CA2082076A1 - Pyridine-2,4 and -2,5-dicarboxamides and their derivatives, process for their preparation, and their use - Google Patents
Pyridine-2,4 and -2,5-dicarboxamides and their derivatives, process for their preparation, and their useInfo
- Publication number
- CA2082076A1 CA2082076A1 CA002082076A CA2082076A CA2082076A1 CA 2082076 A1 CA2082076 A1 CA 2082076A1 CA 002082076 A CA002082076 A CA 002082076A CA 2082076 A CA2082076 A CA 2082076A CA 2082076 A1 CA2082076 A1 CA 2082076A1
- Authority
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- Canada
- Prior art keywords
- alkyl
- alkoxy
- radical
- alkylamino
- hydroxyl
- 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
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
Abstract
Abstract of the Disclosure:
Pyridine-2,4- and -2,5-dicarboxamides and their deriva-tives, process for their preparation, and their use There are described pyridine-2,4- and -2,5-dicarboxamides and their use as pharmaceuticals, in particular as fibrosuppressants adn immunosuppressants.
Pyridine-2,4- and -2,5-dicarboxamides and their deriva-tives, process for their preparation, and their use There are described pyridine-2,4- and -2,5-dicarboxamides and their use as pharmaceuticals, in particular as fibrosuppressants adn immunosuppressants.
Description
20~2~7~
..
~OECI~ST Ai~TIl5~aGE5ELL5C~AFT ElOI~ 91/F 350 Dr.Fl/bw De~scription Pyridine~2,4- and - 2,5-dicar~oxalD.ideE~ asld their der~va tive~, proc~s ~or their praparation, and their use 5 Compound~ whiah irlhibit thz enzyme~ prolin~ hydroxyla~e and lysine hydroxylAE~e c~3.u~e~ a highly ~el~ctive inhibi-tion o~ coll~gen bio~ynt}~esi~3 by a~fecting th~ collagen-specific hydroxylation reactione. During these reaation~, protein-bound proliE~e or ly~ine i~ hydroxylat0d by the 10 enzymes proline hydroxyla~e ar~d lysine hydroxyla~e, re~-pectively. If thi~ r~action is pr~vented by inhibitors, the result i~ a non-funetio~al, subhydr~xylated collag~n molecule, of which o;lly a 3m21ll ~mount ~an be released :~ rc:m the c:ellS~ into the e~tracelluar space~ Moreover, ~he 15 subhydroxylatl3d collagen c:almot be i~oorporated ~nto the collagen matrix and i~ ~ubject to ~ery rapid proteolytic degradation. A~ a ~:orlsequ~nce o~ the~e efiects, the total amount of extrac~llulaxly depo~ited collagen decrea~es .
It is known th~t illhibition oiE proline hydroxylass by known inhibitors, sus:h a~ dipyridyl, re~ult~ in an inhihitioh of the Clq bio~ynthe~i~ of ~a~rophage~
~W. Muller et al., FEB~ Lett. 90 (19783, 218; Immun-biology 155 (1978), 47~. ~he cla~ical pathway o~ c~mpl~-ment activa~ion i~ there~ore not available. Proline hydroxyla~e inhibitor~ therefore al~o act a~ in~uno-depressants, for sxample in Lmmune complex di~order~.
It i8 knowm that the e~zyme proline hydroxyla~e i~
inhibited e~fectively by pyridine-2,4- and -2,5-di-carboxylic aoid ~. Majamaa et al., ~ur. J. ~iochem. 138 ~1984) 239-245). When these compound~ are ueed in aell cultures, however, they only act aq inhibitor~ when present in very high con~entration~ (Tschank, G. et al., ~iochem J. 238 (1987) 625-633).
..
~OECI~ST Ai~TIl5~aGE5ELL5C~AFT ElOI~ 91/F 350 Dr.Fl/bw De~scription Pyridine~2,4- and - 2,5-dicar~oxalD.ideE~ asld their der~va tive~, proc~s ~or their praparation, and their use 5 Compound~ whiah irlhibit thz enzyme~ prolin~ hydroxyla~e and lysine hydroxylAE~e c~3.u~e~ a highly ~el~ctive inhibi-tion o~ coll~gen bio~ynt}~esi~3 by a~fecting th~ collagen-specific hydroxylation reactione. During these reaation~, protein-bound proliE~e or ly~ine i~ hydroxylat0d by the 10 enzymes proline hydroxyla~e ar~d lysine hydroxyla~e, re~-pectively. If thi~ r~action is pr~vented by inhibitors, the result i~ a non-funetio~al, subhydr~xylated collag~n molecule, of which o;lly a 3m21ll ~mount ~an be released :~ rc:m the c:ellS~ into the e~tracelluar space~ Moreover, ~he 15 subhydroxylatl3d collagen c:almot be i~oorporated ~nto the collagen matrix and i~ ~ubject to ~ery rapid proteolytic degradation. A~ a ~:orlsequ~nce o~ the~e efiects, the total amount of extrac~llulaxly depo~ited collagen decrea~es .
It is known th~t illhibition oiE proline hydroxylass by known inhibitors, sus:h a~ dipyridyl, re~ult~ in an inhihitioh of the Clq bio~ynthe~i~ of ~a~rophage~
~W. Muller et al., FEB~ Lett. 90 (19783, 218; Immun-biology 155 (1978), 47~. ~he cla~ical pathway o~ c~mpl~-ment activa~ion i~ there~ore not available. Proline hydroxyla~e inhibitor~ therefore al~o act a~ in~uno-depressants, for sxample in Lmmune complex di~order~.
It i8 knowm that the e~zyme proline hydroxyla~e i~
inhibited e~fectively by pyridine-2,4- and -2,5-di-carboxylic aoid ~. Majamaa et al., ~ur. J. ~iochem. 138 ~1984) 239-245). When these compound~ are ueed in aell cultures, however, they only act aq inhibitor~ when present in very high con~entration~ (Tschank, G. et al., ~iochem J. 238 (1987) 625-633).
2 ~ 7 ~
~ .
D~-A 3~432,0g4 described pyridine-2,4- ~nd ~2,5-di-carboxylic ~cid die~ter~ h~vin~ lWB carbon ~tom~ in the ~st~r alkyl ~oiety a8 pharmaceutic~l~ for ~nhibiting proline hydroxylas~ and ly~ine hydroxyla~e~
5 however, the ~hortcomi~g o $he~e low~r~al~ lated di~sters i~ that they are too rapildly cle~ved in the organism to giv~ th~ a~id~, and that they do ~ot reach the site o~ action in the cel~ in suffici3ntly high concentration~, which ~ak~s th~m le~ ~ultable for possihle admini~trat~on ~ pharma~eutical~
DE-A-3,703,959, D~-A-3,703,962 a~d D~-A-3,703,963 pro~ide the general description of mix~d e~ter/~mide~, higher alkylated die~ter~ and diamide~ of pyridine-2,4- a~d -2,5-dicarboxylic acid which are ef~icien~ inhibitor~ of aollagen bio~ynthesi~ ~n the animal ~odel.
For example, DE-A 3,703,959 de~cribes, inter alia, ths ~: synthe~is of N,N'-bis~2-methoxyethyl)pyridine-2,4-di-oarboxylic diamide and ~ bi~3-i~opropoxypropyl)-pyridine 2,4-dicarboxylio diamide.
. .
German Patent ~pplication~ DE-A-3,825,471 and D~-A-3,828~140 propo~e an impxoved proce~ ~or the i prepara~ion of ~ bis(2-methoxyethyl)pyridine-2,4-di-~arboxylic diamide. German Patent ~pplioation DE~A-3,924,093 propose~ novel ~W'-bi6(alkoxyal~yl~-pyridine-2,4-dicarbo$ylic diamides.
There wa~ ~ need to ~earch for other oompound~ having an ~mproved pharm~cological activity with regard to the inhibition o~ lysine hydroxyla8e and proline hydroxyla~e.
Surpri~ingly, it ha8 n~w been found that thi~ object ia achieved by the following pyridine-2,4- and -2,5-di-carboxylic diamides.
_ 3 _ 2 ~8~7 ~
The invention therefore relat~s to ~:cDIipou~d~ of the ~ormula I
O ~--N--R2 R'~ (I) N ~ ~ ~ ~4 o in which S Rl, R2, R3 and R4 are identical or differ~nt and are A a bran~hed or unbr~n~h~d, aliphatic or ~yclo-aliphatic (C1-Cl2~-alkyl r~di~al, gCl-C~2~-alke~yl radi~al or a (C1-Cl2)-alkynyl radieal, ea~h o~ which is mono~ub-~tituted or poly~ub~tituted, prefer~bly mono~ub~ti.tuted or di~ubstituted, by ~ ~ Cl-C9 ) -alkoxycarbonyloxy, (C1-Ca)-alkXY~( Cl~Ca ) alkoxycarbonyloxy, (C6--Cl2)-aryloxy~arbonyloxyt (C7-C
aralkyloxy~arbonyloxy, (C~-C~ aralkylcarbonyloxy, ,:cinn~moyl, ~innamoyloxy, ~C6-Cl2)-~rylc~rbonyloxy, ~C8-C8~-alkenylcarbonylo~y, ~C3-C~)-al~ynylcarbo~yloxy, (C3oC8)-cycloalkylcarbonyloxy, (C1-C~-alkoxy-(C~-Cl2)-alkoxy, ::~Cl C~)-alkoxy-amino,(C1-C~)-alkoxy-N (C1-C~-alkyl~mino, 12) -alkoxy-~,N (~l-C5)-dialkylamî~o, aarbamoyloxy, N-~C1-C~)-alkylcarb~moyloxy, ~,N-di-(Cl-C8~ yl~arba~oyl, ~:20 N-(C3-C~)-cy~lo lkylcarbamoyl, ~-(C~-Cl2)-ar~lamino, N-(C7 C~ arAlk~lam~no, N-alkyl-aralkylami~o, ~-alkyl-arylamino, (C3-C8 )-cycloalkanoylamino, ~C1 C~)-alkanoyl-~mino, (C6-cl2)-aroylamino~ (C~-C~ aralkanoylsmino, (C~-C8);alkanoyl-(Cl-Ca)-alkylamino,( C3 ~Ca)-cyclo~lkanoyl-(C1-C8)-alkylamino, (C8-Cl2)-aroyl-lCl-C~)-alkyl d no, (C7-C~ aralkanoyl-(Cl-Ca)-alkylamino, (cl-c8)~a mercapto, (C1-CB)-alkyl~ulflnyl, (C1-Ca)-alkylsulfonyl, (C1-C8)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, _ 4 _ 2082~7~
trifluoromethyl~ phenylm~rcapto, phenylsulfonyl~ ph~nyl-sulfinyl, ~ul~amoyl, X3-(Cl-C~-a~ ul~amoyl, ~ di-(Cl-C~)-alkylaulfamoyl, ~Cl-CB)-Alkyl~ulfonamido and ~ryl~ulfonamido, where the ~ d ~ralkyl radicals in S the above ~ubotituents c~n ~l~o h~ve a heteroc:yclic natu:re and/or, lik~ lkyl, are sub~;titut~d ~ 1, 2, 3, 4 or 5 id~ltic:al or d~ ff~ar~nt ~ubl3tituentl3 ~elected :Erom the ~eriee c:omprising halogsn, cy~no, tlitro, trifluoro-methyl, ( Cl~C~ allcyl, hydroxyl, ~ ICl-C,3 ) -hydroxyalkyl, 10 (Cl-C6~-alkoxy, ~Q-tCEI2-~sc~ +, "F" -OCF2Cl, -O-CF2-C~FCl, trif luorom~thyl ~ Cl-Ca ) -alkylDI2roapto ~ B ) -allcyl-~ulfinyl, tCl-C630alkylsulfoslyl, (Cl-~6)-alkylcarbcnyl, ( Cl-C6 ) -alkoxya~rbonyl, I:arbamoyl, N- ( C~-C" ) carbamoyl, N,N-di-(Cl-C~)-alkylc:arbamoyl, ~Cl~C~)-alkyl-carbonyloxy, tC3-C8)-cyaloalkyl, phenyl, b~yl, ph¢noxy, benzylo~y, NR'-R", phenylmercapto, phenyl~ul:Eonyl, phenyl~ulfinyl, ~ulfamoyI, N-~Cl-C4)-alkylsul~a~oyl or ~,N-di-~C1-C4)-al~yl~ulf~moyl, in p~r~icular by up to 3 of the abovementioned identiaal or differeAt ~ub~tituent~r and a CH2 group of the ~lkyl chai~ i~ optionally replaced~
by 0, S, SO, SOz or ~R'9 or by a substituted (C~-C~)-aryl radical or heteroa~yl radical havin~ 1, 2, 3, 4 or S identical or different 6ub~tituent~ from the series ~omprising hydroxyl, tri-fluoromethyl, ~C~oC6)-hydroxyal~yl, -O-[C~2~]3C~2~l8)E~
OCF2Cl, -OCF2 C~FCl, (Cl-C6)-alkylmercapto, ~Cl-C~3-~lkyl-~ulfinyl, (Cl-C6)- lkyl~ul~onyl, ~C~-C6~alkylcarhonyl, ~Cl-C6)-alkoxycaxbonyl, carbamoyl, N-~Cl~C~ yl-carbamoyl, ~,N-di-(Cl-C~)-alkylcarbamoyl, (C~-C~)-alkyl-3Q carbonyloxy, (C3-Ct)-cyclo~lkyl, phenyl, benzyl, ph~noxy, benzyloxy, NR',R", phenylmercapto, phenylsul~onyl, phenyl~ulfinyl, sulfamoyl, N-(Cl-C~)-alkyl~ulf~moyl, N,N-di-~C~-Cs)-alkylsulfamo~l, (Cl-C8)-alkoxycArbonyloxy, (C1-C8)-alkoxy-(Cl-C~)-alkoxycarbonyloxy, (C6-C~)-aryloxy carbonyloxy, (C7-C1l)-aralkyloxycarbonyloxy, ~C7-C1l)-aralkyloarbonyloxy, cinnamoyl, cinna~oyloxy, (C6-C~)-arylcarbonyloxy, ( C3-C~ ) -alkenylcarbonyloxy, ~C3-C8)~
2~7~
alkynylcarbonyloxy, ~C3-C~ ) -cycloalkylcarbonyloxy, (C~-C~)-alkoxy-~C~-Cl23-~lkoxy, ~Cl-Cl2) alko~y-aminv, l~l-Cl2)-~lkoxy-N 5Cl C5)-alkylamino, ~Cl-Cl2~-alkoxy-~l,N
(Cl-C~)-dial~yl~mino~ carbamoyloxy, N-(Cl-C~)-al~yl-c~rbamoyloxy) ~ di-(Cl-CG)-~lkylc~rb~moyl, ~-tC3-C~)-cycloalkylcarbamoyl, N-(c~-c~)-a~yl~mi~o~ ~-(C7-c~
~ralkylamino, N-alkyl-aralkylamlno/ ~ ~lkyl-aryl ~ no, (C3~C8)~Cycloalk~noylamlno~(cl-c~)-alkanoylRmino~(c~-c~)~
aroyl~mino, ~C7-C~ aralkanoylamino, (Cl-C~)-alkanoyl-0 (Cl~c2)-alkylaFino, ~C3-C~) -cyaloalk~noyl-(C~-C~)-alkyl-amino, lC~-C~)-aroyl-(Cl C8~-alky}amino, (~rCl~)-ar alkanoyl-~C1 C~)-alkylamino, tCl-Ca)-alkylmercapto, ~Cl-C8~-alkyloul~inyl, (Cl-Ca) ~lkyl~ulfonyl, (C 8)-~lkylcarbonyl, ~C3-Ca)-~yc}o lkylcarbonyl, nitro, tri-fluoromethyl, phenylmercapto, phenylsulfonyl~ phe~yl-~ 3ll1finyl, ~ulfamoyl, N-(Cl-C6)-alkyl~ulfamoyl, ~ di-- (Cl-C6)-al~ylsulfamoyl, ~CI_C~ alkyl-sulfon~mido ~nd arylsulfonamido, where the aryl and alkyl radi~al~ in the a~ove ~ub~tituents o~n al00 haYe a heterocycli~ nature and~or, like ~lkyl, oan be ~ub~t~tut~d b~ 1~ 2, 3, 4 or 5 identical or different ~ubstituent~ from the ~eri~
comprising halogen, ~yano, nitro, trifluoromethyl, ( C~_CB )-alkyll hydroxyl, (C~-C~3-hydroxyalkyl or (C~-C6)-alkoxY r or by a ~ub~tituted ~C6-Cl2)-aryloxy radical, (C7--Cll)-aralkyloxy radical or hetero~ryloxy radical, ~ach of which ha~ 1, 2, 3, 4 or 5 identi¢al or differe~t ~ub-~tituents selected ~rom the ~eriea ~o~pri~ing hydroxyl, halogen, cyan~, nitro, trifluoromethyl, tCl-C6)-hydroxyalkyl, (C1-C8)-alkoxy~ 2-33~5 ~OCF2-C~FClr tC~ alkylmercapto, (Cl-C6)-allcyl~ul~inyl~
(Cl-Ca)-alkylsulfonyl, tCl-C0)-alkylcarbonyl, tCl-C6)-alkoxycarbonyl, carb~moyl, N-(Cl-C~) alkylcarbamoyl, N,N-di-(Cl-C~)-alkylcarbamoyl, (Cl-C~)-alkylcarbonyloxy, (C3-C5)-cycloalkyl, carboxyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenyl~ulfonyl, phenylsulfinyl, sulfamoyl, N-(Cl-C~)-alkylsulfamoyl, 2~82~
N,N-di-(CI-C4)-alkylsulfamoyl, aminoalkyl, N-~C1-C8)-alkylamino-(Cl-Cl2)-alkyl or N-di-(Cl-Ca)-alkylamino-(Cl-Cl2)-alkyl and which i9 optionally ~ubstituted by up to 3 o~ the abovem~ntioned identical or dif~erent ~ub-~titllent~, and one CH2 group of the alkyl chain i~ option-ally replaeed by O, S, SO, 52 or NR', or by a radical of the formula II
~5 (II) in which R5 is an amino acid bonded via it~ acyl radical, or a derivative of this amino acid, or an alcohol protec-tive group, B a substituted ~C6-C12)aryl radical, (C7-C1l)aralkyl radical or heteroaryl radical, each of which i~ monosub stituted or polycub~titutedJ pre~erably mono- or disubntituted, by hydroxyl, amino ~C~-C8)-alkoxycarbonyl, (Cl-C8)-alkyl~
carbonyloxy, ~ Cl-c8 ) -alkylamino, di-( Cl-C8 )-alkylamino, ~:: (C1-C6)-hydroxyalkyl, -O-~CH2-]XcfH(2~ )F3~ -OCF2C1, -OCF2-CHFCl, carbamoyl, N-~Cl-C8)-alkylcarbamoyl, N,N-di-(Cl-C8)-alkylcarbamoyl, (Cl-C8)-alkylcarbonyloxy, (C3-Ca)-eycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, amLnoalkyl, N-(Cl-C8)-alkylamino (Cl-Cl2)-alkyl or N,N-di-. (cl-ca)-alkylamino-(cl-cl2)-alkyl, (Cl-C8)-alkoxycarbonyl-oxy, (cl-c8)-alkoxy-(cl-c8)-alkoxycarbonyloxy~ (C6-C12)-aryloxycarbonyloxy, (C7-C1l) aralkyloxycarbonyloxy, tC7-Cl1)-aralkylearbonyloxy, cinnamoyl, einnamoyloxy, (Cg-Cl2)-arylearbonyloxy, (C3-Ca)-alkenylearbonyloxy, (C3-C8)-alkynylaarbonyloxy,(C3-Ca)-eyeloalkylcarbonyloxy, (C1-C1z)-alkoxy-(C~-Cl2)-alkoxy, (Cl-Cl2)-alkoxy-amino, (Cl-Cl2)-alkoxy-N (Cl-C6)-alkylamino, (C~-C~2)-alkoxy-N,N
(Cl-C6)-dialkylamino, earbamoyloxy, N-tC1-Ca)-alkylcarbamo-2~82~7~
yloxy, ~, N-di- (C~-C~ alkyl~ 0yl, N- ~C3-C6 ) -cyclo~lkyl-ca~bamoyl~ N-(C~ ryl~lno, N~t~r~ ral~ylamino, N-alkyl-arallcylamino, N~ o, ~C~-Ca)-c:yclo-alkanoylamino, ~Cl-CO) -~lkanoyl~m~no~ ~C~,-C~ royl~no, (C7-C~ aralk~noyl ~ no, (Cl-Ca)A~Llkanoyl-(Cl-C~,)-~lkyl-amino, ~ E9-C~ ycloalkanoyl- (Cl-COJ -ell~c3rla~no t (C3-e~
aro~rl-(Cl-C81-alkylamino, (C7~C~ ralk~oyl-(C~ CO)-nlkyl-A~n~no, ~C1-C8)-a}kylmercapto~ (c~l-c~ k3rl~ulfinyl~
(Cl-~a)-alkyl~lul~onyl~ ~C~-~8)~ carbolly~ 3-C~
10 cyclo~lkylc~rbonyl, nitro, tr~luo~omethyl, ph~nyl-:~ ~er~:apto, phenyl~ulfonyl, phenylsuli~i~yl, 3ulfæmoyl, N-(C1-C6)-alkylaulfamoyl, ~9~ di-~C~-C~ alkyl~ulfamoyl, (Cl-Ct) -alkyl-E~uliEonami do or ~LrylsuliEon2mido, .
C a substituted (Cl-Cl2) ~lkoxy radical, ( 3-C~ cyclo-15 alkoxy, (C6-C~2)-aryloxy rAdical or ~ (C~-C~a)-aral~yloxy radical, each of which i~ ~onosub~itu~ed or polysub~ti-tuted, pre~erably ~OAO- or di~ubstituted, ~y halogen, tri~luoro~ethyl, (C1-C~ alkoxy, hydroxyl~
( Cl-C~ ) -hydroxyalkyl, ~R ' R ~' or cyano 20 where in each ca~e R' and R" are identical or different and are hydrog2n, DC12) -aryl, ( C1-CB) -a ~ C~-C5) -,alkylcarbonyl, (C~-Cl1~-aralkylcar~onyl or tC6-C~ rylcarbonyl, or together with the nitrogen, form a saturated heterocyclic 25- ring, pref~rAbly a 5- or 6-m~ r~d ring, and the abovementioned r~dia~l0 R19 p~2, ~3 ~nd R4 e~ occur ` in combination with n (C~-C12~-alkyl radical whi~h i~ mc~no~ubsti~uted or poly~ubetituted, pre~erably mono- or di~ubstituted, }~y hydrogen, halogen, hydroxyl, cyano, ~mino~ carboxyl, (C1-Cj)-alkoxy, (C1~C~ lkoxyc~rbonyl f (Cl C4)-alkyl-carbonyloxy, (Cl C~)-slkyl~ o~ (Cl-C~)-di~lkylamino or with 2~82~7~
a phenyl ring which i~ ~ono-, di- or txi~ub~tituted by the r~dical~ halogen, n~tro, (C1-C~)-alkyl or ~Cl-C4~-alkoxy, or in ~mbination with an aryl or het~roaryl radiaall ~ach of which ~a~
S turn, optionally be mono-, di- or trisub~tituted by halogen, nitro, cyano, ~Cl-C~ lkyl, ( C~-C4)~ alk9Xy~
including all deri~a~ivas which have a zuitable prot~c-tive group in ~heir ~mino or hydroxyl group~, and the phy~iolo~ically active ~alt~ d n i~ O or 1, f is 1 to 8, preferably 1 to 5, g i~ 0, 1 to (2f+1), ~hd x i~ 0, 1, 2 ox 3, preferably 0 or 1.
Aryl, aryloxy, heter~aryl or heteroa~yloxy ~ompounds are : 15 -~nderstood as meaning, in particular, phenyl and naphthyl rin~8~ or unsub~tituted 5- and 6-~embered heteroaromatic ring~ having l, 2 or 3 ni~rogen and/or oxygen and/or ~ulfur atoms, such a~ pyridyl, pyridazyl, pyrimldyl, pyrazyl, imidazolyl, triazolyl, thienyl, oxazolyl and thiazolyl ~eri~atives, nd their benzo-fused derivative~.
The radical ~C7-C~ aralkyloxy ie preferably u~der~tood as meaning a ~ubstituted phenylalkyloxy radical o~ the ; . formula III
-O -[CH2-lr ~ R~ (III) Rl R9 in which 2t)82~7~
g R8, ~7~ R8 ~nd RlQ are identical or di~fer0nt and ar~
hydrogen, halogen, cyano, nitro, txifluorumethYl, (I~ C5~-alkyl, (Cl-C~ alkoxy, -O-t~2~ CyH~2~ s)F3~ -OCF2Cl~
-O-CF2-CEIFCl, ~ Cl C~ ) -alkylmers~apto, ~ Cl-C~ ~ ~alkylsulf ir~yl, S (C~-C~ alkylsul~onyl, ~C,-Ca)-alkylcarbonY~ G~-alkoxyc:arbonyl, carbaDJoyl, N- t Cl C4 ) -alkylc:arlbamoyl, Il,~-di- ~C~-C~ ~ alkylcarbamoyl, (5~1 C6~ -~lkglcarbonyloxy, C3-C8 ) -~ycloalkyl, phenyl, benzyl, pherloxy, benzyloxy, ~R'-R", suQh as ~mino, anil~no, ~-methylanilino, phenyl-10 mer;:apto, phenyl~ul~onylg ph~yls~ Einyl, ~ulf~moyl,~-~C~-C")~alkylsulf~oyl or N,~-di-ICl-C~3-allcylsulfamoyl, or two adjac~t subst~tuen~r~ together are ~I chain -~CEI2-~n or -CE~-C~-CB~C~-, where a C~2 group of th~ chain i~
optionally rep}aed ~ O, S, SO, SO2 or NR', Y i3 1, 2~
15 3 or 4 ) pref~rably O and 1, and the remaining o~ the substituents R6, R7, R8~.R~ and Rl are a8 de~ined above.
o acids which are preferred fxom among~t those mentioned above are~ in particular, the natural ~-amino ~cid~.
Amino proteative group~ are under~tood ~ aning, in particular, ~u~h group~ aB are de~cribed in R. ~eiger and W. ~nig "The Peptides" Volume 3, "Protection of Func tional Group~ i~ Peptide Synthesi~, B.~. Gro~s, J. Meienhofer ~dit, AGademic Press, ~ew York (1981l, in particular pages 7-4~.
Such groups are also deacribed in ~. ~ubbu~h, S~hutz-gruppen in der Peptidsynthese [ProtectiYe Group~ in Peptide Synth~Eis], Rontakte 3/791 pag~o 14-23.
