-alkyl, ~ ~ :
-O-tCH,.]~-C~H(,~ )F~, -OCF,Cl, OCF2-CHFCl, (Cl-C12)-alkylcarbonyl, (C3-C,)-cyeloalkylcarbonyl, :: . : ~' .
g (C6-Cl2)-arylcarbonyl, (C,-Cl,~-arallcylcarbonyl, (C,-Cl2)-alkoxycarbonyl, (el-e12)-alkoxY-(cl-cl2) alkoxycarbonyl, (C,-Cl2)-aryloxycarbonyl, (C,-Cl,)-aralkoxycarbonyl, (C,-C,)-cycloalkoxycarbonyl, (C2-Cl2)-allcenyloxycarbonyl, (C2-Cl2)-allcynyloxyearbonyl, (C~-C~2)-aryloxy-(Cl-C~)-alkoxycarbonyl, (C7-cl~
aralkoxy-(Cl-C,)-alkoxycarbonyl, (C,-C,)-cycloalkyl-(C1-C~)-allcoxycarbonyl, (C,-C")-eyeloalkoxy-(Cl-C~
al;coxyc:arbonyl, (Cl-Cl2)-allcylearbonyloxy, (C,-C,)-eyeloallcylearbo-nyloxy, (Cc-C12)-arylearbonyloxy, (C7-Cl~)-arallcyl-carbonyloxy, cinna~oyloxy, (C2-Cl2)-alkenyl¢arbonyl-oxy, (C2-Cl2)-alkynylcarbonyloxy, (Cl-Cl2)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(Cl-Cl2)-alkoxycarbonyloxy, (C,-Cl2)-aryloxycarbonyloxy, (C7-Cl6)-aralkyloxycarbonyloxy, (C~-C~)-cycloalkoxycar-bonyloxy, (C2-Cl2)-alkenyloxycarbonyloxy, (C2-Cl2)-alkynyloxycarbonyloxy, carbamoyl, N-(Cl-Cl2)-alkylcarbamoyl, N,N-dl-(Cl-C12)-alkylcarbamoyl, N- (C3-C,) -cyeloalkylcarbamoyl, N,N-d~cyelo- (C3-C,) -alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C,) -cy¢loalkyl¢arbamoyl, N-( (C3-C,) -eycloallcyl-(Cl-C~)-alkyl)carbamoyl, N-(Cl-C~)-alkyl-N-( (C3-C,) -cycloalkyl- (Cl-C6) -alkyl)earbamoyli N-(l)-dehydro-abietylcarb~oyl, N-(C1-C~)-alkyl-N-(I)-dohydro-abiotyl¢a*am!oyl~ N-(C~-Cl~)-aryl¢arb~oyl, N- (C7-Cl~)-aralkyl¢arbamoyl, N-(Cl-c30)-alkyl-N-(cc-clc)-aryl¢arbamoyl, N-(C1-C10~-alkyl-N-(C7-Cl~)-arallcyl-carbamoyl, N- ((Cl-Cl,) -alkoxy- (Cl-C10) -alkyl) -carbamoyl, N- ( (C,-Cl6) -aryloxy- (C1-C10) -alkyl)carbu~oyl, N-((c7-cl~)-aralkyloxy-(cl-clo)-alkyl)carbamoyl, N-(Cl-C"0)-alkyl-N-((Cl-C1O)-alkoxy-(Cl-C1O)-alkyl)-¢arbamoyl, N-(Cl-C10)-alkyl-N-((Cc-Cll)-aryloxy-(Cl-C10)-alkyl)¢arb~noyl, N-(cl-c~o)-alkyl-N-((c7-cl6)--,.
" , ,, ~ .
213~866 .
- 10 - ,, aralkyloxy-(Cl-C10)-allcyl)carbamoyl, CON(C~)h, $n which a C}Iil group can b~ roplaced by O, S, N-(Cl-C,)~
alkyl~m~no, N- (C3-C,) -cycloalkyl~m~no, N-(C,-C~
cycloalkyl-(Cl-C~)-alkyl~m~no, N-(C~-Cl2)-aryl~m~no, N-(C7-Cl6)-aralkyl~m~no or N-(Cl-C")-alkoxy-(Cl-Cs)-alkylimino, and h ic from 3 to 7, carbamoyloxy, N-(C1-C~j,)-alkylcarbamoyloxy, N,N-d~
(Cl-Cl~)-alkylcarbamoyloxy, N-(C~-C~)-cycloallcyl~
carbamoyloxy, N-(C~-Cl~)-arylcarbamoyloxy, N-(C,- `: -~ : j Cl~)-aralkylcarbamoyloxy, N-(Cl-C10)-allcyl-N-(C~
Cll)-arylcarbamoyloxy, N-(cl-clo)-allcyl-N-(c7-cl~
arallcylcarbamoyloxy, N-((Cl-C10)-alkyl)carl:~amoyloxy, N-~(C6-Clj~)-aryloxy-(Cl-C10)-alkyl)carbamoyloxy, N-((C7-Cl6)-aralkyloxy-(Cl-C10)-allcyl)carbamoyloxy, N-(Cl-C10) -alkyl-N- ( (Cl-C10) -alkoxy- (Cl-C~O) -alkyl)carbamoyloxy, N-(cl-clo)-allcyl-N-(( aryloxy-(C,-C10)-allcyl)carbamoyloxy,N-(C1-C10)-allcyl~
N-((C7-Cl6)-arallcyloxy-(C1-C10)-alkyl)carb~oyloxy, : , ; ~ .
amino, (Cl-Cl2) -alkylamino, di-(C1-C1,)-alkylamino, (C3-C,) -cycloalkylamino, (C~-Cl~)-allcenyl~m~no, (C3- ~:~' ,,.. :, .
Cl~)-alkynylamino, N-(C6-Cl~)-arylamino, N-(C7-Cl~
aralkylamino, N-alkyl-arallcylamlno, N-alkyl-aryl- j :; .r: ",' amino, (C1-C1~)-alkoxyamino, (C1-C1~)-alkoxy-N-(C1- :~
C10)-alkylamino, ; ~ . A'.`' (C1-C1,)-alkanoylamlno, (C3-C,) -cycloalkanoylamino, ;.
(C6-C1,)-nroylamlno, (C7-C16)-aralkanoylamino, (C1- ::
C~-alkanoyl-N-(Cl-C10)-alkylamino, (C3-C,) -cyclo- .
alkanoyl-N-(C1-C10)-alkylamino, (C~-C1,)-aroyl-N-(C1- ~
C~0)-alkylamino, (C7-Cll)-aralkanoyl-N-(C1-C10)-alkyl- `
amino, . ~
(Cl-Cl~) -alkanoylamino-(Cl-C~) -alkyl, (C3-C,) _ ` ~ `
cycloalkanoyl~n~no-(Cl-C~)-alkyl, (C6-Cl,)-aroylamino-(C,-C~)-a;Lkyl, (C7-C16)-aralkanoylamino-(C1-C,)-allcyl, amino-(Cl-C10)-allcyl, N-(Cl-C10)-alkylamino-(Cl-C,O)-alkyl, N,N-di-(Cl-C10)-alkylamino-(Cl-ClO)-allcyl, ~. : ~ ~:.. ; .
:.~ ,:. ..
'" "' ' ': ~'~
213~86~
11 .
(C~-C~)-cycloal~ylamino-(Cl-Cl0)-alkyl, (Cl-Cl2)-allcylmercapto, (Cl-Cl2)-allcyl~ulfinyl, (Cl-C~2)-alkylsulfonyl, (C~-Clc)-arylmorcapto, (C~-Cl,)~
aryleulfinyl, (C6-Cl~)-arylsulfonyl, (C7 -Cl~
aralkylmercapto, (C~-Cl~)-aral~yl~ulfinyl or (C7-C16)-aral~ylsulfonyl, Rl and R2 or R2 and R3 form a chain tCH2]o ~n which ono or two CH2 groups of ths chnin, which is ~aturat~d or unuaturated by a C-C doublo bond, are optionally replaced by 0, S, S0, S02 or NR', and o 1~ 3, 4 or 5, and R' i~ hydrogen, (C6-Cl~)-aryl, (Cl-C~)-alkyl, (Cl-C,)-alkoxy-(Cl-C~)-al~yl, (C7-C~ aral~oxy-(Cl-C,)-alkyl, (c6-cl2)-aryloxy-(cl-c~)-al~yl~ (Cl-C10)-al~anoyl, optionally sub~tituted (C7-C~ aral~anoyl or optionally ~ub~titutod (C6-Cl2)-aroyl, whore the radical~ Rl and R2 or R2 and R3, togother with the pyrldine or pyrldazlne carrylng th~m, preferably form a 5, 6, 7, 8-tetrahydrolsoqulnollne rlng, a 5, 6, 7, 8-tetrahydrogulnollne rlng or a 5, 6, 7, 8-tetrahydrocinnoline rlng, or Rl and R2 or Rs and R3 form a carbocycllc or a h-terocycllc, 5- or 6-membered aromatic rlng, where the radlcals Rl and R2 or R2 and R3, together w~th the pyrldlne or pyridazine carrylng them, preferabiy form the followlng optlonally ~ub~tltuted h-terocyclic ring sy~temss Thlenopyrldlne~
Furanopyrldines, Pyridopyrldln-s, Pyrlmidinopyridlne~, Imidazopyridinos, .
i~ :' ~',' '"'' Thiazolopyridinoe, Oxazolopyridinee, Quinolino, ~oguinolino and ;~
Cinnolina, whoro quinolino, ieoquinoline or cinnollno pre~
forably eatiefy the formulae la, lb and lc R~2 ~ ~R~ ~ OR~
1~ 1 b ; : . :. .`
, ,~: ., :: ., :.........
R 2 o ~ Q R~
R22~q~ : ~ :
`N~
1 C , ; ~ .
and the eubstituent~ R~l to Rss, in oach caeo independontly of each othor, have the meaning of Rl, R2 and R3, :
., : ~ I I ' , .,: . : :: . ' R~ ie, if Q iB a bond, halogon, nitrilo or trifluoro-mothyl, or, if Q ie O, S or NR', a braDch-d or unbranched (Cl-CsO)-alkyl radical, an uneub~titutod, :~
~aturatod fluoroalkyl radical of the formula lC~]~
C~H~s~ )F~, a (C~-C1c)-aryl radical, a (Cj-C1,)-aralkyl radical, a heteroaryl radical or a hetoroaralkyl : . .;
radical, . .:
.;'.;,,'.'"'",.:~
,~ ,, ."~
.
213~866 whore the~ rad~cals are s~bstituted by one or more radical~ from th~ group hydroxyl, halogen, cyano, tr~fluoromothyl, n~tro, carboxyl, (C1-C,2)-alkyl, (C3-C,) -cycloalkyl, (C3-C,)-cycloalkyl-(C,-Cl2)-alkyl, (C3-C,) -cycloalkoxy, (C3-C,) -cycloalkyl-(C~-C~)-alkoxy, (C3-c~) -cycloal~yloxy-(C~-C~2)-alkyl, (C3-C,) -cycloalkyloxy- (C,-C,2) -al~oxy, (C3-C,) -cycloalkyl-(C~-C~)-al~yl-(C~-C~)-alkoxy, (C3-C,) -GyC10-alkyl-(C,-C,)-alkoxy-(C,-C,)-alkyl, (C,-C,)-cycloalkyloxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C3-C,) -cycloalkoxy-(C~-C~
alkoxy-(C,-C,)-alkoxy, (C~-C")-aryl, (C7-C") -aral~yl, (C~-Cl2)-alkonyl, (C2-C~)-alkynyl, (Cl-C~2)-al~coxy, (C,-C")-alkoxy-(C1-C~)-alkyl, (c~-c~2)-alkoxY-(c~-c~2)-alkoxy, (C,-C,2)-alkoxy-(C,-C,)-alkoxy-(C,-C,)-alkyl, (C,-Cl,)-aryloxy, (C7-C~c)-aralkyloxy, (C,-C")-aryloxy-(C~
C6)-alkoxy, ~C7-C~)-aralkoxy-(C~-C~)-alkoxy, (C,-C,)-hydroxyalkyl, (Cc-C~)-aryloxy-(C,-C,)-alkyl, (C7-C")-aralkoxy-(C1-C~)-alkyl, (C~-C")-aryloxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C7-C")-aralkyloxy-(C,-C~)-alkoxy-(C~-C~
alkyl, ~O~lC~,]~~C~ lg~F~, -OCF2Cl, -OCF,-CHFCl, ..: :: ,:
(C~-C")-alkylcarbonyl, (C3-C~) -cycloalkylcarbonyl, (C,-C~2)-arylcarbonyl, (C7-C")-aralkylcarbonyl, c~nnamoyl, (C2-C")-alkenylcarbonyl, (C,-C,2)-aklynylcarbonyl, (C~-C~2)-alkoxycarbonyl, (C~-C")-alkoxy-(C~-C")-alkoxy-carbonyl, (C~-C,2)-aryloxycarbonyl, (C7-C~)-aralkoxy-carbonyl, (C3-C,)-cycloalkoxycarbonyl, (C~-C")-alko~yl-oxycarbonyl, (C2-C~2)-~lkynyloxyoarbonyl, (C~-C")-aryl-oxy-(C,-C~)-alkoxycarbonyl, (C7-C")-aralkoxy-(C,-C,)-alkoxycarbonyl~(c3-C~) -cycloalkyl-(C~-C~)-alkoxycarbonyl, (C3-C,) cycloalkoxy-(C~-C~)-alkoxycarbonyl, (C~-C~2)-alkylcaxbonyloxy, (C3-C,) -cycloalkylcarbonyloxy, (C~-C")-arylcarbonyloxy, (C7-C") -aralkylcarbonyloxy, clnnamoyloxy, (C,-C")-alk~nylcarbonyloxy, (C,-C~
alkynylcarbonyloxy, . - :;::: ..,, :.. ., :., (C~-C1,)-alkoxycarbonyloxy,(C~-C~2)-alkoxy-(C,-C,2)-alkoxy-: ::.:; . . ~
213~866 ~ :
- 14 - ~-carbonyloxy, (C,-Cl,)-aryloxycarbonyloxy, (C,-Cl,)-aralkyl-oxycarbonyloxy, (C3-C,)-cycloalkoxycarbonyloxy, (C,-Cl,)-alkenyloxycarbonyloxy, (C,-Cl,)-al~ynyloxycarbonyloxy, carbamoyl, N-(C~-Cs,)-al~ylcarbamoyl, N,N-di-(Cl-C~
alkylcarbamoyl, N- (C3-C,) -cycloalkylcarba~oyl, N,N-dl-cyclo- (C3-C~) -alkylcarbamoyl, N-(Cl-C10~-alkyl-N- (C3 C,) cycloalkylcarbamoyl, N-((C3-C~)-cycloalkyl-(C~-C~
alkyl)carbamoyl, N-(cl-c~)-alkyl-N-((c3-c~) -cycloalkyl-(Cl-C~)-alkyl)carbamoyl, N-(~)-dehydroabi-tylcarbamoyl, ; '~
N-(Cl-C,)-alkyl-N-(~)-dehydroab~etylcarbamoyl, N-(C,-Cl2)-arylcarbamoyl, N- (C7-C") -aralkylcarbamo~l, N-(Cl-C1o)-alkyl-N-(C~-Cl~)-arylcarbamoyl, N-(Cl-Cl0)-al~yl-N- (C7-Cl6)-aralkylcarbamoyl, N((cl-clo)-alkoxy-(cl-clo)- -' alkyl)carbamoyl, N-((C~-Cl~)-aryloxy-(Cl-Cl~)- ; -alkyl)carbamoyl, N-((C7-Cl,)-aralkyloxy-(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-Cl0)-alkyl-N-((Cl-C10)-alkoxy-(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-ClD)-alkyl-N-((C~-Cl~)-aryloxy- ~;
(Cl-Cl0)-alkyl)carbamoyl, N(cl-clo)-alkyl-N-((c7-cl~
aralkyloxy-(C1-Cl0)-alkyl)carbamoyl, CON(CH~)h, in which 20 a CH, group can be replaced by O, S, N-(Cl-C,)-alkyllmino, ;~
N- (C3-C,) -cycloalkyllmlno, N-(C3-C,)-cycloalkyl-(Cl-C~
alkyllmino, N-(C,-Cl,)-aryllmlno, N-(C7-Cl~)-aralkyllmino or N-(Cl-C~)-alkoxy-(Cl-C~)-alkyl~mlno, ~nd h ~e from 3 to 7, or by a carbamoyl radlcal of the formula II
. :' ~ .~ ', ,~'~' ':' ":' R X H ~ :
C O - - N R l ~ `r ( I I ) . ~ :
S ::.. '; ::;':.. -, ln whlch ~ ;~
RY le the eubstituent of an a-amino acld to which the L- and D-amlno acids belong, e le 1, 2, 3, 4 or 5, and T is OH, OR or NR-R--, where . ,,. ~",,.
2134~66 - 15 ~
R-, R--, and R--- are ident~cal or dlfforont and aro hydrogon, (C~-C,2)-aryl, (C7-Cll)-aral~yl, (Cl-C~
alkyl, (C3-C,)-cycloalkyl, (I)-do~ydroabietyl, (C
C,)-allcoxy-(Cl-C~)-alkyl, (C7-Cl~) -aralkoxy-(Cl-C~
alkyl, (C~-Cl~)-aryloxy-(Cl-C~)-alkyl, (Cl-C10)-alkanoyl, optlonally cubctitutod (C~-C16) -aralkanoyl or optionally ~ub~tituted (C,-Cl2)-aroyl, or R and R togother aro -~ ]h~ in w~ch a CEI~ group can be replaced by O, S, SO, SO~, N-aeyla3~no, N-(Cl-C,0)-alkoxycarbonyl~m~no, N-(C1-C,)-~lkylimino, N-(C~-Ca) -cycloallcylimino, N- (C3-C,) -cycloalkyl-(C~-C~)-alkylimino, N- (C6-C~2) -arylimino, N- (C,-C,6)~
aralkylimino or N-(C~-C,)-alkoxy-(C~-C,)-alkyllmino, and h i~ from 3 to 7, or by carbamoyloxy, N- (Cl-C~2) -alkylcarbamoyloxy, N,N-di-(C~
Cl2)-alkylcarbamoyloxy, N-(C3-C~)-cycloalkylcarbamoyloxy, N-(Cc-C,2)-arylcarbamoyloxy, N-(C,-Cl~)-aralkyl-carbamoyloxy,N-(Cl-C10)-alkyl-N- (CC-C12) -arylcarbamoyloxy, N-(Cl-C10)-alkyl-N-(C7-Clc)-aralkylcarbamoyloxy, N-((Cl-C~O)-alkyl)carbamoyloxy, N-((c~-cl2)-aryloxy-(cl-clo) -alkyl)carbamoyloxy, N-((C7-Clc)-aralkyloxy-(Cl-ClO)-alkyl)carba~oyloxy, N-(Cl-C10)-alkyl-N-((Cl-C10)-alkoxy-(C,-C1~)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((C~-Cl2)-aryloxy-(Cl-C,0)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((C7-Cl6)-aralkyloxy-(Cl-C~0)-alkyl)carbamoyloxy, amlno, (Cl-cl2) -alkylamlno, di- (Cl-cl2) -alkylamlno, (C3-C~)-cycloalkylamlno, ~C3-C12) -allcenylamino, (C3-C12)-alkynylamlno, N-(C~-C,2)-arylamino, N-(C,-Cll)-aral~yl-amino, N-alkyl-aralkylamlno, N-alkyl-arylamlno, (Cl-Cl2)-alkoxyamino, (C~-C12) -alkoxy-N-(C,-C,0)-allcyl~ no, (Cl-C,2)-alkanoylamlno, (C3-C,)-cycloalkanoylamlno, (C,-C,2)-aroylamlno, (C,-C,c)-aralkanoylamlno, (Cl-Cl2)-alka-noyl-N-(Cl-C10)-alkylamino, (C3-C,) -cycloallcanoyl-N-(Cl-C10)-alkylamlno, (Cc-Cl2)-aroyl-N-(Cl-ClO)-alkylamlno, (C,-C"~-aralkanoyl-N-(C,-C,0)-alkylamlno, 213~866 (C1-C")-alkanoylamino-(C1-C~)-alkyl, (C3-C,) -eyelo-alkanoylamino-(Cl-C,)-alkyl, (C~-C12) -aroylamino-(Cl-C~)-alkyl, (C7- C16) - aral~anoylamino-(C1-C~)-alkyl, amino-(Cl-C10)-alkyl, N-(C1-C1O)-alkylamlno-(C1-C1O)-alkyl~ N,N-di~C1-C1o)-alkYlamino-(C1-C1O)-alkyl, (C~-C,)-eyeloalkylamlno-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfi~yl, (C1-Cl2)-alkylsulfonyl, (C6-C12) -arylmereapto,(C,-C,)-aryl~ulfinyl, (Cc-Cl2)-arylsulfonyl, (C7-Cl~)-aralkylmorcapto, (C7-Cl6)-aralkylsulfinyl, (C7-C1~)-aralkyl~ulfonyl, sulfamoyl, N-(Cl-C10)-alkyl~ulfamoyl, N,N-di-(Cl-C1o)-alkylsulfamoyl, (C3-Ca)-eyeloalkylsulfamoyl, N-(C~-C12)-aryleulfamoyl, N-(C7-C1c)-aralkylsulfamoyl, N-(C~-C10)-alkyl-N-(C~-Cl2)-arylsulfamoyl, N-(Cl-clo) alkyl-N-(C7-C1~)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamldo, N-((C1-C10)-alkyl)-(Cl-ClO)-alkylsulfonamido, (C7-C~
aralkyl~ulfonamido or N-((C~-C10)-alkyl-(C7-Cl,)-aralkyl-~ulfonamido, where the radleals whieh ¢ontain an aryl radieal ean, for their part, bo sub~tituted on tho aryl by from 1 to 5 ldentieal or differont radioal~ from the group:
hydroxyl, halogon, eyano, trifluoromethyl, nit~o, carboxyl, (C1-C12)-alkyl, (C3-C,) -eyeloalkyl, (C3-C,)-cycloalkyl-(C1-C~2)-alkyl, (C3-C,) -eyeloalkoxy, (C3-C,) -eycloalkyl- (Cl-C12) -alkoxy, (C3-C,) -eycloalkoyloxy-(C1-C1~
alkyl, (C3-C,) ~-eyeloalkyloxy- (C~-C12) -alkoxy, (C,-c~? -cycloalkyl-(Cl-C~)-alkyl-(C1-C~)-alkoxy, (C3-C,) -eyelo-alkyl-(Cl-C,)-alkoxy-(Cl-C~)-alkyl, (C,-C,)-eyeloalkyloxy-(C1-C,)-alkoxy-(C1-C,)-alkyl, (C3-C~) -eyeloalkoxy-(C1-C,)-alkoxy-(Cl-C~)-alkoxy, (C~-C12)-aryl, (C7-C1c~-aralkyl, (C2-C12) -alkenyl, (C2-cl2) -alkynyl, (Cl-cl2) -alkoxy, (C1-Cl2)-alkoxy-(C1-Cl2)-alkyl, (el-C1~)-alkoXy-(cl-cl2)-alkoxy, (Cl-C,2)-alkoxy-(C1-C,)-alkoxy-(C1-C,)-alkyl, (C,-C12)-aryloxy, (C7-C1c)-aral~yloxy, (Cc-Cl2)-aryloxy-(Cl-C,)-alkoxy, (C7-C1,)-aralkoxy-(C1-Cc)-alkoxy, .: . .: : ~:,.' ~:
' .:: .. " :::':i:
. . ~ : . , . :~ ~
,; :
213~866 (Cl-C,)-hydroxyalkyl, (C,-Cl~)-aryloxy-(Cl-C,)-al~yl, (C7-Cl~)-aralkoxy-(C,-C,)-alkyl, (C~-Cl2~-aryloxy-(Cl-C~)-alkoxy-(Cl-C6) -alkyl, (C,-Cl,)-aralkyloxy-(Cl-C~)-alkoxy-(~l-C~
alkyl, -O-[CH~]~-CrH~ )F~, -OCF,Cl~ -OCF,-CHFCl, -~
:: .
(Cl-Cl~)-alkylcarbonyl, (C3-C,)-cycloal~ylcarbonyl, (C,-Cl,)-arylcarbonyl, (C7-Cl~)-arallcylcarbonyl, ;
(Cl-Cl~)-alkoxycarbonyl, (Cl-Cl,)-alkoxy-(Cl-Cl2)-alkoxy-carbonyl, (C~-Cl~)-aryloxycarbonyl, (C7-C~ ralkoxycarb-o~yl, (C3-C~)-cycloalkoxycarbonyl, (C,-C1,)-alkonyloxy-10 carbonyl, (C,-C12) -alkynyloxycarbonyl, (C~-C12) -aryloxy-(Cl-C~)-alkoxycarbonyl, (C7-Cl~)-aralkoxy-(Cl-C~)-alkoxy-carbonyl, (C3-C,)-cycloalkyl-(Cl-C,)-alkoxycarbonyl, (C3-C~)-cycloalkoxy-(Cl-C~)-alkoxycarbonyl, (Cl-Cl,)-alkylcarbonyloxy, (C3-C,)-cycloal~ylcarbonyloxy, ~;~ s 15 (C~-Cl,)-arylcarbonyloxy, (C7-C1~)-aral~ylcarbonyloxy, :~
cinnamoyloxy, (C,-Cl,)-alkonylcarbonyloxy, (C~-Cl,)~
alkynylcarbonyloxy, . ~ !
(Cl-Cl~)-alkoxycarbonyloxy, (Cl-Cl~)-alkOxy- (Cl~Cla) ~
alkoxycarbonylcxy, (C~-Cl~)-aryloxycarbonyloxy, (C7-C
20 aralkyloxycarbonyloxy, (C3-C~)-cycloalkoxycarbonyloxy, :~
(C,-Cl,)-alkonyloxycarbonyloxy, (C,-Cl2)-allcynyloxy~
carbonyloxy, :~
carbamoyl, N-(Cl-Cl~)-alkylcarbamoyl, N,N-dl-(Cl-C1,)- ... :. ~
alkylcarbamoyl, N-(C3-C,)-cycloalkylcarbamoyl, N,N-di- : ;;
cyclo-(C3-C,)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C,)-cycloalkylcarbamoyl, N-((c3-c!)-cycloalkyl-(cl-c~
alkyl)carbamoyl, N-(Cl-C~)-alkyl-N-((C3-C,)-cycloalkyl-(Cl-C~)-alkyl)carbamoyl, N-(l)-dehydroabietylcarbamoyl, : , N-(Cl-C~)-alkyl-N-(~)-dehydroabletylcarb~moyl, N-(C~-C1,~
30 arylcarbamoyl, N-(C7-C1~)-aralkylcarbamoyl, N-(Cl-Clo)- ; ;:~ ::
alkyl-N-(C~-Cl~)-arylcarbamoyl, N-(Cl-Cl0)-al~yl-N-(C7-Cl~)-aralkylcarbamoyl, N-((cl-clo)-alkoxy-(cl-clo) alkyl)carbamoyl, N-((c~-cl~)-aryloxy-(cl-clo)-alkyl)carbamoyl, N-((C7-C1~)-aral~yloxy-(C1-C10)-alkyl)oarbamoyl, N-(Cl-C~0)-alkyl-N-((C1-C10)-alkoxy~
': ~ ' :
- 213~866 ` ~:
(C1-C10)-alkyl)carbamoyl, N-(cl-clo)-al~yl-N-((cc-cl2) -aryloxy-(C,-C10)-al~yl)carbamoyl, N-(C,-C10)-al~yl-N-((C,- .
Cl6)-aralkyloxy-(Cl-C10)-al~yl)carbamoyl, CON(CH2)~, ln . :
which a CH2 group can be replac~d by O, ~, N-(C1-C,)-alkylimino, N-(C,-C,)-cycloalkylimino, N- (C3-C,) -cyclo-alkyl-(C,-C~)-alkylimino, N-(C~-C12)-aryl~m~no, N-(C~-C1~)-aralkylimino or N-(C1-C~)-alkoxy-(C1-C~)-al~ylimi~o, and h i8 from 3 to 7, carbamoyloxy, N-(C1-C")-alkylcarbamoyloxy, N,N-di-(C1-C1~)-alkylcarbamoyloxy, N- (C3-C,) -cycloal~ylcarbamoyloxy, N- (C6-cl6) -arylcarbamoyloxy, N-(C,-Cl~)-aralkyloarbamoyl-oxy, N-(Cl-C10)-alkyl-N- (C6-C12) -aryl~arba~oyloxy, N-(C~
C~0)-alkyl-N- (C7-ClC) -aralkylcarbamoyloxy, N-((Cl-clo) alkyl)carbamoyloxy, N-((C,-Cl~)-arYlXY-(cl-clo)- :; :~
alkyl)carbamoyloxy, N-((C,-Cl,)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((Cl-ClO)-alkoxy-(Cl- ::~
C10)-alkyl)carbamoyloxy, N-(cl-clo)-alkyl-N-((cc-cL~) - : .
aryloxy-(Cl-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C1~)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, . - .
20 amlno, (Cl-C1,)-alkylamino, d~-(C1-C1~)-alkylamino, (C3-C,) -:~
cycloalkylamino, (C3-Cl,) -al~onylamino, (C3-C~) -alkynyl-amino, N-(C,-C1,)-arylamino, N-(C7-C11)-aralkylamlno, N-alkyl-aralkylamino, N-alkyl-arylamino, (Cl-C1,)-alkoxyamlno, (C1-C1,)-alkoxy-N-(C1-C10)-alkyl~no, (C1-C")-alkanoylamino, (C3-C,) -cycloalkanoylamino, (C~
Cl~)-aroylamino, (C,-Cl,)-arallcanoylamino, (Cl-Cl~)-alka- .,'. ::~
noyl-N-(C1-C10~-alkylamino, (C3-C,) -cycloalkanoyl-N-(cl-C10)-alkylamino, (C,-C1,)-aroyl-N-(C1-C10)-alkylamino, (C,-C11)-aralkanoyl-N-(Cl-C10)-alkylam~no, i; ~ ;
(C1-C1,)-alkanoylamino-(C1-C,)-alkyl, (C,-C~)-cyclo-alkanoylamino-(C1-C~)-alkyl, (Cc-C1,)-aroylamino-(C1-C~)- : .- .::.:i::.. :
alkyl, (C,-C1c)-aralkanoylumino-(Cl-C,)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(Cl-ClO)-alkyl, N,N-di-(cl-clo)-alkylamino-(cl-clo)-alkyl~ ( C3 - C,) - cycloalkyl-35 ~mino-(C1-C10)-alkyl, ~ :
- ~', :~'' ~:., ' ! ',, "' ., .. ' ', ~: ' 213~866 (Cl-C12)-alkylmercapto, (Cl-C~ alkylsulfinyl, (C~-C~
al~ylsulfonyl, (C6-Clc)-arylmercapto, (C~-C1,)-aryl-sulfi~yl, (C~-C")-arylsul~onyl, (C7-C")-aralkylmercapto, (C7-C1~)-aralkyleulfinyl or (C7-C~)-aralkyl~ulfonyl, and R~ i~ R", providod that Q ha~ the m~aning of NR', where R~ and R" aro identical or difforent and ar~ hydro-gon, (C,-Cl,)-aryl, (C7-Cl)-aral~yl, (C1-C~)-alkyl, (~1~C~)-alkoxy-(Cl-c~)-alkyl~ (C7-Cl~)-aral~oxy-(C,- ~ 8 C~)-alkyl, (C~-C,2)-aryloxy-(C1-C~)-al~yl, (Cl-C~0)-alkanoyl, optionally ~ubstitut-d (~7-C1,)-aralkanoyl or optionally sub~titut-d (C~-C12) -aroyl, or R' and R" togothor are -~CH,lh, in which a CH~ group can be roplacsd by 0, S, N-acylimino or N-(C1-C~o)~
alkoxycarbonylimino, and ~`;
f i3 l to 8, g is 0 or 1 to (2f~
x i~ 0 to 3, h i8 3 to 7, lncludlng tho physiologically act$ve ~alts, ~ ;
with 3-bonzyloxypyridine-2-carboxyllc acid (L-throonyl)-amido and 3-benzyloxypyrldine-2-carboxylic aoid ((Fmoc-Phg)L-threonyl)amlde hydrochlorlde being xcept-d.
In general, aryl is understood to mean carbocyclic and hoterocycllc aromatlc ring ~ystems. In partlcular, it ~8 ;
under~tood to lnclude phenyl-substituted, blphonyl-~ubstltuted, naphthyl-~ubstltut~d or un~ubstituted 5- and 6-membered heteroaromatlc rlngs havlng 1, 2 or 3 nltrog-n and/or oxygen and/or ~ulfur atoms, 8uch as dQrlvatlv~ of pyrldyl, pyrldazyl, pyrimldyl, pyrazyl, imldazolyl, ; ~ -triazolyl, thlenyl, oxazolyl and thiazolyl, and their benzo-fu~od derivative~
The inv~ntion also mbraces salts of the compounds of th~
formula I.
:: .
213~866 The formation of ~alt~ w~th ba~io reagento can take place once, twice or three times on th~ acidio groups of tho compounds of the formula I (i - radicals B, Rl, R~, R3 and R~), in particular on tho radicals B, R' and/or R~
Examples of reagonts boing usod are nlcoholat~, hy-droxides, carbo~ates, hydrog n carbonatos! hydrogon phosphates, organometallic compounds of tho alkali and alkaline earth element~, the elements of the third and fourth main group~ of tho period~c systom, and tho elements of the transition met~l~
amines, optionally substituted 1 to 3 times by (C,-C,)-hydroxyalkyl, (C,-C~)-alkoxy-(C,-C,)-alkyl, phenyl, benzyl or (C,-C,)-alkyl, which oan be substituted 1 to 3 t~mes by hydroxyl or (Cl-C~)-alkoxy, for example tromethane (Tri~ buffer), 2-aminoethanol, 3-aminopropanol, hydroxylamine, dimothylhydroxylamin-, 2-methoxy~thyl-amine, 3-ethoxypropylamine, and ba~ic amino ac~d~ and amlno dorlvative~, ~uoh a~ amino acid ester~, hl~tidlne, arginine and lysi~e, and their derivatives, and also "" '.: '"' ' ;'~' pharmaceuticals which contain a baslc group, such as, for xample, ~Amiloride, ~Verapamil and beta blocker~
~ - ,. ::: ;j ,- ..~:, The lnventlon al~o r~lates to the compounds according to formula I, plus 3-b-nzyloxypyrldlne-2-carboxyllc acld (L-threonyl)amld~3 and 3-bsnzyloxypyridine-2-carboxylic aoid ((Fmoc-Phg)L-thr~olnyl)~mido hydrochlorldo for uco as pharmaceutlcal~
..` ,~ :
Compound~ of the formula I are of great int-r-~t, ln whlch 30 Q ~ 0, ~, NR' or a bond, X 18 0, ~
Y 1~ CR3 or, ;
lf R~ and Rl form a cycle, Y 1~ N or CR3, , :: .
213~866 m i8 0 or 1 Compounds of tho formula I are vory lmportant, in whieh Q is 0, NR' or a bond, X is 0 5 Compound~ of the formula I aro al~o very lmportant in which Q is 8 and X i~ 0 ~ ~ ;
Compounds of tho formula I aro of particular importa~ee in whieh Q i~ 0, NR' or a bond, ;;, ~ `
1 0 X i 8 0, Y is CR3 or, if R' and R' form a eyelo, N or CR3, m is 0 or 1, A i~ (Cl-C3) -allcyleno whieh is opt~ onally substitutod once by halogon, eyano, trifluoromethyl, (Cl-C,)~
alkyl, (Cl-C6)-hydroxyallcyl, (Cl-C,)-alkoxy or -0-[C}~2~"--Cf~It,f,l ~F~" or A is -CHR5-, whero R5 18 onts of the ~ub~tituents of the a-ear}~on atom of an a-amino aeld, in partieular ~ ;
of a natural L-amino acid and of its D-isom r, B i8 C0~%, :.
R2 is hydrogon, (Cl-C,0)-alkyl, (C,-C,0)-alkonyl, (C,-C,0)-alkynyl, (Cl-C~O)-alkoxy, (C,-C,0)-allcenyloxy, (C2-C,O) -alkynyloxy, r-tinyloxy, (Cl-C~0) -alkoxy- (Cl-C3) -alkyl, (C,-C,0~ -allc-nyloxy- (C1-C~) -alkyl, retinyloxy- (Cl-C~) -alkyl, (C,-C,0) -alkynyloxy- (Cl-C~)-alkyl, halogen, eyano, trifluoromethyl, (Cl-C~
hydroxyalkyl, (Cl-C,0)-alkanoyl, (C7-Cl~)-aralkanoyl, (C~-Cl~) -aroyl, (C~-Cl2) -aryl, (C7-Cl~) -arallcyl, ~O~ ~CH2~"-CrH~t.~l s"F", N}~'Rn, (Cl-C1O) -alkylm-rcapto, (Cl-C10)-alkyl~ulfiDyl, (Cl-C10)-alkylsul~onyl, (C~
Cl,)-arylm~rcapto, (C~-Cl,)-arylsulflnyl~ (C,-Cl,)-arylsulfonyl, (C7-Cl,)-arallcyl~oreapto, '.,''' ~'''',''~'''.,'' :: :: :;: :.::, . . :,:
2l3~s6e (C7-Cl~)-aralkylsulfinyl, (C7-C~2)-aralkylsulfonyl, (Cc-cl2)-aryloxy~ (C7-CI6)-aralkyloxy, earboxyl, (Cl-C20)-alkoxycarbonyl, (Cl-Cl2)-alkoxy- (Cl-Cla) -alkoxy-carbonyl, (C,-Cl2)-aryloxycarbo~yl, (C7-Cl~ ral-koxycarbonyl, (C,-C,)-eycloalkoxyearbonyl, (C,-C20)-alkonyloxycarbonyl, r~tinyloxycarbonyl, (C2-C20)-alkynyloxycarbonyl, (C3-C,) -cyeloalkyl-(Cl-Cc)-alkoxycarbonyl, (C,-C~)-eyeloal~oxy-(Cl-C~
alkoxyearbonyl, (C~-C32)-aryloxy-(Cl-C~)-alkoxy~
carbonyl, (C,-C16) -aralkoxy-(C1-C~)-alkoxyearbonyl, earbamoyl, N-(C1-Cl2)-alkylearbumoyl, N,N-di-(C,-Cl2)~
alkylearbamoyl, N- (C3-C,) -eyeloalkylearbam~yl, N,N-dieyelo (C3-C,) -alkylearbamoyl,N-(Cl-Cl0)-al~yl-N- (C3-C,)-eyeloal~ylearbamoyl, N- (C3-C,) -eyeloalkyl-(C -C~
alkyl)earbamoyl, N-(cl-c~)-alkyl-N-((c3-c~) -eyelo-alkyl-(Cl-C~)-alkyl)earbamoyl, N-(l)-dehydroabietyl-carbamoyl, N-(Cl-C~)-alkyl-N-(~)-dehydroab~otyl~
earbamoyl, N-(C~-C1,)-arylcarbamoyl, N-(C,-C")-aralkylcarbamoyl, N-(Cl-Cl0)-alkyl-N-(C~-Cl~)-aryl-carbamoyl, N-(Cl-Cl0)-alkyl-N-(C7-Cl~)-aralkylcar-bamoyl, N-((Cl-Cl2)-alkoxy-(C -Cl0)-alkyl)earba_oyl, N-((C~-C1~)-aryloxy-(Cl-Cl0)-alkyl)earbamoyl, N-~(C,-Cl~)-aralkyloxy-(C1-Cl0)-alkyl)earbamoyl, N-(Cl-C1o)~
alkyl-N-((Cl-Cl0)-alkoxy-(Cl-C10)-alkyl)earbamoyl, N-(Cl-Cl0)-alkyl-N-((C,-C1,)-aryloxy-(Cl-Cl0)-alkyl)earbamoyl, N-(cl-clo)-alkyl-N-((c7-cl~) aralkyloxy-(C1-C10)-al~yl)earbamoyl, CON(CE~)~, in whieh a C~2 group ean be replaeed by O, S, N-(C1-C,)-alkylimlno, j N! ~C3-C,) -eyeloalkylimino, N- (C3-C,) -eyeloalkyl-(C1-C~)-alkylimino, N-(C~-C1~)-aryllmlno, N- (C7-C~) -aralkyllmlno or N-(C1-C~)-alkoxy-(C1-C,)-alkyllmino, and h i~ from 3 to 7, .
, .., ~ .
where aryl i~ ~ub~tltut-d in tho manner a- defined for and R', 5 R1 and R3 are idontleal or difforont and are hydrogen, halogen, (C1-C1,)-alkyl, (C1-C~2)-alkoxy, -O-[C~ -C~
213~66 ~, (c~-cl2)-alkoxy-(cl-cl2)-al~yl, (~-C~
alkoxy- (C~-C12) -alkoxy, (C,-C,2) -alkoxy-(C~-C~
alkoxy-(C2-C~)-alkyl, (C7-C~) -aralkyloxy, (C3-C,) -cycloalkyl, (C3-C,) -cycloalkyl-(C,-C,)-alkyl, (C3-C~)-cycloalkyloxy, (C3-C,) -cycloal~yl-(C~-C~)-alkoxy, (C3-C,) -cycloalkyloxy-(C,-C,)-~l~yl, (C~-C,)-cyclo-alkyloxy-(C,-C~)-alkoxy, (C,-C,)-cycloal~yl-(C~-C,)-alkyl-(C,-Cc)-alkoxy, (C3-C,) -cycloalkyl-(C~-C~
alkoxy-(C,-C~)-alkyl, (C3-C,) -cycloalkoxy-(C~-C~
alkoxy-(C,-C,)-alkyl, NRYRZ, (C,-C,)-alkylm rcapto, (C,-C,)-alkyl~ulf~nyl or (C~-C,)-alkyl~ulfonyl, (C,-Cl~)-arylmercapto, (C,-C")-aryl~ulfinyl, (C~-C
arylsulfonyl, SCj-C")-aralkylmercapto, (C7-C
aralkyl~ulflnyl, (C7-C,l)-aralkyl~ulfonyl, oubstituted (C~-Cl2)-aryloxy-(C,-C~)-alkyl, (C7-C
aralkoxy-(C1-C6)-alkyl, (C~-Cl~)-aryloxy-(C~-C~
alkoxy-(C,-Cc)-al~yl, (C7-Cl~)-aralkyloxy-(C,-Cs)-alkoxy-(C,-C~)-alkyl, (C,-C1,)-aryloxy, (C7-C,1)~
aralkyloxy, (C6-C12)-aryloxy-(C1-C~)-alkoxy or (C7-C~)-Aralkoxy-(C~-Cc)-alkoxy, wh-ro an aromatic radical carrie~ by 1, 2, 3, 4 or 5 idontical or difforont sub~tituont~ from tho group hydrogen, halogon, cyano, nitro, trlfluoromothyl, (C,-C
alkyl, (C,-C,6) -alkonyl, (C,-C6) -hydroxyalkyl, (C
C16) -alkoxy, (C,-C,6) -alkonyloxy, -O-[CH~]~-C~H~ F~
-OCF~Cl, -O-CF~-CHFCl, (C,-C,)-alkylmorcapto, (C~-C6)-alkylsulfinyl, (C~-C6) -alkyl~ulfonyl, (C,-C~)-al~yl-carbonyl, (C,-C6)-alkoxycarbonyl, carbamoyl, N-(C,-C~)-alkylcarbamoyl, N,N-di-(C~-C~)-alkyl-carbamoyl, (Ç~-C~)-alkylcarbonyloxy, (C,-C~)-cyclo-alkylcarbamoyl, ph-nyl, bonzyl, phenoxy, benzyloxy, NRYRZ, phonylmorcapto, phonylculfonyl, ph~nyl-~ulfinyl, ~ulfamoyl, N-(C,-C~)-alkyloulfamoyl or N,N-di-(C,-C~)-alkylsulfamoyl, or optionally carrie~ up to 3 of tho abovomontloned ldontlcal or diffor-nt ~ub~titu~nt~, and two ad~acont carbon atom~ of th~
aralkyloxy radical togethsr carry a chaln-tCH~
and/or -CH=C~-CH3C~-, whero a C~ group of tho chaln 1~ optionally roplaced by O, S, SO, SO, or NR', 213~86B
R~ and R2 or Rl and R3 form a chain [CH~o~ where o is 3, 4 or 5, or form, together wlth the pyridine or pyridazine carryi~g thQm, a einnollns ring, a quinollno ring or an lsoquinoline ring, R~ i~, if Q is a bond, fluorine, chlorine or bro~ino, or, if Q is 0 or NR', a branehod or unbranehod (C~
C20) -alkyl radieal, wh~eh can eontain up to 3 C-C
multiple bonds, u~ uneubetitutod ~aturatod fluoro-alkyl rndical of the formula tC~2]~-Ct~(2~ F~, a (C6-Cl,)-aryl radieal or a (C7-Cl,)-aralkyl radieal, which can contain up to 2 C-C multiple bonds $n tho alkyl chain, or an h~toroaryl rad$cal or an het~ro-aryl alkyl radical, whero these radieals are ~ubsti-tutod by one or ro radicals from the group ~ydroxyl, fluorine, ehlorine, eyano, tri~luoro-methyl, earboxyl, (Cl-Cl,)-alkyl, (C3-C,) -cyeloalkyl, (C3-C,) -cyeloalkyl-(Cl-Cl~)-alkyl, (C3-C,) -eyelo-alkoxy, (C3-C,) -cyeloalkyl-(Cl-Cl2)-alkoxy, (C3-C,) -cycloalkyloxy-(Cl-Cl,)-alkyl, (C3-C,) -eyeloalkyloxy-(C,-C12)-alkoxy, (C3-C,) -eyeloalkyl-(Cl-C,)-alkyl-(Cl-C6)-alkoxy, (C~-C,)-eyaloalkoxy-(Cl-C,)-alkoxy-(Cl-C,)-alkoxy, (C~-Cl2)-aryl, (C7-Cl~)-aralkyl, (C~-Cl,)-alkenyl, (C2-Cl2)-alkynyl, (Cl-C")-alkoxy, (Cl-Cl2)-alkoxy-(C,-Cl2)-alkoxy, (Cl-Cl,)-alkoxy-(Cl-C~
alkoxy-(Cl-C,)-alkyl, (C~-C12) -aryloxy, (C,-C
aralkyloxy, (C~-C12) -aryloxy-(Cl-C~)-alkoxy, lC7-C16) -aralkoxy-(Cl-C~)-alkoxy, (Cl-C,)-hydroxyalkyl, -0-lCH2.~-c~H~2~ )F~
(Cl-C12) -alkylearbonyl, (C,-C,)-eyeloalkylearbonyl, (C6-C12) -aryloarbonyl, (C7-Clc)-aralkylearbonyl, (Cl-C12) -alkoxyearbonyl, (Cl-cl2) -alkoxy- (Cl-c12) -alkoxyearbonyl, (C6-C~2)-aryloxyearbonyl, (C7-Cl,)-aralkoxycarbonyl, (C~-C~)-¢yeloalkoxyearbo~yl, (C2-Cl2)-alkonyloxyearbonyl, (C2-Cl2)-alkynyloxyearbonyl, 213~86G
(C3-C,) -cycloalkyl-(Cl-C~)-alkoxycarbonyl, (Cl-Cl,)-allcylcarbonyloxy, (C~-C,)-cycloalkyl-carbonyloxy, (C~-C12) -arylcarbonyloxy, (C,-C~
aralkylcarbonyloxy, carbamoyl, N-(Cl-Cl2)-allcylcar- ~ -bamoyl, N,N-d~-(Cl-Cl2)-alkylcarbamoyl, N- (C3-C,) -cycloalkylcarbamoyl, N,N-dicyclo- (C3-C,) -alkyl-carbamoyl, N-(Cl-Cl0)-alkyl-N-(C,-C,)-cyoloallcylcar-b a m o y l, N - ( ( C 3 - C, ) - c y c l o a l k y l - ( Cl- C~
allcyl)carbamoyl, N-(Cl-C,)-alkyl-N-( (C3-C,) -cyelo-alkyl-(C1-Cc)-alkyl)carbamoyl, N-(l)-dehydroabiotyl-carbamoyl, N-(Cl-C~)-allcyl-N-(I)-dohydroabietyl-carbamoyl, N-(C~-Cl,)-arylcarbamoyl, N- (C7-Cl~) -aralkylcarb~moyl, N-(Cl-Cl0)-alkyl-N-(C~-Cl~)-aryl-carbamoyl, N-(Cl-ClO)-alkyl-N-(C,-Cl,)-aralkylcarba-moyl, N-((Cl-Cl0)-alkoxy-(Cl-Cl0)-alkyl)carbamoyl, N-((C~-Cl~)-aryloxy-(Cl-Cl0)-alkyl)carbamoyl, N-((C,-Cl~)-aralkyloxy-(Cl-C,0)-alkyl)carbamoyl, CON(CHl)~ ln whlch a CH2 group can be replaced by O, N-(Cl-C~)-alkyllmino, N-(C3-C8)-cycloalkylimino, N- (C3-C,) -cycloalkyl-(Cl-C~)-alkylim~no, N-(C~-Cl,)-arylimino or N- (C7-Cl~) -aralkylimino, and h 18 from 3 to 6, where the radlcals which contain an aryl radlcal aan, for th-lr part, be ~ub~ltutesd on tho aryl by from 1 to 5 ldontlcal or dlfferent radlcal~ from tho ;~ r "~ ''''~' groups hydroxyl, fluorine, chlor~ne, cyano, trlfluoro-methyl, carboxyl, (Cl-Cl~)-alkyl, (C3-C,) -cyeloalkyl, (Cl-C~)-alkoxy, (C3-C~)-'cycloalkoxy, (C~-Cl2)-alkoxy- ,.
earbonyl, ~ ~
N-(Cl-C~)-alkylcarbamoyl, N,N-d~-(C1-C~)-alkyl- ~ ~ ~'',' ';''''~J'',' carbamoyl or N- (C3-C,) -cycloalkylcarbamoyl, and R~ 1~ R, provided Q ha~ tho m-aning o~ NR', whoro R' and R~ aro id-ntlcal or difforent and are hydrog-n, ;
(Cl-C,)-alkyl, or (C,-Cll)-arallcyl which i~ optlonally 213~866 substituted onco by fluor~ne, chlorine or (C,-C,)- . ;~ ~ ~
alkoxy, ~ ~ .
RY and R~ are identical or difforent and are hydrogon, (C~-C~ aryl, (Cl-C~0)-alkyl, (C~-C10)-cycloal~yl, (C,-C,)-alkoxy-(C,-C~)-alkyl, (C7-cl2) -aralkoxy-(Cl- ~;~
C,)-alkyl, (C,-Cl,)-aryloxy-(Cl-C,)-alkyl, (Cl-C10)-alkanoyl, optionally substituted (C,-Cl,)-aral~anoyl or optionally sub~tituted (C,-Cl,)-aroyl, or RY and R~ together are -[CH,~, in which a CH, group can be replaced by O, S, N-(Cl-C~)-alka~oylimlno or N-(Cl-C~)-alkoxycarbonylimlno, and ~ -f is l to 8, ~ ~
g is 0 or 1 to (2f ~ 1), -:; ;~:.::;.. ~-.. ~.
h is 3 to 6, 15 x is 0 to 3, and n is 3 or 4.
Compound~ of the formula I are preferred in whlch Q i~ O, NR' or a bond, X is O, 20 Y is CR3 or, if Rl and R' form a cycle, N or CR',: ; -m io 0, ~ :
A i~ (Cl-C3)-alkylene which i~ optionally ~ubstituted once by halogen, cyano, trlfluoromethyl, (Cl-C6)-alkyl, (C,-C6~-hydroxyalkyl, (Cl-C6)-alkoxy or -O-lC~,]X-Ct~ F~ or : ::
: I ' ` ~ ! ' ~ .
A i~ -C~R5-, where R5 is one of the substituent~ of th-a-carbon atom of an a-amino acid, ln partioular of a natural ~-amino aoid and of it~ D-lsomor, : :-. ~, ":.. ,:
B is CO,H
:. . :,: ,. : ~, ~:
30 R' is hydrogen,.(Cl-C20)-alkyl, (Cl-C,0)-alkonyl, (C,- ::
C20)-alkenyloxy, (C2-C20)-nlkynyloxy, retinyloxy, '''' "'''.'~"'"
213~866 ~ ~ ~
(Cl-Cl0)-alkoxy-(C,-C,)-alkyl, (C,-C,0)-alkoxy-(C,-C3) -alkyl, (C~-C20)-al~enyloxy-(C~-C~)-alkyl, retinyloxy-(C~-C~-alkyl, (C2-C~o) -alkynyloxy-(C~
C,)-alkyl, (C1-C,0)-alkoxy, haloge~, eyano, trlfluoromethyl, (C~-C")-hydroxyalkyl, (C~-C~0)-alkanoyl, (C7-C~2)-aralkanoyl, (C~-C~)-aroyl, -O-tCH~-C~(s~ F~, Na~a~ (cl-clo) -al~ylmor¢apto, (C~-C~0)-al~yleulf~nyl, (C~-C~)-al~ylsulfonyl, (C~
C~2)-arylmercapto, (Cc-C~)-arylsul~y}, (C~-C~2)-aryl~ulfonyl, (C~-C~aralkylmoseapto, (C7-C")-aralkyleulfinyl, (C7-C,2)-aralkyl~ulfonyl, (C,-C~
aryloxy, (C,-C~)-aral~yloxy, earboxyl, (C,-C,0)-alkoxyearbonyl, (C,-C~2)-alkoxy-(C,-C~
alkoxyearbonyl, (C~-Cl,)-aryloxyearbo~yl, (C,-C")-aralkoxycarbonyl, (C3-C,) -cycloalkoxycarbonyl, (C2-C,0)-alkenyloxycarbonyl,retinyloxycarbonyl, (C~-C20)-alkynyloxyearbonyl, (C3-C~) -cyeloalkyl-(C~-C~
alkoxycarbonyl, (C3-C,)-~ycloalkoxy-(C~-Cc)-alkoxycarbonyl, (C,-C1,)-aryloxy-(C,-C~)-alkoxy-carbonyl, (C7-C,c)-aralkoxy-(C,-C,)-alkoxycarbonyl, carbamoyl, N-(Cl-C")-alkylearbamoyl, N,N-di-(C,-CL,)-alkylcarbamoyl, N-(C3-C~)-cycloalkylearbamoyl, N,N-dicyclo(C3-C~)-alkylearbamoyl,N-(C~-C~0)-alkyl-N-(C3-C~)-cycloalkyl¢arbamoyl, N-(C3-C~)-cyeloalkyl-(C,-Cc)-alkyl)carbamoyl, N-(C,-C,)-alkyl-N-((C3-C,)-cyclo-alkyl-(C~-C~)-alkyl)carbamoyl, N-(~)-dohydroabiotyl-carbamoyl, N-(C,-C,)-alkyl-N-(I)-dehydroabiotyl-carbamoyl, N-(C~-C~ arylcarbamoyl, N-(C,-C~
aralkylcarbamoyl, N-(Cl-C,0)-alkyl-N-(C,-C~,)-aryl-carbamoyl! N-lC1-C~0)-alkyl-N-(C,-C~2)-aralkylcarb-amoyl, N-((C,-C")-alkoxy-(C,-C,0)-alkyi)carbamoyl, N-((C~-C~,)-aryloxy-(C,-C~0)-alkyl)carbamoyl, N-((C7-C~)-aralkyloxy-(C,-C,0)-alkyl)carbamoyl, N-(C1-C~o)~
alkyl-N-((C~-C,0)-alkoxy-(C~-C~O)-alkyl)earbamoyl, N-(C,-C,0)-alkyl-N-((C,-C")--ryloxy-(C,-C~O)-alkyl) carbamoyl, N- (C,-C,0) -alkyl-N- ( (C,-C~
- aralkyloxy- (C,-C,O) -alkyl) carbamoyl, or CON(Cl!I,)h, ln whlch a CH~ group can be replaced by 0, S, N- (Cl-C,) -alkylimino, N- (C3-C,) -cycloalkyllmlno, 213~66 N-(C3-C~)-cycloallcyl-(C1-C4)-allcyl~m~no, N- (C6-C~
aryl~mino, N- (C,-C16) -aralJcyl~m~no or N-(C1-C4)-alkoxy-(Cl-Cc)-alkyl~m~no, and h i~ from 3 to 6, wherQ aryl ls ~ubstituted Jn tho mannQr aEI dof~ned for and R3, Rl and R3 are ident~cal or diff~r-nt and are hydrogen, halogen, (Cl-Cl,)-alkyl, (C1-C~)-alkoxy, -O- lCEI~]J-C~ al~l~ (cl-cl~) -alkoxy-(C1-Cl,)-allcyl, (Cl-C,)-alkoxy-(Cl-Cl,)-alkoxy, (Cl-Cl,)-alkoxy-(C,~
C~)-alkoxy-(C~-C6)-alkyl, (C7-C 1) -~ralkyloxy, (C3-C~)-cycloalkyl, (C3-C~)-cycloalkyl-(C1-C~)-al~cyl, (C3-C,) -cycloallcyloxy, (C3-C,)-cycloalkyl-(Cl-C,)-alkoxy, (C3-C~)-cycloalkyloxy-(Cl-C~)-alkyl, (C3-C,)-cycloalkyloxy-(Cl-C,)-allcoxy, (C3-C,)-cycloallcyl-(Cl-C6) -alkyl-(Cl-C~)-alkoxy, (C3-C,)-cycloalkyl-(Cl-Cc)-alkoxy- (C,,-C6) -allcyl, (C3-C,)-cycloallcoxy-(Cl-cc)-alkoxy-(Cl-C~)-alkyl, NRYRZ, (Cl-C,)-alkylmercapto, (C,-C,)-allcyl~ulfinyl or (Cl-C,)-alkylsulfonyl, (C,-Cl,)-arylmercapto, (C,-Cl,)-aryl~ulfinyl, (C,-Cl2)-aryl~ulfonyl, (C,-Cl,)-aralkylmercapto, (C,-Cl,)-aralkylsulfinyl, (C,-Cll)-aralkylsulfonyl, sub~t~tutod (C6-Cl,)-aryloxy-(Cl-C,)-alkyl, (C,-Cll)-aralkoxy-(Cl-C~)-alkyl, (C~-C1~)-aryloxy-(Cl-C~
alkoxy-(C1-C~)-alkyl, (C7-C~l) -aralkyloxy-(C1-C~
alkoxy-(Cl-C,)-alkyl, (C,-Cl2)-aryloxy, (C7-C~
aralkyloxy, (C,-Cl,)-aryloxy-(Cl-C,)-alkoxy or (C,-Cll)-aralkoxy- (Cl-C6) -alkoxy, where an aromatic radical carri~ by 1, 2, 3, 4 or 5 identlcal or different sub~tituQnt~ from the group hydrogen, halogen, cyano, nitro, trifluoromothyl, (Cl-Cl~
alkyl, (Cl-Cl,)-alkonyl, (Cl-C,)-hydroxyalkyl, (Cl-Cl,) -alkoxy, (Cl-Cl,) -allc-nyloxy, --[CH~]x~CtH(~ F~ -OCF,Cl, -O-CF,-CHFCl, (C1-C,)-alkylmercapto, (Cl-C6)-alkyl~ulfinyl, (Cl-C~)-alkyl-~ulfonyl, (Cl-C,)-alkylcar}~onyl, (Cl-C,)-alkoxy-carbonyl, carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl-C~)-alkylcarba~oyl, (Cl-C,)-alkylcarbonyloxy, ., .,, .: ., 213~86G
(C~-C~)-cycloalkylcarbamioyl, phenyl, b~zyl, phonoxy, benzyloxy, NRYR~i, phenylmercapto, phonylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C1-C,) -alkylsulfamoyl or N,N-di- (Cl-C~) -all~ylsulfamoyl, or optlonally carries up to 3 of tho abovementloned ide~lt~ cal or difforent eubstituents, and two ad~acsnt carbon atoms of the aralkyloxy radlcal togeth~r carry a chain -tCH,-~ and/or -C~l.CEI-CE~.C~I-, whero a C~l~ group of the chain ~8 optionally roplacod by 0, S, SO, SO, : ~ -or NRY, Rl and R' or R2 and R3 can form a chain tC~,] O~ whore o i8 :
3, 4 or 5, and :
", R4 , provided Q is a bond, is chlorine os, if Q i~3 0 or NR~, is a branched or u~branchsd (Cl-C10)-allcyl radical, which can contain one or two C-C multlple ~ ~
bonds, or an unsubstituted fluoroalkyl radical of - :::
the formula - LcH2]~,-c~ 2~ y~F~ or (Cl-C,) -alkoxy- (C~
Cc) -alkyl, (Cl-C,) -alkoxy- (C1-C~) -alkoxy- (Cl-C~) -alkyl ~ ~;
or a radical of the f ormula Z, . .
~: : ::.
-[C H2lV-1O]w-[CHJ, E (Z) ~ : ~; s whero E i~ a oubstitutod phenyl radlcal of the f orsnula F
R~ R~
~ R ~ ( F ) R l C R ; .~. . .
or a (C3-C,)-cycloalkyl radical, whoro v i0 O, 1, 2, 3, 40 5 or 6, w 18 O or 1, and t ~8 O, . ::
1, 2 or 3, with the re~trictlon that v is not egual :~;
to O if w is 1, and R', R7, R~, R9 and R10 are iden- -;
tical or d~fferent and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C,-C~)-alkyl, ;~
,. ,.":
:' :,"' '.:;':' '~';'''',,.,,,'', `.`'''''~'''. "'' ', j (C~-C~)-cycloalkyl, (Cl-C~)-alkoxy, -O-~CH,]~-C~H~
F~, -O~F~Cl, -O-CF, CHFCl, (Cl-Cc)-al~yl~ercapto, (Cl-C~)-hydroxyalkyl, (C1-C~)-alkoxy-(Cl-Cc)-alkoxy, (Cl-C~)-alkoxy-(Cl-C~)-alkyl, (Cl-C~)-alkylsulfinyl, (Cl-C~)-alkylsulfonyl, (C,-C,)-alkylcarbonyl, (Cl-C,)-alkoxycarbonyl, carbamoyl, N-(C~-C,)-alkylcarbu~oyl, N!N-di-(Cl-C,)-alkylcarba yl, (C7-Cll)-aralkylcarba- `
moyl which i~ optionally ~ubetituted by fluorine, ~-chlorine, bromine, trifluorom~thyl or (C~-C~)-alkoxy, N- (C3-C,) -cycloal~ylcarbamoyl, N-(C~-C,)-~ycloal~yl-(Cl-C~)-alkylcarbamoyl, (C1-C,)-alkylcarbonyloxy, phenyl, b~nzyl, phonoxy, b~nzyloxy, NRYR~, ~u¢h a~
amino, nnilino, N-m thylan~lino, ph-nylmercapto, phenyleulfonyl, phonyl~ulflnyl, ~ulfamoyl, N-(Cl-C,)-alkylsulfamoyl or N,N-dil-(Cl-C~)-alkylsulfamoyl, or ~wo ad~acent ~ubetltuents togeth-r ars a chain -~C~ -C~.C~-C~.C~-, where a CH, group of th- cha~n iB optionally r~placed by O, S, SO, SO, or NRY, and where a heteroaryl radical can carry 1, 2 or 3 sub~tituents, and a cycloalkyl radical one ~ ;
sub~tituent, from the above group, and R~ ie R~, providod Q hac the meaning of NR', where ~ ;
R' ~ hydrog~3n or methyl, and ;~ ;
R i~ benzyl, and if Rl and/or R3 have the meaning of (C~-Cl~)-aryloxy, (C7-Cll)-aralkyloxy, (C~-Cl,)-aryloxy-(Cl-C~)-alkoxy, (C7-Cll)-aralkoxy-(Cl-C~)-alkoxy or a corre~ponding radical con-taining terminal cycloalkyl group~, this radical lc ; ; ~ i;
preferably then a radical of tho formula D ~ ~
OZ (D), or ,~ ~
if ~1 and/or R3 havo the moaning of (C7-Cll)-aralkyl, ~ ,`
~C,-Cll)-aryloxy-(Cl-C~)-alkyl, (C7-Cll)-aralkoxy-(Cl-C,)-alkyl or a corro~ponding radical containing torminal ; ```
cycloal~yl groups, thi~ radical i~ pr~forably then a ;~
radical of the formula Z, :: . . : ..
RY and RZ aro ldent~ c81 or difforent and aro hydrogon, : ~:
(C6-Cl2)-aryl, (Cl-ClO)-allcyl, (C3-C10)-cycloallcyl, ~, (Cl-C,)-alkoxy-(Cl-C,)-alkyl, (C7-Cl,)-aral~oxy-(C,-C~)-alkyl, (C~-C,s)-aryloxy-(Cl-C~)-al~yl, (Cl-C10)-alkanoyl, optionally cubstituted (C7-Cl6~-aralkanoyl or optlonally ~ubstitutod (C~-Cl2)-~royl, or RY and RZ aro togothor -tC~2~, in which a CE~ group ca~ ,t.'' be replaced by 0, S, N-(Cl-C~)-alka~oylimino or N- -~
(Cl-C~)-alkoxycarbonylimlno, and ;~
f ~ 1 to 8, . .
g ie 0 or 1 to (2f h i~ 3 to 6, x is 0 to 3, and n is 3 or 4. ; :-~
~ . ~ .. -.~-.... .
lS Co~pound~ o~ tho formula I ar~ particularly pr~ferred in ..
which ;~
X is 0, :; ~ ' ~'J '. ,1.~'~''~''`
Y i~ CR3 and, additionally, N lf Rl and R2 form a cyclo, m i8 0~ '''J''',"'",''~ ,'' A 1~ -CHR~-, whor- R' i~ the ~ubstituont of th- a-carbon atom of an a-amino acid, in partlcular of a :~
natural L-amlno acid or lt~ D-lsomer, B is C02H, .. -R' is hydrogen, bromino, chlorino, cyano, (Cl-C~
alkyl, (C~-C,)-alkoxy, (Cl-Cl,)-alkoxymothyl, (C~-C~
alkonyloxymothyl, (C~-C~)-alkynyloxymothyl, :.:~
carbamoyl, N-(Cl-C10)-al~ylcarbamoyl, N-((Cl-C~2)- .. -alkoxy-(Cl-C~)-alkyl)carbamoyl, N,N-di-(Cl-C,)-alkylcarbamoyl, N(C~-C,)-cycloalkylcarbamoyl, N-(C,- .
- Cl2)-phenylcarbamoyl, N-(C7-Cl2)-phonylalkylcarba- ; `
moyl, N-(Cl-Cc)-alkyl-N-(C,-Cl2)phenylcarbamoyl, N- j : -(Cl-C6)-alkyl-N-(C7-Cl,)-phonylalkylcarbamoyl, :~
,., ,,. .~ ~
'' :' ~`
2 1 3 ~ 8 6 6 N-((C,-C~)-alkoxy-(Cl-C~)-alkyl)earbamoyl, oarboxyl, (Cl-C~O)-allcoxycarbonyl, (C3-C20)-alkenyloxycarbo~yl, ret~nyloxyearbonyl, (C3-C,)-eyoloalkoxyearbonyl, (C3-C~)-eyeloalkyl-(Cl-C~)-al~oxyearbo~yl, (C3-C,)-eyeloalkoxy-(Cl-C,)-alkoxyearbonyl, phenyl-(C~-C~)-alkoxyearbonyl, phonoxy-(Cl-C,)-alkoxyearbonyl or benzyloxy-(Cl-C,)-al~oxyearbonyl, wher- a ph~nyl radleal 1~ su~etituted ln the mann-r ae defined $or Rl and R3, and one of the radieale Rl or R3 ~e hydrogen and the other a radieal from the group hydrogen, fluorln~, ehlorln~, (Cl-C,)-alkyl, (Cl-C1O)-alkoxy, (Cs-C~)-cycloalkyl, (Cs-C~)-cyclo-alkyl-(Cl-C6)-alkyl, (C5-C,) -eyeloalkyloxy, (C5-C,) cycloalkyl-(Cl-C~)-al~oxy, (Cs-C,)-cycloalkyloxy-(C
C~)-alkyl, (C5-C,) -cycloalkyloxy-(C1-C~)-al~oxy, (C5-C,)-eyeloalkyl-(Cl-C~)-alkyl-(Cl-C~)-al~oxy, (Cs-C,)~
cycloalkyl-(Cl-C~)-alkoxy-(Cl-C~)-alkyl, (C5-c~
cycloalkoxy-(Cl-C~)-alkoxy-(Cl-C2)-alkyl, -O-[CH2]~-C~K(2f~l~,F~,(Cl-C,)-alkoxy-(Cl-C~)-alkyl,(Cl-C,)-alkoxy-(Cl-C,)-alkoxy, (Cl-C,)-alkoxy-(Cl-C~
alkoxy-(Cl-C2)-alkyl, eubet~tut~d (C,-Cl2)-ph-noxy, (C7-Cll)-phonylalkyloxy, (C~-Cl2)-phenoxy-(Cl-C~
alkoxy or (C7-cll) -ph-nylalkoxy-(Cl-C~)-alkoxy, phenoxy-(Cl-C~)-alkyl, (C7-Cll)-phenylalkyloxy-(Cl-C~)-alkyl, phenoxy-(Cl-C~)-alkoxy-(Cl-C~-alkyl or (C7-C~l)-phenylalkyloxy-(Cl-C~)-alkoxy-(Cl-C2)-alkyl, whor- an aromatlc radleal le ~ubetltut-d by 1, 2 or 3 ldentlcal or dlfferent subetituents from the group 1uor,1ne, chlorlne, eyano, trifluoro-methyl, (Cl-Cl2)-alkyl, (C2-Cl2)-alkenyl, (C2-Cls)-alkenyloxy or (Cl-Cl~)-alkoxy, Rl and R2, wlth the pyrldlne earrylng them, form a 5, 6, 7, 8-tetrahydrolsoqulnoline rlng, R~ le a branehed or unbraneh~d (Cl-C10)-alkyl rad1eal, (Cl-C~)-alkoxy-(Cl-C~)-alkyl or a radleal of th~
formula Z, ', ~ ~' ;`'' ,''~'''. ' ---`` 213~8~6 ,~CH2lV-1Olw-~cH2J~-E (Z) '' ' whero E i8 a ~ub~t~ tutod phenyl radlcal of tho f onnula F
R ~ R
_~_ RS ( ~
R 1 0 R9 ~ ~ -or a (C3-C,)-eyeloallcyl radleal, wh-r~ v 1EI 0, l, 2 -;
or 3, w i8 O, and t ean b- 0 or 1, and ln wh~ eh R', R7, R', R9 and Rl ~r~ ~dent~cal or differ-nt ~d are hydrogen, fluorine, chlortno~ cyano, trlfluoro-m o t hy l , ( C , - C ~ ) - a l ky l , ( C l - C , ) - a l k oxy , ~O~ ~CH~;]~~C~H~ )Fg~ N- (Cl-C~) -alkylear~amoyl, N,N-di- (C,-C6) -alkylcarbamoyl, N- (C,-C,) -cyeloalkylearba-moyl, N-(~)-dehydroab~otylaminocarbonyl, or (C7-Cll)-phenylalkylcarbamoyl, which ~ s optionally tituted by fluorinn, ehlorine, trlfluoromethyl or (C,-C~)-alkoxy, or whoro RC and R' or R7 and R', ~ a togother w$th the phonyl ring carying th-m, form naphthalono dorivatives ~;
: . . ~ , : , ., If Rl or R' ha~ th- moaning of (C~-Cl2)-phenoxy, (C7-Cll)- ~ ~
~ ,....... .
ph-nylalkyloxy, (C~-Cl,) -phenoxy- (Cl-C~) -alkoxy, (C,-Cl,) -phonylalkoxy- (C,-C,) -alkoxy, (C,-C,) -cycloalkyloxy- (C~-C,) - ~ ~ `
alkoxy, (C,-C~) -eycloalkoxy- (Cl-C,) -alkoxy or (C5-C,) - ~ .~ . ..... ... /
cyeloalkyl- (Cl-C~) -alkyl- (Cl-C~) -alkoxy, thi~ radical i8 th-n, o~pecially, a radical of tho formula D
OZ (D), or - . .:: ~. ::; .
. :,, :. .. ,:,, if Rl or R3 has tho mo~ing of phenyl, phonoxy-(C,-C,)-25 alkyl, (C7-Cll) -ph-nylalkyl (C7-Cll) -phenylalkyloxy- (Cl-C") -alkyl, (C~-C~) -cycloalkyl, (C~-C~) -cycloalkyl- (Cl-C~
allcyl, (C~-C~) -cycloalkoxy- (Cl-C~) -alkyl, (Cs-C~) -eyclo- ~ -alkyl- (Cl-C~) -alkoxy- (Cl-C,) -alkyl or (C,-C~) -cycloalkoxy-'~.',,,,..~
- 213~866 (C,-C~)-alkoxy-(Cl-C,)-alkyl, th~ radlcal i8 thon, e~pocially, a radical of tho formula Z in which, ln both ca~es, v is 1, 2, 3 or 4, w is 0 and t is 0, or v is 1, 2, 3 or 4, w i~ 1 and t is 0, or v is 1, 2, 3 or 4, w ~8 1, t 1~ 1, and f is 1 to 4, .
g i~ 0 or 1 to (2f~
x i~ 0 or 1. ::~
Compounds of the formula I ar~ very particularly pre-f~rred in which -~
Q i8 O, . `
X i~ o, Y i~ CR3, -m is 0, A i~ a -CH2- group which can b~ ~ub~tituted by a ~ - m methyl group, ~ ,":,a 8 is -CO2H, R2 is hydrogen, (Cl-C,)-alkoxy, (Cl-Cl~)-alkoxymothyl, (Cl-Cl~)-alk~nyloxymethyl, retlnyloxymethyl, N-(C1- .
C~0)-alkylcarbamoyl, N-((Cl-Cl,)-alkoxy-(Cl-C3)-alkyl)carbamoyl, N,N-di-(Cl-C~)-alkylcarbamoyl, N~
(C5-C~)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl-(Cl-C~)-alkylcarbamoyl, carboxyl, (C~-Cl~ . P
alkoxycarbonyl, (C2-Cl~)-alk~nyloxycarbonyl, . . ~
ret~nyloxycarbonyl, (C~-C~)-cyclonlkoxycarbonyl, (C5- ~ ,.. ."~,.` ;,;
C,)-cycloalkyl-(Cl-C,)-alkoxycarbonyl or phenyl-(C
C~)-alkoxycarbonyl, where a phonyl radical i~
sub~t~tutod in the manner a~ defined for Rl and R3, and one of th~ radicals R1 or R3 1~ hydrogen and the other radical i~ a radical ;~
from the group hydrog-n, (C,-C~0)-alkoxy, (C,-C,)-cycloalkylo.~y, (C,-C,)-cycloalkyl-(Cl-C,)-alkoxy, ~O~~CH~l~~CtH~s~ g~Fy~ (Cl-C~)-alkoxy-(Cl-C~)-alkoxy, cubstituted (C6-Cl,)-ph~noxy, (C7-C11)-phenylalkyloxy, (C~-C12) -phenoxy-(Cl-C~)-alkoxy or (C7-Cll)-phsnyl-~;, , 213~866 alkoxy-(C~-C,)-al~oxy, wh~r- an aromatic rad~c~l le substitutcd by 1, 2 or 3 ldentical or dlffor-nt eubst~tuente from the group fluorine, chlor~n~s, cyano, trlfluoromothyl, (C1-C10)-alkyl, (Cl-C10)-alkoxy or (Cl-C10)-alkenyloxy, and : ~ " ., ' ~
R~ is a branchod or unbranchod (Cl-C~)-alkyl rad~cal or .. :.. .. `
a r~dlcal of tho formula Z, -lCH~lv-lOlw-lCHalt-E (Z) where B ia a eubstitutod ph~anyl radical o tho lC formula F
R~ R7 ~ R~ ( F ) , ~ ` ~
t o R . .~
.-. :,.`:.
or a (C3-C,)-cycloalkyl radical, whero .
v 1~ O, 1, 2 or 3, w is 0, and t can b- 0 or 1, and ~. -;:: .;;
in which R6, R', R', R9 and Rl aro ~dent~cal or different and aro hydrogen, fluorino, chlorlne, ~ . . .
cyano, trifluoromethyl, (Cl-C~)-alkyl, (C~-C6)- . .:
alkoxy, -O-lCH,~X-CtH~lt~l9)F9, N-(Cl-C,)-alkylcarba-moyl, N,N-dl-(Cl-C~)-alkylcarb~moyl, N-(C,-C,)-cycloalkylcarbamoyl, N-(I)-dohydroabietylamlnocar-bonyl substituted benzyl radlcal, and f i8 1 to 4, ; . :
g l~ 0 or 1 to (2f~ and x 1~ 0 or 1.
Compound~ of the formula I aro partlcularly preferr-d ln ..
whlch . ~:
Q 18 O, X 18 O, .; .
25 Y is CR3, ~:~
m 1~ 0, B 18 -CO2H, A 1~ a -CH~-group, ,. ., ~ .
213~g66 Rl $~ hydrogen, (Cl-C~)-alkoxy or ~O~tC~,]~~C~HO~.lg,Fg, R2 is hydrogen, N-(C~-C,0)-alkylcarbamoyl, N-((Cl-C~
alkoxy-(C,-C,)-alkyl)carbamoyl,N,N-di-(C~-C,)-alkyl-carbamoyl, N-(Cs-Cc)-cycloalkylcarb~moyl, N-phonyl-carbamoyl,N-phenyl-(C~-C~)-alkylcarbamoyl,carboxyl, (C~-C~)-alkoxycarbonyl, (C2-C~)-alkenyloxycarbonyl, rotinyloxycarbonyl, (C~-C,)-cycloalkoxycarbonyl, (C5-C6)-cycloalkyl-(C~-C~)-alkoxycarbonyl or phenyl-(C
C~)-alkoxycarbonyl, whero a phonyl radical 1~
sub~tituted by 1 or 2 ld-ntloal or difforont sub~tituente from the group fluorine, chlorine, cyano, trifluoromethyl, (Cl-C,0)-alkyl, (C,-C,0)-alkenyloxy or (C,-C~0)-alkoxy, and R3 i~ hydrogen, (C,-C5) -alkoxy or (C5-C,) -cycloalkyl-~C,-C2)-alkoxy, wher~ one of the ~ubstltuent~ R1 and R3 i~ hydrogen, ~ 6 i R~ i~ a branched or unbranched (C,-C,)-al~yl radical, or a 2-phonylethyl radlcal, or a bonzyl radical ~ub~tituted by 1 or 2 radlcal~ from tho group flu-orlne, chlorlne, cyano, trlfluoromethyl, (Cl-C,)-alkyl, (C,-C,)-alkoxy, -O-~CX2]~-C~H~ )F~, N-(Cl-C,)-alkylcarba~oyl, N,N-di-(C,-C,)-alkylcarbamoyl,N-(C,-C,)-cycloalkylcarbamoyl or N-(~)-dehydroabletyl-aminocarbonyl, and f 1~ 1 to 4, g 1~ 0 or 1 to (2f~1) and x 1 : : :
Compound~ of the formula I are preferred to the hlghe~t degree ln whlch Q 1~ O, X 1~ O, Y i8 CR3, m i~ 0, A 1~ a -CH,-group, R~ 18 hydrogen, 213~866 R~ i~ hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((Cl-C~
al~oxy-(Cl-C,)-alkyl)carbamoyl, N-~yclohexylcar~
bamoyl, N-phenylcarbamoyl, N-(phenyl-(Cl-Cs)-al~yl)-carbamoyl, whero, in the last two caco~, the phenyl radlcal can carry a fluorins subotituent, (Cl-Clo3-alkyl oub~tituent or (Cl-ClO)-alkoxy cub~tituent, carboxyl, (Cl-Cl,)-alkoxycarbonyl, (Cs-Clc)-alkenyl~
oxycarbonyl, retinyloxycarbonyl, (C5-C~) -cyclo-al~oxycarbonyl or bonzyloxycarbonyl, R3 i8 hydrogan, (Cl-C~)-alkoxy or 2-(cyclohexyl)ethyl-oxy, whore one of tho ~ubet~tuento Rs and R~ io hydrogon, ; ~
R~ i~ a branchod or uDbranched (Cl-C~)-alkyl radical or ~ . .:;
a benzyl radical which ic ~ubotitutod once by flu-orine, chlorino, trifluoromethyl, (Cl-C~)-al~yl or .
( Cl - C3 ) -alkoxy~
Compounds of the formula I are aloo preferred to the ;.
highe3t degree in which Q i~ 8, ;. ;
20 X i8 O, ,.
Y i8 CR3, m io 0, A io a -CHs- group, i l~ - COsH, Rl io hydrogen, Rl io hydrogen, N-(Cl-C10)-al~ylcarbamoyl, N-((Cl-Cl,)-alkoxy- (Cl-C3) -al~yl)carbamoyl, N-cyclohexylcarha-moyl, N-phenylcarbamoyl, N-(phenyl-(Cl-Cs)al~yl)-carb~moyl, wherQ, in the laot two ca~e~, the phenyl radical can carry a fluorin~ ~ubotituent, (Cl-C10)-:.; ::;: :~:
alkyl oubotituent or (Cl-C10)-alkoxy ~ubctituent, ::
carboxyl, (Cl-Cl,)-alkoxycarbonyl, (C~-Cl~)-alkenyl- :.
oxycarbonyl, retinyloxycarbo~yl, (C5-C,)-cycloalk-oxy~arbonyl or benzyloxycarbonyl, ,, ~ ", ,,; "
~' ' ".:. ' `.:
R3 is hydrogen, (Cl-C,)-~lkoxy or 2-(cyclohexyl)-ethyloxy, whore one of tho substituont~ R' and R' ~o hydrogen, and R~ 18 a branched or unbranch-d (~,-C~)-alkyl radical or a benzyl radical which lc substltut-d onco by flu-orine, ohlorln-, trifluoromothyl, (Cl-C~)-alkyl or (Cl-C3)-alkoxy The compound~ of the formula I aro al~o profqrr-d to the highe~t degree ~n wh~ch 10 Q i~ S, ~-Y i8 CR3 m is 0, A is a -CH2-group, -15 B i8 -CO~H, ' ~' ~,,, ~'~ ,'''~'"'',~`'~','~''!'~
Rl iB hydrogen, ~ >-R2 is carboxyl or (Cl-Cl,)-alkoxycarbonyl, R3 is hydrogen, and ;
R~ is a branch-d or unbranch~d (Cl-C~)-alkyl radlcal Tho compound of tho formula I i~ al~o pr-forred to the hlgh-~t dogreo in which Q i~ 0, X ia 0, Y i~ CR3, whor~ R3 i~ hydrogon, ~ -m i~ 0, A 18 a -CH2-group, B is -C02H-, Rl and R2, togethor with th- pyridin- carrying them, form an i~oqulnollno ring havlng an unsubstltut-d b~nzo moloty, and R~ 1~ methyl " ;'~ . ' : ^~;: , ,, ~, ,.., ~
Tho compound of tho formula I 1~ also pref-rr-d to tho highe~t degr-- in which -~
Q ;8 0, t . ''~
'':': ' " ',', "' .', ' " ' '~;
21~866 - 39 - ;
X is 0, Y ie CR3, -~
m ie 0, A ie a -C~-group, 5 B i~ -C0~
Rl is hydrogon, R' and R3, togother with the pyridine carrying them, form a quinolino ring having an unsubstituted benzo ~;
moioty, and R4 is mothyl.
, .
Tho invention al80 ~mbracee prodrugs for tho compound~ o~ :
tho formula (I), which prodrugs bring about an i~hl~it~on -~
of collagon blosynthosie in vivo by liborating compounds ~ i~
of tho formula I or thoir ealte.
,~
"
Finally, the invontion also ~mbracoe prodruga which, by liberating compounide of the formula I or their ealta, bring about i~n lnhlbitory effect in vivo on prolyl-4-hydroxylaee.
.
Prodrug groupinge aro chomical groupe whlch, ln vlvo, -, 0 - aro convortod ~nto the carboxylato group of the compounde of th~ formula I, and/or - can bo cleav~d from the amldo N atom, and/or - can bo converted into a pyrldlno ring. ~ ;~
., -: .~
-, . . ::.::
Thoee prodrug groupe which aro ouitable are known to tho porson skllled in the~art.
:,. :::
~he followlng prodrug grouplngs receive partlcular montlons ;
for the carboxylate group, ester groupe, amlde group~
hydroxymothyl groups and aldehydo group~, and tholr derlvatlvess for the pyrldino N atom, N-oxide~ and N-alky~ deriratlvoe; and fox the pyrldlne rlng, 1,4-dihydropyridine derivatives or tetrahydropyridino derivativee. ~ i '.." ~:
,: ~.,,,i:
213~866 The invention relatos to tho u~e of c Q ounds of tho formula I, and also the phy~iologically tolarated ~alt~
for inhibiting collagon biosynthesis.
The inventlon relatos to the use of compounds of the formula I, and also tho physiologically tolerat~d ~alts, for inhibiting prolyl-4-hydroxylase. ~ -~
The inve~tion also relate~ to the use o~ compou~ds of the ~ ;~
formula I, and al80 the physiologically toleratod salt~
for producing a pharmaceutical against fibrotic disease~
The invention also relates to the use of compound~ of the formula I, and al~o the physiologically tolerated salts, for producing a pharmaceutical against fibrotic diseases of the liver, the lung and the skin.
::
Finally, the invention relates to the compounds of the ~ ;
formula I for use as pharmaceutical~
The invention relate~, in particular, to the compounds of -the formula I for use as fibrosuppressive ag-nte.
The invention al~o relate~ to a procese for pr-paring compounds of the formula I.
20 The oompound~ of the formula I, in whi¢h A i~ a ~
~ubstituted alkylene moiety, B i~ C02~, Y is CR' and m is ;;~ ;
0 or 1, are prepared by ;~
,, ~ j , , , , :
11.) Rea¢ting pyridine-2-carboxylic acids of th- formula II (R~3 is H) with the amino esters of th- formula III to form tho amid- e~ters of the formula IV, or i-i2.) Reacting pyridins-2-carboxylic estere of the for~ula; ; -~
II (R~3 is lower al~yl), under the conditions of aminolysis, to form the compounds of the formula IV;
and ,--ii) liberating the compound~ of the formula I from th~ir eeters of the formula IVs with, whero appropriate, iii) the oompounde of the formula IV boing prepared by alkylation of compounds of the for~ula V with R~
iand, where appropriate, : ; :
: .. . ~
i~) the compounds o~ th~ Formula IV being convert~d, :
pro~ided Q is 0 or NR', into thoir pyridine N-oxidee :-:
IV' (R'~ iB (C3-C3,)-alkyl or benzyl) and the l~Att~r :~:
being hydrolyzod to form the pyridino N-oxid~s of tho formula I' (R2~ ie H). :
Scheme 1 . :
~C22~2~ -c~2l~2~
l V
~ - ~
~ X t ~ ~ ~
", , ... . .. ~.
R
J R2~NH-~-CO2R2~ ~
R~ . ;
O ' . ' ,' " ,., V .-: - .::`.
:, ' ' ', ' ~'', O R ' ~ N - A - t O, 2 A - C O, ~ , "'~ : ; . .
o O : ~ . .','"'.''' :'''::' v~ c,-e")-~ . ~n~
I ~ 12~ N . . ~ ~
' ~ .,; ',;: .
;, . ~ ' ' . ,:
' ,,:,~. ;:.',:",' :''; ~',.'.'' i R~3 ie H or (C,-C16)-alkyl, .
;: :.;. .: ,.
.,, : .:
'".;' .~ ' '" ' ''','', ' ' ~ ' 6", ' ' ;; ~
213~866 R~ i B X, (Cl-Cl,)-alkyl or bonzyl, X ie a leaving group, ln particular halogen, OSO~Me or OSO~phenyl The methods of carboxyl actlvation and the condensatlon reactions known from peptide ch d ~try are sultable procosse~ for the amide formation (reactlon il) The eub~tance~ which are known to the per~on skllled ln the art, such as thlonyl chloride, oxalyl chloride, pivaloyl chloride, chloroformate derivativo~, or N,N'-carbonyldiimidazolo, can b- u~ed a~ roag-nt~ for tho carboxylic acid activatlon The aotlvated dorlvAtive~ of the compounds of the formula II aro prepared ln situ and then rsacted with tho amide derivativee of tho ~ormula III
A~ exa~ple of a euitable conden~ing agent ie the combination of N,N~-dicyclohexylcarbodllmldo/N-hydroxy-lH-benzotriazolo and N-ethylmorphollne Sultablo aolvents aro dichlorom thane, t-trachloro-methane, butyl acotato, othyl acotnt-, tolu-n-, totra-hydrofuran, dlmethoxy-tha~e, 1,4-dloxano, ac-tonltrlle, N,N-dlmethylformamld-, N,N-dim-thylacotam$do, dimothyl ~ulfoxldo, nltromethano and/or pyrldlne The compoundo of the formula I, ln whlch R~ and R3 aro hydrogen and R~ 18 a carboxyl eubstltuent, a carbamoyl ~ub~3titu-nt or an ! est~r ~ub~tltuont, wero proparod a~
outllned ln schomes 1, 2 and 3 ,, , . " . :,. .:
8cheme 2 lllu~trat-r3 th- preparatlon of tho compound~ of the formula TI ln whlch Rl lo a c~rboxyllc acid ~ubstltuont, or lts derlvatlve, and Rl and R' aro hydro-gen :, '. . ,: '" ' ~' Th- 3-~3ubstituted 5-carboxypyridlne-2-carboxyllc e~3ter~
of the formula XI and thelr isomer~ of the for~ula XII
' are prepared from the pyrldlno-2,5-dicarboxyllc die~ti~rs of tho formula VII.
The oxidation of the pyridine-2,5-dicarboxylatos of tho formula VII is d~scribed in J. Chem. Soc. Per~in Tra~.
2, 1978, 34-38 and in J. Org. Chem. 25 (1960) 565 to 568 (M.L. Peterson).
The halogenation (chlorination) of the pyrid~no N-ox~d,~,s of the formula VIII with thionyl chloride and the reac-tion of the 3-chloropyridine-2,5-dicarboxyllc diostor (Formula IX) with alcoholat~s (Q i,s o or 8) can be carried out in analogy with tho proco,~ do,scrlbed in the patent specification 7~H 658 651 (LONZA), where M 18 a singly charged or doubly chargod metal ion, preferably from the first or second mai~ group of the periodic syetem.
In analogy with the known literaturo (7-A: vol. 68, 1968, 68 840 h), the monoesters of tho formula XII are pre~
pared, under hydrolysis condltions, from the substituted pyridine-2,5-dicarboxylic dio~ters of the formula Xb.
Seloctive hydrolysis using ~u(II) salts, J. Delarge in Pharmaceutica Acta Holvetiao 44, 637-643, 1969, repre-,s,-nt~ anothar procos~ for preparing the compounds of the formula XII from tho diesters of the formula Xb. 1~ ;
,:-, . :,.: ,,, . : ;
The compounds of the formula XII thus obtained are reaoted with the,amino estor~ of the formula III to form the compounds of tho formula IV (SchQme 2).
,:~
Ths pyridine-2-carboxylic ester-5-carboxylates of the formula XI can be prepared, under eeiterification condi-tlons, from substituted pyridino-2,5-dicarboxylic acids of tho formula Xa (see CA: vol. 68, 1968, 68840 h).
~ultable conditions are, for examplo, eE,terification with mothanol in the presence of sulfuric acid, it being necessary to choose the reaction time 80 that complete ' " ::' "
"....
II:A . i; i ~ .
' ; . ~;
213~866 - . .
esterification to form tho d~e~ter product only ta~o~
placo to a ~ocondary oxtent, or ~o that tho diostor ~ -products can bo ~oparatsd off a~ by-product~.
Tho compounds of tho formula XI aro convsrtod w~th amlnoo or alcohole $nto ths 5-carboxylic acid doriv~tl~o of the formula XIV (Scheme 3).
These are then hydrolysod to form tho ~iompounds of th~
formula II (R23 i~ ~), which compou~d~ aro sub~oqu-ntly reacted in analogy with Scheme 1.
Scheme 2 RO2C~ 2 ~ ~`CO2R
V l I I
V I I
h~logen~tion ( R ~ H, lower ~Ikyl ) ~
:` ,' '~ ''''".: ' .",' UOR~ e r R O ~ C~O R U ( ~ ) O R ~ R O 2 C~¢~L
~C O 2 R C O 2 R
I X
X a : R H L C I, a ~
X b : R lower ~Ikyl 1~ metd ion, :
~ingly or doubly \ ch rged \ O O . 5 , : '~ '' :`"'"' U 2 C~O R ~C O H
X I R Iower dkylX I I R Iow ~Ikyl H, \l - A - C O 2 R ~
I V ' ., 213~866 , Scheme 3 ROIl o r HNRR
~02C ~R~ X I I I ' R2 QR~
~C 2 low ~1 ~C 2 lower~l X I X I V R2 . COOR, CO-NR R
The 2-hydroxymethylpyridlnes of the ~or~ula VI-, which are dir~clo~ed in ~P-A-O 304 732, EP-A-O 321 385 a~d EP-A-0 208 452, can bo used a~ ~ntermodiatee for preparing ~ -5 derlvativo~ (Rl) which are eubstitut-d in th- 4 posltlon ~ -. .
Scheme 4 ~ -R2 ~ QR Id 1i ~2 R~ CH20H R C02~
V I I I ( R 1 ~ H ) v I o ~ ~ I c : o R 4 O ~ me~yl) V l ~ ~ l l b : O R ~ O i~ n ( ~ n benzyl ) ; ~ -', Th- 3-0-benzyl derlvative~ of the formula VIb were al~o obtained in an analogous manner, a~ de~cribod ln thoso documents .. : ,:
The compounds of the~ formulas VIa and VIb wor- react-d wlth an oxldlzlng agent, preforably wlth RMnO~ ln agueous alkalino msdlum, to form th- pyridino-2-carboxylic acid dorivatlv-s of tho formula TI (of Schemo 4) Th- proparation of sub~tltuted pyridine-2-carboxylic ~ ;
acids 18, for example, dlsclo~od ln DE-A-353 046, and for ~; ,;
3-(3-chlorophonoxy)pyridine-2-carboxylic acld and 3-(3- ~ `
methylphonoxy)pyridlno-2-carboxylic ncid in J Med Chem 1975, 18, pp 1-8, Vlllani ot al ; ~or ' ~
: , . .
213~8S6 -3,5-diethoxypyridine-2-carboxylic acld ln J. Med. Chem.
1974, 17, pp. 172-181, French et al.; and for 3-mothyl-thiopyridine-2-carboxylic acid and 3-benzylthlopyridine-2-carboxylic acid in J. Med. Chem. 1974, 17, pp. 1065-1071, Blank et al.; and for 3-methoxypyridine-2,5-d~car-boxylic acid in CH-PS 658 651.
The compounds of the formula I are iDhlbltors of prolyl-4-hydroxyla~e. Tho lnhibition of thls onzyme w~e determined a~ described by ~aulo und G~nzler in Annal.
Biochem. 184, 219 to 297 (1990).
TAe novel compounda of the formula I pos~ece valuablo pharmacological propertios and exh~bit, in particular, antifibrotic acti~ity.
T~e antifibrotic effect can, for example, be determined u~ing the model of carbon tetrachloride-induced hopatic fibro~is. For this, rats aro troated twic- a waek with CCl~ (1 ml/kg) - dls~olved in olivo oil. Tho oubstanco under te~t is administered daily, whero appropriate oven twice a day, por 08, or intrnperitonoally - dle~olvod in a ~uitable toleratod solvont. Tho extent of tho hopatic fibro~i~ is detormined by hi~tology, and the proportion of collagon in tho llvor 1~ analyzod by means of deter-mining hydroxyproline - a~ describod in Rivirikko t al.
(Anal. Biochem. 19, 249 f. (1967)). The fibrogenic ac-tivity can be meaeur-d by the radioimmunologlcal detor-mination of collagen fragments and procollagon peptidos in the ~erum. Injthis model, the novol,compounds !aro active at a concontration of from 1 to 100 mg/~g.
~ :..-. .
The fibrogenic activlty can be moasured by radiolmmuno-logi¢al determination of the N-terminal propsptido of ¢ollagen type III or of the N-torminal or C-terminal cro~slinking domain of collagen type IV (79 collage~ or type IV collagen NCl) in the serum. - ~ ~;
~ ~ ' For this purposo, mea~urement~ wero made of the ~?~:
213~866 concentrations of hydroxyproline, procollagen III
peptide, 78 collagen and type IV collagen NC in the llver of a) untreated rat~ (control) b) rats which wero adminlster-d carbon tetrachlorido (CCl" control) c) rat~ which were first administered CCl" and tho,n a novel compound (this te~t method 1D described by Rouillor, C., ~xpcri-mental toxlc ln~ury of the llv~r; in Tho Llver, C.
Rouillor, vol. 2, 5. 335 to 476, New York, Acade~ic Press, 1964).
The novel compounds cu~ al~o b- demon~trated to b~ active ln the following ~ystem~
Inhibition of hepatic prolyl-4-biydroxylase ln vlvo~
Thi~ model i~ used to demonstrate the acute inhlbition of prolyl-4-hydroxyla~e in vlvo. For thi~, r~ts of both ~exe~ (healthy or with induced hepat$c flbrosi~) are administered (intraporitoneally, intravonously or per 08) the substance under tast or th- corrosponding ~ohicle and, after thio, aro giv-n 1~C-L-proline (250 ~Ci/kg of bodyweight), which is administerod intraperiton-ally.
There then follows a socond lntraperltoneal admiini~
tration of l"C-L-prolino (250 ~C~/kg of bodywelght).
Finally, the animals are exsang~inat-d under pento-barbital ane~thesla and the liver~ removed. The hepatic collagen was purifiod ~by dlgo~tlon with popsln and fractlonal ammonium eulfate precipitation in conformity with published protocol~ (Ref. 1 and 2). The purifiod liver collagen was hydrolyzed and the content of 1'~C-hydroxyprolino and 1~C-proline wa~ determirod by mean~ of amino acid analy~ls u~ing lon exchange chromatography.
Inhibitlon of prolyl-4-hydroxylaso is s,hown by a d-croase in the quotient 1'~-hydroxyprollne/[1~C-hydroxy~
proline~1"C-proline]. 2,2'-Dipyridyl i~ u~ed as the reference substanco. (1: Cho~kier, M. 1986, Hepatocyte :
21348~6 collagen production $n vivo in normal rat~, J. Clin.
Invest. 78: 333-339 and 2: Oga~a I., qt al. 1991, M~nor contribut$on of hopatocytos to collagen productlon in normal and oarly f$brotic livors, ~opatology 14:
361-367).
Inhibition of prolyl-4-hydroxyla~e in cell cultur-s:
~: , .,; ,;:
The following cell types are us-d for t~sting inhibitor~
of prolyl-4-hydroxyla~o in coll cultur~c: `
Normal _uman skin fibroblasts, (N~DF), rat liver opithelial cells, (ref. 1) and primary fat storing c-lls from rat liver (ref. 2). For thi~, the coll~ ar- oult~
. , , vated in the pro~ence of inhibitors. At the ~amo time, the collagen which iB nowly ~ynthesized during thi~
period ~8 metabolically labelled with 4-3H-L-proline and ;~
~C-prol$ne. The iafluonce of the test cubst~ncee on tho : .~
degree of hydroxylation of the collagen is then deter-mined in iaccordance with the method of Cho~kier et al (ref. 3). 2,2~-Dipyridyl i8 ~mployod as tho r~feronce sub~tance. (1.: Schrode, W., Mecke, D., G-bhard, R. 1990, Induction of glutamine synthqtase in periportal hepato-cyte~ by co-cultivation with a liver pithelial cell line, Eur. ~. Coll. Biol. 53: 35-41; 2. Blomhoff, R., Borg T. 1990, I~olation and cultivation of rat liv-r ~tellate cell~, Mothods Enzymol. 190: 59-71s and 3.:
Cho~kier, M. Peterkofsky, B. Batema~, J. 1980, A new m-thod for dot-rmlning the xtent of prolino hydroxy-lation by m-a~uring changes in the ration of [4-'X]:t~C~
proline in collagenase,dig-sts, Anal. Biochom. 108: 385-393).
Tho compound~ of the formula I may be used as medicament~
in the form of pharmaceutical pr-paration~, which contain tho compound~, whoro appropriat- together with toleratod pharmac-utical oxcipient~. The compounds can bo u~od a~
medicines, for example ln tho form of pharmaceutical ~`
preparation~ which contain the~e compound~ in a mixture together with a pharmaceutical, organic or inorganic ; ;;
':'.: :.. ~ '~
. - .: ,::
::' , :" ' :,; : `~
213~866 excipient which i8 suitablo for ~nteral, percutaneoua or parenteral adm~nietration, such aA, for sxampl~, water, gum arabic, gelat~n, lactoeQ, starch, magneeium stearate, talc, vogetable oilB, polyalkylene glycol~, vaeelino, etc.
Por this purposs, they can be adminietor-d orally ~n doses of from 0.1 to 25 mg/kg/day, proferAbly of fro~
to 5 mg/kg/day, or parenterally ln doeoe of from 0.01 to 5 mg/kg/day, proferably of from 0.01 to 2.5 mg/kg/day, ln particular of from 0.5 to 1.0 mg/kg/d~y. Tho doeage can aleo be increased ln sovere ca~e~. In many casee, how-evor, emaller doeo~ aro al~o sufflcient. Thsee data rofor to an adult of about 75 kg ln weight.
The novel conyounds of tho formula I are doeignatod eubetltutod hoterocyclic carboxyllc acld glycylamidee, prefsrably pyrldlne-2-carboxyllc acld glycylamide~, ln the examplos doecrlbod bolow.
This mode o~ deelgnatlon le underetood to moan subetltutod N-carboxymothylpyridine-2-carboxamldoe.
20 Anothor optlon ie to claseify th~m ae eubetitut-d N- ; ~
(pyridyl-2-carbonyl)glycinee. ,;
Examplo 1 ~ ~ `
3-Mothoxy-4-(2,2,2-trifluoroothyloxy)pyridlns-2-carboxyllc acid glycylamide a) 2-Mothyl-3-methoxy-4-chloropyridine N-oxide 11.2 g (80.5 mmol) of 3-mothoxy-2-mothyl-4(1~)-pyrldone -were heatod under reflux for 10 houro ln 100 ml of -~
phoephorus oxychloride. Subeogu-ntly, th~ mixturo wae conc-ntxated and 30 ml of toluen- were add~d to each 2 ml volume5 concentration thon took placo onco agaln and the r-eldue wa~ takon up ln 150 ml of water, wlth the pH of the mixture then belng adjuetod to 11 wlth ~,CO3; thle mixturo was thon extractod with dichloromethano and tho organic phaee was waehod with wator, dr~ed and freed from ." '; ;~'~'~: ,';;
~ 50 solvent 8 g of ths product were obtained, under ~tandard con-d~tlons, from the pale brown oil (9 g) using m-chloropor-benzoic acid in d~chloromothano, m p 88 to 8gC (fro~
5 petroleum other) ; ;
b) 2-Methyl-3-methoxy-4-(2,2,2-trifluoroethoxy)pyrldino N-oxide 6 7 g of potas~ium tert-butoxide were added ln portions, at -20C, while otirring and undor a nitrogon atmosph-ro, to 20 ml of trifluoroethanol Ater tho mixture had beon warmed to 0C, 5 2 g (30 mmol) of 2-methyl-3-methoxy-4-chloropyridlne N-oxide wero added in portlon~ The mixturo was heated under reflux for 3 hours, ~nd then coolod down to room temperatureS a further 3 45 g of potassium tert-butoxide w~ro then add~d and the mixture was heatod under roflux for 2 hours After it had coolod down, 40 ml of water wore addod to the r~act~on m~xture, ~-which was thon extractod with dichloromethane; the extract was then dried over MgSO~ and freed from ~olvont ln vacuo Tho rosulting oily product wa~ ~ub~-cted to furthor roaction c) 3-Methoxy-4-(2,2,2-trifluoroethoxy)-2-hydroxymethyl-pyr~dlne . ~ .
8 g (33 8 mmol) of tho a~ovo compound wer- dis~olv-d in ~ ~ ;
25 16 ml of glacial acotic acid, and 24 ml of acotic ~ ~;
anhydrid- wore addod, at 80C and while stlrring, to this mixturo The reaction mixturo was hoated at 110C for 2 houra and thon coolod down to 80C; 40 ml of methanol ;-~
wer- th-n addod to it dropwlse Sub~equontly, th~ mixture 30 wa~ conc-ntrated ln vacuo, and tho oily residue addod to ;
75 ml of 2N m thanolic NaOH, with thi~ mixturo boing etirred for 30 minutes Following treatment with active -~
charcoal, and filtration, the mixture was conc~ntrated in ~ .',,',.'.,'t vacuo and 50 ml of water wero addod to tho rosidue, after -~`
~,' ~, "'' ', 213~866 . .
which extract~on took placo w~th dichloromethan~; the extract was dried (NgS0~) and conc~ntratod, and the residue was treatod with dii60propyl othar 3 9 g of the product wero obtained ~n th- form of eolorloss erystal~
m p 107 to 108C
d) 3-Methoxy-4-(2,2,2-trifluoroothyloxy)pyridino-2-earboxylic acid 0 8 g (3 3 mmol) of the abovo alcohol was dis~olv-d in a solution composed of 0 3 g of potao~ium hydroxide and 25 ml of water, and 1 6 g of pota~ium p-rmanganate were addod in portions at 100C and whil- otirring Aft-r decolorlzation, the manganese dioxide which had formed was filtered off with ~uction fro~ the hot m~xture and waehed twice with hot waters ~he filtrat~ wae concen-trated in va~uo to 1/3 of the volume, ad~u~ted to p~with conc agueous hydrochlorlc acid, und eoncentrat~d in vacuo; the rosldue was treatod w~th ~ydrous thanol and tho undis~olved matorial was filtored off 0 73 g of product, m p 157, was obtainod frc~ t~o filtrate ~ . , o) 3-Mothoxy-4-(2,2,2-trifluoroothyloxy)pyridine-2-carboxylic acid (glycyl thyl oster) umlde 0 58 g (2 3 mmol) of tho above carboxyllc acid wae ~u~pendod in 100 ml of anhydrou~ t-trahydrofuran, aft-r whlch 322 mg (2 3 mmol) of glycin- thyl e~ter hydrochlorlde, 0 64 ml (5 mmol) of N--thylmorpholino, 350 mg (2 6 mmol) of l-hydroxy-l~-b-nzotriazole and 53j7 mg (2 6 mmol) of N,N'-dlcyclohexylcarbodilmlde were add-d at 20C and while etlrrlng, and tho mixture was th~n stirred at 20C ~or 48 hours Undls~olvod matorial wa~
th-n f~ltsred off and th~ flltrat- wae eonc-ntrated ln vacuot the residue wa~ tak-n up ln ~thyl acetate ancl undl~eolved materlal wa~ filterod off; th- filtrate wae ~tirred together with 100 ml of a ~aturated, aqueous ~olution of Na bicarbonate, and th- organic phase waB
dried and concontratod in vacuo; the r-eidue wae :, ~:,,;: ..
:, . ,: :, `
213~866 .
cryetallized using diisopropyl othor 0 45 g of tho colorlese cryetalline product wero obtained, m p 80 to f) 0 4 g (1 2 mmol) of tho above oet-r wa~ added to 50 ml of a 1 5 N mothanolic solution of sodium hydroxid~, and this mixturo wa~ ~tirrod at 20C for 30 mi~utes It wae then concantrated in vacuo and tho ros$duo was taken up in 50 ml of wator; this mixtur~ wa~ ad~u~ted to pH 1 with comp aqu00us hydrochlortc acid and tho small amount of undissolved material was flltor~d of~; th- filtrate was concentrated in vacuo and the residue wae treated wlth 50 ml of anhydroue othanol; thi~ mlxturo WaB
filtered and tho filtrate wa~ concentratod and brought to crystallizatlon using diothyl eth-r 0 32 g of the title 15 compound wae obtained, m p 163 to 165C (with gae evolution) Example 2 4-Chloro-3-methoxypyridino-2-carboxylic acid glycylamide a) 4-Chloro-2-hydroxymethyl-3-methoxypyridin-20 30 g (173 mmol~ of 4-chloro-3-methoxy-2-methylpyridine N-oxide (cf Example la) w-r- di~olv~d in 100 ml of glaclal acetic acid, after which 150 ml o~ acetic anhydride w-re added dropwis-, at 80C and while ~tir~
rlng, and th- mixtur~ was then stirred at 110C for 2 25 hours The mixture was thon cooled down to 80C ~nd 200 ml of methanol were added dropwi~e; the mixturo was then heated to boiling for 15 minutes and, aft~r having beon cooled down, concentrated in vacuo; the residue was taken up in methanol and thi~ mixture was allowed to flow into 30 300 ml of a 1 5 N methanolic solution of ~odium hydroxide, with this mixture then boing stlrred at 20C
for 30 minutes and concentrated in vacuo; th- residue wa~
takon up in wator, and this mixture extract~ad three timos with dichloromethane, with the organic phase boing driod and concentratod; tho residuo was crystallizod using .' ',~ ~;
213~866 potroleum athor. 23 g of product were obtainod, m.p. 64 to 6SC.
: -:
b) 4-Chloro-3-methoxypyridino-2-carboxylic acid 8.65 g (50 mmol) of tho above alcohol were di~sol~ed ln a mixturo comFosed of 0.8 g of potasslum hydroxide and 60 ml of wator, after which potas-ium pesm~ganat~ was addod in portions, at 60C and while ~tirring, until no moro discoloration could bo soen (12 g, 75 mmol). Aft-r 1 hous at 60C, the ma3ganeso dioxide was filtered off wlth suction and then washed wlth hot waterS the flltrate was concontrated ln vacuo to 200 ml and ad~ustod, while cooling, to pH 1 with aguoou~ conc. ~Cl. After grindlng, tho product csystallizss out in a~sociation with cooling.
Additional product can be obtalnod from tho mother liguor by troatment with potroleum other. Total guantity, 4.2 g, m.p. 116 to 117C (with ga~ evolution).
, c) 4-Chloro-3-mothoxypyridino-2-carboxyl~cacid(glycyl othyl ester) umide 4.7 g (25 mmol) of ~he above carboxyllc acld were ~uspended ln 200 ml of anhydrou~ dichloromethans, and after that 3.5 g (25 mmol) of glyclne ethyl estor hydrochlorldo, 6.4 ml (50 mmol) of N-ethylmorpholino, 3.8 g (28 mmol) of l-hydroxy-lH-bonzotriazolo and 5.15 g (25 mmol) of N,N'-dicyclohoxylcarbodilmido were added ~eguentially, at 2qC a,nd while tirring, and the mixture was th-n stirred at 20C for 20 hours. ~ndis~olved mat-rial wa~ then ~$1t-rod off and the organic phase was ~haken with a saturated, aguoous solution of odium carbonate, driod and ooncentrated in vacuoS th~ rosiduo (6 g of oil) wa~ chromatographod on ~ilica g~l u-ing ~thyl acetato and 5.4 g of oily product wero obtained.
d) The t$tlo compound wa~ obtain-d by hydrolyz$ng tho abovs othyl ester. For th$~, 0.7 g (2.6 ~mol) of th$~
213~866 est-r wa~ dlssolved in 50 ml of methisnol/water (3 1), and after that 170 mg (7 ~mol) of lithium hydroxldo wero added at 20C and while stirring Aft~r 30 minut~, the mixture wa8 concentrated $n vacuo; tho resldue w brought to p~ 1 with conc aquoous hydrochloric a¢ld and thl~ mlxture was concentrated ln vacuo; the r~slduo was troatod twlce with i~n~ydrous thanol and the ethi~nollc phaso was concentrated; the re~ldue wa~ treated with hot ethyl acetate and the amorphous re~ldu- was drlod on an oil pump 0 31 g of the tltle compound was obtalned Example 3 4-Butyloxy-3-mothoxypyrldine-2-carboxylic acld glycyl-amide M p 137 to 139C (with gas evolutlon, from tetrahydro-furan) ..
-. : . :-.
: . .. ~ . . .,:
ExampleEi 4 to 16 were prepar~d in an analogou~ mannors Example 4 3,4-Dlmethoxypyr$dine-2-carboxylic acld glycylam~d~
Example 5 3-Ethyloxy-4-(3-mothoxybenzyloxy)pyrldlne-2-carboxylic acid glycylamlde Exampl- 6 4-~exyloxy-3-mothoxypyrldine-2-carboxylic acld glycyl~
amlde - ~-.., ~ . .. .
25 Examplo 7 ~ ,",;
3-Mothoxy-4-(3-methyl-1-butyloxy)pyrldlne-2-carboxylic ~ ~-acld glycylamide Example 8 ; ~`~
4-(4-Fluorobenzyloxy)-3-msthoxypyrldlno-2-carboxyllc acid 30 glycylamlde -: :''::''' .":'.
. ~
",, ',,.~ ,: ';
, i ~ . ~ .:: .
:: .
.: : :. ,: .::
2~3~866 Examplo 9 3-Methoxy-4-(4-trifluoromothylbonzyloxy)pyrldlno-2-carboxyllc acid glycyl ~ido Bxamplo 10 3-Mothoxy-4-(2,2,3,3,3-pentafluoropropyloxy)pyridlne-2-carboxylic ac$d glyeylamido :~
Examplo 11 4-(2,2,3,3,4,4,4-~optafluorobutyloxy)-3-methoxypyrldln~
2-carboxylic acid glycylamide .
Example 12 4-(3-Mothoxybenzyloxy)-3-mothoxypyridlno-2-carboxylic acid glycylamido ~;
:
Example 13 3-Ethyloxy-4-(2,2,2-trifluoroothyloxy)pyrldlne-2-carboxy- : .
lic acid glycylamide ~ ' Example 14 4-Butyloxy-3-ethyloxypyrldine-2-carboxyllc acld glycyl-amlde ~. . -::, :~: . ~ . .: . .
Example 15 3-Mothoxy-4-((phenoxyothyl)oxy)pyrldine-2-carboxyllc acid glycylamide :`
: ,,:
Examplo 16 ;~ .; n-3-Ethyloxy-4-bonzyaoxypyridino-2-carboxylie aeld glyeyl- ~ ~.
amide 25 Example 17 :~
3,6-Dimethoxypyridlno-2-carboxylic acid glyeylamide ~ jÇ;~`~
a1 3,6-Dlmethoxy-2-methylpyridino N-oxido .~ -1.15 g (50 mmol) of ~odlum were dis~olvod ln 100 ml of anhydrou~ methanol, and aftor that 7.4 g (40 mmol) of , "".,",",,",,,,,,,~
: . ' ; , .
213~8~6 3-methoxy-2-methyl-6-nitropyridine N-oxide woro added at 20C and while ~tirring The mixture was th~n heatad to reflux for 3 hours and, aft~r having boen cooled down, concentrated in vacuo; tho re~iduo was ta~en up in wat-r And this mixturo was oxtractod with d$chloromethane; the organlc pha~e was dri-d and concentrated and the r~ldue wa~ cry~tallized using diisopropyl ether 7 g of product wore obtained, m p 63 to 65C
.~
b) 3,6-Dimethoxy-2-hydroxymethylpyridine 7 g (41 4 mmol) of the abov~ compound were react-d with glacial acet$c acid/acetic anhydride in analogy with Examplo lc) and the rosulting acetate was hydrolyzed using 1 5 N methanolic sodium hydrox$de solution 5 6 g were obtainod of oily product which wa~ sub~octed to further reaction under c) c) 3,6-Dimethoxypyridine-2-carboxylic acid 5 6 g (33 mmol) of the abovo compound and 2 4 g of potas~ium hydroxide wer- di~solv-d in 150 ml of wat-r, and after that 15 g (100 mmol) of potasslum p-rmanganate w-re addod in portion~ at 60C and whilo ~tirring Th-mangano~- dloxide which had formed wa~ thon filt-r-d off with ~uction and wa~h-d twico with hot wator; the com-bined wator pha~e was concentrated to 100 ml, ad~u~ted to pH 1 with conc agu~ou~ hydrochloric acid while being cool-d with ice, and concentrated in vacuo; the r-~idu~
was treat-d with othyl acetat- and othanol, and undi~
solv-d materlal wa~ filterod off from this mixturo, with th- filtrate being concentrat-d in vacuo The r-sidu- wa~
cry~tallized u~ing di-thyl th-r 4 g of product were obtained, m p 131-132C (with gas volution) d) 3,6-Dimethoxypyridine-2-carboxylic acid (glycyl ethyl oster) amid-2 2 g (12 m~ol) of the abov~ carboxylic acid wero ~'' ' ''''" ''"' ~ ,::; ::':':
, 2~34866 ~:-.
suspended in 300 ml of anhydrous dichloromothano, ~nd after that 1.68 g (12 mmol) of glycine thyl ostor hydrochloride, 3.25 ml (25 mmol) of N-~thylmorpholine, 1.62 g (12 mmol) of l-hydroxy-l~-benzotriazole and 5.2 g (12 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbo-diimide mothyl-p-toluen~ulfonato wero add~d, w~ilo ~tirring, and tho mixtur~ was then ~tirr~d at 20C for 20 hour~. Tho ~mall amount Oe undio~olved mat~rial wa~
then filtered off ~nd the filtr~te wa~ cha~-n once with wator ~d ~hen with a ~aturatod, aquoou~ solution of Nn bicarbonate; the organic pha~e was dr~od and concentrated in vacuo and tho re~idue was crystallizod using diloo-propyl ethor. 2 g of product wore obtainod, m.p. 93 to 95C.
e) The title compound wa~ obtalned by hydrolyzing 0.6 g (2.24 mmol) of the above ethyl oster at 20C u~lng 120 mg of lithium hydroxide in 60 ml of methucol/wator (3 After concentration had taken place in ~acuo, the re~idue was acidified and extracted, at 20C, with tetrahydro-furan; the filtrate wa~ concentrated in vacuo and the yellow, re~inous re~idue wa~ cry~tallized u~ing diethyl ~ -other. 0.14 g wero obtalned of the title compound, m.p.
130C (decomposition), which i~ ~trongly hygroccopic. The re~idue from the in~pis~ated reaction mixturo wae then extracted three tim-~ with 50 ml of hot aceton~ on each occa~ion and the in~pis~ation re~idue wac cryctalllzcd u~lng dlethyl ethor. A further 0.35 g of tho title compound wa~ obtainod, m.p. 155C (decomposition).
Example 18 3,5-Diethoxypyridine-2-carboxylic ac$d ylycylamide ~Sxample 19 3-Methoxy-6-(3-methyl-1-butyloxy)pyridine-2-carboxylic ~ ;
acid glycylamide ~ ;
M.p.: 105 to 107C (from aqueou~ hydrochloric acid, p~ 3 to 4) ":~
213~86~
Exsmple 20 3-Benzyloxy-4-(3-ethyloxypropyloxy)pyridine-2-oarboxyllc scid glycylamide M.p. 118-120C (from acetone) According to lH NMR, tho product contains ~pproximatsly 15 % of the 3-hydroxy dorivativo.