Particularly pre~erred amlno protective group~ are the ~oll~wing:
Aoetamidomethyl, l-Adamantyloxycarbonyl, l-tl-Adamantyl)-l-methyl-ethoxycarbonyl, ~)82~7~
Allyloxycarbonyl, tert-Butyloxycarbonyl, 1~4-Biphenylyl)-l-methylethoxycarbonyl, Dicyclohexylaarbodilmlde, ~,~-DLmethyl-3,5-dimethoxybenzyloxycarbonyl, 4-Dihydroxyborylbenzyloxycarbonyl, 9-Fluorenylmethyloxyc~rbonyl l-~ydroxybenzotriazole, 3-Hydroxy 4-oxo-3,4-dihydro-1,2,3-benz~triazine, I~obornyloxycarbonyl, l-~ethyl-cyclobutylo~yc~rbonyl r 4-Methoxybenzyloxyc~rbonyl~
~ethyl~ulfonylethyloxycarbonyl, 4~Pyridylmethyloxycarbonyl, lS 2,2,~-Trichloro-tert-butyloxycarbonyl, ~enzyloxycarbo~yl, halogen-sub~tituted b~n~yloxycarbo~yl, 4-Nitro-benzyloxycarbonyl J
2-Phosphonoethyloxyc~rbonyl, : 20 Phenyl~ulfonylethoxyG~rbonyl, Toluenesulfonylethoxycarbonyl, ~,3,5 Trimethyl-4-methoxy-phenyl~ul~onyl, Benzotriazol-l-yl-oxy-tri~(dimethylamino)phosphonium hexafluoropho~phate.
2~ Preferred compound~ ~rom amongst tho~e o~ the ~ormula I
who~e amino groups are protected are those whose pro-tected amino group i~ part of this amino acid R5.
Suitabls alcohol protective groups axe, in pa~ticular, ~ub~tituted or unsub~tituted ~ethyl ethere, ethyl ethers, benzyl ether~, silyl ether~, e~ters, carbonates or ~ulfonate~.
rhey embra~e the ollowing compounds:
., .
~ .
:~.
8 ~
A~ ~ubstituted methyl ~thers:
~ethoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyld ~ethyl~ilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, ~4-methoxypheno~y)~methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenylo~ymethyl, ~iloxymethyl, 2-methoxye~hoxymethyl~ 2,2,2-tri~hloro-ethoxymekhyl~ bia~2-chloroe~hoxy)m~thyl, ~-~trLmethyl-3ilyl )ethoxymethyl,tetrahydropyranyl~3-bromotetrahydro-pyranyl, tetrahydrothiopy~anyl~ 1-methoxy~yclohexyl, 4-methoxytetr~hydropyrar,yl, 4-m~thoxytetrahydrothio pyranyl, 4-methoxytetrahydrothiopyrAnyl-S,S dioxo, 1-~2-chloro-4-me~hyl)-phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-20yl, tetrahydrofuranyl J tetrahyfirothio-furanyl.
As sub titut~d ethyl ethers:
1-Ethoxyethyl, 1-(2-chloroethoxy)ethyl, l-methyl-l-methoxyethyl, 1-methyl l-benzyloxy~thyl, l-methyl-1 benzyloxy-2-fluoroethyl, 2,2,~-trichloroethyl, 2-tri-methylsilylethyl, 2-[phenyl~elenyl)ethyl, t butyl, allyl,-p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl.
As ~ubstituted benzyl ethern:
p-Methoxybenzyl, 3,4-dimethoxybenzyl, o nitrobenzyl, p-nitrobenzyl, p-halogenobenzyl, 2,6-dichloxobenzyl, p cyanobenzyl, p-phenylbenzyl, 2- and 4-pioolyl, 3-methyl-2-picolyl-N-oxido, diphenylmethyl, p,p'-di-~itrobenzhydryl, triphenylmethyl, ~-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethy~, di(p-methoxy phenyl~-phenylmethyl, tri(p-methoxyphenyl)~thyl, 4~(4'-bromophena~yloxy)phenyldiphenylmethyl, 4,4',4"--tris(4,5-dichlorophthalimidophenyl)methyl, 4,4'4"-tris(levulinooxyphenyl)methyl, 4,~4 n -tri8-(benzoyloxyphenyl)methyl, 3-(imldazole-1,4~-methyl)bis-(4'4"-dimethoxyphenyl)-methyl, l t 1-bi~(4-me~hoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)x~nthenyl, 9-(9-phenyl-10-oxo)anthryl.
~2~
AB ~ilyl ether~-Tr ~ethylsilyl; triethyl~ilyl, trii~opropylsilyl, dim~thyli~opr~pyl~ilyl~ diethyli~opropyl~ilyl, dLm~thyl-thexyl~ilyl, t butyldLmethyl~ilyl, t-butyldiphenyl~ilyl, tribenzyl~ilyl, ~ri-p-xylyl~ilyl, triph~nyl~ilyl, diphenylmethylsilyl, t-butylmethoxyph~enyl~ilyl.
As e~r~:
Formate~, benzoyl fo~mate~ acat~t~, ch~oroa~etate, dichloroaaet~te, trichlo~oacetate, trif luoroacet~te, 10 Dnethoxya~:etate, triphenylmæthoxyac~etate~ phenoxyacetate, : p-chloroph2noxyacetate, p-P-phenyla~et~te, 3-phenyl-propiorlate, 4-oxoperltanoate t l~vul inate ), 4,J.-(ethylenedithio)pentanoate, pivaloate, adamantoate, cxotonate, 4-1nethoxycrotonate, b~rlzoate, 15 p-phenylbenzoate, 2,4,6-tr~me~thylb~nzoate (m~itoate)~
A~ ~arbonates:
~ethyl, 9-fluorenylmethyl, ~thyl, 2,2,2-tri¢hloroethyl, 2-~trL~ethyl~ilyl)ethyl,2-~ph~nyleulfonyl)ethyl,2-~tri-phenylpho~pho~io)~thyl, isobutyl, vinyl, allyl, p-nitro-phenyl, benzyl, p-methoxybenzyl, 3,4-dim~thoxyb~nzyl, o-nitrobenzyl, p-nitrobenzyl, S-ben~yl thiocarbonates, 4-ethoxy-1-naphthyl, methyl dithiocarbonate~.
Other e~ters:
2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4- ( 1,1, 3, 3 tetramethylbutyl )phenoxyacetate, 2,4-bi~-(1,1-dLmethylpropyl)phenoxyaoetate, chlorodiph~nyl-acetate, isobutyrate, monosuGcinate, (~)-2-~ethyl-2-butenoate (tigloate), O-(methoxycarbo~yl)benzoate, p P-benzoate, ~-naphthoate, nitrate, alkyl N~N,N',N'-tetramethylpho~phorodiamid~te, N-phenyl-carbamate, borate~, dimethylphosphinothioyl, 2,4-dinitro-phenylsulfenate.
:.
- 2~:~2~7~
~ 13 -As ~ulfonat0s:
Sulfatss, methanesulfonate (mesylate), benzyl~ulfonate, tosyl~tee.
The following protective groups are parti~ularly preferred:
(C1-C~-Alkanoyl, (Cs-C~)-alkylcarbamoyl, d~-(C~-Ca)-alkyl~
~arb~moyl, N-( C3-C~ ~-ayclo~lkylcarbamoyl, (Cl-C5)-alkoxy-carbonyl, ( C6-Clz ) -a~yloxycarbonyl, (C~ aralkyl oxycarbcnyl, in part~cular benzyloxycarbonyl, (C8-C~
arylcarbonyl, (C~-C~ aralkylcarbonyl, (C1-CB)-alkyl, (Cl~C~)~alkoxy-(C1-C~)-alkyl, ~arb~oyl-~C1-C~)-alkyl e~ter, (Cl-C1O)-acyloxy-(C~-C6)-~lkyl, pr~ferably (Cl-C10) alkanoyloxy-(Cl-C6 ~; alkyl, benzyloxy-( Cl-C6 ) a~kyl, benzyloxycarbonyloxy-~Cl-C~ alkyl, ~Cl-C~)~
alkoxycarbonyloxy-(Cl CB)-Alkyl, ~mino acid e~ter~ or tetrahydropyranyl.
Preferred compound~ of the formula I are tho~e in whi~h Rl and/or R3 Pre hydrogen or m~thyl and R2 and~or R4 have the abovementioned ~eanings.
Other preferred ~ompound~ of th~ formula I are those in which Rl and~or R3 are hydrogen and R2 nd/or Rb are A a branched or unbranched ~Cl-C12)-alkyl radi~al which is monosubetituted or poly~ub~tituted by ( cl-c8 ) -alkoxycar~onyloxy~ (C~-C8)-alkoxy (Cl-Ca)-alkoxycarbonyloxy, ~C8-Cl2)-aryloxycarbonyloxyl (C~-C11)-aralkyloxycarbonyloxy, (C7 C ~ aralkylcarbonyloxy, (C7-Cll)-arylcarbonyloxy, (C3-C8)-cycloalkylc:arbonyloxy, (Cl-C~2~-alkoxy-~e1-Cl2)-alkoxy, carbamoyloxy, ~-(Cl-C~)-alkylcarbamoyloxy, ~ di-( C1_CA1-alkyloarb~moyl~
~-(C3-C~ cycloalkylcarbamoyl, ~-~C~-Cl~)~
ar~lkylcarbamoyloxy or N-(C6-Cl2)-arylcarbamoyloxy, where the aryl and aralkyl radical~ in the above ~ub~tituent~
can al80 h~ve a heterocyclic nature and/or, like ~lkyl, are sub~tituted by l or 2 identical or different - 14 - 2~82~7~
~uh~tituent~ selected from the ~erie~ comprising halogen, trifluoromethyl, hydroxyl, (C1-Ca)~al~Y~ 3 ) -hydroxyalkyl, (C~-C~)-alkoxy, ~ ~2- ] ~C~2~+~ ~)F6 ~ -OCF2Cl ~
-0-CF2-C~FCl, -(C1-C~-alkoxycarbonyl, sarbdmoyl, ~Cl- C3 ) -alkylcarbonyloxy, (C3Ca~-~ycloalkyl~ phenyl, benZYlr phenoxy or ~enzylo~y, or by a sub&tituted (C8-C~2)-aryl radical or het~roaryl radi~al which h~8 on~ or two iden~ical or diferent substituent~ sel~ct~d ~rom the seri~ c4mpri~ing hydroxyl, trifluoromethyl, [Cl-C3)-hydroxyalkyl, (Cl-C3)-alkoxycarbonyl, ~arbamoyl, NR'R", ~-~Cl-C~ yl carbamoyl, ~ di-( C~-c4 )-alkylcarbamoyl, (Cl-C3)-alkyl-carbonyloxy, A~; noalkyl or N-(C1-C~)-alkylamln-tCl-c~)-alkyl, whare R' and R~ are identical or differen~ ~nd Are hydrogen, ~C~-Clz) aryl or (Cl-C4)-alkyl, or by a substituted (C6-C10)-aryloxy radical or ~C~-C~
aralkyloxy radical which has 1 or 2 identical or dif-fer~nt substituents s~lected ~r~ the nerie~ comprising hydroxyl, halogen, trifluoromethyl, (Cl-C3)-alkyl, (~ a)~
hydroxyalkyl, ( Cl-c3 ) -alkoxy, (Cl-C3)-alkylmercapto, (Cl-C3)-alkyl~ul~inyl, (Cl-C3)-alkylsul~onyl, (Cl-C3)-alkylcarbonyl t ( C1-C3) alkoxycarbonyl, carbamoyl, ~-(C1~C4)-alkylcarbamoyl, N,N-di-~C1-C~)-alkylcarbamoyl, (Cl-C3)-alkylcarbonyloxy or ~R'R~ where R' and R" are identical or dif~er~nt and are hydrogen, (C~-C1O)-~ryl or ~Cl-C4) alkyl, or by a radic21 of the formula II
R5 (II) in which R5 i8 an amino acid bonded via it8 ~cyl radical, or a derlvative of thi~ am1no acid, ~ ~ 2 ~ 7&
B i~ a ~C6-Cl2) aryl or (C7-C~ aralkyl radical, pre-ferably phenyl, benzyl and phenethyl, each o~ which i~
monosub~tituted by hydroxyl, (C~ C4)-alkylaarbonyloxy, (cl-c~)-alkoxycarbonyl~ tCl-C~)-hydroxyalkyl, ~mino, (Cl-C5)-alkylAmino, di- (C~-C5) -alkyl~mino, (Cl~~s)~
alkanoylamino, carbam~yl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl C~ lkyl~arbamoyl t ~rbamoyl, N-(Cl~C4)-alkyl-carbamoyloxy, N,N~ (Cl-C~)-alkylcarbamoyloxy, or C iB a tCl-C6)-alkoxy radical, ~C3-C~)-cy~loalkoxy radical, (CB_C1~ ) -aryloxy radical and ( C7-C~ aralkyloxy radical, : n i~ O or 1, is 1 to 8, preferably 1 to 5, g is 0, 1 to l2~
x i~ 0, l, 2 or 3J pr~f~rably O or 1, and wher~ the a~ovementioned radical~ Rl, R2, R3 and R4 can occur in combination with a (~-Cl2)-alkyl radioal which i5 monosubstituted or poly~ub~tituted, pr~ferably mono- or disubstituted, by hydrogen, haloge~, hydroxyl, amino, (Cl-C4~-alkoxy, (Cl-C4)-alkoxycarbonyl, (Cl-C~)-alkyl- or (C~-C~)-dialkylamino or a phenyl ring which i~ ~on~-, di- or trisubstituted by the radl~als halogen, nitro, (Cl-C4)-alkyl or (Cl-C4)-alkoxy, and also in ~ombination with a~
: 25 aryl or heteroary.l radi¢~l which, ~n turn, can optionally be mono~ub~t~tuted or di~ub~tituted by halogen, (Cl-C4)~
alkyl or (C~-C4)-alkoxy, including all derivatives which have a protective group in the respective amino or hydroxyl group, and the phy~iologically active aalts.
- ~6 - 2~8~
Particularly preferred compound~ of the formula I are those ~n which R1 nnd/or ~9 are hydrog~n and R2 and/or Rh are : A an unbranched (C~-C~)-41kyl r~dical which i~ ~ono-~ubstitut~d by ICl-C~)-alkoxyc~rbonylo~y, ~C1-C~-alkoxy-(Cl-C~)-alkoxycarbonyloxy, (C~-C~)raryloxycarbonYlO~Y, (C~-C~
aralkyloxycarbonyloxy, ~ C7~ r~lkyl~rbonyloxy, ~C6-Cl2)-arylcarbonyloxy, ~ C3-CB )-cycloalkylcarbonyloxy, ~cl-cl2~-alkoxy-(cl-c~)-alkoxy~ (cl-cl2~ kox~-~mino~
(C1~Cl2)-alkoxy-~-(Cl-c6)-alkylamlno~ (Cl-C12~-alkoxy-N,~-(C1-C6)-dialkylamino, ~ di-lCl-C~-alkylcarbamoyl, N-( C3_C~ )-cycloalkylcarbamoyl, ~-(C7C~ aralkylcarbonyl-oxy, N-(C6-Cl23-arylcarbamoyloxy, (~1-C5~-alkanoylamino, (C3-C6~-cycloalkanoylamino, (C5-Cl2)-~roylamino or (C7-Cll)-~: aralkanoylamino, where alkyl, aryl, aryloxy, aralkyl or aralkyloxy, in turn, are ~ub3tituted by h~droxyl or halogen, in particular fluorine, (Cl-C3)-alkyl or (Cl-C3)-alkoxy, or by a phenyl radical which i~ m~nosub~tituted by a hydroxyl group, or a ~ub~tituted phenoxy or benzyloxy radiaal which i~ ~ubstituted by hydroxyl, halogen or ~; (Cl-C~)-alkoxy, or by a radical of the formula II
-0-~3 (II) .:
;: in which R5 i~ an d no ~cid bond~d via it~ acyl radical, or a derivative o~ this amino acid which i~ ~ub~tituted on the amino group, B a (C6-CI2)-aryl or (C7_C~ ara1kY1 radi~al, pre~erably phenyl, b~nzyl and phenethyl, which i8 mono~ubstituted by hydroxyl, and 2~82~ ~
C methoxy.
The invention further~or0 rel~te~ to a proce~s for the preparation of compound~ of the ~ormul~ I which ~omprises reacting a comp~u~d of the ~or~ul~ IV
o ~ - C
; ~ (IV) C - Y
Il O
with a compound of the for~ulae V
H - N .~ or ~ V) : ~' ~: where Rl, R2 or R3, R4 are as defined in formula I and Y i8 halogen or hydroxyl or together with ths carbonyl group form~ an ~ctive ester or a ~ixed ~nhydride, and, if appropriate, ~onverting the reaction products into their ~ physiologically acceptable ~alts.
- The preparation of oompound~ of the formula I and the preparation of the st~rting material~ raquired therofor, unle~ they ar~ com~ercially available, will b~ described hereinafter in greater detail.
~he ~implest way of preparing the compound~ according to the invention i~ to combine the two co~ponent~, the pyridine derivative o~ the formula ~IV~ and the amine of ` - 18 - ~$2~
the formula (V~, in equ~s:)lar am:~unts or in up to ~pproximately 5-~old exce~EI of V, ~.nd ~o react them ~t t~mper4tures of between -3a and 150C, prefarably at 20 to 100C, until th~ reaction i~s QompleteO The end of the reaction can }:~e determined 3by mean~ of thin~ yer chromatography ~DC checlc~. In a varian~ o~ thi3 procea3, the reaction 1~ o~.rriad ou~; ~n a ~3uit~ble solvent ~uch as sliethyl ~ther or di~ethoxye~h~ne D~C tet:rahydro~ura~
chlorinated hydrocarbon~ ~uch a~ .methyl0ne 3:hloride~
10 ~hloroform, tri- or t~rac:hloroethylen~, benz~ne, toluene or ~lse po}ar a301vents such a8 diD~ethy~ ~ormamide or acetone or dimethyl ~ulf oxide .
In thi~ proee~s too, an exceEIY of amine of khe formula (V), which ean be up ~o approx. 5 fold, can be u0ed. The 15 reaction temperatures ~re between rooDI k~mperature and the boiling point o~ the E~olv~nt, temperatures in the range from room temperature o 13û~C being particularly preferredO
The reaction carl equally be carried out ~ria a m:Lxed anhydride such as ethyl ~hloroonmate, or via an acti-vated ~ter ~uch as paranitrophenyl e~ter (Y ~ CIC~2-COO
or NO2-C6~4-O). Suitable ~ethod3 can be found in ~ouben-Weyl, Methoden der Organi0chen Chem1e ~Methods in Organic .Chemistry], Volume XV/2, pages 169 to 183 ~mixed anhy--25 dride method), or pages 13 et s~q. (active e~ter method), fourth ed$tion, Georg Thieme Verlag, Stuttgart 1974.
If appropriate, the reaction can al~o be ~arried out in the presence of base~. 8uitable additional base~ ~re inorganic a¢id scavenger~ ~uch RB c~rbonates or hydrogen-car~onates, for example ~odium carbonate, pota3~iumcarbonate, sodium hydrogencarbonate or potassium hydrogencar~onate, or organic acid ~cavenger~ ~uch a~
tertiary amines, such a~ triethylamine, tributylami~e, ethyl diieopropylamine or heterocyclic amines ~uch as N alkylmorpholine, pyridine, quinoline or 2~2~7~
- lg -dialkyl~niline~ .
The compounds of the formula (IV) are preferably re~cted with ami~s of the formula (V~ with additio~ of a w~ter-el~nating agent ~suc:h ~E~ dialkylcarbodli~nidea where the 5 allcyl radical~ have 1 to 8 carbon ~5to~$3 which, in the casa of the C3-C9-eompound~, can al~o lbe bram:h~d or cyclic:; dicycloh~$ylc:arbodiimide ~ pref~rably ~mpls~y~d.
A s~litable laethod iE~ da~cribed in Elouben WQY1 Volume XV/2, pag~ 103 to ~ thoden der Org~ hen Chemit3 10 [Method3 in Organic ChemiE~try~, 4th ~dition, Georg ~hieme Verlag, Stuttgart, 1974.
I~ appropriate, the product6 can be worked up for ~ample by extraction or by chromatography, ~Eor example using silica gel. The i~3olated prodllct ~an be recrystallized 15 and, i~E appropriatet reac:l:ed with a suit~ble acid to give a physiologioally act:sptable ~alt. 13xamples oiE ~uitable acids are:
.
Mineral acid~ BUCh a~ hydrochloric ~nd hydrobromic ~cid a~ well as sulfurit: acid, pho~phoric ~cid, nitric aoid or perchloric ~cid, or organic acid~ ~uch a~ forn~c acidl acetic acid, propionic acid, ~uooinic ~oid, glycolic acid, lactic acid, malic ~cid, tartaric acid, ~:itric ; acid, maleic acid, fumaric acid, phenylacetic acid, benzoic acid, methanesulfonic acid, toluene~ulfonic acid, oxalic acid, 4-~minobenzoi~ acid, naphthalene-1,5-di : ~ulfonic acid or a~corbic ~oid~
If the ~tarting compounds of the fonmula (V) are not commercially av~ilable, they can be ~ynthe~ized in a ~imple manner (~or example Organikum, organisch Chemisches Grundpraktikum CPractical Foundation in Organic Chemistry], 15th ~dition, VEB Deutscher Verlag der Wissenschaften, 1976; a survey of the various po~si-bilitie~ can be found in khe methodological regi~ter, page 822~.
2 ~ 7 6 For exam~le, the ~tarting compound of the fonmula (IV) can be obtained by reaeting pyridina,-2,4- or -2,5-di-earboxylie acid to give tha corresponding pyridine-2,4-or -2,5-dicarboxylic halide, preferably the chloride (by proce~es ~nown fr~ the litarat,ure, for example Organikum, Organi~ch Chemi3che~ Grundpraktikum [Practical Foundation in Organic Chemistry], 15th ~dition, VEB
Deutsch~r Verlag der Wi~sen~chaften, 1976r page 595 et 8eq. ) ~ which i8 then reacted with ~ ~uitable aloohol, ~or example paranitrobenzyl ~lcohol, to give the aorrespond-ing active ester. Equal1y, the pyridine-2,4- or -2,5-di-carboxylic acid ~an also first be con~erted i~to a mixed anhydride by addition of a ~uitable ~arboxylic acid or : carboxylate, such as ethyl cbloroformate, and this mixed anhydride i8 then reacted with the amine6 (V) to gi~e the product~ accordi~g to the inve~tion. A ~uit~ble methcd i8 described, or example, in ~ouben-Weyl~ ~etho~n der Organischen Chemie tMethod~ in Organic Chemistry], Volume XV/2, pages 169 to 183, 4th Edition, 1~74, Georg ~hieme Verlag Stuttgart.
The ~ompounds of the formula (I) ~ccording ~o the inven-~; tion have valuable pharmacologic~l propertie~ and are, in ; particular, e~fective a6 inhibitor~ of proline hydroxy-aBe and lysine hydroxylase, a~ a fibrodepres~ant r immunodepre~ant and antiathero~clerotic.
;~ The antifibrotic action can be determined with the aid of ~: the carbontetrachloride-induc~d hepatic fibro~is ~odel.
To this end, rat~ are trQated twice weekly with CCl4 (1 ~l/kg) dissolved in olive oil. ~he test sub~t~noe i~
administered daily, if appropxiste even twice daily, or~lly or intraperitoneally, dissolved in a ~uitable acceptable solvent- The extent of hepatic fibrosis i~
determined hy~tologically and the amount of oollagen in the liver i8 analy~ed by hydroxyproline determination as described by Kivirikko et al. (Anal. Biochem. 19, 249 et ~eq. ~1967)~. The fibrogenetic ~ctivity can be determined 2Q8207~
by radio ~ unological det~r~instion o~ ~oll~gen ~ra~ments and procollage~ peptides in ~he ~erum. I~ thi~ mode~, the compounds according to th~ inv~ntion are active at a concentration of I-100 mg/kg.
5 The fibrogenet~c activity ~an be determined by radio~
unological determi~ation o~ the ~-terminal propeptide of the type III collagen or th~ N- or Co~ermi~al cro8~-linking domain of ~he type IV collagen (7~ ~ollagen or . type IV ~ollagen ~C1~ in the h~rum.
~o this end, the concentration of hydroxyproline, procollagen III peptide, 7~ collagen ~nd type IV ~ollagen NC in the liver wer~ measured in a) untreated rat~ (control), b) rat~ who had been adminis~red carbon tetrachloride (CCl; control) and ~) rats who had been administered ~irst CCl~ ~ollowed by a c~mpound according to the invention ~: ~thi~ te~t method i~ de~erib0d by Rouiller, CO ~ Experi-mental toxic injury o~ the liver; in The Liver, C. Rouiller, Vol. 2, page~ 335-476, N~w York, Academi~
Press, 1964).
Another model for evaluating the antibiotic action i8 that of bleo~ycin-induced pul~onary fibrosis ~s described by Kelley et al. (J. ~ab. Cli~. ~ed. 96, 954, (1980))~
~he ootton ball granuloma ~odel, as de~crib0d by ~eier et al., ~xperimentia 6, 4S9 (1950), ca~ be u~ed for evaluating the action of the ¢ompounds according to the invention on the granulation ti3~ue.
The compounds of the formula I aAn be uned a0 medicam~nt~
in the form of pharmaceutioal preparations which compri~e the compound3 of the formula I if appropriate together with acc~ptable pharma~eutical ~xcip;ents. ~he aompounds oan be u6ed aR drugs, for example in the ~orm o~ pharma-ceutical preparations, which compri~e these oompound~ in 2~82~7~
the f orm of ~ mixture with a pharmaceutic:dl, organic or inorgar~ic excip~ent which i~ 8uitable for enteral, percu-taneou~ or parenteral admini~tratl on ~uch as, for example, inter alia, water, gum nrabic:, gelatine, 5 lactose, starch, ~agn~ tearate, t~lc, ~regetab~
oil~, pc:lyalkylene glycc3ls and vaseline.
To thi~; end, they a~n be dmini~atered orally at do~age rates o~ 0.1-25 mg/kg/day, preferably 1-5 mgrkg/day, or parenterally at doE~age rates of 0.01-S ~g/kg/d y, pr~fer-10 ably 0.01-2.5 mg/kg/day, in pa:rticlllar D.5-1.0 mg/lcg/day.
In ~evere c:a8e8 ~ the dosage ra~e~ an ~150 be increa~ed.
In many c:a~es, however, lower do age rate~ ~uf~ice. q~hese data are based on an ~dl~lt per~3Qn of ~ bcdy w~ight of approximately 75 kg.
~` 15 ~he invention furthermore compri~e~ the u~e o:E the compound~ according to the invention in the preparation of pharmaceutic:als which can be employed for the treat-me~t and prophylaxi~ o~ the metabo1ic disorder~ :mentioned ~ above.
: 20 A further object of the invention are pharmaceutical3 :compri~inq one or more compound~ o~ the formula I acGord-ing to the invention and/or phy~iologically acceptable ~alts thereof.
The pharmaceutical~ are prep~red ~y proaesses which ~re known per ~e ~na ~amiliar to e person skilled in the art.
A~ pharmaceutical~, the pharmacologically active ~om-pounds ~ e active substance) according to the invention are employed either as such or, preferably, in combinn-tion with suitable pharmaceutical adjuvant~ or excipient~
in the form of tablets, coated tablet~, cap~ule~, ~up-positories, emulsions, ~u3pensions ox solutions, the active substance content being up to approximately 95%, advantageou~ly between 10 and 75%~
2~82~76 Suitable adjuvants or excipient~ for the desir~d pharma-ceutical ~ormulation are ~ be~ides ~olvents, g~lling agents, bases ~or 8Uppo8itorie8, tableting adjuvant~ and other aetive sub~tanc~ ~xcipi~nt~ for example ~l~o antioxidant~, di~persan~r ~mul~l~ier~, dsfoamers, flAvor improvers, preaervatives, ~olubilizer~ ~r colorant~.
The invention will be illustrat~d in greater detail hereinafter with the aid of example~.
~xample 1 lQ Bis-N,N'-~3'-benzoyloxypropyl)pyridl~é-2,4 ~ arboxamide a~ 25 g (128 mmol3 of dimethyl pyridine~ dicarboxylate are dissolved in 500 ~1 of ethanol and xe~luxed for 4 hour~ together with 22 ml l282 mmol~ of 3-amino-~ 1-propanol.
; 15 After the mixkure ha~ bean allowed to ~tand ovexnight at room temperature, the ~olvent i~ distilled off in vacuo, and the residue i~ ~rystallized from hot ethyl aaetate;
28.7 g m.p. 102-105C.
b) 0.7 g ~2.5 mmol) of the resulting pyridine-2,4-dicarboxylic bi~-N,N'-(3-hydroxypropyl)~mide are combined with 100 ml of di~hloro~eth~e and treated with 0.2 g of 4-~,N-dimethylaLlnopyridine, 0.8 ml (6 mmoll of triethylamine and dropwi~e ~ith 0.6 ml (5 mmol) of benzoyl ~hloride. After 1 hourt the mixtur~ i8 concentrated and the ~o~centrate i8 ta~en up in water.
After 1 hour, the mixtur~ i~ extracted twice by 3haki~g with water ~nd ~he organic ph~e i~ concentrated. The crude product i~ chro~atographed over silica gel using ethyl acetate, yield: 0.95 g of colorle~ oil.
Bmpirical formula: C27~27N3O8 (489) MS: m/e G 490 (M ~
- 24 - 2 ~2 ~ 7 ~xample 2 ~is-N,N~-~2-(2~m~thylbenzoyloxy)propyl3pyridine-2,4-diaarbox ~ de The title compou~d i8 obtained analogou~ly to ~xample 1 fro~ 0.7 g ~2.5 mmol~ of pyridine-~4-di~rboxyllc bis-~N~-(3-hydr~xypropyl)amide A~ 0.66 ml ~5 ~mol~ of 2-methylbenzoyl chloride, yield: 0.9l0 g of colorl~s~ oil.
~mpirical formula: C2~3lN306 ~517) ~S: m/e = 518 tM ~
, s~ 10 ~xample 3 2-N-~3-Methoxypropyl)-4-N-[3-(2-methylbenzoyloxy)propyl]
pyridine-2,4-di~arboxamide .3 g (40 mmol) o~ 4~benzyloxy¢arboDylpyxidine-~: 2-carboxylic acid Ar~ dis~olved in 160 nl of anhydrous tetrahydrofuran ~nd, at 0C, treated with 6 ml ~43 mmo~
-~ of triethylamine. After lO minutes, 4.1 ml (43 mmol~ of ethyl chloroformate are ~dded dropwi~e, and the mixture i8 ~tirred ~or 30 minutes at 0C-4.4 ml (43 mmol) of 3-methoxypropylam1ne are then added, the mix$ure i8 ~tirred for 1 hour at 0C and concentrated : in vacuo at room temperaturet the product i~ t~ken up in dichloromethane, the ~ xture iB wa~hed with ~aturated Na~C03 solution, dried ~d ~reed from ~olvent, ~nd 11.2 g of 4 benzyloxyaarbonyl~ 3-methoxypropyl)pyridi~-2~ 2-carboxamide are obtai~ed. 6~0 g (18.3 ~mol) of this compound are combined ~ith 15 ml of 3-amino-1-propanol and the mixture i~ stirred for 1 hour at 80C. The exce~.
reagent i~ distilled of~ in v~cuo and the residue i~
crystallized ~rom ethyl acetate, yield: 4.8 g o~
2-N-(3-methoxypropyl)-4-N~(3-hydroxypropyl)pyridine-2,4-dicarboxamide, m.p. 71-73C.
2~82~76 2 . O g of this c:o~pound are ~cylat~d ~nalogoll~ly to ~xample 1 u~i~g 2-methylbenzoyl chlorl~e7 A:Eter ~ilic~
gel chromatography using ~thyl ac:~tate, 2 . 4 g o~ the title compound are obtained ;~ a t:olorlsss;, oily prQduct.
S Bmpirical f o~mulal: C~ 2~N305 ( 413 . 5 ) MS: m/e ~ 414 (M ~ ~) }Sx~mple 4 2 -N- ~ 3-~ydroxypropyl 3 -4-~- l 3- ~ 2-methy:Lbenzoyloxy ) propyl ~ -pyridine-2, 4-dicarboxamide 1.6 g ~3.86 mmol~of the title compound of ~xample 3 are con~ined with 50 ml of di~:hlorome~hane, and 4.5 ml ol~ 1 N
boron tribromide solution in hexane ( 4 . 5 ~mol I are a~de :1 dropwise at -25C. After DC eh~k, a further 1.5 ml of this solution are added dropwl~e, and, aft~r 0.5 hour, the mixture i~ he~tad to room templ3rature and extracted .~ by ~haking with ~3atur~ted N~EIC03 ~olutiorl, the organic pha~3e i8 dried and s:oncentrated, and the oily re3idue i~
chromatographed on silica gel u~ g ethyl acetate /-methanol . O . 61 g o~ the title c:ompound crys~tallize ~rom 2 0 ethyl acetate, m.p- 78-80C
Empirical ~ormula: C2l~25N35 (399-4) ~S: m/e ~ 400 (M + ~) ~xampl~ 5 2-N-~3-~ethoxypropyl)-4-N-[3-(N-cyclohexyl~arbamoyloxy~-propyl]pyridi~-2,4-dicarbox~mide 2.0 g (6.8 mmol~ of ~-N-(3-methoxypropyl)-4-N-(3-hydroxy-pxopyl)pyridine-2,4-dic~rboxamide (c~0 Bxample 3) are dissolved in 250 ml of dichlorometha~e, and 1.05 ml 30 (705 mmol) of cyclohexyl isocyanate are added at 0C with stirring. The mlxture i8 sub3equently refluxed ~or 1 hour, the reaction i~ checked by mean~ of DC, a ~urther 2~8~7~
- ~6 -1.1 ml o~ cyclohexyl i~ocyanate ar~ added, the mixture i~
heated ~or a further hour, ~ wed to cool ~nd treated with water, the organic pha~e i~ dried ~nd con~entr ted, ~nd the oily re~due i~ ¢hromato~r~phsd on silic~ gel u~ing ethyl acet~te.
Suitable fractions are co~centxated and crystallized using diethyl ether; yield: 1.1 g o~ the colorle~s crystalline title compound, m.p. 95-98Co ~xample 6 2-N-~2-Methoxyethyl)-4-N ~3~benzoy}oxyethyl)pyridine-2,4-dicarbox ~ de a) 150 g of pyridine-2,4-dicarboxylic acid are ~o~bi~ed with 1.8 1 o~ methanol and 53.5 g of ~ulfuxic a~id (98~) and heated ~o ~oiling for 3 hour~. ~fter 1 hour, the pyridine-2,4-dicarboxylic acid i8 largely di~olved. Only a ~light cloudine~s remain~ in the mixture~ ~he miYture i8 poured into ice-water and the fi~ely-crystalline precipitate i~ allswed to settle~ the ~uper~atant i~
decanted off, the re~idue iB ~iltered o~E with ~ùction, washed with water and then with a very small amount of ice-cold MeO~. Yield 70-75 g of 2-methyl-oxycarbonylpyEidine-4~carboxylic acid, m.p. 246-24~C
(decomp.). The filtrate iB extracted 3 time~ u~ing C~2Cl2, the organic phases are dried and evaporat~d, the re3idue i~ taken up in ethyl Acstate, and the mlxture i~ ~iltersd cver ~ilica gel (appro~. 1 kg). The filtrate i8 evapor-ted in vacuo. Yield 90 95 g of dLm~thylpyridine-2,4~di-carboxylat~, ~.p. 61-62C.
.
b) 50 g of 2-methyloxycarbonylpyridine-4-carboxylic acid and lS0 ~1 of 2-methoxyethyl~mine give 32.5 g of 2-N-(2-methoxyethyl)-4-oarboxamidopyridine-4-carboxylic acid, m.p. 145.5-146C ~from water).
2~8~76 c) 30 g of the ~bove compound ~re co~bined with 10 ml o~
thionyl chlorid~ in lBO ml of toluens and 1 drop of d ~ethyl~or~mide, the ~ixture i~ heat~d ~or 3 hours.
When cold, 39 ml of triethylam~ne ~re added, iollowed by ~nhydrou3 meth~nol. Filtr~ion wi~h e~hyl ac~tate through silica gel and recry~tallization :ErQm methanol/water gives l9.B g of ~-methyloxycarbonyl~N~ ~ethoxy~thyl) pyridine-2~carboxamide, m.p. 68-68.5'DC.
d~ 5.0 g of tb~ ~bove compound are co~bined with 10 nl of tha~olaml~e and thè mlxture i~ heatod to ~oil~ng for 30 minutes. 3.0 g of 2-~-[2-me~hoxyethyl)-4-N-[2-hydroxy-ethyl)-pyridine-2,4-dio~rboxamide, ~.p. 124-125C, are obtained in the form of ~olorles~ ~rystal~
e) The title c~mpound i~ obtained, analogou~ly to Example 1 from the above compound ~y reaeting it ~ith benzoyl chloride in the presence of tri~thylamine and 4-NrN-di-methylaminopyridine, a~ colorle6~ ~ry~tals, m.p. 77-78C
Empirical ~ormula: C1~zlN305 (371) ~s: m/e - 372 !M ~
2Q Bxample 7 2-N-(2-Methoxyethyl)-4-N-(2-benzoyloxypropyl~pyridine-2,4-dicarboxamlde Th~ compound i~ obtained analogou~ly to Bxampl~ 6d) ~nd 6e) a~ a colorle~ oil, ~mpirical ~ormula: C20~23~3~S (385l ~S: m/e - 386 ~M + E~) r ,::
2~2~7~
~xample 8 2-N-(2~ethoxyethyl)-4-N- r 2-(4-hydroxypheny~)ethyll-pyridine-2,4-dicarboxamide ~ he kitle ~ompound i8 obtained from 0.24 g of 4-methyl-oxycarbonyl-2-~-~2-methoxyethyl~pyridin~-2~arboxamide (cf. ~xample 6c)j by ~eltlng it wi~h 2-(4 hydroxyphenyl)-ethylamine ~tyr~mine3. FiltratîGn with ethyl ~cetate through 8iliC~ ~el give~ 70 mg of colorle~ ne~dles; m.p.
181-181.5C ~rom ethyl ~cetate~;
Empirical ~ormula: C1B~21N30~ (343) MS: m/e = 344 (M +
Example 9 Bi~-N,N'-~2-~4-methylben~oyloxy)-ethyl]pyridine-2 r 4 -di-carboxamide ~he title compound i~ obtained analogou31y to ~xampLe lb) ~rom bis(N f N'-(2-hydroxyethyl)pyridine-2,4-diaarboxamide and 4-methylbenzoyl chloride a~ ¢olorle8s ~ry8tal powder, .p. 1~5-16~C.
Empirical formula: C27~2~N3O6 ~489) MS: ~/e - 490 ~M + B~) Example 10 Bi~ 2-ben~oyloxyethyl)pyridine-2~4-dicarboxa~ide analogou~ly to ~ample lb) colorle~ needl~s, ~.p. 13g-140C
~mpirical ~ormula: C25~23N3O6 (461) MS: m/e ~ 462 (M ~ ~t) The meanings in the tables below are as follow~:
Ph phenyl Me methyl 30 ~t ethyl - 29 2~82~
Pr propyl Bu butyl ~n benzyl Pen p~ntyl S ~ex hexyl T~P tetrahydropyr~noyl n unbranched ohain c cycl~
i i~o.
Rl/R2 and R3/R~ ~eans that aither Rl or R2 and R3 or R4, r~peetivsly, i~ the rad~cal ~entioned. The sub~tituent which remain~ in each case i~ hydrogen.
The ~ompQunds are in each ca~e 2,4-di~ubstituted pyridine derivatives.
_ 3~ - 2~2 ~ 7 ~
r~ ----E~ . Rlt~2 R~
11 CH2 C:H2 0 CO Ph U~, CH~ O CC~ ~h 12 CH2 CH2 0 CO ~h ~ ~a C~Ha O CO NH Et . . ___ _ 13 CH2 Ctl2 0 CO Ph CH2 CH2 0 CO NH-n~u . . .
14 ~H2 CH2 O CO OEt CH2 ~ 2 0 Cl:) Ph . . _ _ CH, CH, ~ Ct~ O~ OH, OH, O C:O NH
16 C;H2 CH2 0 CO NH n-8u :;H2 CH2 0 CO Ph . _ __ . 17 CH, CH, O CO NH ~I~u C--~ CH, O Cc NR n-~u 18 CH2 CH2 O CO NH CH2 CH2 OH CH2 Cl 12 CO NH n Bu __ . CH2 CH2 0 CO Ntl CH2 CH2 OH CH2 CH~ O C:O NH CH2 CH2 OH
, ~ ~
21 t:;H2 CH2 0 THP CH2 CH2 0 CO Ph . ~
22 CH2 CH;, CH2 0 CO Ph CH2 CH2 t:H2 0 ::O Ph _ . _ .
23 CH2 CH2 CH2 O CO Ph CH2 CH2 t;H2 0 GO NH Et ~ ~--24 CH2 CH2 CH2 C) CO Ph CH2 CH2 CH2 0 CO NH n-Bu __ . _ , . , , __ CH2 CH2 CH2 0 CO O Et Ctl2 OH2 CH2 0 C:O Ph _ ~ __ _ , _ _ 26 OH2 CH2 CH2 O O:~ O l~t C~~ CH, CH, l~ CD n~
27 CH2 Cl~2 CH2 0 CO NH n-Bu CH2 CH2 CH2 0 CO Ph _ . . ~ . , . , _ 28 CH2 CH2 CH2 0 ~O NH n-Bu CH2 CH2 CH2 0 CO NH n-Bu .
_ ~
2~2~7~
_~
E ~ . R-~2 ~3/R4 29 CH2 CH2 CHa O t;O NH CH2- C~ C::Ha C:H2 C:tl,2 0 C 0 NH n-Bu OH
. , . _____ CH2 CH2 CH2 O C :) NH CH2- C H2 CH2 C:H2 CH2 O I C) NH ~C~2 OH C:H2 OH
...... .. _ . _ _ _ _ _ . ~ 11 31CH;~ CH2 CH2 ~P OH2 GHa CH2 0 TllP
~ _ . ~
32CH, C--, CH, O ll ll' CH2 Cl~ CH, O CO I'h 33CH2 CH2 O CH3 CH2 t::H2 C:H2 0 CO c-H~x 34CH2 t: H2 0 CH3 CH2 CH2 C;H2 0 CO ~-Pen _ , , , . . . _ _ ~
35CH2 CH2 t:) CH3 C:H2 C:H2 CH2 0 C:O O Et l _ . _ ,_ 36CH2 CH2 0 CH3 CH2 CH2 CH~ O CO O n-Bu .. _ ~ ~
37 CH2 CH2 O OH3 CH2 CH2 CH2 O GO O G Hex _ .
38 CH2 CH2 0 ~H3 CH2 C:H2 C:H2 0 CO Ph _ 39 CH2 CH2 C) CH3 CH2 CH2 CH2 t:~ CO i-Pr _ . . . . . _ ~_ _. - ~- I
40CH2 CH2 0 Ct 13 C:H2 C:H2 CH2 0 CO O Ph ~_ . _ _.
41C H2 CH2 0 ~H3 CH2 ~H2 CH2 O CH2 CH2 0 Me ¦
~ . . __ . __ 42 CH2 CH2 0 ~ H3 C;H2 CH2 CH2 O CH2 9;;H2 0 Et ~_ 43CH2 CH2 0 CH3 GH2 CH2 CH2 Q CH2 CH2 0 Ph 1 - - - - - . , . ... ... ~
44~H2 CH2 O CH~ ~;Hz C;H2 CH2 O Ph I _ _ ._ . ""_ CH2 CH2 0 CH3 ~ CH2 CH2 CH2 0 THP
~_ . . _ . - , ........ ... .__ 46 CH2 CH2 0 CH3 CH2 C:H2 CH2 O CO NH Et _ _ _ _ . , , l 47 CH2 CH2 0 CH3 CH2 CH2 CH2 0 CO NH Pr ~ __ _ ___ _ _ . ~ , .
48 CH2 CH2 0 CH3 CH2 CH2 CH2 0 C~ N~l ~ Bu 2~82~76 .
~_ ~ .__I
E x . Rl/R2 R~/R~
_~ ~ ~ I
49 CH2 CH2 O CH3 CH2 GH;, CH2 0 CC) NH c-Hex , . ,~ . . . ~ I
CH2 CH2 OH CH2 CH;~ CHa O CO c-Hex l . ._ . _ ~
51 CH2 CH2 0~1 CH2 GH2 CH2 1 ) CO c-P~nt _ , _ , , .
52 CH2 CH2 OH CH2 t::H2 CHi Q C;O O Et ,,, . ,, , _ 53 CH2 CHa OH GH~ CHa CH2 O CO O n-Bu ,., ~
54 CH2 CH2 OH CH2 ~H2 CH2 0 CC) O c-H~x CH2 CH2 OH O~, CH, CH, O CO (~ Ph 56 CH2 CH2 OH C~l2 CH2 CH~ C) CO ~2-Me Ph) CH, CH, OH CH2 C:H2 CH2 0 CO Ph ~8 CH2 CH2 OH C:H2 CH2 CH2 0 CH2 CH2 CH
O- lUle ~ ~ .. . , . . .. _ _ ~:~ ~ O- Et 60CH2 CH2 OH ~2 ~ t~2 CH2 O CH2 CH2 C:H
O Ph ~ _ . _ 61CH2 CH2 ~ CH2 CH2 CH2 O Ph l I
62O--, CH, 011 CH, C--, CH, O T--P
63CH2 CH2 OH CH2 C:H2 C:H2 CO NW Et l _ _ .. . I
64 CH2 CH2 OH C~12 CH2 CH2 0 CO NH Pr .. _ _ _ . .. _ _ . ....... ._~._. . --l 65 . CH2 CH2 OH CH2 CH2 CH2 0 ~ 0 NH n-Bu 66 CH2 CH2 OH CH2 CH2 CH2 0 C:O NH c-Hex. . _ -. . _ I
67 CH2 CH2 OH ___ CH2 CH2 CH2 O CO NH Ph l 2~2~7~
.
_ ~ I
E ,~ R1/R~ R3/R4 I ~__ ~ , ._ ~ I
68 C ~2 C~H2 CH2 ~ CH3 ~H2 ~H2 ~Ha t O C-HBX
._v____ - _ ~ I
69 - C H2 C~H2 ~H2 ~ HJ ~H2 ~H2 ~;H2 CO C- P~n . . .__ . I
~H2 ~ i i2 C H2 O CH3 CH2 CH~ CH2 C ) CC) O Eth _ , ~--~
71 CH2 CH2 CH2 0 CH~ . 5;H2 ICH2 CHa O CO t) n-8u . ~ _~
72 CH2 t~H2 ~H2 ~ HJ ~H2 CH2 CH2 C ) CO O c-Hex , ~ . ~ _~
73 CH2 ~ H2 ~; H2 O CH3 CH2 CHa Cl'l2 CO Ph I . ~.
7~ CH;2 CH2 C::H2 0 CH3 CH2 ~H2 CH;~ C) CO i-Pr _ ~
1 75 CH2 Ct12 CH2 O CH3 CH~ C H2 C H2 O Ce) O Ph I ~, I76 CH2CH2CH2O~H3 CH2CH2CH2OCH2~H2M@
.
I77 CH2 CH2 C~2 O CH3 ~2 C H2 ~ H2 CH2 CH2 O Et _ _ . . ,_ ~ _ I78 CH2 ~ H2 CHa C3 ~H3 ~ H2 ~ H2 t~H2 O CH2 CH2 O Ph ~ . - ....... .. __ . . ~
79 CH2 CH2 ~H2 ~H3 CH2 eH2 CH2 Ph 80 CH2 C~H2 ~H2 ~ H3 CH2 CH2 ~ H2 THP
_ . , . , .. . 11 ~ R1 CH2 CH2 CH2 0 CH3 CH2 CH2 CH2 0 CO NH Et ~ , , , . _ . . , . .... ~
l ~2 CH2 C~2 CH2 0 CH3 CH2 CH2 CH2 0 CO NH Pr - ~ A
83 CH2 ~H2 ~ H2 O C~l3 CH2 CH2 CH2 O CO NH n-Bu 84 CH2 CH2 CH2 0 ~H3 C:H2 CH2 C:H2 0 CO NH c-Hex , , Ctl2 CH2 CH2 OH CH2 C:H2 CH2 0 CO c~tlex _ _ ~ ~ ~ _ ...... ... ~, _. --86 CH2 CH2 CH2 OH CH2 CH2 CH2 0 C:O c-Pen __ _ _ __ , ~ , . ~ _ ~
I 87 t:~H2 ~H2 CH2 OH CH2 ~ :H2 ~H2 CO C-Et _ _ , " ", " " .. , 1 88 C;H2 CH2 CH2 OH CH2 C:H2 CH2 0 C:O C n~Bu _ __ . .__ __ . ~
_CH~ CH2 t::H2 OH _ CH2 CH2 CH2 0 ~O O c-Hex 2~2~7~
_ I
E~. R /R R3/~4 I . ., ~ I
CH2 CH2 CH2 OH ~ C~ 1`4 ~ CO O Ph 91 t J'12 ~ H2 CH2 OH ~ ~a e H2 C~z ~ CO ~2~Me Ph) ! ~
92 CH2 CH2 CH2 OH C:H2 CH2 C ~2 C~ Ph . . ~
~ Ms _ _ I
94CH2 CH~ CH2 OH GH2 GH2 t :H2 O CH2 CH2 CH2 O- Et _ 95CH2 CH2 5H2 OH CH2 CH2 CH2 O ~H2 ~H2 CH2 O- Ph I . .. __ v~_u ~
1 96CH2 ::H2 CH2 OH CH2 CH2 CH2 O Ph _ ~ ~
97CH2 CH2 CH2 OH CH2 CH2 Ctl2 O THP
. . ....
_ _ _ , _,_,_ __, _ _ r . ,_ ::
l 99CH2 C:H2 CH2 OH GH2 CH2 CH2 0 CO NH Pr _ _ , . ..... .. ~ -- _ 1100 CH2 CH2 CH~ OH CH2 CH2 CH2 0 CO NH n-Bu .. . _ ,, ~ _ .
1 101 CH2 CH2 Ctl2 OH CH2 CH2 CH2 0 CO NH c-Hex . _ ., 10Z CH2 CH2 CH2 OH CH, C~, CH, O CO N~l Ph ¦ 103 C~2 CH2 CH2 0 CO c-Hex CH2 CH2 0 ~Ae . . . _ __ 104 ~2 ~;H2 CH2 0 CO c-Pen C:H2 CH2 0 M~
_ , . ..... .. _ l 105 CH2 CH2 CH2 O CO O Et CH2 CH2 O Me l __ _ ~ -- . ~ .. .....
106 CH2 CH2 CH2 0 CO O n-Bu CH2 CH2 M~
_ __. _ _ , _ , _ 1 107 CH2 CH2 CH2 0 C :) O c-Hex CH2 CH2 0 Me . . _ _ - ._ . _ I 108 Cl12 Ctl2 GH, O CO O Ph CH2 CH2 0 Me 2~82~7~
~--.__~
E x . F~' /R' R'j~' 109 ~H2 ~H2 CH2 O C 2-M~ Ph t~H2 ~H2 O MB
_ ~ .
110 C:H2 CH2 CH2 0 C:O Ph CH2 C;H2 0 Me~
,. _~
111 t::H2 CH2 CH2 0 C:H2 CH2 CHa ~ CH2 ICHa O Me Me I ~__ 112 C:H2 C:H2 CH2 0 THP CHa CH2 0 M~
,_~
113 C;H2 CH2 C:H2 0 CO NH Et CHa CH2 Q M~
_ -.. ---- ............. _ ___ . ~_ , 1 1 4 CH2 CH2 C H2 0 CO NH Pr CH2 CH2 ~ M~ -_ , . _ _ I 1~5 CH2 CH2 CH2 0 C NH n B~ ~H2 CH2 M~
~ ,, _ _ _ _ _ .
I 116 CH2 CH2 t~H2 0 CO NH C-H~X ~;H2 ~H~ O M~
_ ~
¦ 1~7 CH2 CH2 CH2 0 CO NH Ph CH2 CH2 0 Me r 118 Ctl2 C:tl2 CH2 0 CO c:-H~x GH2 C:Ha C:H2 0 Me . ~ - ~ _ _ _ ~ ...... _ ~ I
I 119 CH2 CH2 CH2 C ~-Pen ~H2 ~H~7 CH2 Me ~ _ ~
120 CH2CH2CH2OCOOEt C:H2CH2C~2OM~ l ... . ~ .. __ __ , , I
1 121 C:H2 CH2 CH2 0 CO O n-BuCH2 CH2 CH2 0 Me ,_ , . - ._ ~ , ~
122 CH2 CH2 CH2 0 CO O c-HexCH2 CH2 CH2 0 Me _ , ,_, ..
123CH2 CH2 CH2 C) CO O PA CH2 CH2 CHa O Mi~
r _ -- -- -- -- _ _ 124 CH2 Clt2 CH2 0 CO 2-Me Ph CH2 CH2 t H2 0 Me __ , ,,, _- ~
125 CH2 CH2 CH2 O CO Ph C~2 CH2 C:tl2 0 Me _ ~ _ _ _ _ I
126 CH2CH2CH20CH2CH2S~H20 CH2CH2~H20Me Me _ ~ _ _ 127 CH2 CH2 CH2 THP CH2 CH2 CH2 Me __ . . __ 128 CH2 CH2 CH2 0 CO NH Et CH2 CH2 CH2 0 Me .