Example 21 3-Benzyloxy-4-hexyloxypyridi~o-2-csrboxylic acid glycyl-M.p. i30 to 132C (from agueou~ hydrochloric acid) Example 22 ~ ,j?~
6-(2-Butoxyethyloxy)-3-mothoxypyridlne-2-carboxyllc ac~d glycylamide : ,,., ~.... ~
Example 23 6-(2-Cyclohexyl)ethyl)oxy-3-methoxypyridine-2-carboxylic acid glycylam~do ~-M.p. from 70C (~intering from 50C, from aqueou~ hydro-chloric ac~d, p~ 3) Examplo 24 20 3-Ethyloxy-6-~ethylpyridino-2-carboxylic acid glycyl- ````~
amid~
: ', , .: ,', . . .
Example 25 6-Bonzyloxy-3-methoxypyr;d~ne-2-carboxylic acid glycyl-amide "' . ,. ~
25 Example 26 '! ' ;,.. ',.' 3-Benzyloxypyr$dine-2-carboxylic acid glycylam~do M.p. 142-144C
Examplo 27.1 3-Methoxypyrldine-2-carboxyli¢ acid glycylamlde amorphous ~ub~tanco, pr-pared by hydrolyzing tho 3-methoxypyridine-2-carboXlic acid (glycyl othyl ost-r) amlde, m.p. 141 to 142C (with ga~ ovolutlon, from 2~ 3~866 diothyl other).
This ethyl ester was obtalned by catalytic hydrogenation of 4-chloro-3-methoxypyridine-2-carboxylic acid (glycyl othyl estor~ ~mido (ooo ~x~mple 2c), whlch wa~ obtainod from 4-chloro-3-mothoxypyrldine-2-carboxylic acid (m.p.
119 to 120C, from 4-chloro-3-mothoxy-2-mothylpyridine N-oxide by reaction with acotic anhydride/glacial acotic acid and subseguont oxidation of tho 2-hydroxy~ethyl-pyridino dorivativo) (~oe Examplo 2a, b3 ~nd glyclno othyl ootor hydrochlorido.
Example 27.2 3-Methoxypyridino-2-carboxylic acid glycylamlde hydrochloride a) 4-Chloro-3-methoxypyridine-2-carboxylicacid(glycyl benzyl e~ter) ~do ~ ~-The product was obtained, in analogy with Examplo 90a), ~ ~', ,'`''''',J~
from 4-chloro-3-methoxypyridino-2-carboxyllc acid (cf.
Example 2b), glycine benzyl ostor tosylate, N-ethylmor-pholine, l-hydroxy-lH-benzotriazole and CMC, m.p. 57-20 58C. ~ ~
..: , ,., , :' b) The title compound wao obtained by hydrog-nating the above product in mothanol/tetrahydrofuran (1:1) uoing Pd ;~
on charcoal (10 %) in a hydrogenatlon v-~el. After removing the catalyot, and freeing from the oolv-nt, the product was crystallized using acetone, m.p. 168C (with foaming). ;~
' ~: ~ ' '.:, Examplo 28 3~Ethoxypyridins-2-carboxylic acid glycylamide ~ - ~
: ' ' ' , :, .
Examplo 29 ;
3-Propyloxypyridine-2-carboxylic acid glycylamide .
213~866 Example 30 3-Butyloxypyr~d~ne-2-carboxyl~c acid glycylam~de a) 3-n-Butyloxypyr~dine-2-carboxyl~c ac~d :"-, 6 g ~150 mmol) of N~H (60 %, in minoral oil) were added in portions, at 20C and whll- stirrlng, to 9 8 g (70 mmol) of 3-hydroxypyridino-2-carboxyli~ acld ln 150 ml of N,N-dimothylac-tamide Aftor 30 m~nut-s, 15 ml (140 mmol) of butyl bromide wero added dropwiso and the mixture was hoatod at between 95C and 125C for 2 5 hour~ After havlng boen cooled down, ~he mixture wa~
concentrated ~n vacuo, treatod w~th an aqu-ou~ solution of Ni~ blcarbonato and oxtractod wlth dichloromethanes aftor drying, tho residuo was puri~ied by chromatography on sllica gel uolng ethyl acetate The 13 g of oily product thus obtained were lntroducod into 250 ml of a 1 5 N mothanollc ~olutlon of sodlum hydroxide, and the m~xturo wa~ then ~tlrrod at 20C for 30 minutes and concentrated ln vacuo; the residue was ta~en up in 200 ml of water and thi~ mixturo wae extracted with dichloromethano and the ~quoouo phas- was ad~u~t-d to pH 1 with conc aquoou~ hydrochlorlc acld~
conc-ntration took place ln vacuo and tho re~ldue wao troatod wlth othyl acetato and thon wlth anhydrous ethanol Tho r-~ultlng ~olutions wore conc~ntr~tod and the reoidue wa~ crystallized using acetono 9 3 g were obtained of product (m p 93-95C) which, accordlng to lH
NMR, otlll contalnod approxlmately 20 % of 3-hydroxy-pyrldino-2-carboxylic acld b) 2 8 g (20 mmol) of glyclne ethyl ster hydrochlorld-, 5 2 ml (40 mmol) of N-ethylmorphollno, 2 7 g (20 mmol) of l-hydro~y-lH-benzotrlazole and 3 0 ml (20 mmol) of N,N'-dllsopropylcarbodilmid- were added, at 20C and whlle stirrlng, to 4 g (20 mmol) of th- above product in 200 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous acetonltrile, and the m~xture wa~ then otlrred at 20C for 20 hours , ,''': .
Aftor wor~ing up ~treatmont with Na bicarbonate oolution, removal of precipitated diisopropyluroa), 3 5 g of oily -product, which ~till contained N,N'-diisopropyluroa, w~ro ~ -obtained following chromatography on oilica gol (ethyl ac-tato/n-hoptane 1 1; then puro othyl acotato) Thi~ mixture was introduced, at 20C and whllo ~tirring, ~ ;
into 150 ml of a l S N methanolic ~olution of sodlum hydroxide and the total mixtur- wa~ stirred for 30 ~ ;s-minutes Thi~ latter mixtur- wa~ th n conoontrat-d in vacuo and the re~idue wao ta~en up in waterS thi~ mixtur- wac ~n turn oxtractod with 200 ml of dlchlorom than- and the agueou~ pha~e wa~ brought to pH 1 u~ing conc aqueouc 8Cl and concentrated in vacuo; th- residuo wao tr-at-d with anhydrous ethanol and thon with N,N-dim thylfo-m~mide, wlth ach extract boing f~lt-r-d to romove undis~olved mat~rial and th-n con¢entrat-d and each of the r-oiduoo ~- m;-being cry~talliz-d u~ing thyl acetat- 1 65 g of th~
title compound w re obtained from the ethanol phaoe ~
20 (~lightly contaminat-d according to '8 NMR, m p 170C ~ ~"X, with gac evolution) and a furth-r 0 63 g from the dimethylformamide phaoo (m p 182C, with ga~ ovolution) ~xa~plo 31 ~ -3-~4-Chlorob-nzyloxy)pyridino-2-carboxylic acid glycyl-amld-a) 4-Chlorob-nzyl 3-(4-chlorob-nzyloxy)pyrldine-2-carboxylate 8 4 g (60 mmol) of 3-hydroxypyridine-2-carboxyllc acid w-r- alkylated (3 houro, 110C) with 5 2 g (approximatoly 130 Iol~ 60 ~) of ~odium hydride and 19 3 g (120 mmDl) of 4-chlorobonzyl chlorld- ln N,N-dlm-thylacotamido in analogy with ~xampl- 30a) Aft-r concontration in ~acuo and xtraction wlth Na bicarbonate solution, th- r-cidu-wao purifi-d on oillca gol u~lng h-ptano/ethyl aoetat-(lsl), and 14 8 g of th- product were cry~tallizod from appropriate fractiono u~ing diioopropyl eth-r, m p 92 to 213~866 .
94C.
b) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid 9.7 g (25 mmol) of the above e~ter were hydrolyzed w$th 200 ml of a 1.5 N mothanolic ~olution of eodlum hydroxide (24 h, 20C). After working up (concontratlon, taking up of the reslduo in wator, extraction w~th dlchlorometh~ne and acidificatlon), 6.5 g of product were obtainod, ~.p.
144C (from water, decompo~ition).
c) 3-(4-Chlorobenzyloxy)pyrldine-2-car~oxyllc (glycyl othyl ostor~ amide 3.2 g (12 mmol) of the above pyridine-2-carboxylic acid were reactod, in analogy with example 17d), with 1.7 g (12 mmol) of glycine ethyl ~ster hydrochlorido, 1.62 g (12 mmol) of l-hydroxy-(lH)-benzotriazolo, 3.3 ml (25 mmol) of N-ethylmorpholine and 5.2 g (12 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimlde ~othyl-p-toluene~ulfonat~. After working up, 3.0 g of tho product were cry~tallized u~ing dii~opropyl ether, m.p. 106 to 108C.
.
d) Th~ title ¢ompound wa~ obtnined by hydrolyzi~g the abov- ethyl e~t-r. 120 mg (5 mmol) of lithium hydroxide w-re added to 0.9 g (2.5 ",ol) of the ethyl e~ter in 60 ml of methanol/wator (3:1), and the mlxtur~ wae ~tirrod at 20C for l hour. It wa~ then concentratod in vacuo and the re~ulting agueou~ pha~- was ad~u~tod to pH 3; the ro~ulting precipitate wa~ filtored off with ~uction, wa~hed with water and dried in vacuo. 0.52 g of tho title compound wa~ obtained, m.p. 155 to 157C. ~-Examplo 32 3-(3-Nethoxybenzyloxy)pyridine-2-carboxylic acid glycyl-amlde ' ,: '', '~`;' .,, "
~ ":,''' "
213 ~866 a) 3-Methoxybenzyl 3-(3-mothoxybenzyloxy)pyrldlno-2-carboxylate In analogy with Examplo 38a), 10 g of ths product woro obtalned as a colorles~ oil, which was sub~octed to further reactlon, from 8.4 g (60 mmol) of 3-hydroxy~
pyrid~na-2-carboxylic acid and 3-methoxybenzyl chlorlde following chromatography on ~ilica gol.
i ~ . ~", b) 3-(3-Methoxybenzyloxy)pyr$dlne-2-carboxyllc acid 10 g of the above e~tsr were hydrolyz-d in 300 ml of a ;~
1.5 N methanolic eolutlon of eodlum hydroxide. 7.5 g of product were obtained, m.p. 147C (docomposltion, from agueou~ hydrochlorlc acld) c) 3-(3-Me~hoxybenzyloxy)pyrldlne-2-carboxyllc acid ;
(glycyl ethyI ester) amlde 3.2 g (12 mmol) of th~ above car~oxyllc ncid were reacted in analogy wlth Example 31c). 3.6 g of olly crudo product wero i~olated which, accordlng to the H NMR opectrum, etill contalned N-ethylmorphollne. The pure cub~tanc-, m.p. 135 to 137C (from dlleopropyl ether/ethyl acetate) wa~ obtalned from thl~ crude product.
d) 2.1 g (6 mmol) of the above product wor~ hydrolyzed u~lng O.4 g of NaO~ ln 60 ml of methanol. Followlng acldlflcatlon to p~ 3, 1.6 g of th~ title compound wore obtained aa a colorle~s cry~talline ~ub~tanco, m.p. 89 to 91C (from aguoou~ hydrochlorlc acid).
Ex~mplo 33 3-(2-Phonylethyloxy)pyridlne-2-carboxyllc acld glyayl-amld- ~odlum salt ~, a) 3-(2-Phenylethyloxy)pyrldine-2-carboxyllc acld In analogy with Example 30a), 8.4 g (60 mmol) of 213~866 3-hydroxypyrid$ne-2-carboxylic acid w~re al~ylatad with Na~/2-phenylethyl bromide in N,N-dim~thylacetamide. The 10 g of oily product obtained after purification by column chromatography were hydrolyzod w~th methanoliG
eod~um hydroxide solution in analogy with Examplo 30a).
3 g of product were obtained (m.p. 145C (with fo~ming~
from acetono)) which, according to the 1~ NMR spectrum, contained approximately 25 % of 3-hydroxypicolinic acid.
:-, :, :.- ,.
b) 3-((2-Phenylothyl)oxy)pyridin--2-carboxylic acld (glycyl ethyl ester) ~do , -: " ~
2.9 g of the abo~e compound wer~ roacted, ln ~nalogy w~th Example 30b), w~th glycino ethyl estor hydrochloride, N-ethylmorpholine, 1-hydroxy-lH-benzotriazole and N,N-dicyclohexylcarbodiimide. After working up, the crude product wa~ chromatographed on ailica g-1 using ethyl acetate. 3-Hydroxypyridine-2-carboxylic acid (glyoyl ethyl e~ter) amide was initlally eluted ao a by-product and cry~tallized fro~ appropriate fraction~ using petro-leum other; 1.1 g (m.p. 86 to 88C, strong fluore~conce in W light). The product was then crystallized from appropriate fractions using diisopropyl ethor, and 1.7 g of the product wero obtained, m.p. 73-75C.
c) The titl- compound wa~ obtained by hydrolyzing 0.99 g (3 mmol) of the above ethyl e~ter using 100 ml of a lN methanolic solution of sodium hydroxide. After the mixture had been stirred at 20C for 1 hour, it wa~
conc-ntrated and the rosldue was dissolved ln a little water~ this latter mixture was extracted wlth dichloro-methano and the agueous pha~e was acidified, while being cooled with i¢e, to p~ 1 using conc. agusou~ hydrochloric a~id and then concontrated in vacuo; the residuo was oxtracted twico with totrahydrofuran and the extracts were concentrated~ the r-sidue was di~solvod in a little water/tstrahydrofuran (lsl), and 252 mg (3 mmol) of ~odium bicarbonate wore added to thls ~olution. This mlxture was concentrat-d to dryne~ and th- r-~idue was , 213~866 crystallizsd using anhydrous ~thanol. 0.38 g of the title compound was obtained as sodium ~alt, m.p. ~ 300C. ~ ~ -Exismple 34 ~ -~
3-(4-Trifluoromethylbonzyloxy)pyridiae-2-carboxyllc acid glycylamide M.p. 161 to 163C (from aquoous hydrochloric acid, pH 3) , ~ .; :.. :,-Example 35 3-(4-(2-Propyl)benzyloxy)pyridine-2-carboxylic acid ` j ;
glycylamide ~odium ~alt 10 M.p.-108C (with decomp., from d~l~opsopyl other) Example 36 ~;
3-(4-Fluorobenzyloxy)pyridino-2-carboxylic acid glycyl-amide M.p.: 135 to 138C (from agueous hydrochloric acid, pH 3 to 4) Example 37 3-(4-(2-(4-Msthoxyphenyl)ethylamino)carbonyl)b nzyloxy)-pyridine-2-carboxylic acid glycylamid-M.p. 168-170C (from dichloromothan-) -Tho following xample no~. 38-64 w-re preparod in an analogous manner:
Exi~mple 38 3-(2,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid glycylamido , ;~
25 Examplo 39 , 3-(3-Fluorobonzyloxy)pyridine-2-carboxylic acid glycyl- ~;~
amido ~:.... ,:; .
Exunplo 40 - 3-(3-Chlorobenzyloxy)pyridine-2-carboxyllc acid glycyl-30 i3mide ;~
, ,, ., :: ::
, ~'' ' ~`', "' '''", : ' ' ~ ,', ` ':
213~866 . , Example 41 .
3-(3,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid glycylamide -- .
Example 42 5 3-(3-Trifluoromotkylbenzyloxy)pyridine-2-carboxylic acid ; :::
glycylamido Examplo 43 . ~
3-(4-Trifluoromethoxybonzyloxy)pyridine-2-carboxylic acld ::
glycylamide Example 44 3-(3-Ethoxybenzyloxy)pyridino-2-carboxylic acid glycyl-amido .
Example 45 3-(4-Cyanobenzyloxy)pyridino-2-carboxylic acid glycyl-amide Exa~plo ~6 3-((2-Pyridylmethyl)oxy)pyridine-2-carboxylic acid : :
glycylamido hydrochloride :'.' . '..'.
Exampl- 47 ~ .
3-((3-Pyrldylmothyl)oxy)pyridine-2-carboxylic acid glycylamido hydrochloride .. :
Examplo 48 .~:
3-((4-Pyrldylmethyl)oxy)pyridino-2-carboxylic acid ~ ~:
glycylamido hydrochlorido ~:
Examplo 49 3-((2-Thionylmethyl)oxy)pyridino-2-oarboxylic acid glycylamldo Exampl- 50 ~.;
3-(3,5-Dim~thoxybenzyloxy)pyridino-2-carboxylic acid 30 glycylamide -~
:. ~, ": :, : ~ . ., :. .
... ,-.. .
,,: , :
213~866 - 67 - ;~
, Example 51 3-Cyclohoxyloxypyridine-2-carboxyllc acid glyeyla~ido Example 52 ~ ~ :
3-(3-Phenylpropyloxy)pyridine-2-carboxylic acid glycyl- . -amide . :~
Examplo 53 .
3-(4-Phenylbutyloxy)pyridino-2-carboxylic aeid glycyl-amide :
Examplo 54 3-(((4-Nethoxy-2-pyridyl)methyl)oxy)pyridino-2^earboxylic acid glyeylamide :
Example 55 3-(((4-Ethoxy-2-pyridyl)mothyl)oxy)pyr~dino-2-carboxylic -acid glyeylamide -: -Example 56 3-Methylthiopyridine-2-earboxylic acid glycylamide ~
~ .
Example 57 3-Ben~ylthiopyridino-2-earboxylic aeid glyeylamide : ~:;
Examplo 58 ~ .
3-(3-Chloroph-noxy)pyridine-2-earboxylie aeid glyeyl~
amide Ex~mple 59 :~
3-~3-Methoxyphonoxy)pyridino-2-earboxylie aeld glyeyl-amido . ,.:.. :: .. : ::
~: . :..;.:: ~ ,:
25 Example 60 :~
3-Phenoxypyridine-2-earboxylie acid glyeylamide :::, : ., Example 61 3-~utyloxypyridine-2-earboxylie aeid ~-alanylamide ~ .. ..
..:..:.
Example 62 3-Butyloxypyridino-2-cnrboxylic acid D-alanylamido ' Example 63 3-Benzyloxypyridine-2-carboxylic acid ~-alanyl~nide Example 64 3-(3-Methylbutyloxy)pyridino-2-carboxyllc ac~d ~-leucyl-amide Example 65 4-Methoxyi~oquinoline-3-carboxylic acid glycylamide a) Methyl 1,2-dihydro-4-hydroxy-1-oxoi~oqulnoline-3-carboxylato, wa~ propared a~ de~cribed (~. Suzuki et ;~
al., Synthe~ie 1978, 461). -b) Mothyl 1,2-dihydro-4-methoxy-1-oxoisoguinoline-3-carboxylato, from a) u~i~g (trimethyl~ilyl)-diazomethano in methanol/ac-tonitrile, m.p. 177 to ;
179C (ethyl acetate/hoptano).
c) Mothyl 1-chloro-4-mothoxyi~oquinolin--3-carboxylate, from b) using pho~phoru~ oxychlorido, m.p. 108C
(othyl ac-tate).
~' .~ .. ,', ' ., .:
20 d) Mothyl 4-mothoxyisoguinolino-3-carboxylate, from c) ;
uoi~g hydrogon/Pd/C, m.p. 129C (from mothyl tert- ~ ~`
butyl other).
',":':,':
o) 4-Methoxyi~oguinolino-3-carboxylic acid, from d) by ~ -hydroly~i~, m.p. 185-189C (from aguoouc hydro-chloric acid). ``
f) 4-Mothoxyi~oquinolino-3-¢arboxylic ~cid (glycyl ~ ~;
mothyl o~tor) amido, from e) u~ing glycine mothyl e~tor hydrochlorido, DCC, HOBT, THF and NEM, oily ~ubstance (crude product).
,:., ''.'"'",,;' '''' 213~866 g) The titlo compound wae obtained by hydrolyzing the abovs ~ethyl eetor, m.p. 147C (fram agueoue hydro-chloric acid) Examplss 66 to 76 were obtained in an analogou~ mannsr from ths correeponding ieoguinoline-3-carboxylia acid~ or the 5,6,7,8-tetrahydro derivativos, reepecti~sly~
Exampls 66 4-Ethoxyisoquinoline-3-carboxylic acid glycylumlde Examplo 67 10 4-Propyloxyieoguinoline-3-carboxylic acid glycylamido .
~xampls 68 4-(3-Nethylbutyloxy)ieoguinolin~-3-carboxylic acid glycylamide .,:. :,, Example 69 - ~
4-Methoxy-5,6,7,8-tetrAhydroieoquinoline-3-carboxylic ~ :
acid glycylamide . I ~, ~ .
Examplo 70 4-(3-Mothylbutyloxy)-5,6,7,8-tetrahydroieoguinoline-3-carboxylic acid glycylamido : :. . .,:. ~";.
20 Examplo 71 . ::~
4-Ethoxy-5,6,7,8-tstrahydroieoguinollno-3-carboxylic acid 01ycylamide ~,~ ;,:':,.'~.;~::' , ~ ~, ,, . .:
Examplo 72 4-Bsnzyloxy-5,6,7,8-t~trahydroieoguinolino-3-carboxylic 25 acid glycylamide -.
Examplo 73 4-Benzyloxyi~oguinoline-3-carboxylic acid glycylamids : ~: '~A .
''~ ~''~`"''''''.
213~866 Example 74 4-(3-Methoxybenzyloxy)-5,6,7,8-tetrahydroisoguinoline-3-carboxylic acid glycylamide Example 75 7-Bromo-4-methoxyisoguinollno-3-carboxylic acid glycyl-amide Example 76 7-Methoxy-4-methoxyisoguinolin~-3-carboxyllc acid glycylamide Example 77 3-Mothoxy-6-((3-methylbutyloxy)methyl)pyridlne-2-carboxylic acid glycylamlde ~
.,~ ; : ~ :,, Example 78 3-Methoxy-6-((cyclohexyloxy)methyl)pyrldln--2-carboxylic 15 acld glycylamide ;
Ex~mplo 79 , 3-Methoxy-6-benzyloxymothylpyridine-2-carboxylic acld glycylamide Exampl~ 80 to 91 were propared ln accordanco wlth the procesc-s de~crib~d in Schemes 1, 2 and 3 Example 80 5-Carboxy-3-methoxypyridlne-2-carboxyllc acld glycyl-amlde 270 mg of tho tltle compound ~rom Example 81 wer-hydrolyzod at 20C uslng 50 ml of lN methanollo NaO~
After 30 minute~, the mlxture was concentrated ln vacuo and tho resldue wae dl~solved in 50 ml of water; thl~
~olutlon was oxtracted with dlethyl ethor and tho aguoous ;
phase wa~ ad~u~ted to p~ 1 wlth conc~ agueou~ hydro- ;~
chloric acid and thon concentrated ln vacuo; tho wator was removed azeotropioally from the resldue u~lng ethyl 213~866 acetate and the ros~due wa~ then troated with othanol and thi~ mixture wa~ concentrated; the r~iduo was cry~tal-lized u~ing d~ethyl othor. 230 mg ware obtainod of the titlo compound, m.p. 173C (with gas evolution, sintering at 170C), whlch, according to the lH NMR sp-ctrum, ~till contain~ approximatoly 20 ~ of an impurity.
.
The title compound wa~ al~o obtained by hydrolyzing 0.45 g of 5-((-1-butyloxy)carbonyl)-3-methoxypyridin--2-carboxylic acid N-(((1-butyloxy)carbonyl)me~hyl)amido, m.p. 80-81C (from petroloum ether~, using 50 ml of 1.5 N ~;~
methanolic NaO~. 0.23 g was obtainod of tho titlo com-pound, m.p. 198-200~ (from an othanolic pha~o w~o~o re~idue, following concontration, wa~ crystallizod ucing diethyl ethor). According to tho '~ NMR ~poctrum and MS, the aub~tance contain~ approximately 5-10 % of it~ othyl e~tor.
The isomeric 2-carboxy-3-methoxypyridine-5-carboxylic acid glycylamido wa~ obtalned in an nnalogou~ mann-r, m.p. from 65C (~intering from 45C, with foaming, from 20 diethyl othor, ~ygroscopic). -'' ; ': ~ :: :
Examplo 81 ~ ~ `
5-M-thoxycarbonyl-3-methoxypyridine-2-carboxylic acid ;~
glycylamid~
a) 5-Nethoxycarbonylpyridine-2-cnrboxylic acld l-ox~de 12 g (60 mmol) of dimothyl pyridine-2,5-dicarboxylato woro ~uspsnded in 30 ml of glacial acotic acid, and aft-r -~ ;
that 13 ml of hydrogen peroxid- ~35 %) wer- added at 20C
and whil- ctirring. Tho mixture wa~ than hoat-d to 100C
(intornal temp-rature), whilo ~tirring, with a clear solution boing for~od at 50C. Aftor the mixturo had b-en ~tirred at 100C for g0 minut-s, it wae allowed to cool down to 20C and the cry~talline precipitate was filt~r-d off w$th ~uction and wa~hed with wator; After drying, 7.5 g of product wero obtained, m.p. 160C (decomp.).
. .
, . ,::
213~866 b) Dimethyl 3-chloropyridin~-2,5-dicarboxylate 17 ml of thionyl chlorido, 35 ~1 of anhydrous chloroform and 1 5 ml of N,N-dim-thylformamide wore hoated to 60C, whilo stirring, and 7 5 g of tho above product w~ro then added in portions at thi~ tomperatur~ The mixturo was thon stirred at 60C for a further 60 minuto~, and, after cooling, tho solvent and exeo88 rsagsnt were di~tllled off in vacuo; dichloromethano wa~ added to the re~ldue, and the N,N-dimethylform~m~de x ~Cl complex wns filtor-d off with ~uetion and wa~hed w$th dichloromethuno Approximately 15 ml of triethylamin- and 10 ml of methanol wore addod, whil- ¢ooling, to the mothor liguor and the mixturo was stirrod for 30 minute~ After eoneon-trating by evaporation in vacuo, tho residuo was dia-solvod ~n 50 ml of wator and this mixture wAs thenextracted 3 x with dichloromethane; th- organie phase was dried and concentr~tod, and tho rssidue wa~ chr o to-graphed on silica g-l u~ing n-heptano and n-heptane ethyl acetate ~3 1) 5 3 g of product were crystallizsd, using potroleum ether, from appropriato fractlon~, m~p 36 to c) 3-Mothoxypyridln--2,5-dlcarboxylic acid 53 g (0 231 mol) of tho abovo dloster wore di~solved in 500 ml of metha~ol, and after that 150 ml (0 81 1) of eodlum methoxide solutlon (30 % ln mothanol) were added, at 20C and whilo ~tirring, whereupon tho temporaturo roeo to 30C The mixturo was heatod undor r-flux for 4 5 houre, 300 ml of wator wer~ add-d at 20C, and tho mlxturo was thon ~tirrod at 35C for 30 minutes The oxces~ mothanol w~s distillod off ln vacuo and the aquoous phase was ad~u~ted to p~ 2, while eooling, with half-concentrated aqueous hydrochloric ac~ds the color-le88 crystalline product wa~ filtered off with euctlon and dried 49 g were obtalned, m p 185C (gas vo-lution); 2S5C (decomp ) ~ .
',,.,,, , ., ,/" ,,",."~.. ... ..... .... ...
213~866 .
d~ Dimothyl 3-methoxypyr~dino-2,5-dicarboxylato, cf.
Exa~ple 90a) o) S-Mothoxycarbonyl-3-msthoxypyrldin--2-carboxylic ~cid -.
The compound was obtain-d, as a mixture with tho ~someric monomethyl sster (Gf. Examplo 90a)), fro~ 3.4 g (15 ol) of the above dia~ter by hydroly~i~ with a d~lute olutio~
of methanolic sodium hydroxide (0.54 g of NaOH (13.5 mmol)). 1.8 g of monoo~ter m~xture, m.p. 152C, w~r-obtatned in addltion to 0.8 g of unreaoted die~t-r.
::, .~, ;.:~.., f) 5-Methoxycarbonyl-3-methoxypyridlne-2-carboxylic acid (glycyl benzyl ester) amido ;~
1.8 g of tho above mixturo wore cond~nsod, in analogy with Examplo 90b), wlth 2.9 g (8.6 mmol) of glyclne benzyl eeter tosylat- in tho pre~once of N--thylmor-pholine, l-hydroxy-l~-bonzotriazole and CMC. A~tor working up, 2.3 g of oily mixture wore chromatogra~hed on ~ilica gel u~ing dichloromothane ~in the pres-nco of ~p to 2 % methanol). 0.82 g of product wa~ obt~lnod, m.p.
108C. 0.6 g of th- olly l~omor was al~o lsolatod.
g) The tltle compound wa~ obtained by di~solvlng 65Q mg of tho above benzyl ~ster ln 100 ml of totrahydrofuran/
methanol (1:1) and hydrogenatlng it u~ing Pd/C ~n a hydrogenation vessel. Onco the cataly~t had b~en filtorod off wlth ~uctlo~, the filtrato was concontrated and tho reslduo was cry~tallizod u~lng diothyl othor. 380 mg woro obtal~ed of a colorles~ crystalllne product, m.p. 158 to 160C. ;;
Ex~mple 82 5-(3-Pentyloxy)carbonyl-3-methoxypyrldine-2-carboxyllc acld glycylamlde ;~;
.~ . ., ~.Z~,`.
, . . ,:.,,: , .. . .... .
Example 83 5-Cyclohexyloxycarbonyl-3-methoxypyridino-2-carboxyllc acid glycyl~mide Examplo 84 5-(n-Butylam$nocarbonyl)-3-methoxypyridino-2-carboxylic acid glycylamide Example 85 -5-(2-Msthyl-2-butylaminocarbonyl)-3-methoxypyrid~ne-2-carboxylic acid glycylamide 10 Example 86 - ;~
5-(Cyclohexylaminocarbonyl)-3-methoxypyridine-2-car- , -~
boxylic acid glycylamide a) 5-(Cyclohexylaminocarbonyl)-3-methoxypyridine-2-car-boxylic acid Tho product was obtained, ln analogy with Ex mple 90b), from 5-carboxy-3-m-thoxypyridin--2-carboxylic acid and cyclohexylamine, m.p. 155C (sintering at 80C, from aqu-ouc hydrochloric acid).
:..~ . :: .. :.. 0 b) 5-~Cyclohexylaminocarbonyl)-3-methoxypyrldino-2-carboxyllc acld ~glycyl ethyl e~ter) amlde The product wa~ obtaln-d, ln analogy with Example 90c), from th- above compound, m.p. 187 to 188C (from dl-thyl eth~r) c) The colorle~ crystalllne title compound wa~
obtalned by hydrolyzlng the abovo compound ln analogy wlth Example 90c), m.p. 110C (wlth foamlng, a desp-blac~ coloratlon at 240C).
Examplo 87 5-(Cyclohexylaminocarbonyl)-3-ethyloxypyridin--2-car-boxylic acid glycylamido - :, .,~; , ' . . ~: ~ .., 213~866 Exampl~ 88 5-((2-Phonylothyl)aminocarbonyl)-3-mothoxypyridine-2~
carboxylic acid glycylamido --Examplo 89 5~ )-Dehydroabietylaminoearbonyl)-3-methoxypyrldine-2-carboxylic acid glycyl~mide a) 5-(~)-Dohydroabi~tylamlnocarbonyl)-3-methoxy- ;- ~;
pyridine-2-carboxyllc acid The resinou~ product wa~ obta~nod, in analogy with Examplo 90n), fro~ 5-carboxy-3-mothoxypyridin--2-oar-boxylic ~cid and ~I)-dehydroabiotyl~mine.
b) 5-((+)-Dehydroabi-tylaminocarbonyl)-3-mothoxy-pyridino-2-carboxyllc acld (glycyl thyl e~ter) amide The product WaB obtained in analogy with Exa~ple 90c), from the above compound, m.p. from 150C with foaming, ~intering at 120C, from di-thyl ethor).
c) Tho tltlo compound wa~ obtalnod by h~drolyzin~ th-above compound ln analogy wlth ~xampl- 90 d), m.p. 215C (sintoring at 150C, from aquoous hydrochloric acld).
" ~"r~
Example 90 5-((2-(4-Fluoroph-nyl)othyl)aminocarbonyl)-3-methoxy- ; ~ ;~
pyrldine-2-carboxylic acid glycyl~mid-a) Mothyl 5-carboxy-3-mothoxypyridin--2-carboxylate 10 g (50.7 ~mol) of the 3-mothoxypyridine-2,5-dicar-boxyllc acid (Example 81c) were ~uspended ln 150 ml of ;
anhydrou~ m-thanol, and after that 2 ml of concentrat-d ~ulfurlc acid wer- add-d and the mlxture was heatod under reflux for 3 hour~. Half of tho methanol was then di~tilled off in vacuo and the residue was lntroduced ~;
, ~ , . .;: ,:
213486~
into 400 ml of ic8 water; the cry~talline re~idue wa~
filtered off with suction and wa~hed w~th water; the residue wao dissolvod in 150 ml of a ~aturatod, aqueous ~olution of Na bicarbonate and this mixtur~ was extracted twice with 80 ml of dichloromethane on each occa~ion; the bicarbonate phaso was adju~ted to p~ 1, while cooling, with half-concentrated aqueous hydrochloric acid and the precipitat0d product was flltered o~f with ouction and driod. 5 g of colorl-ss, crystalline ~ub~tance wore obtained, m.p. 196 to 197C. 1.7 g of dimethyl e~ter, m.p. 53 to 55C (from petrol-um sther), wero obtainod from the dichloromethane phaoo.
b) 5-(((2-(4-Fluorophonyl)othyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic ~cid 3.2 g of methyl 5-carboxy-3-methoxypyridine-2-oarboxylate were eu~pend~d in 300 ml of anhydrous dichloromethano, and after that 2.0 ml (15 ~mol) of 2-(4-fluorophenyl)-ethylamine, 1.95 ml (15 mmol) of N-ethylmorphollne, 2.2 g (16.5 m~ol) of 1-hydroxy-1~-benzotriazole and 6.35 g (15 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodi-imide methyl-p-tolueneoulfonato (CMC) were added sequen-tially, at 20C and whilo otirring, and the mixture wao otlrrod for 24 hours. Ths undis~olvod matorial wa~ then filterod off and tho organic pha~e was extracted, in each ca~e 3 x, with an aqueou~ solution of Na ~icarbonate, with lN aqueous hydrochloric acid and w$th water, and the organic pha~e was dried and concentrated. 3.7 g were obtainod of methyl oster, m.p. 168 to 169C, which was introduoed into 150 ml of 1.5N methanolic NaO~. After 30 minuteo, tho mlxture was concontratod and d~ssolved in 100 ml of wator, and this mlxture wa~ adjustod to p~ 1 with ~onc. aqueouo hydrochloric acid; the crystalline precipitato was filterod off with suction, washed with water and dried. 3.4 g of product wero obtained, m.p.
110C (with foaming, ~intering at 75~
213~86~
c) 5-(((2-(4-Fluorophenyl)othyl)amino)carbonyl)-3-mothoxypyridine-2-carboxylic ncid (glycyl ~thyl eeter) amide In analogy with Exa~ple 90a), 3.2 g (10 mmol) of the above compound wero reactod with 1.4 g (10 m~ol) of glycine othyl eeter hydrochloride, N-othylmorpholine, 1-hydroxy-lH-benzotrlAzole and CMC. Following analogous working up, 2.8 g of the colorless cryetallin~ product were cryatallized using diisopropyl othsr, m.p. 170 to 171C.
d) The titlo compound wae obtained by hydrolyeing 1.0 g of the above glycine othyl estor, at 20C, ln 1.5N
methanolic NaOH. 0.95 g of product, m.p. 206C (with foaming) crystallizoe from aqueoue medium at p~ 3.
Example 91 5-((2-(4-Methoxyphenyl)othyl)aminocarbonyl)-3-ethyloxy-pyridine-2-carboxylic acid glycylamide .
Examples 92 to 105 were obtained from the corre~pondingly eubst~tuted pyridine-2-carboxylic acid derivativee of the formula II and glycine ethyl e~tor hydrochloride and with ~ubeequent hydrolyeis of the glycine othyl ester com-pound-.
Example 92 5-Chloro-3-othyloxypyridine-2-carboxyl~c acid glycyl-25 amldo ~;
.: .: . ;: ' ~`Example 93 5-Chloro-3-mothyloxypyridino-2-carboxylic acid glycyl-amido Example 94 30 5-Cyclohoxyloxymothyl-3-methoxypyridine-2-carboxylic acid -~
glycylamide ' ' ' ' 213~86~
Example 95 5-(3-Methylbutyl)oxymothyl-3-m~thoxypyridlno-2-carboxyllc acid glycylamido Example 96 5-Benzyloxymethyl-3-ethyloxypyrtd$ne-2-carboxylic aoid glycylamide Example 97 .
3-((Cyclohoxyl)mothyloxy)pyrid~ne-2-carboxylic acid glycylamido ~ :. ;.
:
Example 98 3-((2-Cyclohexyl)othyloxy)pyridine-2-carboxylic acid glycylamide ~-~
Example 99 3-((3-Cyclohexyl)propyloxy)pyridino-2-cnrboxylic acid glycylamide Example 100 3-(3-Methylbutyloxy)pyridino-2-carboxylic ac~d glycyl-amido Example 101 3-~exyloxypyrldine-2-carboxylic acid glycylamide Example 102 3-(4-Ethylbonzyloxy)pyridine-2-carboxylic acid glycyl- . :
amid~
,:
Example 103 3-(4-Propylbonzyloxy~pyridine-2-ca~boxylic acid glycyl-amide ~, '' ', Example 104 3-(4-~utylbenzyloxy)pyridine-2-carboxylic acid glycyl-amide ; ..
213~866 Example 105 3-(4-tert-Butylbonzyloxy)pyridine-2-carboxyl~c ac~d glycylamide Examplee 106 to 188 wore prepared in ~alogy with Examplee 80 to 91.
Example 106 5-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridine-2-carboxylic acid glycyl~mide a) 3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic acid In analogy with Example 81c), 3.5 g (146 mmol) of sodium wero di~solved in 350 ml of 2-methyl-1-propanol (i80-butyl alcohol), and a~ter that 13.7 g (55 mmol) of 3-chloropyridine-2-carboxylic acid ~thyl eet~r 5-carbox-ylic acid methyl ostor (pr~pared in analogy with kxample81b)) wore addod at 20C and while stirsing. The mixturo was thon etirred at 80C for 90 minute~ and, aft~r cooling, concentrat~d in ~acuo; tho reeiduo wae takon up in 200 ml of 1 N methanolic NaOH and this mixturo wae stirred at 20C. Aftor 15 minutes, tho eolution bocamo cloudy. Water wae added untll a clear solution wae obtainod and thie wae etirrod for 1 hour and thon concen-trated in vacuo; the aqueoue eolution wae acldifiod with agueous hydrochloric acid and tho cry~tallino product was $iltered off with euction, waahed and dri~d, and 10.6 g , of dicarboxylic acid were obtained, m.p. 192C (decomp.).
b) Dimethyl 3-(2-met~yl-1-propylo~y)pyrld~n~-2,5-dicar-boxylate The oily product wae obtained from the abovo dicarboxylic acid undor eeterification conditions (methanol/sulfuric acid) and after working up (washing w~th water and extracting with ethyl acetate). ~; -. , ,, :
~,""i,.. '~,fi ,~ "", ,,,,,"
213~66 c) S-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridino-2-carboxylic acid (glycyl banzyl oeter) anido 0.48 g (12 mmol) of NaO~, diseol~od in 50 ml of methanol, wae added to 3.2 g (12 mmol) of the abovo dioeter ~n 25 ml of mothanol, and tho mixturo wae etirred at 65C
for 90 minutee. The mixture was thon acldifi-d, whilo being coolod, with diluto agueoue hydrochloric acid and froed from methanol in vacuo. 2.5 g (10 mmol) of tho monoester mixture thus obtainod woro ~tirrod, ln analogy with Examplo 90b), in 250 ~1 of dlchloro~e~hano, ~t 20C
for 24 hour~, together with 3.4 g (10 ~m~l) of glyc~ne benzyl e~ter toeylate, 1.4 g (lO ,,ol) of l-hydroxy-(l~)-benzotriazole, 2.6 ml ~20 mmol) of N-sthylmorpholine and 4.3 g (10 mmol) of CMC.
The undieeol~ed materlal was thon iltered off with euction and tho filtrate was extracted with an agueous solution of Na bicarbonate, with diluto hydroahloric acid and with water; the organic phaee was drlod and concen-tratsd and tho residue was chromatographod on eilica gal uslng n-heptane/ethyl acetate (1:1). 0.8 g of aolorlese product wae obtained from appropriate fra¢tiono, m.p. 103 to 105C. 1.1 g of the ieomeric roeinoue product were al~o obtained.
d) Tho titlo compound wae obtained by dieeolving 0.7 g of the above compound in 100 ml of totrahydrofuran/
mothanol (lsl) and hydrogenating it for 2 hour~ ueing Pd on charcoal (10 %) in a hydrogenation ~oeeol. Tho cata-lyet wae then filtor~d off with euction and the flltrate : : . .
wae concentrated; tho reeidue wae cryetallized using diieopropylether and 0.45 g wae obtainod of the titlo compound, j~
m.p. approximatoly 70C (with foaming).
Tho isomeric compound wae obtainod in an analogoue ;~
manner, m.p. approximately 60C (with foaming, from diieopropyl ether).
'., '':" -,,'' ~-~ ''' `'`'' Example 107 5-Ethoxycarbonyl-3-(2-mothyl-1-propyloxy)pyrid~ 2-carboxylic acid glycylamido Examplo 108 5 5-Mothoxycarbonyl-3-(3-mothyl-1-butyloxy)pyridino-2-carboxylic acid glycylamido Examplo 109 5-Ethoxycarbonyl-3-ethoxypyridine-2-carboxyllc ~eid glycylamide 10 Example 110 5-Ethoxycarbonyl-3-(1-propyloxy)pyridino-2-carboxyl~c acid glyeylamido : ~:
Examplo 111 -5-Ethoxycarbollyl-3-(2-propyloxy)pyridlne-2-carboxyl$c :~
15 acid glycylamido Example 112 ~.:
3-Benzyloxy-5-othoxycarbonylpyridine-2-carboxylle acid ~ ~ :
glycylamido Example 113 20 3- (4-Chlorob~nzyloxy) -5-ethoxycarbonylpyridine-2-earboxylie aeid glycylamido Examplo 114 5-E thoxyearbonyl-3- (4-fluorobenzyloxy) pyridine-2- -: :
earboxylie acid glycylamido .
25 Examplo 115 5-Ethoxyearbonyl-3- (4- (tr~ fluoromethyl) - :~
benzyloxy)pyridino-2-carboxylic aeid glycylamldo ;
Examplo 116 . .
5-Ethoxyearbonyl-3- (4- (trifluoromethoxy)be~zyloxy) - -~: :
pyridino-2-carboxylic acid glycyl~ide ~-''''"
Example 117 5-Ethoxycarbonyl-3-(4-(2-propyl~benzyloxy)pyridino-2-carboxylic acid glycylamide Example 118 3-(4-Ethoxybenzyloxy)-5-ethoxycarbonylpyridine-2-car-boxylic acid glycyla~ide Example 119 5-~thoxycarbonyl-3-(3,4-dimethoxybenzyloxy)pyridi~-2-carboxylic ac$d glycylamide Exa~ple 120 5-Ethoxycarbonyl-3-(2-(4-fluorophenyl)ethyloxy)pyridine-2-carboxylic acid glycyl~mide Example 121 ~ ~;
5-Ethoxycarbonyl-3-(2,2,2-trifluoroothyloxy)pyridine-2-carboxylic acid glycylamide Example 122 -3-Cyclohexyloxy-5-ethoxycarbonylpyridine-2-carboxylic acid glycylamide ::
Example 123 5-Ethoxycarbonyl-3-(naphthyl-2-methyloxy)pyridine-2-carboxylic ~cid glycylamido Exampls 124 .;
5-Ethoxycarbonyl-3-(naphthyl-1-mothyloxy)pyridine-2-carboxylic acid glycylamide Example 125 5-Carboxy-3-(2-methyl-1-propyloxy)pyridine-2-carboxylic acid glycylamide The title compound wa~ obtained by hydrolyzing 0.3 g of -:
th~ title compound from Example 106, at 20~, in 50 ml of a lN methanolic solution of ~odium hydroxide. After 1 hour, the ~ixture was concentrated in ~acuo and ~ -~
:
2131~66 "
extracted with diethyl other; the agueous pha~o wae acidified, while bei~g coolod, with agueous hydroohlorlc acid; the aqueou~ phass was concentrated and then fre~d from water azeotropically using ethyl acetato and the residuo was treatod with acetone; the solution W~8 concentrated and the residue was ery~talliz~d uoing petroleum ethsr. 0.27 g of product was obtained, m.p.
80C (with foaming).
Exampla 126 5-Carboxy-3-(3-methyl-1-butyloxy)pyridine-2-earboxylic acid glycylamide Example 127 5-Carboxy-3-ethoxypyridine-2-carboxylic aeid glycylamide ~ -Example 128 ;;~
5-Carboxy-3-propyloxypyridine-2-earboxylic acid glyeyl-amide `~
Example 129 ; -5-Carboxy-3-(2-propyloxy)pyridine-2-earboxylie acid glycylamide Examplo 130 3-Bonzyloxy-5-carboxypyridine-2-carboxylie aeid glyeyl-amide . :.~ '.
Example 131 ; -5-Carboxy-3-(4-ehlorobenzyloxy)-2-carboxylicacidglycyl-25 amide ;
Example 132 5-Car~oxy-3-(4-fluorobenzyloxy)pyridine-2-carboxylie ac~d glyeylamide Example 133 5-Carboxy-3-((4-trifluoromethyl)benzyloxy)pyridino-2-carboxylie acid glyeylamide 213~8~6 :
' Bxample 134 :-~ 5^Carboxy-3-((4-trifluoromethoxy)banzyloxy)pyrldlne-2-' carboxylic acid glycylamide ,~i 1 Examplq 135 -1 5 5-Carbo~y-3-(4-(2-propyl)benzy~loxy)pyridi~-2-carboxylic ;~ acid glycylamide ~xample 136 :-5-Car~oxy-3-(4-ethoxybenzyloxy)pyridine-2-carboxyllc acid `~
glycylamids :~
:: :
Example 137 5-Carboxy-3-(3,4-dimethoxybanzyloxy)pyridine-2-carboxylic E ;~
acid glycylamide Example 138 ~`
~ . 5-Carboxy-3-(2-(4-fluorophe~yl)sthyloxy) pyr~dine-2- :~
: 15 carboxylic acid glycylamide ~. -~ ' '. ~ ' '~, ~xample 139 5-Carboxy-3-(2,2,2-trifluoroethyloxy)pysidi~e-2-: ~' carboxylic acid gylcylamlde : ' '~
Example 140 20 5-Carboxy-3-cyclohexyloxypyridine-2-carboxylic a~ld ~` ;
glycylamide ~, . .
~x~mple 141 5-Carboxy-3-(naphthyll2-~ethyloxy)pyridine-2-carboxylic acid glycylamide Example 142 S-Carboxy-3-(naphthyl-~-methyloxy)pyridin2-2-carboxylic acid glycyl~mide Example 143 5-(3-Pentyloxy)carbonyl-3-(2-m~thyl-1-propyloxy)pyridine~
2-carboxylic acid glycylamid~
. :
;~ .
21~866 Example 144 5-(3-Pentyloxy)carbonyl-3-(3-me~hyl-1-butyloxy)pyridlne-2-carboxylic aeid glycylamide Example 145 3-Ethoxypyridine-5-(3-pentyloxy)earbonyl-2-e~rboxylic acid glyeylamide --Example 146 5-(3-Psntyloxy)earbonyl-3-propyloxypyridine-2-earboxylie acid glyeylamide Example 147 5-(3-Pentyloxy)carbonyl-3-(2-propyloxy)pyridine-2- :
carboxylie acid glycylamide Example 148 3-~enzyloxy-5-(3-pentyloxy)earbonylpyridino-2-carboxylie acid glyeylamide Example 149 3-(4-Chlorobenzyloxy)-5-(3-pentyloxy)earbonylpyridine-2- -carboxylie acid glycylamide , ~
Example 150 :
3-(4-Fluorobenzyloxy)-5-(3-pentyloxy)carbonylpyridine-2-earboxylie acid glycylamlde Example 151 5-(3-Pentyloxy)earbonyl-3-((4-trifluorclmethyl)benzyloxy)-pyridine-2-earboxylic acid glycylamide Example 152 5-(3-Pentyloxy)carbonyl-3-((4-trifluoromethoxy)benzyl-oxy)pyridine-2-earboxylie aeicl glyeylamid~
Example 153 5-(3-Pentyloxy)earbonyl-3-(4-(2-propyl)benzyloxy)-pyridine-2-earboxylic aeid glycylamide ~; ~
213~866 Example 154 3-(4-Ethoxybsnzyloxy)-5-(3-pontyloxy)earbo~ylpyridino-2- ~ -carboxylie acid glyeylamido Examplo lS5 S 3-(3,4-Dimethoxybenzyloxy)-5-(3-pentyloxy)carbonyl-pyridino-2-carboxylic acid glycyla~ido Example 156 3-(2-(4-Fluorophenyl)-thyloxy)-5-(3-p~ntyloxy)carbo~yl-pyrldine-2-carboxylic aeid glyeylamide Exæmplo 157 5-(3-Pentyloxy)earbonyl-3-(2,2,2-trifluoroothyloxy)-pyrldino-2-earboxylle aeld glyeylamido ~ -Examplo 158 3-Cyelohoxyloxy-5-(3-pentyloxy)earbonylpyridine-2-15 earboxylie aeid glyeylamide ;~
Exa~ple 159 3-(Naphthyl-2-m-thyloxy)-5-(3-pontyloxy)earbonylpyr~dino-2-earboxylle aeid glyeylamido Exampl- 160 3-(Naphthyl-1-m-thyloxy)-5-(3-pentyloxy)carbonylpyrldine-2-earboxylie aeid glycylamido Example 161 5-(4-~optyloxy)earbonyl-3-(2-methyl-1-propyloxy)pyridino-, 2-earboxyllc aeld glycylfimldo Examplo 162 5-(4-Hoptyloxy)carbonyl-3-othoxypyridine-2-earboxylic `~
acid glycyla~ide Example 163 3-Benzyloxy-5-(4-heptyloxy)carbonylpyridino-2-carboxylie 30 aeid glyoylamido ;-~, ..
.
2134~66 Example 164 3-(4-Chlorobenzyloxy)-5-(4-heptyloxy)carbonylpyridi~-2-carboxylic ac~d glycylamide Examplo 165 3-(4-Fluorobenzyloxy)-5-(4-heptyloxy)pyrid~ne-2-carboxylic acid glycylamide Example 166 5-(4-Heptyloxy)carbonyl-3-(4-(2-propyl)be~zyloxy)-pyridine-2-carboxyliG acid glycylamido Examplo 167 3-(2-Methyl-1-propyloxy)-5-(5-nonyloxy)carbonylpyridine- - -2-carboxylic acid glycyl~m$de . .
Example 168 ~ , 3-Benzyloxy-5-(5-nonyloxy)carbonyl)pyridino-2-carboxylic ac~d glycylamide :, Example 169 3-(4-Fluorobenzyloxy)-5-(5-nonyloxy)carbonylpyr~dine-2- . ~:
carboxylic acid glycylamide Example 170 5-(5-Nonyloxy)carbonyl-3-(4-(2-propyl)benzyloxy)pyridi~e-2-carboxylic acid glycylamide Example 171 5-Geranyloxycarbonyl-3-othoxypyridine-2-aarboxylic acid glycylamido 25 Ex~mplo 172 -3-Benzyloxy-5-(geranyloxycarbonyl)pyridin~-2-carboxylic : ;~:
acid glycylamide ~: :
Examplo 173 3-(4-Chlorobenzyloxy)-5-(geranyloxycarbonyl)pyridi~e-2-carboxylic acid glycylamide . ' ~' .
,: ''' ~`~ <:
21~866 Example 174 3-(4-Fluorobenzyloxy)-5-(goranyloxyc~rbonyl)pyrid$ne-2-carboxylic acid glycylamide Example 175 5-Geranyloxycarbonyl-3-(2-propyloxy)pyrid$ne-2-carboxylic acid glycylamlde Example 176 5-Farnosyloxycarbonyl-3-(2-propyloxy)pyr$din~-2-car-boxylic acid glycylamide 10 Example 177 -~
3-Bonzyloxy-5-(farne~yloxycarbonyl)pyridine-2-carboxylic acld glycylamlde ~ :~
Example 178 ::
5-Farnesyloxycarbonyl-3-(4-fluorobenzyloxy)pyr$dlno-2- ~;
carboxylic acid glycylamide Example 179 . ~ :
5-Farn-~yloxycarbonyl-3-othoxypyridine-2-carboxylic acid glycylamide Examplo 180 3-Methoxy-5-(retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide ~., .
Example 181 3-Ethoxy-5-(rotinyloxycarbonyl)pyridine-2-carboxylic acid glycylamlde Example 182 3-(2-Propyloxy)-5-(ret~nyloxycarbonyl)pyrldine-2-carboxylic acid glycylamide . . ~
213~86G
- 8~ -Example 183 3-Benzyloxy-5-(retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 184 3-(4-Fluorobenzyloxy)-5-(retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 185 3-(3-Methoxybenzyloxy)-5-(ret~nyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 186 5-Benzyloxycarbonyl-3-(4-(2-propyloxy)benzyloxy)pyridine-2-carboxyllc acid glycylamide .
Example 187 -: ;
5-Benzyloxycarbonyl-3-(4-fluorobenzyloxy)pyridine-2-car-boxylic acid glycylamide Example 188 5-Butyloxycarbonyl-3-benzyloxypyridine-2-carboxyllc acid glycylamide Example 189 5-(((4-Ethoxyphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid glycylamid~, analogouely to Exa~ple 191 Example 190 5-(((4-Ethoxyphenyl)amino)carbonyl)-3-benzyloxypyridine-2-carboxylic acid glycylamide ~xamplo 191 5-(((4-(1-Butyloxy)phonyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid glycylamide ~ :
a) Methyl 5-(((4-(1-butyloxy)phenyl)amino)carbonyl)-3- . .
methoxypyridine-2-carboxylat~
' : ' 213486~
- so -3.2 g (15 mmol) of methyl S-carboxy-3-methoxypyrid~ne-2-carboxylate (cf. Example 90a)) were reacted, ln nnalogy with Example 90b), with 2.5 g (15 mmol) of 4-n-butoxy-anillne and the reagents do~cribed in that example. 3.9 g of product were crystallized using diethyl ~th~r (m.p.
138 to 141C.
~ .
b) 5-(((4-(1-Butyloxy)phenyl)amino)car~o~yl)-3-methoxy-pyridino-2-carboxylic ac$d ~-~
3.2 g of the above e~ter were hydrolyzed at 20C ucing 100 ml of 1.5 N mathanolic aodium hydroxide oolution.
2.7 g of product were obta~ned from agueous hydrochloric acid, m.p. 128 to 130C, sintering from 120C.
c) 5-(((4-(1-Butyloxy)phenyl)amino)c rbonyl)-3-~othoxy-pyridine-2-carboxylic acid N-~(ethoxyc~rbonyl)-methyl) am~de 2.7 g (7.8 mmol) of the a~ovo pyridine-2-carboxylic acid were stirred in 500 ml of anhydroue dichloromethano, at 20C for 24 h, togather with 1.1 g (7.8 mmol) of glycine ethyl oster hydrochlorido, 3.0 ml (23.4 ~^1) of N-ethylmorpholine, 1.2 g (8.6 m~ol) of 1-hydroxy-1~-bonzo-trlazolQ and 3.3 g (7.8 mmol) of CMC.
Tho undissolved material was then filtored off and tho organic pha~e was extracted ~equentially with 200 ml each of water, aquoous Na bicarbonato ~olution, lN aqueous hydrochloric acid and water, dried over Mg sulfate and concentrated in vacuo; the residue wa~ cry~tallized ueing diethyl ethor. 2.4 g of product were obtained, m.p. 193-195C.
d) The titlo compound was obtained by hydrolyzing 1.0 g of the above glycine oster, at 20C, in 100 ml of a 1.5 N
methanolic solution of sodium hydroxide. After 30 m~n, the mixturo wa~ concontrate~ in vacuo ~nd the roEidue wa~
diesolved i~ water; this solution was oxtracted with 2~3~86~
:'``
diethyl ether and the aqueous solut~on ad~u~tod to p~ 3 u~ing agueous hydrochloric ~cid. When tke ~olution wa~
cooled with ice, 390 mg of the title compound crystal-lized, m.p. 230C, sinterlng at 193C.
5 Example 192 .
5-(((4-(1-Butyloxy)phenyl)amino)carbonyl)-3-(4-fluoro-benzyloxy)pyridine-2-c~rboxyllc acid glycylamide Example 193 5-(((4-(1-Butyloxy)ph~nyl)amlno)carbonyl)-3-b~nzyloxy-pyridine-3-carboxylic acid glycylamide Example 194 3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic acid diglycylæmide N.p. 103-105C (from 0thyl acetate) Example 195 5-(Di-N,N-ethylaminocarbonyl)-3-~thoxypyridin~-2-car-boxylic acid glycylamide, amorphou3 ~ub~tance, prepared-~ ~ :
in analogy with Ex~ple 223 u~ing N,N-di~thylamino.
Example 196 5-(N-Bonzyl-N-methylamlnocarbonyl)-3-methoxypyridine-2-carboxylic acld glycylamlde Ex~mple 197 5-Farne~yloxyc~rbo~yl-3-mothoxypyridine-2-carboxylic acid -:
glycylamide Example 198 5-Geranyloxycarbonyl-3-methoxypyrldin~-2-carboxylic acid ::
glycylamide -~
.
Example 199 5-(Farnesyloxymethyl)-3-methoxypyridins-2-cArboxylic acid glycylamide 213 ~866 Example 200 5-(Geranyloxymethyl)-3-methoxypyridille-2-carboxyl~c acid glycylamide Example 201 5 5-Retinyloxymethyl-3-methoxypyridine-2-carboxylic acid glycylamide Example 202 5-Retinyloxymethyl-3-ethyloxypyridi~e-2-carboxylic ac:id glycylamide 10 Example 203 N-(Carboxymethyl)-4-methoxycinnoline-3-carboxamide Examples 204 to 209 were prepared in ~nalogy with Example 191: ~ -Example 204 15 5- (((4-(1-Hexyloxy)phenyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-(carboxy~ethyl)am$de a) Methyl 5-(((4-(1-hexyloxy)phenyl)amino)car}~onyl)-3-methoxy-2-carboxylate was E~repared from methyl 5-carboxy-3-mqthoxypyridine-2-carboxylate and 4-hexyl-oxyaniline, m.p. 118-119C (from diethyl ether). ;~-b) 5-(((4-(1-Hexyloxy)phenyl)~mino)carbonyl)-3-methoxy- ;
pyridine-2-carboxylic acid, 160-162C, ~intering at 148C (from aqueouc hydrochloric acid/tetrahydrofuran) c) 5-(((4-(l Hexyloxy)phenyl)amino)carbonyl)-3-methoxy-pyridin0-2-carboxylic acid N-((ethoxycarbonyl)-me~thyl)amide was obtain~d, in analogy with Example l91c), from 4.2 g of the above compound. 4.0 g of product were crystallized u~ing ethyl acetate, m.p.
157-159C.
213 186~
:`.