- 36 2~8~
~ ~ ~_ I
E~ . R~/~ R3/~
. . . _ . . ~
129 ~ ~2 C~2 C H2 CO NH Pr CH2 CH2 CH2 0 M~
. I
13D CH2 C:H2 OH2 0 GO NH n-Bu g:tl2 CH2 CH2 O M~
, _ . . ... _ 131 C;H2 C:H2 t;ll2 0 ~O NH c-H~x C:Ha tCH2 CH2 O Me .
132 CH2 CH2 C:H2 ~ CO Nl I Ph CH2 CH2 CH2 0 M~
. ~ ~
133 C:H2 CH2 OH2 0 CO e-Hex OHa CH2 CH2 OH
. . ___ ;
134 CH2 CH2 C:i 42 CC) c-~n GH2 CH2 C:H2 OH
. . _ . .
13~ CH2 CH2 CH2 0 CO O Et C:H~ CH2 CH2 C)H
. _ . _ I
136 CH2 CH2 CH2 O eo o n-Bu C;H,2 CH2 CH2 OH
_, .
137 CH2 Ctl2 CH2 O CO O c-l lex C:H2 :::H2 C :H2 OH
~ _ 138 CH~ CH2 t;H2 O CQ O Ph OH2 CH2 CH2 OH
139 CH2 CH2 CH2 O CO 2-Me Ph ~ ~2 C:H2 C:H2 OH
. . ~
140 CH2 CH2 CH2 0 CO Ph CH2 CH2 CH2 OH l ~ .~ ~
141 OH2 CH2 CH2 0 Ch2 CH2 CH2 - CH2 Ctl2 1~ OH
Me ~ ~ - ~ - - I
142 Ctt2 CH2 CH2 0 THP GH2 CH2 CH2 OH
~ _ _ _ _ __ _ 143 C:H2 CH2 CH2 0 CO Nll Et t::H2 CH2 CH2 OH
_ _ ___ .
144 t::H2 CH2 CH2 0 C:O NH Pr CH2 CH2 CH2 OH l _ . . , _ _ I
~45 CH2 CH2 CH2 0 CO NH n-Bu CH2 CH2 CH2 C)H
_ _ ~ I
146 ~H2 CH2 CH2 O CO NH c-ttex CH2 CH2 C:H2 OH
._ . ~ __ _ , , _ 147 CH2 CH2 CH2 0 CO NH Ph CH2 CH~ CH,2 OH l _ _ . ~ I
148 CH2 CH2 CH2 O CO c-Hex CH2 CH2 OH l __ . . . _ . _ . _ _ I
149 CH2 CH2 CH2 0 CO c-Pen CH2 Ctl2 OH
.
- 37 - 2 ~82 ~ 7 ~
Es. R /R ~/~
150 CH2 CH2CH2O CO O R CH2C~2 OH
_ __~
151 CH2 Ctl2 C:H2 0 t:O ~ n-E~u CH2 Cl 1~ OH
__ __ 1~2 CH2CH2CH2O CO O C Hex CH~ CH2OH
. ~
. 153 CHaCH2CH2O CO O Ph . CH2 C~2 ~H
_ ~
~4 ~H2 CH2 CH2 O CO 2-Me Ph I::H;~ CH2 OH
155 CH2 C:H2 CH2 O CO Ph CHa Cl 12 OH
., _ , . _ ~.. ,, . ,, _ , ~
156 CH2 CH2 CH2 t:) CH2 CH2 CH2 - C;H2 CH2 OH
Me _ . . . _ ~_ : 157 ~2 ~H2 CH2 O THP CH2 CH2 OH
, ~ ~
158 CH2 CH2 CH2 0 CO NH E~ C:H2 CH2 OH
. _ 159 CH2 CH2 Clt2 0 CO NH Pr CH2 C;H2 ~H
_ 160 CH2 CH2 CH2 C) CO NH n-Bu CH2 Ct''12 OH
_ ~
161 GH2 C~12 CH2 0 CO NH c-Hex CH2 CH2 OH
162 CH2 ~H2 CH2 0 CO NH Ph CH, Ol l, (~11 ~` ~xample 163 Bi~-~,N'-[2-(4-hydroxyphenyl)-ethyl~pyridine-2 J 4 -di-carboxamide Analogously to B~mple 8 from dL~ethyl pyridine-2,4-di-carboxylate and tyrnminecolorle~s cry~t~l~, m.p. 165-166C
~mpirical formula: C23~23N3O4 ~4D5) MS: m/e - 40 (M + ~) 2~2~
. - 38 --Example 16~
Bi 8 t~ thoxy--N-methyl~pyridine-2,4-dic~rbox ~ de 5.1 g ~40 mmol) of N-ethylmo~pholene are ~dded ~t 20C
with stirring to 1.67 g (10 mmoll of 2~4-pyridinedi-carboxylic acid, ~u~pended in 100 ml of diahloromethane, ~.9 ml (20 ~mol~ o~ i~obutyl chloro~ormate are ~ubse-qu~ntly added dropwi~e ~t -15C, and the ~ixture i~
~tirred for 20 minute~ at lO~C~ 1995 ~lacuna~ (20 mmol) o~ ~,O-dimethylhydroxyl~mi~e hydrochlorid~ are then added, the mixture i~ ~tirred for 1 hour ~t -15C and allowed to come to 20C o~ernight, wat~r i8 add~d, the mixtur~ i8 extracted with dichloxomethane, a~d, after puri~ication o-E ~he crude product by column ~hrom~-tography over silica gel (ethyl acetate/methanol ~ lOJl)~
1.6 g of the ti~le co~pound are obtained a~ a colorl~s oil, Empirical formula: C~ 5~304 (253) MS: m/e - 254 (M + ~+) Example 165 2-N~ -Methoxyethyl)-4-N-(ethyloxy(N-tert.butyloxy-carbonylglycyl))pyri~ine-2,4-dicarboxamlde 0.8 g (3 mmol) of ~-N-(2-~ethoxyethyl)o4-N-~2-hydroxy-ethyl)pyridine-2,4-dic~rbox~mide ~aompound o~.x~mple 6d) i8 combined with 25 ml of anhydrou3 ~cetonitrile and ~25 mg (3 mmol) of N-butyloxycarbonylglycine, 0.4 ml (3 mmol) o~ N-ethylmorpholine~ 0O45 g ~3.3 m~ol) of N-hydroxybenzotriazole and 0.62 g (3 mmol) of ~ di-cyclohexylcarbodilmide, And the mixture i~ ~tirred for 20 hours ~t 25C. ~he resulting N,N-dicyclohexylurea is filtered off with suction, washed with acetonitrile ~nd concentrated, the product i~ taken up in dichloromethane, the mixture i6 extracted with saturated aqueous Na~CO3 801ution, the extract i~ ~haken with 10~ atrength ~queous 2~82~7~
citric acid, dried ~nd freed from solvent~ and the residue i8 chromatographed over ~ilica gel.
~mpirical formula: Cl~29N407 (4~4) ~S~ 425 ~
~urther ~xamples are: I ynths~ized ~rom the ~ompound 2-N-(2-mathoxyethyl)-4-~-(2 hydroxyethyl~pyridine-2,4-carboxamide described in ~x~mple 6d), or from ~nalogou~ ~ompound~, by benzylation) 2-~ (2-Methoxyethyl~-4-~-(2-benzyloxye~hyl)pyridine-2,4-dicarboxamide 2-N-(2~ydroxye~hyl)-4-N-(2-benzyloxye~hyl~pyridine~
2,4-dicarbox~mlde 2-N-~3-~ethoxypropyl)-4-~-(2-ben~yloxyethyl)pyridine-2,4-dicarboxamide 2-N-~2-~ydroxypropyl)-4-N-(2-benzyloxyethyl)pyridine-2,4-dicarboxam~de Bis-N,N'-[benzyloxyethyl)pyridine-2,4-dioa:rboxami~e (N,N'-Benzyloxypropyl)pyridine-2~4-dicarboxamid~
2-N-(2-Methoxyethyl)-4-N-[2-~4-fluorobenzyloxy)ethyl3-pyridi~e-2,4-d~carb~xamide 2-N-~2-~ydroxyethy~)-4-N-l2-(4~fluorobenzyloxy)ethyl]-pyridine-2,4-dicarboxamide 2-N-(3-~ydroxypropyl)-4 N-[2-(4-fluoro~enzyloxy)ethyl]-pyridine-2,4-dicarboxamide 2-N-(2-Methoxyethyl)-4 N-~2-(4-methoxybenzyloxy)ethylJ-: pyridine-2,4-dicarboxamide 2082~ ~6 2-N-~2-~ydroxysthyl)-4-N- r 2-(4-methoxybenzyloxy)ethyl]
pyridine-2,4-dicarboxamlde 2-N-(2-~ydroxypropyl)-4-N-t2-(4-~ethoxybenæyloxy)ethyl]~
pyridine 2,4-dicarbox~mide 2-N-~2-Benzyloxyethyl34-~-(4-hydroxyethyl~pyridine-2,4-dic2rboxnmlde 2-M-(2-~enzyloxyethyl)-4-N~(4-hydroxypropyl)pyridine-2,4-dicarboxamlde 2-N-~2-Benzyloxypropyl)-4-N-33-hydroxypropyl)pyridine-2,4-di~arboxamide 2~ 2-(4-Chlorobenzyloxy)ethyl~-4-~-(2-hydroxyethyl)-pyridine-2,4-dicarboxamide 2-N-~2~ Chlorobenzyloxy)ethyl]-4-~-(3-hydroxypropyl)-:~ pyridine-2,4-dicarboxa~ide 2-N-~2-Methoxyethyl)-4-N-t2-benzy~oxypropyl~pyridine-2,4-dicarboxamide 2-N-(2-~ydroxyethyl) 4-N-~2-benzyloxypropyl)pyridine-2,4-dicarboxamide 2-N-(3-Methoxypropyl)-4~ 2 benzyloxypropyl)pyridine-~;~ 20 2,4-di~arboxamide 2~ 2-~ydroxypropyl)-4-~-(2-benzyloxypropyl)pyridine-2,4-dicarboxamide 2-N-(2-Methoxyethyl)-4-~[2-(4-fluorobenzyloxy)propyl]-pyridine-2,4-dicarboxamide 2-~-[2-Hydroxyethyl)-4-N-[2 (4-fluorobenzyloxy)propyl]-pyridine-2,4-diaarboxamide ~08207bj 2-N-(3-~ydroxypropyl~-4-N-[2-(4-fluorobenzyloxy)propyl3-pyridine-2,4-dicarboxamlde 2-N-(2-~ethoxy~thyl)-4~ 2-~4-msthoxybe~æyloxy)propyl~-pyridine-2~4-dioarbox~mide 2-N ~2-~ydro~yethyl~-4-~-t2-~4-methoxybenzyloxy)propyl]
pyridine-2,4-dicarboxamide 2-N-~2-~ydroxypropyl)~4-~-t2~(4-methoxybenzyloxy)propyl]-pyridine-2,4-d~carboxamide 2-N-(2~Benæyloxypropyl)-4-N-t2-hydroxyethyl~pyridine-2,4-dicarboxamide 2-N-~2-Benzyloxypropyl)-4-~-(3-hydroxypropyl)pyridine-2,4-dicarboxamide 2-N-[2-t4-Chlorobenzyloxy)propyl]-4-N-~2-hydroxyethylj-pyridine-2,4-dic~rbox2mide 2-N-1~-(4-hlorobenzyloxy)propyll~4-N-~3-hydroxypropyl)-pyridine-2,4-dicarboxamide 2-N-(2-~ethoxyethyl)-5-N-~2-benzyloxyethyl)pyridine-2,5-dicarboxa~ide 2-~-(2-~ydroxyethyl~-5-~-(2-be~zyloxyethyl~pyridine-2~5-dicarboxamide 2~ 3-Methoxyp~opyl)-5-~-(2-b~nzyloxy~thyl~ pyridin~-2,5-dicarboxa~ide 2-N-~2-~ydroxypropyl)-5-N-~2-benæyloxyethyl~pyridine-2,5-dicarboxamide Bi~-N f ~ benzyloxyethyl)pyridine-2,5-dicarboxamide 2~g~07~
.
(N,N~-Ben~yloxypropyl)pyridi~e-2~5-dioarboxamlde 2~ 2-Methoxyethyl~ N-t2-(4-fluorob~nzyloxy)ethyl3-pyridine-2,5-dicarboxamide 2-N-~2-~ydroxy~thyl)-5~N-[2 (4-fluorobenzyloxy~et~yl]
pyridi~e-2,5-dicarboxamide 2-N-(3-Hydroxypropyl)-5~ 2-(4-~luQrobenzyloxy )ethylJ-pyr~dine-2,5-dic~rbox~mide , :~ 2-N-(2-Methoxyethyl~-S-N-t2-(4-methoxybenzyloxy)ethyl~-pyridine-~,5-dicarbox~mide 2-N-(2-~ydroxyethyl)-5-N-[2-~4-~thoxyben~yloxy3ethylJ-pyridine-2,5-dicarboxamide 2-N (2-~ydroxypropyl) o5-N- 1 2- (~-~ethoxybenzyloxy3ethyl]-~ pyridine-2,5-di¢arboxamide : 2-N-(~-Benzyloxye~hyl)-5 N-t2-~2-hydroxye~hyl)pyridine-2,5-dicarbox~ide ~-N-(2-Benzyloxyethyl)-~-N-[2-(3-hydroxypropyl)pyridine-2,5-dicarboxa~ide 2 -N ( 2 -Ben zyloxypropyl ) ~5~~~ t 2 - ( 3-h~droxypropyl ) pyridine-2, 5 dicarboxami~e 2-N-[2-~4-Chloroben~yloxy)ethyl~-5-N-( 2 -hydroxyethyl ~ -pyridine-2,5-dicarboxamide 2-N-[2-(4-Chlorobenzyloxy~ethyl~-5-N-l3-hydroxypropyl) pyridine-2,5-dicarboxamide
~ .
D~-A 3~432,0g4 described pyridine-2,4- ~nd ~2,5-di-carboxylic ~cid die~ter~ h~vin~ lWB carbon ~tom~ in the ~st~r alkyl ~oiety a8 pharmaceutic~l~ for ~nhibiting proline hydroxylas~ and ly~ine hydroxyla~e~
5 however, the ~hortcomi~g o $he~e low~r~al~ lated di~sters i~ that they are too rapildly cle~ved in the organism to giv~ th~ a~id~, and that they do ~ot reach the site o~ action in the cel~ in suffici3ntly high concentration~, which ~ak~s th~m le~ ~ultable for possihle admini~trat~on ~ pharma~eutical~
DE-A-3,703,959, D~-A-3,703,962 a~d D~-A-3,703,963 pro~ide the general description of mix~d e~ter/~mide~, higher alkylated die~ter~ and diamide~ of pyridine-2,4- a~d -2,5-dicarboxylic acid which are ef~icien~ inhibitor~ of aollagen bio~ynthesi~ ~n the animal ~odel.
For example, DE-A 3,703,959 de~cribes, inter alia, ths ~: synthe~is of N,N'-bis~2-methoxyethyl)pyridine-2,4-di-oarboxylic diamide and ~ bi~3-i~opropoxypropyl)-pyridine 2,4-dicarboxylio diamide.
. .
German Patent ~pplication~ DE-A-3,825,471 and D~-A-3,828~140 propo~e an impxoved proce~ ~or the i prepara~ion of ~ bis(2-methoxyethyl)pyridine-2,4-di-~arboxylic diamide. German Patent ~pplioation DE~A-3,924,093 propose~ novel ~W'-bi6(alkoxyal~yl~-pyridine-2,4-dicarbo$ylic diamides.
There wa~ ~ need to ~earch for other oompound~ having an ~mproved pharm~cological activity with regard to the inhibition o~ lysine hydroxyla8e and proline hydroxyla~e.
Surpri~ingly, it ha8 n~w been found that thi~ object ia achieved by the following pyridine-2,4- and -2,5-di-carboxylic diamides.
_ 3 _ 2 ~8~7 ~
The invention therefore relat~s to ~:cDIipou~d~ of the ~ormula I
O ~--N--R2 R'~ (I) N ~ ~ ~ ~4 o in which S Rl, R2, R3 and R4 are identical or differ~nt and are A a bran~hed or unbr~n~h~d, aliphatic or ~yclo-aliphatic (C1-Cl2~-alkyl r~di~al, gCl-C~2~-alke~yl radi~al or a (C1-Cl2)-alkynyl radieal, ea~h o~ which is mono~ub-~tituted or poly~ub~tituted, prefer~bly mono~ub~ti.tuted or di~ubstituted, by ~ ~ Cl-C9 ) -alkoxycarbonyloxy, (C1-Ca)-alkXY~( Cl~Ca ) alkoxycarbonyloxy, (C6--Cl2)-aryloxy~arbonyloxyt (C7-C
aralkyloxy~arbonyloxy, (C~-C~ aralkylcarbonyloxy, ,:cinn~moyl, ~innamoyloxy, ~C6-Cl2)-~rylc~rbonyloxy, ~C8-C8~-alkenylcarbonylo~y, ~C3-C~)-al~ynylcarbo~yloxy, (C3oC8)-cycloalkylcarbonyloxy, (C1-C~-alkoxy-(C~-Cl2)-alkoxy, ::~Cl C~)-alkoxy-amino,(C1-C~)-alkoxy-N (C1-C~-alkyl~mino, 12) -alkoxy-~,N (~l-C5)-dialkylamî~o, aarbamoyloxy, N-~C1-C~)-alkylcarb~moyloxy, ~,N-di-(Cl-C8~ yl~arba~oyl, ~:20 N-(C3-C~)-cy~lo lkylcarbamoyl, ~-(C~-Cl2)-ar~lamino, N-(C7 C~ arAlk~lam~no, N-alkyl-aralkylami~o, ~-alkyl-arylamino, (C3-C8 )-cycloalkanoylamino, ~C1 C~)-alkanoyl-~mino, (C6-cl2)-aroylamino~ (C~-C~ aralkanoylsmino, (C~-C8);alkanoyl-(Cl-Ca)-alkylamino,( C3 ~Ca)-cyclo~lkanoyl-(C1-C8)-alkylamino, (C8-Cl2)-aroyl-lCl-C~)-alkyl d no, (C7-C~ aralkanoyl-(Cl-Ca)-alkylamino, (cl-c8)~a mercapto, (C1-CB)-alkyl~ulflnyl, (C1-Ca)-alkylsulfonyl, (C1-C8)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, _ 4 _ 2082~7~
trifluoromethyl~ phenylm~rcapto, phenylsulfonyl~ ph~nyl-sulfinyl, ~ul~amoyl, X3-(Cl-C~-a~ ul~amoyl, ~ di-(Cl-C~)-alkylaulfamoyl, ~Cl-CB)-Alkyl~ulfonamido and ~ryl~ulfonamido, where the ~ d ~ralkyl radicals in S the above ~ubotituents c~n ~l~o h~ve a heteroc:yclic natu:re and/or, lik~ lkyl, are sub~;titut~d ~ 1, 2, 3, 4 or 5 id~ltic:al or d~ ff~ar~nt ~ubl3tituentl3 ~elected :Erom the ~eriee c:omprising halogsn, cy~no, tlitro, trifluoro-methyl, ( Cl~C~ allcyl, hydroxyl, ~ ICl-C,3 ) -hydroxyalkyl, 10 (Cl-C6~-alkoxy, ~Q-tCEI2-~sc~ +, "F" -OCF2Cl, -O-CF2-C~FCl, trif luorom~thyl ~ Cl-Ca ) -alkylDI2roapto ~ B ) -allcyl-~ulfinyl, tCl-C630alkylsulfoslyl, (Cl-~6)-alkylcarbcnyl, ( Cl-C6 ) -alkoxya~rbonyl, I:arbamoyl, N- ( C~-C" ) carbamoyl, N,N-di-(Cl-C~)-alkylc:arbamoyl, ~Cl~C~)-alkyl-carbonyloxy, tC3-C8)-cyaloalkyl, phenyl, b~yl, ph¢noxy, benzylo~y, NR'-R", phenylmercapto, phenyl~ul:Eonyl, phenyl~ulfinyl, ~ulfamoyI, N-~Cl-C4)-alkylsul~a~oyl or ~,N-di-~C1-C4)-al~yl~ulf~moyl, in p~r~icular by up to 3 of the abovementioned identiaal or differeAt ~ub~tituent~r and a CH2 group of the ~lkyl chai~ i~ optionally replaced~
by 0, S, SO, SOz or ~R'9 or by a substituted (C~-C~)-aryl radical or heteroa~yl radical havin~ 1, 2, 3, 4 or S identical or different 6ub~tituent~ from the series ~omprising hydroxyl, tri-fluoromethyl, ~C~oC6)-hydroxyal~yl, -O-[C~2~]3C~2~l8)E~
OCF2Cl, -OCF2 C~FCl, (Cl-C6)-alkylmercapto, ~Cl-C~3-~lkyl-~ulfinyl, (Cl-C6)- lkyl~ul~onyl, ~C~-C6~alkylcarhonyl, ~Cl-C6)-alkoxycaxbonyl, carbamoyl, N-~Cl~C~ yl-carbamoyl, ~,N-di-(Cl-C~)-alkylcarbamoyl, (C~-C~)-alkyl-3Q carbonyloxy, (C3-Ct)-cyclo~lkyl, phenyl, benzyl, ph~noxy, benzyloxy, NR',R", phenylmercapto, phenylsul~onyl, phenyl~ulfinyl, sulfamoyl, N-(Cl-C~)-alkyl~ulf~moyl, N,N-di-~C~-Cs)-alkylsulfamo~l, (Cl-C8)-alkoxycArbonyloxy, (C1-C8)-alkoxy-(Cl-C~)-alkoxycarbonyloxy, (C6-C~)-aryloxy carbonyloxy, (C7-C1l)-aralkyloxycarbonyloxy, ~C7-C1l)-aralkyloarbonyloxy, cinnamoyl, cinna~oyloxy, (C6-C~)-arylcarbonyloxy, ( C3-C~ ) -alkenylcarbonyloxy, ~C3-C8)~
2~7~
alkynylcarbonyloxy, ~C3-C~ ) -cycloalkylcarbonyloxy, (C~-C~)-alkoxy-~C~-Cl23-~lkoxy, ~Cl-Cl2) alko~y-aminv, l~l-Cl2)-~lkoxy-N 5Cl C5)-alkylamino, ~Cl-Cl2~-alkoxy-~l,N
(Cl-C~)-dial~yl~mino~ carbamoyloxy, N-(Cl-C~)-al~yl-c~rbamoyloxy) ~ di-(Cl-CG)-~lkylc~rb~moyl, ~-tC3-C~)-cycloalkylcarbamoyl, N-(c~-c~)-a~yl~mi~o~ ~-(C7-c~
~ralkylamino, N-alkyl-aralkylamlno/ ~ ~lkyl-aryl ~ no, (C3~C8)~Cycloalk~noylamlno~(cl-c~)-alkanoylRmino~(c~-c~)~
aroyl~mino, ~C7-C~ aralkanoylamino, (Cl-C~)-alkanoyl-0 (Cl~c2)-alkylaFino, ~C3-C~) -cyaloalk~noyl-(C~-C~)-alkyl-amino, lC~-C~)-aroyl-(Cl C8~-alky}amino, (~rCl~)-ar alkanoyl-~C1 C~)-alkylamino, tCl-Ca)-alkylmercapto, ~Cl-C8~-alkyloul~inyl, (Cl-Ca) ~lkyl~ulfonyl, (C 8)-~lkylcarbonyl, ~C3-Ca)-~yc}o lkylcarbonyl, nitro, tri-fluoromethyl, phenylmercapto, phenylsulfonyl~ phe~yl-~ 3ll1finyl, ~ulfamoyl, N-(Cl-C6)-alkyl~ulfamoyl, ~ di-- (Cl-C6)-al~ylsulfamoyl, ~CI_C~ alkyl-sulfon~mido ~nd arylsulfonamido, where the aryl and alkyl radi~al~ in the a~ove ~ub~tituents o~n al00 haYe a heterocycli~ nature and~or, like ~lkyl, oan be ~ub~t~tut~d b~ 1~ 2, 3, 4 or 5 identical or different ~ubstituent~ from the ~eri~
comprising halogen, ~yano, nitro, trifluoromethyl, ( C~_CB )-alkyll hydroxyl, (C~-C~3-hydroxyalkyl or (C~-C6)-alkoxY r or by a ~ub~tituted ~C6-Cl2)-aryloxy radical, (C7--Cll)-aralkyloxy radical or hetero~ryloxy radical, ~ach of which ha~ 1, 2, 3, 4 or 5 identi¢al or differe~t ~ub-~tituents selected ~rom the ~eriea ~o~pri~ing hydroxyl, halogen, cyan~, nitro, trifluoromethyl, tCl-C6)-hydroxyalkyl, (C1-C8)-alkoxy~ 2-33~5 ~OCF2-C~FClr tC~ alkylmercapto, (Cl-C6)-allcyl~ul~inyl~
(Cl-Ca)-alkylsulfonyl, tCl-C0)-alkylcarbonyl, tCl-C6)-alkoxycarbonyl, carb~moyl, N-(Cl-C~) alkylcarbamoyl, N,N-di-(Cl-C~)-alkylcarbamoyl, (Cl-C~)-alkylcarbonyloxy, (C3-C5)-cycloalkyl, carboxyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenyl~ulfonyl, phenylsulfinyl, sulfamoyl, N-(Cl-C~)-alkylsulfamoyl, 2~82~
N,N-di-(CI-C4)-alkylsulfamoyl, aminoalkyl, N-~C1-C8)-alkylamino-(Cl-Cl2)-alkyl or N-di-(Cl-Ca)-alkylamino-(Cl-Cl2)-alkyl and which i9 optionally ~ubstituted by up to 3 o~ the abovem~ntioned identical or dif~erent ~ub-~titllent~, and one CH2 group of the alkyl chain i~ option-ally replaeed by O, S, SO, 52 or NR', or by a radical of the formula II
~5 (II) in which R5 is an amino acid bonded via it~ acyl radical, or a derivative of this amino acid, or an alcohol protec-tive group, B a substituted ~C6-C12)aryl radical, (C7-C1l)aralkyl radical or heteroaryl radical, each of which i~ monosub stituted or polycub~titutedJ pre~erably mono- or disubntituted, by hydroxyl, amino ~C~-C8)-alkoxycarbonyl, (Cl-C8)-alkyl~
carbonyloxy, ~ Cl-c8 ) -alkylamino, di-( Cl-C8 )-alkylamino, ~:: (C1-C6)-hydroxyalkyl, -O-~CH2-]XcfH(2~ )F3~ -OCF2C1, -OCF2-CHFCl, carbamoyl, N-~Cl-C8)-alkylcarbamoyl, N,N-di-(Cl-C8)-alkylcarbamoyl, (Cl-C8)-alkylcarbonyloxy, (C3-Ca)-eycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, amLnoalkyl, N-(Cl-C8)-alkylamino (Cl-Cl2)-alkyl or N,N-di-. (cl-ca)-alkylamino-(cl-cl2)-alkyl, (Cl-C8)-alkoxycarbonyl-oxy, (cl-c8)-alkoxy-(cl-c8)-alkoxycarbonyloxy~ (C6-C12)-aryloxycarbonyloxy, (C7-C1l) aralkyloxycarbonyloxy, tC7-Cl1)-aralkylearbonyloxy, cinnamoyl, einnamoyloxy, (Cg-Cl2)-arylearbonyloxy, (C3-Ca)-alkenylearbonyloxy, (C3-C8)-alkynylaarbonyloxy,(C3-Ca)-eyeloalkylcarbonyloxy, (C1-C1z)-alkoxy-(C~-Cl2)-alkoxy, (Cl-Cl2)-alkoxy-amino, (Cl-Cl2)-alkoxy-N (Cl-C6)-alkylamino, (C~-C~2)-alkoxy-N,N
(Cl-C6)-dialkylamino, earbamoyloxy, N-tC1-Ca)-alkylcarbamo-2~82~7~
yloxy, ~, N-di- (C~-C~ alkyl~ 0yl, N- ~C3-C6 ) -cyclo~lkyl-ca~bamoyl~ N-(C~ ryl~lno, N~t~r~ ral~ylamino, N-alkyl-arallcylamino, N~ o, ~C~-Ca)-c:yclo-alkanoylamino, ~Cl-CO) -~lkanoyl~m~no~ ~C~,-C~ royl~no, (C7-C~ aralk~noyl ~ no, (Cl-Ca)A~Llkanoyl-(Cl-C~,)-~lkyl-amino, ~ E9-C~ ycloalkanoyl- (Cl-COJ -ell~c3rla~no t (C3-e~
aro~rl-(Cl-C81-alkylamino, (C7~C~ ralk~oyl-(C~ CO)-nlkyl-A~n~no, ~C1-C8)-a}kylmercapto~ (c~l-c~ k3rl~ulfinyl~
(Cl-~a)-alkyl~lul~onyl~ ~C~-~8)~ carbolly~ 3-C~
10 cyclo~lkylc~rbonyl, nitro, tr~luo~omethyl, ph~nyl-:~ ~er~:apto, phenyl~ulfonyl, phenylsuli~i~yl, 3ulfæmoyl, N-(C1-C6)-alkylaulfamoyl, ~9~ di-~C~-C~ alkyl~ulfamoyl, (Cl-Ct) -alkyl-E~uliEonami do or ~LrylsuliEon2mido, .
C a substituted (Cl-Cl2) ~lkoxy radical, ( 3-C~ cyclo-15 alkoxy, (C6-C~2)-aryloxy rAdical or ~ (C~-C~a)-aral~yloxy radical, each of which i~ ~onosub~itu~ed or polysub~ti-tuted, pre~erably ~OAO- or di~ubstituted, ~y halogen, tri~luoro~ethyl, (C1-C~ alkoxy, hydroxyl~
( Cl-C~ ) -hydroxyalkyl, ~R ' R ~' or cyano 20 where in each ca~e R' and R" are identical or different and are hydrog2n, DC12) -aryl, ( C1-CB) -a ~ C~-C5) -,alkylcarbonyl, (C~-Cl1~-aralkylcar~onyl or tC6-C~ rylcarbonyl, or together with the nitrogen, form a saturated heterocyclic 25- ring, pref~rAbly a 5- or 6-m~ r~d ring, and the abovementioned r~dia~l0 R19 p~2, ~3 ~nd R4 e~ occur ` in combination with n (C~-C12~-alkyl radical whi~h i~ mc~no~ubsti~uted or poly~ubetituted, pre~erably mono- or di~ubstituted, }~y hydrogen, halogen, hydroxyl, cyano, ~mino~ carboxyl, (C1-Cj)-alkoxy, (C1~C~ lkoxyc~rbonyl f (Cl C4)-alkyl-carbonyloxy, (Cl C~)-slkyl~ o~ (Cl-C~)-di~lkylamino or with 2~82~7~
a phenyl ring which i~ ~ono-, di- or txi~ub~tituted by the r~dical~ halogen, n~tro, (C1-C~)-alkyl or ~Cl-C4~-alkoxy, or in ~mbination with an aryl or het~roaryl radiaall ~ach of which ~a~
S turn, optionally be mono-, di- or trisub~tituted by halogen, nitro, cyano, ~Cl-C~ lkyl, ( C~-C4)~ alk9Xy~
including all deri~a~ivas which have a zuitable prot~c-tive group in ~heir ~mino or hydroxyl group~, and the phy~iolo~ically active ~alt~ d n i~ O or 1, f is 1 to 8, preferably 1 to 5, g i~ 0, 1 to (2f+1), ~hd x i~ 0, 1, 2 ox 3, preferably 0 or 1.
Aryl, aryloxy, heter~aryl or heteroa~yloxy ~ompounds are : 15 -~nderstood as meaning, in particular, phenyl and naphthyl rin~8~ or unsub~tituted 5- and 6-~embered heteroaromatic ring~ having l, 2 or 3 ni~rogen and/or oxygen and/or ~ulfur atoms, such a~ pyridyl, pyridazyl, pyrimldyl, pyrazyl, imidazolyl, triazolyl, thienyl, oxazolyl and thiazolyl ~eri~atives, nd their benzo-fused derivative~.
The radical ~C7-C~ aralkyloxy ie preferably u~der~tood as meaning a ~ubstituted phenylalkyloxy radical o~ the ; . formula III
-O -[CH2-lr ~ R~ (III) Rl R9 in which 2t)82~7~
g R8, ~7~ R8 ~nd RlQ are identical or di~fer0nt and ar~
hydrogen, halogen, cyano, nitro, txifluorumethYl, (I~ C5~-alkyl, (Cl-C~ alkoxy, -O-t~2~ CyH~2~ s)F3~ -OCF2Cl~
-O-CF2-CEIFCl, ~ Cl C~ ) -alkylmers~apto, ~ Cl-C~ ~ ~alkylsulf ir~yl, S (C~-C~ alkylsul~onyl, ~C,-Ca)-alkylcarbonY~ G~-alkoxyc:arbonyl, carbaDJoyl, N- t Cl C4 ) -alkylc:arlbamoyl, Il,~-di- ~C~-C~ ~ alkylcarbamoyl, (5~1 C6~ -~lkglcarbonyloxy, C3-C8 ) -~ycloalkyl, phenyl, benzyl, pherloxy, benzyloxy, ~R'-R", suQh as ~mino, anil~no, ~-methylanilino, phenyl-10 mer;:apto, phenyl~ul~onylg ph~yls~ Einyl, ~ulf~moyl,~-~C~-C")~alkylsulf~oyl or N,~-di-ICl-C~3-allcylsulfamoyl, or two adjac~t subst~tuen~r~ together are ~I chain -~CEI2-~n or -CE~-C~-CB~C~-, where a C~2 group of th~ chain i~
optionally rep}aed ~ O, S, SO, SO2 or NR', Y i3 1, 2~
15 3 or 4 ) pref~rably O and 1, and the remaining o~ the substituents R6, R7, R8~.R~ and Rl are a8 de~ined above.
o acids which are preferred fxom among~t those mentioned above are~ in particular, the natural ~-amino ~cid~.
Amino proteative group~ are under~tood ~ aning, in particular, ~u~h group~ aB are de~cribed in R. ~eiger and W. ~nig "The Peptides" Volume 3, "Protection of Func tional Group~ i~ Peptide Synthesi~, B.~. Gro~s, J. Meienhofer ~dit, AGademic Press, ~ew York (1981l, in particular pages 7-4~.
Such groups are also deacribed in ~. ~ubbu~h, S~hutz-gruppen in der Peptidsynthese [ProtectiYe Group~ in Peptide Synth~Eis], Rontakte 3/791 pag~o 14-23.
Particularly pre~erred amlno protective group~ are the ~oll~wing:
Aoetamidomethyl, l-Adamantyloxycarbonyl, l-tl-Adamantyl)-l-methyl-ethoxycarbonyl, ~)82~7~
Allyloxycarbonyl, tert-Butyloxycarbonyl, 1~4-Biphenylyl)-l-methylethoxycarbonyl, Dicyclohexylaarbodilmlde, ~,~-DLmethyl-3,5-dimethoxybenzyloxycarbonyl, 4-Dihydroxyborylbenzyloxycarbonyl, 9-Fluorenylmethyloxyc~rbonyl l-~ydroxybenzotriazole, 3-Hydroxy 4-oxo-3,4-dihydro-1,2,3-benz~triazine, I~obornyloxycarbonyl, l-~ethyl-cyclobutylo~yc~rbonyl r 4-Methoxybenzyloxyc~rbonyl~
~ethyl~ulfonylethyloxycarbonyl, 4~Pyridylmethyloxycarbonyl, lS 2,2,~-Trichloro-tert-butyloxycarbonyl, ~enzyloxycarbo~yl, halogen-sub~tituted b~n~yloxycarbo~yl, 4-Nitro-benzyloxycarbonyl J
2-Phosphonoethyloxyc~rbonyl, : 20 Phenyl~ulfonylethoxyG~rbonyl, Toluenesulfonylethoxycarbonyl, ~,3,5 Trimethyl-4-methoxy-phenyl~ul~onyl, Benzotriazol-l-yl-oxy-tri~(dimethylamino)phosphonium hexafluoropho~phate.
2~ Preferred compound~ ~rom amongst tho~e o~ the ~ormula I
who~e amino groups are protected are those whose pro-tected amino group i~ part of this amino acid R5.
Suitabls alcohol protective groups axe, in pa~ticular, ~ub~tituted or unsub~tituted ~ethyl ethere, ethyl ethers, benzyl ether~, silyl ether~, e~ters, carbonates or ~ulfonate~.
rhey embra~e the ollowing compounds:
., .
~ .
:~.
8 ~
A~ ~ubstituted methyl ~thers:
~ethoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyld ~ethyl~ilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, ~4-methoxypheno~y)~methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenylo~ymethyl, ~iloxymethyl, 2-methoxye~hoxymethyl~ 2,2,2-tri~hloro-ethoxymekhyl~ bia~2-chloroe~hoxy)m~thyl, ~-~trLmethyl-3ilyl )ethoxymethyl,tetrahydropyranyl~3-bromotetrahydro-pyranyl, tetrahydrothiopy~anyl~ 1-methoxy~yclohexyl, 4-methoxytetr~hydropyrar,yl, 4-m~thoxytetrahydrothio pyranyl, 4-methoxytetrahydrothiopyrAnyl-S,S dioxo, 1-~2-chloro-4-me~hyl)-phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-20yl, tetrahydrofuranyl J tetrahyfirothio-furanyl.
As sub titut~d ethyl ethers:
1-Ethoxyethyl, 1-(2-chloroethoxy)ethyl, l-methyl-l-methoxyethyl, 1-methyl l-benzyloxy~thyl, l-methyl-1 benzyloxy-2-fluoroethyl, 2,2,~-trichloroethyl, 2-tri-methylsilylethyl, 2-[phenyl~elenyl)ethyl, t butyl, allyl,-p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl.
As ~ubstituted benzyl ethern:
p-Methoxybenzyl, 3,4-dimethoxybenzyl, o nitrobenzyl, p-nitrobenzyl, p-halogenobenzyl, 2,6-dichloxobenzyl, p cyanobenzyl, p-phenylbenzyl, 2- and 4-pioolyl, 3-methyl-2-picolyl-N-oxido, diphenylmethyl, p,p'-di-~itrobenzhydryl, triphenylmethyl, ~-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethy~, di(p-methoxy phenyl~-phenylmethyl, tri(p-methoxyphenyl)~thyl, 4~(4'-bromophena~yloxy)phenyldiphenylmethyl, 4,4',4"--tris(4,5-dichlorophthalimidophenyl)methyl, 4,4'4"-tris(levulinooxyphenyl)methyl, 4,~4 n -tri8-(benzoyloxyphenyl)methyl, 3-(imldazole-1,4~-methyl)bis-(4'4"-dimethoxyphenyl)-methyl, l t 1-bi~(4-me~hoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)x~nthenyl, 9-(9-phenyl-10-oxo)anthryl.
~2~
AB ~ilyl ether~-Tr ~ethylsilyl; triethyl~ilyl, trii~opropylsilyl, dim~thyli~opr~pyl~ilyl~ diethyli~opropyl~ilyl, dLm~thyl-thexyl~ilyl, t butyldLmethyl~ilyl, t-butyldiphenyl~ilyl, tribenzyl~ilyl, ~ri-p-xylyl~ilyl, triph~nyl~ilyl, diphenylmethylsilyl, t-butylmethoxyph~enyl~ilyl.
As e~r~:
Formate~, benzoyl fo~mate~ acat~t~, ch~oroa~etate, dichloroaaet~te, trichlo~oacetate, trif luoroacet~te, 10 Dnethoxya~:etate, triphenylmæthoxyac~etate~ phenoxyacetate, : p-chloroph2noxyacetate, p-P-phenyla~et~te, 3-phenyl-propiorlate, 4-oxoperltanoate t l~vul inate ), 4,J.-(ethylenedithio)pentanoate, pivaloate, adamantoate, cxotonate, 4-1nethoxycrotonate, b~rlzoate, 15 p-phenylbenzoate, 2,4,6-tr~me~thylb~nzoate (m~itoate)~
A~ ~arbonates:
~ethyl, 9-fluorenylmethyl, ~thyl, 2,2,2-tri¢hloroethyl, 2-~trL~ethyl~ilyl)ethyl,2-~ph~nyleulfonyl)ethyl,2-~tri-phenylpho~pho~io)~thyl, isobutyl, vinyl, allyl, p-nitro-phenyl, benzyl, p-methoxybenzyl, 3,4-dim~thoxyb~nzyl, o-nitrobenzyl, p-nitrobenzyl, S-ben~yl thiocarbonates, 4-ethoxy-1-naphthyl, methyl dithiocarbonate~.
Other e~ters:
2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4- ( 1,1, 3, 3 tetramethylbutyl )phenoxyacetate, 2,4-bi~-(1,1-dLmethylpropyl)phenoxyaoetate, chlorodiph~nyl-acetate, isobutyrate, monosuGcinate, (~)-2-~ethyl-2-butenoate (tigloate), O-(methoxycarbo~yl)benzoate, p P-benzoate, ~-naphthoate, nitrate, alkyl N~N,N',N'-tetramethylpho~phorodiamid~te, N-phenyl-carbamate, borate~, dimethylphosphinothioyl, 2,4-dinitro-phenylsulfenate.
:.
- 2~:~2~7~
~ 13 -As ~ulfonat0s:
Sulfatss, methanesulfonate (mesylate), benzyl~ulfonate, tosyl~tee.
The following protective groups are parti~ularly preferred:
(C1-C~-Alkanoyl, (Cs-C~)-alkylcarbamoyl, d~-(C~-Ca)-alkyl~
~arb~moyl, N-( C3-C~ ~-ayclo~lkylcarbamoyl, (Cl-C5)-alkoxy-carbonyl, ( C6-Clz ) -a~yloxycarbonyl, (C~ aralkyl oxycarbcnyl, in part~cular benzyloxycarbonyl, (C8-C~
arylcarbonyl, (C~-C~ aralkylcarbonyl, (C1-CB)-alkyl, (Cl~C~)~alkoxy-(C1-C~)-alkyl, ~arb~oyl-~C1-C~)-alkyl e~ter, (Cl-C1O)-acyloxy-(C~-C6)-~lkyl, pr~ferably (Cl-C10) alkanoyloxy-(Cl-C6 ~; alkyl, benzyloxy-( Cl-C6 ) a~kyl, benzyloxycarbonyloxy-~Cl-C~ alkyl, ~Cl-C~)~
alkoxycarbonyloxy-(Cl CB)-Alkyl, ~mino acid e~ter~ or tetrahydropyranyl.
Preferred compound~ of the formula I are tho~e in whi~h Rl and/or R3 Pre hydrogen or m~thyl and R2 and~or R4 have the abovementioned ~eanings.
Other preferred ~ompound~ of th~ formula I are those in which Rl and~or R3 are hydrogen and R2 nd/or Rb are A a branched or unbranched ~Cl-C12)-alkyl radi~al which is monosubetituted or poly~ub~tituted by ( cl-c8 ) -alkoxycar~onyloxy~ (C~-C8)-alkoxy (Cl-Ca)-alkoxycarbonyloxy, ~C8-Cl2)-aryloxycarbonyloxyl (C~-C11)-aralkyloxycarbonyloxy, (C7 C ~ aralkylcarbonyloxy, (C7-Cll)-arylcarbonyloxy, (C3-C8)-cycloalkylc:arbonyloxy, (Cl-C~2~-alkoxy-~e1-Cl2)-alkoxy, carbamoyloxy, ~-(Cl-C~)-alkylcarbamoyloxy, ~ di-( C1_CA1-alkyloarb~moyl~
~-(C3-C~ cycloalkylcarbamoyl, ~-~C~-Cl~)~
ar~lkylcarbamoyloxy or N-(C6-Cl2)-arylcarbamoyloxy, where the aryl and aralkyl radical~ in the above ~ub~tituent~
can al80 h~ve a heterocyclic nature and/or, like ~lkyl, are sub~tituted by l or 2 identical or different - 14 - 2~82~7~
~uh~tituent~ selected from the ~erie~ comprising halogen, trifluoromethyl, hydroxyl, (C1-Ca)~al~Y~ 3 ) -hydroxyalkyl, (C~-C~)-alkoxy, ~ ~2- ] ~C~2~+~ ~)F6 ~ -OCF2Cl ~
-0-CF2-C~FCl, -(C1-C~-alkoxycarbonyl, sarbdmoyl, ~Cl- C3 ) -alkylcarbonyloxy, (C3Ca~-~ycloalkyl~ phenyl, benZYlr phenoxy or ~enzylo~y, or by a sub&tituted (C8-C~2)-aryl radical or het~roaryl radi~al which h~8 on~ or two iden~ical or diferent substituent~ sel~ct~d ~rom the seri~ c4mpri~ing hydroxyl, trifluoromethyl, [Cl-C3)-hydroxyalkyl, (Cl-C3)-alkoxycarbonyl, ~arbamoyl, NR'R", ~-~Cl-C~ yl carbamoyl, ~ di-( C~-c4 )-alkylcarbamoyl, (Cl-C3)-alkyl-carbonyloxy, A~; noalkyl or N-(C1-C~)-alkylamln-tCl-c~)-alkyl, whare R' and R~ are identical or differen~ ~nd Are hydrogen, ~C~-Clz) aryl or (Cl-C4)-alkyl, or by a substituted (C6-C10)-aryloxy radical or ~C~-C~
aralkyloxy radical which has 1 or 2 identical or dif-fer~nt substituents s~lected ~r~ the nerie~ comprising hydroxyl, halogen, trifluoromethyl, (Cl-C3)-alkyl, (~ a)~
hydroxyalkyl, ( Cl-c3 ) -alkoxy, (Cl-C3)-alkylmercapto, (Cl-C3)-alkyl~ul~inyl, (Cl-C3)-alkylsul~onyl, (Cl-C3)-alkylcarbonyl t ( C1-C3) alkoxycarbonyl, carbamoyl, ~-(C1~C4)-alkylcarbamoyl, N,N-di-~C1-C~)-alkylcarbamoyl, (Cl-C3)-alkylcarbonyloxy or ~R'R~ where R' and R" are identical or dif~er~nt and are hydrogen, (C~-C1O)-~ryl or ~Cl-C4) alkyl, or by a radic21 of the formula II
R5 (II) in which R5 i8 an amino acid bonded via it8 ~cyl radical, or a derlvative of thi~ am1no acid, ~ ~ 2 ~ 7&
B i~ a ~C6-Cl2) aryl or (C7-C~ aralkyl radical, pre-ferably phenyl, benzyl and phenethyl, each o~ which i~
monosub~tituted by hydroxyl, (C~ C4)-alkylaarbonyloxy, (cl-c~)-alkoxycarbonyl~ tCl-C~)-hydroxyalkyl, ~mino, (Cl-C5)-alkylAmino, di- (C~-C5) -alkyl~mino, (Cl~~s)~
alkanoylamino, carbam~yl, N-(Cl-C~)-alkylcarbamoyl, N,N-di-(Cl C~ lkyl~arbamoyl t ~rbamoyl, N-(Cl~C4)-alkyl-carbamoyloxy, N,N~ (Cl-C~)-alkylcarbamoyloxy, or C iB a tCl-C6)-alkoxy radical, ~C3-C~)-cy~loalkoxy radical, (CB_C1~ ) -aryloxy radical and ( C7-C~ aralkyloxy radical, : n i~ O or 1, is 1 to 8, preferably 1 to 5, g is 0, 1 to l2~
x i~ 0, l, 2 or 3J pr~f~rably O or 1, and wher~ the a~ovementioned radical~ Rl, R2, R3 and R4 can occur in combination with a (~-Cl2)-alkyl radioal which i5 monosubstituted or poly~ub~tituted, pr~ferably mono- or disubstituted, by hydrogen, haloge~, hydroxyl, amino, (Cl-C4~-alkoxy, (Cl-C4)-alkoxycarbonyl, (Cl-C~)-alkyl- or (C~-C~)-dialkylamino or a phenyl ring which i~ ~on~-, di- or trisubstituted by the radl~als halogen, nitro, (Cl-C4)-alkyl or (Cl-C4)-alkoxy, and also in ~ombination with a~
: 25 aryl or heteroary.l radi¢~l which, ~n turn, can optionally be mono~ub~t~tuted or di~ub~tituted by halogen, (Cl-C4)~
alkyl or (C~-C4)-alkoxy, including all derivatives which have a protective group in the respective amino or hydroxyl group, and the phy~iologically active aalts.
- ~6 - 2~8~
Particularly preferred compound~ of the formula I are those ~n which R1 nnd/or ~9 are hydrog~n and R2 and/or Rh are : A an unbranched (C~-C~)-41kyl r~dical which i~ ~ono-~ubstitut~d by ICl-C~)-alkoxyc~rbonylo~y, ~C1-C~-alkoxy-(Cl-C~)-alkoxycarbonyloxy, (C~-C~)raryloxycarbonYlO~Y, (C~-C~
aralkyloxycarbonyloxy, ~ C7~ r~lkyl~rbonyloxy, ~C6-Cl2)-arylcarbonyloxy, ~ C3-CB )-cycloalkylcarbonyloxy, ~cl-cl2~-alkoxy-(cl-c~)-alkoxy~ (cl-cl2~ kox~-~mino~
(C1~Cl2)-alkoxy-~-(Cl-c6)-alkylamlno~ (Cl-C12~-alkoxy-N,~-(C1-C6)-dialkylamino, ~ di-lCl-C~-alkylcarbamoyl, N-( C3_C~ )-cycloalkylcarbamoyl, ~-(C7C~ aralkylcarbonyl-oxy, N-(C6-Cl23-arylcarbamoyloxy, (~1-C5~-alkanoylamino, (C3-C6~-cycloalkanoylamino, (C5-Cl2)-~roylamino or (C7-Cll)-~: aralkanoylamino, where alkyl, aryl, aryloxy, aralkyl or aralkyloxy, in turn, are ~ub3tituted by h~droxyl or halogen, in particular fluorine, (Cl-C3)-alkyl or (Cl-C3)-alkoxy, or by a phenyl radical which i~ m~nosub~tituted by a hydroxyl group, or a ~ub~tituted phenoxy or benzyloxy radiaal which i~ ~ubstituted by hydroxyl, halogen or ~; (Cl-C~)-alkoxy, or by a radical of the formula II
-0-~3 (II) .:
;: in which R5 i~ an d no ~cid bond~d via it~ acyl radical, or a derivative o~ this amino acid which i~ ~ub~tituted on the amino group, B a (C6-CI2)-aryl or (C7_C~ ara1kY1 radi~al, pre~erably phenyl, b~nzyl and phenethyl, which i8 mono~ubstituted by hydroxyl, and 2~82~ ~
C methoxy.
The invention further~or0 rel~te~ to a proce~s for the preparation of compound~ of the ~ormul~ I which ~omprises reacting a comp~u~d of the ~or~ul~ IV
o ~ - C
; ~ (IV) C - Y
Il O
with a compound of the for~ulae V
H - N .~ or ~ V) : ~' ~: where Rl, R2 or R3, R4 are as defined in formula I and Y i8 halogen or hydroxyl or together with ths carbonyl group form~ an ~ctive ester or a ~ixed ~nhydride, and, if appropriate, ~onverting the reaction products into their ~ physiologically acceptable ~alts.
- The preparation of oompound~ of the formula I and the preparation of the st~rting material~ raquired therofor, unle~ they ar~ com~ercially available, will b~ described hereinafter in greater detail.
~he ~implest way of preparing the compound~ according to the invention i~ to combine the two co~ponent~, the pyridine derivative o~ the formula ~IV~ and the amine of ` - 18 - ~$2~
the formula (V~, in equ~s:)lar am:~unts or in up to ~pproximately 5-~old exce~EI of V, ~.nd ~o react them ~t t~mper4tures of between -3a and 150C, prefarably at 20 to 100C, until th~ reaction i~s QompleteO The end of the reaction can }:~e determined 3by mean~ of thin~ yer chromatography ~DC checlc~. In a varian~ o~ thi3 procea3, the reaction 1~ o~.rriad ou~; ~n a ~3uit~ble solvent ~uch as sliethyl ~ther or di~ethoxye~h~ne D~C tet:rahydro~ura~
chlorinated hydrocarbon~ ~uch a~ .methyl0ne 3:hloride~
10 ~hloroform, tri- or t~rac:hloroethylen~, benz~ne, toluene or ~lse po}ar a301vents such a8 diD~ethy~ ~ormamide or acetone or dimethyl ~ulf oxide .
In thi~ proee~s too, an exceEIY of amine of khe formula (V), which ean be up ~o approx. 5 fold, can be u0ed. The 15 reaction temperatures ~re between rooDI k~mperature and the boiling point o~ the E~olv~nt, temperatures in the range from room temperature o 13û~C being particularly preferredO
The reaction carl equally be carried out ~ria a m:Lxed anhydride such as ethyl ~hloroonmate, or via an acti-vated ~ter ~uch as paranitrophenyl e~ter (Y ~ CIC~2-COO
or NO2-C6~4-O). Suitable ~ethod3 can be found in ~ouben-Weyl, Methoden der Organi0chen Chem1e ~Methods in Organic .Chemistry], Volume XV/2, pages 169 to 183 ~mixed anhy--25 dride method), or pages 13 et s~q. (active e~ter method), fourth ed$tion, Georg Thieme Verlag, Stuttgart 1974.