_ 93 _ d) The title compound wa~ obtainsd by hydrolyzing 1.2 g of tho above oster, at 20C, ueing 100 ml of a 1.5N
methanolic solution of codium ~ydroxide. Following concentration ln vacuo, acidi~icatio~ to p~ 1 took place in water/totrahydrofuran u~ing aquoou~ hydro-chloric acid; tho mlxturo was concontrated in v~cuo and the reeidue wa~ cry~tallized ufling acetone. 840 mg of product were obtained, m.p. 193-195C.
Example 205 5-(((4-(1-Decyloxy)phenyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-(carboxy~ethyl)amide Example 206 -5-(((4-(1-Decyl)phenyl)~;no)carbonyl)-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide -'- .
a) 5-(((4-(1-Decyl)phenyl)amino)carbonyl)-3-mothoxy-pyridine-2-carboxylic acid N-((othoxycarbonyl)-methyl)amide was prepared from 5-(((4-n-decyl-phenyl)amino)carbonyl)-3-methoxypyridin~-2-carboxylic acid (m.p. 160C (decomp.); from aqueou~
hydrochlorlc acid/THF) and glycin~ othyl ~ter hydrochloride, m.p. 155-157C (fron dii~opropyl othsr).
~ -: . .
b) The title compound wa~ obtained by hydrolyzing 1.5 g of tho abovo eeter in 200 ml of a 1 N methanolic ~olution of ~odium hydroxido. 1.4 g of product, m.p.
195C ~decomp.), were isolated from aqu~ou~ hydro-chloric acid/t~trahydrofura~.
Examplo 207 5-(((4-~eranyloxyphenyl)amino)carbonyl)-3-mothoxy-pyrldine-2-carboxylic acid N-(carboxymethyl)amide 21318~6 Example 208 5-(((4-(1-Octyloxy)phenyl)am~no~carbonyl)-3-~ethoxy-pyridine-2-carboxylic acid N-(carboxymethyl)a~lde Example 209 5-(((3-(1-Octyloxy)propyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-~car~oxymethyl)umide Example 210 5-((1-Butoxy)mothyl)-3-mothoxypyridi~e-2-carboxylic ac~d N-(carboxymethyl)am~do Example 211 5-((1-Hoxyloxy)methyl)-3-mothoxypyridine-2-Carboxylic acid N-(carboxymethyl)amido Example 212 ~ :
5-((1-Octyloxy)methyl)-3-mothoxypyridine-2-carboxylic 15 acid N-(carboxymethyl)amide ~ ~ :
Examplo 213 -5-((1-~ex-3-onyloxy)methyl)-3-methoxypyridine-2-car-boxylic acid N-(carboxymothyl)amide :p Exa~ple 214 20 5-((1-Docyloxy)methyl)-3-m~thoxypyridine-2-carboxylic : . :
acid N-(carboxymethyl~amide Examplo 215 5-((l-Dodecyloxy)methyl)-3-methoxypyrldine-2-carboxylic :~
acid N-(carboxymothyl)amide -~
25 Example 216 ~:
5-((1-~exadecyloxy)methyl)-3-methoxypyridlne-2-carboxyllc acid N-(carboxymethyl)amide Examplo 217 3-S4-(((+)-Dohydroabietylamino)carbonyl)benzyloxy)pyri-30 di~e-2-carboxylic acid N-(carboxymethyl)amido : :
213~866 ;
a) 4-(((~)-Dehydroabietylamino)oarbonyl)chloromethyl-benzeno was obtained from 4-chloromethylbonzoic acid and (~)-dehydroabiotyl~mine, ~.p. 170-172C (from othyl acetate/hoptano (1:1)).
b) 3-(4-(((~)-Dehydroabiotylamino)carbonyl)benzyloxy)-pyridino-2-carboxylic acid N-((~thyloxycarbonyl)-mothyl)amido, m.p. approximat~ly 80C (a~orphou~
substance, from ethyl aootato).
c) Tho titlo compound was obtained by hydrolyzing the above es10r, m.p. 125C (w~th ~oaming, ~rom dii~o-propyl ether).
Example 218 3-Mothoxyguinoline-2-carboxylic acid N-(oarboxymothyl)-amido a) 2-Acetyl-3-hydroxyquinoline, ~nown from D.W. Bayne et al., J. Chem. Soc. Chem. Comm. 1975, 782 (M.p.
106C from agueouR hydrochloric acid).
.: ',' .
b) 2-Acetyl-3-mothoxyquinolino, from a) ucing pota~sium carbonate/methyl lodido in acotone, oily crude ;~
product.
c) 3-Methoxyguinoline-2-carboxylic acid, from b) u~ing potaa~ium hypochlorite in water/dioxane, m.p. 123C
(from methyl tort-butyl ether).
.
d) 3-Methoxyguinoline-2-carboxylic acid N-((methoxy-carbonyl)methyl)amido, from c) u~ing DCC~ ~OBT, THP, NEM and glyc$ne mothyl o~tor hydrochlorido.
o) Tho title co~pound wa~ obtained by hydrolyzing the above ester, m.p. 106C (from othyl ac~tate).
'' ~' '' ':
213~866 Example 219 5-(((4-(1-Butyloxy)phenyl)amino)carbonyl)-3-chloropyri-dine-2-carboxylic acid N-(carboxyme~hyl)amid~
a) Methyl 5-carboxy-3-chloropyridine-2-csr~oxylate w~s prepared in analogy with Example 90a), m.p. 182-184C (from aqueou~ hydrochloric acid).
.
b) Methyl 5-(((1-butyloxy)phenyl)amino)carbonyl)-3-chloropyridine-2-carboxylate wa~ obtalned from the above ~ompound us~ng oxalyl chloride and 4-(1-butyl-oxy)aniline, m.p. 121-123C (from di~thyl other).
c) 5-(((4-(1-Butyloxy)phenyl)smino)carbonyl)-3-~hloro-pyrldine-2-carboxylic acid by hydrolyzing the product from b), m.p. 163-164C (from agueou~ hydro-chloric acid).
d) 5-(((4-(1-Butyloxy)phenyl)æmino~carbonyl~-3-~hloro-pyridine-2-carboxyli~ acid N-((ethyloxycarbonyl)-methyl)amide waa obtained, in ~nalogy with ~xample 90b), from tho abo~e ~u~tsnce by conden~ation (N-ethylmorpholine, l-hydroxy-lH-benzotrlszole and CMC) with glyclne ethyl ostor hydrochloride, m.p. 177-179C (from othanol).
e) ~he titlo compound was obtainad by hydrolyzi~g the above o~tor, M.p. 190C (with docompo~ition, from aqueou~ hydrochlorlc acid).
Example 220 3-(N-Benzyl-N-methylamino)-5-(((4-(1-butyloxy)phe~yl)-smlno)carbonyl)pyr~dine-2-carboxylic Acid N-(carboxy-methyl)amide 0.5 g (1.23 mmol) of the title compound from Exampl~ 219 wa~ stirred ln 10 ml of N-be~zyl-N-methylamino, firstly at 100-110C for 2 h and then at 130C for a further 2 h.
After the mixture had been cooled down, it was introduced . ~. ...
2~34866 ~nto 100 ml of lN hydrochloric acid ~nd th~ h~lf-crystalline precipitate wa~ taken up in dichloromethane;
the undiseolved mat~rial was filtersd off and the residue was crystallized; 0.2 g of the title compound, m.p. 155-5 157 C .
~xample 221 3-(N-Benzylamino)-5-(((4-(1-butyloxy)phenyl)amino)car-bonyl)pyridine-2-carboxylic acid N-(carboxy~ethyl)A~de -~
0.5 g (1.23 mmol) of the title compound from Example 219 wa~ ~tirred in 10 ml of bon~ylamine, fir~tly at 120C for 2 h and then at 135C for 1.5 h. After the mixture hnd been cooled down, it was acidifiod and the precipitat~d re~in wae dissolved in dichloromethane; thi~ ~olution wa~
dried and conaentrated and the re~idue wa8 chromato-graphed on ~ilica gel us$ng ethyl ac~tate (with the addition o~ up to 20 % methanol). 0.1 g of th~ titl~
compound wa~ cry~tallized from appropriate f~action~
u~ing dii~opropyl other, m.p. 185-190C.
Example 222 :
3-(4-Chlorobenzyloxy)pyridine-2-carboxyllc acid N-(carboxymethyl)amide 1-oxido a) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid N-((ethyloxy)methyl)amide 1-oxide 0.7 g (2 mmol) of the compound from Example 31c) wa~
di~olved in dichloromethane and roacted with 1.41 ~
g of 3-chloroperbenzoic acid. After the mixtura had ~;
been ~tirrod at 20C for 1 h, ammonia wa~ pa~ed in ;
until thero wac no further pr~cipitation; tho procipitats wa~ filtered off and the filtrate waa ~-concontratod and the oily residuo cryctallized ucing diethyl ether, m.p. 70-72C.
b) 0.18 g of the title compound, m.p. 206-208C
213~866 (sintering at 200C, fro~ aqueous hydrochloric acid) was obtained by hydrolyzing 0.3 g of tke above compound.
Example 223 5-(((3-(1-Butyloxy)propyl)P~no)carbonyl)-3-methoxypyri-dine-2-c~rboxylic acid N-(carboxymethyl)amido a) Methyl 5-(((3-(l-butyloxy)propyl) a~ no)carbonyl)-3-methoxypyridine-2-carboxylic acid 1.7 ml of oxalyl chloride (20 mmol), and al80 2 drops of N,N-dimethylformamide, dissolved in tctrahydrofuran, were added dropwiEie, at 10C and whlle itirr~ng, to 2.1 g (10 mmol) of methyl 5-carboxy-3-methoxypyridine-2-car-boxylate in 100 ml of i~nhydrouEi totrahydrofurian and the reaction mixture wa~i ~itirred at 10C for 30 min and at 20C for 1 h. It was then concentrated and the residue was dis~iolved in dichloromethane; 6.8 ~l (50 mmol) of triethyla~ine, and then 1.3 g (1.5 ml, 10 mmol) of 3-butoxypropylamine, diseolved i~ dichloromsthanei, wore added, at 0C, to thi~i siolution.
Aftor 30 min, the mlxture was allowed to warm to room tomperature and waE extracted with water, a Eiolution of Na bicarbonate and aqueouE lN ~Cl; the organic phas~ waEi dried and concentrated and the residue wa~i crystallized u~ing diethyleth~r/petroleium ether (3:1). 2.3 g of product were obtained, m.p. 51-53C.
b) 5-(((3-(1-Butyloxy)propyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-((benzyloxycarbonyl)-methyl)a~ide ~ . . .
The above subEitance was hydrolyz0d by Eitandard pro-c0dures, and 1.5 g (5 mmol) of the amorphous 5-(((3-(1-butyloxy)propyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid, which wa~i dried on an o~l pump, was reacted with glycine benzyl oster toEiylate, ;
.
213~866 N-ethylmorpholine, l-hydroxy-l~-benzotriazole and ~MC (a8 de~cribed). 1.42 g of the product were cry~tallized using acetone, m.p. 97-99C. -c) 1.3 g of the above benzyl e~ter were hydrogenatod in 100 ml of tetrahydro~uran/methanol (1:1) u~$ng Pd/C
(10 %) in a hydrogenation ves~el. 0.8 g of the title compound wae crystallized u~ing diethyl othor, m.p.
155-157C.
Example 224 5-(((3-(1-Lauryloxy)propyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxyllc acid N-(carboxym~thyl)amide a) 5-(((3-Lauryloxypropyl)am$no)c~rbonyl)-3-methoxy- -pyridine-2-carboxyl~c acid N-((benzyloxycarbonyl)-methyl) mide was obtained, i~ analogy with Example 223, u~ing 3-lauryloxypropylamine, m.p. from 109-111C (from diisopropyl ether).
b) 1.3 g of the above benzyl e~ter were hydrogenated aa dQscribed under 223c). 0.9 g of the titlo compound wero obtained from petroloum ether, m.p. from 120C.
20 Example 225 -;
5-(((2-Methoxyethyl)amino)carbonyl)-3-methoxypyridine-2- ~ - -carboxylic acid N-(carboxymethyl)amide ~ i The title compound wa~ prepared in analogy with Example 223 u~ing 2-methoxyethylamine.
a) 5-(~(2-Methoxyethyl)amino)carbonyl)-3-~ethoxypyri-dine-2-sarboxyllc acid, m.p. 160-161C (wlth ga~
evolution, from ethyl acetate) b) 5-(((2-Methoxyethyl)amino)carbo~yl)-3-methoxypyri-dine-2-carboxylic acid N-((benzyloxycarbonyl)-methyl)amide wa~ ~ry~tallized u~ing dii~opropyl ether, m.p. 129-131C.
:
213~366 c) The title compound was obtained, aa above, from the benzyl ester, m.p. 186-188C (from diethyl ether).
Example 226 N-(3-Benzyloxypyridyl-2-carbonyl)alanine racemate, M.p. 186-187C (from pentane/ethyl acetate) Example 227 N-(3-Benzyloxypyr~dyl-2-carbonyl)-L-phenylalanine, M.p. 100-101C (from pentane/ethyl acetate).
Example 228 5-((1-Butyloxy)carbonyl)-3-methoxypyridin~-2-carboxylic acid N-(carboxymethyl)amide trifluoroacetate a) Di-(1-butyl) 3-methoxypyr~dine-~,5-dicarboxylate 5.0 g of dimethyl 3-methoxypyridine-2,5-dicarboxylate (cf. Example 90a)) were dissolvod in 100 ml of 1-butanol, and after that 1.5 ml of conc. ~ulfuric were added and the mixture wa~ hoated to boiling for 2 h, with a part of the solvent bsing distilled off. After the mixture had been cooled, it was concentrated in vacuo and the rosidue was taken up ~n dichloro~ethane; this solution wa~
oxtr~ct-d with a oaturated, aqueou~ ~olution of Na bicarbonato and the organic phase was dried and concen-trated. 6 g of o$1y crude product.
., .
b) ~is[5-((1-butyloxy)carbonyl)-3-methoxypyridine-2-carboxylic acid]-Cu(II) complex .
6 g (20 mmol) of the above product were addod, disaolved in 10 ml of mothanol, to a solution of 4.8 g (20 mmol) of Cu(II) nitrate x 3 ~,0 in 100 ml of methanol, and t:he mixture was heated to boiling for 4 h. It wa~ then cooled down to 0-5C and the cry~talline precipitate was fil-terod off with suction and washed with diethyl ether.
4.2 g of bluo-groen, cry~talline product were obtained, .p. 267C (wlth decomposition).
'' ;' `' '' ~' ' .: ~
2i31866 c) 5-((1-Butyloxy)carbonyl)-3-mothoxypyridine-2-car-boxylic acid 4 g of the above Cu complex were suisipended in 75 ~1 of 1,4-dioxane. ~2S gaisi w~,~i pai~ised in, while the mixture was being stirred, for 30 min, ~nd the eedlment ~CuS) wh~ich had precipitated out wai~i filtered off with i~iuction through kie3elguhr and then washed with 1,4-dioxane (continued introduct~on Or H,S did not l~ad to any further precipitation); the filtrate w~i6i concentratod in vacuo. The residue wae crystii~llized uciiny potroleum ether, m.p. 96-9SC.
d3 5-((1-Butyloxy)carbo~yl)-3-methoxypyridino-2-carboxylic acid N-((tert-butyloxyc~rbonyl)-methyl)amide 0.76 g (3 mmol) of the a~ovo pyridinecarboxylic acid wa,~
condensed with 0.52 g (3 mmol) of glycine tert-butyl ester hydrochloride, 1.2 ~1 (9 ol) of N-~thylmorpho-line, 0.45 g (3.3 ~mol) of 1-hydroxy~ )-benzotriazole and 1.3 g (3 mmol) of CMC. 0.8 g of product wa~c obtained, m.p. 50-52C (from peitroleum ther).
ei) The title compound wac obtain~d by ~dding 2.7 ml of trlfluoroacetic acid, at 20C, to 0.4 g of the above tert-butyl ei~iteir in dichloromethane. Aftsr 20 h, the mixture was concentrated in vacuo and 0.2 g W~8 obtained of the colorleei~i, cryi~tall$ne, strongly hygroi~icop~c product, which, on being filtered off with ,aiuction, deliquesced on the suction filteir.
Example 22g 5-Ethyloxycarbonyl-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Example 230 3-Methoxy-5-((1-propyloxy)carbonyl)pyridine-2-carboxyl~c acid N-(carboxymethyl)amide 213~866 Example 231 5-(~ exyloxy)carbonyl)-3-mathoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Exa~ple 232 ~-3-Methoxy-5-((1-pentyloxy)carbonyl)pyr$dino-2-carboxylic acid N-(carboxymethyl)amido Example 233 5-((1-Heptyloxy)carbo~yl)-3-methoxypyridino-2-carboxyl~c acid N-(carboxymethyl)amlde Example 234 3-Methoxy-5-((1-octyloxy)carbonyl)pyridine-2-carboxylic acid N-~carboxymethyl)amide ~xamples 235-238 were prepared in an analogous manner to Example 228 proceeding from 3-(2-propyloxy)pyridine-2,5-dicarboxylic acid or the corre~ponding dial~yl esters.
Examplo 235 5-Ethyloxycarbonyl-3-(2-propyloxy)pyridine-2-carboxylic acid N-(carboxymethyl)amide ~`
~ ..
Examplo 236 5-((1-Butyloxy)carbonyl)-3-(2-propyloxy)pyridine-2-carboxylic acid N-(carboxymethyl)amide Example 237 . .
5-((1-Hexyloxy)carbonyl)-3-(2-propyloxy)pyridino-2- :
carboxylic acid N-(carboxymethyl)amide ", 25 Example 238 - --.;
5-((-1-Octyloxy)carbonyl)-3-(2-propylc-xy)pyridine 2-carboxylic acid N-(c~rboxymethyl)amide Example 239 5-Carboxy-3-(methylthio)pyridine-2-carboxylic ~cid N-(carboxymethyl)amide di~odium salt ' ' ~
2134~66 a) 3-(Methylthio)pyridino-2,5-dicarboxyllc acid 4.6 g (12 mmol) of dibenzyl 3-c~loropyridine-2,5-dicar-boxylate were dissolvod, at 20C ~nd while ~tirring, in 30 ml of dimethyl sulfoxido, and aftor that 5.0 g (70 mmol) of sodium thiomethoxido wore ~ddod, in as~oci-ation with which the temperaturo roce to 80C. The reaction mixture was he~tod ~t 140C for 1 h and then cooled down; water wa~ added ~nd tho oily layor w~
~eparatod off; conc. hydrochloric acid (p~ 1) was ~dded to the aqueouo DMS0 pha~e and the preciplt~tod product waQ filter0d off with suction. 2.8 g wsro obtained of a yellow cry~talline product, m.p. 223C (with decom-position).
b) Dimethyl 3-(methylthio)pyridine-2,5-dicarboxylate 50 ml of 1,4-dioxane, 40 ml of tetrahydrofuran and 0.5 ml of conc. ~ulfuric aoid were added to 2.8 g of the above compound in 150 ml of mothanol, ~nd tho mixture w2s heated ~o reflux for 2 h, during which tim0 a eolution wa~ formed. After tho ~olution had been cooled down, it was concentrated in vacuo and 100 ml of an aqueou~
solution of Na bicarbonato were addod to the rosidue; the latter mixture wae oxtracted with dichloro~ethane and the organic phase was dried a~d concentrated. 1.4 g were obtained of tho yellow, crystallino product, ~.p. 103-105C.
c) 5-Methoxycarbonyl-3-(methylthio)pyridine-2 carboxylic acid-Cu(II) complex 1.3 g of the ~bova dimethyl 3-msthylthiopyridine-2,5-dicarboxylate were reacted in analogy with Example 228~
1.3 g of grsenish/cry~talline product were obtained, m.p.
~ 330C.
d) 5-Methoxy-3-(methylthio)pyridine-2-carboxylic acid - ::
213~866 1.3 g of the above compound were ro~cted in analogy with Example 228c), 0.72 g of product, m.p. 183-185C.
e) 5-Methoxycarbonyl-3-(methylthio)pyr~din~-2-carboxylicac$dN-((1-butyloxy)carbonyl)methyl)amldo S ~he compound was obtained by condensing O.68 g (3 mmol) of the above pyridinecarboxylic acid wit~ 0.91 g (3 ol) of glycine 1-butyl e~ter tosylata (1-hydroxy-1~-benzotri-azole, N-ethylmorpholine ~nd CMC). 0.55 g of pale yellow product was obtained, m.p. 47-49C (frcm potroleum 10 ether) .
f) The title compound wa~ obtained by hydroly~ing O.45 g (1.3 mmol) of the above e~ter u~ing 50 ml of 1 N
methanolic NaO~. The clear yollow ~olution hecamo cloudy after 30 min. Aftor 2 h, the precipitate was filtered off with ~uction, washed twice w~th ~ethanol and dried in vacuo. 0.32 g of the title compound wa~ obtained, m.p.
345C (decomp.).
' ~' : .
~:: - . .
.~ - ,,~ , - "~ ~
, ~, ,,,.,~-,,.
-., ~:
,'' ~',' ''' -,' ,'.''`' ~' ,: ,; .~ . . .
: : .
tetrazolyl, imidazolyl or 3-hydroxyl~oxazolyl, whore Rn' is aryl, h-teroaryl, (C3-C7)-cycloalkyl or (C,-C~)-alkyl, optionally noeubstitutod by (C~-C,l)-aryl, heteroaryl, OH, SH, (C,-C~)-alkyl, (C1-C~)-alkoxy, (C~-C~)-thioalkyl, (C,-C~ ulfinyl, ;~
(C~-C~)-sulfo~yl, CF3, Cl, Br, F, I, NO" -COOH, 0 (C,-C5) -alkoxycarbonyl,NE~,mono-(C~-C~-alkyl)-amlno, di-(Cl-C~-alkyl)-amino or (C~-C~)-perfluoroalkyl, Rl, R~ and R3 aro identical or difforont and ar~ ~ydrogon, hydroxyl, halogen, cyano, tri~luoromethyl, nitro, carboxyl, (C,-C20)-alkyl, (C,-C,)-cycloalkyl, (C3-C,)-cycloalkyl-(C~-C")-alkyl, (C3-C,)-cycloalkoxy, (C3-C,)-cycloalkyl-(C,-Cl,)-alkoxy, (C3-C,)-cyclo- ~;~
alkyloxy-(C1-C~)-alkyl, (Cl-C~)-cycloalkyloxy-(C~
C")-alkoxy, (C3-C,) -cycloalkyl-(C,-C,)-alkyl-(C,-C~)-alkoxy, (C3-C,) -cycloalkyl-(C,-C,)-alkoxy-(C,-C6)-alkyl, (C3-C,) -cycloalkyloxy-(C,-C~)-alkoxy-(C~
C6)-alkyl, (C3-C,)-cyGloalkoxy-(C~-C~)-alkoxy-(C~ "'~
C,)-alkoxy, (C~-C,2)-aryl, (C7-C")-aralkyl, (C7-C") - .`; :~`f :`;
aralkenyl, (C7-C,c)-aralkynyl, (Cs-C,0)-alkonyl, (Cl- ~ t Cl0)-alkynyl, (C,-C~0)-alkoxy, (C~-C~0)-alkenyloxy, (Cl-Cl0)-alkynyloxy, retlnyloxy, (C1-Cl0)-alkoxy-(C,- .
C,l)-alkyl, (C,-C,l)-alkoxy-(C,-C,l)-alkoxy, (C,-C,l)-alkoxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C~-C")-aryloxy, (C7-ClC) -aralkyloxy, (Cc-C")-aryloxy-(Cl-Cc)-alkoxy, . ~'!.. ',,~,~",'.'`.
(C~-C~)-aralkoxy-(C~-Cc)-alkoxy, (C~-C~)-hydroxy-' '; '~' ';'` ,`,.!, '~'', ',' alkyl, (C~-C~)-aryloxy-(C~-C~)-alkyl, (C7-Cl,)-aralkoxy-(C,-C,)-alkyl, (C~-C")-aryloxy-(C,-C,)~
alkoxy-(CI-C~)-alkyl, (C7-C") -aralkyloxy-(C,-C,)-alkoxy-(C,-C~)-alkyl, (C,-C,0)-alk~nyloxy-(C,-C~
alkyl, (C~-C,0)-alkynyloxy-(C~-C,)-alkyl, r-tinyloxy-(C,-C~)-alkyl, -O-tC~ -C~H~ )F~, -OCF,Cl, -OCF,-CHFCl, . .~
'~: ,: ." ' . . ~ .
(Cl-Cl0)-alkylcarbonyl, (C3-C,)-cycloalkylcarbonyl, .;~
.: ., .::
" , .:, ,.;, .
(C,-Cl2)-arylcarbonyl, (C7-C~,)-arallcylcarbonyl, s:~nnamoyl, (C2-C,0)-alk~slylcarbonyl, (C,-C20)-alkynylcarbonyl, (C,-C20)-alkoxycarbonyl, (c1-c12)-alkoxY-(c~-cl2) alkoxycarbonyl, (C6-C12)-aryloxy¢arbonyl, (C7-C1~
aralkoxycarbonyl, (C3-C,) -cycloalkoxycarbonyl, (C2-C20)-alkenyloxycarbonyl, rotinyloxycarbonyl, (C,-C,0)-alkynyloxycarbonyl, (C,-C1~)-aryloxy-(C1-Cc)-alkoxy-carbonyl, (C7-Cl~)-aralkoxy-(Cl-C~)-alkoxycarbollyl, (C3-C,)-cycloallcyl-(C1-C~)-alkoxycarbonyl, (C3-C,,)-cycloalkoxy-(C,-C~)-alkoxycarbonyl, (C~-C~2)-alkylcarbonyloxy, (C3-C:~)-cycloalkylcarbon-yloxy, (C6-C,2)-arylcarbonyloxy, (C7-C1,)-aralkyl-carbonyloxy, cinnamoyloxy, (C2-C12)-alkonylcarbonyl-oxy, (C2-C12)-alkynylcarbonyloxy, ~C,-C,2)-alkoxycarbonyloxy, (C,-C,2)-alkoxy-(C,-C,2)-alkoxycarbonyloxy, (C,-C,2)-aryloxycarbonyloxy, (C7-C,6)-aralkyloxycarbonyloxy, (C3-C,)-cycloalkoxycar-bs~nyloxy, (C2-C~2)-alkcnyloxycarbonyloxy, (C,-Cls)-alkynyloxycarbonyloxy, .':. ~'.';''"'~:
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-Cl2)-alkylcarbamoyl, N-(C3-C~)-cycloalkylcarbamoyl, N,N-dicyclo- (C3 - C,) -alkylcarbamoyl, N-(C1-C10)-alkyl-N- (C3-C,) -cycloalkylcarbamoyl, N-((C3-C~) -cycloalkyl-(C~-C6)-alkyl)carbamoyl, N-(cl-c~)-alkyl-N-((c3-c~
cycloalkyl (C~-C6?,-alkyl)carbamoyl, N-(l)-dehydro-abietyl¢arbamoyl, N-(C1-C,)-alkyl-N-(+)-dchydro-abietylcarbamoyl, N-(C,-C12)-arylcarbamoyl, N- (C7-C16)-aralkylcarbamoyl, N-(C1-Clo)-alkyl-N-(cc-c~
arylcarbamoyl, N-(C,-C~0)-alkyl-N-(C,-Cl~)-aralkyl-carbamoyl, N-((C1-C1,)-alkoxy-(C1-C,0)-alkyl)car!~a-moyl, N-((C,-C,6)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-Cl6)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10) -alkyl-N- ( (C1-C10) -alkoxy- (C,-C,0) -alkyl) carbamoyl, N-(C1-C1o) -alkyl-N-((C,-C,2)-.. ........
213~866 aryloxy(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-C~O)-al~cyl-N-((C7-Cl6)-aralkyloxy-(C,-C10)-allcyl)carbamoyl, or ~ ~ :
CON(C}I,)h, in which a C}12 group can be r~plac~d by O, S, N-(Cl-C~)-allcylimino, N- (C3-C,) -cycloallcylimino, N- (C3-C,) -cycloalkyl-(Cl-C~)-alkyl~ino, N-(C,-Cl,)-arylimino, N- (C7-Cl~) -arallcyli~no or N-(C1-C~)-alkoxy-(Cl-C,)-alkylimino, and h ic from 3 to 7, a aarbamoyl radical of tho fonhula II
- 1 , " ~
R' H
--CO~ I NR ~~~--T ( I I ), ~ ~;
in which R~ ie the subetituent of an a-amis~o acid to wh~oh the L- and D-amino acidc belong, e ie 1, 2, 3, 4 or 5, and T ie OH, OR or NR-R--, whore R-, R^- and R--- are ~dentical or diffsront and are hydrogen, (C6-Cl2)-aryl, (C7-Cll)-arallcyl, (Cl-C,)-alkyl, (C3-C,)-cycloalkyl, (~)-dehydroabiotyl, (Cl-C~ lkoxy-(Cl-C~)-alkyl,(C7-Cl,)-aralkoxy-(Cl-C,)-alkyl, (C~-Cl~)-aryloxy-(Cl-C~)-alkyl, (Cl-Cl0)-alkanoyl, optionally eubetituted (C7-Cl~)-aralk-anoyl or optionally eubetituted (C~-Cl,)-aroyl, or R~ and R-- togothor are -lCE~,]b, in which a C~, group oan be roplac~d by O, S, SO, SO" N-acylamlno, N-(Cl-C~0)~allcoxy~arbonyl~n~no, N-(Cl~C~)-alkylimino, N- (C3-C,) -cycloallcylimino, N-(C~-C~)-cycloallcyl-(Cl-C~)-alkylimino, N-(C~-Cl~)-arylimino, N-(C7Cl~
aralkylimino or N-(Cl-C~)-alkoxy-(Cl-C~)-alkyl-imino, and h ie from 3 to 7, carbamoyloxy, N-(C,-C")-alkylcarbamoyloxy, N,N-dl-(Cl-Cl2)-alkylcarbamoyloxy, N- (C3-C,) -cycloalkylcarb-amoyloxy, N- (C~-C,;,)-arylcarbamoyloxy, ' ' .'' '' .: "" ' ",., `` 213~866 : ~ ~
_ N-(C7-C~-aralkylcarbamoyloxy, N-(Cl-C10)-al ~l-N-(C6-Cl2)-arylci~rbamoyloxy,N-(C~-ClO)-alkyl-N-(C7-C~
aralkylcarbamoyloxy, N-((Cl-C~0)-al ~l)carbamoyloxy, N-((C,-C,2)-aryloxy-(C,-C10)-al~yl)car~ ~ ylo ~, N-((C7-C") -aralkyloxy-(C~-C,0)-al ~l)carbamoyloxy, N-(cl-clo)-al~yl-N-((cl-clo)-alkoxy-(cl-clo)-al~yl)-carbAmnyloxy, N-(C,-C10)-al~l-N-(~C~-C~2)-arylo~-(C,-C10)-alkyl)carbamoylo~, N-(C~-C,0)-alkyl-N-((C7-C~
aralkyloxy-(C,-C,0)-alkyl)carbamoyloxy, amino, (Cl-C,2)-alkylamino, di-(C,-Clj)-al ~1 ~ no, (C,-C,)-cycloal~ylamino, (C3-C~2)-alk~nyl ~ no, (C3-Cl2)-alkynylamino, N-(C,-C,2)-aryl~no, N-(C7-C1~
aralkylamino, N-alkyl-aralkylamino, N-al ~l-aryl-amino, (C,-Cl2)-alkoxyA~no, (C,-C12)-alkoxy-N-(C,-C~0)-alkyl ~ino, (C,-C,3) -alk~oylamino, (C3-C~)-cycloalkanoylamino, (C~-C~2)-aroyl ~ino, (C7-Cl6)-aral~anoyl~no, (C~
C,2)-alkanoyl-N-(C,-C,0)-alkylamino, (C3-C,)-cyclo-alkanoyl-N-(C~-C10)-alkylamino, (C~-C~2)-aroyl-N-(C,-C,0)-alkyl ~ no, (c7-cll)-aralkanoyl-N-(cl-clo) alkylamino, ~C,-C,2)-alkanoylamino-(C,-C,)-alkyl, (C3-C,)-cyclo-alkanoylamino-(C,-C~)-alkyl, (C~-C12)-aroylamlno-(C,-C,)-alkyl, (C7-C,6)-aralkanoyl ~ no-(C,-C~)-alkyl, 2i amlno-(C,-C,0)-alkyl, N-(Cl-C,0)-alkylamlno-(C,-i~O)~
alkyl, N,N-dl(C,-C,o)-alkylamino-(C~-C~0)-alkyl, (C~
C,?-cycloalkylamino-(C,-C10)-alkyl, (C~-C20)-al~yl-mercapto, (C1-C20)-alkyloulfinyl, (C1-C20)-alkyloul-fonyl, (C~-C~2)-arylm-rcapto, (C~-C~2)-arylculfinyl, (C~-C~2)-aryloulfonyl, (C7-C~)-aralkylmorcapto, (C7-C~6)-aralkylculfinyl, (C7-C,6)-aralkyl~ulfonyl, (Cl-C12)-alkylmercapto-(C~-C~)-alkyl, (C,-C,j)-alkyl~
culf$nyl-(C~-C~)-alkyl, (C~-C~2)-alkylsulfonyl-(C~-C~)-alkyl, ~C~-Cl2)-arylmerc~pto-(C,-C~)-alkyl, (C~-C,2)-arylsulfinyl-(Cl-C,)-alkyl,(C~-Cl2)-aryloulfonyl-(Cl-C6)-alkyl, (C7-C,~)-aral ~lmorcapto-(C,-C~)-alkyl, ::~:: ::. .:
(C7-C16) -aralkylsulfinyl-(Cl-C~)-alkyl, (C7-c~
aralkylsulforyl-(C1-C~)-alkyl, : ~ ;
~ulfamoyl, N-(Cl-Cl0)-alkyl~ulfamoyl, N,N-di-(Cl-Clo)- ~ :
alkylsulfamoyl, (C,-C,)-cyeloalkyl~ulfamoyl, : ~
N-(C,-C,2)-aryleulfamoyl, - .~-N-(C7-Cl~)-aralkylsulfamoyl, : , .;
N-(C~-C,O)-alkyl-N-(C~-C~l)-arylsulfamoyl, ~ .
N-(C~-C,O)-alkyl-N- (C7-C") -aralkylsulfamoyl, (C1-C,0)-alkyl~ulfona~ido, N-((C,-C,0)-alkyl)-(C~-C,0)-alkylsulfonam~do,~C7-C
aralkyl~ùlfona~ldo or N-((C~-C~O)-alkyl- (C7-C~
aralkylsulfonamido, where the radlcals whieh conta~n an aryl radleal can, for the~r part, bs ~ubstltuted on the aryl by from 1 to 5 idontical or dlfforant radlcal~ from the hydroxyl, halogon, cyano, trifluoromethyl, nltro, carboxyl, (C,-C~)-alkyl, (C3-C,)-cyclo-lkyl, (C3-C~ ".,~
cycloalkyl-(Cl-Cl,)-alkyl, (C3-C,) -cycloalkoxy, (C 3-C~) -C y C 1 0 a 1 k y 1 - (Cl- Cl,) - a 1 k o x y, :~
(C3-C,) -cycloalkyloxy-(Cl-Cl,)-alkyl, (C,-C,)-cyclo-alkyloxy-(Cl-Cl,)-alkoxy, (C3-C,) -cycloalkyl-(Cl-C~
alkyl-(Cl-C,)-alkoxy, (C3-C,) -cycloalkyl-(Cl-C,)-alkoxy-(Cl-C,)-al~yl, (C3-C,) -cycloalkyloxy-(Cl-C~
alkoxy-(Cl-C~)-alkyl, (C3-C,) -cycloalkoxy-(Cl-C,)- .
alkoxy-(Cl-C,)-alkoxy, (C,-Cl,)-aryl, (C7-C,~) -aralkyl, (C~-Cl~)-allcenyl, (C,-Cl,)-alkynyl, (Cl-Cl~)-alkoxy, ... ;''.~', ,',:`:.
(Cl-Cl,)-alkanyloxy, (Cl-Cl,)-alkoxy-(Cl-Cl,)-alkyl, ~` `' .; .;~
(Cl-Cl~)-alkoxy- (Cl-C12) -alkoxy, (Cl-Cl,)-alkoxy-(Cl- .. .
C,)-alkoxy-(Cl-C~)-alkyl, (C~-Cl,)-aryloxy, (C7-C
aralkyloxy, (C~-Cl2)-aryloxy-(Cl-C~)-alkoxy, (C7-C
aralkoxy-(Cl-C,)-alkoxy, (Cl-C,)-hydroxyalkyl, (C~
Cl~)-aryloxy-(Cl-C,)-alkyl, (C7-Cl~)-aralkoxy-(Cl-C~)- :~-: : ;
alkyl, (C~-Cl,)-aryloxy-(Cl-C,)-alkoxy-(Cl-C,)-alkyl, `.. ~.
( C7-Cl~) - aralkyloxy-(Cl-C,)-alkoxy-(Cl-C,)-alkyl, ~ ~ :
-O-tCH,.]~-C~H(,~ )F~, -OCF,Cl, OCF2-CHFCl, (Cl-C12)-alkylcarbonyl, (C3-C,)-cyeloalkylcarbonyl, :: . : ~' .
g (C6-Cl2)-arylcarbonyl, (C,-Cl,~-arallcylcarbonyl, (C,-Cl2)-alkoxycarbonyl, (el-e12)-alkoxY-(cl-cl2) alkoxycarbonyl, (C,-Cl2)-aryloxycarbonyl, (C,-Cl,)-aralkoxycarbonyl, (C,-C,)-cycloalkoxycarbonyl, (C2-Cl2)-allcenyloxycarbonyl, (C2-Cl2)-allcynyloxyearbonyl, (C~-C~2)-aryloxy-(Cl-C~)-alkoxycarbonyl, (C7-cl~
aralkoxy-(Cl-C,)-alkoxycarbonyl, (C,-C,)-cycloalkyl-(C1-C~)-allcoxycarbonyl, (C,-C")-eyeloalkoxy-(Cl-C~
al;coxyc:arbonyl, (Cl-Cl2)-allcylearbonyloxy, (C,-C,)-eyeloallcylearbo-nyloxy, (Cc-C12)-arylearbonyloxy, (C7-Cl~)-arallcyl-carbonyloxy, cinna~oyloxy, (C2-Cl2)-alkenyl¢arbonyl-oxy, (C2-Cl2)-alkynylcarbonyloxy, (Cl-Cl2)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(Cl-Cl2)-alkoxycarbonyloxy, (C,-Cl2)-aryloxycarbonyloxy, (C7-Cl6)-aralkyloxycarbonyloxy, (C~-C~)-cycloalkoxycar-bonyloxy, (C2-Cl2)-alkenyloxycarbonyloxy, (C2-Cl2)-alkynyloxycarbonyloxy, carbamoyl, N-(Cl-Cl2)-alkylcarbamoyl, N,N-dl-(Cl-C12)-alkylcarbamoyl, N- (C3-C,) -cyeloalkylcarbamoyl, N,N-d~cyelo- (C3-C,) -alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C,) -cy¢loalkyl¢arbamoyl, N-( (C3-C,) -eycloallcyl-(Cl-C~)-alkyl)carbamoyl, N-(Cl-C~)-alkyl-N-( (C3-C,) -cycloalkyl- (Cl-C6) -alkyl)earbamoyli N-(l)-dehydro-abietylcarb~oyl, N-(C1-C~)-alkyl-N-(I)-dohydro-abiotyl¢a*am!oyl~ N-(C~-Cl~)-aryl¢arb~oyl, N- (C7-Cl~)-aralkyl¢arbamoyl, N-(Cl-c30)-alkyl-N-(cc-clc)-aryl¢arbamoyl, N-(C1-C10~-alkyl-N-(C7-Cl~)-arallcyl-carbamoyl, N- ((Cl-Cl,) -alkoxy- (Cl-C10) -alkyl) -carbamoyl, N- ( (C,-Cl6) -aryloxy- (C1-C10) -alkyl)carbu~oyl, N-((c7-cl~)-aralkyloxy-(cl-clo)-alkyl)carbamoyl, N-(Cl-C"0)-alkyl-N-((Cl-C1O)-alkoxy-(Cl-C1O)-alkyl)-¢arbamoyl, N-(Cl-C10)-alkyl-N-((Cc-Cll)-aryloxy-(Cl-C10)-alkyl)¢arb~noyl, N-(cl-c~o)-alkyl-N-((c7-cl6)--,.
" , ,, ~ .
213~866 .
- 10 - ,, aralkyloxy-(Cl-C10)-allcyl)carbamoyl, CON(C~)h, $n which a C}Iil group can b~ roplaced by O, S, N-(Cl-C,)~
alkyl~m~no, N- (C3-C,) -cycloalkyl~m~no, N-(C,-C~
cycloalkyl-(Cl-C~)-alkyl~m~no, N-(C~-Cl2)-aryl~m~no, N-(C7-Cl6)-aralkyl~m~no or N-(Cl-C")-alkoxy-(Cl-Cs)-alkylimino, and h ic from 3 to 7, carbamoyloxy, N-(C1-C~j,)-alkylcarbamoyloxy, N,N-d~
(Cl-Cl~)-alkylcarbamoyloxy, N-(C~-C~)-cycloallcyl~
carbamoyloxy, N-(C~-Cl~)-arylcarbamoyloxy, N-(C,- `: -~ : j Cl~)-aralkylcarbamoyloxy, N-(Cl-C10)-allcyl-N-(C~
Cll)-arylcarbamoyloxy, N-(cl-clo)-allcyl-N-(c7-cl~
arallcylcarbamoyloxy, N-((Cl-C10)-alkyl)carl:~amoyloxy, N-~(C6-Clj~)-aryloxy-(Cl-C10)-alkyl)carbamoyloxy, N-((C7-Cl6)-aralkyloxy-(Cl-C10)-allcyl)carbamoyloxy, N-(Cl-C10) -alkyl-N- ( (Cl-C10) -alkoxy- (Cl-C~O) -alkyl)carbamoyloxy, N-(cl-clo)-allcyl-N-(( aryloxy-(C,-C10)-allcyl)carbamoyloxy,N-(C1-C10)-allcyl~
N-((C7-Cl6)-arallcyloxy-(C1-C10)-alkyl)carb~oyloxy, : , ; ~ .
amino, (Cl-Cl2) -alkylamino, di-(C1-C1,)-alkylamino, (C3-C,) -cycloalkylamino, (C~-Cl~)-allcenyl~m~no, (C3- ~:~' ,,.. :, .
Cl~)-alkynylamino, N-(C6-Cl~)-arylamino, N-(C7-Cl~
aralkylamino, N-alkyl-arallcylamlno, N-alkyl-aryl- j :; .r: ",' amino, (C1-C1~)-alkoxyamino, (C1-C1~)-alkoxy-N-(C1- :~
C10)-alkylamino, ; ~ . A'.`' (C1-C1,)-alkanoylamlno, (C3-C,) -cycloalkanoylamino, ;.
(C6-C1,)-nroylamlno, (C7-C16)-aralkanoylamino, (C1- ::
C~-alkanoyl-N-(Cl-C10)-alkylamino, (C3-C,) -cyclo- .
alkanoyl-N-(C1-C10)-alkylamino, (C~-C1,)-aroyl-N-(C1- ~
C~0)-alkylamino, (C7-Cll)-aralkanoyl-N-(C1-C10)-alkyl- `
amino, . ~
(Cl-Cl~) -alkanoylamino-(Cl-C~) -alkyl, (C3-C,) _ ` ~ `
cycloalkanoyl~n~no-(Cl-C~)-alkyl, (C6-Cl,)-aroylamino-(C,-C~)-a;Lkyl, (C7-C16)-aralkanoylamino-(C1-C,)-allcyl, amino-(Cl-C10)-allcyl, N-(Cl-C10)-alkylamino-(Cl-C,O)-alkyl, N,N-di-(Cl-C10)-alkylamino-(Cl-ClO)-allcyl, ~. : ~ ~:.. ; .
:.~ ,:. ..
'" "' ' ': ~'~
213~86~
11 .
(C~-C~)-cycloal~ylamino-(Cl-Cl0)-alkyl, (Cl-Cl2)-allcylmercapto, (Cl-Cl2)-allcyl~ulfinyl, (Cl-C~2)-alkylsulfonyl, (C~-Clc)-arylmorcapto, (C~-Cl,)~
aryleulfinyl, (C6-Cl~)-arylsulfonyl, (C7 -Cl~
aralkylmercapto, (C~-Cl~)-aral~yl~ulfinyl or (C7-C16)-aral~ylsulfonyl, Rl and R2 or R2 and R3 form a chain tCH2]o ~n which ono or two CH2 groups of ths chnin, which is ~aturat~d or unuaturated by a C-C doublo bond, are optionally replaced by 0, S, S0, S02 or NR', and o 1~ 3, 4 or 5, and R' i~ hydrogen, (C6-Cl~)-aryl, (Cl-C~)-alkyl, (Cl-C,)-alkoxy-(Cl-C~)-al~yl, (C7-C~ aral~oxy-(Cl-C,)-alkyl, (c6-cl2)-aryloxy-(cl-c~)-al~yl~ (Cl-C10)-al~anoyl, optionally sub~tituted (C7-C~ aral~anoyl or optionally ~ub~titutod (C6-Cl2)-aroyl, whore the radical~ Rl and R2 or R2 and R3, togother with the pyrldine or pyrldazlne carrylng th~m, preferably form a 5, 6, 7, 8-tetrahydrolsoqulnollne rlng, a 5, 6, 7, 8-tetrahydrogulnollne rlng or a 5, 6, 7, 8-tetrahydrocinnoline rlng, or Rl and R2 or Rs and R3 form a carbocycllc or a h-terocycllc, 5- or 6-membered aromatic rlng, where the radlcals Rl and R2 or R2 and R3, together w~th the pyrldlne or pyridazine carrylng them, preferabiy form the followlng optlonally ~ub~tltuted h-terocyclic ring sy~temss Thlenopyrldlne~
Furanopyrldines, Pyridopyrldln-s, Pyrlmidinopyridlne~, Imidazopyridinos, .
i~ :' ~',' '"'' Thiazolopyridinoe, Oxazolopyridinee, Quinolino, ~oguinolino and ;~
Cinnolina, whoro quinolino, ieoquinoline or cinnollno pre~
forably eatiefy the formulae la, lb and lc R~2 ~ ~R~ ~ OR~
1~ 1 b ; : . :. .`
, ,~: ., :: ., :.........
R 2 o ~ Q R~
R22~q~ : ~ :
`N~
1 C , ; ~ .
and the eubstituent~ R~l to Rss, in oach caeo independontly of each othor, have the meaning of Rl, R2 and R3, :
., : ~ I I ' , .,: . : :: . ' R~ ie, if Q iB a bond, halogon, nitrilo or trifluoro-mothyl, or, if Q ie O, S or NR', a braDch-d or unbranched (Cl-CsO)-alkyl radical, an uneub~titutod, :~
~aturatod fluoroalkyl radical of the formula lC~]~
C~H~s~ )F~, a (C~-C1c)-aryl radical, a (Cj-C1,)-aralkyl radical, a heteroaryl radical or a hetoroaralkyl : . .;
radical, . .:
.;'.;,,'.'"'",.:~
,~ ,, ."~
.
213~866 whore the~ rad~cals are s~bstituted by one or more radical~ from th~ group hydroxyl, halogen, cyano, tr~fluoromothyl, n~tro, carboxyl, (C1-C,2)-alkyl, (C3-C,) -cycloalkyl, (C3-C,)-cycloalkyl-(C,-Cl2)-alkyl, (C3-C,) -cycloalkoxy, (C3-C,) -cycloalkyl-(C~-C~)-alkoxy, (C3-c~) -cycloal~yloxy-(C~-C~2)-alkyl, (C3-C,) -cycloalkyloxy- (C,-C,2) -al~oxy, (C3-C,) -cycloalkyl-(C~-C~)-al~yl-(C~-C~)-alkoxy, (C3-C,) -GyC10-alkyl-(C,-C,)-alkoxy-(C,-C,)-alkyl, (C,-C,)-cycloalkyloxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C3-C,) -cycloalkoxy-(C~-C~
alkoxy-(C,-C,)-alkoxy, (C~-C")-aryl, (C7-C") -aral~yl, (C~-Cl2)-alkonyl, (C2-C~)-alkynyl, (Cl-C~2)-al~coxy, (C,-C")-alkoxy-(C1-C~)-alkyl, (c~-c~2)-alkoxY-(c~-c~2)-alkoxy, (C,-C,2)-alkoxy-(C,-C,)-alkoxy-(C,-C,)-alkyl, (C,-Cl,)-aryloxy, (C7-C~c)-aralkyloxy, (C,-C")-aryloxy-(C~
C6)-alkoxy, ~C7-C~)-aralkoxy-(C~-C~)-alkoxy, (C,-C,)-hydroxyalkyl, (Cc-C~)-aryloxy-(C,-C,)-alkyl, (C7-C")-aralkoxy-(C1-C~)-alkyl, (C~-C")-aryloxy-(C~-C~)-alkoxy-(C~-C~)-alkyl, (C7-C")-aralkyloxy-(C,-C~)-alkoxy-(C~-C~
alkyl, ~O~lC~,]~~C~ lg~F~, -OCF2Cl, -OCF,-CHFCl, ..: :: ,:
(C~-C")-alkylcarbonyl, (C3-C~) -cycloalkylcarbonyl, (C,-C~2)-arylcarbonyl, (C7-C")-aralkylcarbonyl, c~nnamoyl, (C2-C")-alkenylcarbonyl, (C,-C,2)-aklynylcarbonyl, (C~-C~2)-alkoxycarbonyl, (C~-C")-alkoxy-(C~-C")-alkoxy-carbonyl, (C~-C,2)-aryloxycarbonyl, (C7-C~)-aralkoxy-carbonyl, (C3-C,)-cycloalkoxycarbonyl, (C~-C")-alko~yl-oxycarbonyl, (C2-C~2)-~lkynyloxyoarbonyl, (C~-C")-aryl-oxy-(C,-C~)-alkoxycarbonyl, (C7-C")-aralkoxy-(C,-C,)-alkoxycarbonyl~(c3-C~) -cycloalkyl-(C~-C~)-alkoxycarbonyl, (C3-C,) cycloalkoxy-(C~-C~)-alkoxycarbonyl, (C~-C~2)-alkylcaxbonyloxy, (C3-C,) -cycloalkylcarbonyloxy, (C~-C")-arylcarbonyloxy, (C7-C") -aralkylcarbonyloxy, clnnamoyloxy, (C,-C")-alk~nylcarbonyloxy, (C,-C~
alkynylcarbonyloxy, . - :;::: ..,, :.. ., :., (C~-C1,)-alkoxycarbonyloxy,(C~-C~2)-alkoxy-(C,-C,2)-alkoxy-: ::.:; . . ~
213~866 ~ :
- 14 - ~-carbonyloxy, (C,-Cl,)-aryloxycarbonyloxy, (C,-Cl,)-aralkyl-oxycarbonyloxy, (C3-C,)-cycloalkoxycarbonyloxy, (C,-Cl,)-alkenyloxycarbonyloxy, (C,-Cl,)-al~ynyloxycarbonyloxy, carbamoyl, N-(C~-Cs,)-al~ylcarbamoyl, N,N-di-(Cl-C~
alkylcarbamoyl, N- (C3-C,) -cycloalkylcarba~oyl, N,N-dl-cyclo- (C3-C~) -alkylcarbamoyl, N-(Cl-C10~-alkyl-N- (C3 C,) cycloalkylcarbamoyl, N-((C3-C~)-cycloalkyl-(C~-C~
alkyl)carbamoyl, N-(cl-c~)-alkyl-N-((c3-c~) -cycloalkyl-(Cl-C~)-alkyl)carbamoyl, N-(~)-dehydroabi-tylcarbamoyl, ; '~
N-(Cl-C,)-alkyl-N-(~)-dehydroab~etylcarbamoyl, N-(C,-Cl2)-arylcarbamoyl, N- (C7-C") -aralkylcarbamo~l, N-(Cl-C1o)-alkyl-N-(C~-Cl~)-arylcarbamoyl, N-(Cl-Cl0)-al~yl-N- (C7-Cl6)-aralkylcarbamoyl, N((cl-clo)-alkoxy-(cl-clo)- -' alkyl)carbamoyl, N-((C~-Cl~)-aryloxy-(Cl-Cl~)- ; -alkyl)carbamoyl, N-((C7-Cl,)-aralkyloxy-(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-Cl0)-alkyl-N-((Cl-C10)-alkoxy-(Cl-Cl0)-alkyl)carbamoyl, N-(Cl-ClD)-alkyl-N-((C~-Cl~)-aryloxy- ~;
(Cl-Cl0)-alkyl)carbamoyl, N(cl-clo)-alkyl-N-((c7-cl~
aralkyloxy-(C1-Cl0)-alkyl)carbamoyl, CON(CH~)h, in which 20 a CH, group can be replaced by O, S, N-(Cl-C,)-alkyllmino, ;~
N- (C3-C,) -cycloalkyllmlno, N-(C3-C,)-cycloalkyl-(Cl-C~
alkyllmino, N-(C,-Cl,)-aryllmlno, N-(C7-Cl~)-aralkyllmino or N-(Cl-C~)-alkoxy-(Cl-C~)-alkyl~mlno, ~nd h ~e from 3 to 7, or by a carbamoyl radlcal of the formula II
. :' ~ .~ ', ,~'~' ':' ":' R X H ~ :
C O - - N R l ~ `r ( I I ) . ~ :
S ::.. '; ::;':.. -, ln whlch ~ ;~
RY le the eubstituent of an a-amino acld to which the L- and D-amlno acids belong, e le 1, 2, 3, 4 or 5, and T is OH, OR or NR-R--, where . ,,. ~",,.
2134~66 - 15 ~
R-, R--, and R--- are ident~cal or dlfforont and aro hydrogon, (C~-C,2)-aryl, (C7-Cll)-aral~yl, (Cl-C~
alkyl, (C3-C,)-cycloalkyl, (I)-do~ydroabietyl, (C
C,)-allcoxy-(Cl-C~)-alkyl, (C7-Cl~) -aralkoxy-(Cl-C~
alkyl, (C~-Cl~)-aryloxy-(Cl-C~)-alkyl, (Cl-C10)-alkanoyl, optlonally cubctitutod (C~-C16) -aralkanoyl or optionally ~ub~tituted (C,-Cl2)-aroyl, or R and R togother aro -~ ]h~ in w~ch a CEI~ group can be replaced by O, S, SO, SO~, N-aeyla3~no, N-(Cl-C,0)-alkoxycarbonyl~m~no, N-(C1-C,)-~lkylimino, N-(C~-Ca) -cycloallcylimino, N- (C3-C,) -cycloalkyl-(C~-C~)-alkylimino, N- (C6-C~2) -arylimino, N- (C,-C,6)~
aralkylimino or N-(C~-C,)-alkoxy-(C~-C,)-alkyllmino, and h i~ from 3 to 7, or by carbamoyloxy, N- (Cl-C~2) -alkylcarbamoyloxy, N,N-di-(C~
Cl2)-alkylcarbamoyloxy, N-(C3-C~)-cycloalkylcarbamoyloxy, N-(Cc-C,2)-arylcarbamoyloxy, N-(C,-Cl~)-aralkyl-carbamoyloxy,N-(Cl-C10)-alkyl-N- (CC-C12) -arylcarbamoyloxy, N-(Cl-C10)-alkyl-N-(C7-Clc)-aralkylcarbamoyloxy, N-((Cl-C~O)-alkyl)carbamoyloxy, N-((c~-cl2)-aryloxy-(cl-clo) -alkyl)carbamoyloxy, N-((C7-Clc)-aralkyloxy-(Cl-ClO)-alkyl)carba~oyloxy, N-(Cl-C10)-alkyl-N-((Cl-C10)-alkoxy-(C,-C1~)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((C~-Cl2)-aryloxy-(Cl-C,0)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((C7-Cl6)-aralkyloxy-(Cl-C~0)-alkyl)carbamoyloxy, amlno, (Cl-cl2) -alkylamlno, di- (Cl-cl2) -alkylamlno, (C3-C~)-cycloalkylamlno, ~C3-C12) -allcenylamino, (C3-C12)-alkynylamlno, N-(C~-C,2)-arylamino, N-(C,-Cll)-aral~yl-amino, N-alkyl-aralkylamlno, N-alkyl-arylamlno, (Cl-Cl2)-alkoxyamino, (C~-C12) -alkoxy-N-(C,-C,0)-allcyl~ no, (Cl-C,2)-alkanoylamlno, (C3-C,)-cycloalkanoylamlno, (C,-C,2)-aroylamlno, (C,-C,c)-aralkanoylamlno, (Cl-Cl2)-alka-noyl-N-(Cl-C10)-alkylamino, (C3-C,) -cycloallcanoyl-N-(Cl-C10)-alkylamlno, (Cc-Cl2)-aroyl-N-(Cl-ClO)-alkylamlno, (C,-C"~-aralkanoyl-N-(C,-C,0)-alkylamlno, 213~866 (C1-C")-alkanoylamino-(C1-C~)-alkyl, (C3-C,) -eyelo-alkanoylamino-(Cl-C,)-alkyl, (C~-C12) -aroylamino-(Cl-C~)-alkyl, (C7- C16) - aral~anoylamino-(C1-C~)-alkyl, amino-(Cl-C10)-alkyl, N-(C1-C1O)-alkylamlno-(C1-C1O)-alkyl~ N,N-di~C1-C1o)-alkYlamino-(C1-C1O)-alkyl, (C~-C,)-eyeloalkylamlno-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfi~yl, (C1-Cl2)-alkylsulfonyl, (C6-C12) -arylmereapto,(C,-C,)-aryl~ulfinyl, (Cc-Cl2)-arylsulfonyl, (C7-Cl~)-aralkylmorcapto, (C7-Cl6)-aralkylsulfinyl, (C7-C1~)-aralkyl~ulfonyl, sulfamoyl, N-(Cl-C10)-alkyl~ulfamoyl, N,N-di-(Cl-C1o)-alkylsulfamoyl, (C3-Ca)-eyeloalkylsulfamoyl, N-(C~-C12)-aryleulfamoyl, N-(C7-C1c)-aralkylsulfamoyl, N-(C~-C10)-alkyl-N-(C~-Cl2)-arylsulfamoyl, N-(Cl-clo) alkyl-N-(C7-C1~)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamldo, N-((C1-C10)-alkyl)-(Cl-ClO)-alkylsulfonamido, (C7-C~
aralkyl~ulfonamido or N-((C~-C10)-alkyl-(C7-Cl,)-aralkyl-~ulfonamido, where the radleals whieh ¢ontain an aryl radieal ean, for their part, bo sub~tituted on tho aryl by from 1 to 5 ldentieal or differont radioal~ from the group:
hydroxyl, halogon, eyano, trifluoromethyl, nit~o, carboxyl, (C1-C12)-alkyl, (C3-C,) -eyeloalkyl, (C3-C,)-cycloalkyl-(C1-C~2)-alkyl, (C3-C,) -eyeloalkoxy, (C3-C,) -eycloalkyl- (Cl-C12) -alkoxy, (C3-C,) -eycloalkoyloxy-(C1-C1~
alkyl, (C3-C,) ~-eyeloalkyloxy- (C~-C12) -alkoxy, (C,-c~? -cycloalkyl-(Cl-C~)-alkyl-(C1-C~)-alkoxy, (C3-C,) -eyelo-alkyl-(Cl-C,)-alkoxy-(Cl-C~)-alkyl, (C,-C,)-eyeloalkyloxy-(C1-C,)-alkoxy-(C1-C,)-alkyl, (C3-C~) -eyeloalkoxy-(C1-C,)-alkoxy-(Cl-C~)-alkoxy, (C~-C12)-aryl, (C7-C1c~-aralkyl, (C2-C12) -alkenyl, (C2-cl2) -alkynyl, (Cl-cl2) -alkoxy, (C1-Cl2)-alkoxy-(C1-Cl2)-alkyl, (el-C1~)-alkoXy-(cl-cl2)-alkoxy, (Cl-C,2)-alkoxy-(C1-C,)-alkoxy-(C1-C,)-alkyl, (C,-C12)-aryloxy, (C7-C1c)-aral~yloxy, (Cc-Cl2)-aryloxy-(Cl-C,)-alkoxy, (C7-C1,)-aralkoxy-(C1-Cc)-alkoxy, .: . .: : ~:,.' ~:
' .:: .. " :::':i:
. . ~ : . , . :~ ~
,; :
213~866 (Cl-C,)-hydroxyalkyl, (C,-Cl~)-aryloxy-(Cl-C,)-al~yl, (C7-Cl~)-aralkoxy-(C,-C,)-alkyl, (C~-Cl2~-aryloxy-(Cl-C~)-alkoxy-(Cl-C6) -alkyl, (C,-Cl,)-aralkyloxy-(Cl-C~)-alkoxy-(~l-C~
alkyl, -O-[CH~]~-CrH~ )F~, -OCF,Cl~ -OCF,-CHFCl, -~
:: .