If appropriate, the reaction can al~o be ~arried out in the presence of base~. 8uitable additional base~ ~re inorganic a¢id scavenger~ ~uch RB c~rbonates or hydrogen-car~onates, for example ~odium carbonate, pota3~iumcarbonate, sodium hydrogencarbonate or potassium hydrogencar~onate, or organic acid ~cavenger~ ~uch a~
tertiary amines, such a~ triethylamine, tributylami~e, ethyl diieopropylamine or heterocyclic amines ~uch as N alkylmorpholine, pyridine, quinoline or 2~2~7~
- lg -dialkyl~niline~ .
The compounds of the formula (IV) are preferably re~cted with ami~s of the formula (V~ with additio~ of a w~ter-el~nating agent ~suc:h ~E~ dialkylcarbodli~nidea where the 5 allcyl radical~ have 1 to 8 carbon ~5to~$3 which, in the casa of the C3-C9-eompound~, can al~o lbe bram:h~d or cyclic:; dicycloh~$ylc:arbodiimide ~ pref~rably ~mpls~y~d.
A s~litable laethod iE~ da~cribed in Elouben WQY1 Volume XV/2, pag~ 103 to ~ thoden der Org~ hen Chemit3 10 [Method3 in Organic ChemiE~try~, 4th ~dition, Georg ~hieme Verlag, Stuttgart, 1974.
I~ appropriate, the product6 can be worked up for ~ample by extraction or by chromatography, ~Eor example using silica gel. The i~3olated prodllct ~an be recrystallized 15 and, i~E appropriatet reac:l:ed with a suit~ble acid to give a physiologioally act:sptable ~alt. 13xamples oiE ~uitable acids are:
.
Mineral acid~ BUCh a~ hydrochloric ~nd hydrobromic ~cid a~ well as sulfurit: acid, pho~phoric ~cid, nitric aoid or perchloric ~cid, or organic acid~ ~uch a~ forn~c acidl acetic acid, propionic acid, ~uooinic ~oid, glycolic acid, lactic acid, malic ~cid, tartaric acid, ~:itric ; acid, maleic acid, fumaric acid, phenylacetic acid, benzoic acid, methanesulfonic acid, toluene~ulfonic acid, oxalic acid, 4-~minobenzoi~ acid, naphthalene-1,5-di : ~ulfonic acid or a~corbic ~oid~
If the ~tarting compounds of the fonmula (V) are not commercially av~ilable, they can be ~ynthe~ized in a ~imple manner (~or example Organikum, organisch Chemisches Grundpraktikum CPractical Foundation in Organic Chemistry], 15th ~dition, VEB Deutscher Verlag der Wissenschaften, 1976; a survey of the various po~si-bilitie~ can be found in khe methodological regi~ter, page 822~.
2 ~ 7 6 For exam~le, the ~tarting compound of the fonmula (IV) can be obtained by reaeting pyridina,-2,4- or -2,5-di-earboxylie acid to give tha corresponding pyridine-2,4-or -2,5-dicarboxylic halide, preferably the chloride (by proce~es ~nown fr~ the litarat,ure, for example Organikum, Organi~ch Chemi3che~ Grundpraktikum [Practical Foundation in Organic Chemistry], 15th ~dition, VEB
Deutsch~r Verlag der Wi~sen~chaften, 1976r page 595 et 8eq. ) ~ which i8 then reacted with ~ ~uitable aloohol, ~or example paranitrobenzyl ~lcohol, to give the aorrespond-ing active ester. Equal1y, the pyridine-2,4- or -2,5-di-carboxylic acid ~an also first be con~erted i~to a mixed anhydride by addition of a ~uitable ~arboxylic acid or : carboxylate, such as ethyl cbloroformate, and this mixed anhydride i8 then reacted with the amine6 (V) to gi~e the product~ accordi~g to the inve~tion. A ~uit~ble methcd i8 described, or example, in ~ouben-Weyl~ ~etho~n der Organischen Chemie tMethod~ in Organic Chemistry], Volume XV/2, pages 169 to 183, 4th Edition, 1~74, Georg ~hieme Verlag Stuttgart.
The ~ompounds of the formula (I) ~ccording ~o the inven-~; tion have valuable pharmacologic~l propertie~ and are, in ; particular, e~fective a6 inhibitor~ of proline hydroxy-aBe and lysine hydroxylase, a~ a fibrodepres~ant r immunodepre~ant and antiathero~clerotic.
;~ The antifibrotic action can be determined with the aid of ~: the carbontetrachloride-induc~d hepatic fibro~is ~odel.
To this end, rat~ are trQated twice weekly with CCl4 (1 ~l/kg) dissolved in olive oil. ~he test sub~t~noe i~
administered daily, if appropxiste even twice daily, or~lly or intraperitoneally, dissolved in a ~uitable acceptable solvent- The extent of hepatic fibrosis i~
determined hy~tologically and the amount of oollagen in the liver i8 analy~ed by hydroxyproline determination as described by Kivirikko et al. (Anal. Biochem. 19, 249 et ~eq. ~1967)~. The fibrogenetic ~ctivity can be determined 2Q8207~
by radio ~ unological det~r~instion o~ ~oll~gen ~ra~ments and procollage~ peptides in ~he ~erum. I~ thi~ mode~, the compounds according to th~ inv~ntion are active at a concentration of I-100 mg/kg.
5 The fibrogenet~c activity ~an be determined by radio~
unological determi~ation o~ the ~-terminal propeptide of the type III collagen or th~ N- or Co~ermi~al cro8~-linking domain of ~he type IV collagen (7~ ~ollagen or . type IV ~ollagen ~C1~ in the h~rum.
~o this end, the concentration of hydroxyproline, procollagen III peptide, 7~ collagen ~nd type IV ~ollagen NC in the liver wer~ measured in a) untreated rat~ (control), b) rat~ who had been adminis~red carbon tetrachloride (CCl; control) and ~) rats who had been administered ~irst CCl~ ~ollowed by a c~mpound according to the invention ~: ~thi~ te~t method i~ de~erib0d by Rouiller, CO ~ Experi-mental toxic injury o~ the liver; in The Liver, C. Rouiller, Vol. 2, page~ 335-476, N~w York, Academi~
Press, 1964).
Another model for evaluating the antibiotic action i8 that of bleo~ycin-induced pul~onary fibrosis ~s described by Kelley et al. (J. ~ab. Cli~. ~ed. 96, 954, (1980))~
~he ootton ball granuloma ~odel, as de~crib0d by ~eier et al., ~xperimentia 6, 4S9 (1950), ca~ be u~ed for evaluating the action of the ¢ompounds according to the invention on the granulation ti3~ue.
The compounds of the formula I aAn be uned a0 medicam~nt~
in the form of pharmaceutioal preparations which compri~e the compound3 of the formula I if appropriate together with acc~ptable pharma~eutical ~xcip;ents. ~he aompounds oan be u6ed aR drugs, for example in the ~orm o~ pharma-ceutical preparations, which compri~e these oompound~ in 2~82~7~
the f orm of ~ mixture with a pharmaceutic:dl, organic or inorgar~ic excip~ent which i~ 8uitable for enteral, percu-taneou~ or parenteral admini~tratl on ~uch as, for example, inter alia, water, gum nrabic:, gelatine, 5 lactose, starch, ~agn~ tearate, t~lc, ~regetab~
oil~, pc:lyalkylene glycc3ls and vaseline.
To thi~; end, they a~n be dmini~atered orally at do~age rates o~ 0.1-25 mg/kg/day, preferably 1-5 mgrkg/day, or parenterally at doE~age rates of 0.01-S ~g/kg/d y, pr~fer-10 ably 0.01-2.5 mg/kg/day, in pa:rticlllar D.5-1.0 mg/lcg/day.
In ~evere c:a8e8 ~ the dosage ra~e~ an ~150 be increa~ed.
In many c:a~es, however, lower do age rate~ ~uf~ice. q~hese data are based on an ~dl~lt per~3Qn of ~ bcdy w~ight of approximately 75 kg.
~` 15 ~he invention furthermore compri~e~ the u~e o:E the compound~ according to the invention in the preparation of pharmaceutic:als which can be employed for the treat-me~t and prophylaxi~ o~ the metabo1ic disorder~ :mentioned ~ above.
: 20 A further object of the invention are pharmaceutical3 :compri~inq one or more compound~ o~ the formula I acGord-ing to the invention and/or phy~iologically acceptable ~alts thereof.
The pharmaceutical~ are prep~red ~y proaesses which ~re known per ~e ~na ~amiliar to e person skilled in the art.
A~ pharmaceutical~, the pharmacologically active ~om-pounds ~ e active substance) according to the invention are employed either as such or, preferably, in combinn-tion with suitable pharmaceutical adjuvant~ or excipient~
in the form of tablets, coated tablet~, cap~ule~, ~up-positories, emulsions, ~u3pensions ox solutions, the active substance content being up to approximately 95%, advantageou~ly between 10 and 75%~
2~82~76 Suitable adjuvants or excipient~ for the desir~d pharma-ceutical ~ormulation are ~ be~ides ~olvents, g~lling agents, bases ~or 8Uppo8itorie8, tableting adjuvant~ and other aetive sub~tanc~ ~xcipi~nt~ for example ~l~o antioxidant~, di~persan~r ~mul~l~ier~, dsfoamers, flAvor improvers, preaervatives, ~olubilizer~ ~r colorant~.
The invention will be illustrat~d in greater detail hereinafter with the aid of example~.
~xample 1 lQ Bis-N,N'-~3'-benzoyloxypropyl)pyridl~é-2,4 ~ arboxamide a~ 25 g (128 mmol3 of dimethyl pyridine~ dicarboxylate are dissolved in 500 ~1 of ethanol and xe~luxed for 4 hour~ together with 22 ml l282 mmol~ of 3-amino-~ 1-propanol.
; 15 After the mixkure ha~ bean allowed to ~tand ovexnight at room temperature, the ~olvent i~ distilled off in vacuo, and the residue i~ ~rystallized from hot ethyl aaetate;
28.7 g m.p. 102-105C.
b) 0.7 g ~2.5 mmol) of the resulting pyridine-2,4-dicarboxylic bi~-N,N'-(3-hydroxypropyl)~mide are combined with 100 ml of di~hloro~eth~e and treated with 0.2 g of 4-~,N-dimethylaLlnopyridine, 0.8 ml (6 mmoll of triethylamine and dropwi~e ~ith 0.6 ml (5 mmol) of benzoyl ~hloride. After 1 hourt the mixtur~ i8 concentrated and the ~o~centrate i8 ta~en up in water.
After 1 hour, the mixtur~ i~ extracted twice by 3haki~g with water ~nd ~he organic ph~e i~ concentrated. The crude product i~ chro~atographed over silica gel using ethyl acetate, yield: 0.95 g of colorle~ oil.
Bmpirical formula: C27~27N3O8 (489) MS: m/e G 490 (M ~
- 24 - 2 ~2 ~ 7 ~xample 2 ~is-N,N~-~2-(2~m~thylbenzoyloxy)propyl3pyridine-2,4-diaarbox ~ de The title compou~d i8 obtained analogou~ly to ~xample 1 fro~ 0.7 g ~2.5 mmol~ of pyridine-~4-di~rboxyllc bis-~N~-(3-hydr~xypropyl)amide A~ 0.66 ml ~5 ~mol~ of 2-methylbenzoyl chloride, yield: 0.9l0 g of colorl~s~ oil.
~mpirical formula: C2~3lN306 ~517) ~S: m/e = 518 tM ~
, s~ 10 ~xample 3 2-N-~3-Methoxypropyl)-4-N-[3-(2-methylbenzoyloxy)propyl]
pyridine-2,4-di~arboxamide .3 g (40 mmol) o~ 4~benzyloxy¢arboDylpyxidine-~: 2-carboxylic acid Ar~ dis~olved in 160 nl of anhydrous tetrahydrofuran ~nd, at 0C, treated with 6 ml ~43 mmo~
-~ of triethylamine. After lO minutes, 4.1 ml (43 mmol~ of ethyl chloroformate are ~dded dropwi~e, and the mixture i8 ~tirred ~or 30 minutes at 0C-4.4 ml (43 mmol) of 3-methoxypropylam1ne are then added, the mix$ure i8 ~tirred for 1 hour at 0C and concentrated : in vacuo at room temperaturet the product i~ t~ken up in dichloromethane, the ~ xture iB wa~hed with ~aturated Na~C03 solution, dried ~d ~reed from ~olvent, ~nd 11.2 g of 4 benzyloxyaarbonyl~ 3-methoxypropyl)pyridi~-2~ 2-carboxamide are obtai~ed. 6~0 g (18.3 ~mol) of this compound are combined ~ith 15 ml of 3-amino-1-propanol and the mixture i~ stirred for 1 hour at 80C. The exce~.
reagent i~ distilled of~ in v~cuo and the residue i~
crystallized ~rom ethyl acetate, yield: 4.8 g o~
2-N-(3-methoxypropyl)-4-N~(3-hydroxypropyl)pyridine-2,4-dicarboxamide, m.p. 71-73C.
2~82~76 2 . O g of this c:o~pound are ~cylat~d ~nalogoll~ly to ~xample 1 u~i~g 2-methylbenzoyl chlorl~e7 A:Eter ~ilic~
gel chromatography using ~thyl ac:~tate, 2 . 4 g o~ the title compound are obtained ;~ a t:olorlsss;, oily prQduct.
S Bmpirical f o~mulal: C~ 2~N305 ( 413 . 5 ) MS: m/e ~ 414 (M ~ ~) }Sx~mple 4 2 -N- ~ 3-~ydroxypropyl 3 -4-~- l 3- ~ 2-methy:Lbenzoyloxy ) propyl ~ -pyridine-2, 4-dicarboxamide 1.6 g ~3.86 mmol~of the title compound of ~xample 3 are con~ined with 50 ml of di~:hlorome~hane, and 4.5 ml ol~ 1 N
boron tribromide solution in hexane ( 4 . 5 ~mol I are a~de :1 dropwise at -25C. After DC eh~k, a further 1.5 ml of this solution are added dropwl~e, and, aft~r 0.5 hour, the mixture i~ he~tad to room templ3rature and extracted .~ by ~haking with ~3atur~ted N~EIC03 ~olutiorl, the organic pha~3e i8 dried and s:oncentrated, and the oily re3idue i~
chromatographed on silica gel u~ g ethyl acetate /-methanol . O . 61 g o~ the title c:ompound crys~tallize ~rom 2 0 ethyl acetate, m.p- 78-80C
Empirical ~ormula: C2l~25N35 (399-4) ~S: m/e ~ 400 (M + ~) ~xampl~ 5 2-N-~3-~ethoxypropyl)-4-N-[3-(N-cyclohexyl~arbamoyloxy~-propyl]pyridi~-2,4-dicarbox~mide 2.0 g (6.8 mmol~ of ~-N-(3-methoxypropyl)-4-N-(3-hydroxy-pxopyl)pyridine-2,4-dic~rboxamide (c~0 Bxample 3) are dissolved in 250 ml of dichlorometha~e, and 1.05 ml 30 (705 mmol) of cyclohexyl isocyanate are added at 0C with stirring. The mlxture i8 sub3equently refluxed ~or 1 hour, the reaction i~ checked by mean~ of DC, a ~urther 2~8~7~
- ~6 -1.1 ml o~ cyclohexyl i~ocyanate ar~ added, the mixture i~
heated ~or a further hour, ~ wed to cool ~nd treated with water, the organic pha~e i~ dried ~nd con~entr ted, ~nd the oily re~due i~ ¢hromato~r~phsd on silic~ gel u~ing ethyl acet~te.
Suitable fractions are co~centxated and crystallized using diethyl ether; yield: 1.1 g o~ the colorle~s crystalline title compound, m.p. 95-98Co ~xample 6 2-N-~2-Methoxyethyl)-4-N ~3~benzoy}oxyethyl)pyridine-2,4-dicarbox ~ de a) 150 g of pyridine-2,4-dicarboxylic acid are ~o~bi~ed with 1.8 1 o~ methanol and 53.5 g of ~ulfuxic a~id (98~) and heated ~o ~oiling for 3 hour~. ~fter 1 hour, the pyridine-2,4-dicarboxylic acid i8 largely di~olved. Only a ~light cloudine~s remain~ in the mixture~ ~he miYture i8 poured into ice-water and the fi~ely-crystalline precipitate i~ allswed to settle~ the ~uper~atant i~
decanted off, the re~idue iB ~iltered o~E with ~ùction, washed with water and then with a very small amount of ice-cold MeO~. Yield 70-75 g of 2-methyl-oxycarbonylpyEidine-4~carboxylic acid, m.p. 246-24~C
(decomp.). The filtrate iB extracted 3 time~ u~ing C~2Cl2, the organic phases are dried and evaporat~d, the re3idue i~ taken up in ethyl Acstate, and the mlxture i~ ~iltersd cver ~ilica gel (appro~. 1 kg). The filtrate i8 evapor-ted in vacuo. Yield 90 95 g of dLm~thylpyridine-2,4~di-carboxylat~, ~.p. 61-62C.
.
b) 50 g of 2-methyloxycarbonylpyridine-4-carboxylic acid and lS0 ~1 of 2-methoxyethyl~mine give 32.5 g of 2-N-(2-methoxyethyl)-4-oarboxamidopyridine-4-carboxylic acid, m.p. 145.5-146C ~from water).
2~8~76 c) 30 g of the ~bove compound ~re co~bined with 10 ml o~
thionyl chlorid~ in lBO ml of toluens and 1 drop of d ~ethyl~or~mide, the ~ixture i~ heat~d ~or 3 hours.
When cold, 39 ml of triethylam~ne ~re added, iollowed by ~nhydrou3 meth~nol. Filtr~ion wi~h e~hyl ac~tate through silica gel and recry~tallization :ErQm methanol/water gives l9.B g of ~-methyloxycarbonyl~N~ ~ethoxy~thyl) pyridine-2~carboxamide, m.p. 68-68.5'DC.
d~ 5.0 g of tb~ ~bove compound are co~bined with 10 nl of tha~olaml~e and thè mlxture i~ heatod to ~oil~ng for 30 minutes. 3.0 g of 2-~-[2-me~hoxyethyl)-4-N-[2-hydroxy-ethyl)-pyridine-2,4-dio~rboxamide, ~.p. 124-125C, are obtained in the form of ~olorles~ ~rystal~
e) The title c~mpound i~ obtained, analogou~ly to Example 1 from the above compound ~y reaeting it ~ith benzoyl chloride in the presence of tri~thylamine and 4-NrN-di-methylaminopyridine, a~ colorle6~ ~ry~tals, m.p. 77-78C
Empirical ~ormula: C1~zlN305 (371) ~s: m/e - 372 !M ~
2Q Bxample 7 2-N-(2-Methoxyethyl)-4-N-(2-benzoyloxypropyl~pyridine-2,4-dicarboxamlde Th~ compound i~ obtained analogou~ly to Bxampl~ 6d) ~nd 6e) a~ a colorle~ oil, ~mpirical ~ormula: C20~23~3~S (385l ~S: m/e - 386 ~M + E~) r ,::
2~2~7~
~xample 8 2-N-(2~ethoxyethyl)-4-N- r 2-(4-hydroxypheny~)ethyll-pyridine-2,4-dicarboxamide ~ he kitle ~ompound i8 obtained from 0.24 g of 4-methyl-oxycarbonyl-2-~-~2-methoxyethyl~pyridin~-2~arboxamide (cf. ~xample 6c)j by ~eltlng it wi~h 2-(4 hydroxyphenyl)-ethylamine ~tyr~mine3. FiltratîGn with ethyl ~cetate through 8iliC~ ~el give~ 70 mg of colorle~ ne~dles; m.p.
181-181.5C ~rom ethyl ~cetate~;
Empirical ~ormula: C1B~21N30~ (343) MS: m/e = 344 (M +
Example 9 Bi~-N,N'-~2-~4-methylben~oyloxy)-ethyl]pyridine-2 r 4 -di-carboxamide ~he title compound i~ obtained analogou31y to ~xampLe lb) ~rom bis(N f N'-(2-hydroxyethyl)pyridine-2,4-diaarboxamide and 4-methylbenzoyl chloride a~ ¢olorle8s ~ry8tal powder, .p. 1~5-16~C.
Empirical formula: C27~2~N3O6 ~489) MS: ~/e - 490 ~M + B~) Example 10 Bi~ 2-ben~oyloxyethyl)pyridine-2~4-dicarboxa~ide analogou~ly to ~ample lb) colorle~ needl~s, ~.p. 13g-140C
~mpirical ~ormula: C25~23N3O6 (461) MS: m/e ~ 462 (M ~ ~t) The meanings in the tables below are as follow~:
Ph phenyl Me methyl 30 ~t ethyl - 29 2~82~
Pr propyl Bu butyl ~n benzyl Pen p~ntyl S ~ex hexyl T~P tetrahydropyr~noyl n unbranched ohain c cycl~
i i~o.
Rl/R2 and R3/R~ ~eans that aither Rl or R2 and R3 or R4, r~peetivsly, i~ the rad~cal ~entioned. The sub~tituent which remain~ in each case i~ hydrogen.
The ~ompQunds are in each ca~e 2,4-di~ubstituted pyridine derivatives.
_ 3~ - 2~2 ~ 7 ~
r~ ----E~ . Rlt~2 R~
11 CH2 C:H2 0 CO Ph U~, CH~ O CC~ ~h 12 CH2 CH2 0 CO ~h ~ ~a C~Ha O CO NH Et . . ___ _ 13 CH2 Ctl2 0 CO Ph CH2 CH2 0 CO NH-n~u . . .
14 ~H2 CH2 O CO OEt CH2 ~ 2 0 Cl:) Ph . . _ _ CH, CH, ~ Ct~ O~ OH, OH, O C:O NH
16 C;H2 CH2 0 CO NH n-8u :;H2 CH2 0 CO Ph . _ __ . 17 CH, CH, O CO NH ~I~u C--~ CH, O Cc NR n-~u 18 CH2 CH2 O CO NH CH2 CH2 OH CH2 Cl 12 CO NH n Bu __ . CH2 CH2 0 CO Ntl CH2 CH2 OH CH2 CH~ O C:O NH CH2 CH2 OH
, ~ ~
21 t:;H2 CH2 0 THP CH2 CH2 0 CO Ph . ~
22 CH2 CH;, CH2 0 CO Ph CH2 CH2 t:H2 0 ::O Ph _ . _ .
23 CH2 CH2 CH2 O CO Ph CH2 CH2 t;H2 0 GO NH Et ~ ~--24 CH2 CH2 CH2 C) CO Ph CH2 CH2 CH2 0 CO NH n-Bu __ . _ , . , , __ CH2 CH2 CH2 0 CO O Et Ctl2 OH2 CH2 0 C:O Ph _ ~ __ _ , _ _ 26 OH2 CH2 CH2 O O:~ O l~t C~~ CH, CH, l~ CD n~
27 CH2 Cl~2 CH2 0 CO NH n-Bu CH2 CH2 CH2 0 CO Ph _ . . ~ . , . , _ 28 CH2 CH2 CH2 0 ~O NH n-Bu CH2 CH2 CH2 0 CO NH n-Bu .
_ ~
2~2~7~
_~
E ~ . R-~2 ~3/R4 29 CH2 CH2 CHa O t;O NH CH2- C~ C::Ha C:H2 C:tl,2 0 C 0 NH n-Bu OH
. , . _____ CH2 CH2 CH2 O C :) NH CH2- C H2 CH2 C:H2 CH2 O I C) NH ~C~2 OH C:H2 OH
...... .. _ . _ _ _ _ _ . ~ 11 31CH;~ CH2 CH2 ~P OH2 GHa CH2 0 TllP
~ _ . ~
32CH, C--, CH, O ll ll' CH2 Cl~ CH, O CO I'h 33CH2 CH2 O CH3 CH2 t::H2 C:H2 0 CO c-H~x 34CH2 t: H2 0 CH3 CH2 CH2 C;H2 0 CO ~-Pen _ , , , . . . _ _ ~
35CH2 CH2 t:) CH3 C:H2 C:H2 CH2 0 C:O O Et l _ . _ ,_ 36CH2 CH2 0 CH3 CH2 CH2 CH~ O CO O n-Bu .. _ ~ ~
37 CH2 CH2 O OH3 CH2 CH2 CH2 O GO O G Hex _ .
38 CH2 CH2 0 ~H3 CH2 C:H2 C:H2 0 CO Ph _ 39 CH2 CH2 C) CH3 CH2 CH2 CH2 t:~ CO i-Pr _ . . . . . _ ~_ _. - ~- I
40CH2 CH2 0 Ct 13 C:H2 C:H2 CH2 0 CO O Ph ~_ . _ _.
41C H2 CH2 0 ~H3 CH2 ~H2 CH2 O CH2 CH2 0 Me ¦
~ . . __ . __ 42 CH2 CH2 0 ~ H3 C;H2 CH2 CH2 O CH2 9;;H2 0 Et ~_ 43CH2 CH2 0 CH3 GH2 CH2 CH2 Q CH2 CH2 0 Ph 1 - - - - - . , . ... ... ~
44~H2 CH2 O CH~ ~;Hz C;H2 CH2 O Ph I _ _ ._ . ""_ CH2 CH2 0 CH3 ~ CH2 CH2 CH2 0 THP
~_ . . _ . - , ........ ... .__ 46 CH2 CH2 0 CH3 CH2 C:H2 CH2 O CO NH Et _ _ _ _ . , , l 47 CH2 CH2 0 CH3 CH2 CH2 CH2 0 CO NH Pr ~ __ _ ___ _ _ . ~ , .
48 CH2 CH2 0 CH3 CH2 CH2 CH2 0 C~ N~l ~ Bu 2~82~76 .
~_ ~ .__I
E x . Rl/R2 R~/R~
_~ ~ ~ I
49 CH2 CH2 O CH3 CH2 GH;, CH2 0 CC) NH c-Hex , . ,~ . . . ~ I
CH2 CH2 OH CH2 CH;~ CHa O CO c-Hex l . ._ . _ ~
51 CH2 CH2 0~1 CH2 GH2 CH2 1 ) CO c-P~nt _ , _ , , .
52 CH2 CH2 OH CH2 t::H2 CHi Q C;O O Et ,,, . ,, , _ 53 CH2 CHa OH GH~ CHa CH2 O CO O n-Bu ,., ~
54 CH2 CH2 OH CH2 ~H2 CH2 0 CC) O c-H~x CH2 CH2 OH O~, CH, CH, O CO (~ Ph 56 CH2 CH2 OH C~l2 CH2 CH~ C) CO ~2-Me Ph) CH, CH, OH CH2 C:H2 CH2 0 CO Ph ~8 CH2 CH2 OH C:H2 CH2 CH2 0 CH2 CH2 CH
O- lUle ~ ~ .. . , . . .. _ _ ~:~ ~ O- Et 60CH2 CH2 OH ~2 ~ t~2 CH2 O CH2 CH2 C:H
O Ph ~ _ . _ 61CH2 CH2 ~ CH2 CH2 CH2 O Ph l I
62O--, CH, 011 CH, C--, CH, O T--P
63CH2 CH2 OH CH2 C:H2 C:H2 CO NW Et l _ _ .. . I
64 CH2 CH2 OH C~12 CH2 CH2 0 CO NH Pr .. _ _ _ . .. _ _ . ....... ._~._. . --l 65 . CH2 CH2 OH CH2 CH2 CH2 0 ~ 0 NH n-Bu 66 CH2 CH2 OH CH2 CH2 CH2 0 C:O NH c-Hex. . _ -. . _ I
67 CH2 CH2 OH ___ CH2 CH2 CH2 O CO NH Ph l 2~2~7~
.
_ ~ I
E ,~ R1/R~ R3/R4 I ~__ ~ , ._ ~ I
68 C ~2 C~H2 CH2 ~ CH3 ~H2 ~H2 ~Ha t O C-HBX
._v____ - _ ~ I
69 - C H2 C~H2 ~H2 ~ HJ ~H2 ~H2 ~;H2 CO C- P~n . . .__ . I
~H2 ~ i i2 C H2 O CH3 CH2 CH~ CH2 C ) CC) O Eth _ , ~--~
71 CH2 CH2 CH2 0 CH~ . 5;H2 ICH2 CHa O CO t) n-8u . ~ _~
72 CH2 t~H2 ~H2 ~ HJ ~H2 CH2 CH2 C ) CO O c-Hex , ~ . ~ _~
73 CH2 ~ H2 ~; H2 O CH3 CH2 CHa Cl'l2 CO Ph I . ~.
7~ CH;2 CH2 C::H2 0 CH3 CH2 ~H2 CH;~ C) CO i-Pr _ ~
1 75 CH2 Ct12 CH2 O CH3 CH~ C H2 C H2 O Ce) O Ph I ~, I76 CH2CH2CH2O~H3 CH2CH2CH2OCH2~H2M@
.
I77 CH2 CH2 C~2 O CH3 ~2 C H2 ~ H2 CH2 CH2 O Et _ _ . . ,_ ~ _ I78 CH2 ~ H2 CHa C3 ~H3 ~ H2 ~ H2 t~H2 O CH2 CH2 O Ph ~ . - ....... .. __ . . ~
79 CH2 CH2 ~H2 ~H3 CH2 eH2 CH2 Ph 80 CH2 C~H2 ~H2 ~ H3 CH2 CH2 ~ H2 THP
_ . , . , .. . 11 ~ R1 CH2 CH2 CH2 0 CH3 CH2 CH2 CH2 0 CO NH Et ~ , , , . _ . . , . .... ~
l ~2 CH2 C~2 CH2 0 CH3 CH2 CH2 CH2 0 CO NH Pr - ~ A
83 CH2 ~H2 ~ H2 O C~l3 CH2 CH2 CH2 O CO NH n-Bu 84 CH2 CH2 CH2 0 ~H3 C:H2 CH2 C:H2 0 CO NH c-Hex , , Ctl2 CH2 CH2 OH CH2 C:H2 CH2 0 CO c~tlex _ _ ~ ~ ~ _ ...... ... ~, _. --86 CH2 CH2 CH2 OH CH2 CH2 CH2 0 C:O c-Pen __ _ _ __ , ~ , . ~ _ ~
I 87 t:~H2 ~H2 CH2 OH CH2 ~ :H2 ~H2 CO C-Et _ _ , " ", " " .. , 1 88 C;H2 CH2 CH2 OH CH2 C:H2 CH2 0 C:O C n~Bu _ __ . .__ __ . ~
_CH~ CH2 t::H2 OH _ CH2 CH2 CH2 0 ~O O c-Hex 2~2~7~
_ I
E~. R /R R3/~4 I . ., ~ I
CH2 CH2 CH2 OH ~ C~ 1`4 ~ CO O Ph 91 t J'12 ~ H2 CH2 OH ~ ~a e H2 C~z ~ CO ~2~Me Ph) ! ~
92 CH2 CH2 CH2 OH C:H2 CH2 C ~2 C~ Ph . . ~
~ Ms _ _ I
94CH2 CH~ CH2 OH GH2 GH2 t :H2 O CH2 CH2 CH2 O- Et _ 95CH2 CH2 5H2 OH CH2 CH2 CH2 O ~H2 ~H2 CH2 O- Ph I . .. __ v~_u ~
1 96CH2 ::H2 CH2 OH CH2 CH2 CH2 O Ph _ ~ ~
97CH2 CH2 CH2 OH CH2 CH2 Ctl2 O THP
. . ....
_ _ _ , _,_,_ __, _ _ r . ,_ ::
l 99CH2 C:H2 CH2 OH GH2 CH2 CH2 0 CO NH Pr _ _ , . ..... .. ~ -- _ 1100 CH2 CH2 CH~ OH CH2 CH2 CH2 0 CO NH n-Bu .. . _ ,, ~ _ .
1 101 CH2 CH2 Ctl2 OH CH2 CH2 CH2 0 CO NH c-Hex . _ ., 10Z CH2 CH2 CH2 OH CH, C~, CH, O CO N~l Ph ¦ 103 C~2 CH2 CH2 0 CO c-Hex CH2 CH2 0 ~Ae . . . _ __ 104 ~2 ~;H2 CH2 0 CO c-Pen C:H2 CH2 0 M~
_ , . ..... .. _ l 105 CH2 CH2 CH2 O CO O Et CH2 CH2 O Me l __ _ ~ -- . ~ .. .....
106 CH2 CH2 CH2 0 CO O n-Bu CH2 CH2 M~
_ __. _ _ , _ , _ 1 107 CH2 CH2 CH2 0 C :) O c-Hex CH2 CH2 0 Me . . _ _ - ._ . _ I 108 Cl12 Ctl2 GH, O CO O Ph CH2 CH2 0 Me 2~82~7~
~--.__~
E x . F~' /R' R'j~' 109 ~H2 ~H2 CH2 O C 2-M~ Ph t~H2 ~H2 O MB
_ ~ .
110 C:H2 CH2 CH2 0 C:O Ph CH2 C;H2 0 Me~
,. _~
111 t::H2 CH2 CH2 0 C:H2 CH2 CHa ~ CH2 ICHa O Me Me I ~__ 112 C:H2 C:H2 CH2 0 THP CHa CH2 0 M~
,_~
113 C;H2 CH2 C:H2 0 CO NH Et CHa CH2 Q M~
_ -.. ---- ............. _ ___ . ~_ , 1 1 4 CH2 CH2 C H2 0 CO NH Pr CH2 CH2 ~ M~ -_ , . _ _ I 1~5 CH2 CH2 CH2 0 C NH n B~ ~H2 CH2 M~
~ ,, _ _ _ _ _ .
I 116 CH2 CH2 t~H2 0 CO NH C-H~X ~;H2 ~H~ O M~
_ ~
¦ 1~7 CH2 CH2 CH2 0 CO NH Ph CH2 CH2 0 Me r 118 Ctl2 C:tl2 CH2 0 CO c:-H~x GH2 C:Ha C:H2 0 Me . ~ - ~ _ _ _ ~ ...... _ ~ I
I 119 CH2 CH2 CH2 C ~-Pen ~H2 ~H~7 CH2 Me ~ _ ~
120 CH2CH2CH2OCOOEt C:H2CH2C~2OM~ l ... . ~ .. __ __ , , I
1 121 C:H2 CH2 CH2 0 CO O n-BuCH2 CH2 CH2 0 Me ,_ , . - ._ ~ , ~
122 CH2 CH2 CH2 0 CO O c-HexCH2 CH2 CH2 0 Me _ , ,_, ..
123CH2 CH2 CH2 C) CO O PA CH2 CH2 CHa O Mi~
r _ -- -- -- -- _ _ 124 CH2 Clt2 CH2 0 CO 2-Me Ph CH2 CH2 t H2 0 Me __ , ,,, _- ~
125 CH2 CH2 CH2 O CO Ph C~2 CH2 C:tl2 0 Me _ ~ _ _ _ _ I
126 CH2CH2CH20CH2CH2S~H20 CH2CH2~H20Me Me _ ~ _ _ 127 CH2 CH2 CH2 THP CH2 CH2 CH2 Me __ . . __ 128 CH2 CH2 CH2 0 CO NH Et CH2 CH2 CH2 0 Me .
- 36 2~8~
~ ~ ~_ I
E~ . R~/~ R3/~
. . . _ . . ~
129 ~ ~2 C~2 C H2 CO NH Pr CH2 CH2 CH2 0 M~
. I
13D CH2 C:H2 OH2 0 GO NH n-Bu g:tl2 CH2 CH2 O M~
, _ . . ... _ 131 C;H2 C:H2 t;ll2 0 ~O NH c-H~x C:Ha tCH2 CH2 O Me .
132 CH2 CH2 C:H2 ~ CO Nl I Ph CH2 CH2 CH2 0 M~
. ~ ~
133 C:H2 CH2 OH2 0 CO e-Hex OHa CH2 CH2 OH
. . ___ ;
134 CH2 CH2 C:i 42 CC) c-~n GH2 CH2 C:H2 OH
. . _ . .
13~ CH2 CH2 CH2 0 CO O Et C:H~ CH2 CH2 C)H
. _ . _ I
136 CH2 CH2 CH2 O eo o n-Bu C;H,2 CH2 CH2 OH
_, .
137 CH2 Ctl2 CH2 O CO O c-l lex C:H2 :::H2 C :H2 OH
~ _ 138 CH~ CH2 t;H2 O CQ O Ph OH2 CH2 CH2 OH
139 CH2 CH2 CH2 O CO 2-Me Ph ~ ~2 C:H2 C:H2 OH
. . ~
140 CH2 CH2 CH2 0 CO Ph CH2 CH2 CH2 OH l ~ .~ ~
141 OH2 CH2 CH2 0 Ch2 CH2 CH2 - CH2 Ctl2 1~ OH
Me ~ ~ - ~ - - I
142 Ctt2 CH2 CH2 0 THP GH2 CH2 CH2 OH
~ _ _ _ _ __ _ 143 C:H2 CH2 CH2 0 CO Nll Et t::H2 CH2 CH2 OH
_ _ ___ .
144 t::H2 CH2 CH2 0 C:O NH Pr CH2 CH2 CH2 OH l _ . . , _ _ I
~45 CH2 CH2 CH2 0 CO NH n-Bu CH2 CH2 CH2 C)H
_ _ ~ I
146 ~H2 CH2 CH2 O CO NH c-ttex CH2 CH2 C:H2 OH
._ . ~ __ _ , , _ 147 CH2 CH2 CH2 0 CO NH Ph CH2 CH~ CH,2 OH l _ _ . ~ I
148 CH2 CH2 CH2 O CO c-Hex CH2 CH2 OH l __ . . . _ . _ . _ _ I
149 CH2 CH2 CH2 0 CO c-Pen CH2 Ctl2 OH
.
- 37 - 2 ~82 ~ 7 ~
Es. R /R ~/~
150 CH2 CH2CH2O CO O R CH2C~2 OH
_ __~
151 CH2 Ctl2 C:H2 0 t:O ~ n-E~u CH2 Cl 1~ OH
__ __ 1~2 CH2CH2CH2O CO O C Hex CH~ CH2OH
. ~
. 153 CHaCH2CH2O CO O Ph . CH2 C~2 ~H
_ ~
~4 ~H2 CH2 CH2 O CO 2-Me Ph I::H;~ CH2 OH
155 CH2 C:H2 CH2 O CO Ph CHa Cl 12 OH
., _ , . _ ~.. ,, . ,, _ , ~
156 CH2 CH2 CH2 t:) CH2 CH2 CH2 - C;H2 CH2 OH
Me _ . . . _ ~_ : 157 ~2 ~H2 CH2 O THP CH2 CH2 OH
, ~ ~
158 CH2 CH2 CH2 0 CO NH E~ C:H2 CH2 OH
. _ 159 CH2 CH2 Clt2 0 CO NH Pr CH2 C;H2 ~H
_ 160 CH2 CH2 CH2 C) CO NH n-Bu CH2 Ct''12 OH
_ ~
161 GH2 C~12 CH2 0 CO NH c-Hex CH2 CH2 OH
162 CH2 ~H2 CH2 0 CO NH Ph CH, Ol l, (~11 ~` ~xample 163 Bi~-~,N'-[2-(4-hydroxyphenyl)-ethyl~pyridine-2 J 4 -di-carboxamide Analogously to B~mple 8 from dL~ethyl pyridine-2,4-di-carboxylate and tyrnminecolorle~s cry~t~l~, m.p. 165-166C
~mpirical formula: C23~23N3O4 ~4D5) MS: m/e - 40 (M + ~) 2~2~
. - 38 --Example 16~
Bi 8 t~ thoxy--N-methyl~pyridine-2,4-dic~rbox ~ de 5.1 g ~40 mmol) of N-ethylmo~pholene are ~dded ~t 20C
with stirring to 1.67 g (10 mmoll of 2~4-pyridinedi-carboxylic acid, ~u~pended in 100 ml of diahloromethane, ~.9 ml (20 ~mol~ o~ i~obutyl chloro~ormate are ~ubse-qu~ntly added dropwi~e ~t -15C, and the ~ixture i~
~tirred for 20 minute~ at lO~C~ 1995 ~lacuna~ (20 mmol) o~ ~,O-dimethylhydroxyl~mi~e hydrochlorid~ are then added, the mixture i~ ~tirred for 1 hour ~t -15C and allowed to come to 20C o~ernight, wat~r i8 add~d, the mixtur~ i8 extracted with dichloxomethane, a~d, after puri~ication o-E ~he crude product by column ~hrom~-tography over silica gel (ethyl acetate/methanol ~ lOJl)~
1.6 g of the ti~le co~pound are obtained a~ a colorl~s oil, Empirical formula: C~ 5~304 (253) MS: m/e - 254 (M + ~+) Example 165 2-N~ -Methoxyethyl)-4-N-(ethyloxy(N-tert.butyloxy-carbonylglycyl))pyri~ine-2,4-dicarboxamlde 0.8 g (3 mmol) of ~-N-(2-~ethoxyethyl)o4-N-~2-hydroxy-ethyl)pyridine-2,4-dic~rbox~mide ~aompound o~.x~mple 6d) i8 combined with 25 ml of anhydrou3 ~cetonitrile and ~25 mg (3 mmol) of N-butyloxycarbonylglycine, 0.4 ml (3 mmol) o~ N-ethylmorpholine~ 0O45 g ~3.3 m~ol) of N-hydroxybenzotriazole and 0.62 g (3 mmol) of ~ di-cyclohexylcarbodilmide, And the mixture i~ ~tirred for 20 hours ~t 25C. ~he resulting N,N-dicyclohexylurea is filtered off with suction, washed with acetonitrile ~nd concentrated, the product i~ taken up in dichloromethane, the mixture i6 extracted with saturated aqueous Na~CO3 801ution, the extract i~ ~haken with 10~ atrength ~queous 2~82~7~
citric acid, dried ~nd freed from solvent~ and the residue i8 chromatographed over ~ilica gel.
~mpirical formula: Cl~29N407 (4~4) ~S~ 425 ~
~urther ~xamples are: I ynths~ized ~rom the ~ompound 2-N-(2-mathoxyethyl)-4-~-(2 hydroxyethyl~pyridine-2,4-carboxamide described in ~x~mple 6d), or from ~nalogou~ ~ompound~, by benzylation) 2-~ (2-Methoxyethyl~-4-~-(2-benzyloxye~hyl)pyridine-2,4-dicarboxamide 2-N-(2~ydroxye~hyl)-4-N-(2-benzyloxye~hyl~pyridine~
2,4-dicarbox~mlde 2-N-~3-~ethoxypropyl)-4-~-(2-ben~yloxyethyl)pyridine-2,4-dicarboxamide 2-N-~2-~ydroxypropyl)-4-N-(2-benzyloxyethyl)pyridine-2,4-dicarboxam~de Bis-N,N'-[benzyloxyethyl)pyridine-2,4-dioa:rboxami~e (N,N'-Benzyloxypropyl)pyridine-2~4-dicarboxamid~
2-N-(2-Methoxyethyl)-4-N-[2-~4-fluorobenzyloxy)ethyl3-pyridi~e-2,4-d~carb~xamide 2-N-~2-~ydroxyethy~)-4-N-l2-(4~fluorobenzyloxy)ethyl]-pyridine-2,4-dicarboxamide 2-N-(3-~ydroxypropyl)-4 N-[2-(4-fluoro~enzyloxy)ethyl]-pyridine-2,4-dicarboxamide 2-N-(2-Methoxyethyl)-4 N-~2-(4-methoxybenzyloxy)ethylJ-: pyridine-2,4-dicarboxamide 2082~ ~6 2-N-~2-~ydroxysthyl)-4-N- r 2-(4-methoxybenzyloxy)ethyl]
pyridine-2,4-dicarboxamlde 2-N-(2-~ydroxypropyl)-4-N-t2-(4-~ethoxybenæyloxy)ethyl]~
pyridine 2,4-dicarbox~mide 2-N-~2-Benzyloxyethyl34-~-(4-hydroxyethyl~pyridine-2,4-dic2rboxnmlde 2-M-(2-~enzyloxyethyl)-4-N~(4-hydroxypropyl)pyridine-2,4-dicarboxamlde 2-N-~2-Benzyloxypropyl)-4-N-33-hydroxypropyl)pyridine-2,4-di~arboxamide 2~ 2-(4-Chlorobenzyloxy)ethyl~-4-~-(2-hydroxyethyl)-pyridine-2,4-dicarboxamide 2-N-~2~ Chlorobenzyloxy)ethyl]-4-~-(3-hydroxypropyl)-:~ pyridine-2,4-dicarboxa~ide 2-N-~2-Methoxyethyl)-4-N-t2-benzy~oxypropyl~pyridine-2,4-dicarboxamide 2-N-(2-~ydroxyethyl) 4-N-~2-benzyloxypropyl)pyridine-2,4-dicarboxamide 2-N-(3-Methoxypropyl)-4~ 2 benzyloxypropyl)pyridine-~;~ 20 2,4-di~arboxamide 2~ 2-~ydroxypropyl)-4-~-(2-benzyloxypropyl)pyridine-2,4-dicarboxamide 2-N-(2-Methoxyethyl)-4-~[2-(4-fluorobenzyloxy)propyl]-pyridine-2,4-dicarboxamide 2-~-[2-Hydroxyethyl)-4-N-[2 (4-fluorobenzyloxy)propyl]-pyridine-2,4-diaarboxamide ~08207bj 2-N-(3-~ydroxypropyl~-4-N-[2-(4-fluorobenzyloxy)propyl3-pyridine-2,4-dicarboxamlde 2-N-(2-~ethoxy~thyl)-4~ 2-~4-msthoxybe~æyloxy)propyl~-pyridine-2~4-dioarbox~mide 2-N ~2-~ydro~yethyl~-4-~-t2-~4-methoxybenzyloxy)propyl]
pyridine-2,4-dicarboxamide 2-N-~2-~ydroxypropyl)~4-~-t2~(4-methoxybenzyloxy)propyl]-pyridine-2,4-d~carboxamide 2-N-(2~Benæyloxypropyl)-4-N-t2-hydroxyethyl~pyridine-2,4-dicarboxamide 2-N-~2-Benzyloxypropyl)-4-~-(3-hydroxypropyl)pyridine-2,4-dicarboxamide 2-N-[2-t4-Chlorobenzyloxy)propyl]-4-N-~2-hydroxyethylj-pyridine-2,4-dic~rbox2mide 2-N-1~-(4-hlorobenzyloxy)propyll~4-N-~3-hydroxypropyl)-pyridine-2,4-dicarboxamide 2-N-(2-~ethoxyethyl)-5-N-~2-benzyloxyethyl)pyridine-2,5-dicarboxa~ide 2-~-(2-~ydroxyethyl~-5-~-(2-be~zyloxyethyl~pyridine-2~5-dicarboxamide 2~ 3-Methoxyp~opyl)-5-~-(2-b~nzyloxy~thyl~ pyridin~-2,5-dicarboxa~ide 2-N-~2-~ydroxypropyl)-5-N-~2-benæyloxyethyl~pyridine-2,5-dicarboxamide Bi~-N f ~ benzyloxyethyl)pyridine-2,5-dicarboxamide 2~g~07~
.
(N,N~-Ben~yloxypropyl)pyridi~e-2~5-dioarboxamlde 2~ 2-Methoxyethyl~ N-t2-(4-fluorob~nzyloxy)ethyl3-pyridine-2,5-dicarboxamide 2-N-~2-~ydroxy~thyl)-5~N-[2 (4-fluorobenzyloxy~et~yl]
pyridi~e-2,5-dicarboxamide 2-N-(3-Hydroxypropyl)-5~ 2-(4-~luQrobenzyloxy )ethylJ-pyr~dine-2,5-dic~rbox~mide , :~ 2-N-(2-Methoxyethyl~-S-N-t2-(4-methoxybenzyloxy)ethyl~-pyridine-~,5-dicarbox~mide 2-N-(2-~ydroxyethyl)-5-N-[2-~4-~thoxyben~yloxy3ethylJ-pyridine-2,5-dicarboxamide 2-N (2-~ydroxypropyl) o5-N- 1 2- (~-~ethoxybenzyloxy3ethyl]-~ pyridine-2,5-di¢arboxamide : 2-N-(~-Benzyloxye~hyl)-5 N-t2-~2-hydroxye~hyl)pyridine-2,5-dicarbox~ide ~-N-(2-Benzyloxyethyl)-~-N-[2-(3-hydroxypropyl)pyridine-2,5-dicarboxa~ide 2 -N ( 2 -Ben zyloxypropyl ) ~5~~~ t 2 - ( 3-h~droxypropyl ) pyridine-2, 5 dicarboxami~e 2-N-[2-~4-Chloroben~yloxy)ethyl~-5-N-( 2 -hydroxyethyl ~ -pyridine-2,5-dicarboxamide 2-N-[2-(4-Chlorobenzyloxy~ethyl~-5-N-l3-hydroxypropyl) pyridine-2,5-dicarboxamide
Claims (12)
1. A compound of the formula I
(I) in which R1, R2, R3 and R4 are identical or different and are A a branched or unbranched, aliphatic or cyclo-aliphatic (C1-C12)-alkyl radical, (C1-C12)-alkenyl radical or a (C1-C12)-alkynyl radical, each of which is monosubstituted or polysubstituted, preferably monosubstituted or disubstituted, by a (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyl-oxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkyl-carbonyloxy, cinnamoyl, cinnamoyloxy, (C6-C12)-arylcarbonyloxy, C3-C6)-alkenylcarbonyloxy, (C3-C8)-alkynylcarbonyloxy, (C3-C6)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N (C1-C6)-alkylamino, (C1-C12)-alkoxy-N,N-(C1-C6)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C6)-cycloalkylcarbamoyl, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C3-C6)-cycloalkanoylamino, (C1-C6)-alkanoylamino, (C6-C12)-aroylamino, (C7-C11)-aralkanoylamino, (C1-C8)-alkanoyl-(C1-C8)-alkylamino, (C3-C6)-cycloalkanoyl-(C1-C8)-alkylamino, (C6-C12)-aroyl-(C1-C6)-alkylamino, (C7-C11)-aralkanoyl-(C1-C6)-alkylamino, (C1-C8)-alkylmercapto, (C1-C8)-alkyl-sulfinyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, tri-flurormethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C6)-alkylsulfamoyl, N,N-di-(C1-C6)-alkylaulfamoyl, (C1-C8)-alkyl-sulfon-amido and arylsulfonamido, where the aryl and aralkyl radicals in the above substituents can also have a heterocyclic nature and/or, like alkyl, are substituted by 1, 2, 3, 4 or 5 identical or dif-ferent substituents selected from the series com-prising halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, hydroxyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, trifluoromethyl (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C8)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cyclo-alkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, in particular by up to 3 of the abovementioned identical or different substituents, and a CH2 group of the alkyl chain is optionally replaced by O, S, SO, SO2, or NR', or by a substituted (C6-C12)-aryl radical or hetero-aryl radical having 1, 2, 3, 4 or 5 identical or different substituents from the series comprising hydroxyl, trifluoromethyl, (C1-C8)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C8)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-sulfonyl, (C1-C6)-alkycarbonyl, (C1-C6)-alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyl-oxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl, N,N-di-(C1-C4)-alkylsulfamoyl, (C1-C8)-alkoxy-carbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C11)-aralkyloxy-carbonyloxy, (C7-C11)-aralkylcarbonyloxy, cinnamoyl, cinnamoyloxy, (C6-C12)-arylcarbonyloxy, (C3-C8)-alkenylcarbonyloxy, (C3-C8)-alkynylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N (C1-C8)-alkylamino, (C1-C12)-alkoxy-N,N
(C1-C6)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkyl-carbamoyloxy, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C8-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C3-C8)-cycloalkanoylamino, (C1-C8)-alkanoylamino, (C6-C12)-aroylamino, (C7-C11)-aralkanoylamino, (C1-C8)-alkanoyl-(C1-C8)-alkylamino, (C3-C8)-cycloalkanoyl-(C1-C8)-alkylamino, (C8-C12)-aroyl-(C1-C8)-alkylamino, (C7-C11)-aralkanoyl-(C1-C8)-alkylamino, (C1-C8)-alkylmercapto, (C1-C8)-alkyl-sulfinyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, tri-fluoromethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkylsulfamoyl, N,N-di-(C1-C8)-alkylsulfamoyl, (C1-C8)-alkyl-sulfon-amido and arylsulfonamido, where the aryl and alkyl radicals in the above substituents can also have a hererocyclic nature and/or, like alkyl, can be substituted by 1, 2, 3, 4 or 5 identical or dif-ferent substituents from the series comprising halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, hydroxyl, (C1-C8)-hydroxyalkyl or (C1-C6)-alkoxy, or by a substituted (C6-C12)-aryloxy radical, (C7-C11)-aralkyloxy radical or heteroaryloxy radical, each of which has 1, 2, 3, 4 or 5 identical or different substituents selected from the series comprising hydroxyl, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-hydroxyalkyl, (C1-C5)-alkoxy, [CH2-]xCfH(2f+1-g)Fg, -OCF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cyclo-alkyl, carboxyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenyl-sulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl, N,N-di-(C1-C4)-alkylsulfamoyl, aminoalkyl, N-(C1-C8)-alkylamino-(C1-C12)-alkyl or N-di-(C1-C8)-alkylamino-(C1-C12)-alkyl and which is substituted by, in particular, up to 3 of the abovementioned identical or different substituents, and one CH2 group of the alkyl chain is optionally replaced by O, S, SO, SO2 or NR', or by a radical of the formula II
-O-R5 (II) in which R5 is an amino acid bonded via its acyl radical, or a derivative of this amino acid, or an alcohol protective group, B a substituted (C5-C12)aryl radical, (C7-C11)aralkyl radical or heteroaryl radical, each of which is monosubstituted or polysubstituted, preferably mono-or disubstituted, by hydroxyl, amino (C1-C8)-alkoxycarbonyl, (C1-C8)-alkylcarbonyloxy, (C1-C8)-alkylamino, di-(C1-C8)-alkylamino, (C1-C6)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C8)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, (C1-C8)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, aminoalkyl, N-(C4-C8)-alkylamino (C1-C12)-alkyl or N,N-di-(C1-C8)-alkylamino-(C1-C12)-alkyl, (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkyl-carbonyloxy, cinnamoyl, cinnamoyloxy, (C6-C12)-arylcarbonyloxy, (C3-C8)-alkenylcarbonyloxy, (C3-C6)-alkynylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N (C1-C6)-alkylamino, (C1-C12)-alkoxy-N,N (C1-C8)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkyl-carbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkyl-amino, N-alkyl-arylamino, (C3-C8)-cycloalkanoylamino, (C1-C8)-alkanoylamino, (C8-C12)-aroylamino, (C7-C11)-aralkanoylamino, (C1-C8)-alkanoyl-(C1-C8)-alkylamino, (C3-C8)-cycloalkanoyl-(C1-C8)-alkylamino, (C8-C12)-aroyl-(C1-C8)-alkylamino, (C7-C11)-aralkanoyl-(C1-C8)-alkylamino, (C1-C8)-alkylmercapto, (C1-C8)-alkyl-sulfinyl, (C3-C6)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, tri-fluoromethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkylsulfamoyl, N,N-di-(C1-C8)-alkylsulfamoyl, (C1-C8)-alkyl-sulfon-amido or arylsulfonamido, C a substituted (C1-C12)alkoxy radical, (C3-C8)-cycloalkoxy, (C6-C12)-aryloxy radical or a (C7-C11)-aralkyloxy radical, each of which is monosubstituted or polysubstituted, preferably mono- or disub-stituted, by halogen, trifluoromethyl, (C1-C6)-alkoxy, hydroxyl, (C1-C8)-hydroxyalkyl, NR'R" or cyano where in each case R' and R" are identical or different and are hydro-gen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8)-alkyl-carbonyl, (C7-C11)-aralkylcarbonyl or (C6-C12)-aryl-carbonyl, or together with the nitrogen, form a saturated heterocyclic ring, preferably a 5- or 6-membered ring, and the abovementioned radicals R1, R2, R3 and R4 can occur in combination with a (C1-C12)-alkyl radical which is monosub-stituted or polysubstituted, preferably mono- or disubstituted, by hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, (C1-C4)-alkoxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyloxy, (C1-C4)-alkyl- or (C1-C4)-dialkylamino or with a phenyl ring which is mono-, di- or trisubstituted by the radi-cals halogen, nitro, (C1-C4)-alkyl or (C1-C4)-alkoxy, or in combination with an aryl or heteroaryl radical, each of which can, in turn, optionally be mono-, di- or trisub-stituted by halogen, nitro, cyano, (C1-C4)-alkyl, (C1-C4)-alkoxy, including all derivatives which have a suitable protective group in their amino or hydroxyl groups, and the physiologically active salts, and n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0, 1 to (2f+1), and x is 0, 1, 2 or 3, preferably 0 or 1.