(Cl-Cl~)-alkylcarbonyl, (C3-C,)-cycloal~ylcarbonyl, (C,-Cl,)-arylcarbonyl, (C7-Cl~)-arallcylcarbonyl, ;
(Cl-Cl~)-alkoxycarbonyl, (Cl-Cl,)-alkoxy-(Cl-Cl2)-alkoxy-carbonyl, (C~-Cl~)-aryloxycarbonyl, (C7-C~ ralkoxycarb-o~yl, (C3-C~)-cycloalkoxycarbonyl, (C,-C1,)-alkonyloxy-10 carbonyl, (C,-C12) -alkynyloxycarbonyl, (C~-C12) -aryloxy-(Cl-C~)-alkoxycarbonyl, (C7-Cl~)-aralkoxy-(Cl-C~)-alkoxy-carbonyl, (C3-C,)-cycloalkyl-(Cl-C,)-alkoxycarbonyl, (C3-C~)-cycloalkoxy-(Cl-C~)-alkoxycarbonyl, (Cl-Cl,)-alkylcarbonyloxy, (C3-C,)-cycloal~ylcarbonyloxy, ~;~ s 15 (C~-Cl,)-arylcarbonyloxy, (C7-C1~)-aral~ylcarbonyloxy, :~
cinnamoyloxy, (C,-Cl,)-alkonylcarbonyloxy, (C~-Cl,)~
alkynylcarbonyloxy, . ~ !
(Cl-Cl~)-alkoxycarbonyloxy, (Cl-Cl~)-alkOxy- (Cl~Cla) ~
alkoxycarbonylcxy, (C~-Cl~)-aryloxycarbonyloxy, (C7-C
20 aralkyloxycarbonyloxy, (C3-C~)-cycloalkoxycarbonyloxy, :~
(C,-Cl,)-alkonyloxycarbonyloxy, (C,-Cl2)-allcynyloxy~
carbonyloxy, :~
carbamoyl, N-(Cl-Cl~)-alkylcarbamoyl, N,N-dl-(Cl-C1,)- ... :. ~
alkylcarbamoyl, N-(C3-C,)-cycloalkylcarbamoyl, N,N-di- : ;;
cyclo-(C3-C,)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C,)-cycloalkylcarbamoyl, N-((c3-c!)-cycloalkyl-(cl-c~
alkyl)carbamoyl, N-(Cl-C~)-alkyl-N-((C3-C,)-cycloalkyl-(Cl-C~)-alkyl)carbamoyl, N-(l)-dehydroabietylcarbamoyl, : , N-(Cl-C~)-alkyl-N-(~)-dehydroabletylcarb~moyl, N-(C~-C1,~
30 arylcarbamoyl, N-(C7-C1~)-aralkylcarbamoyl, N-(Cl-Clo)- ; ;:~ ::
alkyl-N-(C~-Cl~)-arylcarbamoyl, N-(Cl-Cl0)-al~yl-N-(C7-Cl~)-aralkylcarbamoyl, N-((cl-clo)-alkoxy-(cl-clo) alkyl)carbamoyl, N-((c~-cl~)-aryloxy-(cl-clo)-alkyl)carbamoyl, N-((C7-C1~)-aral~yloxy-(C1-C10)-alkyl)oarbamoyl, N-(Cl-C~0)-alkyl-N-((C1-C10)-alkoxy~
': ~ ' :
- 213~866 ` ~:
(C1-C10)-alkyl)carbamoyl, N-(cl-clo)-al~yl-N-((cc-cl2) -aryloxy-(C,-C10)-al~yl)carbamoyl, N-(C,-C10)-al~yl-N-((C,- .
Cl6)-aralkyloxy-(Cl-C10)-al~yl)carbamoyl, CON(CH2)~, ln . :
which a CH2 group can be replac~d by O, ~, N-(C1-C,)-alkylimino, N-(C,-C,)-cycloalkylimino, N- (C3-C,) -cyclo-alkyl-(C,-C~)-alkylimino, N-(C~-C12)-aryl~m~no, N-(C~-C1~)-aralkylimino or N-(C1-C~)-alkoxy-(C1-C~)-al~ylimi~o, and h i8 from 3 to 7, carbamoyloxy, N-(C1-C")-alkylcarbamoyloxy, N,N-di-(C1-C1~)-alkylcarbamoyloxy, N- (C3-C,) -cycloal~ylcarbamoyloxy, N- (C6-cl6) -arylcarbamoyloxy, N-(C,-Cl~)-aralkyloarbamoyl-oxy, N-(Cl-C10)-alkyl-N- (C6-C12) -aryl~arba~oyloxy, N-(C~
C~0)-alkyl-N- (C7-ClC) -aralkylcarbamoyloxy, N-((Cl-clo) alkyl)carbamoyloxy, N-((C,-Cl~)-arYlXY-(cl-clo)- :; :~
alkyl)carbamoyloxy, N-((C,-Cl,)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(Cl-C10)-alkyl-N-((Cl-ClO)-alkoxy-(Cl- ::~
C10)-alkyl)carbamoyloxy, N-(cl-clo)-alkyl-N-((cc-cL~) - : .
aryloxy-(Cl-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C1~)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, . - .
20 amlno, (Cl-C1,)-alkylamino, d~-(C1-C1~)-alkylamino, (C3-C,) -:~
cycloalkylamino, (C3-Cl,) -al~onylamino, (C3-C~) -alkynyl-amino, N-(C,-C1,)-arylamino, N-(C7-C11)-aralkylamlno, N-alkyl-aralkylamino, N-alkyl-arylamino, (Cl-C1,)-alkoxyamlno, (C1-C1,)-alkoxy-N-(C1-C10)-alkyl~no, (C1-C")-alkanoylamino, (C3-C,) -cycloalkanoylamino, (C~
Cl~)-aroylamino, (C,-Cl,)-arallcanoylamino, (Cl-Cl~)-alka- .,'. ::~
noyl-N-(C1-C10~-alkylamino, (C3-C,) -cycloalkanoyl-N-(cl-C10)-alkylamino, (C,-C1,)-aroyl-N-(C1-C10)-alkylamino, (C,-C11)-aralkanoyl-N-(Cl-C10)-alkylam~no, i; ~ ;
(C1-C1,)-alkanoylamino-(C1-C,)-alkyl, (C,-C~)-cyclo-alkanoylamino-(C1-C~)-alkyl, (Cc-C1,)-aroylamino-(C1-C~)- : .- .::.:i::.. :
alkyl, (C,-C1c)-aralkanoylumino-(Cl-C,)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(Cl-ClO)-alkyl, N,N-di-(cl-clo)-alkylamino-(cl-clo)-alkyl~ ( C3 - C,) - cycloalkyl-35 ~mino-(C1-C10)-alkyl, ~ :
- ~', :~'' ~:., ' ! ',, "' ., .. ' ', ~: ' 213~866 (Cl-C12)-alkylmercapto, (Cl-C~ alkylsulfinyl, (C~-C~
al~ylsulfonyl, (C6-Clc)-arylmercapto, (C~-C1,)-aryl-sulfi~yl, (C~-C")-arylsul~onyl, (C7-C")-aralkylmercapto, (C7-C1~)-aralkyleulfinyl or (C7-C~)-aralkyl~ulfonyl, and R~ i~ R", providod that Q ha~ the m~aning of NR', where R~ and R" aro identical or difforent and ar~ hydro-gon, (C,-Cl,)-aryl, (C7-Cl)-aral~yl, (C1-C~)-alkyl, (~1~C~)-alkoxy-(Cl-c~)-alkyl~ (C7-Cl~)-aral~oxy-(C,- ~ 8 C~)-alkyl, (C~-C,2)-aryloxy-(C1-C~)-al~yl, (Cl-C~0)-alkanoyl, optionally ~ubstitut-d (~7-C1,)-aralkanoyl or optionally sub~titut-d (C~-C12) -aroyl, or R' and R" togothor are -~CH,lh, in which a CH~ group can be roplacsd by 0, S, N-acylimino or N-(C1-C~o)~
alkoxycarbonylimino, and ~`;
f i3 l to 8, g is 0 or 1 to (2f~
x i~ 0 to 3, h i8 3 to 7, lncludlng tho physiologically act$ve ~alts, ~ ;
with 3-bonzyloxypyridine-2-carboxyllc acid (L-throonyl)-amido and 3-benzyloxypyrldine-2-carboxylic aoid ((Fmoc-Phg)L-threonyl)amlde hydrochlorlde being xcept-d.
In general, aryl is understood to mean carbocyclic and hoterocycllc aromatlc ring ~ystems. In partlcular, it ~8 ;
under~tood to lnclude phenyl-substituted, blphonyl-~ubstltuted, naphthyl-~ubstltut~d or un~ubstituted 5- and 6-membered heteroaromatlc rlngs havlng 1, 2 or 3 nltrog-n and/or oxygen and/or ~ulfur atoms, 8uch as dQrlvatlv~ of pyrldyl, pyrldazyl, pyrimldyl, pyrazyl, imldazolyl, ; ~ -triazolyl, thlenyl, oxazolyl and thiazolyl, and their benzo-fu~od derivative~
The inv~ntion also mbraces salts of the compounds of th~
formula I.
:: .
213~866 The formation of ~alt~ w~th ba~io reagento can take place once, twice or three times on th~ acidio groups of tho compounds of the formula I (i - radicals B, Rl, R~, R3 and R~), in particular on tho radicals B, R' and/or R~
Examples of reagonts boing usod are nlcoholat~, hy-droxides, carbo~ates, hydrog n carbonatos! hydrogon phosphates, organometallic compounds of tho alkali and alkaline earth element~, the elements of the third and fourth main group~ of tho period~c systom, and tho elements of the transition met~l~
amines, optionally substituted 1 to 3 times by (C,-C,)-hydroxyalkyl, (C,-C~)-alkoxy-(C,-C,)-alkyl, phenyl, benzyl or (C,-C,)-alkyl, which oan be substituted 1 to 3 t~mes by hydroxyl or (Cl-C~)-alkoxy, for example tromethane (Tri~ buffer), 2-aminoethanol, 3-aminopropanol, hydroxylamine, dimothylhydroxylamin-, 2-methoxy~thyl-amine, 3-ethoxypropylamine, and ba~ic amino ac~d~ and amlno dorlvative~, ~uoh a~ amino acid ester~, hl~tidlne, arginine and lysi~e, and their derivatives, and also "" '.: '"' ' ;'~' pharmaceuticals which contain a baslc group, such as, for xample, ~Amiloride, ~Verapamil and beta blocker~
~ - ,. ::: ;j ,- ..~:, The lnventlon al~o r~lates to the compounds according to formula I, plus 3-b-nzyloxypyrldlne-2-carboxyllc acld (L-threonyl)amld~3 and 3-bsnzyloxypyridine-2-carboxylic aoid ((Fmoc-Phg)L-thr~olnyl)~mido hydrochlorldo for uco as pharmaceutlcal~
..` ,~ :
Compound~ of the formula I are of great int-r-~t, ln whlch 30 Q ~ 0, ~, NR' or a bond, X 18 0, ~
Y 1~ CR3 or, ;
lf R~ and Rl form a cycle, Y 1~ N or CR3, , :: .
213~866 m i8 0 or 1 Compounds of tho formula I are vory lmportant, in whieh Q is 0, NR' or a bond, X is 0 5 Compound~ of the formula I aro al~o very lmportant in which Q is 8 and X i~ 0 ~ ~ ;
Compounds of tho formula I aro of particular importa~ee in whieh Q i~ 0, NR' or a bond, ;;, ~ `
1 0 X i 8 0, Y is CR3 or, if R' and R' form a eyelo, N or CR3, m is 0 or 1, A i~ (Cl-C3) -allcyleno whieh is opt~ onally substitutod once by halogon, eyano, trifluoromethyl, (Cl-C,)~
alkyl, (Cl-C6)-hydroxyallcyl, (Cl-C,)-alkoxy or -0-[C}~2~"--Cf~It,f,l ~F~" or A is -CHR5-, whero R5 18 onts of the ~ub~tituents of the a-ear}~on atom of an a-amino aeld, in partieular ~ ;
of a natural L-amino acid and of its D-isom r, B i8 C0~%, :.
R2 is hydrogon, (Cl-C,0)-alkyl, (C,-C,0)-alkonyl, (C,-C,0)-alkynyl, (Cl-C~O)-alkoxy, (C,-C,0)-allcenyloxy, (C2-C,O) -alkynyloxy, r-tinyloxy, (Cl-C~0) -alkoxy- (Cl-C3) -alkyl, (C,-C,0~ -allc-nyloxy- (C1-C~) -alkyl, retinyloxy- (Cl-C~) -alkyl, (C,-C,0) -alkynyloxy- (Cl-C~)-alkyl, halogen, eyano, trifluoromethyl, (Cl-C~
hydroxyalkyl, (Cl-C,0)-alkanoyl, (C7-Cl~)-aralkanoyl, (C~-Cl~) -aroyl, (C~-Cl2) -aryl, (C7-Cl~) -arallcyl, ~O~ ~CH2~"-CrH~t.~l s"F", N}~'Rn, (Cl-C1O) -alkylm-rcapto, (Cl-C10)-alkyl~ulfiDyl, (Cl-C10)-alkylsul~onyl, (C~
Cl,)-arylm~rcapto, (C~-Cl,)-arylsulflnyl~ (C,-Cl,)-arylsulfonyl, (C7-Cl,)-arallcyl~oreapto, '.,''' ~'''',''~'''.,'' :: :: :;: :.::, . . :,:
2l3~s6e (C7-Cl~)-aralkylsulfinyl, (C7-C~2)-aralkylsulfonyl, (Cc-cl2)-aryloxy~ (C7-CI6)-aralkyloxy, earboxyl, (Cl-C20)-alkoxycarbonyl, (Cl-Cl2)-alkoxy- (Cl-Cla) -alkoxy-carbonyl, (C,-Cl2)-aryloxycarbo~yl, (C7-Cl~ ral-koxycarbonyl, (C,-C,)-eycloalkoxyearbonyl, (C,-C20)-alkonyloxycarbonyl, r~tinyloxycarbonyl, (C2-C20)-alkynyloxycarbonyl, (C3-C,) -cyeloalkyl-(Cl-Cc)-alkoxycarbonyl, (C,-C~)-eyeloal~oxy-(Cl-C~
alkoxyearbonyl, (C~-C32)-aryloxy-(Cl-C~)-alkoxy~
carbonyl, (C,-C16) -aralkoxy-(C1-C~)-alkoxyearbonyl, earbamoyl, N-(C1-Cl2)-alkylearbumoyl, N,N-di-(C,-Cl2)~
alkylearbamoyl, N- (C3-C,) -eyeloalkylearbam~yl, N,N-dieyelo (C3-C,) -alkylearbamoyl,N-(Cl-Cl0)-al~yl-N- (C3-C,)-eyeloal~ylearbamoyl, N- (C3-C,) -eyeloalkyl-(C -C~
alkyl)earbamoyl, N-(cl-c~)-alkyl-N-((c3-c~) -eyelo-alkyl-(Cl-C~)-alkyl)earbamoyl, N-(l)-dehydroabietyl-carbamoyl, N-(Cl-C~)-alkyl-N-(~)-dehydroab~otyl~
earbamoyl, N-(C~-C1,)-arylcarbamoyl, N-(C,-C")-aralkylcarbamoyl, N-(Cl-Cl0)-alkyl-N-(C~-Cl~)-aryl-carbamoyl, N-(Cl-Cl0)-alkyl-N-(C7-Cl~)-aralkylcar-bamoyl, N-((Cl-Cl2)-alkoxy-(C -Cl0)-alkyl)earba_oyl, N-((C~-C1~)-aryloxy-(Cl-Cl0)-alkyl)earbamoyl, N-~(C,-Cl~)-aralkyloxy-(C1-Cl0)-alkyl)earbamoyl, N-(Cl-C1o)~
alkyl-N-((Cl-Cl0)-alkoxy-(Cl-C10)-alkyl)earbamoyl, N-(Cl-Cl0)-alkyl-N-((C,-C1,)-aryloxy-(Cl-Cl0)-alkyl)earbamoyl, N-(cl-clo)-alkyl-N-((c7-cl~) aralkyloxy-(C1-C10)-al~yl)earbamoyl, CON(CE~)~, in whieh a C~2 group ean be replaeed by O, S, N-(C1-C,)-alkylimlno, j N! ~C3-C,) -eyeloalkylimino, N- (C3-C,) -eyeloalkyl-(C1-C~)-alkylimino, N-(C~-C1~)-aryllmlno, N- (C7-C~) -aralkyllmlno or N-(C1-C~)-alkoxy-(C1-C,)-alkyllmino, and h i~ from 3 to 7, .
, .., ~ .
where aryl i~ ~ub~tltut-d in tho manner a- defined for and R', 5 R1 and R3 are idontleal or difforont and are hydrogen, halogen, (C1-C1,)-alkyl, (C1-C~2)-alkoxy, -O-[C~ -C~
213~66 ~, (c~-cl2)-alkoxy-(cl-cl2)-al~yl, (~-C~
alkoxy- (C~-C12) -alkoxy, (C,-C,2) -alkoxy-(C~-C~
alkoxy-(C2-C~)-alkyl, (C7-C~) -aralkyloxy, (C3-C,) -cycloalkyl, (C3-C,) -cycloalkyl-(C,-C,)-alkyl, (C3-C~)-cycloalkyloxy, (C3-C,) -cycloal~yl-(C~-C~)-alkoxy, (C3-C,) -cycloalkyloxy-(C,-C,)-~l~yl, (C~-C,)-cyclo-alkyloxy-(C,-C~)-alkoxy, (C,-C,)-cycloal~yl-(C~-C,)-alkyl-(C,-Cc)-alkoxy, (C3-C,) -cycloalkyl-(C~-C~
alkoxy-(C,-C~)-alkyl, (C3-C,) -cycloalkoxy-(C~-C~
alkoxy-(C,-C,)-alkyl, NRYRZ, (C,-C,)-alkylm rcapto, (C,-C,)-alkyl~ulf~nyl or (C~-C,)-alkyl~ulfonyl, (C,-Cl~)-arylmercapto, (C,-C")-aryl~ulfinyl, (C~-C
arylsulfonyl, SCj-C")-aralkylmercapto, (C7-C
aralkyl~ulflnyl, (C7-C,l)-aralkyl~ulfonyl, oubstituted (C~-Cl2)-aryloxy-(C,-C~)-alkyl, (C7-C
aralkoxy-(C1-C6)-alkyl, (C~-Cl~)-aryloxy-(C~-C~
alkoxy-(C,-Cc)-al~yl, (C7-Cl~)-aralkyloxy-(C,-Cs)-alkoxy-(C,-C~)-alkyl, (C,-C1,)-aryloxy, (C7-C,1)~
aralkyloxy, (C6-C12)-aryloxy-(C1-C~)-alkoxy or (C7-C~)-Aralkoxy-(C~-Cc)-alkoxy, wh-ro an aromatic radical carrie~ by 1, 2, 3, 4 or 5 idontical or difforont sub~tituont~ from tho group hydrogen, halogon, cyano, nitro, trlfluoromothyl, (C,-C
alkyl, (C,-C,6) -alkonyl, (C,-C6) -hydroxyalkyl, (C
C16) -alkoxy, (C,-C,6) -alkonyloxy, -O-[CH~]~-C~H~ F~
-OCF~Cl, -O-CF~-CHFCl, (C,-C,)-alkylmorcapto, (C~-C6)-alkylsulfinyl, (C~-C6) -alkyl~ulfonyl, (C,-C~)-al~yl-carbonyl, (C,-C6)-alkoxycarbonyl, carbamoyl, N-(C,-C~)-alkylcarbamoyl, N,N-di-(C~-C~)-alkyl-carbamoyl, (Ç~-C~)-alkylcarbonyloxy, (C,-C~)-cyclo-alkylcarbamoyl, ph-nyl, bonzyl, phenoxy, benzyloxy, NRYRZ, phonylmorcapto, phonylculfonyl, ph~nyl-~ulfinyl, ~ulfamoyl, N-(C,-C~)-alkyloulfamoyl or N,N-di-(C,-C~)-alkylsulfamoyl, or optionally carrie~ up to 3 of tho abovomontloned ldontlcal or diffor-nt ~ub~titu~nt~, and two ad~acont carbon atom~ of th~
aralkyloxy radical togethsr carry a chaln-tCH~
and/or -CH=C~-CH3C~-, whero a C~ group of tho chaln 1~ optionally roplaced by O, S, SO, SO, or NR', 213~86B
R~ and R2 or Rl and R3 form a chain [CH~o~ where o is 3, 4 or 5, or form, together wlth the pyridine or pyridazine carryi~g thQm, a einnollns ring, a quinollno ring or an lsoquinoline ring, R~ i~, if Q is a bond, fluorine, chlorine or bro~ino, or, if Q is 0 or NR', a branehod or unbranehod (C~
C20) -alkyl radieal, wh~eh can eontain up to 3 C-C
multiple bonds, u~ uneubetitutod ~aturatod fluoro-alkyl rndical of the formula tC~2]~-Ct~(2~ F~, a (C6-Cl,)-aryl radieal or a (C7-Cl,)-aralkyl radieal, which can contain up to 2 C-C multiple bonds $n tho alkyl chain, or an h~toroaryl rad$cal or an het~ro-aryl alkyl radical, whero these radieals are ~ubsti-tutod by one or ro radicals from the group ~ydroxyl, fluorine, ehlorine, eyano, tri~luoro-methyl, earboxyl, (Cl-Cl,)-alkyl, (C3-C,) -cyeloalkyl, (C3-C,) -cyeloalkyl-(Cl-Cl~)-alkyl, (C3-C,) -eyelo-alkoxy, (C3-C,) -cyeloalkyl-(Cl-Cl2)-alkoxy, (C3-C,) -cycloalkyloxy-(Cl-Cl,)-alkyl, (C3-C,) -eyeloalkyloxy-(C,-C12)-alkoxy, (C3-C,) -eyeloalkyl-(Cl-C,)-alkyl-(Cl-C6)-alkoxy, (C~-C,)-eyaloalkoxy-(Cl-C,)-alkoxy-(Cl-C,)-alkoxy, (C~-Cl2)-aryl, (C7-Cl~)-aralkyl, (C~-Cl,)-alkenyl, (C2-Cl2)-alkynyl, (Cl-C")-alkoxy, (Cl-Cl2)-alkoxy-(C,-Cl2)-alkoxy, (Cl-Cl,)-alkoxy-(Cl-C~
alkoxy-(Cl-C,)-alkyl, (C~-C12) -aryloxy, (C,-C
aralkyloxy, (C~-C12) -aryloxy-(Cl-C~)-alkoxy, lC7-C16) -aralkoxy-(Cl-C~)-alkoxy, (Cl-C,)-hydroxyalkyl, -0-lCH2.~-c~H~2~ )F~
(Cl-C12) -alkylearbonyl, (C,-C,)-eyeloalkylearbonyl, (C6-C12) -aryloarbonyl, (C7-Clc)-aralkylearbonyl, (Cl-C12) -alkoxyearbonyl, (Cl-cl2) -alkoxy- (Cl-c12) -alkoxyearbonyl, (C6-C~2)-aryloxyearbonyl, (C7-Cl,)-aralkoxycarbonyl, (C~-C~)-¢yeloalkoxyearbo~yl, (C2-Cl2)-alkonyloxyearbonyl, (C2-Cl2)-alkynyloxyearbonyl, 213~86G
(C3-C,) -cycloalkyl-(Cl-C~)-alkoxycarbonyl, (Cl-Cl,)-allcylcarbonyloxy, (C~-C,)-cycloalkyl-carbonyloxy, (C~-C12) -arylcarbonyloxy, (C,-C~
aralkylcarbonyloxy, carbamoyl, N-(Cl-Cl2)-allcylcar- ~ -bamoyl, N,N-d~-(Cl-Cl2)-alkylcarbamoyl, N- (C3-C,) -cycloalkylcarbamoyl, N,N-dicyclo- (C3-C,) -alkyl-carbamoyl, N-(Cl-Cl0)-alkyl-N-(C,-C,)-cyoloallcylcar-b a m o y l, N - ( ( C 3 - C, ) - c y c l o a l k y l - ( Cl- C~
allcyl)carbamoyl, N-(Cl-C,)-alkyl-N-( (C3-C,) -cyelo-alkyl-(C1-Cc)-alkyl)carbamoyl, N-(l)-dehydroabiotyl-carbamoyl, N-(Cl-C~)-allcyl-N-(I)-dohydroabietyl-carbamoyl, N-(C~-Cl,)-arylcarbamoyl, N- (C7-Cl~) -aralkylcarb~moyl, N-(Cl-Cl0)-alkyl-N-(C~-Cl~)-aryl-carbamoyl, N-(Cl-ClO)-alkyl-N-(C,-Cl,)-aralkylcarba-moyl, N-((Cl-Cl0)-alkoxy-(Cl-Cl0)-alkyl)carbamoyl, N-((C~-Cl~)-aryloxy-(Cl-Cl0)-alkyl)carbamoyl, N-((C,-Cl~)-aralkyloxy-(Cl-C,0)-alkyl)carbamoyl, CON(CHl)~ ln whlch a CH2 group can be replaced by O, N-(Cl-C~)-alkyllmino, N-(C3-C8)-cycloalkylimino, N- (C3-C,) -cycloalkyl-(Cl-C~)-alkylim~no, N-(C~-Cl,)-arylimino or N- (C7-Cl~) -aralkylimino, and h 18 from 3 to 6, where the radlcals which contain an aryl radlcal aan, for th-lr part, be ~ub~ltutesd on tho aryl by from 1 to 5 ldontlcal or dlfferent radlcal~ from tho ;~ r "~ ''''~' groups hydroxyl, fluorine, chlor~ne, cyano, trlfluoro-methyl, carboxyl, (Cl-Cl~)-alkyl, (C3-C,) -cyeloalkyl, (Cl-C~)-alkoxy, (C3-C~)-'cycloalkoxy, (C~-Cl2)-alkoxy- ,.
earbonyl, ~ ~
N-(Cl-C~)-alkylcarbamoyl, N,N-d~-(C1-C~)-alkyl- ~ ~ ~'',' ';''''~J'',' carbamoyl or N- (C3-C,) -cycloalkylcarbamoyl, and R~ 1~ R, provided Q ha~ tho m-aning o~ NR', whoro R' and R~ aro id-ntlcal or difforent and are hydrog-n, ;
(Cl-C,)-alkyl, or (C,-Cll)-arallcyl which i~ optlonally 213~866 substituted onco by fluor~ne, chlorine or (C,-C,)- . ;~ ~ ~
alkoxy, ~ ~ .
RY and R~ are identical or difforent and are hydrogon, (C~-C~ aryl, (Cl-C~0)-alkyl, (C~-C10)-cycloal~yl, (C,-C,)-alkoxy-(C,-C~)-alkyl, (C7-cl2) -aralkoxy-(Cl- ~;~
C,)-alkyl, (C,-Cl,)-aryloxy-(Cl-C,)-alkyl, (Cl-C10)-alkanoyl, optionally substituted (C,-Cl,)-aral~anoyl or optionally sub~tituted (C,-Cl,)-aroyl, or RY and R~ together are -[CH,~, in which a CH, group can be replaced by O, S, N-(Cl-C~)-alka~oylimlno or N-(Cl-C~)-alkoxycarbonylimlno, and ~ -f is l to 8, ~ ~
g is 0 or 1 to (2f ~ 1), -:; ;~:.::;.. ~-.. ~.
h is 3 to 6, 15 x is 0 to 3, and n is 3 or 4.
Compound~ of the formula I are preferred in whlch Q i~ O, NR' or a bond, X is O, 20 Y is CR3 or, if Rl and R' form a cycle, N or CR',: ; -m io 0, ~ :
A i~ (Cl-C3)-alkylene which i~ optionally ~ubstituted once by halogen, cyano, trlfluoromethyl, (Cl-C6)-alkyl, (C,-C6~-hydroxyalkyl, (Cl-C6)-alkoxy or -O-lC~,]X-Ct~ F~ or : ::
: I ' ` ~ ! ' ~ .
A i~ -C~R5-, where R5 is one of the substituent~ of th-a-carbon atom of an a-amino acid, ln partioular of a natural ~-amino aoid and of it~ D-lsomor, : :-. ~, ":.. ,:
B is CO,H
:. . :,: ,. : ~, ~:
30 R' is hydrogen,.(Cl-C20)-alkyl, (Cl-C,0)-alkonyl, (C,- ::
C20)-alkenyloxy, (C2-C20)-nlkynyloxy, retinyloxy, '''' "'''.'~"'"
213~866 ~ ~ ~
(Cl-Cl0)-alkoxy-(C,-C,)-alkyl, (C,-C,0)-alkoxy-(C,-C3) -alkyl, (C~-C20)-al~enyloxy-(C~-C~)-alkyl, retinyloxy-(C~-C~-alkyl, (C2-C~o) -alkynyloxy-(C~
C,)-alkyl, (C1-C,0)-alkoxy, haloge~, eyano, trlfluoromethyl, (C~-C")-hydroxyalkyl, (C~-C~0)-alkanoyl, (C7-C~2)-aralkanoyl, (C~-C~)-aroyl, -O-tCH~-C~(s~ F~, Na~a~ (cl-clo) -al~ylmor¢apto, (C~-C~0)-al~yleulf~nyl, (C~-C~)-al~ylsulfonyl, (C~
C~2)-arylmercapto, (Cc-C~)-arylsul~y}, (C~-C~2)-aryl~ulfonyl, (C~-C~aralkylmoseapto, (C7-C")-aralkyleulfinyl, (C7-C,2)-aralkyl~ulfonyl, (C,-C~
aryloxy, (C,-C~)-aral~yloxy, earboxyl, (C,-C,0)-alkoxyearbonyl, (C,-C~2)-alkoxy-(C,-C~
alkoxyearbonyl, (C~-Cl,)-aryloxyearbo~yl, (C,-C")-aralkoxycarbonyl, (C3-C,) -cycloalkoxycarbonyl, (C2-C,0)-alkenyloxycarbonyl,retinyloxycarbonyl, (C~-C20)-alkynyloxyearbonyl, (C3-C~) -cyeloalkyl-(C~-C~
alkoxycarbonyl, (C3-C,)-~ycloalkoxy-(C~-Cc)-alkoxycarbonyl, (C,-C1,)-aryloxy-(C,-C~)-alkoxy-carbonyl, (C7-C,c)-aralkoxy-(C,-C,)-alkoxycarbonyl, carbamoyl, N-(Cl-C")-alkylearbamoyl, N,N-di-(C,-CL,)-alkylcarbamoyl, N-(C3-C~)-cycloalkylearbamoyl, N,N-dicyclo(C3-C~)-alkylearbamoyl,N-(C~-C~0)-alkyl-N-(C3-C~)-cycloalkyl¢arbamoyl, N-(C3-C~)-cyeloalkyl-(C,-Cc)-alkyl)carbamoyl, N-(C,-C,)-alkyl-N-((C3-C,)-cyclo-alkyl-(C~-C~)-alkyl)carbamoyl, N-(~)-dohydroabiotyl-carbamoyl, N-(C,-C,)-alkyl-N-(I)-dehydroabiotyl-carbamoyl, N-(C~-C~ arylcarbamoyl, N-(C,-C~
aralkylcarbamoyl, N-(Cl-C,0)-alkyl-N-(C,-C~,)-aryl-carbamoyl! N-lC1-C~0)-alkyl-N-(C,-C~2)-aralkylcarb-amoyl, N-((C,-C")-alkoxy-(C,-C,0)-alkyi)carbamoyl, N-((C~-C~,)-aryloxy-(C,-C~0)-alkyl)carbamoyl, N-((C7-C~)-aralkyloxy-(C,-C,0)-alkyl)carbamoyl, N-(C1-C~o)~
alkyl-N-((C~-C,0)-alkoxy-(C~-C~O)-alkyl)earbamoyl, N-(C,-C,0)-alkyl-N-((C,-C")--ryloxy-(C,-C~O)-alkyl) carbamoyl, N- (C,-C,0) -alkyl-N- ( (C,-C~
- aralkyloxy- (C,-C,O) -alkyl) carbamoyl, or CON(Cl!I,)h, ln whlch a CH~ group can be replaced by 0, S, N- (Cl-C,) -alkylimino, N- (C3-C,) -cycloalkyllmlno, 213~66 N-(C3-C~)-cycloallcyl-(C1-C4)-allcyl~m~no, N- (C6-C~
aryl~mino, N- (C,-C16) -aralJcyl~m~no or N-(C1-C4)-alkoxy-(Cl-Cc)-alkyl~m~no, and h i~ from 3 to 6, wherQ aryl ls ~ubstituted Jn tho mannQr aEI dof~ned for and R3, Rl and R3 are ident~cal or diff~r-nt and are hydrogen, halogen, (Cl-Cl,)-alkyl, (C1-C~)-alkoxy, -O- lCEI~]J-C~ al~l~ (cl-cl~) -alkoxy-(C1-Cl,)-allcyl, (Cl-C,)-alkoxy-(Cl-Cl,)-alkoxy, (Cl-Cl,)-alkoxy-(C,~
C~)-alkoxy-(C~-C6)-alkyl, (C7-C 1) -~ralkyloxy, (C3-C~)-cycloalkyl, (C3-C~)-cycloalkyl-(C1-C~)-al~cyl, (C3-C,) -cycloallcyloxy, (C3-C,)-cycloalkyl-(Cl-C,)-alkoxy, (C3-C~)-cycloalkyloxy-(Cl-C~)-alkyl, (C3-C,)-cycloalkyloxy-(Cl-C,)-allcoxy, (C3-C,)-cycloallcyl-(Cl-C6) -alkyl-(Cl-C~)-alkoxy, (C3-C,)-cycloalkyl-(Cl-Cc)-alkoxy- (C,,-C6) -allcyl, (C3-C,)-cycloallcoxy-(Cl-cc)-alkoxy-(Cl-C~)-alkyl, NRYRZ, (Cl-C,)-alkylmercapto, (C,-C,)-allcyl~ulfinyl or (Cl-C,)-alkylsulfonyl, (C,-Cl,)-arylmercapto, (C,-Cl,)-aryl~ulfinyl, (C,-Cl2)-aryl~ulfonyl, (C,-Cl,)-aralkylmercapto, (C,-Cl,)-aralkylsulfinyl, (C,-Cll)-aralkylsulfonyl, sub~t~tutod (C6-Cl,)-aryloxy-(Cl-C,)-alkyl, (C,-Cll)-aralkoxy-(Cl-C~)-alkyl, (C~-C1~)-aryloxy-(Cl-C~
alkoxy-(C1-C~)-alkyl, (C7-C~l) -aralkyloxy-(C1-C~
alkoxy-(Cl-C,)-alkyl, (C,-Cl2)-aryloxy, (C7-C~
aralkyloxy, (C,-Cl,)-aryloxy-(Cl-C,)-alkoxy or (C,-Cll)-aralkoxy- (Cl-C6) -alkoxy, where an aromatic radical carri~ by 1, 2, 3, 4 or 5 identlcal or different sub~tituQnt~ from the group hydrogen, halogen, cyano, nitro, trifluoromothyl, (Cl-Cl~
alkyl, (Cl-Cl,)-alkonyl, (Cl-C,)-hydroxyalkyl, (Cl-Cl,) -alkoxy, (Cl-Cl,) -allc-nyloxy, --[CH~]x~CtH(~ F~ -OCF,Cl, -O-CF,-CHFCl, (C1-C,)-alkylmercapto, (Cl-C6)-alkyl~ulfinyl, (Cl-C~)-alkyl-~ulfonyl, (Cl-C,)-alkylcar}~onyl, (Cl-C,)-alkoxy-carbonyl, carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl-C~)-alkylcarba~oyl, (Cl-C,)-alkylcarbonyloxy, ., .,, .: ., 213~86G
(C~-C~)-cycloalkylcarbamioyl, phenyl, b~zyl, phonoxy, benzyloxy, NRYR~i, phenylmercapto, phonylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C1-C,) -alkylsulfamoyl or N,N-di- (Cl-C~) -all~ylsulfamoyl, or optlonally carries up to 3 of tho abovementloned ide~lt~ cal or difforent eubstituents, and two ad~acsnt carbon atoms of the aralkyloxy radlcal togeth~r carry a chain -tCH,-~ and/or -C~l.CEI-CE~.C~I-, whero a C~l~ group of the chain ~8 optionally roplacod by 0, S, SO, SO, : ~ -or NRY, Rl and R' or R2 and R3 can form a chain tC~,] O~ whore o i8 :
3, 4 or 5, and :
", R4 , provided Q is a bond, is chlorine os, if Q i~3 0 or NR~, is a branched or u~branchsd (Cl-C10)-allcyl radical, which can contain one or two C-C multlple ~ ~
bonds, or an unsubstituted fluoroalkyl radical of - :::
the formula - LcH2]~,-c~ 2~ y~F~ or (Cl-C,) -alkoxy- (C~
Cc) -alkyl, (Cl-C,) -alkoxy- (C1-C~) -alkoxy- (Cl-C~) -alkyl ~ ~;
or a radical of the f ormula Z, . .
~: : ::.
-[C H2lV-1O]w-[CHJ, E (Z) ~ : ~; s whero E i~ a oubstitutod phenyl radlcal of the f orsnula F
R~ R~
~ R ~ ( F ) R l C R ; .~. . .
or a (C3-C,)-cycloalkyl radical, whoro v i0 O, 1, 2, 3, 40 5 or 6, w 18 O or 1, and t ~8 O, . ::
1, 2 or 3, with the re~trictlon that v is not egual :~;
to O if w is 1, and R', R7, R~, R9 and R10 are iden- -;
tical or d~fferent and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C,-C~)-alkyl, ;~
,. ,.":
:' :,"' '.:;':' '~';'''',,.,,,'', `.`'''''~'''. "'' ', j (C~-C~)-cycloalkyl, (Cl-C~)-alkoxy, -O-~CH,]~-C~H~
F~, -O~F~Cl, -O-CF, CHFCl, (Cl-Cc)-al~yl~ercapto, (Cl-C~)-hydroxyalkyl, (C1-C~)-alkoxy-(Cl-Cc)-alkoxy, (Cl-C~)-alkoxy-(Cl-C~)-alkyl, (Cl-C~)-alkylsulfinyl, (Cl-C~)-alkylsulfonyl, (C,-C,)-alkylcarbonyl, (Cl-C,)-alkoxycarbonyl, carbamoyl, N-(C~-C,)-alkylcarbu~oyl, N!N-di-(Cl-C,)-alkylcarba yl, (C7-Cll)-aralkylcarba- `
moyl which i~ optionally ~ubetituted by fluorine, ~-chlorine, bromine, trifluorom~thyl or (C~-C~)-alkoxy, N- (C3-C,) -cycloal~ylcarbamoyl, N-(C~-C,)-~ycloal~yl-(Cl-C~)-alkylcarbamoyl, (C1-C,)-alkylcarbonyloxy, phenyl, b~nzyl, phonoxy, b~nzyloxy, NRYR~, ~u¢h a~
amino, nnilino, N-m thylan~lino, ph-nylmercapto, phenyleulfonyl, phonyl~ulflnyl, ~ulfamoyl, N-(Cl-C,)-alkylsulfamoyl or N,N-dil-(Cl-C~)-alkylsulfamoyl, or ~wo ad~acent ~ubetltuents togeth-r ars a chain -~C~ -C~.C~-C~.C~-, where a CH, group of th- cha~n iB optionally r~placed by O, S, SO, SO, or NRY, and where a heteroaryl radical can carry 1, 2 or 3 sub~tituents, and a cycloalkyl radical one ~ ;
sub~tituent, from the above group, and R~ ie R~, providod Q hac the meaning of NR', where ~ ;
R' ~ hydrog~3n or methyl, and ;~ ;
R i~ benzyl, and if Rl and/or R3 have the meaning of (C~-Cl~)-aryloxy, (C7-Cll)-aralkyloxy, (C~-Cl,)-aryloxy-(Cl-C~)-alkoxy, (C7-Cll)-aralkoxy-(Cl-C~)-alkoxy or a corre~ponding radical con-taining terminal cycloalkyl group~, this radical lc ; ; ~ i;
preferably then a radical of tho formula D ~ ~
OZ (D), or ,~ ~
if ~1 and/or R3 havo the moaning of (C7-Cll)-aralkyl, ~ ,`
~C,-Cll)-aryloxy-(Cl-C~)-alkyl, (C7-Cll)-aralkoxy-(Cl-C,)-alkyl or a corro~ponding radical containing torminal ; ```
cycloal~yl groups, thi~ radical i~ pr~forably then a ;~
radical of the formula Z, :: . . : ..
RY and RZ aro ldent~ c81 or difforent and aro hydrogon, : ~:
(C6-Cl2)-aryl, (Cl-ClO)-allcyl, (C3-C10)-cycloallcyl, ~, (Cl-C,)-alkoxy-(Cl-C,)-alkyl, (C7-Cl,)-aral~oxy-(C,-C~)-alkyl, (C~-C,s)-aryloxy-(Cl-C~)-al~yl, (Cl-C10)-alkanoyl, optionally cubstituted (C7-Cl6~-aralkanoyl or optlonally ~ubstitutod (C~-Cl2)-~royl, or RY and RZ aro togothor -tC~2~, in which a CE~ group ca~ ,t.'' be replaced by 0, S, N-(Cl-C~)-alka~oylimino or N- -~
(Cl-C~)-alkoxycarbonylimlno, and ;~
f ~ 1 to 8, . .
g ie 0 or 1 to (2f h i~ 3 to 6, x is 0 to 3, and n is 3 or 4. ; :-~
~ . ~ .. -.~-.... .
lS Co~pound~ o~ tho formula I ar~ particularly pr~ferred in ..
which ;~
X is 0, :; ~ ' ~'J '. ,1.~'~''~''`
Y i~ CR3 and, additionally, N lf Rl and R2 form a cyclo, m i8 0~ '''J''',"'",''~ ,'' A 1~ -CHR~-, whor- R' i~ the ~ubstituont of th- a-carbon atom of an a-amino acid, in partlcular of a :~
natural L-amlno acid or lt~ D-lsomer, B is C02H, .. -R' is hydrogen, bromino, chlorino, cyano, (Cl-C~
alkyl, (C~-C,)-alkoxy, (Cl-Cl,)-alkoxymothyl, (C~-C~
alkonyloxymothyl, (C~-C~)-alkynyloxymothyl, :.:~
carbamoyl, N-(Cl-C10)-al~ylcarbamoyl, N-((Cl-C~2)- .. -alkoxy-(Cl-C~)-alkyl)carbamoyl, N,N-di-(Cl-C,)-alkylcarbamoyl, N(C~-C,)-cycloalkylcarbamoyl, N-(C,- .
- Cl2)-phenylcarbamoyl, N-(C7-Cl2)-phonylalkylcarba- ; `
moyl, N-(Cl-Cc)-alkyl-N-(C,-Cl2)phenylcarbamoyl, N- j : -(Cl-C6)-alkyl-N-(C7-Cl,)-phonylalkylcarbamoyl, :~
,., ,,. .~ ~
'' :' ~`
2 1 3 ~ 8 6 6 N-((C,-C~)-alkoxy-(Cl-C~)-alkyl)earbamoyl, oarboxyl, (Cl-C~O)-allcoxycarbonyl, (C3-C20)-alkenyloxycarbo~yl, ret~nyloxyearbonyl, (C3-C,)-eyoloalkoxyearbonyl, (C3-C~)-eyeloalkyl-(Cl-C~)-al~oxyearbo~yl, (C3-C,)-eyeloalkoxy-(Cl-C,)-alkoxyearbonyl, phenyl-(C~-C~)-alkoxyearbonyl, phonoxy-(Cl-C,)-alkoxyearbonyl or benzyloxy-(Cl-C,)-al~oxyearbonyl, wher- a ph~nyl radleal 1~ su~etituted ln the mann-r ae defined $or Rl and R3, and one of the radieale Rl or R3 ~e hydrogen and the other a radieal from the group hydrogen, fluorln~, ehlorln~, (Cl-C,)-alkyl, (Cl-C1O)-alkoxy, (Cs-C~)-cycloalkyl, (Cs-C~)-cyclo-alkyl-(Cl-C6)-alkyl, (C5-C,) -eyeloalkyloxy, (C5-C,) cycloalkyl-(Cl-C~)-al~oxy, (Cs-C,)-cycloalkyloxy-(C
C~)-alkyl, (C5-C,) -cycloalkyloxy-(C1-C~)-al~oxy, (C5-C,)-eyeloalkyl-(Cl-C~)-alkyl-(Cl-C~)-al~oxy, (Cs-C,)~
cycloalkyl-(Cl-C~)-alkoxy-(Cl-C~)-alkyl, (C5-c~
cycloalkoxy-(Cl-C~)-alkoxy-(Cl-C2)-alkyl, -O-[CH2]~-C~K(2f~l~,F~,(Cl-C,)-alkoxy-(Cl-C~)-alkyl,(Cl-C,)-alkoxy-(Cl-C,)-alkoxy, (Cl-C,)-alkoxy-(Cl-C~
alkoxy-(Cl-C2)-alkyl, eubet~tut~d (C,-Cl2)-ph-noxy, (C7-Cll)-phonylalkyloxy, (C~-Cl2)-phenoxy-(Cl-C~
alkoxy or (C7-cll) -ph-nylalkoxy-(Cl-C~)-alkoxy, phenoxy-(Cl-C~)-alkyl, (C7-Cll)-phenylalkyloxy-(Cl-C~)-alkyl, phenoxy-(Cl-C~)-alkoxy-(Cl-C~-alkyl or (C7-C~l)-phenylalkyloxy-(Cl-C~)-alkoxy-(Cl-C2)-alkyl, whor- an aromatlc radleal le ~ubetltut-d by 1, 2 or 3 ldentlcal or dlfferent subetituents from the group 1uor,1ne, chlorlne, eyano, trifluoro-methyl, (Cl-Cl2)-alkyl, (C2-Cl2)-alkenyl, (C2-Cls)-alkenyloxy or (Cl-Cl~)-alkoxy, Rl and R2, wlth the pyrldlne earrylng them, form a 5, 6, 7, 8-tetrahydrolsoqulnoline rlng, R~ le a branehed or unbraneh~d (Cl-C10)-alkyl rad1eal, (Cl-C~)-alkoxy-(Cl-C~)-alkyl or a radleal of th~
formula Z, ', ~ ~' ;`'' ,''~'''. ' ---`` 213~8~6 ,~CH2lV-1Olw-~cH2J~-E (Z) '' ' whero E i8 a ~ub~t~ tutod phenyl radlcal of tho f onnula F
R ~ R
_~_ RS ( ~
R 1 0 R9 ~ ~ -or a (C3-C,)-eyeloallcyl radleal, wh-r~ v 1EI 0, l, 2 -;
or 3, w i8 O, and t ean b- 0 or 1, and ln wh~ eh R', R7, R', R9 and Rl ~r~ ~dent~cal or differ-nt ~d are hydrogen, fluorine, chlortno~ cyano, trlfluoro-m o t hy l , ( C , - C ~ ) - a l ky l , ( C l - C , ) - a l k oxy , ~O~ ~CH~;]~~C~H~ )Fg~ N- (Cl-C~) -alkylear~amoyl, N,N-di- (C,-C6) -alkylcarbamoyl, N- (C,-C,) -cyeloalkylearba-moyl, N-(~)-dehydroab~otylaminocarbonyl, or (C7-Cll)-phenylalkylcarbamoyl, which ~ s optionally tituted by fluorinn, ehlorine, trlfluoromethyl or (C,-C~)-alkoxy, or whoro RC and R' or R7 and R', ~ a togother w$th the phonyl ring carying th-m, form naphthalono dorivatives ~;
: . . ~ , : , ., If Rl or R' ha~ th- moaning of (C~-Cl2)-phenoxy, (C7-Cll)- ~ ~
~ ,....... .
ph-nylalkyloxy, (C~-Cl,) -phenoxy- (Cl-C~) -alkoxy, (C,-Cl,) -phonylalkoxy- (C,-C,) -alkoxy, (C,-C,) -cycloalkyloxy- (C~-C,) - ~ ~ `
alkoxy, (C,-C~) -eycloalkoxy- (Cl-C,) -alkoxy or (C5-C,) - ~ .~ . ..... ... /
cyeloalkyl- (Cl-C~) -alkyl- (Cl-C~) -alkoxy, thi~ radical i8 th-n, o~pecially, a radical of tho formula D
OZ (D), or - . .:: ~. ::; .
. :,, :. .. ,:,, if Rl or R3 has tho mo~ing of phenyl, phonoxy-(C,-C,)-25 alkyl, (C7-Cll) -ph-nylalkyl (C7-Cll) -phenylalkyloxy- (Cl-C") -alkyl, (C~-C~) -cycloalkyl, (C~-C~) -cycloalkyl- (Cl-C~
allcyl, (C~-C~) -cycloalkoxy- (Cl-C~) -alkyl, (Cs-C~) -eyclo- ~ -alkyl- (Cl-C~) -alkoxy- (Cl-C,) -alkyl or (C,-C~) -cycloalkoxy-'~.',,,,..~
- 213~866 (C,-C~)-alkoxy-(Cl-C,)-alkyl, th~ radlcal i8 thon, e~pocially, a radical of tho formula Z in which, ln both ca~es, v is 1, 2, 3 or 4, w is 0 and t is 0, or v is 1, 2, 3 or 4, w i~ 1 and t is 0, or v is 1, 2, 3 or 4, w ~8 1, t 1~ 1, and f is 1 to 4, .
g i~ 0 or 1 to (2f~
x i~ 0 or 1. ::~
Compounds of the formula I ar~ very particularly pre-f~rred in which -~
Q i8 O, . `
X i~ o, Y i~ CR3, -m is 0, A i~ a -CH2- group which can b~ ~ub~tituted by a ~ - m methyl group, ~ ,":,a 8 is -CO2H, R2 is hydrogen, (Cl-C,)-alkoxy, (Cl-Cl~)-alkoxymothyl, (Cl-Cl~)-alk~nyloxymethyl, retlnyloxymethyl, N-(C1- .
C~0)-alkylcarbamoyl, N-((Cl-Cl,)-alkoxy-(Cl-C3)-alkyl)carbamoyl, N,N-di-(Cl-C~)-alkylcarbamoyl, N~
(C5-C~)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl-(Cl-C~)-alkylcarbamoyl, carboxyl, (C~-Cl~ . P
alkoxycarbonyl, (C2-Cl~)-alk~nyloxycarbonyl, . . ~
ret~nyloxycarbonyl, (C~-C~)-cyclonlkoxycarbonyl, (C5- ~ ,.. ."~,.` ;,;
C,)-cycloalkyl-(Cl-C,)-alkoxycarbonyl or phenyl-(C
C~)-alkoxycarbonyl, where a phonyl radical i~
sub~t~tutod in the manner a~ defined for Rl and R3, and one of th~ radicals R1 or R3 1~ hydrogen and the other radical i~ a radical ;~
from the group hydrog-n, (C,-C~0)-alkoxy, (C,-C,)-cycloalkylo.~y, (C,-C,)-cycloalkyl-(Cl-C,)-alkoxy, ~O~~CH~l~~CtH~s~ g~Fy~ (Cl-C~)-alkoxy-(Cl-C~)-alkoxy, cubstituted (C6-Cl,)-ph~noxy, (C7-C11)-phenylalkyloxy, (C~-C12) -phenoxy-(Cl-C~)-alkoxy or (C7-Cll)-phsnyl-~;, , 213~866 alkoxy-(C~-C,)-al~oxy, wh~r- an aromatic rad~c~l le substitutcd by 1, 2 or 3 ldentical or dlffor-nt eubst~tuente from the group fluorine, chlor~n~s, cyano, trlfluoromothyl, (C1-C10)-alkyl, (Cl-C10)-alkoxy or (Cl-C10)-alkenyloxy, and : ~ " ., ' ~
R~ is a branchod or unbranchod (Cl-C~)-alkyl rad~cal or .. :.. .. `
a r~dlcal of tho formula Z, -lCH~lv-lOlw-lCHalt-E (Z) where B ia a eubstitutod ph~anyl radical o tho lC formula F
R~ R7 ~ R~ ( F ) , ~ ` ~
t o R . .~
.-. :,.`:.
or a (C3-C,)-cycloalkyl radical, whero .
v 1~ O, 1, 2 or 3, w is 0, and t can b- 0 or 1, and ~. -;:: .;;
in which R6, R', R', R9 and Rl aro ~dent~cal or different and aro hydrogen, fluorino, chlorlne, ~ . . .
cyano, trifluoromethyl, (Cl-C~)-alkyl, (C~-C6)- . .:
alkoxy, -O-lCH,~X-CtH~lt~l9)F9, N-(Cl-C,)-alkylcarba-moyl, N,N-dl-(Cl-C~)-alkylcarb~moyl, N-(C,-C,)-cycloalkylcarbamoyl, N-(I)-dohydroabietylamlnocar-bonyl substituted benzyl radlcal, and f i8 1 to 4, ; . :
g l~ 0 or 1 to (2f~ and x 1~ 0 or 1.
Compound~ of the formula I aro partlcularly preferr-d ln ..
whlch . ~:
Q 18 O, X 18 O, .; .
25 Y is CR3, ~:~
m 1~ 0, B 18 -CO2H, A 1~ a -CH~-group, ,. ., ~ .
213~g66 Rl $~ hydrogen, (Cl-C~)-alkoxy or ~O~tC~,]~~C~HO~.lg,Fg, R2 is hydrogen, N-(C~-C,0)-alkylcarbamoyl, N-((Cl-C~
alkoxy-(C,-C,)-alkyl)carbamoyl,N,N-di-(C~-C,)-alkyl-carbamoyl, N-(Cs-Cc)-cycloalkylcarb~moyl, N-phonyl-carbamoyl,N-phenyl-(C~-C~)-alkylcarbamoyl,carboxyl, (C~-C~)-alkoxycarbonyl, (C2-C~)-alkenyloxycarbonyl, rotinyloxycarbonyl, (C~-C,)-cycloalkoxycarbonyl, (C5-C6)-cycloalkyl-(C~-C~)-alkoxycarbonyl or phenyl-(C
C~)-alkoxycarbonyl, whero a phonyl radical 1~
sub~tituted by 1 or 2 ld-ntloal or difforont sub~tituente from the group fluorine, chlorine, cyano, trifluoromethyl, (Cl-C,0)-alkyl, (C,-C,0)-alkenyloxy or (C,-C~0)-alkoxy, and R3 i~ hydrogen, (C,-C5) -alkoxy or (C5-C,) -cycloalkyl-~C,-C2)-alkoxy, wher~ one of the ~ubstltuent~ R1 and R3 i~ hydrogen, ~ 6 i R~ i~ a branched or unbranched (C,-C,)-al~yl radical, or a 2-phonylethyl radlcal, or a bonzyl radical ~ub~tituted by 1 or 2 radlcal~ from tho group flu-orlne, chlorlne, cyano, trlfluoromethyl, (Cl-C,)-alkyl, (C,-C,)-alkoxy, -O-~CX2]~-C~H~ )F~, N-(Cl-C,)-alkylcarba~oyl, N,N-di-(C,-C,)-alkylcarbamoyl,N-(C,-C,)-cycloalkylcarbamoyl or N-(~)-dehydroabletyl-aminocarbonyl, and f 1~ 1 to 4, g 1~ 0 or 1 to (2f~1) and x 1 : : :
Compound~ of the formula I are preferred to the hlghe~t degree ln whlch Q 1~ O, X 1~ O, Y i8 CR3, m i~ 0, A 1~ a -CH,-group, R~ 18 hydrogen, 213~866 R~ i~ hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((Cl-C~
al~oxy-(Cl-C,)-alkyl)carbamoyl, N-~yclohexylcar~
bamoyl, N-phenylcarbamoyl, N-(phenyl-(Cl-Cs)-al~yl)-carbamoyl, whero, in the last two caco~, the phenyl radlcal can carry a fluorins subotituent, (Cl-Clo3-alkyl oub~tituent or (Cl-ClO)-alkoxy cub~tituent, carboxyl, (Cl-Cl,)-alkoxycarbonyl, (Cs-Clc)-alkenyl~
oxycarbonyl, retinyloxycarbonyl, (C5-C~) -cyclo-al~oxycarbonyl or bonzyloxycarbonyl, R3 i8 hydrogan, (Cl-C~)-alkoxy or 2-(cyclohexyl)ethyl-oxy, whore one of tho ~ubet~tuento Rs and R~ io hydrogon, ; ~
R~ i~ a branchod or uDbranched (Cl-C~)-alkyl radical or ~ . .:;
a benzyl radical which ic ~ubotitutod once by flu-orine, chlorino, trifluoromethyl, (Cl-C~)-al~yl or .
( Cl - C3 ) -alkoxy~
Compounds of the formula I are aloo preferred to the ;.
highe3t degree in which Q i~ 8, ;. ;
20 X i8 O, ,.
Y i8 CR3, m io 0, A io a -CHs- group, i l~ - COsH, Rl io hydrogen, Rl io hydrogen, N-(Cl-C10)-al~ylcarbamoyl, N-((Cl-Cl,)-alkoxy- (Cl-C3) -al~yl)carbamoyl, N-cyclohexylcarha-moyl, N-phenylcarbamoyl, N-(phenyl-(Cl-Cs)al~yl)-carb~moyl, wherQ, in the laot two ca~e~, the phenyl radical can carry a fluorin~ ~ubotituent, (Cl-C10)-:.; ::;: :~:
alkyl oubotituent or (Cl-C10)-alkoxy ~ubctituent, ::
carboxyl, (Cl-Cl,)-alkoxycarbonyl, (C~-Cl~)-alkenyl- :.
oxycarbonyl, retinyloxycarbo~yl, (C5-C,)-cycloalk-oxy~arbonyl or benzyloxycarbonyl, ,, ~ ", ,,; "
~' ' ".:. ' `.:
R3 is hydrogen, (Cl-C,)-~lkoxy or 2-(cyclohexyl)-ethyloxy, whore one of tho substituont~ R' and R' ~o hydrogen, and R~ 18 a branched or unbranch-d (~,-C~)-alkyl radical or a benzyl radical which lc substltut-d onco by flu-orine, ohlorln-, trifluoromothyl, (Cl-C~)-alkyl or (Cl-C3)-alkoxy The compound~ of the formula I aro al~o profqrr-d to the highe~t degree ~n wh~ch 10 Q i~ S, ~-Y i8 CR3 m is 0, A is a -CH2-group, -15 B i8 -CO~H, ' ~' ~,,, ~'~ ,'''~'"'',~`'~','~''!'~
Rl iB hydrogen, ~ >-R2 is carboxyl or (Cl-Cl,)-alkoxycarbonyl, R3 is hydrogen, and ;
R~ is a branch-d or unbranch~d (Cl-C~)-alkyl radlcal Tho compound of tho formula I i~ al~o pr-forred to the hlgh-~t dogreo in which Q i~ 0, X ia 0, Y i~ CR3, whor~ R3 i~ hydrogon, ~ -m i~ 0, A 18 a -CH2-group, B is -C02H-, Rl and R2, togethor with th- pyridin- carrying them, form an i~oqulnollno ring havlng an unsubstltut-d b~nzo moloty, and R~ 1~ methyl " ;'~ . ' : ^~;: , ,, ~, ,.., ~
Tho compound of tho formula I 1~ also pref-rr-d to tho highe~t degr-- in which -~
Q ;8 0, t . ''~
'':': ' " ',', "' .', ' " ' '~;
21~866 - 39 - ;
X is 0, Y ie CR3, -~
m ie 0, A ie a -C~-group, 5 B i~ -C0~
Rl is hydrogon, R' and R3, togother with the pyridine carrying them, form a quinolino ring having an unsubstituted benzo ~;
moioty, and R4 is mothyl.