(I) in which R1, R2, R3 and R4 are identical or different and are A a branched or unbranched, aliphatic or cyclo-aliphatic (C1-C12)-alkyl radical, (C1-C12)-alkenyl radical or a (C1-C12)-alkynyl radical, each of which is monosubstituted or polysubstituted, preferably monosubstituted or disubstituted, by a (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyl-oxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkyl-carbonyloxy, cinnamoyl, cinnamoyloxy, (C6-C12)-arylcarbonyloxy, C3-C6)-alkenylcarbonyloxy, (C3-C8)-alkynylcarbonyloxy, (C3-C6)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N (C1-C6)-alkylamino, (C1-C12)-alkoxy-N,N-(C1-C6)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C6)-cycloalkylcarbamoyl, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C3-C6)-cycloalkanoylamino, (C1-C6)-alkanoylamino, (C6-C12)-aroylamino, (C7-C11)-aralkanoylamino, (C1-C8)-alkanoyl-(C1-C8)-alkylamino, (C3-C6)-cycloalkanoyl-(C1-C8)-alkylamino, (C6-C12)-aroyl-(C1-C6)-alkylamino, (C7-C11)-aralkanoyl-(C1-C6)-alkylamino, (C1-C8)-alkylmercapto, (C1-C8)-alkyl-sulfinyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, tri-flurormethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C6)-alkylsulfamoyl, N,N-di-(C1-C6)-alkylaulfamoyl, (C1-C8)-alkyl-sulfon-amido and arylsulfonamido, where the aryl and aralkyl radicals in the above substituents can also have a heterocyclic nature and/or, like alkyl, are substituted by 1, 2, 3, 4 or 5 identical or dif-ferent substituents selected from the series com-prising halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, hydroxyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, trifluoromethyl (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C8)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cyclo-alkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, in particular by up to 3 of the abovementioned identical or different substituents, and a CH2 group of the alkyl chain is optionally replaced by O, S, SO, SO2, or NR', or by a substituted (C6-C12)-aryl radical or hetero-aryl radical having 1, 2, 3, 4 or 5 identical or different substituents from the series comprising hydroxyl, trifluoromethyl, (C1-C8)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C8)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-sulfonyl, (C1-C6)-alkycarbonyl, (C1-C6)-alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyl-oxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl, N,N-di-(C1-C4)-alkylsulfamoyl, (C1-C8)-alkoxy-carbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C11)-aralkyloxy-carbonyloxy, (C7-C11)-aralkylcarbonyloxy, cinnamoyl, cinnamoyloxy, (C6-C12)-arylcarbonyloxy, (C3-C8)-alkenylcarbonyloxy, (C3-C8)-alkynylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N (C1-C8)-alkylamino, (C1-C12)-alkoxy-N,N
(C1-C6)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkyl-carbamoyloxy, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C8-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C3-C8)-cycloalkanoylamino, (C1-C8)-alkanoylamino, (C6-C12)-aroylamino, (C7-C11)-aralkanoylamino, (C1-C8)-alkanoyl-(C1-C8)-alkylamino, (C3-C8)-cycloalkanoyl-(C1-C8)-alkylamino, (C8-C12)-aroyl-(C1-C8)-alkylamino, (C7-C11)-aralkanoyl-(C1-C8)-alkylamino, (C1-C8)-alkylmercapto, (C1-C8)-alkyl-sulfinyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, tri-fluoromethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkylsulfamoyl, N,N-di-(C1-C8)-alkylsulfamoyl, (C1-C8)-alkyl-sulfon-amido and arylsulfonamido, where the aryl and alkyl radicals in the above substituents can also have a hererocyclic nature and/or, like alkyl, can be substituted by 1, 2, 3, 4 or 5 identical or dif-ferent substituents from the series comprising halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, hydroxyl, (C1-C8)-hydroxyalkyl or (C1-C6)-alkoxy, or by a substituted (C6-C12)-aryloxy radical, (C7-C11)-aralkyloxy radical or heteroaryloxy radical, each of which has 1, 2, 3, 4 or 5 identical or different substituents selected from the series comprising hydroxyl, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-hydroxyalkyl, (C1-C5)-alkoxy, [CH2-]xCfH(2f+1-g)Fg, -OCF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cyclo-alkyl, carboxyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-R", phenylmercapto, phenylsulfonyl, phenyl-sulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl, N,N-di-(C1-C4)-alkylsulfamoyl, aminoalkyl, N-(C1-C8)-alkylamino-(C1-C12)-alkyl or N-di-(C1-C8)-alkylamino-(C1-C12)-alkyl and which is substituted by, in particular, up to 3 of the abovementioned identical or different substituents, and one CH2 group of the alkyl chain is optionally replaced by O, S, SO, SO2 or NR', or by a radical of the formula II
-O-R5 (II) in which R5 is an amino acid bonded via its acyl radical, or a derivative of this amino acid, or an alcohol protective group, B a substituted (C5-C12)aryl radical, (C7-C11)aralkyl radical or heteroaryl radical, each of which is monosubstituted or polysubstituted, preferably mono-or disubstituted, by hydroxyl, amino (C1-C8)-alkoxycarbonyl, (C1-C8)-alkylcarbonyloxy, (C1-C8)-alkylamino, di-(C1-C8)-alkylamino, (C1-C6)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C8)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, (C1-C8)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, aminoalkyl, N-(C4-C8)-alkylamino (C1-C12)-alkyl or N,N-di-(C1-C8)-alkylamino-(C1-C12)-alkyl, (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkyl-carbonyloxy, cinnamoyl, cinnamoyloxy, (C6-C12)-arylcarbonyloxy, (C3-C8)-alkenylcarbonyloxy, (C3-C6)-alkynylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N (C1-C6)-alkylamino, (C1-C12)-alkoxy-N,N (C1-C8)-dialkylamino, carbamoyloxy, N-(C1-C8)-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkyl-carbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-alkyl-aralkyl-amino, N-alkyl-arylamino, (C3-C8)-cycloalkanoylamino, (C1-C8)-alkanoylamino, (C8-C12)-aroylamino, (C7-C11)-aralkanoylamino, (C1-C8)-alkanoyl-(C1-C8)-alkylamino, (C3-C8)-cycloalkanoyl-(C1-C8)-alkylamino, (C8-C12)-aroyl-(C1-C8)-alkylamino, (C7-C11)-aralkanoyl-(C1-C8)-alkylamino, (C1-C8)-alkylmercapto, (C1-C8)-alkyl-sulfinyl, (C3-C6)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C3-C8)-cycloalkylcarbonyl, nitro, tri-fluoromethyl, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C8)-alkylsulfamoyl, N,N-di-(C1-C8)-alkylsulfamoyl, (C1-C8)-alkyl-sulfon-amido or arylsulfonamido, C a substituted (C1-C12)alkoxy radical, (C3-C8)-cycloalkoxy, (C6-C12)-aryloxy radical or a (C7-C11)-aralkyloxy radical, each of which is monosubstituted or polysubstituted, preferably mono- or disub-stituted, by halogen, trifluoromethyl, (C1-C6)-alkoxy, hydroxyl, (C1-C8)-hydroxyalkyl, NR'R" or cyano where in each case R' and R" are identical or different and are hydro-gen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8)-alkyl-carbonyl, (C7-C11)-aralkylcarbonyl or (C6-C12)-aryl-carbonyl, or together with the nitrogen, form a saturated heterocyclic ring, preferably a 5- or 6-membered ring, and the abovementioned radicals R1, R2, R3 and R4 can occur in combination with a (C1-C12)-alkyl radical which is monosub-stituted or polysubstituted, preferably mono- or disubstituted, by hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, (C1-C4)-alkoxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyloxy, (C1-C4)-alkyl- or (C1-C4)-dialkylamino or with a phenyl ring which is mono-, di- or trisubstituted by the radi-cals halogen, nitro, (C1-C4)-alkyl or (C1-C4)-alkoxy, or in combination with an aryl or heteroaryl radical, each of which can, in turn, optionally be mono-, di- or trisub-stituted by halogen, nitro, cyano, (C1-C4)-alkyl, (C1-C4)-alkoxy, including all derivatives which have a suitable protective group in their amino or hydroxyl groups, and the physiologically active salts, and n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0, 1 to (2f+1), and x is 0, 1, 2 or 3, preferably 0 or 1.
2. A compound as claimed in claim 1 in which R1 and/or R3 are hydrogen or methyl and R2 and/or R4 are as defined in claim 1.
3. A compound as claimed in claim 1 or 2, in which and/or R3 are/is hydrogen and R2 and/or R4 wherein A a branched or unbranched (C1-C12)-alkyl radical which is monosubstituted or polysubstituted by (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkyl-carbonyloxy, (C7-C11)-arylcarbonyloxy, (C3-C5)-cycloalkylcarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy, carbamoyloxy, N-(C1-C8)-alkylcarbamoyloxy, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-(C7-C11)-aralkylcarbamoyloxy or N-(C8-C12)-arylcarbamoyloxy, where the aryl and aralkyl radicals in the above substituents can also have a heterocyclic nature and/or, like alkyl, are substituted by 1 or 2 identical or different substituents selected from the series comprising halogen, trifluoromethyl, hydroxyl, (C1-C3)-alkyl, (C1-C3)-hydroxyalkyl, (C1-C9)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, -(C1-C3)-alkoxycarbonyl, carbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cyoloalkyl, phenyl, benzyl, phenoxy or benzyloxy, or by a substituted (C5-C12)-aryl radical or hetero-aryl radical which has one or two identical or different substituents selected from the series comprising hydroxyl, trifluoromethyl, (C1-C3)-hydroxyalkyl, (C1-C3)-alkoxycarbonyl, carbamoyl, NR'R'', N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C3)-alkylcarbonyloxy, aminoalkyl or N-(C1-C4)-alkylamino-(C1-C6)-alkyl, where R' and R'' are identical or different and are hydrogen, (C6-C12)-aryl or (C1-C4)-alkyl, or by a substituted (C5-C10)-aryloxy radical or (C7-C11)-aralkyloxy radical which has 1 or 2 identi-cal or different substituents selected from the series comprising hydroxyl, halogen, trifluoro-methyl, (C1-C3)-alkyl, (C1-C3)-hydroxyalkyl, (C1-C3)-alkoxy, (C1-C3)-alkylmercapto, (C1-C3)-alkylsulfinyl, (C1-C3)-alkylsulfonyl, (C1-C3)-alkylcarbonyl, (Cl-C3)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C3)-alkylcarbonyl-oxy or NR'R'' where R' and R'' are identical or different and are hydrogen (C6-C10)-aryl or (C1-C4)-alkyl, or by a radical of the formula II
-O-R5 (II) in which R5 is an amino acid bonded via its acyl radical, or a derivative of this amino acid, B is a (C6-C12) aryl or (C7-C11)-aralkyl radidal, pre-ferably phenyl, benzyl and phenethyl, each of which is monosubstituted by hydroxyl, (C1-C4)-alkyl-carbonyloxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-hydroxy-alkyl, amino, (C1-C5)-alkylamino, di-(C1-C5)-alkyl-amino, (C1-C5)-alkanoylamino, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, carbamoyl, N-(C1-C4)-alkylcarbamoyloxy, N,N-di-(C1-C4)-alkylcarbamoyloxy, or C is a (C1-C6)-alkoxy radical, (C3-C6)-cycloalkoxy radical, (C8-C12)-aryloxy radical and (C7-C11)-aralkyloxy radical, n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0, 1 to (2f + 1), x is 0, 1, 2 or 3, preferably 0 or 1, and where the abovementioned radicals R1, R2, R3 and can occur in combination with a (C1-C12)-alkyl radical which is monosub-stituted or polysubstituted, preferably mono- or disubstituted, by hydrogen, hydroxyl, amino, (C1-C4)-alkoxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkyl- or (C1-C4)-dialkylamino or a phenyl ring which is mono-, di- or trisubstituted by the radicals halogen, nitro, (C1-C4)-alkyl or (C1-C4)-alkoxy, and also in combination aryl or heteroaryl radical which, in turn, can optionally be monosubstituted or disubstituted by halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy, including all derivatives which have a protective group in the respective amino or hydroxyl group, and the physiologically active salts.
-O-R5 (II) in which R5 is an amino acid bonded via its acyl radical, or a derivative of this amino acid, B is a (C6-C12) aryl or (C7-C11)-aralkyl radidal, pre-ferably phenyl, benzyl and phenethyl, each of which is monosubstituted by hydroxyl, (C1-C4)-alkyl-carbonyloxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-hydroxy-alkyl, amino, (C1-C5)-alkylamino, di-(C1-C5)-alkyl-amino, (C1-C5)-alkanoylamino, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, carbamoyl, N-(C1-C4)-alkylcarbamoyloxy, N,N-di-(C1-C4)-alkylcarbamoyloxy, or C is a (C1-C6)-alkoxy radical, (C3-C6)-cycloalkoxy radical, (C8-C12)-aryloxy radical and (C7-C11)-aralkyloxy radical, n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0, 1 to (2f + 1), x is 0, 1, 2 or 3, preferably 0 or 1, and where the abovementioned radicals R1, R2, R3 and can occur in combination with a (C1-C12)-alkyl radical which is monosub-stituted or polysubstituted, preferably mono- or disubstituted, by hydrogen, hydroxyl, amino, (C1-C4)-alkoxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkyl- or (C1-C4)-dialkylamino or a phenyl ring which is mono-, di- or trisubstituted by the radicals halogen, nitro, (C1-C4)-alkyl or (C1-C4)-alkoxy, and also in combination aryl or heteroaryl radical which, in turn, can optionally be monosubstituted or disubstituted by halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy, including all derivatives which have a protective group in the respective amino or hydroxyl group, and the physiologically active salts.
4. A compound as claimed in any of claims 1 to 3, in which R1 and/or R3 are/is hydrogen and R2 and/or R4 are/is A an unbranched (C1-C12)-alkyl radioal which is monosubstituted by (C1-C8)-alkoxycarbonyloxy, (C1-C8)-alkoxy-(C1-C8)-alkoxycarbonyloxy, (C8-C12)-aryloxycarbonyloxy, (C7-C11)-aralkyloxycarbonyloxy, (C7-C11)-aralkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C3-C8)-cyclo-alkylcarbonyloxy, (C6-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-amino, (C1-C12)-alkoxy-N-(C1-C8)-alkylamino, (C1-C12)-alkoxy-N,N (C1-C6)-dialkylamino, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-(C7-C11)-aralkylcarbonyloxy, N-(C6-C12)-arylcarbamoyloxy, (C1-C5)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino or (C7-C11)-aralkanoylamino, where alkyl, aryl, aryl-oxy, aralkyl or aralkyloxy, in turn are sustituted by hydroxyl or halogen, in particular fluorine, (C1-C3)-alkyl or (C1-C3)alkoxy, or by a phenyl radical which is monoubstituted by a hydroxyl group, or a substituted phenoxy or benzyloxy radical which is substituted by hydroxyl, halogen or (C1-C4)-alkoxy, or by a radical of the formula II
-O-R5 (II) in which R5 is an amino acid bonded via its acyl radical, or a derivative of this amino acid which is substituted on the amino group, B a (C6-C12)-aryl or (C7-C11)-aralkyl radical, prefer-ably phenyl, benzyl and phenethyl, which is monosub-stituted by hydroxyl, and C methoxy.
-O-R5 (II) in which R5 is an amino acid bonded via its acyl radical, or a derivative of this amino acid which is substituted on the amino group, B a (C6-C12)-aryl or (C7-C11)-aralkyl radical, prefer-ably phenyl, benzyl and phenethyl, which is monosub-stituted by hydroxyl, and C methoxy.
5. A compound as claimed in any one of claims 1 to 4, wherein a compound of the formula (III) (III) in which R6, R7, R8 and R10 are identical or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C8)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C8)-alkyl-carbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkyl-carbamoyl, (C1-C8)-alkarbonyloxy, (C3-C8)-cyclo,-alkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'-Rn", such as amino, anilino, N-methylanilino, phenyl-mercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkyl-sulfamoyl, or two adjacent substituents together are a chain -[CH2-]n or -CH=CH-CH=CH-, where one CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NR', Y is 1, 2, 3 or 4, preferably 0 and 1, and the remaining of the substituents R6, R7, R8, R9 and R10 are as defined above are employed as the radical (C7-C11)-aralkyloxy.
6. A process for the preparation of a compound as claimed in any of claims 1 to 5, which comprises reacting a compound of the formula IV
(IV) and of the formulae or (V) where R1, R2 or R3, R4 have the meanings given in claims 1 to 5, and Y is halogen or hydroxyl or together with the carbonyl group forms an active ester or a mixed anhydride, and, if appropriate, converting the reaction products into their physio-logically acceptable salts..
(IV) and of the formulae or (V) where R1, R2 or R3, R4 have the meanings given in claims 1 to 5, and Y is halogen or hydroxyl or together with the carbonyl group forms an active ester or a mixed anhydride, and, if appropriate, converting the reaction products into their physio-logically acceptable salts..
7. A compound as claimed in one of claims 1 to 5 for inhibiting proline hydroxylase and lysine hydroxy-lase.
8. A compound as claimed in any of claims 1 to 5 for use as fibrodepressants and immunodepressants.
9. A pharmaceutical comprising a compound of the formula I and an acceptable pharmaceutical excipient.
10. The use of a compound of the formula I for influenc-ing the metabolism of collagen end collagen-like substances as well as the biosynthesis of Clq.
11. The use of a compound of the formula I for treating disorders of the metabolism of collagen and collagen like substances and the biosynthesis of Clq.
12. A process for the preparation of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances as well as the biosynthesis of Clq, wherein the pharmaceutical comprises a compound of the formula I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4136380.9 | 1991-11-05 | ||
| DE4136380 | 1991-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2082076A1 true CA2082076A1 (en) | 1993-05-06 |
Family
ID=6444113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002082076A Abandoned CA2082076A1 (en) | 1991-11-05 | 1992-11-04 | Pyridine-2,4 and -2,5-dicarboxamides and their derivatives, process for their preparation, and their use |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0541042A1 (en) |
| JP (1) | JPH05221993A (en) |
| CA (1) | CA2082076A1 (en) |
| ZA (1) | ZA928495B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6881743B2 (en) | 2001-02-14 | 2005-04-19 | Warner-Lambert Company | Pyridine matrix metalloproteinase inhibitors |
| US6936616B2 (en) | 2001-02-14 | 2005-08-30 | Warner-Lambert Company | Pyrimidine matrix metalloproteinase inhibitors |
| US6995151B2 (en) | 2001-02-14 | 2006-02-07 | Warner-Lambert Company | Isophthalic acid derivatives as matrix metalloproteinase inhibitors |
| US7132424B2 (en) | 2002-08-13 | 2006-11-07 | Warner-Lambert Company Llc | Monocyclic derivatives as matrix metalloproteinase inhibitors |
| US7160893B2 (en) | 2002-08-13 | 2007-01-09 | Warner-Lambert Company | Pyrimidine-2,4-dione derivatives as matrix metalloproteinase inhibitors |
| US7179822B2 (en) | 2002-08-13 | 2007-02-20 | Warner-Lambert Company | Hetero biaryl derivatives as matrix metalloproteinase inhibitors |
| US20100105741A1 (en) * | 2002-04-11 | 2010-04-29 | L'oreal | Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss |
| US10835468B2 (en) | 2014-12-22 | 2020-11-17 | L'oreal | Particular pyridinedicarboxylic acid derivative/antioxidant combination |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0650961T3 (en) * | 1993-11-02 | 1997-09-15 | Hoechst Ag | Substituted heterocyclic carboxylic acid amides, their preparation and their use as drugs. |
| ES2101420T3 (en) * | 1993-11-02 | 1997-07-01 | Hoechst Ag | ESTERS-AMIDES OF SUBSTITUTED HETERO-CYCLIC CARBOXYL ACIDS, THEIR PREPARATION AND THEIR USE AS MEDICINES. |
| DE4410480A1 (en) * | 1994-03-25 | 1995-09-28 | Hoechst Ag | Sulfonamidocarbonylpyridine-2-carboxylic acid ester amides and their pyridine N-oxides, processes for their preparation and their use as medicaments |
| IL135495A (en) * | 1995-09-28 | 2002-12-01 | Hoechst Ag | Intermediate compounds for the preparation of substituted quinoline-2-carboxylic acid amides |
| EP1399435A2 (en) * | 2000-09-01 | 2004-03-24 | Biogen, Inc. | Pyridine derivatives useful as cd40:cd154 binding interruptors and use thereof to treat immunological complications |
| CA3208361A1 (en) | 2021-02-19 | 2022-08-25 | Anjali Pandey | Tyk2 inhibitors and uses thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3703959A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| ES2065355T3 (en) * | 1988-08-04 | 1995-02-16 | Hoechst Ag | IMPROVED PROCEDURE FOR THE PREPARATION OF N, N'-BIS (ALCOXIALKYL) -DIAMIDES OF PIRIDINE-2,4-DICARBOXYLIC ACIDS. |
| DE3924093A1 (en) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| ZA91291B (en) * | 1990-01-16 | 1991-09-25 | Hoechst Ag | Di(nitroxyalkyl)amides of pyridine-2,4-and-2,5-dicarboxylic acids,a process for the preparation thereof,and the use thereof |
-
1992
- 1992-11-03 EP EP92118814A patent/EP0541042A1/en not_active Withdrawn
- 1992-11-04 CA CA002082076A patent/CA2082076A1/en not_active Abandoned
- 1992-11-04 JP JP4295096A patent/JPH05221993A/en active Pending
- 1992-11-04 ZA ZA928495A patent/ZA928495B/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6881743B2 (en) | 2001-02-14 | 2005-04-19 | Warner-Lambert Company | Pyridine matrix metalloproteinase inhibitors |
| US6936616B2 (en) | 2001-02-14 | 2005-08-30 | Warner-Lambert Company | Pyrimidine matrix metalloproteinase inhibitors |
| US6995151B2 (en) | 2001-02-14 | 2006-02-07 | Warner-Lambert Company | Isophthalic acid derivatives as matrix metalloproteinase inhibitors |
| US7015237B2 (en) | 2001-02-14 | 2006-03-21 | Warner-Lambert Company | Pyridine matrix metalloproteinase inhibitors |
| US7214712B2 (en) | 2001-02-14 | 2007-05-08 | Warner-Lambert Company | Isophthalic acid derivatives as matrix metalloproteinase inhibitors |
| US20100105741A1 (en) * | 2002-04-11 | 2010-04-29 | L'oreal | Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss |
| US9107847B2 (en) | 2002-04-11 | 2015-08-18 | Societe L'oreal S.A. | Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss |
| US7132424B2 (en) | 2002-08-13 | 2006-11-07 | Warner-Lambert Company Llc | Monocyclic derivatives as matrix metalloproteinase inhibitors |
| US7160893B2 (en) | 2002-08-13 | 2007-01-09 | Warner-Lambert Company | Pyrimidine-2,4-dione derivatives as matrix metalloproteinase inhibitors |
| US7179822B2 (en) | 2002-08-13 | 2007-02-20 | Warner-Lambert Company | Hetero biaryl derivatives as matrix metalloproteinase inhibitors |
| US10835468B2 (en) | 2014-12-22 | 2020-11-17 | L'oreal | Particular pyridinedicarboxylic acid derivative/antioxidant combination |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0541042A1 (en) | 1993-05-12 |
| ZA928495B (en) | 1993-05-03 |
| JPH05221993A (en) | 1993-08-31 |
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| Date | Code | Title | Description |
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| FZDE | Dead |