, .
Tho invention al80 ~mbracee prodrugs for tho compound~ o~ :
tho formula (I), which prodrugs bring about an i~hl~it~on -~
of collagon blosynthosie in vivo by liborating compounds ~ i~
of tho formula I or thoir ealte.
,~
"
Finally, the invontion also ~mbracoe prodruga which, by liberating compounide of the formula I or their ealta, bring about i~n lnhlbitory effect in vivo on prolyl-4-hydroxylaee.
.
Prodrug groupinge aro chomical groupe whlch, ln vlvo, -, 0 - aro convortod ~nto the carboxylato group of the compounde of th~ formula I, and/or - can bo cleav~d from the amldo N atom, and/or - can bo converted into a pyrldlno ring. ~ ;~
., -: .~
-, . . ::.::
Thoee prodrug groupe which aro ouitable are known to tho porson skllled in the~art.
:,. :::
~he followlng prodrug grouplngs receive partlcular montlons ;
for the carboxylate group, ester groupe, amlde group~
hydroxymothyl groups and aldehydo group~, and tholr derlvatlvess for the pyrldino N atom, N-oxide~ and N-alky~ deriratlvoe; and fox the pyrldlne rlng, 1,4-dihydropyridine derivatives or tetrahydropyridino derivativee. ~ i '.." ~:
,: ~.,,,i:
213~866 The invention relatos to tho u~e of c Q ounds of tho formula I, and also the phy~iologically tolarated ~alt~
for inhibiting collagon biosynthesis.
The inventlon relatos to the use of compounds of the formula I, and also tho physiologically tolerat~d ~alts, for inhibiting prolyl-4-hydroxylase. ~ -~
The inve~tion also relate~ to the use o~ compou~ds of the ~ ;~
formula I, and al80 the physiologically toleratod salt~
for producing a pharmaceutical against fibrotic disease~
The invention also relates to the use of compound~ of the formula I, and al~o the physiologically tolerated salts, for producing a pharmaceutical against fibrotic diseases of the liver, the lung and the skin.
::
Finally, the invention relates to the compounds of the ~ ;
formula I for use as pharmaceutical~
The invention relate~, in particular, to the compounds of -the formula I for use as fibrosuppressive ag-nte.
The invention al~o relate~ to a procese for pr-paring compounds of the formula I.
20 The oompound~ of the formula I, in whi¢h A i~ a ~
~ubstituted alkylene moiety, B i~ C02~, Y is CR' and m is ;;~ ;
0 or 1, are prepared by ;~
,, ~ j , , , , :
11.) Rea¢ting pyridine-2-carboxylic acids of th- formula II (R~3 is H) with the amino esters of th- formula III to form tho amid- e~ters of the formula IV, or i-i2.) Reacting pyridins-2-carboxylic estere of the for~ula; ; -~
II (R~3 is lower al~yl), under the conditions of aminolysis, to form the compounds of the formula IV;
and ,--ii) liberating the compound~ of the formula I from th~ir eeters of the formula IVs with, whero appropriate, iii) the oompounde of the formula IV boing prepared by alkylation of compounds of the for~ula V with R~
iand, where appropriate, : ; :
: .. . ~
i~) the compounds o~ th~ Formula IV being convert~d, :
pro~ided Q is 0 or NR', into thoir pyridine N-oxidee :-:
IV' (R'~ iB (C3-C3,)-alkyl or benzyl) and the l~Att~r :~:
being hydrolyzod to form the pyridino N-oxid~s of tho formula I' (R2~ ie H). :
Scheme 1 . :
~C22~2~ -c~2l~2~
l V
~ - ~
~ X t ~ ~ ~
", , ... . .. ~.
R
J R2~NH-~-CO2R2~ ~
R~ . ;
O ' . ' ,' " ,., V .-: - .::`.
:, ' ' ', ' ~'', O R ' ~ N - A - t O, 2 A - C O, ~ , "'~ : ; . .
o O : ~ . .','"'.''' :'''::' v~ c,-e")-~ . ~n~
I ~ 12~ N . . ~ ~
' ~ .,; ',;: .
;, . ~ ' ' . ,:
' ,,:,~. ;:.',:",' :''; ~',.'.'' i R~3 ie H or (C,-C16)-alkyl, .
;: :.;. .: ,.
.,, : .:
'".;' .~ ' '" ' ''','', ' ' ~ ' 6", ' ' ;; ~
213~866 R~ i B X, (Cl-Cl,)-alkyl or bonzyl, X ie a leaving group, ln particular halogen, OSO~Me or OSO~phenyl The methods of carboxyl actlvation and the condensatlon reactions known from peptide ch d ~try are sultable procosse~ for the amide formation (reactlon il) The eub~tance~ which are known to the per~on skllled ln the art, such as thlonyl chloride, oxalyl chloride, pivaloyl chloride, chloroformate derivativo~, or N,N'-carbonyldiimidazolo, can b- u~ed a~ roag-nt~ for tho carboxylic acid activatlon The aotlvated dorlvAtive~ of the compounds of the formula II aro prepared ln situ and then rsacted with tho amide derivativee of tho ~ormula III
A~ exa~ple of a euitable conden~ing agent ie the combination of N,N~-dicyclohexylcarbodllmldo/N-hydroxy-lH-benzotriazolo and N-ethylmorphollne Sultablo aolvents aro dichlorom thane, t-trachloro-methane, butyl acotato, othyl acotnt-, tolu-n-, totra-hydrofuran, dlmethoxy-tha~e, 1,4-dloxano, ac-tonltrlle, N,N-dlmethylformamld-, N,N-dim-thylacotam$do, dimothyl ~ulfoxldo, nltromethano and/or pyrldlne The compoundo of the formula I, ln whlch R~ and R3 aro hydrogen and R~ 18 a carboxyl eubstltuent, a carbamoyl ~ub~3titu-nt or an ! est~r ~ub~tltuont, wero proparod a~
outllned ln schomes 1, 2 and 3 ,, , . " . :,. .:
8cheme 2 lllu~trat-r3 th- preparatlon of tho compound~ of the formula TI ln whlch Rl lo a c~rboxyllc acid ~ubstltuont, or lts derlvatlve, and Rl and R' aro hydro-gen :, '. . ,: '" ' ~' Th- 3-~3ubstituted 5-carboxypyridlne-2-carboxyllc e~3ter~
of the formula XI and thelr isomer~ of the for~ula XII
' are prepared from the pyrldlno-2,5-dicarboxyllc die~ti~rs of tho formula VII.
The oxidation of the pyridine-2,5-dicarboxylatos of tho formula VII is d~scribed in J. Chem. Soc. Per~in Tra~.
2, 1978, 34-38 and in J. Org. Chem. 25 (1960) 565 to 568 (M.L. Peterson).
The halogenation (chlorination) of the pyrid~no N-ox~d,~,s of the formula VIII with thionyl chloride and the reac-tion of the 3-chloropyridine-2,5-dicarboxyllc diostor (Formula IX) with alcoholat~s (Q i,s o or 8) can be carried out in analogy with tho proco,~ do,scrlbed in the patent specification 7~H 658 651 (LONZA), where M 18 a singly charged or doubly chargod metal ion, preferably from the first or second mai~ group of the periodic syetem.
In analogy with the known literaturo (7-A: vol. 68, 1968, 68 840 h), the monoesters of tho formula XII are pre~
pared, under hydrolysis condltions, from the substituted pyridine-2,5-dicarboxylic dio~ters of the formula Xb.
Seloctive hydrolysis using ~u(II) salts, J. Delarge in Pharmaceutica Acta Holvetiao 44, 637-643, 1969, repre-,s,-nt~ anothar procos~ for preparing the compounds of the formula XII from tho diesters of the formula Xb. 1~ ;
,:-, . :,.: ,,, . : ;
The compounds of the formula XII thus obtained are reaoted with the,amino estor~ of the formula III to form the compounds of tho formula IV (SchQme 2).
,:~
Ths pyridine-2-carboxylic ester-5-carboxylates of the formula XI can be prepared, under eeiterification condi-tlons, from substituted pyridino-2,5-dicarboxylic acids of tho formula Xa (see CA: vol. 68, 1968, 68840 h).
~ultable conditions are, for examplo, eE,terification with mothanol in the presence of sulfuric acid, it being necessary to choose the reaction time 80 that complete ' " ::' "
"....
II:A . i; i ~ .
' ; . ~;
213~866 - . .
esterification to form tho d~e~ter product only ta~o~
placo to a ~ocondary oxtent, or ~o that tho diostor ~ -products can bo ~oparatsd off a~ by-product~.
Tho compounds of tho formula XI aro convsrtod w~th amlnoo or alcohole $nto ths 5-carboxylic acid doriv~tl~o of the formula XIV (Scheme 3).
These are then hydrolysod to form tho ~iompounds of th~
formula II (R23 i~ ~), which compou~d~ aro sub~oqu-ntly reacted in analogy with Scheme 1.
Scheme 2 RO2C~ 2 ~ ~`CO2R
V l I I
V I I
h~logen~tion ( R ~ H, lower ~Ikyl ) ~
:` ,' '~ ''''".: ' .",' UOR~ e r R O ~ C~O R U ( ~ ) O R ~ R O 2 C~¢~L
~C O 2 R C O 2 R
I X
X a : R H L C I, a ~
X b : R lower ~Ikyl 1~ metd ion, :
~ingly or doubly \ ch rged \ O O . 5 , : '~ '' :`"'"' U 2 C~O R ~C O H
X I R Iower dkylX I I R Iow ~Ikyl H, \l - A - C O 2 R ~
I V ' ., 213~866 , Scheme 3 ROIl o r HNRR
~02C ~R~ X I I I ' R2 QR~
~C 2 low ~1 ~C 2 lower~l X I X I V R2 . COOR, CO-NR R
The 2-hydroxymethylpyridlnes of the ~or~ula VI-, which are dir~clo~ed in ~P-A-O 304 732, EP-A-O 321 385 a~d EP-A-0 208 452, can bo used a~ ~ntermodiatee for preparing ~ -5 derlvativo~ (Rl) which are eubstitut-d in th- 4 posltlon ~ -. .
Scheme 4 ~ -R2 ~ QR Id 1i ~2 R~ CH20H R C02~
V I I I ( R 1 ~ H ) v I o ~ ~ I c : o R 4 O ~ me~yl) V l ~ ~ l l b : O R ~ O i~ n ( ~ n benzyl ) ; ~ -', Th- 3-0-benzyl derlvative~ of the formula VIb were al~o obtained in an analogous manner, a~ de~cribod ln thoso documents .. : ,:
The compounds of the~ formulas VIa and VIb wor- react-d wlth an oxldlzlng agent, preforably wlth RMnO~ ln agueous alkalino msdlum, to form th- pyridino-2-carboxylic acid dorivatlv-s of tho formula TI (of Schemo 4) Th- proparation of sub~tltuted pyridine-2-carboxylic ~ ;
acids 18, for example, dlsclo~od ln DE-A-353 046, and for ~; ,;
3-(3-chlorophonoxy)pyridine-2-carboxylic acld and 3-(3- ~ `
methylphonoxy)pyridlno-2-carboxylic ncid in J Med Chem 1975, 18, pp 1-8, Vlllani ot al ; ~or ' ~
: , . .
213~8S6 -3,5-diethoxypyridine-2-carboxylic acld ln J. Med. Chem.
1974, 17, pp. 172-181, French et al.; and for 3-mothyl-thiopyridine-2-carboxylic acid and 3-benzylthlopyridine-2-carboxylic acid in J. Med. Chem. 1974, 17, pp. 1065-1071, Blank et al.; and for 3-methoxypyridine-2,5-d~car-boxylic acid in CH-PS 658 651.
The compounds of the formula I are iDhlbltors of prolyl-4-hydroxyla~e. Tho lnhibition of thls onzyme w~e determined a~ described by ~aulo und G~nzler in Annal.
Biochem. 184, 219 to 297 (1990).
TAe novel compounda of the formula I pos~ece valuablo pharmacological propertios and exh~bit, in particular, antifibrotic acti~ity.
T~e antifibrotic effect can, for example, be determined u~ing the model of carbon tetrachloride-induced hopatic fibro~is. For this, rats aro troated twic- a waek with CCl~ (1 ml/kg) - dls~olved in olivo oil. Tho oubstanco under te~t is administered daily, whero appropriate oven twice a day, por 08, or intrnperitonoally - dle~olvod in a ~uitable toleratod solvont. Tho extent of tho hopatic fibro~i~ is detormined by hi~tology, and the proportion of collagon in tho llvor 1~ analyzod by means of deter-mining hydroxyproline - a~ describod in Rivirikko t al.
(Anal. Biochem. 19, 249 f. (1967)). The fibrogenic ac-tivity can be meaeur-d by the radioimmunologlcal detor-mination of collagen fragments and procollagon peptidos in the ~erum. Injthis model, the novol,compounds !aro active at a concontration of from 1 to 100 mg/~g.
~ :..-. .
The fibrogenic activlty can be moasured by radiolmmuno-logi¢al determination of the N-terminal propsptido of ¢ollagen type III or of the N-torminal or C-terminal cro~slinking domain of collagen type IV (79 collage~ or type IV collagen NCl) in the serum. - ~ ~;
~ ~ ' For this purposo, mea~urement~ wero made of the ~?~:
213~866 concentrations of hydroxyproline, procollagen III
peptide, 78 collagen and type IV collagen NC in the llver of a) untreated rat~ (control) b) rats which wero adminlster-d carbon tetrachlorido (CCl" control) c) rat~ which were first administered CCl" and tho,n a novel compound (this te~t method 1D described by Rouillor, C., ~xpcri-mental toxlc ln~ury of the llv~r; in Tho Llver, C.
Rouillor, vol. 2, 5. 335 to 476, New York, Acade~ic Press, 1964).
The novel compounds cu~ al~o b- demon~trated to b~ active ln the following ~ystem~
Inhibition of hepatic prolyl-4-biydroxylase ln vlvo~
Thi~ model i~ used to demonstrate the acute inhlbition of prolyl-4-hydroxyla~e in vlvo. For thi~, r~ts of both ~exe~ (healthy or with induced hepat$c flbrosi~) are administered (intraporitoneally, intravonously or per 08) the substance under tast or th- corrosponding ~ohicle and, after thio, aro giv-n 1~C-L-proline (250 ~Ci/kg of bodyweight), which is administerod intraperiton-ally.
There then follows a socond lntraperltoneal admiini~
tration of l"C-L-prolino (250 ~C~/kg of bodywelght).
Finally, the animals are exsang~inat-d under pento-barbital ane~thesla and the liver~ removed. The hepatic collagen was purifiod ~by dlgo~tlon with popsln and fractlonal ammonium eulfate precipitation in conformity with published protocol~ (Ref. 1 and 2). The purifiod liver collagen was hydrolyzed and the content of 1'~C-hydroxyprolino and 1~C-proline wa~ determirod by mean~ of amino acid analy~ls u~ing lon exchange chromatography.
Inhibitlon of prolyl-4-hydroxylaso is s,hown by a d-croase in the quotient 1'~-hydroxyprollne/[1~C-hydroxy~
proline~1"C-proline]. 2,2'-Dipyridyl i~ u~ed as the reference substanco. (1: Cho~kier, M. 1986, Hepatocyte :
21348~6 collagen production $n vivo in normal rat~, J. Clin.
Invest. 78: 333-339 and 2: Oga~a I., qt al. 1991, M~nor contribut$on of hopatocytos to collagen productlon in normal and oarly f$brotic livors, ~opatology 14:
361-367).
Inhibition of prolyl-4-hydroxyla~e in cell cultur-s:
~: , .,; ,;:
The following cell types are us-d for t~sting inhibitor~
of prolyl-4-hydroxyla~o in coll cultur~c: `
Normal _uman skin fibroblasts, (N~DF), rat liver opithelial cells, (ref. 1) and primary fat storing c-lls from rat liver (ref. 2). For thi~, the coll~ ar- oult~
. , , vated in the pro~ence of inhibitors. At the ~amo time, the collagen which iB nowly ~ynthesized during thi~
period ~8 metabolically labelled with 4-3H-L-proline and ;~
~C-prol$ne. The iafluonce of the test cubst~ncee on tho : .~
degree of hydroxylation of the collagen is then deter-mined in iaccordance with the method of Cho~kier et al (ref. 3). 2,2~-Dipyridyl i8 ~mployod as tho r~feronce sub~tance. (1.: Schrode, W., Mecke, D., G-bhard, R. 1990, Induction of glutamine synthqtase in periportal hepato-cyte~ by co-cultivation with a liver pithelial cell line, Eur. ~. Coll. Biol. 53: 35-41; 2. Blomhoff, R., Borg T. 1990, I~olation and cultivation of rat liv-r ~tellate cell~, Mothods Enzymol. 190: 59-71s and 3.:
Cho~kier, M. Peterkofsky, B. Batema~, J. 1980, A new m-thod for dot-rmlning the xtent of prolino hydroxy-lation by m-a~uring changes in the ration of [4-'X]:t~C~
proline in collagenase,dig-sts, Anal. Biochom. 108: 385-393).
Tho compound~ of the formula I may be used as medicament~
in the form of pharmaceutical pr-paration~, which contain tho compound~, whoro appropriat- together with toleratod pharmac-utical oxcipient~. The compounds can bo u~od a~
medicines, for example ln tho form of pharmaceutical ~`
preparation~ which contain the~e compound~ in a mixture together with a pharmaceutical, organic or inorganic ; ;;
':'.: :.. ~ '~
. - .: ,::
::' , :" ' :,; : `~
213~866 excipient which i8 suitablo for ~nteral, percutaneoua or parenteral adm~nietration, such aA, for sxampl~, water, gum arabic, gelat~n, lactoeQ, starch, magneeium stearate, talc, vogetable oilB, polyalkylene glycol~, vaeelino, etc.
Por this purposs, they can be adminietor-d orally ~n doses of from 0.1 to 25 mg/kg/day, proferAbly of fro~
to 5 mg/kg/day, or parenterally ln doeoe of from 0.01 to 5 mg/kg/day, proferably of from 0.01 to 2.5 mg/kg/day, ln particular of from 0.5 to 1.0 mg/kg/d~y. Tho doeage can aleo be increased ln sovere ca~e~. In many casee, how-evor, emaller doeo~ aro al~o sufflcient. Thsee data rofor to an adult of about 75 kg ln weight.
The novel conyounds of tho formula I are doeignatod eubetltutod hoterocyclic carboxyllc acld glycylamidee, prefsrably pyrldlne-2-carboxyllc acld glycylamide~, ln the examplos doecrlbod bolow.
This mode o~ deelgnatlon le underetood to moan subetltutod N-carboxymothylpyridine-2-carboxamldoe.
20 Anothor optlon ie to claseify th~m ae eubetitut-d N- ; ~
(pyridyl-2-carbonyl)glycinee. ,;
Examplo 1 ~ ~ `
3-Mothoxy-4-(2,2,2-trifluoroothyloxy)pyridlns-2-carboxyllc acid glycylamide a) 2-Mothyl-3-methoxy-4-chloropyridine N-oxide 11.2 g (80.5 mmol) of 3-mothoxy-2-mothyl-4(1~)-pyrldone -were heatod under reflux for 10 houro ln 100 ml of -~
phoephorus oxychloride. Subeogu-ntly, th~ mixturo wae conc-ntxated and 30 ml of toluen- were add~d to each 2 ml volume5 concentration thon took placo onco agaln and the r-eldue wa~ takon up ln 150 ml of water, wlth the pH of the mixture then belng adjuetod to 11 wlth ~,CO3; thle mixturo was thon extractod with dichloromethano and tho organic phaee was waehod with wator, dr~ed and freed from ." '; ;~'~'~: ,';;
~ 50 solvent 8 g of ths product were obtained, under ~tandard con-d~tlons, from the pale brown oil (9 g) using m-chloropor-benzoic acid in d~chloromothano, m p 88 to 8gC (fro~
5 petroleum other) ; ;
b) 2-Methyl-3-methoxy-4-(2,2,2-trifluoroethoxy)pyrldino N-oxide 6 7 g of potas~ium tert-butoxide were added ln portions, at -20C, while otirring and undor a nitrogon atmosph-ro, to 20 ml of trifluoroethanol Ater tho mixture had beon warmed to 0C, 5 2 g (30 mmol) of 2-methyl-3-methoxy-4-chloropyridlne N-oxide wero added in portlon~ The mixturo was heated under reflux for 3 hours, ~nd then coolod down to room temperatureS a further 3 45 g of potassium tert-butoxide w~ro then add~d and the mixture was heatod under roflux for 2 hours After it had coolod down, 40 ml of water wore addod to the r~act~on m~xture, ~-which was thon extractod with dichloromethane; the extract was then dried over MgSO~ and freed from ~olvont ln vacuo Tho rosulting oily product wa~ ~ub~-cted to furthor roaction c) 3-Methoxy-4-(2,2,2-trifluoroethoxy)-2-hydroxymethyl-pyr~dlne . ~ .
8 g (33 8 mmol) of tho a~ovo compound wer- dis~olv-d in ~ ~ ;
25 16 ml of glacial acotic acid, and 24 ml of acotic ~ ~;
anhydrid- wore addod, at 80C and while stlrring, to this mixturo The reaction mixturo was hoated at 110C for 2 houra and thon coolod down to 80C; 40 ml of methanol ;-~
wer- th-n addod to it dropwlse Sub~equontly, th~ mixture 30 wa~ conc-ntrated ln vacuo, and tho oily residue addod to ;
75 ml of 2N m thanolic NaOH, with thi~ mixturo boing etirred for 30 minutes Following treatment with active -~
charcoal, and filtration, the mixture was conc~ntrated in ~ .',,',.'.,'t vacuo and 50 ml of water wero addod to tho rosidue, after -~`
~,' ~, "'' ', 213~866 . .
which extract~on took placo w~th dichloromethan~; the extract was dried (NgS0~) and conc~ntratod, and the residue was treatod with dii60propyl othar 3 9 g of the product wero obtained ~n th- form of eolorloss erystal~
m p 107 to 108C
d) 3-Methoxy-4-(2,2,2-trifluoroothyloxy)pyridino-2-earboxylic acid 0 8 g (3 3 mmol) of the abovo alcohol was dis~olv-d in a solution composed of 0 3 g of potao~ium hydroxide and 25 ml of water, and 1 6 g of pota~ium p-rmanganate were addod in portions at 100C and whil- otirring Aft-r decolorlzation, the manganese dioxide which had formed was filtered off with ~uction fro~ the hot m~xture and waehed twice with hot waters ~he filtrat~ wae concen-trated in va~uo to 1/3 of the volume, ad~u~ted to p~with conc agueous hydrochlorlc acid, und eoncentrat~d in vacuo; the rosldue was treatod w~th ~ydrous thanol and tho undis~olved matorial was filtored off 0 73 g of product, m p 157, was obtainod frc~ t~o filtrate ~ . , o) 3-Mothoxy-4-(2,2,2-trifluoroothyloxy)pyridine-2-carboxylic acid (glycyl thyl oster) umlde 0 58 g (2 3 mmol) of tho above carboxyllc acid wae ~u~pendod in 100 ml of anhydrou~ t-trahydrofuran, aft-r whlch 322 mg (2 3 mmol) of glycin- thyl e~ter hydrochlorlde, 0 64 ml (5 mmol) of N--thylmorpholino, 350 mg (2 6 mmol) of l-hydroxy-l~-b-nzotriazole and 53j7 mg (2 6 mmol) of N,N'-dlcyclohexylcarbodilmlde were add-d at 20C and while etlrrlng, and tho mixture was th~n stirred at 20C ~or 48 hours Undls~olvod matorial wa~
th-n f~ltsred off and th~ flltrat- wae eonc-ntrated ln vacuot the residue wa~ tak-n up ln ~thyl acetate ancl undl~eolved materlal wa~ filterod off; th- filtrate wae ~tirred together with 100 ml of a ~aturated, aqueous ~olution of Na bicarbonate, and th- organic phase waB
dried and concontratod in vacuo; the r-eidue wae :, ~:,,;: ..
:, . ,: :, `
213~866 .
cryetallized using diisopropyl othor 0 45 g of tho colorlese cryetalline product wero obtained, m p 80 to f) 0 4 g (1 2 mmol) of tho above oet-r wa~ added to 50 ml of a 1 5 N mothanolic solution of sodium hydroxid~, and this mixturo wa~ ~tirrod at 20C for 30 mi~utes It wae then concantrated in vacuo and tho ros$duo was taken up in 50 ml of wator; this mixtur~ wa~ ad~u~ted to pH 1 with comp aqu00us hydrochlortc acid and tho small amount of undissolved material was flltor~d of~; th- filtrate was concentrated in vacuo and the residue wae treated wlth 50 ml of anhydroue othanol; thi~ mlxturo WaB
filtered and tho filtrate wa~ concentratod and brought to crystallizatlon using diothyl eth-r 0 32 g of the title 15 compound wae obtained, m p 163 to 165C (with gae evolution) Example 2 4-Chloro-3-methoxypyridino-2-carboxylic acid glycylamide a) 4-Chloro-2-hydroxymethyl-3-methoxypyridin-20 30 g (173 mmol~ of 4-chloro-3-methoxy-2-methylpyridine N-oxide (cf Example la) w-r- di~olv~d in 100 ml of glaclal acetic acid, after which 150 ml o~ acetic anhydride w-re added dropwis-, at 80C and while ~tir~
rlng, and th- mixtur~ was then stirred at 110C for 2 25 hours The mixture was thon cooled down to 80C ~nd 200 ml of methanol were added dropwi~e; the mixturo was then heated to boiling for 15 minutes and, aft~r having beon cooled down, concentrated in vacuo; the residue was taken up in methanol and thi~ mixture was allowed to flow into 30 300 ml of a 1 5 N methanolic solution of ~odium hydroxide, with this mixture then boing stlrred at 20C
for 30 minutes and concentrated in vacuo; th- residue wa~
takon up in wator, and this mixture extract~ad three timos with dichloromethane, with the organic phase boing driod and concentratod; tho residuo was crystallizod using .' ',~ ~;
213~866 potroleum athor. 23 g of product were obtainod, m.p. 64 to 6SC.
: -:
b) 4-Chloro-3-methoxypyridino-2-carboxylic acid 8.65 g (50 mmol) of tho above alcohol were di~sol~ed ln a mixturo comFosed of 0.8 g of potasslum hydroxide and 60 ml of wator, after which potas-ium pesm~ganat~ was addod in portions, at 60C and while ~tirring, until no moro discoloration could bo soen (12 g, 75 mmol). Aft-r 1 hous at 60C, the ma3ganeso dioxide was filtered off wlth suction and then washed wlth hot waterS the flltrate was concontrated ln vacuo to 200 ml and ad~ustod, while cooling, to pH 1 with aguoou~ conc. ~Cl. After grindlng, tho product csystallizss out in a~sociation with cooling.
Additional product can be obtalnod from tho mother liguor by troatment with potroleum other. Total guantity, 4.2 g, m.p. 116 to 117C (with ga~ evolution).
, c) 4-Chloro-3-mothoxypyridino-2-carboxyl~cacid(glycyl othyl ester) umide 4.7 g (25 mmol) of ~he above carboxyllc acld were ~uspended ln 200 ml of anhydrou~ dichloromethans, and after that 3.5 g (25 mmol) of glyclne ethyl estor hydrochlorldo, 6.4 ml (50 mmol) of N-ethylmorpholino, 3.8 g (28 mmol) of l-hydroxy-lH-bonzotriazolo and 5.15 g (25 mmol) of N,N'-dicyclohoxylcarbodilmido were added ~eguentially, at 2qC a,nd while tirring, and the mixture was th-n stirred at 20C for 20 hours. ~ndis~olved mat-rial wa~ then ~$1t-rod off and the organic phase was ~haken with a saturated, aguoous solution of odium carbonate, driod and ooncentrated in vacuoS th~ rosiduo (6 g of oil) wa~ chromatographod on ~ilica g~l u-ing ~thyl acetato and 5.4 g of oily product wero obtained.
d) The t$tlo compound wa~ obtain-d by hydrolyz$ng tho abovs othyl ester. For th$~, 0.7 g (2.6 ~mol) of th$~
213~866 est-r wa~ dlssolved in 50 ml of methisnol/water (3 1), and after that 170 mg (7 ~mol) of lithium hydroxldo wero added at 20C and while stirring Aft~r 30 minut~, the mixture wa8 concentrated $n vacuo; tho resldue w brought to p~ 1 with conc aquoous hydrochloric a¢ld and thl~ mlxture was concentrated ln vacuo; the r~slduo was troatod twlce with i~n~ydrous thanol and the ethi~nollc phaso was concentrated; the re~ldue wa~ treated with hot ethyl acetate and the amorphous re~ldu- was drlod on an oil pump 0 31 g of the tltle compound was obtalned Example 3 4-Butyloxy-3-mothoxypyrldine-2-carboxylic acld glycyl-amide M p 137 to 139C (with gas evolutlon, from tetrahydro-furan) ..
-. : . :-.
: . .. ~ . . .,:
ExampleEi 4 to 16 were prepar~d in an analogou~ mannors Example 4 3,4-Dlmethoxypyr$dine-2-carboxylic acld glycylam~d~
Example 5 3-Ethyloxy-4-(3-mothoxybenzyloxy)pyrldlne-2-carboxylic acid glycylamlde Exampl- 6 4-~exyloxy-3-mothoxypyrldine-2-carboxylic acld glycyl~
amlde - ~-.., ~ . .. .
25 Examplo 7 ~ ,",;
3-Mothoxy-4-(3-methyl-1-butyloxy)pyrldlne-2-carboxylic ~ ~-acld glycylamide Example 8 ; ~`~
4-(4-Fluorobenzyloxy)-3-msthoxypyrldlno-2-carboxyllc acid 30 glycylamlde -: :''::''' .":'.
. ~
",, ',,.~ ,: ';
, i ~ . ~ .:: .
:: .
.: : :. ,: .::
2~3~866 Examplo 9 3-Methoxy-4-(4-trifluoromothylbonzyloxy)pyrldlno-2-carboxyllc acid glycyl ~ido Bxamplo 10 3-Mothoxy-4-(2,2,3,3,3-pentafluoropropyloxy)pyridlne-2-carboxylic ac$d glyeylamido :~
Examplo 11 4-(2,2,3,3,4,4,4-~optafluorobutyloxy)-3-methoxypyrldln~
2-carboxylic acid glycylamide .
Example 12 4-(3-Mothoxybenzyloxy)-3-mothoxypyridlno-2-carboxylic acid glycylamido ~;
:
Example 13 3-Ethyloxy-4-(2,2,2-trifluoroothyloxy)pyrldlne-2-carboxy- : .
lic acid glycylamide ~ ' Example 14 4-Butyloxy-3-ethyloxypyrldine-2-carboxyllc acld glycyl-amlde ~. . -::, :~: . ~ . .: . .
Example 15 3-Mothoxy-4-((phenoxyothyl)oxy)pyrldine-2-carboxyllc acid glycylamide :`
: ,,:
Examplo 16 ;~ .; n-3-Ethyloxy-4-bonzyaoxypyridino-2-carboxylie aeld glyeyl- ~ ~.
amide 25 Example 17 :~
3,6-Dimethoxypyridlno-2-carboxylic acid glyeylamide ~ jÇ;~`~
a1 3,6-Dlmethoxy-2-methylpyridino N-oxido .~ -1.15 g (50 mmol) of ~odlum were dis~olvod ln 100 ml of anhydrou~ methanol, and aftor that 7.4 g (40 mmol) of , "".,",",,",,,,,,,~
: . ' ; , .
213~8~6 3-methoxy-2-methyl-6-nitropyridine N-oxide woro added at 20C and while ~tirring The mixture was th~n heatad to reflux for 3 hours and, aft~r having boen cooled down, concentrated in vacuo; tho re~iduo was ta~en up in wat-r And this mixturo was oxtractod with d$chloromethane; the organlc pha~e was dri-d and concentrated and the r~ldue wa~ cry~tallized using diisopropyl ether 7 g of product wore obtained, m p 63 to 65C
.~
b) 3,6-Dimethoxy-2-hydroxymethylpyridine 7 g (41 4 mmol) of the abov~ compound were react-d with glacial acet$c acid/acetic anhydride in analogy with Examplo lc) and the rosulting acetate was hydrolyzed using 1 5 N methanolic sodium hydrox$de solution 5 6 g were obtainod of oily product which wa~ sub~octed to further reaction under c) c) 3,6-Dimethoxypyridine-2-carboxylic acid 5 6 g (33 mmol) of the abovo compound and 2 4 g of potas~ium hydroxide wer- di~solv-d in 150 ml of wat-r, and after that 15 g (100 mmol) of potasslum p-rmanganate w-re addod in portion~ at 60C and whilo ~tirring Th-mangano~- dloxide which had formed wa~ thon filt-r-d off with ~uction and wa~h-d twico with hot wator; the com-bined wator pha~e was concentrated to 100 ml, ad~u~ted to pH 1 with conc agu~ou~ hydrochloric acid while being cool-d with ice, and concentrated in vacuo; the r-~idu~
was treat-d with othyl acetat- and othanol, and undi~
solv-d materlal wa~ filterod off from this mixturo, with th- filtrate being concentrat-d in vacuo The r-sidu- wa~
cry~tallized u~ing di-thyl th-r 4 g of product were obtained, m p 131-132C (with gas volution) d) 3,6-Dimethoxypyridine-2-carboxylic acid (glycyl ethyl oster) amid-2 2 g (12 m~ol) of the abov~ carboxylic acid wero ~'' ' ''''" ''"' ~ ,::; ::':':
, 2~34866 ~:-.
suspended in 300 ml of anhydrous dichloromothano, ~nd after that 1.68 g (12 mmol) of glycine thyl ostor hydrochloride, 3.25 ml (25 mmol) of N-~thylmorpholine, 1.62 g (12 mmol) of l-hydroxy-l~-benzotriazole and 5.2 g (12 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbo-diimide mothyl-p-toluen~ulfonato wero add~d, w~ilo ~tirring, and tho mixtur~ was then ~tirr~d at 20C for 20 hour~. Tho ~mall amount Oe undio~olved mat~rial wa~
then filtered off ~nd the filtr~te wa~ cha~-n once with wator ~d ~hen with a ~aturatod, aquoou~ solution of Nn bicarbonate; the organic pha~e was dr~od and concentrated in vacuo and tho re~idue was crystallizod using diloo-propyl ethor. 2 g of product wore obtainod, m.p. 93 to 95C.
e) The title compound wa~ obtalned by hydrolyzing 0.6 g (2.24 mmol) of the above ethyl oster at 20C u~lng 120 mg of lithium hydroxide in 60 ml of methucol/wator (3 After concentration had taken place in ~acuo, the re~idue was acidified and extracted, at 20C, with tetrahydro-furan; the filtrate wa~ concentrated in vacuo and the yellow, re~inous re~idue wa~ cry~tallized u~ing diethyl ~ -other. 0.14 g wero obtalned of the title compound, m.p.
130C (decomposition), which i~ ~trongly hygroccopic. The re~idue from the in~pis~ated reaction mixturo wae then extracted three tim-~ with 50 ml of hot aceton~ on each occa~ion and the in~pis~ation re~idue wac cryctalllzcd u~lng dlethyl ethor. A further 0.35 g of tho title compound wa~ obtainod, m.p. 155C (decomposition).
Example 18 3,5-Diethoxypyridine-2-carboxylic ac$d ylycylamide ~Sxample 19 3-Methoxy-6-(3-methyl-1-butyloxy)pyridine-2-carboxylic ~ ;
acid glycylamide ~ ;
M.p.: 105 to 107C (from aqueou~ hydrochloric acid, p~ 3 to 4) ":~
213~86~
Exsmple 20 3-Benzyloxy-4-(3-ethyloxypropyloxy)pyridine-2-oarboxyllc scid glycylamide M.p. 118-120C (from acetone) According to lH NMR, tho product contains ~pproximatsly 15 % of the 3-hydroxy dorivativo.
Example 21 3-Benzyloxy-4-hexyloxypyridi~o-2-csrboxylic acid glycyl-M.p. i30 to 132C (from agueou~ hydrochloric acid) Example 22 ~ ,j?~
6-(2-Butoxyethyloxy)-3-mothoxypyridlne-2-carboxyllc ac~d glycylamide : ,,., ~.... ~
Example 23 6-(2-Cyclohexyl)ethyl)oxy-3-methoxypyridine-2-carboxylic acid glycylam~do ~-M.p. from 70C (~intering from 50C, from aqueou~ hydro-chloric ac~d, p~ 3) Examplo 24 20 3-Ethyloxy-6-~ethylpyridino-2-carboxylic acid glycyl- ````~
amid~
: ', , .: ,', . . .
Example 25 6-Bonzyloxy-3-methoxypyr;d~ne-2-carboxylic acid glycyl-amide "' . ,. ~
25 Example 26 '! ' ;,.. ',.' 3-Benzyloxypyr$dine-2-carboxylic acid glycylam~do M.p. 142-144C
Examplo 27.1 3-Methoxypyrldine-2-carboxyli¢ acid glycylamlde amorphous ~ub~tanco, pr-pared by hydrolyzing tho 3-methoxypyridine-2-carboXlic acid (glycyl othyl ost-r) amlde, m.p. 141 to 142C (with ga~ ovolutlon, from 2~ 3~866 diothyl other).
This ethyl ester was obtalned by catalytic hydrogenation of 4-chloro-3-methoxypyridine-2-carboxylic acid (glycyl othyl estor~ ~mido (ooo ~x~mple 2c), whlch wa~ obtainod from 4-chloro-3-mothoxypyrldine-2-carboxylic acid (m.p.
119 to 120C, from 4-chloro-3-mothoxy-2-mothylpyridine N-oxide by reaction with acotic anhydride/glacial acotic acid and subseguont oxidation of tho 2-hydroxy~ethyl-pyridino dorivativo) (~oe Examplo 2a, b3 ~nd glyclno othyl ootor hydrochlorido.
Example 27.2 3-Methoxypyridino-2-carboxylic acid glycylamlde hydrochloride a) 4-Chloro-3-methoxypyridine-2-carboxylicacid(glycyl benzyl e~ter) ~do ~ ~-The product was obtained, in analogy with Examplo 90a), ~ ~', ,'`''''',J~
from 4-chloro-3-methoxypyridino-2-carboxyllc acid (cf.
Example 2b), glycine benzyl ostor tosylate, N-ethylmor-pholine, l-hydroxy-lH-benzotriazole and CMC, m.p. 57-20 58C. ~ ~
..: , ,., , :' b) The title compound wao obtained by hydrog-nating the above product in mothanol/tetrahydrofuran (1:1) uoing Pd ;~
on charcoal (10 %) in a hydrogenatlon v-~el. After removing the catalyot, and freeing from the oolv-nt, the product was crystallized using acetone, m.p. 168C (with foaming). ;~
' ~: ~ ' '.:, Examplo 28 3~Ethoxypyridins-2-carboxylic acid glycylamide ~ - ~
: ' ' ' , :, .
Examplo 29 ;
3-Propyloxypyridine-2-carboxylic acid glycylamide .
213~866 Example 30 3-Butyloxypyr~d~ne-2-carboxyl~c acid glycylam~de a) 3-n-Butyloxypyr~dine-2-carboxyl~c ac~d :"-, 6 g ~150 mmol) of N~H (60 %, in minoral oil) were added in portions, at 20C and whll- stirrlng, to 9 8 g (70 mmol) of 3-hydroxypyridino-2-carboxyli~ acld ln 150 ml of N,N-dimothylac-tamide Aftor 30 m~nut-s, 15 ml (140 mmol) of butyl bromide wero added dropwiso and the mixture was hoatod at between 95C and 125C for 2 5 hour~ After havlng boen cooled down, ~he mixture wa~
concentrated ~n vacuo, treatod w~th an aqu-ou~ solution of Ni~ blcarbonato and oxtractod wlth dichloromethanes aftor drying, tho residuo was puri~ied by chromatography on sllica gel uolng ethyl acetate The 13 g of oily product thus obtained were lntroducod into 250 ml of a 1 5 N mothanollc ~olutlon of sodlum hydroxide, and the m~xturo wa~ then ~tlrrod at 20C for 30 minutes and concentrated ln vacuo; the residue was ta~en up in 200 ml of water and thi~ mixturo wae extracted with dichloromethano and the ~quoouo phas- was ad~u~t-d to pH 1 with conc aquoou~ hydrochlorlc acld~
conc-ntration took place ln vacuo and tho re~ldue wao troatod wlth othyl acetato and thon wlth anhydrous ethanol Tho r-~ultlng ~olutions wore conc~ntr~tod and the reoidue wa~ crystallized using acetono 9 3 g were obtained of product (m p 93-95C) which, accordlng to lH
NMR, otlll contalnod approxlmately 20 % of 3-hydroxy-pyrldino-2-carboxylic acld b) 2 8 g (20 mmol) of glyclne ethyl ster hydrochlorld-, 5 2 ml (40 mmol) of N-ethylmorphollno, 2 7 g (20 mmol) of l-hydro~y-lH-benzotrlazole and 3 0 ml (20 mmol) of N,N'-dllsopropylcarbodilmid- were added, at 20C and whlle stirrlng, to 4 g (20 mmol) of th- above product in 200 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous acetonltrile, and the m~xture wa~ then otlrred at 20C for 20 hours , ,''': .
Aftor wor~ing up ~treatmont with Na bicarbonate oolution, removal of precipitated diisopropyluroa), 3 5 g of oily -product, which ~till contained N,N'-diisopropyluroa, w~ro ~ -obtained following chromatography on oilica gol (ethyl ac-tato/n-hoptane 1 1; then puro othyl acotato) Thi~ mixture was introduced, at 20C and whllo ~tirring, ~ ;
into 150 ml of a l S N methanolic ~olution of sodlum hydroxide and the total mixtur- wa~ stirred for 30 ~ ;s-minutes Thi~ latter mixtur- wa~ th n conoontrat-d in vacuo and the re~idue wao ta~en up in waterS thi~ mixtur- wac ~n turn oxtractod with 200 ml of dlchlorom than- and the agueou~ pha~e wa~ brought to pH 1 u~ing conc aqueouc 8Cl and concentrated in vacuo; th- residuo wao tr-at-d with anhydrous ethanol and thon with N,N-dim thylfo-m~mide, wlth ach extract boing f~lt-r-d to romove undis~olved mat~rial and th-n con¢entrat-d and each of the r-oiduoo ~- m;-being cry~talliz-d u~ing thyl acetat- 1 65 g of th~
title compound w re obtained from the ethanol phaoe ~
20 (~lightly contaminat-d according to '8 NMR, m p 170C ~ ~"X, with gac evolution) and a furth-r 0 63 g from the dimethylformamide phaoo (m p 182C, with ga~ ovolution) ~xa~plo 31 ~ -3-~4-Chlorob-nzyloxy)pyridino-2-carboxylic acid glycyl-amld-a) 4-Chlorob-nzyl 3-(4-chlorob-nzyloxy)pyrldine-2-carboxylate 8 4 g (60 mmol) of 3-hydroxypyridine-2-carboxyllc acid w-r- alkylated (3 houro, 110C) with 5 2 g (approximatoly 130 Iol~ 60 ~) of ~odium hydride and 19 3 g (120 mmDl) of 4-chlorobonzyl chlorld- ln N,N-dlm-thylacotamido in analogy with ~xampl- 30a) Aft-r concontration in ~acuo and xtraction wlth Na bicarbonate solution, th- r-cidu-wao purifi-d on oillca gol u~lng h-ptano/ethyl aoetat-(lsl), and 14 8 g of th- product were cry~tallizod from appropriate fractiono u~ing diioopropyl eth-r, m p 92 to 213~866 .
94C.
b) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid 9.7 g (25 mmol) of the above e~ter were hydrolyzed w$th 200 ml of a 1.5 N mothanolic ~olution of eodlum hydroxide (24 h, 20C). After working up (concontratlon, taking up of the reslduo in wator, extraction w~th dlchlorometh~ne and acidificatlon), 6.5 g of product were obtainod, ~.p.
144C (from water, decompo~ition).
c) 3-(4-Chlorobenzyloxy)pyrldine-2-car~oxyllc (glycyl othyl ostor~ amide 3.2 g (12 mmol) of the above pyridine-2-carboxylic acid were reactod, in analogy with example 17d), with 1.7 g (12 mmol) of glycine ethyl ~ster hydrochlorido, 1.62 g (12 mmol) of l-hydroxy-(lH)-benzotriazolo, 3.3 ml (25 mmol) of N-ethylmorpholine and 5.2 g (12 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimlde ~othyl-p-toluene~ulfonat~. After working up, 3.0 g of tho product were cry~tallized u~ing dii~opropyl ether, m.p. 106 to 108C.
.
d) Th~ title ¢ompound wa~ obtnined by hydrolyzi~g the abov- ethyl e~t-r. 120 mg (5 mmol) of lithium hydroxide w-re added to 0.9 g (2.5 ",ol) of the ethyl e~ter in 60 ml of methanol/wator (3:1), and the mlxtur~ wae ~tirrod at 20C for l hour. It wa~ then concentratod in vacuo and the re~ulting agueou~ pha~- was ad~u~tod to pH 3; the ro~ulting precipitate wa~ filtored off with ~uction, wa~hed with water and dried in vacuo. 0.52 g of tho title compound wa~ obtained, m.p. 155 to 157C. ~-Examplo 32 3-(3-Nethoxybenzyloxy)pyridine-2-carboxylic acid glycyl-amlde ' ,: '', '~`;' .,, "
~ ":,''' "
213 ~866 a) 3-Methoxybenzyl 3-(3-mothoxybenzyloxy)pyrldlno-2-carboxylate In analogy with Examplo 38a), 10 g of ths product woro obtalned as a colorles~ oil, which was sub~octed to further reactlon, from 8.4 g (60 mmol) of 3-hydroxy~
pyrid~na-2-carboxylic acid and 3-methoxybenzyl chlorlde following chromatography on ~ilica gol.
i ~ . ~", b) 3-(3-Methoxybenzyloxy)pyr$dlne-2-carboxyllc acid 10 g of the above e~tsr were hydrolyz-d in 300 ml of a ;~
1.5 N methanolic eolutlon of eodlum hydroxide. 7.5 g of product were obtained, m.p. 147C (docomposltion, from agueou~ hydrochlorlc acld) c) 3-(3-Me~hoxybenzyloxy)pyrldlne-2-carboxyllc acid ;
(glycyl ethyI ester) amlde 3.2 g (12 mmol) of th~ above car~oxyllc ncid were reacted in analogy wlth Example 31c). 3.6 g of olly crudo product wero i~olated which, accordlng to the H NMR opectrum, etill contalned N-ethylmorphollne. The pure cub~tanc-, m.p. 135 to 137C (from dlleopropyl ether/ethyl acetate) wa~ obtalned from thl~ crude product.
d) 2.1 g (6 mmol) of the above product wor~ hydrolyzed u~lng O.4 g of NaO~ ln 60 ml of methanol. Followlng acldlflcatlon to p~ 3, 1.6 g of th~ title compound wore obtained aa a colorle~s cry~talline ~ub~tanco, m.p. 89 to 91C (from aguoou~ hydrochlorlc acid).
Ex~mplo 33 3-(2-Phonylethyloxy)pyridlne-2-carboxyllc acld glyayl-amld- ~odlum salt ~, a) 3-(2-Phenylethyloxy)pyrldine-2-carboxyllc acld In analogy with Example 30a), 8.4 g (60 mmol) of 213~866 3-hydroxypyrid$ne-2-carboxylic acid w~re al~ylatad with Na~/2-phenylethyl bromide in N,N-dim~thylacetamide. The 10 g of oily product obtained after purification by column chromatography were hydrolyzod w~th methanoliG
eod~um hydroxide solution in analogy with Examplo 30a).
3 g of product were obtained (m.p. 145C (with fo~ming~
from acetono)) which, according to the 1~ NMR spectrum, contained approximately 25 % of 3-hydroxypicolinic acid.
:-, :, :.- ,.
b) 3-((2-Phenylothyl)oxy)pyridin--2-carboxylic acld (glycyl ethyl ester) ~do , -: " ~
2.9 g of the abo~e compound wer~ roacted, ln ~nalogy w~th Example 30b), w~th glycino ethyl estor hydrochloride, N-ethylmorpholine, 1-hydroxy-lH-benzotriazole and N,N-dicyclohexylcarbodiimide. After working up, the crude product wa~ chromatographed on ailica g-1 using ethyl acetate. 3-Hydroxypyridine-2-carboxylic acid (glyoyl ethyl e~ter) amide was initlally eluted ao a by-product and cry~tallized fro~ appropriate fraction~ using petro-leum other; 1.1 g (m.p. 86 to 88C, strong fluore~conce in W light). The product was then crystallized from appropriate fractions using diisopropyl ethor, and 1.7 g of the product wero obtained, m.p. 73-75C.
c) The titl- compound wa~ obtained by hydrolyzing 0.99 g (3 mmol) of the above ethyl e~ter using 100 ml of a lN methanolic solution of sodium hydroxide. After the mixture had been stirred at 20C for 1 hour, it wa~
conc-ntrated and the rosldue was dissolved ln a little water~ this latter mixture was extracted wlth dichloro-methano and the agueous pha~e was acidified, while being cooled with i¢e, to p~ 1 using conc. agusou~ hydrochloric a~id and then concontrated in vacuo; the residuo was oxtracted twico with totrahydrofuran and the extracts were concentrated~ the r-sidue was di~solvod in a little water/tstrahydrofuran (lsl), and 252 mg (3 mmol) of ~odium bicarbonate wore added to thls ~olution. This mlxture was concentrat-d to dryne~ and th- r-~idue was , 213~866 crystallizsd using anhydrous ~thanol. 0.38 g of the title compound was obtained as sodium ~alt, m.p. ~ 300C. ~ ~ -Exismple 34 ~ -~
3-(4-Trifluoromethylbonzyloxy)pyridiae-2-carboxyllc acid glycylamide M.p. 161 to 163C (from aquoous hydrochloric acid, pH 3) , ~ .; :.. :,-Example 35 3-(4-(2-Propyl)benzyloxy)pyridine-2-carboxylic acid ` j ;
glycylamide ~odium ~alt 10 M.p.-108C (with decomp., from d~l~opsopyl other) Example 36 ~;
3-(4-Fluorobenzyloxy)pyridino-2-carboxylic acid glycyl-amide M.p.: 135 to 138C (from agueous hydrochloric acid, pH 3 to 4) Example 37 3-(4-(2-(4-Msthoxyphenyl)ethylamino)carbonyl)b nzyloxy)-pyridine-2-carboxylic acid glycylamid-M.p. 168-170C (from dichloromothan-) -Tho following xample no~. 38-64 w-re preparod in an analogous manner:
Exi~mple 38 3-(2,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid glycylamido , ;~
25 Examplo 39 , 3-(3-Fluorobonzyloxy)pyridine-2-carboxylic acid glycyl- ~;~
amido ~:.... ,:; .
Exunplo 40 - 3-(3-Chlorobenzyloxy)pyridine-2-carboxyllc acid glycyl-30 i3mide ;~
, ,, ., :: ::
, ~'' ' ~`', "' '''", : ' ' ~ ,', ` ':
213~866 . , Example 41 .
3-(3,4-Dichlorobenzyloxy)pyridine-2-carboxylic acid glycylamide -- .
Example 42 5 3-(3-Trifluoromotkylbenzyloxy)pyridine-2-carboxylic acid ; :::
glycylamido Examplo 43 . ~
3-(4-Trifluoromethoxybonzyloxy)pyridine-2-carboxylic acld ::
glycylamide Example 44 3-(3-Ethoxybenzyloxy)pyridino-2-carboxylic acid glycyl-amido .
Example 45 3-(4-Cyanobenzyloxy)pyridino-2-carboxylic acid glycyl-amide Exa~plo ~6 3-((2-Pyridylmethyl)oxy)pyridine-2-carboxylic acid : :
glycylamido hydrochloride :'.' . '..'.
Exampl- 47 ~ .
3-((3-Pyrldylmothyl)oxy)pyridine-2-carboxylic acid glycylamido hydrochloride .. :
Examplo 48 .~:
3-((4-Pyrldylmethyl)oxy)pyridino-2-carboxylic acid ~ ~:
glycylamido hydrochlorido ~:
Examplo 49 3-((2-Thionylmethyl)oxy)pyridino-2-oarboxylic acid glycylamldo Exampl- 50 ~.;
3-(3,5-Dim~thoxybenzyloxy)pyridino-2-carboxylic acid 30 glycylamide -~
:. ~, ": :, : ~ . ., :. .
... ,-.. .
,,: , :
213~866 - 67 - ;~
, Example 51 3-Cyclohoxyloxypyridine-2-carboxyllc acid glyeyla~ido Example 52 ~ ~ :
3-(3-Phenylpropyloxy)pyridine-2-carboxylic acid glycyl- . -amide . :~
Examplo 53 .
3-(4-Phenylbutyloxy)pyridino-2-carboxylic aeid glycyl-amide :
Examplo 54 3-(((4-Nethoxy-2-pyridyl)methyl)oxy)pyridino-2^earboxylic acid glyeylamide :
Example 55 3-(((4-Ethoxy-2-pyridyl)mothyl)oxy)pyr~dino-2-carboxylic -acid glyeylamide -: -Example 56 3-Methylthiopyridine-2-earboxylic acid glycylamide ~
~ .
Example 57 3-Ben~ylthiopyridino-2-earboxylic aeid glyeylamide : ~:;
Examplo 58 ~ .
3-(3-Chloroph-noxy)pyridine-2-earboxylie aeid glyeyl~
amide Ex~mple 59 :~
3-~3-Methoxyphonoxy)pyridino-2-earboxylie aeld glyeyl-amido . ,.:.. :: .. : ::
~: . :..;.:: ~ ,:
25 Example 60 :~
3-Phenoxypyridine-2-earboxylie acid glyeylamide :::, : ., Example 61 3-~utyloxypyridine-2-earboxylie aeid ~-alanylamide ~ .. ..
..:..:.
Example 62 3-Butyloxypyridino-2-cnrboxylic acid D-alanylamido ' Example 63 3-Benzyloxypyridine-2-carboxylic acid ~-alanyl~nide Example 64 3-(3-Methylbutyloxy)pyridino-2-carboxyllc ac~d ~-leucyl-amide Example 65 4-Methoxyi~oquinoline-3-carboxylic acid glycylamide a) Methyl 1,2-dihydro-4-hydroxy-1-oxoi~oqulnoline-3-carboxylato, wa~ propared a~ de~cribed (~. Suzuki et ;~
al., Synthe~ie 1978, 461). -b) Mothyl 1,2-dihydro-4-methoxy-1-oxoisoguinoline-3-carboxylato, from a) u~i~g (trimethyl~ilyl)-diazomethano in methanol/ac-tonitrile, m.p. 177 to ;
179C (ethyl acetate/hoptano).
c) Mothyl 1-chloro-4-mothoxyi~oquinolin--3-carboxylate, from b) using pho~phoru~ oxychlorido, m.p. 108C
(othyl ac-tate).
~' .~ .. ,', ' ., .:
20 d) Mothyl 4-mothoxyisoguinolino-3-carboxylate, from c) ;
uoi~g hydrogon/Pd/C, m.p. 129C (from mothyl tert- ~ ~`
butyl other).
',":':,':
o) 4-Methoxyi~oguinolino-3-carboxylic acid, from d) by ~ -hydroly~i~, m.p. 185-189C (from aguoouc hydro-chloric acid). ``
f) 4-Mothoxyi~oquinolino-3-¢arboxylic ~cid (glycyl ~ ~;
mothyl o~tor) amido, from e) u~ing glycine mothyl e~tor hydrochlorido, DCC, HOBT, THF and NEM, oily ~ubstance (crude product).
,:., ''.'"'",,;' '''' 213~866 g) The titlo compound wae obtained by hydrolyzing the abovs ~ethyl eetor, m.p. 147C (fram agueoue hydro-chloric acid) Examplss 66 to 76 were obtained in an analogou~ mannsr from ths correeponding ieoguinoline-3-carboxylia acid~ or the 5,6,7,8-tetrahydro derivativos, reepecti~sly~
Exampls 66 4-Ethoxyisoquinoline-3-carboxylic acid glycylumlde Examplo 67 10 4-Propyloxyieoguinoline-3-carboxylic acid glycylamido .
~xampls 68 4-(3-Nethylbutyloxy)ieoguinolin~-3-carboxylic acid glycylamide .,:. :,, Example 69 - ~
4-Methoxy-5,6,7,8-tetrAhydroieoquinoline-3-carboxylic ~ :
acid glycylamide . I ~, ~ .
Examplo 70 4-(3-Mothylbutyloxy)-5,6,7,8-tetrahydroieoguinoline-3-carboxylic acid glycylamido : :. . .,:. ~";.
20 Examplo 71 . ::~
4-Ethoxy-5,6,7,8-tstrahydroieoguinollno-3-carboxylic acid 01ycylamide ~,~ ;,:':,.'~.;~::' , ~ ~, ,, . .:
Examplo 72 4-Bsnzyloxy-5,6,7,8-t~trahydroieoguinolino-3-carboxylic 25 acid glycylamide -.
Examplo 73 4-Benzyloxyi~oguinoline-3-carboxylic acid glycylamids : ~: '~A .
''~ ~''~`"''''''.
213~866 Example 74 4-(3-Methoxybenzyloxy)-5,6,7,8-tetrahydroisoguinoline-3-carboxylic acid glycylamide Example 75 7-Bromo-4-methoxyisoguinollno-3-carboxylic acid glycyl-amide Example 76 7-Methoxy-4-methoxyisoguinolin~-3-carboxyllc acid glycylamide Example 77 3-Mothoxy-6-((3-methylbutyloxy)methyl)pyridlne-2-carboxylic acid glycylamlde ~
.,~ ; : ~ :,, Example 78 3-Methoxy-6-((cyclohexyloxy)methyl)pyrldln--2-carboxylic 15 acld glycylamide ;
Ex~mplo 79 , 3-Methoxy-6-benzyloxymothylpyridine-2-carboxylic acld glycylamide Exampl~ 80 to 91 were propared ln accordanco wlth the procesc-s de~crib~d in Schemes 1, 2 and 3 Example 80 5-Carboxy-3-methoxypyridlne-2-carboxyllc acld glycyl-amlde 270 mg of tho tltle compound ~rom Example 81 wer-hydrolyzod at 20C uslng 50 ml of lN methanollo NaO~
After 30 minute~, the mlxture was concentrated ln vacuo and tho resldue wae dl~solved in 50 ml of water; thl~
~olutlon was oxtracted with dlethyl ethor and tho aguoous ;
phase wa~ ad~u~ted to p~ 1 wlth conc~ agueou~ hydro- ;~
chloric acid and thon concentrated ln vacuo; tho wator was removed azeotropioally from the resldue u~lng ethyl 213~866 acetate and the ros~due wa~ then troated with othanol and thi~ mixture wa~ concentrated; the r~iduo was cry~tal-lized u~ing d~ethyl othor. 230 mg ware obtainod of the titlo compound, m.p. 173C (with gas evolution, sintering at 170C), whlch, according to the lH NMR sp-ctrum, ~till contain~ approximatoly 20 ~ of an impurity.
.
The title compound wa~ al~o obtained by hydrolyzing 0.45 g of 5-((-1-butyloxy)carbonyl)-3-methoxypyridin--2-carboxylic acid N-(((1-butyloxy)carbonyl)me~hyl)amido, m.p. 80-81C (from petroloum ether~, using 50 ml of 1.5 N ~;~
methanolic NaO~. 0.23 g was obtainod of tho titlo com-pound, m.p. 198-200~ (from an othanolic pha~o w~o~o re~idue, following concontration, wa~ crystallizod ucing diethyl ethor). According to tho '~ NMR ~poctrum and MS, the aub~tance contain~ approximately 5-10 % of it~ othyl e~tor.
The isomeric 2-carboxy-3-methoxypyridine-5-carboxylic acid glycylamido wa~ obtalned in an nnalogou~ mann-r, m.p. from 65C (~intering from 45C, with foaming, from 20 diethyl othor, ~ygroscopic). -'' ; ': ~ :: :
Examplo 81 ~ ~ `
5-M-thoxycarbonyl-3-methoxypyridine-2-carboxylic acid ;~
glycylamid~
a) 5-Nethoxycarbonylpyridine-2-cnrboxylic acld l-ox~de 12 g (60 mmol) of dimothyl pyridine-2,5-dicarboxylato woro ~uspsnded in 30 ml of glacial acotic acid, and aft-r -~ ;
that 13 ml of hydrogen peroxid- ~35 %) wer- added at 20C
and whil- ctirring. Tho mixture wa~ than hoat-d to 100C
(intornal temp-rature), whilo ~tirring, with a clear solution boing for~od at 50C. Aftor the mixturo had b-en ~tirred at 100C for g0 minut-s, it wae allowed to cool down to 20C and the cry~talline precipitate was filt~r-d off w$th ~uction and wa~hed with wator; After drying, 7.5 g of product wero obtained, m.p. 160C (decomp.).
. .
, . ,::
213~866 b) Dimethyl 3-chloropyridin~-2,5-dicarboxylate 17 ml of thionyl chlorido, 35 ~1 of anhydrous chloroform and 1 5 ml of N,N-dim-thylformamide wore hoated to 60C, whilo stirring, and 7 5 g of tho above product w~ro then added in portions at thi~ tomperatur~ The mixturo was thon stirred at 60C for a further 60 minuto~, and, after cooling, tho solvent and exeo88 rsagsnt were di~tllled off in vacuo; dichloromethano wa~ added to the re~ldue, and the N,N-dimethylform~m~de x ~Cl complex wns filtor-d off with ~uetion and wa~hed w$th dichloromethuno Approximately 15 ml of triethylamin- and 10 ml of methanol wore addod, whil- ¢ooling, to the mothor liguor and the mixturo was stirrod for 30 minute~ After eoneon-trating by evaporation in vacuo, tho residuo was dia-solvod ~n 50 ml of wator and this mixture wAs thenextracted 3 x with dichloromethane; th- organie phase was dried and concentr~tod, and tho rssidue wa~ chr o to-graphed on silica g-l u~ing n-heptano and n-heptane ethyl acetate ~3 1) 5 3 g of product were crystallizsd, using potroleum ether, from appropriato fractlon~, m~p 36 to c) 3-Mothoxypyridln--2,5-dlcarboxylic acid 53 g (0 231 mol) of tho abovo dloster wore di~solved in 500 ml of metha~ol, and after that 150 ml (0 81 1) of eodlum methoxide solutlon (30 % ln mothanol) were added, at 20C and whilo ~tirring, whereupon tho temporaturo roeo to 30C The mixturo was heatod undor r-flux for 4 5 houre, 300 ml of wator wer~ add-d at 20C, and tho mlxturo was thon ~tirrod at 35C for 30 minutes The oxces~ mothanol w~s distillod off ln vacuo and the aquoous phase was ad~u~ted to p~ 2, while eooling, with half-concentrated aqueous hydrochloric ac~ds the color-le88 crystalline product wa~ filtered off with euctlon and dried 49 g were obtalned, m p 185C (gas vo-lution); 2S5C (decomp ) ~ .
',,.,,, , ., ,/" ,,",."~.. ... ..... .... ...
213~866 .
d~ Dimothyl 3-methoxypyr~dino-2,5-dicarboxylato, cf.
Exa~ple 90a) o) S-Mothoxycarbonyl-3-msthoxypyrldin--2-carboxylic ~cid -.
The compound was obtain-d, as a mixture with tho ~someric monomethyl sster (Gf. Examplo 90a)), fro~ 3.4 g (15 ol) of the above dia~ter by hydroly~i~ with a d~lute olutio~
of methanolic sodium hydroxide (0.54 g of NaOH (13.5 mmol)). 1.8 g of monoo~ter m~xture, m.p. 152C, w~r-obtatned in addltion to 0.8 g of unreaoted die~t-r.
::, .~, ;.:~.., f) 5-Methoxycarbonyl-3-methoxypyridlne-2-carboxylic acid (glycyl benzyl ester) amido ;~
1.8 g of tho above mixturo wore cond~nsod, in analogy with Examplo 90b), wlth 2.9 g (8.6 mmol) of glyclne benzyl eeter tosylat- in tho pre~once of N--thylmor-pholine, l-hydroxy-l~-bonzotriazole and CMC. A~tor working up, 2.3 g of oily mixture wore chromatogra~hed on ~ilica gel u~ing dichloromothane ~in the pres-nco of ~p to 2 % methanol). 0.82 g of product wa~ obt~lnod, m.p.
108C. 0.6 g of th- olly l~omor was al~o lsolatod.
g) The tltle compound wa~ obtained by di~solvlng 65Q mg of tho above benzyl ~ster ln 100 ml of totrahydrofuran/
methanol (1:1) and hydrogenatlng it u~ing Pd/C ~n a hydrogenation vessel. Onco the cataly~t had b~en filtorod off wlth ~uctlo~, the filtrato was concontrated and tho reslduo was cry~tallizod u~lng diothyl othor. 380 mg woro obtal~ed of a colorles~ crystalllne product, m.p. 158 to 160C. ;;
Ex~mple 82 5-(3-Pentyloxy)carbonyl-3-methoxypyrldine-2-carboxyllc acld glycylamlde ;~;
.~ . ., ~.Z~,`.
, . . ,:.,,: , .. . .... .
Example 83 5-Cyclohexyloxycarbonyl-3-methoxypyridino-2-carboxyllc acid glycyl~mide Examplo 84 5-(n-Butylam$nocarbonyl)-3-methoxypyridino-2-carboxylic acid glycylamide Example 85 -5-(2-Msthyl-2-butylaminocarbonyl)-3-methoxypyrid~ne-2-carboxylic acid glycylamide 10 Example 86 - ;~
5-(Cyclohexylaminocarbonyl)-3-methoxypyridine-2-car- , -~
boxylic acid glycylamide a) 5-(Cyclohexylaminocarbonyl)-3-methoxypyridine-2-car-boxylic acid Tho product was obtained, ln analogy with Ex mple 90b), from 5-carboxy-3-m-thoxypyridin--2-carboxylic acid and cyclohexylamine, m.p. 155C (sintering at 80C, from aqu-ouc hydrochloric acid).
:..~ . :: .. :.. 0 b) 5-~Cyclohexylaminocarbonyl)-3-methoxypyrldino-2-carboxyllc acld ~glycyl ethyl e~ter) amlde The product wa~ obtaln-d, ln analogy with Example 90c), from th- above compound, m.p. 187 to 188C (from dl-thyl eth~r) c) The colorle~ crystalllne title compound wa~
obtalned by hydrolyzlng the abovo compound ln analogy wlth Example 90c), m.p. 110C (wlth foamlng, a desp-blac~ coloratlon at 240C).
Examplo 87 5-(Cyclohexylaminocarbonyl)-3-ethyloxypyridin--2-car-boxylic acid glycylamido - :, .,~; , ' . . ~: ~ .., 213~866 Exampl~ 88 5-((2-Phonylothyl)aminocarbonyl)-3-mothoxypyridine-2~
carboxylic acid glycylamido --Examplo 89 5~ )-Dehydroabietylaminoearbonyl)-3-methoxypyrldine-2-carboxylic acid glycyl~mide a) 5-(~)-Dohydroabi~tylamlnocarbonyl)-3-methoxy- ;- ~;
pyridine-2-carboxyllc acid The resinou~ product wa~ obta~nod, in analogy with Examplo 90n), fro~ 5-carboxy-3-mothoxypyridin--2-oar-boxylic ~cid and ~I)-dehydroabiotyl~mine.
b) 5-((+)-Dehydroabi-tylaminocarbonyl)-3-mothoxy-pyridino-2-carboxyllc acld (glycyl thyl e~ter) amide The product WaB obtained in analogy with Exa~ple 90c), from the above compound, m.p. from 150C with foaming, ~intering at 120C, from di-thyl ethor).
c) Tho tltlo compound wa~ obtalnod by h~drolyzin~ th-above compound ln analogy wlth ~xampl- 90 d), m.p. 215C (sintoring at 150C, from aquoous hydrochloric acld).
" ~"r~
Example 90 5-((2-(4-Fluoroph-nyl)othyl)aminocarbonyl)-3-methoxy- ; ~ ;~
pyrldine-2-carboxylic acid glycyl~mid-a) Mothyl 5-carboxy-3-mothoxypyridin--2-carboxylate 10 g (50.7 ~mol) of the 3-mothoxypyridine-2,5-dicar-boxyllc acid (Example 81c) were ~uspended ln 150 ml of ;
anhydrou~ m-thanol, and after that 2 ml of concentrat-d ~ulfurlc acid wer- add-d and the mlxture was heatod under reflux for 3 hour~. Half of tho methanol was then di~tilled off in vacuo and the residue was lntroduced ~;
, ~ , . .;: ,:
213486~
into 400 ml of ic8 water; the cry~talline re~idue wa~
filtered off with suction and wa~hed w~th water; the residue wao dissolvod in 150 ml of a ~aturatod, aqueous ~olution of Na bicarbonate and this mixtur~ was extracted twice with 80 ml of dichloromethane on each occa~ion; the bicarbonate phaso was adju~ted to p~ 1, while cooling, with half-concentrated aqueous hydrochloric acid and the precipitat0d product was flltered o~f with ouction and driod. 5 g of colorl-ss, crystalline ~ub~tance wore obtained, m.p. 196 to 197C. 1.7 g of dimethyl e~ter, m.p. 53 to 55C (from petrol-um sther), wero obtainod from the dichloromethane phaoo.
b) 5-(((2-(4-Fluorophonyl)othyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic ~cid 3.2 g of methyl 5-carboxy-3-methoxypyridine-2-oarboxylate were eu~pend~d in 300 ml of anhydrous dichloromethano, and after that 2.0 ml (15 ~mol) of 2-(4-fluorophenyl)-ethylamine, 1.95 ml (15 mmol) of N-ethylmorphollne, 2.2 g (16.5 m~ol) of 1-hydroxy-1~-benzotriazole and 6.35 g (15 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodi-imide methyl-p-tolueneoulfonato (CMC) were added sequen-tially, at 20C and whilo otirring, and the mixture wao otlrrod for 24 hours. Ths undis~olvod matorial wa~ then filterod off and tho organic pha~e was extracted, in each ca~e 3 x, with an aqueou~ solution of Na ~icarbonate, with lN aqueous hydrochloric acid and w$th water, and the organic pha~e was dried and concentrated. 3.7 g were obtainod of methyl oster, m.p. 168 to 169C, which was introduoed into 150 ml of 1.5N methanolic NaO~. After 30 minuteo, tho mlxture was concontratod and d~ssolved in 100 ml of wator, and this mlxture wa~ adjustod to p~ 1 with ~onc. aqueouo hydrochloric acid; the crystalline precipitato was filterod off with suction, washed with water and dried. 3.4 g of product wero obtained, m.p.
110C (with foaming, ~intering at 75~
213~86~
c) 5-(((2-(4-Fluorophenyl)othyl)amino)carbonyl)-3-mothoxypyridine-2-carboxylic ncid (glycyl ~thyl eeter) amide In analogy with Exa~ple 90a), 3.2 g (10 mmol) of the above compound wero reactod with 1.4 g (10 m~ol) of glycine othyl eeter hydrochloride, N-othylmorpholine, 1-hydroxy-lH-benzotrlAzole and CMC. Following analogous working up, 2.8 g of the colorless cryetallin~ product were cryatallized using diisopropyl othsr, m.p. 170 to 171C.
d) The titlo compound wae obtained by hydrolyeing 1.0 g of the above glycine othyl estor, at 20C, ln 1.5N
methanolic NaOH. 0.95 g of product, m.p. 206C (with foaming) crystallizoe from aqueoue medium at p~ 3.
Example 91 5-((2-(4-Methoxyphenyl)othyl)aminocarbonyl)-3-ethyloxy-pyridine-2-carboxylic acid glycylamide .
Examples 92 to 105 were obtained from the corre~pondingly eubst~tuted pyridine-2-carboxylic acid derivativee of the formula II and glycine ethyl e~tor hydrochloride and with ~ubeequent hydrolyeis of the glycine othyl ester com-pound-.
Example 92 5-Chloro-3-othyloxypyridine-2-carboxyl~c acid glycyl-25 amldo ~;
.: .: . ;: ' ~`Example 93 5-Chloro-3-mothyloxypyridino-2-carboxylic acid glycyl-amido Example 94 30 5-Cyclohoxyloxymothyl-3-methoxypyridine-2-carboxylic acid -~
glycylamide ' ' ' ' 213~86~
Example 95 5-(3-Methylbutyl)oxymothyl-3-m~thoxypyridlno-2-carboxyllc acid glycylamido Example 96 5-Benzyloxymethyl-3-ethyloxypyrtd$ne-2-carboxylic aoid glycylamide Example 97 .
3-((Cyclohoxyl)mothyloxy)pyrid~ne-2-carboxylic acid glycylamido ~ :. ;.
:
Example 98 3-((2-Cyclohexyl)othyloxy)pyridine-2-carboxylic acid glycylamide ~-~
Example 99 3-((3-Cyclohexyl)propyloxy)pyridino-2-cnrboxylic acid glycylamide Example 100 3-(3-Methylbutyloxy)pyridino-2-carboxylic ac~d glycyl-amido Example 101 3-~exyloxypyrldine-2-carboxylic acid glycylamide Example 102 3-(4-Ethylbonzyloxy)pyridine-2-carboxylic acid glycyl- . :
amid~
,:
Example 103 3-(4-Propylbonzyloxy~pyridine-2-ca~boxylic acid glycyl-amide ~, '' ', Example 104 3-(4-~utylbenzyloxy)pyridine-2-carboxylic acid glycyl-amide ; ..
213~866 Example 105 3-(4-tert-Butylbonzyloxy)pyridine-2-carboxyl~c ac~d glycylamide Examplee 106 to 188 wore prepared in ~alogy with Examplee 80 to 91.
Example 106 5-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridine-2-carboxylic acid glycyl~mide a) 3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic acid In analogy with Example 81c), 3.5 g (146 mmol) of sodium wero di~solved in 350 ml of 2-methyl-1-propanol (i80-butyl alcohol), and a~ter that 13.7 g (55 mmol) of 3-chloropyridine-2-carboxylic acid ~thyl eet~r 5-carbox-ylic acid methyl ostor (pr~pared in analogy with kxample81b)) wore addod at 20C and while stirsing. The mixturo was thon etirred at 80C for 90 minute~ and, aft~r cooling, concentrat~d in ~acuo; tho reeiduo wae takon up in 200 ml of 1 N methanolic NaOH and this mixturo wae stirred at 20C. Aftor 15 minutes, tho eolution bocamo cloudy. Water wae added untll a clear solution wae obtainod and thie wae etirrod for 1 hour and thon concen-trated in vacuo; the aqueoue eolution wae acldifiod with agueous hydrochloric acid and tho cry~tallino product was $iltered off with euction, waahed and dri~d, and 10.6 g , of dicarboxylic acid were obtained, m.p. 192C (decomp.).
b) Dimethyl 3-(2-met~yl-1-propylo~y)pyrld~n~-2,5-dicar-boxylate The oily product wae obtained from the abovo dicarboxylic acid undor eeterification conditions (methanol/sulfuric acid) and after working up (washing w~th water and extracting with ethyl acetate). ~; -. , ,, :
~,""i,.. '~,fi ,~ "", ,,,,,"
213~66 c) S-Methoxycarbonyl-3-(2-methyl-1-propyloxy)pyridino-2-carboxylic acid (glycyl banzyl oeter) anido 0.48 g (12 mmol) of NaO~, diseol~od in 50 ml of methanol, wae added to 3.2 g (12 mmol) of the abovo dioeter ~n 25 ml of mothanol, and tho mixturo wae etirred at 65C
for 90 minutee. The mixture was thon acldifi-d, whilo being coolod, with diluto agueoue hydrochloric acid and froed from methanol in vacuo. 2.5 g (10 mmol) of tho monoester mixture thus obtainod woro ~tirrod, ln analogy with Examplo 90b), in 250 ~1 of dlchloro~e~hano, ~t 20C
for 24 hour~, together with 3.4 g (10 ~m~l) of glyc~ne benzyl e~ter toeylate, 1.4 g (lO ,,ol) of l-hydroxy-(l~)-benzotriazole, 2.6 ml ~20 mmol) of N-sthylmorpholine and 4.3 g (10 mmol) of CMC.
The undieeol~ed materlal was thon iltered off with euction and tho filtrate was extracted with an agueous solution of Na bicarbonate, with diluto hydroahloric acid and with water; the organic phaee was drlod and concen-tratsd and tho residue was chromatographod on eilica gal uslng n-heptane/ethyl acetate (1:1). 0.8 g of aolorlese product wae obtained from appropriate fra¢tiono, m.p. 103 to 105C. 1.1 g of the ieomeric roeinoue product were al~o obtained.
d) Tho titlo compound wae obtained by dieeolving 0.7 g of the above compound in 100 ml of totrahydrofuran/
mothanol (lsl) and hydrogenating it for 2 hour~ ueing Pd on charcoal (10 %) in a hydrogenation ~oeeol. Tho cata-lyet wae then filtor~d off with euction and the flltrate : : . .
wae concentrated; tho reeidue wae cryetallized using diieopropylether and 0.45 g wae obtainod of the titlo compound, j~
m.p. approximatoly 70C (with foaming).
Tho isomeric compound wae obtainod in an analogoue ;~
manner, m.p. approximately 60C (with foaming, from diieopropyl ether).
'., '':" -,,'' ~-~ ''' `'`'' Example 107 5-Ethoxycarbonyl-3-(2-mothyl-1-propyloxy)pyrid~ 2-carboxylic acid glycylamido Examplo 108 5 5-Mothoxycarbonyl-3-(3-mothyl-1-butyloxy)pyridino-2-carboxylic acid glycylamido Examplo 109 5-Ethoxycarbonyl-3-ethoxypyridine-2-carboxyllc ~eid glycylamide 10 Example 110 5-Ethoxycarbonyl-3-(1-propyloxy)pyridino-2-carboxyl~c acid glyeylamido : ~:
Examplo 111 -5-Ethoxycarbollyl-3-(2-propyloxy)pyridlne-2-carboxyl$c :~
15 acid glycylamido Example 112 ~.:
3-Benzyloxy-5-othoxycarbonylpyridine-2-carboxylle acid ~ ~ :
glycylamido Example 113 20 3- (4-Chlorob~nzyloxy) -5-ethoxycarbonylpyridine-2-earboxylie aeid glycylamido Examplo 114 5-E thoxyearbonyl-3- (4-fluorobenzyloxy) pyridine-2- -: :
earboxylie acid glycylamido .
25 Examplo 115 5-Ethoxyearbonyl-3- (4- (tr~ fluoromethyl) - :~
benzyloxy)pyridino-2-carboxylic aeid glycylamldo ;
Examplo 116 . .
5-Ethoxyearbonyl-3- (4- (trifluoromethoxy)be~zyloxy) - -~: :
pyridino-2-carboxylic acid glycyl~ide ~-''''"
Example 117 5-Ethoxycarbonyl-3-(4-(2-propyl~benzyloxy)pyridino-2-carboxylic acid glycylamide Example 118 3-(4-Ethoxybenzyloxy)-5-ethoxycarbonylpyridine-2-car-boxylic acid glycyla~ide Example 119 5-~thoxycarbonyl-3-(3,4-dimethoxybenzyloxy)pyridi~-2-carboxylic ac$d glycylamide Exa~ple 120 5-Ethoxycarbonyl-3-(2-(4-fluorophenyl)ethyloxy)pyridine-2-carboxylic acid glycyl~mide Example 121 ~ ~;
5-Ethoxycarbonyl-3-(2,2,2-trifluoroothyloxy)pyridine-2-carboxylic acid glycylamide Example 122 -3-Cyclohexyloxy-5-ethoxycarbonylpyridine-2-carboxylic acid glycylamide ::
Example 123 5-Ethoxycarbonyl-3-(naphthyl-2-methyloxy)pyridine-2-carboxylic ~cid glycylamido Exampls 124 .;
5-Ethoxycarbonyl-3-(naphthyl-1-mothyloxy)pyridine-2-carboxylic acid glycylamide Example 125 5-Carboxy-3-(2-methyl-1-propyloxy)pyridine-2-carboxylic acid glycylamide The title compound wa~ obtained by hydrolyzing 0.3 g of -:
th~ title compound from Example 106, at 20~, in 50 ml of a lN methanolic solution of ~odium hydroxide. After 1 hour, the ~ixture was concentrated in ~acuo and ~ -~
:
2131~66 "
extracted with diethyl other; the agueous pha~o wae acidified, while bei~g coolod, with agueous hydroohlorlc acid; the aqueou~ phass was concentrated and then fre~d from water azeotropically using ethyl acetato and the residuo was treatod with acetone; the solution W~8 concentrated and the residue was ery~talliz~d uoing petroleum ethsr. 0.27 g of product was obtained, m.p.
80C (with foaming).
Exampla 126 5-Carboxy-3-(3-methyl-1-butyloxy)pyridine-2-earboxylic acid glycylamide Example 127 5-Carboxy-3-ethoxypyridine-2-carboxylic aeid glycylamide ~ -Example 128 ;;~
5-Carboxy-3-propyloxypyridine-2-earboxylic acid glyeyl-amide `~
Example 129 ; -5-Carboxy-3-(2-propyloxy)pyridine-2-earboxylie acid glycylamide Examplo 130 3-Bonzyloxy-5-carboxypyridine-2-carboxylie aeid glyeyl-amide . :.~ '.
Example 131 ; -5-Carboxy-3-(4-ehlorobenzyloxy)-2-carboxylicacidglycyl-25 amide ;
Example 132 5-Car~oxy-3-(4-fluorobenzyloxy)pyridine-2-carboxylie ac~d glyeylamide Example 133 5-Carboxy-3-((4-trifluoromethyl)benzyloxy)pyridino-2-carboxylie acid glyeylamide 213~8~6 :
' Bxample 134 :-~ 5^Carboxy-3-((4-trifluoromethoxy)banzyloxy)pyrldlne-2-' carboxylic acid glycylamide ,~i 1 Examplq 135 -1 5 5-Carbo~y-3-(4-(2-propyl)benzy~loxy)pyridi~-2-carboxylic ;~ acid glycylamide ~xample 136 :-5-Car~oxy-3-(4-ethoxybenzyloxy)pyridine-2-carboxyllc acid `~
glycylamids :~
:: :
Example 137 5-Carboxy-3-(3,4-dimethoxybanzyloxy)pyridine-2-carboxylic E ;~
acid glycylamide Example 138 ~`
~ . 5-Carboxy-3-(2-(4-fluorophe~yl)sthyloxy) pyr~dine-2- :~
: 15 carboxylic acid glycylamide ~. -~ ' '. ~ ' '~, ~xample 139 5-Carboxy-3-(2,2,2-trifluoroethyloxy)pysidi~e-2-: ~' carboxylic acid gylcylamlde : ' '~
Example 140 20 5-Carboxy-3-cyclohexyloxypyridine-2-carboxylic a~ld ~` ;
glycylamide ~, . .
~x~mple 141 5-Carboxy-3-(naphthyll2-~ethyloxy)pyridine-2-carboxylic acid glycylamide Example 142 S-Carboxy-3-(naphthyl-~-methyloxy)pyridin2-2-carboxylic acid glycyl~mide Example 143 5-(3-Pentyloxy)carbonyl-3-(2-m~thyl-1-propyloxy)pyridine~
2-carboxylic acid glycylamid~
. :
;~ .
21~866 Example 144 5-(3-Pentyloxy)carbonyl-3-(3-me~hyl-1-butyloxy)pyridlne-2-carboxylic aeid glycylamide Example 145 3-Ethoxypyridine-5-(3-pentyloxy)earbonyl-2-e~rboxylic acid glyeylamide --Example 146 5-(3-Psntyloxy)earbonyl-3-propyloxypyridine-2-earboxylie acid glyeylamide Example 147 5-(3-Pentyloxy)carbonyl-3-(2-propyloxy)pyridine-2- :
carboxylie acid glycylamide Example 148 3-~enzyloxy-5-(3-pentyloxy)earbonylpyridino-2-carboxylie acid glyeylamide Example 149 3-(4-Chlorobenzyloxy)-5-(3-pentyloxy)earbonylpyridine-2- -carboxylie acid glycylamide , ~
Example 150 :
3-(4-Fluorobenzyloxy)-5-(3-pentyloxy)carbonylpyridine-2-earboxylie acid glycylamlde Example 151 5-(3-Pentyloxy)earbonyl-3-((4-trifluorclmethyl)benzyloxy)-pyridine-2-earboxylic acid glycylamide Example 152 5-(3-Pentyloxy)carbonyl-3-((4-trifluoromethoxy)benzyl-oxy)pyridine-2-earboxylie aeicl glyeylamid~
Example 153 5-(3-Pentyloxy)earbonyl-3-(4-(2-propyl)benzyloxy)-pyridine-2-earboxylic aeid glycylamide ~; ~
213~866 Example 154 3-(4-Ethoxybsnzyloxy)-5-(3-pontyloxy)earbo~ylpyridino-2- ~ -carboxylie acid glyeylamido Examplo lS5 S 3-(3,4-Dimethoxybenzyloxy)-5-(3-pentyloxy)carbonyl-pyridino-2-carboxylic acid glycyla~ido Example 156 3-(2-(4-Fluorophenyl)-thyloxy)-5-(3-p~ntyloxy)carbo~yl-pyrldine-2-carboxylic aeid glyeylamide Exæmplo 157 5-(3-Pentyloxy)earbonyl-3-(2,2,2-trifluoroothyloxy)-pyrldino-2-earboxylle aeld glyeylamido ~ -Examplo 158 3-Cyelohoxyloxy-5-(3-pentyloxy)earbonylpyridine-2-15 earboxylie aeid glyeylamide ;~
Exa~ple 159 3-(Naphthyl-2-m-thyloxy)-5-(3-pontyloxy)earbonylpyr~dino-2-earboxylle aeid glyeylamido Exampl- 160 3-(Naphthyl-1-m-thyloxy)-5-(3-pentyloxy)carbonylpyrldine-2-earboxylie aeid glycylamido Example 161 5-(4-~optyloxy)earbonyl-3-(2-methyl-1-propyloxy)pyridino-, 2-earboxyllc aeld glycylfimldo Examplo 162 5-(4-Hoptyloxy)carbonyl-3-othoxypyridine-2-earboxylic `~
acid glycyla~ide Example 163 3-Benzyloxy-5-(4-heptyloxy)carbonylpyridino-2-carboxylie 30 aeid glyoylamido ;-~, ..
.
2134~66 Example 164 3-(4-Chlorobenzyloxy)-5-(4-heptyloxy)carbonylpyridi~-2-carboxylic ac~d glycylamide Examplo 165 3-(4-Fluorobenzyloxy)-5-(4-heptyloxy)pyrid~ne-2-carboxylic acid glycylamide Example 166 5-(4-Heptyloxy)carbonyl-3-(4-(2-propyl)be~zyloxy)-pyridine-2-carboxyliG acid glycylamido Examplo 167 3-(2-Methyl-1-propyloxy)-5-(5-nonyloxy)carbonylpyridine- - -2-carboxylic acid glycyl~m$de . .
Example 168 ~ , 3-Benzyloxy-5-(5-nonyloxy)carbonyl)pyridino-2-carboxylic ac~d glycylamide :, Example 169 3-(4-Fluorobenzyloxy)-5-(5-nonyloxy)carbonylpyr~dine-2- . ~:
carboxylic acid glycylamide Example 170 5-(5-Nonyloxy)carbonyl-3-(4-(2-propyl)benzyloxy)pyridi~e-2-carboxylic acid glycylamide Example 171 5-Geranyloxycarbonyl-3-othoxypyridine-2-aarboxylic acid glycylamido 25 Ex~mplo 172 -3-Benzyloxy-5-(geranyloxycarbonyl)pyridin~-2-carboxylic : ;~:
acid glycylamide ~: :
Examplo 173 3-(4-Chlorobenzyloxy)-5-(geranyloxycarbonyl)pyridi~e-2-carboxylic acid glycylamide . ' ~' .
,: ''' ~`~ <:
21~866 Example 174 3-(4-Fluorobenzyloxy)-5-(goranyloxyc~rbonyl)pyrid$ne-2-carboxylic acid glycylamide Example 175 5-Geranyloxycarbonyl-3-(2-propyloxy)pyrid$ne-2-carboxylic acid glycylamlde Example 176 5-Farnosyloxycarbonyl-3-(2-propyloxy)pyr$din~-2-car-boxylic acid glycylamide 10 Example 177 -~
3-Bonzyloxy-5-(farne~yloxycarbonyl)pyridine-2-carboxylic acld glycylamlde ~ :~
Example 178 ::
5-Farnesyloxycarbonyl-3-(4-fluorobenzyloxy)pyr$dlno-2- ~;
carboxylic acid glycylamide Example 179 . ~ :
5-Farn-~yloxycarbonyl-3-othoxypyridine-2-carboxylic acid glycylamide Examplo 180 3-Methoxy-5-(retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide ~., .
Example 181 3-Ethoxy-5-(rotinyloxycarbonyl)pyridine-2-carboxylic acid glycylamlde Example 182 3-(2-Propyloxy)-5-(ret~nyloxycarbonyl)pyrldine-2-carboxylic acid glycylamide . . ~
213~86G
- 8~ -Example 183 3-Benzyloxy-5-(retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 184 3-(4-Fluorobenzyloxy)-5-(retinyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 185 3-(3-Methoxybenzyloxy)-5-(ret~nyloxycarbonyl)pyridine-2-carboxylic acid glycylamide Example 186 5-Benzyloxycarbonyl-3-(4-(2-propyloxy)benzyloxy)pyridine-2-carboxyllc acid glycylamide .
Example 187 -: ;
5-Benzyloxycarbonyl-3-(4-fluorobenzyloxy)pyridine-2-car-boxylic acid glycylamide Example 188 5-Butyloxycarbonyl-3-benzyloxypyridine-2-carboxyllc acid glycylamide Example 189 5-(((4-Ethoxyphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid glycylamid~, analogouely to Exa~ple 191 Example 190 5-(((4-Ethoxyphenyl)amino)carbonyl)-3-benzyloxypyridine-2-carboxylic acid glycylamide ~xamplo 191 5-(((4-(1-Butyloxy)phonyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid glycylamide ~ :
a) Methyl 5-(((4-(1-butyloxy)phenyl)amino)carbonyl)-3- . .
methoxypyridine-2-carboxylat~
' : ' 213486~
- so -3.2 g (15 mmol) of methyl S-carboxy-3-methoxypyrid~ne-2-carboxylate (cf. Example 90a)) were reacted, ln nnalogy with Example 90b), with 2.5 g (15 mmol) of 4-n-butoxy-anillne and the reagents do~cribed in that example. 3.9 g of product were crystallized using diethyl ~th~r (m.p.
138 to 141C.
~ .
b) 5-(((4-(1-Butyloxy)phenyl)amino)car~o~yl)-3-methoxy-pyridino-2-carboxylic ac$d ~-~
3.2 g of the above e~ter were hydrolyzed at 20C ucing 100 ml of 1.5 N mathanolic aodium hydroxide oolution.
2.7 g of product were obta~ned from agueous hydrochloric acid, m.p. 128 to 130C, sintering from 120C.
c) 5-(((4-(1-Butyloxy)phenyl)amino)c rbonyl)-3-~othoxy-pyridine-2-carboxylic acid N-~(ethoxyc~rbonyl)-methyl) am~de 2.7 g (7.8 mmol) of the a~ovo pyridine-2-carboxylic acid were stirred in 500 ml of anhydroue dichloromethano, at 20C for 24 h, togather with 1.1 g (7.8 mmol) of glycine ethyl oster hydrochlorido, 3.0 ml (23.4 ~^1) of N-ethylmorpholine, 1.2 g (8.6 m~ol) of 1-hydroxy-1~-bonzo-trlazolQ and 3.3 g (7.8 mmol) of CMC.
Tho undissolved material was then filtored off and tho organic pha~e was extracted ~equentially with 200 ml each of water, aquoous Na bicarbonato ~olution, lN aqueous hydrochloric acid and water, dried over Mg sulfate and concentrated in vacuo; the residue wa~ cry~tallized ueing diethyl ethor. 2.4 g of product were obtained, m.p. 193-195C.
d) The titlo compound was obtained by hydrolyzing 1.0 g of the above glycine oster, at 20C, in 100 ml of a 1.5 N
methanolic solution of sodium hydroxide. After 30 m~n, the mixturo wa~ concontrate~ in vacuo ~nd the roEidue wa~
diesolved i~ water; this solution was oxtracted with 2~3~86~
:'``
diethyl ether and the aqueous solut~on ad~u~tod to p~ 3 u~ing agueous hydrochloric ~cid. When tke ~olution wa~
cooled with ice, 390 mg of the title compound crystal-lized, m.p. 230C, sinterlng at 193C.
5 Example 192 .
5-(((4-(1-Butyloxy)phenyl)amino)carbonyl)-3-(4-fluoro-benzyloxy)pyridine-2-c~rboxyllc acid glycylamide Example 193 5-(((4-(1-Butyloxy)ph~nyl)amlno)carbonyl)-3-b~nzyloxy-pyridine-3-carboxylic acid glycylamide Example 194 3-(2-Methyl-1-propyloxy)pyridine-2,5-dicarboxylic acid diglycylæmide N.p. 103-105C (from 0thyl acetate) Example 195 5-(Di-N,N-ethylaminocarbonyl)-3-~thoxypyridin~-2-car-boxylic acid glycylamide, amorphou3 ~ub~tance, prepared-~ ~ :
in analogy with Ex~ple 223 u~ing N,N-di~thylamino.
Example 196 5-(N-Bonzyl-N-methylamlnocarbonyl)-3-methoxypyridine-2-carboxylic acld glycylamlde Ex~mple 197 5-Farne~yloxyc~rbo~yl-3-mothoxypyridine-2-carboxylic acid -:
glycylamide Example 198 5-Geranyloxycarbonyl-3-methoxypyrldin~-2-carboxylic acid ::
glycylamide -~
.
Example 199 5-(Farnesyloxymethyl)-3-methoxypyridins-2-cArboxylic acid glycylamide 213 ~866 Example 200 5-(Geranyloxymethyl)-3-methoxypyridille-2-carboxyl~c acid glycylamide Example 201 5 5-Retinyloxymethyl-3-methoxypyridine-2-carboxylic acid glycylamide Example 202 5-Retinyloxymethyl-3-ethyloxypyridi~e-2-carboxylic ac:id glycylamide 10 Example 203 N-(Carboxymethyl)-4-methoxycinnoline-3-carboxamide Examples 204 to 209 were prepared in ~nalogy with Example 191: ~ -Example 204 15 5- (((4-(1-Hexyloxy)phenyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-(carboxy~ethyl)am$de a) Methyl 5-(((4-(1-hexyloxy)phenyl)amino)car}~onyl)-3-methoxy-2-carboxylate was E~repared from methyl 5-carboxy-3-mqthoxypyridine-2-carboxylate and 4-hexyl-oxyaniline, m.p. 118-119C (from diethyl ether). ;~-b) 5-(((4-(1-Hexyloxy)phenyl)~mino)carbonyl)-3-methoxy- ;
pyridine-2-carboxylic acid, 160-162C, ~intering at 148C (from aqueouc hydrochloric acid/tetrahydrofuran) c) 5-(((4-(l Hexyloxy)phenyl)amino)carbonyl)-3-methoxy-pyridin0-2-carboxylic acid N-((ethoxycarbonyl)-me~thyl)amide was obtain~d, in analogy with Example l91c), from 4.2 g of the above compound. 4.0 g of product were crystallized u~ing ethyl acetate, m.p.
157-159C.
213 186~
:`.
_ 93 _ d) The title compound wa~ obtainsd by hydrolyzing 1.2 g of tho above oster, at 20C, ueing 100 ml of a 1.5N
methanolic solution of codium ~ydroxide. Following concentration ln vacuo, acidi~icatio~ to p~ 1 took place in water/totrahydrofuran u~ing aquoou~ hydro-chloric acid; tho mlxturo was concontrated in v~cuo and the reeidue wa~ cry~tallized ufling acetone. 840 mg of product were obtained, m.p. 193-195C.
Example 205 5-(((4-(1-Decyloxy)phenyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-(carboxy~ethyl)amide Example 206 -5-(((4-(1-Decyl)phenyl)~;no)carbonyl)-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide -'- .
a) 5-(((4-(1-Decyl)phenyl)amino)carbonyl)-3-mothoxy-pyridine-2-carboxylic acid N-((othoxycarbonyl)-methyl)amide was prepared from 5-(((4-n-decyl-phenyl)amino)carbonyl)-3-methoxypyridin~-2-carboxylic acid (m.p. 160C (decomp.); from aqueou~
hydrochlorlc acid/THF) and glycin~ othyl ~ter hydrochloride, m.p. 155-157C (fron dii~opropyl othsr).
~ -: . .
b) The title compound wa~ obtained by hydrolyzing 1.5 g of tho abovo eeter in 200 ml of a 1 N methanolic ~olution of ~odium hydroxido. 1.4 g of product, m.p.
195C ~decomp.), were isolated from aqu~ou~ hydro-chloric acid/t~trahydrofura~.
Examplo 207 5-(((4-~eranyloxyphenyl)amino)carbonyl)-3-mothoxy-pyrldine-2-carboxylic acid N-(carboxymethyl)amide 21318~6 Example 208 5-(((4-(1-Octyloxy)phenyl)am~no~carbonyl)-3-~ethoxy-pyridine-2-carboxylic acid N-(carboxymethyl)a~lde Example 209 5-(((3-(1-Octyloxy)propyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-~car~oxymethyl)umide Example 210 5-((1-Butoxy)mothyl)-3-mothoxypyridi~e-2-carboxylic ac~d N-(carboxymethyl)am~do Example 211 5-((1-Hoxyloxy)methyl)-3-mothoxypyridine-2-Carboxylic acid N-(carboxymethyl)amido Example 212 ~ :
5-((1-Octyloxy)methyl)-3-mothoxypyridine-2-carboxylic 15 acid N-(carboxymethyl)amide ~ ~ :
Examplo 213 -5-((1-~ex-3-onyloxy)methyl)-3-methoxypyridine-2-car-boxylic acid N-(carboxymothyl)amide :p Exa~ple 214 20 5-((1-Docyloxy)methyl)-3-m~thoxypyridine-2-carboxylic : . :
acid N-(carboxymethyl~amide Examplo 215 5-((l-Dodecyloxy)methyl)-3-methoxypyrldine-2-carboxylic :~
acid N-(carboxymothyl)amide -~
25 Example 216 ~:
5-((1-~exadecyloxy)methyl)-3-methoxypyridlne-2-carboxyllc acid N-(carboxymethyl)amide Examplo 217 3-S4-(((+)-Dohydroabietylamino)carbonyl)benzyloxy)pyri-30 di~e-2-carboxylic acid N-(carboxymethyl)amido : :
213~866 ;
a) 4-(((~)-Dehydroabietylamino)oarbonyl)chloromethyl-benzeno was obtained from 4-chloromethylbonzoic acid and (~)-dehydroabiotyl~mine, ~.p. 170-172C (from othyl acetate/hoptano (1:1)).
b) 3-(4-(((~)-Dehydroabiotylamino)carbonyl)benzyloxy)-pyridino-2-carboxylic acid N-((~thyloxycarbonyl)-mothyl)amido, m.p. approximat~ly 80C (a~orphou~
substance, from ethyl aootato).
c) Tho titlo compound was obtained by hydrolyzing the above es10r, m.p. 125C (w~th ~oaming, ~rom dii~o-propyl ether).
Example 218 3-Mothoxyguinoline-2-carboxylic acid N-(oarboxymothyl)-amido a) 2-Acetyl-3-hydroxyquinoline, ~nown from D.W. Bayne et al., J. Chem. Soc. Chem. Comm. 1975, 782 (M.p.
106C from agueouR hydrochloric acid).
.: ',' .
b) 2-Acetyl-3-mothoxyquinolino, from a) ucing pota~sium carbonate/methyl lodido in acotone, oily crude ;~
product.
c) 3-Methoxyguinoline-2-carboxylic acid, from b) u~ing potaa~ium hypochlorite in water/dioxane, m.p. 123C
(from methyl tort-butyl ether).
.
d) 3-Methoxyguinoline-2-carboxylic acid N-((methoxy-carbonyl)methyl)amido, from c) u~ing DCC~ ~OBT, THP, NEM and glyc$ne mothyl o~tor hydrochlorido.
o) Tho title co~pound wa~ obtained by hydrolyzing the above ester, m.p. 106C (from othyl ac~tate).
'' ~' '' ':
213~866 Example 219 5-(((4-(1-Butyloxy)phenyl)amino)carbonyl)-3-chloropyri-dine-2-carboxylic acid N-(carboxyme~hyl)amid~
a) Methyl 5-carboxy-3-chloropyridine-2-csr~oxylate w~s prepared in analogy with Example 90a), m.p. 182-184C (from aqueou~ hydrochloric acid).
.
b) Methyl 5-(((1-butyloxy)phenyl)amino)carbonyl)-3-chloropyridine-2-carboxylate wa~ obtalned from the above ~ompound us~ng oxalyl chloride and 4-(1-butyl-oxy)aniline, m.p. 121-123C (from di~thyl other).
c) 5-(((4-(1-Butyloxy)phenyl)smino)carbonyl)-3-~hloro-pyrldine-2-carboxylic acid by hydrolyzing the product from b), m.p. 163-164C (from agueou~ hydro-chloric acid).
d) 5-(((4-(1-Butyloxy)phenyl)æmino~carbonyl~-3-~hloro-pyridine-2-carboxyli~ acid N-((ethyloxycarbonyl)-methyl)amide waa obtained, in ~nalogy with ~xample 90b), from tho abo~e ~u~tsnce by conden~ation (N-ethylmorpholine, l-hydroxy-lH-benzotrlszole and CMC) with glyclne ethyl ostor hydrochloride, m.p. 177-179C (from othanol).
e) ~he titlo compound was obtainad by hydrolyzi~g the above o~tor, M.p. 190C (with docompo~ition, from aqueou~ hydrochlorlc acid).
Example 220 3-(N-Benzyl-N-methylamino)-5-(((4-(1-butyloxy)phe~yl)-smlno)carbonyl)pyr~dine-2-carboxylic Acid N-(carboxy-methyl)amide 0.5 g (1.23 mmol) of the title compound from Exampl~ 219 wa~ stirred ln 10 ml of N-be~zyl-N-methylamino, firstly at 100-110C for 2 h and then at 130C for a further 2 h.
After the mixture had been cooled down, it was introduced . ~. ...
2~34866 ~nto 100 ml of lN hydrochloric acid ~nd th~ h~lf-crystalline precipitate wa~ taken up in dichloromethane;
the undiseolved mat~rial was filtersd off and the residue was crystallized; 0.2 g of the title compound, m.p. 155-5 157 C .
~xample 221 3-(N-Benzylamino)-5-(((4-(1-butyloxy)phenyl)amino)car-bonyl)pyridine-2-carboxylic acid N-(carboxy~ethyl)A~de -~
0.5 g (1.23 mmol) of the title compound from Example 219 wa~ ~tirred in 10 ml of bon~ylamine, fir~tly at 120C for 2 h and then at 135C for 1.5 h. After the mixture hnd been cooled down, it was acidifiod and the precipitat~d re~in wae dissolved in dichloromethane; thi~ ~olution wa~
dried and conaentrated and the re~idue wa8 chromato-graphed on ~ilica gel us$ng ethyl ac~tate (with the addition o~ up to 20 % methanol). 0.1 g of th~ titl~
compound wa~ cry~tallized from appropriate f~action~
u~ing dii~opropyl other, m.p. 185-190C.
Example 222 :
3-(4-Chlorobenzyloxy)pyridine-2-carboxyllc acid N-(carboxymethyl)amide 1-oxido a) 3-(4-Chlorobenzyloxy)pyridine-2-carboxylic acid N-((ethyloxy)methyl)amide 1-oxide 0.7 g (2 mmol) of the compound from Example 31c) wa~
di~olved in dichloromethane and roacted with 1.41 ~
g of 3-chloroperbenzoic acid. After the mixtura had ~;
been ~tirrod at 20C for 1 h, ammonia wa~ pa~ed in ;
until thero wac no further pr~cipitation; tho procipitats wa~ filtered off and the filtrate waa ~-concontratod and the oily residuo cryctallized ucing diethyl ether, m.p. 70-72C.
b) 0.18 g of the title compound, m.p. 206-208C
213~866 (sintering at 200C, fro~ aqueous hydrochloric acid) was obtained by hydrolyzing 0.3 g of tke above compound.
Example 223 5-(((3-(1-Butyloxy)propyl)P~no)carbonyl)-3-methoxypyri-dine-2-c~rboxylic acid N-(carboxymethyl)amido a) Methyl 5-(((3-(l-butyloxy)propyl) a~ no)carbonyl)-3-methoxypyridine-2-carboxylic acid 1.7 ml of oxalyl chloride (20 mmol), and al80 2 drops of N,N-dimethylformamide, dissolved in tctrahydrofuran, were added dropwiEie, at 10C and whlle itirr~ng, to 2.1 g (10 mmol) of methyl 5-carboxy-3-methoxypyridine-2-car-boxylate in 100 ml of i~nhydrouEi totrahydrofurian and the reaction mixture wa~i ~itirred at 10C for 30 min and at 20C for 1 h. It was then concentrated and the residue was dis~iolved in dichloromethane; 6.8 ~l (50 mmol) of triethyla~ine, and then 1.3 g (1.5 ml, 10 mmol) of 3-butoxypropylamine, diseolved i~ dichloromsthanei, wore added, at 0C, to thi~i siolution.
Aftor 30 min, the mlxture was allowed to warm to room tomperature and waE extracted with water, a Eiolution of Na bicarbonate and aqueouE lN ~Cl; the organic phas~ waEi dried and concentrated and the residue wa~i crystallized u~ing diethyleth~r/petroleium ether (3:1). 2.3 g of product were obtained, m.p. 51-53C.
b) 5-(((3-(1-Butyloxy)propyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxylic acid N-((benzyloxycarbonyl)-methyl)a~ide ~ . . .
The above subEitance was hydrolyz0d by Eitandard pro-c0dures, and 1.5 g (5 mmol) of the amorphous 5-(((3-(1-butyloxy)propyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid, which wa~i dried on an o~l pump, was reacted with glycine benzyl oster toEiylate, ;
.
213~866 N-ethylmorpholine, l-hydroxy-l~-benzotriazole and ~MC (a8 de~cribed). 1.42 g of the product were cry~tallized using acetone, m.p. 97-99C. -c) 1.3 g of the above benzyl e~ter were hydrogenatod in 100 ml of tetrahydro~uran/methanol (1:1) u~$ng Pd/C
(10 %) in a hydrogenation ves~el. 0.8 g of the title compound wae crystallized u~ing diethyl othor, m.p.
155-157C.
Example 224 5-(((3-(1-Lauryloxy)propyl)amino)carbonyl)-3-methoxy-pyridine-2-carboxyllc acid N-(carboxym~thyl)amide a) 5-(((3-Lauryloxypropyl)am$no)c~rbonyl)-3-methoxy- -pyridine-2-carboxyl~c acid N-((benzyloxycarbonyl)-methyl) mide was obtained, i~ analogy with Example 223, u~ing 3-lauryloxypropylamine, m.p. from 109-111C (from diisopropyl ether).
b) 1.3 g of the above benzyl e~ter were hydrogenated aa dQscribed under 223c). 0.9 g of the titlo compound wero obtained from petroloum ether, m.p. from 120C.
20 Example 225 -;
5-(((2-Methoxyethyl)amino)carbonyl)-3-methoxypyridine-2- ~ - -carboxylic acid N-(carboxymethyl)amide ~ i The title compound wa~ prepared in analogy with Example 223 u~ing 2-methoxyethylamine.
a) 5-(~(2-Methoxyethyl)amino)carbonyl)-3-~ethoxypyri-dine-2-sarboxyllc acid, m.p. 160-161C (wlth ga~
evolution, from ethyl acetate) b) 5-(((2-Methoxyethyl)amino)carbo~yl)-3-methoxypyri-dine-2-carboxylic acid N-((benzyloxycarbonyl)-methyl)amide wa~ ~ry~tallized u~ing dii~opropyl ether, m.p. 129-131C.
:
213~366 c) The title compound was obtained, aa above, from the benzyl ester, m.p. 186-188C (from diethyl ether).
Example 226 N-(3-Benzyloxypyridyl-2-carbonyl)alanine racemate, M.p. 186-187C (from pentane/ethyl acetate) Example 227 N-(3-Benzyloxypyr~dyl-2-carbonyl)-L-phenylalanine, M.p. 100-101C (from pentane/ethyl acetate).
Example 228 5-((1-Butyloxy)carbonyl)-3-methoxypyridin~-2-carboxylic acid N-(carboxymethyl)amide trifluoroacetate a) Di-(1-butyl) 3-methoxypyr~dine-~,5-dicarboxylate 5.0 g of dimethyl 3-methoxypyridine-2,5-dicarboxylate (cf. Example 90a)) were dissolvod in 100 ml of 1-butanol, and after that 1.5 ml of conc. ~ulfuric were added and the mixture wa~ hoated to boiling for 2 h, with a part of the solvent bsing distilled off. After the mixture had been cooled, it was concentrated in vacuo and the rosidue was taken up ~n dichloro~ethane; this solution wa~
oxtr~ct-d with a oaturated, aqueou~ ~olution of Na bicarbonato and the organic phase was dried and concen-trated. 6 g of o$1y crude product.
., .
b) ~is[5-((1-butyloxy)carbonyl)-3-methoxypyridine-2-carboxylic acid]-Cu(II) complex .
6 g (20 mmol) of the above product were addod, disaolved in 10 ml of mothanol, to a solution of 4.8 g (20 mmol) of Cu(II) nitrate x 3 ~,0 in 100 ml of methanol, and t:he mixture was heated to boiling for 4 h. It wa~ then cooled down to 0-5C and the cry~talline precipitate was fil-terod off with suction and washed with diethyl ether.
4.2 g of bluo-groen, cry~talline product were obtained, .p. 267C (wlth decomposition).
'' ;' `' '' ~' ' .: ~
2i31866 c) 5-((1-Butyloxy)carbonyl)-3-mothoxypyridine-2-car-boxylic acid 4 g of the above Cu complex were suisipended in 75 ~1 of 1,4-dioxane. ~2S gaisi w~,~i pai~ised in, while the mixture was being stirred, for 30 min, ~nd the eedlment ~CuS) wh~ich had precipitated out wai~i filtered off with i~iuction through kie3elguhr and then washed with 1,4-dioxane (continued introduct~on Or H,S did not l~ad to any further precipitation); the filtrate w~i6i concentratod in vacuo. The residue wae crystii~llized uciiny potroleum ether, m.p. 96-9SC.
d3 5-((1-Butyloxy)carbo~yl)-3-methoxypyridino-2-carboxylic acid N-((tert-butyloxyc~rbonyl)-methyl)amide 0.76 g (3 mmol) of the a~ovo pyridinecarboxylic acid wa,~
condensed with 0.52 g (3 mmol) of glycine tert-butyl ester hydrochloride, 1.2 ~1 (9 ol) of N-~thylmorpho-line, 0.45 g (3.3 ~mol) of 1-hydroxy~ )-benzotriazole and 1.3 g (3 mmol) of CMC. 0.8 g of product wa~c obtained, m.p. 50-52C (from peitroleum ther).
ei) The title compound wac obtain~d by ~dding 2.7 ml of trlfluoroacetic acid, at 20C, to 0.4 g of the above tert-butyl ei~iteir in dichloromethane. Aftsr 20 h, the mixture was concentrated in vacuo and 0.2 g W~8 obtained of the colorleei~i, cryi~tall$ne, strongly hygroi~icop~c product, which, on being filtered off with ,aiuction, deliquesced on the suction filteir.
Example 22g 5-Ethyloxycarbonyl-3-methoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Example 230 3-Methoxy-5-((1-propyloxy)carbonyl)pyridine-2-carboxyl~c acid N-(carboxymethyl)amide 213~866 Example 231 5-(~ exyloxy)carbonyl)-3-mathoxypyridine-2-carboxylic acid N-(carboxymethyl)amide Exa~ple 232 ~-3-Methoxy-5-((1-pentyloxy)carbonyl)pyr$dino-2-carboxylic acid N-(carboxymethyl)amido Example 233 5-((1-Heptyloxy)carbo~yl)-3-methoxypyridino-2-carboxyl~c acid N-(carboxymethyl)amlde Example 234 3-Methoxy-5-((1-octyloxy)carbonyl)pyridine-2-carboxylic acid N-~carboxymethyl)amide ~xamples 235-238 were prepared in an analogous manner to Example 228 proceeding from 3-(2-propyloxy)pyridine-2,5-dicarboxylic acid or the corre~ponding dial~yl esters.
Examplo 235 5-Ethyloxycarbonyl-3-(2-propyloxy)pyridine-2-carboxylic acid N-(carboxymethyl)amide ~`
~ ..
Examplo 236 5-((1-Butyloxy)carbonyl)-3-(2-propyloxy)pyridine-2-carboxylic acid N-(carboxymethyl)amide Example 237 . .
5-((1-Hexyloxy)carbonyl)-3-(2-propyloxy)pyridino-2- :
carboxylic acid N-(carboxymethyl)amide ", 25 Example 238 - --.;
5-((-1-Octyloxy)carbonyl)-3-(2-propylc-xy)pyridine 2-carboxylic acid N-(c~rboxymethyl)amide Example 239 5-Carboxy-3-(methylthio)pyridine-2-carboxylic ~cid N-(carboxymethyl)amide di~odium salt ' ' ~
2134~66 a) 3-(Methylthio)pyridino-2,5-dicarboxyllc acid 4.6 g (12 mmol) of dibenzyl 3-c~loropyridine-2,5-dicar-boxylate were dissolvod, at 20C ~nd while ~tirring, in 30 ml of dimethyl sulfoxido, and aftor that 5.0 g (70 mmol) of sodium thiomethoxido wore ~ddod, in as~oci-ation with which the temperaturo roce to 80C. The reaction mixture was he~tod ~t 140C for 1 h and then cooled down; water wa~ added ~nd tho oily layor w~
~eparatod off; conc. hydrochloric acid (p~ 1) was ~dded to the aqueouo DMS0 pha~e and the preciplt~tod product waQ filter0d off with suction. 2.8 g wsro obtained of a yellow cry~talline product, m.p. 223C (with decom-position).
b) Dimethyl 3-(methylthio)pyridine-2,5-dicarboxylate 50 ml of 1,4-dioxane, 40 ml of tetrahydrofuran and 0.5 ml of conc. ~ulfuric aoid were added to 2.8 g of the above compound in 150 ml of mothanol, ~nd tho mixture w2s heated ~o reflux for 2 h, during which tim0 a eolution wa~ formed. After tho ~olution had been cooled down, it was concentrated in vacuo and 100 ml of an aqueou~
solution of Na bicarbonato were addod to the rosidue; the latter mixture wae oxtracted with dichloro~ethane and the organic phase was dried a~d concentrated. 1.4 g were obtained of tho yellow, crystallino product, ~.p. 103-105C.
c) 5-Methoxycarbonyl-3-(methylthio)pyridine-2 carboxylic acid-Cu(II) complex 1.3 g of the ~bova dimethyl 3-msthylthiopyridine-2,5-dicarboxylate were reacted in analogy with Example 228~
1.3 g of grsenish/cry~talline product were obtained, m.p.
~ 330C.
d) 5-Methoxy-3-(methylthio)pyridine-2-carboxylic acid - ::
213~866 1.3 g of the above compound were ro~cted in analogy with Example 228c), 0.72 g of product, m.p. 183-185C.
e) 5-Methoxycarbonyl-3-(methylthio)pyr~din~-2-carboxylicac$dN-((1-butyloxy)carbonyl)methyl)amldo S ~he compound was obtained by condensing O.68 g (3 mmol) of the above pyridinecarboxylic acid wit~ 0.91 g (3 ol) of glycine 1-butyl e~ter tosylata (1-hydroxy-1~-benzotri-azole, N-ethylmorpholine ~nd CMC). 0.55 g of pale yellow product was obtained, m.p. 47-49C (frcm potroleum 10 ether) .
f) The title compound wa~ obtained by hydroly~ing O.45 g (1.3 mmol) of the above e~ter u~ing 50 ml of 1 N
methanolic NaO~. The clear yollow ~olution hecamo cloudy after 30 min. Aftor 2 h, the precipitate was filtered off with ~uction, washed twice w~th ~ethanol and dried in vacuo. 0.32 g of the title compound wa~ obtained, m.p.
345C (decomp.).
' ~' : .
~:: - . .
.~ - ,,~ , - "~ ~
, ~, ,,,.,~-,,.
-., ~:
,'' ~',' ''' -,' ,'.''`' ~' ,: ,; .~ . . .
: : .
Claims (24)
1. A compound of the formula I
(I), in which Q is O, S, NR' or a bond, X is O or S, Y is C-R3 or, if R1 and R2 form a cycle, Y is N or CR3, m is 0 or 1, A is (C1-C4)-alkylene, which is optionally substi-tuted by one or two substituents from the group halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Halg, preferably (C1-C8)-fluoro-alkoxy, (C1-C8)-fluoroalkenyloxy, (C1-C8)-fluoro-alkynyloxy, -OCF2Cl or -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylani-lino, phenylmercapto, phenylsulfonyl, phenylsul-finyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or by a substituted (C1-C12)-aryloxy, (C7-C11)-aralk-yloxy, (C6-C12)-aryl or (C7-C11)-aralkyl radical which carries in the aryl moiety 1, 2, 3, 4 or 5 identical or different substituents from the group halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2]c-CfH(2f+1-g)Halg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkyl-mercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-sulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkyl-carbonyloxy, (C3-C8) -cycloalkyl, sulfamoyl, N-(C1-C4)-alkylaulfamoyl or N,N-di-(C1-C4)-alkyl-sulfamoyl, or by the substituents R3 of the a-carbon atom of an a-amino acid, it being possible to use the natural L-amino acids and their D-isomers;
B is an acid grouping from he group -CO2H, -CONHCORn"', -CONHSOR'", CONHSO2Rn"', -NHSO2CF3, tetrazolyl, imidazolyl or 3-hydroxyisoxazolyl, where R"' is aryl, heteroaryl, (C3-C7)-cycloalkyl or (C1-C4)-alkyl, optionally monosubstituted by (C6-C12)-aryl, heteroaryl, OH, SH, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-thioalkyl, (C1-C4)-sul-finyl, (C1-C4)-sulfonyl, CF3, Cl, Br, F, I, NO2, -COOH, (C2-C5)-alkoxycarbonyl, NH2, mono-(C1-C4)-alkyl)-amino, di-(C1-C4-alkyl)-amino or (C1-C4)-perfluoroalkyl, R1, R2 and R3 are identical or different and are hydrogen, hydroxyl, halogen, cyano, trifluoro-methyl, nitro, carboxyl, (C1-C20)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cyclo-alkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyclo-alkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cyclo-alkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C7-C16)-aralkenyl, ( C 7 - C 1 6 ) - a r a l k y n y l, ( C 2 - C 2 0 ) - a l k e n y l, (C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyl-oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C16)-hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C2-C20)-alkonyloxy-(C1-C6)-alkyl, (C2-C20)-alkynyloxy-(C1-C6)-alkyl, retinyloxy-(C1-C6)-alkyl, -O-[CH2-]-xCfH(2f+1=g)Fg, -OCF2Cl, -OCF,-CHFCl, (C1-C20)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C15)-aralkylcarbonyl, cinnamoyl, (C2-C20)-alkenylcarbonyl, (C2-C20)-alkynylcarbonyl, (C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C20)-alkonyloxycarbonyl, retinyloxycarbonyl, (C2-C20)-alkynyloxycarbonyl, (C6-C23)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl,(C3-C8)-cycloalkyl-(C1-C6)-alkoxy-carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-carbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-bonyloxy, (C6 -C12)-arylcarbonyloxy, (C7-C26)-aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyl-oxy,(C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cyclo-alkoxycarbonyloxy, (C2-C12) -alkenyloxycarbonyloxy, (C2-C12)-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-Cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C11)-arylcarbamoyl, N-(C7-C16)-aralkylcarb-amoyl, N-(C1-C10)-alkyl-N-(C7-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl, N-((C1-C18)-alkoxy-(C1-C10)alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, or CON(CCH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, a carbamoyl radical of the formula II
(II), in which Rx is the substituent of an .alpha.-amino acid to which the L- and D-amino acids belong, s is 1, 2, 3, 4 or 5, and T is OH, OR or NR*R**, where R*, R** and R*** are identical or different and are hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (+)-dehydroabietyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or R* and R** together are -[CH2]h, in which a CH2 group can be replaced by O, S, SO, SO2, N-acylamino, N-(C1-C10)-alkoxycarbonylimino, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cyclo-alkylcarbamoyloxy, N-(C1-C12)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl) carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-alkyl) carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl) carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy,N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl) carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C11)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-a l k a n o y l - N - ( C1 - C10 ) - a l k y l a m i n o , (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aral-kanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroyl-amino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkyl-amino-(C1-C10)-alkyl, N,N-di(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C10)-alkylmorcapto, (C1-C20)-alkyls-ulfinyl, (C1-C20)-alkylsulfonyl, (C6-C12)-aryl-mercapto, (C6-C12)-arylsulflnyl, (C6-C12)-aryl-sulfonyl, (C7-C16)-aralkylmorcapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-aralkylsulfonyl, (C1-C12)-alkylmorcapto-(C1-C6)-alkyl, (C1-C12)-alkyl-sulfinyl-(C1-C6)-alkyl,(C1-C12)-alkylsulfonyl-(C1-C6)-alkyl, (C6-C12)-arylmercapto-(C1-C6)-alkyl, (C6-C12)-arylsulfinyl-(C1-C6)-alkyl, (C6-C12)-aryl-sulfonyl-(C1-C6)-alkyl, (C7-C16)-aralkylmercapto-(C1-C6)-alkyl, (C7-C16)-aralkylsulfinyl-(C1-C6)-alkyl, (C7-C16)-aralkylsulfonyl-(C1-C6)-alkyl, sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C12)-arylsulfamoyl, N-(C7-C16)-aralkylsulfamoyl, N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl, N-(C1-C10)alkyl-N-(C7-C16)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, N-((C1-C10)-alkyl)-(C1-C10)-alkylsulfonamido, (C7-C16)-arnlkylsulfonamido or N-((C1-C10)-alkyl-(C7-C16)-aralkylsulfonamido, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by from 1 to 5 identical or different radicals from the group:
hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C16)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyaloalkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cyclo-alkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C16)-alkonyl, (C2-C12)-alkynyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2]x-C-CfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12) -alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-Cl2)-alkyny-loxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-carbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-bonyyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxy-carbonyloxy, (C3-C8)-cycloalkoxycarbonyloxy, (C2-C12)-alkonyloxycarbonyloxy, (C2-C12)-alkynyloxy-carbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkyl-carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl, N-((C1-C16)-alkoxy-(C1-Cl0)-alkyl)-carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkyl-imino and h is from 3 to 7, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cyclo-alkylcarbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7 C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl)-carba-moyloxy,N-((C6-C12)-aryloxy-((C1-C10)-alkyl)-carba-moyloxy, N-((C7-C12)-aralkyloxy-(C1-C10)-alkyl)-carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C3-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamlno, N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C2)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroyl-amino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkyl-amino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl or (C7-C16)-aralkyloulfonyl, R1 and R2 or R2 and R3 form a chain [CH2]o in which one or two CH, groups of the chain, which is saturated or unsaturated by a C=C double bond, are optionally replaced by O, S, SO, SO2 or NR', and o is 3, 4 or 5, and R' is hydrogen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C3-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralk-anoyl or optionally substituted (C6-C12)-aroyl, where the radicals R' and R2 or R2 and R3, together with the pyridine or pyridazine carrying them, preferably form a 5, 6, 7, 8-tetrahydroiso-quinolins ring, a 5, 6, 7, 8-tetrahydroquinoline ring or a 5, 6, 7, 8-tetrahydrocinnoline ring, or R1 and R2 or R2 and R3 form a carbocyclic or a heterocyclic, 5- or 6-membered aromatic ring, where the radicals R1 and R2 or R2 and R3, together with the pyridine or pyridazine carrying them, preferably form the following optionally substi-tuted heterocyclic ring systems:
Thienopyridines, Furanopyridines, Pyridopyridines, Pyrimidinopyridines, Imidazopyridines, Thiazolopyridines, Oxazolopyridines, Quinoline, isoquinoline and Cinnoline, where quinoline, isoquinoline or cinnoline pre-ferably satisfy the formulae 1a, 1b and 1c 1a 1b 1c and the substituents R11 to R22, in each case inde-pendently of each other, have the meaning of R1, R2 and R3, R4 is if Q is a bond, halogen, nitrile or trifluoro-methyl, or, if Q is O, S or NR', a branched or unbranched (C1-C10-alkyl radical, an unsubstituted, saturated fluoroalkyl radical of the formula [CH2]x-CfH(2f+1-g)Fg, a (C6-C16)-aryl radical, a (C7-C16)-aralkyl radical, a heteroaryl radical or R heteroaralkyl radical, where these radicals are substituted by one or more radicals from the group hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8) -cyclo-alkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8) -cycloalkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkyl,(C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2]x-CH2(2f+1-g)Fg, -OCF2Cl, -OCF,-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, cinnamoyl, (C2-C12)-alkonylcarbonyl, (C2-C12)-alkynylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-bonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkyl-carbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcar-bonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxycar-bonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydro-abietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydro-abietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl,N((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, or by a carbamoyl radical of the formula II
(II), in which Rx is the substituent of an .alpha.-amino acid to which the L- and D-amino acids belong, s is 1, 2, 3, 4 or 5, and T is OH, OR or NR*R**, where R*, R**, and R*** are identical or different and are hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (+)-dehydroabietyl, (C1-C8)-alkoxy-(C1-C8)-alkyl,(C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or R* and R** together are -[CH2]h, in which a CH2 group can be replaced by O, S, SO, SO2, N-acylamino, N-(C1-C10)-alkoxycarbonylimino, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, or by carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyloxy, N-(C6-C12)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy,N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyloxy, N-((C1-C10)-alkyl)carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7,-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-aryl-amino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkyl amino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-alkyl, N,N-di(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C2)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-aralkylsulfonyl, sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C12)-arylsulfamoyl, N-(C7-C16)-aralkylsulfamoyl, N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, N-((C1-C10)-alkyl) (C1-C10)-alkylsulfonamido,(C7-C16)-aralkylsulfonamido or N-(C1-C10)-alkyl-(C7-C16)-aralkylsulfonamido, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by from 1 to 5 identical or different radicals from the group:
hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cyclo-alkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8) -cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl, (C1-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C7-C16)-aryloxy-(C1-C6)-alkyl, (C7-C16)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2-]x-CfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralk-ylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12) -alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12)-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8) -cycloalkylcarbamoyl, N-((C3-C8) -cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydro-abietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydro-abietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)-carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl)carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C2-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-aryl-amino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-(C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aral-kylmercapto, (C7-C16)-aralkylsulfinyl or (C7-C16)-aralkylsulfonyl, and R4 is R", provided that Q has ths meaning of NR', where R' and R" are identical or different and are hydro-gen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12(-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or R' and R" together are -[CH2]h, in which a CH2 group can be replaced by O, S, N-acylimino or N-(C1-C10)-alkoxycarbonylimino, and f is 1 to 8, g is 0 or 1 to (2f+1), x is 0 to 3, h is 3 to 7, 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.
(I), in which Q is O, S, NR' or a bond, X is O or S, Y is C-R3 or, if R1 and R2 form a cycle, Y is N or CR3, m is 0 or 1, A is (C1-C4)-alkylene, which is optionally substi-tuted by one or two substituents from the group halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Halg, preferably (C1-C8)-fluoro-alkoxy, (C1-C8)-fluoroalkenyloxy, (C1-C8)-fluoro-alkynyloxy, -OCF2Cl or -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylani-lino, phenylmercapto, phenylsulfonyl, phenylsul-finyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or by a substituted (C1-C12)-aryloxy, (C7-C11)-aralk-yloxy, (C6-C12)-aryl or (C7-C11)-aralkyl radical which carries in the aryl moiety 1, 2, 3, 4 or 5 identical or different substituents from the group halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2]c-CfH(2f+1-g)Halg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkyl-mercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-sulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkyl-carbonyloxy, (C3-C8) -cycloalkyl, sulfamoyl, N-(C1-C4)-alkylaulfamoyl or N,N-di-(C1-C4)-alkyl-sulfamoyl, or by the substituents R3 of the a-carbon atom of an a-amino acid, it being possible to use the natural L-amino acids and their D-isomers;
B is an acid grouping from he group -CO2H, -CONHCORn"', -CONHSOR'", CONHSO2Rn"', -NHSO2CF3, tetrazolyl, imidazolyl or 3-hydroxyisoxazolyl, where R"' is aryl, heteroaryl, (C3-C7)-cycloalkyl or (C1-C4)-alkyl, optionally monosubstituted by (C6-C12)-aryl, heteroaryl, OH, SH, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-thioalkyl, (C1-C4)-sul-finyl, (C1-C4)-sulfonyl, CF3, Cl, Br, F, I, NO2, -COOH, (C2-C5)-alkoxycarbonyl, NH2, mono-(C1-C4)-alkyl)-amino, di-(C1-C4-alkyl)-amino or (C1-C4)-perfluoroalkyl, R1, R2 and R3 are identical or different and are hydrogen, hydroxyl, halogen, cyano, trifluoro-methyl, nitro, carboxyl, (C1-C20)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cyclo-alkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyclo-alkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cyclo-alkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C7-C16)-aralkenyl, ( C 7 - C 1 6 ) - a r a l k y n y l, ( C 2 - C 2 0 ) - a l k e n y l, (C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyl-oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C16)-hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C2-C20)-alkonyloxy-(C1-C6)-alkyl, (C2-C20)-alkynyloxy-(C1-C6)-alkyl, retinyloxy-(C1-C6)-alkyl, -O-[CH2-]-xCfH(2f+1=g)Fg, -OCF2Cl, -OCF,-CHFCl, (C1-C20)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C15)-aralkylcarbonyl, cinnamoyl, (C2-C20)-alkenylcarbonyl, (C2-C20)-alkynylcarbonyl, (C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C20)-alkonyloxycarbonyl, retinyloxycarbonyl, (C2-C20)-alkynyloxycarbonyl, (C6-C23)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl,(C3-C8)-cycloalkyl-(C1-C6)-alkoxy-carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-carbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-bonyloxy, (C6 -C12)-arylcarbonyloxy, (C7-C26)-aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyl-oxy,(C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cyclo-alkoxycarbonyloxy, (C2-C12) -alkenyloxycarbonyloxy, (C2-C12)-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-Cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C11)-arylcarbamoyl, N-(C7-C16)-aralkylcarb-amoyl, N-(C1-C10)-alkyl-N-(C7-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl, N-((C1-C18)-alkoxy-(C1-C10)alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, or CON(CCH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, a carbamoyl radical of the formula II
(II), in which Rx is the substituent of an .alpha.-amino acid to which the L- and D-amino acids belong, s is 1, 2, 3, 4 or 5, and T is OH, OR or NR*R**, where R*, R** and R*** are identical or different and are hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (+)-dehydroabietyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or R* and R** together are -[CH2]h, in which a CH2 group can be replaced by O, S, SO, SO2, N-acylamino, N-(C1-C10)-alkoxycarbonylimino, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cyclo-alkylcarbamoyloxy, N-(C1-C12)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl) carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-alkyl) carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl) carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy,N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl) carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C11)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-a l k a n o y l - N - ( C1 - C10 ) - a l k y l a m i n o , (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aral-kanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroyl-amino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkyl-amino-(C1-C10)-alkyl, N,N-di(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C10)-alkylmorcapto, (C1-C20)-alkyls-ulfinyl, (C1-C20)-alkylsulfonyl, (C6-C12)-aryl-mercapto, (C6-C12)-arylsulflnyl, (C6-C12)-aryl-sulfonyl, (C7-C16)-aralkylmorcapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-aralkylsulfonyl, (C1-C12)-alkylmorcapto-(C1-C6)-alkyl, (C1-C12)-alkyl-sulfinyl-(C1-C6)-alkyl,(C1-C12)-alkylsulfonyl-(C1-C6)-alkyl, (C6-C12)-arylmercapto-(C1-C6)-alkyl, (C6-C12)-arylsulfinyl-(C1-C6)-alkyl, (C6-C12)-aryl-sulfonyl-(C1-C6)-alkyl, (C7-C16)-aralkylmercapto-(C1-C6)-alkyl, (C7-C16)-aralkylsulfinyl-(C1-C6)-alkyl, (C7-C16)-aralkylsulfonyl-(C1-C6)-alkyl, sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C12)-arylsulfamoyl, N-(C7-C16)-aralkylsulfamoyl, N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl, N-(C1-C10)alkyl-N-(C7-C16)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, N-((C1-C10)-alkyl)-(C1-C10)-alkylsulfonamido, (C7-C16)-arnlkylsulfonamido or N-((C1-C10)-alkyl-(C7-C16)-aralkylsulfonamido, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by from 1 to 5 identical or different radicals from the group:
hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C16)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyaloalkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cyclo-alkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C16)-alkonyl, (C2-C12)-alkynyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2]x-C-CfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12) -alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-Cl2)-alkyny-loxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-carbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-bonyyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxy-carbonyloxy, (C3-C8)-cycloalkoxycarbonyloxy, (C2-C12)-alkonyloxycarbonyloxy, (C2-C12)-alkynyloxy-carbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkyl-carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl, N-((C1-C16)-alkoxy-(C1-Cl0)-alkyl)-carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkyl-imino and h is from 3 to 7, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cyclo-alkylcarbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7 C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl)-carba-moyloxy,N-((C6-C12)-aryloxy-((C1-C10)-alkyl)-carba-moyloxy, N-((C7-C12)-aralkyloxy-(C1-C10)-alkyl)-carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C3-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamlno, N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C2)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroyl-amino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkyl-amino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl or (C7-C16)-aralkyloulfonyl, R1 and R2 or R2 and R3 form a chain [CH2]o in which one or two CH, groups of the chain, which is saturated or unsaturated by a C=C double bond, are optionally replaced by O, S, SO, SO2 or NR', and o is 3, 4 or 5, and R' is hydrogen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C3-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralk-anoyl or optionally substituted (C6-C12)-aroyl, where the radicals R' and R2 or R2 and R3, together with the pyridine or pyridazine carrying them, preferably form a 5, 6, 7, 8-tetrahydroiso-quinolins ring, a 5, 6, 7, 8-tetrahydroquinoline ring or a 5, 6, 7, 8-tetrahydrocinnoline ring, or R1 and R2 or R2 and R3 form a carbocyclic or a heterocyclic, 5- or 6-membered aromatic ring, where the radicals R1 and R2 or R2 and R3, together with the pyridine or pyridazine carrying them, preferably form the following optionally substi-tuted heterocyclic ring systems:
Thienopyridines, Furanopyridines, Pyridopyridines, Pyrimidinopyridines, Imidazopyridines, Thiazolopyridines, Oxazolopyridines, Quinoline, isoquinoline and Cinnoline, where quinoline, isoquinoline or cinnoline pre-ferably satisfy the formulae 1a, 1b and 1c 1a 1b 1c and the substituents R11 to R22, in each case inde-pendently of each other, have the meaning of R1, R2 and R3, R4 is if Q is a bond, halogen, nitrile or trifluoro-methyl, or, if Q is O, S or NR', a branched or unbranched (C1-C10-alkyl radical, an unsubstituted, saturated fluoroalkyl radical of the formula [CH2]x-CfH(2f+1-g)Fg, a (C6-C16)-aryl radical, a (C7-C16)-aralkyl radical, a heteroaryl radical or R heteroaralkyl radical, where these radicals are substituted by one or more radicals from the group hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8) -cyclo-alkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8) -cycloalkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkyl,(C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2]x-CH2(2f+1-g)Fg, -OCF2Cl, -OCF,-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, cinnamoyl, (C2-C12)-alkonylcarbonyl, (C2-C12)-alkynylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkylcar-bonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkyl-carbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcar-bonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxycar-bonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydro-abietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydro-abietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl,N((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, or by a carbamoyl radical of the formula II
(II), in which Rx is the substituent of an .alpha.-amino acid to which the L- and D-amino acids belong, s is 1, 2, 3, 4 or 5, and T is OH, OR or NR*R**, where R*, R**, and R*** are identical or different and are hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (+)-dehydroabietyl, (C1-C8)-alkoxy-(C1-C8)-alkyl,(C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or R* and R** together are -[CH2]h, in which a CH2 group can be replaced by O, S, SO, SO2, N-acylamino, N-(C1-C10)-alkoxycarbonylimino, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, or by carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyloxy, N-(C6-C12)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy,N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyloxy, N-((C1-C10)-alkyl)carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7,-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-aryl-amino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkyl amino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-alkyl, N,N-di(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C2)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-aralkylsulfonyl, sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C12)-arylsulfamoyl, N-(C7-C16)-aralkylsulfamoyl, N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, N-((C1-C10)-alkyl) (C1-C10)-alkylsulfonamido,(C7-C16)-aralkylsulfonamido or N-(C1-C10)-alkyl-(C7-C16)-aralkylsulfonamido, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by from 1 to 5 identical or different radicals from the group:
hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-cyclo-alkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C3-C8) -cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl, (C1-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, (C7-C16)-aryloxy-(C1-C6)-alkyl, (C7-C16)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2-]x-CfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralk-ylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenylcarbonyloxy, (C2-C12)-alkynylcarbonyloxy, (C1-C12) -alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12)-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8) -cycloalkylcarbamoyl, N-((C3-C8) -cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydro-abietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydro-abietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)-carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyloxy, N-((C1-C10)-alkyl)carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C2-C10)-alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-aryl-amino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-(C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cyclo-alkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aral-kylmercapto, (C7-C16)-aralkylsulfinyl or (C7-C16)-aralkylsulfonyl, and R4 is R", provided that Q has ths meaning of NR', where R' and R" are identical or different and are hydro-gen, (C6-C12)-aryl, (C7-C11)-aralkyl, (C1-C8)-alkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12(-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or R' and R" together are -[CH2]h, in which a CH2 group can be replaced by O, S, N-acylimino or N-(C1-C10)-alkoxycarbonylimino, and f is 1 to 8, g is 0 or 1 to (2f+1), x is 0 to 3, h is 3 to 7, including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-threonyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
2. A compound of the formula I as claimed in claim 1, in which Q is O, S, NR' or a bond, X is O, Y is CR3, or, if R1 and R2 form a cycle, Y is N or CR3, m is 0 or 1.
3. A compound of the formula I as claimed in claims 1 and 2, in which Q is O, NR' or a bond, and X is O.
4. A compound of the formula I as claimed in claims 1 and 2, in which Q is S, and X is O, and m is 0 or 1.
5. A compound of the formula I as claimed in claims 1, 2 and 4, in which Q is S, X is O, and m is 0.
6. A compound of the formula I as claimed in claims 1 to 3, in which Q is O, NR' or a bond, X is O, Y is CR3 or, if R1 and R2 form a cycle, N or CR3, m is 0 or 1, A is (C1-C3)-alkylene which is optionally substi-tuted once by halogen, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy or -O-[CH2]x-CfH(2f+1-g)Fg, or A is -CHR5-, where R5 is one of the substitutents of the .alpha.-carbon atom of an .alpha.-amino acid, in particu-lar of a natural L-amino acid and of its D-isomer, B is CO2H, R2 is hydrogen, (C1-C20)-alkyl (C2-C20)-alkenyl, (C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyloxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-alkoxy-(C1-C3)-alkyl, (C2-C20)-alkenyloxy-(C1-C3)-alkyl, retinyloxy-(C1-C3)-alkyl, (C2-C20)-alkynyloxy-(C1-C3)-alkyl, halogen, cyano, trifluoromethyl, (C10 C8)-hydroxyalkyl, (C1-C20)-alkanoyl, (C7-C16)-aralkanoyl, (C6-C12)-aroyl, (C6-C12)-aryl, (C7-C16)-aralkyl, -O-[CH2]x-CfH(2f+1-g)Fg, NR'R", (C1-C10)-alkylmercapto, (C1-C10)-alkylsulfinyl, (C1-C10)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C12)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C12)-aralkylmercapto, (C7-C12)-aralkylsulfinyl, (C7-C12)-aralkylsulfonyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, carboxyl, (C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C20)-alkenyl-oxycarbonyl, retinyloxycarbonyl, (C2-C20)-alkynyl-oxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-carbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N,N-dicyclo(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-(C3-C8) cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkyl-carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 7, where aryl is substituted in the manner as defined for R1 and R3, R1 and R3 are identical or different and are hydro-gen, halogen, (C1-C12)-alkyl, (C1-C12)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Halg, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C8)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C2-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C3-C8)-cycloalkyloxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C8)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy, (C3-C8)-cyclo-alkyl-(C1-C6)-alkyl-(C1-C8)-alkoxy, (C3-C8)-cyclo-alkyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, NRYRZ, (C1-C8)-alkylmercapto, (C1-C8)-alkylsulfinyl or (C1-C8)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C12)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C12)-aralkylmercapto, (C7-C11)-aralkylsulfinyl, (C7-C11)-aralkylsulfonyl, substituted (C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C7-C11)-aralkyloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy or (C7-C11)-aralkoxy-(C1-C6)-alkoxy, where an aromatic radical carries 1, 2, 3, 4 or 5 identical or different substi-tuents from the group hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C16)-alkyl, (C1-C16)-alkenyl, (C1-C6)-hydroxyalkyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy, -O-[CH2]x-CfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkyl-sulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkyl-carbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NRYRZ, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsul-famoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or optionally carries up to 3 of the abovementioned identical or different substituents, and two adjacent carbon atoms of the aralkyloxy radical together carry a chain -[CH2-] and/or -CH=CH-CH=CH-, where a CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NR'.
R1 and R2 or R2 and R3 form a chain [CH2]o, where o is 3, 4 or 5, or form together with the pyridine or pyridazine carrying them, a cinnoline ring, a quinoline ring or an isoquinoline ring, R4 is, if Q is a bond, fluorine, chlorine or bro-mine, or, if Q is O or NR', a branched or unbranched (C1-C20)-alkyl radical, which can con-tain up to 3 C-C multiple bonds, an unsubstituted saturated fluoroalkyl radical of the formula [CH2]x-CfH(2f+1-g)Fg, a (C6-C16)-aryl radical or a (C7-C16)-aralkyl radical, which can contain up to 2 C-C multiple bonds in the alkyl chain, or heteroaryl radical or a heteroaryl alkyl radical, where these radicals are substitued by one or more radicals from the group hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkocy, (C3-C8)-cyclo-alkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, -O-[CH2-]x-CfH(2f+1-g)Fg, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C12) -arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcar-bamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h in which a CH2 group can be replaced by O, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino or N-(C7-C16)-aralkylimino, and h is from 3 to 6, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by from 1 to 5 identical or different radicals from the group:
hydroxyl, fluorine, chlorine, cyano, trifluoro-methyl, carboxyl, (C1-C12)-alkyl, (C3-C8)-cyclo-alkyl, (C1-C8)-alkoxy, (C3-C8)-cycloalkoxy, (C1-C12)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-(C1-C6)-alkyl-carbamoyl or N-(C3-C8)-cycloalkylcarbamoyl, and R4 is R", provided Q has the meaning of NR', where R' and R" are identical or different and are hydrogen, (C1-C8)-alkyl, or (C7-C11)-aralkyl which is optionally substituted once by fluorine, chlorine or (C1-C4)-alkoxy, RY and RZ are identical or different and are hydro-gen, (C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or RY and RZ together are -[CH2]h-, in which a CH2 group can be replaced by O, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)-alkoxycarbonylimino, and f is 1 to 8, g is 0 or 1 to (2f + 1), h is 3 to 6, x is 0 to 3, and n is 3 or 4, including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-threonyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
R1 and R2 or R2 and R3 form a chain [CH2]o, where o is 3, 4 or 5, or form together with the pyridine or pyridazine carrying them, a cinnoline ring, a quinoline ring or an isoquinoline ring, R4 is, if Q is a bond, fluorine, chlorine or bro-mine, or, if Q is O or NR', a branched or unbranched (C1-C20)-alkyl radical, which can con-tain up to 3 C-C multiple bonds, an unsubstituted saturated fluoroalkyl radical of the formula [CH2]x-CfH(2f+1-g)Fg, a (C6-C16)-aryl radical or a (C7-C16)-aralkyl radical, which can contain up to 2 C-C multiple bonds in the alkyl chain, or heteroaryl radical or a heteroaryl alkyl radical, where these radicals are substitued by one or more radicals from the group hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cycloalkocy, (C3-C8)-cyclo-alkyl-(C1-C12)-alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-(C1-C6)-alkoxy, (C1-C8)-hydroxyalkyl, -O-[CH2-]x-CfH(2f+1-g)Fg, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C12) -arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-aryl-carbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcar-bamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, CON(CH2)h in which a CH2 group can be replaced by O, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino or N-(C7-C16)-aralkylimino, and h is from 3 to 6, where the radicals which contain an aryl radical can, for their part, be substituted on the aryl by from 1 to 5 identical or different radicals from the group:
hydroxyl, fluorine, chlorine, cyano, trifluoro-methyl, carboxyl, (C1-C12)-alkyl, (C3-C8)-cyclo-alkyl, (C1-C8)-alkoxy, (C3-C8)-cycloalkoxy, (C1-C12)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-(C1-C6)-alkyl-carbamoyl or N-(C3-C8)-cycloalkylcarbamoyl, and R4 is R", provided Q has the meaning of NR', where R' and R" are identical or different and are hydrogen, (C1-C8)-alkyl, or (C7-C11)-aralkyl which is optionally substituted once by fluorine, chlorine or (C1-C4)-alkoxy, RY and RZ are identical or different and are hydro-gen, (C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substituted (C7-C16)-aralkanoyl or optionally substituted (C6-C12)-aroyl, or RY and RZ together are -[CH2]h-, in which a CH2 group can be replaced by O, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)-alkoxycarbonylimino, and f is 1 to 8, g is 0 or 1 to (2f + 1), h is 3 to 6, x is 0 to 3, and n is 3 or 4, including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-threonyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
7. A compound of the formula I as claimed in claims 1 to 3 and 6, in which Q is O, NR' or a bond, X is O, Y is CR3 or, if R1 and R2 form a cycle, N or CR3, m is 0, A is (C1-C3)-alkylene which is optionally substi-tuted once by halogen, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy or -O-[CH2]x-CfH(2f+1-g)Fg or A is -CHR5-, where R5 is one of the substituents of the .alpha.-carbon atom of an .alpha.-amino acid, in par-ticular of a natural L-amino acid and of its D-isomer, B is CO2H, R2 is hydrogen, (C1-C20)-alkyl, (C2-C20)-alkenyl, (C2-C20)-alkenyloxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-alkoxy-(C1-C3)-alkyl, (C1-C20)-alkoxy-(C1-C3)-alkyl, (C2-C20)-alkenyloxy-(C1-C3)-alkyl, retinyloxy-(C1-C3)-alkyl, (C2-C20)-alkynyloxy-(C1-C3)-alkyl, (C1-C20)-alkoxy, halogen, cyano, trifluoromethyl, (C1-C16)-hydroxyalkyl, (C1-C20)-alkanoyl, (C7-C12)-aralkanoyl, (C6-C12)-aroyl, -O-[CH2]x-CfH(2f+1-g)Fg, NR'R", (C1-C10)-alkylmercapto, (C1-C10)-alkylsulfinyl, (C1-C10)-alkylsulfonyl, (C1-C10)-arylmercapto, (C6-C12)-arylsulfinyl), (C7-C12)-arylsulfonyl, (C7-C12)-aralkylmercapto, (C7-C12)-aralkylsulfinyl, (C7-C12)-aralkylsulfonyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, carboxyl, (C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C20)-alkenyloxy-carbonyl, retinyloxycarbonyl, (C2-C20)-alkynyl-oxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxy-carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-carbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-(C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-C12)-arylcarbamoyl, N-(C1-C10)-aralkyl-carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C12)-aralkyl-carbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl ,N-(C1-C10)-alkyl-N-((C7-C16-aral-kyloxy-(C1-C10)-alkyl)carbamoyl, or CON(CH2)h, in which a CH2 group can be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-alkoxy-(C1-C6)-alkylimino, and h is from 3 to 6, where aryl is substituted in the manner as defined for R1 and R3, R1 and R3 are identical or different and are hydro-gen, halogen, (C1-C12)-alkyl, (C1-C12)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Halg, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C8)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C8)-alkoxy-(C2-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-C8)-cycloalkyl, (C3-C8)-cyclo-alkyl-(C1-C8)-alkyl, (C3-C8)-cycloalkyloxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy, (C3-C8)-cycloalkyl-oxy-(C1-C8)-alkyl, (C3-C8)-cycloalkyloxy-(C1,-C8)-alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, NRYRZ, (C1-C8)-alkylmercapto, (C1-C8)-alkylsulfinyl or (C1-C8)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-Cl2)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C12)-aralkylmercapto, (C7-C11)-aralkylsulfinyl, (C7-C11)-aralkylsulfonyl, substituted (C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C7-C11)-aralkyloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy or (C7-C11)-aralkoxy-(C1-C5)-alkoxy, where an aromatic radical carries by 1, 2, 3, 4 or 5 identical or different substituents from the group hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C12)-alkyl, (C1-C12)-alkenyl, (C1-C6)-hydroxyalkyl, (C1-C 1 2 ) - a l k o x y , ( C 1 - C 1 2 ) - a l k e n y l o x y, -O-[CH2]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NRYRZ, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or optionally carries up to 3 of the abovementioned identical or different substituents, and two adjacent carbon atoms of the aralkyloxy radical together carry a chain -[CH2-] and/or -CH=CH-CH=CH-, where a CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NRY, R1 and R2 or R2 and R3 can form a chain [CH2]o, where o is 3, 4 or 5, and R4 is, provided Q is a bond, chlorine or, if Q is O
or NR', is a branched or unbranched (C1-C10)-alkyl radical, which can contain one or two C-C
multiple bonds, or an unsubstituted fluoroalkyl radical of the formula -[CH2]x-CfH(2f+1-g)Fg or (C1-C8)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkyl or a radical of the formula Z, -[CH2]v-[O]w-[CH2]t-E (Z) where E is a substituted phenyl radical of the formula F
(F), or a (C3-C8)-cycloalkyl radical, where v is 0, 1, 2, 3, 4, 5 or 6, w is 0 or 1, and t is 0, 1, 2 or 3, with the restriction that v is not equal to 0 if w is 1, and R6, R7, R8, R8 and R10 are identical or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsul-fonyl, (C1-C6)-alkylcarbonyl, (C1-C8)-alkoxy-carbonyl, carbamoyl, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, (C7-C11)-aralkyl-carbamoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl or (C1-C6)-alkoxy, N-(C3-C8)-cycloalkylcarbamoyl, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, phenyl, benzyl, phenoxy, benzyloxy, NRYXZ, such as amino, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkyl-sulfamoyl or N,N-di-(C1-C8)-alkylsulfamoyl, or two adjacent substituents together are a chain -[CH2-]n or -CH=CH-CH=CH-, where a CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NRY, and where a heteroaryl radical can carry 1, 2 or 3 substituents, and a cycloalkyl radical one substituent, from the above group, and R4 is R", provided Q has the meaning of NR', where R' is hydrogen or methyl, and R" is benzyl, and if R1 and/or R3 have the meaning of (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C11)-aralkoxy-(C1-C6)-alkoxy or a corresponding radical containing terminal cycloalkyl groups, this radical is preferably then a radical of the formula D
OZ (D), or if R1 and/or R3 have the meaning of (C7-C11)-aralkyl, (C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-alkyl or a corresponding radical containing terminal cycloalkyl groups, this radical is pre-ferably then a radical of the formula Z, RY and RZ are identical or different and are hydro-gen, (C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substi-tuted (C7-C16)-aralkanoyl or optionally substi-tuted (C6-C12)-aroyl, or RY and RZ are together -[CH2]h-, in which a CH2 group can be replaced by O, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)-alkoxycarbonylimino, and f is 1 to 8, g is 0 or 1 to (2f+1), h 3 to 6, x is 0 to 3, and n is 3 or 4, including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-thre-onyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
or NR', is a branched or unbranched (C1-C10)-alkyl radical, which can contain one or two C-C
multiple bonds, or an unsubstituted fluoroalkyl radical of the formula -[CH2]x-CfH(2f+1-g)Fg or (C1-C8)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkyl or a radical of the formula Z, -[CH2]v-[O]w-[CH2]t-E (Z) where E is a substituted phenyl radical of the formula F
(F), or a (C3-C8)-cycloalkyl radical, where v is 0, 1, 2, 3, 4, 5 or 6, w is 0 or 1, and t is 0, 1, 2 or 3, with the restriction that v is not equal to 0 if w is 1, and R6, R7, R8, R8 and R10 are identical or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsul-fonyl, (C1-C6)-alkylcarbonyl, (C1-C8)-alkoxy-carbonyl, carbamoyl, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, (C7-C11)-aralkyl-carbamoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl or (C1-C6)-alkoxy, N-(C3-C8)-cycloalkylcarbamoyl, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, phenyl, benzyl, phenoxy, benzyloxy, NRYXZ, such as amino, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkyl-sulfamoyl or N,N-di-(C1-C8)-alkylsulfamoyl, or two adjacent substituents together are a chain -[CH2-]n or -CH=CH-CH=CH-, where a CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NRY, and where a heteroaryl radical can carry 1, 2 or 3 substituents, and a cycloalkyl radical one substituent, from the above group, and R4 is R", provided Q has the meaning of NR', where R' is hydrogen or methyl, and R" is benzyl, and if R1 and/or R3 have the meaning of (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C11)-aralkoxy-(C1-C6)-alkoxy or a corresponding radical containing terminal cycloalkyl groups, this radical is preferably then a radical of the formula D
OZ (D), or if R1 and/or R3 have the meaning of (C7-C11)-aralkyl, (C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-alkyl or a corresponding radical containing terminal cycloalkyl groups, this radical is pre-ferably then a radical of the formula Z, RY and RZ are identical or different and are hydro-gen, (C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally substi-tuted (C7-C16)-aralkanoyl or optionally substi-tuted (C6-C12)-aroyl, or RY and RZ are together -[CH2]h-, in which a CH2 group can be replaced by O, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)-alkoxycarbonylimino, and f is 1 to 8, g is 0 or 1 to (2f+1), h 3 to 6, x is 0 to 3, and n is 3 or 4, including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-thre-onyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
8. A compound of the formula I as claimed in claims 1 to 5, in which Q is O, X is O, Y is CR3 and, additionally, N if R1 and R2 form a cycle, m is 0, A is -CHR5-, where R5 is the substituent of the .alpha.-carbon atom of an .alpha.-amino acid, in particular of a natural L-amino acid or its D-isomer, B is CO2H, R2 is hydrogen, bromine, chlorine, cyano, (C1-C18)-alkyl, (C1-C8)-alkoxy, (C1-C18)-alkoxymethyl, (C2-C18)-alkenyloxymethyl, (C2-C18)-alkynyloxymethyl, carbamoyl, N-(C1-C10)-alkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C4)-alkyl)carbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C12)-phenylcarbamoyl, N-(C7-C12)-phenylalkyl-carbamoyl, N-(C1-C6)-alkyl-N-(C6-C12)phenyl-carbamoyl, N-(C1-C6)-alkyl-N-(C7-C12)-phenylalkyl-carbamoyl, N-((C1-C6)-alkoxy-(C1-C6)-alkyl)carbamoyl, carboxyl, (C1-C20)-alkoxy-carbonyl, (C2-C20)-alkenyloxycarbonyl, retinyl-oxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C3-C8)-cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cyclo-alkoxy-(C1-C6)-alkoxycarbonyl, phenyl-(C1-C6)-alkoxycarbonyl, phenoxy-(C1-C6)-alkoxycarbonyl or benzyloxy-(C1-C6)-alkoxycarbonyl, where a phenyl radical is substituted in the manner as defined for R1 and R3, and one of the radicals R1 or R3 is hydrogen and the other a radical from the group hydrogen, fluorine, chlorine, (C1-C8)-alkyl, (C1-C10)-alkoxy, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C6)-alkyl, (C5-C6)-cycloalkyl-oxy, (C5-C6)-cycloalkyl-(C1-C6)-alkoxy, (C5-C6)-cycloalkyloxy-(C1-C6)-alkyl, (C5-C6)-cycloalkyl-oxy-(C1-C6)-alkoxy, (C5-C6)-cycloalkyl-(C1-C4)-alkyl-(C1-C4)-alkoxy, (C5-C6)-cycloalkyl-(C1-C4)-alkoxy-(C1-C2)-alkyl, (C5-C6)-cycloalkoxy-(C1-C4)-alkoxy-(C1-C2)-alkyl, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C2)-alkyl, substituted (C6-C12)-phenoxy, (C7-C11)-phenylalkyloxy, (C6-C12)-phenoxy-(C1-C6)-alkoxy or (C7-C11)-phenylalkoxy-(C1-C6)-alkoxy, phenoxy-(C1-C4)-alkyl, (C7-C11)-phenylalkyloxy-(C1-C4)-alkyl, phenoxy-(C1-C4)-alkoxy-(C1-C2)-alkyl or (C7-C11)-phenylalkyloxy-(C1-C4)-alkoxy-(C1-C2)-alkyl, where an aromatic radical is substituted by 1, 2 or 3 identical or different substitutents from the group fluorine, chlorine, cyano, trifluoro-methyl, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkenyloxy or (C1-C12)-alkoxy, R1 and R2, with the pyridine carrying them, form a 5, 6, 7, 8-tetrahydroisoquinoline ring, R4 is a branched or unbranched (C1-C10)-alkyl radical, (C1-C4)-alkoxy-(C1-C4)-alkyl or a radical of the formula Z, -[CH2]v-[O]w-[CH2]t-E (Z) where E is a substituted phenyl radical of the formula F
(F) , or a (C3-C8)-cycloalkyl radical, whero v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R6, R7, R8, R9 and R10 are identical or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C6)-cyclo-alkylcarbamoyl, N-(+)-dehydroabietylamino-carbonyl, or (C7-C11)-phenylalkylcarbamoyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl and (C1-C6)-alkoxy, or where R6 and R7 or R7 and R8, together with the phenyl ring carrying them, form naphthalene derivatives, or if R1 or R3 has the meaning of (C6-C12)-phenoxy, (C7-C11)-phenylalkyloxy, (C6-C12)-phenoxy-(C1-C6)-alkoxy, (C7-C11)-phenylalkoxy-(C1-C6-alkoxy, (C5-C6)-cycloalkyloxy, (C5-C6) cycloalkyl-(C1-C6)-alkoxy, (C5-C6)-cycloalkoxy-(C1-C6)-alkoxy or (C5-C6)-cycloalkyl-(C1-C4)-alkyl-(C1-C4)-alkoxy, this radical is then, especially, a radical of the formula D
OZ (D), or if R1 or R3 has the meaning of phenyl, phenoxy-(C1-C6)-alkyl, (C7-C11)-phenylalkyl, (C7-C11)-phenylalkyloxy-(C1-C4)-alkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C5-C6)-alkyl, (C5-C6)-cyclo-alkoxy-(C1-C4)-alkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkoxy-(C1-C2)-alkyl or (C5-C6)-cycloalkoxy-(C1-C4)-alkoxy-(C1-C2)-alkyl, this radical is then, especially, a radical of the formula Z in which, in both cases, v is 1, 2, 3 or 4, w is 0 and t is 0, or v is 1, 2, 3 or 4, w is 1 and t is 0, or v is 1, 2, 3 or 4, w is 1, t is 1, and f is 1 to 4, g is 0 or 1 to (2f+1), x is 0 or 1 including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-thre-onyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
(F) , or a (C3-C8)-cycloalkyl radical, whero v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R6, R7, R8, R9 and R10 are identical or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C6)-cyclo-alkylcarbamoyl, N-(+)-dehydroabietylamino-carbonyl, or (C7-C11)-phenylalkylcarbamoyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl and (C1-C6)-alkoxy, or where R6 and R7 or R7 and R8, together with the phenyl ring carrying them, form naphthalene derivatives, or if R1 or R3 has the meaning of (C6-C12)-phenoxy, (C7-C11)-phenylalkyloxy, (C6-C12)-phenoxy-(C1-C6)-alkoxy, (C7-C11)-phenylalkoxy-(C1-C6-alkoxy, (C5-C6)-cycloalkyloxy, (C5-C6) cycloalkyl-(C1-C6)-alkoxy, (C5-C6)-cycloalkoxy-(C1-C6)-alkoxy or (C5-C6)-cycloalkyl-(C1-C4)-alkyl-(C1-C4)-alkoxy, this radical is then, especially, a radical of the formula D
OZ (D), or if R1 or R3 has the meaning of phenyl, phenoxy-(C1-C6)-alkyl, (C7-C11)-phenylalkyl, (C7-C11)-phenylalkyloxy-(C1-C4)-alkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C5-C6)-alkyl, (C5-C6)-cyclo-alkoxy-(C1-C4)-alkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkoxy-(C1-C2)-alkyl or (C5-C6)-cycloalkoxy-(C1-C4)-alkoxy-(C1-C2)-alkyl, this radical is then, especially, a radical of the formula Z in which, in both cases, v is 1, 2, 3 or 4, w is 0 and t is 0, or v is 1, 2, 3 or 4, w is 1 and t is 0, or v is 1, 2, 3 or 4, w is 1, t is 1, and f is 1 to 4, g is 0 or 1 to (2f+1), x is 0 or 1 including the physiologically active salts, with 3-benzyloxypyridine-2-carboxylic acid (L-thre-onyl)amide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)L-threonyl)amide hydrochloride being excepted.
9. A compound of the formula I ae claimed in claims 1 to 6, in which Q is O, X is O, Y is CR3, m is 0, A is a -CH2- group which can be substituted by a methyl group, B is CO2H, R2 is hydrogen, (C1-C8)-alkoxy, (C1-C16)-alkoxymethyl, (C2-C16)-alkenyloxymethyl, retinyloxymethyl, N-(C1-C10)-alkylcarbamoyl,N-((C1-C12)-alkoxy-(C1-C3)-alkyl)carbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C5-C6)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl-(C1-C4)-alkylcarbamoyl, carboxy, (C1-C16)-alkoxycarbonyl, (C2-C16)-alkenyloxycarbonyl, retinyloxycarbonyl, (C5-C6)-cycloalkoxycarbonyl, (C5-C6)-cycloalkyl-(C1-C6)-alkoxycarbonyl or phenyl-(C1-C6)-alkoxycarbonyl, where a phenyl radical is substituted in a manner as defined for R1 and R3, and one of the radicals R1 or R3 is hydrogen and the other radical is a radical from the group hydrogen, (C1-C10)-alkoxy, (C5-C6)-cycloalkyloxy, (C5-C6)-cycloalkyl-(C1-C2)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C4)-alkoxy-(C1-C4)-alkoxy, substituted (C6-C12)-phenoxy, (C7-C11)-phenylalkyloxy, (C6-C12)-phenoxy-(C1-C4)-alkoxy or (C7-C11)-phenylalkoxy-(C1-C4)-alkoxy, where an aromatic radical is substituted by 1, 2 or 3 identical or different substituents from the group fluorine, chlorine, cyano, trifluoromethyl, (C1-C10)-alkyl, (C1-C10)-alkoxy or (C1-C10)-alkenyloxy, and R4 is a branched or unbranched (C1-C8)-alkyl radical or a radical of the formula Z, -[CH2]v-[O]w-[CH2]t-E (Z).
where E is a substituted phenyl radical of the formula F
(F) , or a (C3-C8)-cycloalkyl radical, where v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R6, R7, R8, R9 and R10 are identical or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, N-(Cl-C8)-alkylcarbamoyl, N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C6)-cycloalkylcarbamoyl, N-(+)-dehydro-abietylaminocarbonyl substituted benzyl radical, and f is 1 to 4, g is 0 or 1 to (2f+1) and x is 0 or 1 including the physiologically active salts.
where E is a substituted phenyl radical of the formula F
(F) , or a (C3-C8)-cycloalkyl radical, where v is 0, 1, 2 or 3, w is 0, and t can be 0 or 1, and in which R6, R7, R8, R9 and R10 are identical or different and are hydrogen, fluorine, chlorine, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2-]x-CfH(2f+1-g)Fg, N-(Cl-C8)-alkylcarbamoyl, N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C6)-cycloalkylcarbamoyl, N-(+)-dehydro-abietylaminocarbonyl substituted benzyl radical, and f is 1 to 4, g is 0 or 1 to (2f+1) and x is 0 or 1 including the physiologically active salts.
10. A compound of the formula I as claimed in claims 1 to 3 and 6 to 9, in which Q is O, X is O, Y is CR3, m is 0, A is a -CH2 group, B is CO2H, R1 is hydrogen, (C1-C6)-alkoxy or -O-[CH2]x-CfH(2f+1-g)Fg, R2 is hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C3)-alkyl)carbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl,N-(C5-C6)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl-(C1-C2)-alkyl-carbamoyl, carboxyl, (C1-C16)-alkoxycarbonyl, (C2-C16)-alkenyloxycarbonyl, retinyloxycarbonyl, (C5-C6)-cycloalkoxycarbonyl, (C5-C6)-cycloalkyl-(C1-C6)-alkoxycarbonyl or phenyl-(C1-C6)-alkoxy-carbonyl, where a phenyl radical is substituted by 1 or 2 identical or different substituents from the group fluorine, chlorine, cyano, triflu-oromethyl, (C1-C10)-alkyl, (C1-C10)-alkoxy or (C1-C10)-alkenyloxy, and R3 is hydrogen, (C1-C5)-alkoxy or (C5-C6)-cycloalkyl-(C1-C2)-alkoxy, where one of the substituents R1 and R3 is hydrogen, R4 is a branched or unbranched (C1-C6) alkyl radical, or a 2-phenylethyl radical, or a benzyl radical substituted by 1 or 2 radicals from the group fluorine, chlorine, cyano, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, N-(C1-C8)-alkylcarbamoyl, N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C6)-cycloalkylcarbamoyl or N-(+)-dehydroabietylaminocarbonyl, and f is 1 to 4, g is 0 or 1 to (2f+1) and x is 1, including the physiologically active salts.
11. Compounds of the formula I as claimed in claims 1 to 3 and 6 to 10, in which Q is O, X is O, Y is CR3, m is 0, A is a -CH2-group, B is CO2H, R1 is hydrogen, R2 is hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C3)-alkyl)carbamoyl, N-cyclo-hexylcarbamoyl, N-phenylcarbamoyl, N-(phenyl-(C1-C2)-alkyl)carbamoyl, where, in the last two cases, the phenyl radical can carry a fluorine substituent, a (C1-C1o)-alkyl substituent or (C1-C10)-alkoxy substituent, carboxyl, (C1-C16)-alkoxycarbonyl, (C2-C16)-alknyloxycarbonyl, retinyloxycarbonyl, (C5-C6)-cycloalkoxycarbonyl or benzyloxycarbonyl, R3 is hydrogen, (C1-C6)-alkoxy or 2-(cyolohexyl)-ethyloxy, where one of the substituents R2 and R3 is hydrogen, R4 is a branched or unbranched (C1-C4)-alkyl radical or a benzyl radical which is substituted once by fluorine, chlorine, trifluoromethyl, (C1-C4)-alkyl or (C1-C3)-alkoxy, including the physio-logically active salts.
12. A compound of the formula I as claimed in claims 1 to 3 and 6, in which Q is O
X is O, Y is CR3, where R3 is hydrogen, m is 0, A is a -CH2 group, B is -CO2H, and R1 and R2, together with the pyridine carrying them, form an isoquinoline ring having an unsubstituted benzo moiety, and R4 is methyl.
X is O, Y is CR3, where R3 is hydrogen, m is 0, A is a -CH2 group, B is -CO2H, and R1 and R2, together with the pyridine carrying them, form an isoquinoline ring having an unsubstituted benzo moiety, and R4 is methyl.
13. A compound of formula I as claimed in claims 1 to 3 and 6, in which Q is O, X is O
Y is CR3, m is 0, A is a -CH2 group, B is -CO2H, R1 is hydrogen, and R2 and R3, together with the pyridine carrying them, form a quinoline ring having an unsubstituted benzo moiety, and R4 is methyl.
Y is CR3, m is 0, A is a -CH2 group, B is -CO2H, R1 is hydrogen, and R2 and R3, together with the pyridine carrying them, form a quinoline ring having an unsubstituted benzo moiety, and R4 is methyl.
14. A compound of the formula I as claimed in claims 1, 2, 4 and 5, in which Q is S, X is O, Y is CR3, m is 0, A is a -CH2 group, B is -CO2H, R1 is hydrogen, R2 is hydrogen, N-(C1-C10)-alkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C3)alkyl)carbamoyl, N-cyclohexyl-carbamoyl, N-phenylcarbamoyl, N-(phenyl-(C1-C2)alkyl)carbamoyl, where, in the last two cases, the phenyl radical can carry a fluorine substituent, (C1-C10)-alkyl substituent or (C1-C10)-alkoxy substituent, carboxyl, (C1-C16)-alkoxycarbonyl, (C2-C16)-alkenyloxycarbonyl, retinyloxycarbonyl, (C5-C5)-cycloalkoxycarbonyl or benzyloxycarbonyl, R3 is hydrogen, (C1-C6)-alkoxy or 2-(cyclohexyl)-ethyloxy, where one of the substituents R2 and R3 is hydrogen, and R4 is a branched or unbranched (C1-C4)-alkyl radical or a benzyl radical which is substituted once by fluorine, chlorine, trifluoromethyl, (C1-C4)-alkyl or (C1-C3)-alkoxy.
15. A compound of the formula I as claimed in claims 1, 2, 4, 5 and 14, in which Q is S, X is O, Y is CR3, m is 0, A is a -CH, group, B is -CO2H, R1 is hydrogen, R2 is carboxyl or (C1-C16)-alkoxycarbonyl, R3 is hydrogen, and R4 is an unbranched or branched (C1-C4)-alkyl radical.
16. A compound of the formula I as claimed in claims 1 to 15, plus 3-benzyloxypyridine-2-carboxylic acid L-threonylamide and 3-benzyloxypyridine-2-carboxylic acid ((Fmoc-Phg)-L-threonyl)amide for use as pharma-ceuticals.
17. A compound as claimed in claims 1 to 16 to be used for inhibiting collagen biosynthesis.
18. A compound as claimed in claims 1 to 16 as an inhibitor of prolyl hydroxylase.
19. A compound as claimed in claims 1 to 16 for use as a fibrosuppressive agent.
20. A compound as claimed in claims 1 to 16 for pre-paring a pharmaceutical against fibrotic diseases.
21. A compound as claimed in claims 1 to 16 for pre-paring a pharmaceutical against fibrotic diseases of the liver.
22. A compound as claimed in claims 1 to 16 for pre-paring a pharmaceutical against fibrotic diseases of the lung.
23. A compound as claimed in claims 1 to 16 for pre-paring a pharmaceutical against fibrotic diseases of the skin.
24. A process for preparing compounds according to formula I as claimed in claims 1 to 15, in which formula A is a substituted alkylene moiety, B is CO2H, Y is CR3 and m is 0 or 1, by i1.) reacting pyridine-2-carboxylic acids of the formula II (R23 is H) with the amino esters of the formula III (R2) is (C1-C16)-alkyl or benzyl) to form the amide esters of the formula IV, or i2.) reacting pyridine-2-carboxylic esters of the formula II (R2) is lower alkyl), under the conditions of aminolysis, to form the compounds of the formula IV;
and III
II IV
ii) liberating the compounds of the formula I from their esters of the formula IV;
with, where appropriate, iii) the compounds of the formula IV (R4 is alkyl) being prepared by alkylation of compounds of the formula V (R4 is H) with R4X, , IV I
, V IV
where X is a leaving group, in particular halogen, OSO2Me or OSO2 phenyl, and, where appropriate, iv) the compounds of the formula IV, provided Q is O, S or NR', being converted into their pyridine N-oxides (IV') IV' and, where appropriate, the latter being hydrolysed to form the compounds of the formula I' (R24 is H).
and III
II IV
ii) liberating the compounds of the formula I from their esters of the formula IV;
with, where appropriate, iii) the compounds of the formula IV (R4 is alkyl) being prepared by alkylation of compounds of the formula V (R4 is H) with R4X, , IV I
, V IV
where X is a leaving group, in particular halogen, OSO2Me or OSO2 phenyl, and, where appropriate, iv) the compounds of the formula IV, provided Q is O, S or NR', being converted into their pyridine N-oxides (IV') IV' and, where appropriate, the latter being hydrolysed to form the compounds of the formula I' (R24 is H).
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. |
| DEP4337271.6 | 1993-11-02 | ||
| DEP4410881.8 | 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. |
| DEP4433928.3 | 1994-09-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2134866A1 true CA2134866A1 (en) | 1995-05-03 |
Family
ID=27205714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002134866A Abandoned CA2134866A1 (en) | 1993-11-02 | 1994-11-01 | Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticals |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0650961B1 (en) |
| JP (1) | JPH07228571A (en) |
| KR (1) | KR950014072A (en) |
| CN (1) | CN1107145A (en) |
| AT (1) | ATE149486T1 (en) |
| AU (1) | AU676775B2 (en) |
| CA (1) | CA2134866A1 (en) |
| CY (1) | CY2120B1 (en) |
| CZ (1) | CZ289356B6 (en) |
| DE (1) | DE59401924D1 (en) |
| DK (1) | DK0650961T3 (en) |
| ES (1) | ES2101421T3 (en) |
| GR (1) | GR3023174T3 (en) |
| HK (1) | HK1006711A1 (en) |
| IL (1) | IL111454A (en) |
| MY (1) | MY112413A (en) |
| NO (1) | NO301880B1 (en) |
| NZ (1) | NZ264821A (en) |
| PL (1) | PL179794B1 (en) |
| TW (1) | TW399046B (en) |
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| DE19746287A1 (en) * | 1997-10-20 | 1999-04-22 | Hoechst Marion Roussel De Gmbh | Substituted isoquinoline-2-carboxylic acid amides, their preparation and their use as medicaments |
| FR2803592A1 (en) * | 2000-01-06 | 2001-07-13 | Aventis Cropscience Sa | NOVEL DERIVATIVES OF 3-HYDROXYPICOLINIC ACID, PROCESS FOR THEIR PREPARATION AND FUNGICIDAL COMPOSITIONS CONTAINING SAME |
| DE50206476D1 (en) | 2001-05-08 | 2006-05-24 | Schering Ag | CYANOANTHRANYLAMID DERIVATIVES AND THEIR USE AS DRUGS |
| DE10123573B4 (en) * | 2001-05-08 | 2005-06-02 | Schering Ag | N-Oxidanthranylamide derivatives and their use as pharmaceuticals |
| DE10123587B4 (en) * | 2001-05-08 | 2005-04-07 | Schering Ag | Cyanoanthranylamide derivatives and their use as pharmaceuticals |
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| 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 |
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-
1994
- 1994-10-27 EP EP94117018A patent/EP0650961B1/en not_active Expired - Lifetime
- 1994-10-27 DE DE59401924T patent/DE59401924D1/en not_active Expired - Fee Related
- 1994-10-27 DK DK94117018.5T patent/DK0650961T3/en active
- 1994-10-27 ES ES94117018T patent/ES2101421T3/en not_active Expired - Lifetime
- 1994-10-27 AT AT94117018T patent/ATE149486T1/en not_active IP Right Cessation
- 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 NZ NZ264821A patent/NZ264821A/en unknown
- 1994-10-31 MY MYPI94002894A patent/MY112413A/en unknown
- 1994-10-31 AU AU77564/94A patent/AU676775B2/en not_active Ceased
- 1994-11-01 NO NO944162A patent/NO301880B1/en not_active IP Right Cessation
- 1994-11-01 CZ CZ19942683A patent/CZ289356B6/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
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| US10118897B2 (en) | 2012-07-16 | 2018-11-06 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| US10272078B2 (en) | 2012-07-16 | 2019-04-30 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| US9371288B2 (en) | 2012-07-16 | 2016-06-21 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| US9340511B2 (en) | 2012-07-16 | 2016-05-17 | Fibrogen, Inc. | Process for making isoquinoline compounds |
| US9115085B2 (en) | 2012-07-16 | 2015-08-25 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| US9643928B2 (en) | 2013-01-24 | 2017-05-09 | Fibrogen, Inc. | Crystalline forms of {[1-cyano-5-(4-chlorophenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59401924D1 (en) | 1997-04-10 |
| GR3023174T3 (en) | 1997-07-30 |
| EP0650961A1 (en) | 1995-05-03 |
| NZ264821A (en) | 1997-02-24 |
| KR950014072A (en) | 1995-06-15 |
| IL111454A0 (en) | 1994-12-29 |
| DK0650961T3 (en) | 1997-09-15 |
| JPH07228571A (en) | 1995-08-29 |
| PL179794B1 (en) | 2000-10-31 |
| CN1107145A (en) | 1995-08-23 |
| AU7756494A (en) | 1995-05-18 |
| ES2101421T3 (en) | 1997-07-01 |
| NO944162L (en) | 1995-05-03 |
| CY2120B1 (en) | 2002-04-26 |
| ATE149486T1 (en) | 1997-03-15 |
| AU676775B2 (en) | 1997-03-20 |
| TW399046B (en) | 2000-07-21 |
| CZ268394A3 (en) | 1995-05-17 |
| IL111454A (en) | 2001-08-08 |
| MY112413A (en) | 2001-06-30 |
| NO301880B1 (en) | 1997-12-22 |
| HK1006711A1 (en) | 1999-03-12 |
| EP0650961B1 (en) | 1997-03-05 |
| NO944162D0 (en) | 1994-11-01 |
| PL305646A1 (en) | 1995-05-15 |
| CZ289356B6 (en) | 2002-01-16 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |