CA2095206A1 - 4- or 5-(sulf)imido- and -(sulfon)amidopyridines and their pyridine n-oxides, processes for their preparation, and their use as medicaments - Google Patents

4- or 5-(sulf)imido- and -(sulfon)amidopyridines and their pyridine n-oxides, processes for their preparation, and their use as medicaments

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Publication number
CA2095206A1
CA2095206A1 CA002095206A CA2095206A CA2095206A1 CA 2095206 A1 CA2095206 A1 CA 2095206A1 CA 002095206 A CA002095206 A CA 002095206A CA 2095206 A CA2095206 A CA 2095206A CA 2095206 A1 CA2095206 A1 CA 2095206A1
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Prior art keywords
alkyl
amino
alkoxy
carbamoyl
alkylamino
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CA002095206A
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French (fr)
Inventor
Klaus Weidmann
Martin Bickel
Volkmar Gunzler-Pukall
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Hoechst AG
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Hoechst AG
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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Abstract of the disclosure 4- or 5-(Sulf)imido- and -(sulfon)amidopyridines and their pyridine N-oxides, processes for their preparation, and their use as medicaments Novel 4- or 5-(sulf)imido- and -(sulfon)amidopyridines and the corresponding pyridine N-oxides according to formula I
are described. The invention also relates to a process for the preparation of these compounds, and to their use as medicaments against fibrotic diseases.

Description

~95206 ~OEC~ST AXTIEN(~ESELLSC~AFT HOE 92/F 121K Dr. FI/PP

De~cription 4- or 5-~ulf)imido- and -(~ulfon)~midopyridines and their pyridine N-oxide~, proce~se~ for their preparation, and their use as medicament~

The invention relates to 4- or 5-(~ul)imido- and -(sulfon)amidopyridines ~nd their pyridine N-oxide~, and to their use as medicaments ~gain~t fibrotic diseasesO

~Compounds which inhibit the enzymes proline hydroxyla~e -10 and ly~ine hydroxyla6e effect very selective inhibition of collagen biosynthesis by influencing collagen-epecific hydroxylation reactions. In the cour~e thereo~, protein-bound proline or lysine i8 hydroxylated by the enzymes proline hydroxylase or, respectively, lysine hydroxyla~e.
If this reaction i5 ~uppressed by inhibitors, a hypo-hydroxylated collagen mole~ule which i8 not capable of functioning and can be released by cell~ into the extra-cellul r ~pace in only a small amount i8 formed. The hypohydroxylated collagen moreover cannot be incorporated into the collagen matrix, and i8 very easily broken down proteolytically. As a consequence of the~e ef~ects, the total amount of collagen depo~ited in the extracellular ~pace is reduced.

Inhibitors of proline hydroxylase are therefore suitable sub~tances in the therapy of di6ea~e~ where colla~en depo~ition makes a decisive contribution to the fiyndrome.
These include, inter alia, fibroses o~ the lung, liver and skin (scleroderma) and atherosclerosis.

It is known that the enzyme proline hydroxylase i8 inhibited ef~ectively by pyridine-2,4- and -2,5-dicarb-oxylic acid (K. Majamaa et al., Eur. J. ~iochem. 138 (1984) 239-245). Howeverl in cell culture, these 209~2~6 compound~ are active aB inhibitors only in very high concentration~ (Tschank, G. et al~, Biochem. J. 238 (1987) 625-633). 5-Sulfonylimlde~ of pyridine-2,5-dicarboxylic acid are de~cri~ed in J.Ned.Chem. 1992, 35, page~ 800;804.

Pyridine-2,4- and -2,5-dicarboxylic acid die~ter~ having 1-6 carbon atom~ in the ester alkyl part are de~cribed in DE-A 34 32 094 as medicament~ or inhibition o proline hydroxylaee and ly~ine hydroxyla~e.

These lower alkylated diefiters have the di~advantage, however, that they are ~plit into the acids too quickly in the organism, do not arrive at their action æite in the cell in a sufficiently high concentration, and there-fore are less auitable for possible administratiorL a~
medicamentæ.

DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 de~-cribe, in a general form, mixed ester/amides, more highly alkylated die6ters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid which actively inhîbit collagen biosynthesie in an animal model.

There was thus the object of searching for compounds which have a more potent antifibrotic action than the compounds known to date.

The object i5 achieved by the provision of 4- or 5-(sulf)imido- and (sulfon)amidopyridines and related compounds and their pyridine N-oxides o~ the general formula I A
R ~ B

R~ ~ N ~ R2 ( )n in which A is R3 and ~ i5 -X~R5R7 or B i8 R3 and A i~ -XNR6R7 and X is ~ingle bond or -CO-, 5 and Rl, R2 and R3 are identical or different and are hydrvgen~
unsub~tituted or ~ubstituted (C~ C~)-alkyl, (C~-C~)-alkoxy, halogen, in particular ~luorine, chlorine or bromine, nitrile, hydroxyl or amino, R6 is hydrogen, ~Cl-C20)-alkyl or an N prot~ctive group, ~uch a~ acyl, (C1-C20~-alkanoyl, (C~-C20)-alkenoyl, -C20)-alkynoyl, (C7-C20)-aralkanoyl, (C6-C~8)-aroyl, (cl-c6)-alkylcarbamoyl~ (C~-C6)-alkoxycarbonyl, benzyloxycarbonyl, (C~-C~0)-acyloxy-(Cl-C6)-alJcyl, 1~ preferab}y ~cl-clo~-alkanoyloxy-(cl-c6)oalkyl~
benzoyloxy-~Cl-C6)-alkyl, benzyloxycarbonyloxy-(C~-C6)-alkyl or ~Cl-C6~-alkoxycarbonyloxy-~Cl~C)~alkyl, a physiologically suitable cation, ~uch a~ Na~, R~, Mg2~ Ca2~ A13~ or an ammonium ion, if deslred monosubstituted to tri~ubstituted by (Cl Cl6)-alkyl, (Cl-cl6)-hYdroxyalkyl~ (C1-C~)-alkoxy-~C1-C16)-alkyl, phenyl, benzyl or ~Cl-C16)-alkyl which may be ~o~o~
~ubstituted to trisubstituted by hydroxyl or (Cl-C8)-alkoxy, or a cation of a basic amino acid derivative, where any aryl moiety pre~ent may be ~ub~tituted, R7 is a radical Y R8, in which Y is -SO2-, -CO-, -CONR9 or -SO2NR9 and R8 and ~8 are ~C-~]r-D-W, in which C i8 a bond or a branched or straight-chain aliphatic (Cl-Cl6)-alkanediyl or cycloaliphatic (C3-Cl0~-alkanediyl radical or a branched or straight-chain (C2-C16)-alkenediyl or cycloalkenediyl radical or a (C2-Cl6)-alkynediyl radical or a (C2-Cl6)~
alkenynediyl radical, each of which may contain 2 ~ 0 ~
one or more C-C multiple bond~, U i8 a bond or hydrogen or a radical selected from the ~erie~ comprising the S following heteroatom groups t -CO- ~ -O ( CO ) - ~
-(CO)-O-, ~(CO)NR , -NR(CO)-, -O-, -SO , SOz ~r -NR, in which R i~ ~C1-C3~-alkyl, (C,-C8)-alkanoyl, (C~-C16~-aralkanoyl, (C6-C12)oaroyl or hydro~en, r i~ 1, 2, 3 or 4, D is a bond or hydrogen or a bran~hed or straight-chain aliphatio ~Cl-C10)-: alkanediyl radical or a branched or straight-chain ~C1;C1D) -alkenediyl radical, a (C2-C1O)-alkynediyl radical or a (C2-Cl~)-alkenynediyl radical, eaeh of which may contain one or more C-C multiple bonds, W i~ a bond or hydrog~n or a ~C3-C10) cyclo~liphatic alkyl, alkenyl, alkynyl or alkenynyl radical or a (C6-C1B)-aryl radical or a 5-membered or : Ç-membered heteroaryl xadical, at least one of the variables C or D or W not being a bond and U
being a heteroatom group only when C i~ not a bond, and C, D and/or W, where they are not a bond or hydrogen, and are preferably in turn sub~tituted, or R8 and R~ are furthermore bonded via 3-6 carbon atoms, -NR~Ra forming a heterocyclic rin~, with N
a~ a hetexoatom, or Ra is R6 and lC~U]r-D-W is not -SO2H, and - 5 ~
R4 is a radical which can be converted physiologically, in particular in the li~er, into a carboxylate group or salts thereo~, e~ter~ and ~mide~ being excepted, and n is 0 or 1, f i8 1 to 8, preferably 1 to 5, g i8 0 or 1 to (2f+1) and x i~ 0 to 8, preferably 0 or 1.

Preferred compound~ of the form~la I are tho~e in which X iR a ~ingle bond or -CD-, Rl, R2 and R3 are identical or different and are hydrogen, (C1-C8)-alkyl, [C1-C6)-alkoxy, halogen, in particular 1uorine, chlorine or bromine, nitrile, hydroxyl, amino, unsubstituted or mono- or disubstituted by (C1-C4)-alkyl, hydroxy;(C1-C4)-alkyl or (C1-C6)-alkylcarbonyloxy, RG is hydrogen, (C1-C20)-alkyl or an N protective group, such as acyl, (C1-C20)~alkanoyl, (C1-C20)-alkenoyl, (C1-C20)-alkynoyl, (C~C20)-aralkanoyl, (C~-C~8)-aroyl, (C1-C6)-alkylcarbamoyl, (cl-c6)-alkoxycarbonyl~
benzyloxy~arbonyl, (C1-C~0)-acyloxy-(C~-C6)-alkyl, prefe~ably (cl-clo)~alkano~loxy-(cl-c6)-alkyl~
benzoyloxy-(C1-C6)-alkyl, benzyloxycarbonyloxy-(C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C~-C6)-alkyl, a physiologically ~uitable cation, ~uch as ~a~, K~, Mg2~, Ca2Q, Al3~ or an ammonium ion, un3ubstituted or monosubstituted to trisubstituted by (C1-C16~-alkyl, (C~-C16)-hydroxyalkyl, ~C1-Ca)~alkoxy-~C1-C16)-alkyl, phenyl, benzyl or ~C1-C16)-alkyl which may be monosubstituted to tri~ubstituted by hydroxyl or ~C1-C8)-alkoxy, or a oation of a basic amino acid derivative, where any aryl moiety pre~ent may be substituted, and R7 is a radical Y R8, in which Y i~ -SO2-, -CO-, -CONRD or -SO~NR~
and 2~9~20g R8 and R9 are [C-U~r-D-W, in whi~h C i5 a bond or a branched or ~traight-chain aliphatic (Cl-C~6)-alkansdiyl or cycloaliphatic ~C3-C10)-alkanediyl radioal or a branched or ~traight-chain (C2-C16~-alkenediyl or cycloalkenediyl radical or a (C2~C1B)-alkynediyl xadical or a (C2~cl5)~
alkeninediyl radical, each of which may contain onP or more C-C multiple bonds, lQ U i3 a bond or : hydrogen or a radical selected from the ~erie~ compri~ing the following heteroatom group~: -CO-, -O(CO~-, -(CO)-O-, (CO)NR-, -NR~CO)-~ -O-, -SO-, -SO2-, -NR, in which R iB ( C1-C3 ) -alkyl, ( C1_CB ) -a1kanOY1 (C7-Cl6)-aralkanoyl, (C6-Cl2)-aroyl or hydrogen, r is l, 2, 3 or 4, D is a bond or hydrogen or a branched or straight-chain aliphatic (Cl-C
alkanediyl radical or a branched or ~traight~chain (C1-C1O)-alkenediyl radical, a ~Cz-ClO)-alkynediyl radical or a (C2-C1O)-~lkenynediyl radical, each of which may contain one or more C-C multiple bond~, W i~ hydrogen or a (C3-C10) cycloaliphatic alkyl, alkenyl, alkynyl or alkenynyl radical or a (C6-C1B)-aryl radical or a 5-membered or 6-membered heteroaryl radical, at lea~t one of the variables C or D or W not being a bond and U
being a heteroatom group only when C i~ not a bond, and C, D and/or W, where they are not a bond or hydrogen, are preferably in turn substituted by a combination of up to 5 identical or di~ferent substituents ~elected from the seri~s comprising hydroxyl, halogen, cyano, txifluorom~thyl, nitro, carboxyl, (Cl-Cl2)-alkyl, (C3-C8)-sycloalkyl, 209~2~6 (C6-Cl2)-aryl, (C7-C1~)-aralkyl, (C3-C12)-alkenyl, (C3-~l2)oalkYnyll (Cl-Cl2)-alkoxy, (C1-C12)-alkoxy-~Cl-clz)-al~yll(cl-cl2)-alkoxy-~ cl2)-alk~xy~c6~
C~2)-aryloxy, (C~ 6)-ar~lkyloxy, ~C~-Ca)~
S hydroxyalkyl, -O-[C~2J~C~2~1~)Fs, -OCF2Cl,-OCF2-C~Cl, (Cl-C12)-alkylearbonyl, ~ C3 C0 )-cyeloalkylcarbonyl, (C6-Cl2)-arylearbonyl, (C~-Cl6~ aralkylearbonyl, C inllamGyl ~ ( C3-Clz )-alkenylcarbo~yl, (C3-Cl2)~
alkynylcarbonyl, (Cl-Cl2)-alkoxycarbonyl, ~Cl-C12~-alkoxy-(Cl-Cl2)-alkoxycarbonyl, (C6-Cl~)-aryloxyearbonyl, ~C7-Cl6J
aralkoxycarbonyl, ( C3-C~ ) -eyeloalkoxyc8rbo~yl, (C3-C12)-alkenyloxyearbonyl, (C3~cl2~~
alkynyloxycarbonyl, (cl-cl2)-alkylcarbonyloxy~ ~C3-Cg)-ey~loalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7~Cl6)-aralkylcarbonyloxy, einnamoyloxy, ~C3~cl2)~
alkenylcarbonyloxy, (C3-C12)-alkynylearbonyloxy, (C~-Cl2)-alkoxycarbonylXy, (Cl-C~)-alkoxy-(C1-C~)~
alkoxycarbonyloxy, (C6-C12)-aryloxyearbonyloxy, (C7-cl6)-aralkyloxycarbonyloxy, ( C3_CB ) -~ycloalk-oxycarbonyloxy, (C3-Cl2)-alkenyloxyaarbonylvxy, (C3-C12) alkynyloxyearbonyloxy, carbamoyl, N-(C~-Cl2)-alkylearbamoyl, N,~-di-(Cl-C~) alkylearbamoyl, N- ~C3_CB )-cyeloalkyl~arbamoyl, N-(C6-C~6)-arylearbamoyl, N-(C~-C~
aralkylearbamoyl, N-(cl-clo)-alkyl-N-(c6-cl6) arylearbamoyl, N-(C1-ClO)-alkyl-N-(c7-cl6) aralkylcarbamoyl, N-(~cl-clo)-alkoxy-(cl-C1O)alkyl)earbamoyl, N-((C6-C16)-aryloxy-(C1-C~O~alkyl)carbamoyl, ~9~0~
~ 8 -N-~C7~C~6)-aralkyloxy ~Cl-ClO)alkyl)c2rbamoyl~
N~ clo)-alkyl-N-~cl-clol-alkoxy-(clo C~O)alkyl)carbamoyl, N-(C1-ClO)-alkyl-N-~(c~-cl~-arYlXY~(Cl~ClO)alkyl)~arbamoyl, N-(Cl C,0)-alkyl-N-(~c7-cl6)~aralkyloxy-(cl-clo)alkyl)carbamoyl~

carbamoyloxy, N-~C~-C~2)-alkyl~arbamoyloxy, N,~-di-(Cl-Cl21-alkylcarbamoyloxy, N-(C3~Ca~~
cycloalkylcarbamoyloxyO N-(C6-Cl0)oarylcar~amoyl-oxy, ~-(C~-C~6)-aralkylcarbamoyloxy, N-~Cl-C1o~-alkyl N-( C6-Cl2 )arylcarbamoyl~xy,N-~Cl-C10~-alkyl-N-(C7-Cl6)-aralkylcarb~moyloxy,N-(~C1 C10)-alkoxy-(C1-ClO)alkyl)carb~moyloxy, N-((C6-C~6)~arYlXY~(C1~
ClO)alkyl)carbamoyloxy~-((c7-cl6)-aralkyloxy-5cl-C~o)alkyl)carbamoyloxy~ N~(C~-Clo)-alkYl~N~((C~~
Cl~)~alkoxy-(Cl-C~O)alkyl)car~amoyloxy, N-(C~-C1o~-alkyl-N-((c6-cl6)-aryloxy-~cl-clo)alkyl)-c~rbamoyloxy, ~ ~Clo ) -alkyl-N- ( ( C7-C~o ) -aralkyloxy- ~ CloClo ) al}cyl ) caxbamoyloxy, : amino, (C~-Cl2)~alkylamino, di-(C1-C12~alkylamino, (C3-CB)-cycloalkylamino, ~C3-Cl2)-alkenylamlno, (C3-Cl2)-alkynylamino~N-(c~-cl2)-arylamino~N-(c7-c~
aralkylamino,N-(C1-C1O)alkyl-(C~-C1O)aralkylamino, N-~l-ClO)alkyl-N ( C6-Cl2 ) aryl~mino, ( C1-C12 ) ~
alkoxyamino, (c1-C12)-alkoxY-5Cl-clO)-alkylamino~

~C1-C1a)-alkanoylamlno, ~C3-C~ ) -cycloalkanoylamino, (C6 C12)-aroylamino, (c7-cl6)-aralkanoylamino~
(C~-C~2)-alkanoyl-NotC~-C~O)-alkylamino~ ( C3_CB ) ~
cycloalkanoyl-N~(C1-C1~)-alkyl d no, tC6-Cl2)-aroyl-N-(C1-C10)-alkylamino, (C~-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (cl-cl2)-alkanoylamino-~cl-c0)-alkyl~ tC3~Cs)~
cycloalkanoylamino (Cl-C~)alkyl, (C6-C10)-aroylamino-(Cl-C~)-a}kyl, (C7-C16)-aralkanoylamino-(C1-C~)-alkyl, amino-~C1-C10)-alky~, 2 V 9 a 2 0 6 g ~
N-(cl-clo)allcylamino~ clo)alky~l N,N-di(Cl-C1O~alkyla~ino~(C1-C1O)alkyl~ (C3~s)~
cycloalkylamino-~Cl-C~O)alkyl, (Cl Cl2~-alkylmercapto,(cl-Cl2)-al3cylsulfinYl~(C
S C12)-alkyl~ul~onyl, ~c6-cl6)-arylmexcapto~(ca-cl~)-arylsulfinyl, (~6~~l6)-arylBulfonyl, ~C7-Cl6)-aralkylmercapto, (C~-C16)~aralkyl3ulfinyl~ (C~-C16~-aralkyl~ulfonyl, sulfamoyl, N-(Cl-C10)-alkyl~ulf~moyl, N,N-di-~Cl-lQ C10)-alkylsulfamoyl~ (C3-C8)-cycloalkylsulfamoyl, N-(C6-Cl6)-aryl~ulfamoyl, N-(C7~Clt,)-aralkyl-sulfamoyl, N -(cl-clo)-alky~ tc6-cl6) arylsulfamoyl, N-(cl-clo)-alkyl-N-(c7~cl8) aralkyl~ulfamoyl, (C1-C~O)-alkylsulfonamido, N-((cl-~lo)alkyl)-( C1O)alkyl~ulfonamido, (C7-Cl6)-aralkyleulfonamido, N-~(C1-C1o~alkyl~( C7~c lB l-aralkyl 8ul ~onamido, where the radical~ which contain an aryl radical may in turn be ~ub~tituted on the ~ryl by 1, 2, 3, 4 or 5 identical or different sub~tituent~
selected from the ~eri~ c~mprising hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C,-C,2)-alkyl, ( C3 - CB ) - ~ycloalkyl, ( CB_C12 ) - a:ryl, (C,-C16)-aralkyl, (C3-C,2)-alkenyl, (c3-C12)-alkynYl, (C~-c~2)-alkoxy,(c~-cl2)-alkoxy-(c~-cl2)-alkyl~( Cl2)~alkoxy-~C1-C12)-alkoxy, (C6-C12)-aryloxy, ~ C7-C 1B ) - aralkyloxy, ( C1-C6 ) -hydroxyalkyl, -0-~ CH2-]XCfHt2f~1-8)F8 ~ -ocF2cl, -OC~2-C~FCl, ( Cl-C 12 ) -alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-C~6)-aralkylcarbonyl, cinnamoyl, (C3-C12)-alkenylcarbonyl, (C3-Cl2)-alkynylcarbonyl, '~0~S20~

( Cl-~12 ) ~alkoxycarbonyl, (Cl; C12 ) -alkoxy-(cl-clz)-alkoxy-earbonyl,(C~-Cl2 3-aryloxyearbonyl,~C7-Cl6)-axalkoxyearbonyl, ~ C3~CB ) _CYC1Oa1kOXYCarbOnY1 ~C3-Cl2)-alkenyl-oxycarbonyl, (C3-~12);
alkynylcarbo~yl, (Cl-C12) alkylcarbonyloxy, (c3-cs) carbonyloxy, (c6-cl2)-a~lcarborlyloxy~ ~C7-Cl6)-aralkylcarbonyloxy, cinnamoyloxy, (C3-C12)~
alkenylearbonyloxy, (C3-Cl2~-alkynyl-earbonyloxy, ~ Cl-C12 ~ -alkoxycarbonyloxy, ( Cl-~12 ) -alkoxy-( C12)-alkoxyearbonyloxy, (c6-~l2~-aryloxy~
carbonyloxy, ~C7-Cl6)-aralkyloxyearbonyloxy, (C~-C8)-cyeloalkoxyearbonyloxy, (C3-Cl23~alkenyloxy-carbonyloxy, (C3-C1z)-alkynyloxycarbonyloxy, carbamoyl, N-(Cl-C1z)~alkylearbamoyl, N,N-di-(C1-C1a)-alkylearbamoyl, N-( C3-CB) ~
eyeloalkylearb~moyl, N-~C6-C16)~arylearbamoyl, N-~C7-Cl6]-aralkylearbamoyl, N-(cl~c~o)-alkyl-N-~c6-Cl6)arylearbamoyl, N-(cl-clo)-alkyl-N-(~7 ` C16 3 -aralkylearbamoyl, N-((Cl-C10)-alkoxy-~Cl-Cla)alkyl)-earbamoyl, N-~C6-Cl6)-aryloxy-(C~-C~alkyl)-earbamoyl, N-((C7-C16~-aralkyloxy-(C,r~C,O)alkyl)earbamoyl, N (C1~clo)~alkyl-N-(~cl-clo)-alkoxy-(cl-ClO~alkyl)earbamoyl, N-(Cl-C10)-alky}-N-((C6 Cl6)-aryloxy-(Cl-ClO)alkyl3aarbzmoyl, N-lCl C10)-alkyl-N-((C7-Cl6~-aralkyloxy-(Cl-C10~alkyl)-earbamoyl, earbamoyloxy, N (Cl-C12)-alkylearbamoyloxy, N,N-di-tCl-C12)-alkylearbamoyloxy, N-( C3-~
eyeloalkylearbamoyloxy, N-(C 6-C16) -arylearbamoyloxy,N-(C7-C16)-aralkylearbamoyl-oxy, N-(Cl-C10)-alkyl-N-(C6~Cl2~arylearbamoyloxy, N-(cl-clo3-alky~ 7-cl6)-aralkylcarbamoyloxy 09~20~

N-~cl-clo)-alkoxy-~cl-clo)alkyl)carbamoyloxy~ N-((C6-C16)- ryloxy-(C1-C1O)alkyl) carbamoyloxy, ~-( ~c7-cl6)-a~l3cyloxy-~c~ o)Alk~ carbamoyloxyr N-(Cl-C1o)~alkyl~~N~((C1~C1o) alkoxy-(C~ C1O~alkyl)-carbamoyloxy,N-~C1-C10)-alkyl-N-((C6-C~6)-aryloxy (Cl-C10~ carbamoyloxy~ C1-c1D)-alkyl-N-~(C~-C16) aralkyloxy-(Cl-C10)alkyl)carbamoyloxy t amino, (C~-Cl2)-31kylamino, di-(C1-C~z)alkylamino, ( C3_C9 ) -CYC10a1kY1am1n, t C3_CI2 ) -al~enylam1~o~ ~ C3-C,2) alkynylamino, N-(C6-C~2)-arylamino, ~-(C~-C~
aralkylamino, N-(C,-C~O)-alkyloN-(c7-cl6) aralkylamlno, M-(C1-CIO)~alkyl-N-(C6-C~)-arylamino, (cl-c~2)-alkoxyamino~ (Cl-Cl2)-alkoxy-N-(C~C~O)~
: alkylamino, (C1-C1~)-alkanoylamino, ( C3-C8 )-cycloalkanoyl~ino, (C6-Cl2)-aroylamino, (C7-Cl6)-aralkanoylamino, (Cl-C~2)-alkanoyl-N-(Cl-C~O)-alkylamino, tC3-C~)~
cycloalkanoyl-N-(cl-clo)-alkylamlno~ (C6-Cl2)-aroyl-N-~C1-C~O)-alkylamino, (c7-c~ ara C1O)-alkylamino, (c~-cl2)-alkanoylamlno-~cl-c9)-alkyl~ ( C3_CB )-cyclo-alkanoylamino-(Cl-C6)alkyl, (C6-Cl6)-aroylamlno-(C1-C8)-alkyl, (C7-Cl6)-aralkanoylamin~tCl~c8)~
alkyl, amino-~Cl~C10~-alkyl~ ~-(Cl-C10)alkylamîno-(Cl-C10)alkyl, N,N-di(C~ C10)alkylamino-(Cl-C~O)-alkyl, (C3-C8)cycloalkylamino-(C1-C1D)alkyl, (Cl-Cl2)-alkylmercapto,(C~-Cl2)-alkylsulfinyl,(Cl-C~2)-alkylsulfonyl,(Ci~-C~6)-arylmercapto,tC6-Cl6)-arylsulfinyl, (C6-C16)-arylsulfo~yl, ~C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl, (C7-Cl6)-aralkyl-sulfonyl, 2~952~6 ~ulfamoyl, N-(C1-C10)-alkylsulfamQyl~ N,~-di-(Cl-Cl;~)-alkyl~;ulfamoyl~ ~C3 C~ cycloalkyll3ul~amoyl, N-(c6~cl6)-arylsulfamoy~ C7~C16) aralkyl~ulfamoyl, ~-(C1~C10)-alkyl-N-~C6-Cl8)-aryl~ulfamoyl, N-(C1 C~0)-alkyl-N-( aralkyl~ul~amoyl, ~C1-C10)-alkyl~ulfonamldo, N-(~cl-clo~alkyl)-(cl ClO)-alkylsulfonamido, (C7-C~6~-ax~lkylsulfonamido, N~((C1-C10)-alkyl)-(C7-Cl6~-aralkyl 6ul fonamldo, or R8 and R3 Are furthermore bonded via 3-6 carbon atoms -NR8R9 form a heterocyclic ring, with N az a h~teroatom, : or R9 is R6 and ~C-~r-D-W i~ not -SO2H, a~d R4 is a (Cl C10)-alkyl group which may be ~u~stituted by hydroxyl or (C1-C6)-alkoxy, or i an aldehyde, imino, N-(C1-C8)-alkylimi~o, acetal, thioacetal or cyclic acetal group, a cyclio thioacetal group or another group equivalent to the aldehyde group or -C~2oR5, in which Rs is hydrogen or the radical of a physiologically tolerated alcohol protective group which preferably can be eliminated in the liver under phy~iological conditions, and n i8 0 or lr f is 1 to 8, preferably 1 to 5, g i~ 0 ox l to ~2~1) and x i~ 0 to 8, preferably 0 or 1.

Aryl, aryloxy, heteroaryl and heteroaryloxy compound~ are understood a~ meaning, in particular, phenyl, biphenyl or naphthyl ring~ or un~ubstituted 5- or 6-membered hetero-20.~2~

aromatic rings having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur ~tom~, ~uch as pyridyl, pyridazyl, pyrim-idyl, pyrazyl, imidazolyl, triazolyl, thianyl, oxazolyl and thiazolyl derivative~, and benzo-fused derivative~
thersof.

Possible alcohol-protectiYe groups are, in particular, sub~tituted or unsubstituted me~hyl ethers, ethyl eth0r~, benzyl ethers, 8ilyl ethers, e~ter~, carbonates or sulfonate~

These include the following compound~:

As subetituted methyl ethors:
methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldime hyl~ilyl~methoxymethyl, benzyloxymethyl, p methoxybenzyloxymethyl/ (4-methoxyphenoxy)methyl, guaia-colmethyl, t-butoxymethyl, 4-pentenyloxymethyl, ~iloxy-methyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxy-methyl, bis(2-chloroethoxy)methyl, 2-~trimethylsilyl)-ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyran-yl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-meth-oxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl-S,S-dioxo, 1-[2-chloro-4-methyl)phenyl]-4-methoxypiperid-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl and tetrahydrothiofuranyl.

A~ substituted ethyl e~ters:
1-ethoxyethyl, 1-t2-chloroethoxy)ethyl, l-methyl-l-methoxyethyl, 1-methyl-1-benzyloxyethyl, l-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroe~hyl, 2-tri-methy}silylethyl, 2-(phenylselenyl)ethql, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

As substituted benzyl ethers:
p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-h~logenobenzyl, 2,6-dichlorobenzyl~

20~20~
- 14 ~
p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl-N-oxido, diphenylmethyl, p,p'-dinitrobenzhydry1, tripheny1methy1, ~-naphthyldiphenylmethyl, p~methoxyphenyldiphenylmethyl, 5 di- ( p-methoxyphenyl ) phenylmethyl, tri ~ p-methoxyphenyl ) methyl, 4-[4'-bromophenacyloxy)-phenyldiphenylmethyl, 4~4~,4ll-tri~(4,5-dichlorophthal-imidophenyl ) methyl, 4, 4 ', 4 " -tris ( levulinooxy-phenyl ) methyl, 4, 4 ~, 4 ~ -tri~ ( benzoyloxyphenyl ) methyl, 3-10 ( ~midazol-1, 4 ~ -methyl ) bis ~ 4 ~, 4 ~-dimethoxyphenyl ) -methyl, 1,1-bi~4-methoxyphenyl)~ pyrenylmethyl, 9-anth~yl, 9-(9-phenyl)xanthenyl and 9-(9-phenyl-lO~oxo)anthryl.

As ~ilyl ether~:
trimethyl~ilyl, triethyl 8ilyl, trii~opropyl~ilyl, dimethyli~opropylsilyl, diethyli~opropylsilyl, dimethyl-hexylsilyl, t-butyldimethyl~ilyl, t-butyldiphenyl~ilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenyl~ilyl, diphenylmethylsilyl and t-butylmethoxyphenyl~ilyl.

As esters:
formate, benzoylfoxmate, acetate , propionate, butyrate, valerate, caproate, heptanoate, caprylate, caprate, laurate, palmitate, stearate, chloroacetate, dichloro-acetate, trichloroacetate, trifluoroacetate, methoxy-acetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-chlorophenylacetat~, 3-phenyl-propionate r 4-oxopentanoate (levu~inate), 4l4-(ethylenedithio)pentanoate, pivalate, adamantate, crotonate, 4-methoxycrotonate~ benzoate, p-phenyl-benzoate, 2,4,6 trimethylbenzoate (mesitoate), 2-methylbenzate, 2-methylpropionate, 3-methylbutyrat~, 4-methylvalerate, 2-ethylbutyrate, ~urther esters with mono- or polyunsaturated fatty acids, 6uch as, for example, oleic acid, sorbic acid, linoleic acid and linolenic acid, esters with trolox, gallic acid~, such as, for example, cholic acid, lithocholic acid, chenode~oxycholic acid and ur60desoxycholic acid.

- 15 - 2 a 9r~2 0 The carboxyllc acid component may al~o contain further carboxyl group~. In thi~ ca~e, one or more carboxyl group~ are e~t~rified with radical~ of formula I in which R4 i~ C~2O~. Examples of th~e di- and polycarboxylic S acids are oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, citric ~cid, phthalic acid, isophthalic acid, terephthalic acid and adipic acid.

As carbonates:
methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trime~hyl~ilyl)ethyl; 2-(phenylsul~onyl)ethyl, 2-(triphenylpho~phonio)ethyl, i~obutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-me hoxybenzyl, 3 t 4-dimethoxy--benzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbon-ates, 4-ethoxy-1-naphthyl and methyldithiocarbonates.

Other esters:
2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bi~(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, i~obutyrate, monosuccinate, (E)-2-methyl-2-butenoate (tigloate)~ O-(methoxycarbonyl)benzoate, p-benzoate, ~-naphthoate, nitrate, alkyl N,N,N~,N~-tetramethylpho~-phorodiamidate, N-phenylcarbamate, borates, dimethyl-phosphinothioyl and 2,4-dinitrophenyl6ulfenate.

As 6ulfonates:
~ulfates, methane~ulfonate (mesylate), benzyl6ulfonate and tosylates.

The following protective group~ are particularly preferred:
(C1-C20)-alkanoyl, (Cl-C20)-alkenoyl, (Cl-C20)-alkynoyl, (C1-C~8)-alkylcarbamoyl, di-(Cl-C1B)-alkylcarbamoyl, N-( C3-C~ ) -CyC loalkylcarbamoyl, (Cl-C~8)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, ( C7-C~ aralkyloxycarbonyl, in particular benzyloxycarbonyl, (C~-C~2)-arylcarbonyl, (C7-C11)-aralkylcarbonyl, (C1-C~)-alkyl, unsubstituted or sub~tituted (C7-C~ aralkyl, (Cl-Cl2l-alkoxy-(C1-C12~~alkYl, carbamoyl-(C1-C6)-alkyl e~tçr, ~c1-C1~)-acyloxy-(C~-C6)-alkyl, preferably (C1~Cl~)-alkanoyloxy-(C1-CB)~alkyl, benzyloxy-(CI-C~)-alkyl, ben~yloxycarbonyloxy-(Cl-C5)-alkyl and (Cl-C1~)-alkoxycarbonyloxy-(C1-C6)-alkyl, where these group~ may carry further ~ubstituent~, tetrahydropyra~yl, amino acid e~ter~ or e~ter~ with polypeptide~/polypeptide derivatives, preferably diD and tripeptides which in particular are esterified via their terminal carboxyl group.

In the components which contain amino aoid~, the natllral ~-amino acids are particularly preferred, it being possible for their amino group to be derivatized with amino protective ~roups.

Amino-protective group~ are understood a3 meaning, in particular, tho~e groups which are described in R. Ge:iger and W. Konig ~The Peptides~ Volume 3, "Protection of Functional Groups in Peptide Synthe6is", E.G. Gro~, J.
Meienhofer ~dit, Academic Press, New York (1981), in particular pages 7 - 46.

Such groups are likewi~e de3cribed in A. Hubbuch, Schutz-gruppen in der Peptidsynthe~e (Protective Groups in Peptide Synthesis), Kontakte 3/79, page~ 14-23.

The following amino-protective group~ axe particularly preferred:

acetamidomethyl, 1-adamantyloxycarbonyl, 1-(1-adamantyl)-1-methyl-ethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, 1-(4-biphe~ylyl)-1-methyl-ethoxycarbonyl, ~,~ dimethyl-3 r 5-dimethoxybenzyloxycarbonyl, 4-dihydroxyborylbenzyloxycarbonyl, o ~

9-fluorenylmethyloxycarbonyl, isobornyloxycarbonyl, l-methyl-cyclobutyloxycarbonyl, 4~methoxybenzyloxycarbonyl, methylffulfonylethyloxycarbonyl t 4-pyridylmethyloxycarbonyl, 2,2,2-trichloro-tert-butyloxycarbonyl, benzyloxycarbonyl, halogen-substituted benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 2-phosphonoethyloxycarbonyl, phenyl~ulfonylethoxycarbonyl, toluenesulfonylethoxycarbonyl and 2,3,5-trimethyl-4-methoxy-phenylsulfo~yl.

Preferred compounds of the general formula I are those in which X i~ a ~ingle bond and Y i8 -802- or -CO- or X i8 -CO- and Y i~ -SO2-, -CO- or -CONR~ in which R1, R2 and R3 are identical or di~ferent and are hydrogen, ~C1-C6)-alkyl~ (Cl-C6)-alkoxy~ halogen, in particular fluorine and hlorine, hydroxyl, amino or hydroxy-( C~-C4 ) -alkyl, R6 i8 hydrogen, (C1-C2~)-alkyl or an N protective group, BUCh as acyl, (C~-C20)-alkan~yl, (C1-C20)-alkenoyl, (Cl-C20~-alkynoyl~ (C7-C20)-aralkanoyl~ (C6-Cla)-aroyl, (C~-C6)-alkylcarbamoyl, ( C1_CB ) -a1kOXYCarbOnY1~
benzyloxycarbonyl, (C1-C1~)-acyloxy-(C~-C6)-alkyl, preferably lcl-cl~)-alkanoyloxy-(cl-~6)-alkyl~
benzoyloxy-(C1-C6~-alkyl, benzyloxycarbonyloxy-(C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkyl, a physiolo~ically ~uitable cation, ~uch as Na~, K~, Mg2~, Ca2~, Al3~ or an ammonium ion, un~ubstituted or monosubstituted to tri~ubstituted by (C1-C16)-alkyl, (C1-Cl6)-hydroxyalkyl, (C1-Ca)-alkoxy-(C1-C16)-alkyl, phenyl, benzyl or (C1-C16)-alkyl which may be mono~ubstituted to tri~ub~tituted by hydroxyl or (C1-C6)-alkoxy, or a cation of a basic ~o~o~
1~ -~nino acid derivative, it being po85ible for any aryl moiety pre~ent to be sub~tituted, R7 i~ a radical Y Ra, in which Y ha~ the abovementioned meaning and Ra and R9 are [C-U~r-D-W, in which C .is a bond or a branched or ~traight-chain aliphatic (C~ C12 alkanediyl radical or a branched or straight-chain ~C2-C12)-alk~nediyl radioal, a ~C2 C12)-alkynediyl radical or a tC2-Cl2)-alkeninediyl radical which may contain one or more C-C multiple bonds, U is a bond or hydrogen or a radical selected from the ~exies comprising the following heteroatom group~:
-(CO)NR-, -NR(CO)-, -O-, -SO- or -SO2-, in which R is (C1-C3)-alkyl, (C1-C8)-alkanoyl, (C7-C10)-aralkanoyl, ~C6-C1~)-aroyl or hydrogen, r i~ 1 or 2, D i~ a bond or hydrogen or a branched or straight-chain aliphatic (C1-C8)-alkanediyl radical or a branched or ~traight-chain (C2-C~)-alkenecliyl radical or (C2-C~)-alkynediyl radical and W is hydrogen ox a (C3-C10)-cycloaliphatic alkyl, alkenyl~ alkynyl or alkenynyl radioal or a (C6-C~ aryl radical or a 5-membered or ~-membered heteroaryl radicalp at least one of the variable~ C or D or W not beiny a bond and U
being a heteroatom group only when C i8 not a bond and Cl D and/or W, where they are not a bond or hydrogen, are preferably in turn ~ub~tituted by a combination of up to 5 identical or difEerent 21~9~206 ~ub~tituent~ selected from the ~eries compri~ing hydroxyl~ haloyen, cya~o, trifluoromethyl, ~itro, carboxyl, (C1-C12~-alkyl, ~3 Ca ) -cyC
(C6-Cl2)-aryl, (C7-C16)-aralkyl, (c3-rl2)-alkenyl~
(C3-Cl2)-alkynyl, (Cl-C12)-alkoxy, (C1-C12)-alkoxy-(C~-C12)~alkyl,(Cl-Cl2 ) -alk~xy-(cl-cl2) alkXY~(~6-~12 ~-aryloxy, (C7-C16~-aralkyloxy, (Cl-C~)-hydroxy-alkyl~ O-[c~z-]xc~H(2~+l-~)F~ -OCF2Cl, -OCF2~CHFCl, (C1-C12)-alkylcarbonyl, (C3-C~ ) ~cycloalkyl-carbonyl, (c6-cl2l-arylcarbonyl~ (C~-Cl6)-aralkylcarbonyl, cinnamoyl J (C3-Cl2) alkenyl-carbonyl, (C3-C12)-alkynylcarbonyl, (C1-Cl2)-alkoxycarbonyl, tcl-cl~)-alkoxy-(cl-cl2) alkoxycarbonyl, (C6-Clz)-aryloxycarbonyl, (C~-C16)-aralkoxycarbonyl, (C3-C8)ocycloalkoxyaarbonyl, ( C3-C 12 ) -alkenyloxycarbonyl, (C3-C12)-alkynyloxyl-carbonyl, ~C~ 2)-alkylcarbonyloxy, (~3-cs)-cycloalkyl-carbonyloxy, (C6-C~2 ) -arylcarbonyloxy, ~C7-C16)-aralkylcarbonyloxy, cinnamoyloxy~ ~C3-~12) alkenylcarbonyloxy, ~C3-C12)~alkynylcarbonyloxy, carbamoyl, N (Cl-Cl2)-alkylcarbamoyl, N,N-di-(Cl-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C16) arylcarbamoyl~ N-lC~-C1B)oaralkyl carbamoyl, N (Cl-clo)-alkyl-N-(c6-cl6)-aryl-carbamoyl, N-(C1-C10)-alkyl-N-~C7-Cl6)-aralkyl-carbamoyl, N-((cl-clo)-alkoxy-~cl-clo)~lkyl) carbamoyl, N-((C6-Cl6)-arYlxy-~cl-clo)~lkyl) carbamoyl, N-((C7-C16)-aralk~loxy-(C1-C1O)alkyl)~
carbamoyl,N-(Cl-C10)-alkyl-N-~(cl-clo)-alkoxy-(cl Clo)alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((c6-cl6)-aryloxy-(Cl-C10)alkyl)carbamoyl, N-(Cl-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C1O)alkyl)carbamoyl, 2~2~6 amino, ~Cl-C12)-alkylamino, di-(C1-C1z)alkyl~mino, (c3-cs)-cycloalkylamirlo~ (C3-Cl2)-alkenylamino, (C3-C12)-alkynylamino, N-~C6-C12)-arylamlno, N (C7 Cl1)-aralkylamino, N-~cl~cs)-alkyl-N~(c7-clo) aral~ylaminor N-(C1-C53-alkyl-N- (CB c1~)-arylamino, (C1-C~2~-alkoxyamino, (Cl~Cla)~alkoXy N-(Cl-Clo)-alkylamino, (Cl-Cl~-alkanoylamino, (C3-CB)-c~ycloalkanoylamino, (~6-C12)-aroylaminO, tC7-cl6)~aralkanoylamino~
(C1-Cl2~-alkanoyl-N (C~-C10)-alkylamino, ( ~3-C~ ) -CYC1Oa1kanOY1~N-(C1-C1O)-a1kY1am1nO~
(C6~cl2)~aroyl~N-~cl-clo)-alkylamino~ (C7~Cll)~
aralkanoyl-N-(Cl-C10)-alkylamino, (C1-C12~-alkanoylamino-(Cl-C8~ alkyl, ( C3 CB J ~
cycloalkanoylamino-(C1-C8)-alXyl, (C6-C16~~
aroylam1no-~Cl-C3)-alkyl, (C7-Cl6)-aralkanoylamino-~ a)~alkYl~ amino-(C1-C1O)-alkyl, N-(C1-C1o)~
alkylamino-(C1-ClO)-alkyl, N,N-di(G1-C1O)alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-(Cl-C10)-alkyl, (Cl-Cl2)-alkylmercapto,(Cl-Cl2)-alkyl~ulfinYl,(Cl-C12)-alkylsulfonyl, (C:6-Cl6)-arylmercapto/ (C6-Cl6)-aryl~ulfinyl, (C6-C16)-aryl~ulfonyl, (C7-C16)-aralkylmercapto,~C~-C1~)-aralkyl~ulfi~yl, (c7-cl6)-aralkylsulfonyl~

it being possible for the radicals which contain : ~ an aryl radical in turn to be ~ubstituted on the aryl by 1, 2, 3, 4 or 5 identical or di~ferent substituents selected from the series comprising hydrogen, hydroxyl, halogen, cyano, trifluoro-methyll nitro, carboxyl, (Cl-C~2) alkyl, (C3-C8)-cycloalkyl, (C6~C12)-aryl, (C,-C16) aralkyl, (C3-Cl2)-alkenyl, (C3-Cl2)-alkynyl, (Cl-Cl2)-alkoxy, 2~9~20~

(C1-Cl2)-alkoxy-(Cl-C12)-alkyl, (C~-C12)-alkoxy-~C1-Cl2)alkoxyt (C6-Cl2)-aryloxy, (t:~7-ClB)-Arall~loxy, (Cl-C6)-hydroxyalkyl,~O-[CH2-]2~CrH~2~l8,F8,-OCF2Cll -OCF2-CHE'Cl, (cl-cl2)-a~ carbonyl, (~3~Ca~~
cycloalkylcarbonyl, tC6-C~-arylcarbonylt (C7o Cl6)-aralkylcarbQnyl~ cinnallloylr (C3-t~12)~
alkenylcarbonyl, ~C3-Cl2)-alkynylcaxbonyl, (C1-C1z)-alkoxycar~onyl, (cl-C12)-alkoxy-(C1-C12~-alkoxycarbonyl, (C6-Cl~) aryloxycarbonyl, (C7-Cl63-aralkoxycarbonyl, ( C3CB~-CYC loalkoxycarbonyl, (C3-Cl2)-alkenyloxycarbonyl, (C3-Cla)-alkynyloxy-carbo~yl, (cl-c~z)-alkylcarbonyloxy~ ~ C3_C~) -cycloalkyl-~
car~onyloxy, (C6-C12~-arylcarbonyloxy~ (C~ Cl6)-aralkylcarbonyloxy, ci~namoyloxy, (C3-C,12)-alkenylcarbonyloxy, (C3~C12)-alXyny~carbonylo~y, carbamoyl, N-(Cl-Cl2)-alkylcarbamoyl, ~,N-di-(Cl-Cl2)-alkylcarbamoyl, N-(C3-C~j-cycloalkylcarbamoyl, N-(C6-Cl6)-arylcarbamoyl, ~-(C~-C16)-aralkyl~
carbamoyl, ~-tCl-clo)-alkyl-N-(c6 C16)-aryl-carbamoyl, N~(cl-clO)-alkyl-N-(c~-cl6)-aralk carbamoyl, N-(tcl-clo)-alkoxy-(cl-clo)-alkyl) carbamoyl, N-~(~6-cl6)-aryloxy-(cl-~lo)-alkyl~-carbamoyl, N-((C~-Cl6)-aralkyloxy-(Cl-ClO)-alkyl)-carbamoyl,N-(cl-clo)-alkyl-N-((cl-clo)-alkoxy-(cl C1o)~alkyl)carbamoyl, N~(Cl-C10)-alkyl-N-(~C6-Cl8)-aryloxy-(Cl-C10)-alkyl~carbamoyl,N-(Cl-C10)-alkyl-N-((C7-Cl6)-aralkyloxy-(Cl-C10)-alkyl)carbamoyl, amino, (Cl-Cl2)-alkylamino, di-(Cl-Cl2) alkylamino, (C3-C~)-cycloalkylamino, (C3-Cl2)-alkenylamino, (C3-Cl2)-alkynylamino,N-(C6-Cl2)-arylamino,N-(C~-Cll)-aralkylamino, N-~ Cl-CS )-alkyl-(C7-Cl~)~aralkyl-amino, N~~Cl~C5)~alkyl-(C6-C12)-arylamino/

2~9~20~

(Cl-~,2)-alkoxyamino, (~ 1z)-alkoxy-~-(Cl-ClO)-alkylamino, ~ -alkanoylamino, (C3-Ca)-cycloalkanoylamino, ~C6-C12)-aroylamino, ( C7 C1a)-aralkanoylamino, (Cl-C12)-alkanoYl-N-(C1-Cl03-al~ylamino, ~C3-C8)-cyclo alkanoyl-N-(cl-clo)-alkylamino~ (C6-Cl2)-aroyl-N-~C,-ClO)-alkylamino~(c,-cll)-aralkanoyl-N-(cl-clo) alkylamino, (Cl-Cl2)-alkanoylamino-~C1-C8)-alkyl, (~3~Cs);
cycloalkanoylamino-(Cl-C8)-alkyl, ~C6-C~6~~
aroylamino-(cl-c~)-alkyl~ ( C7 Cl6~-aralk~noyl-amino-(Cl-C8)-alkyl, ~mino-~C1-C~ alkyl, N-(Cl-Clo)-alkylamino-(cl-clo)-alkyl~ ~I,N-di(Cl-C,o)-alkylamino-(Cl-C10) alkyl, t C3-~ ) -CyClOalkyl -amino-(cl-clo)-alkyl~

(Cl-Cl7)-alkylmercapto,(Cl-Cl2)-alkyl3ulfinyl,tCl-Cl2)-all~yl9ulfon~ CE;-Cl8)-arylmercapto,~C6-Cl6)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7~cl6)~
aralkylmercapto, (C~-Cl6)-aralkyl~ulfinyl, (C7-Cl6)-aralkylsulfonyl, or R8 and R8 are furthermore bonded via 3-6 carbon atoms, -NR8R~ forming a heterocyclic ring, ~ith as a heteroatom, ~5 or R~ is R6 and [C-U~-D-W i& not -SO2H, and R4 is a methyl group or -CH2oR5, in which R5 is hydrogen or the radical of a physiologically tolerated alcohol protective group which prefera~ly can be eliminated in the liver under physiological conditions, ~9~
- ~3 -and n i~ 0 or l, f i8 1 to 8, preferably l to 5, g i~ 0 or ~ to (2f+1) and x i~ 0 to 8, in particular 0 or 1.

Particularly preferred protec~ive groups are the following:
tCl~c2o)-alkanoyl~ (C1-C2a)-alkenoyl~ ~Cl-Cz0)-alkynoyl, (C1-C18)-alkylcarbamoyl, di-(C1-C1A!~alkylcarbamoyl, N-~C3-C8)-cycloalkylcarbamoyl, ( C1-C1B ) -alkoxycarbonyl, ( C~-C12 ) -aryloxycarbonyl, (C~-C1~-aralkyloxycarbonyl, in particular benzyloxycarbonyl, (~6-cl2)-arylcarbonyl~
tC7-C~ aralkylcarbonyl, (C~-C1a)-alkyl, unsubstituted or ~ubstituted benzyl, (C1-c6J-alkxY-~cl-cl2) alkyl, carbamoyl-(C1-C12~-alkyl ester, (Cl-Cl8~-acyloxy (C1-C6)~
alkyl, preferably (cl-cl6)-alkanoyloxy-(cl~c6)-al}
benzyloxy-(C1-C8)-alkyl, benzyloxycarbonYloxy-(cl-c~)-alkyl, (Cl-C~8)-alkoxycarbonyloxy-(C1-C6)-a}kyl, it being possible for these groups to carry furthcr substituenta, tetrahydropyranyl, amino acid ester~ or eeters with polypeptides/polypeptide derivatives, preferably ~i- and tripeptides which are esterified in particular via their terminal carboxyl group.

Particularly preferred compounds of the general formula I are those in which A is R3 and ~ i8 -XNR6R7, X i6 a single bond and Y i~ ~SO2- or CO, or X i8 CO and Y i8 -82 or -CONR9, and R1, R2 and R3 are identical or di~ferent and are hydrogen or ~C1-C3)-alkyl, ~Cl-C3)-alkoxy, hydroxyl, fluorine or chlorine, R6 is hydrogen, (C1-C12) alkyl or an N protective group, ~uch as acyl, ~C~-C1A)-alkanoyl, (C1-C~ alkenoyl, unsubstituted or substituted benzoyl, ~ monovalent, divalent, trivalent or tetravalent phy~iologically suitable cation, in particular Na~, R~, Ca2~, Mg2~, 21~ ~5206 - ~4 -Al3~ or an ammonium ion, unYub~tituted or mono~ub-stit~ted to tri~ub~tituted by (Cl-Cl2~-alkY~ lWCl2)-hydroxyalkyl, (C1-C4)-alkoxy-~C1-C10)-alkyl~ phenyl, benzyl or (Cl-Cl2)-alkyl which may be monosubetituted to tri~ub~tituted by hydroxyl or (Cl-C~)-alkoxy, it being pos~ibl~ for an aryl radical to be ~ub~tituted, or a cation of a baaio amino acid derivativ~, R7 is a radical Y R8, in which Y has the a~ove meanin~
and Ra i8 EC-U]r-D-W, i~l which C i6 3 bond or a tCl C:6)-alkanediyl radical, U i~ a bond or hydrogen or -O-, r is 1, D is a bond or hydrogen or a 6traight-chain aliphatic (C1-C~)-alkanediyl radical and W i5 hydrogen I a ( C6-Clz ) -aryl radical c)x a 5-membered or 6-membered heteroaryl radical, at lea~t one of the ~ariabl~ C or D or W not being a bond and U being a heteroatom group only when C i8 not a bond ~nd W, i~ it i~ not hydrogen, i~
preferably in turn sub~tituted by up to 3 identical or different ~ub~tituent~ ~elected from the serLes compri~ing hydroxyl, haloqen, oyano, tri~luoromethyl, nitro, carboxyl, (Cl-C~)-alkyl, C3-C8 ) -cyc loalkyl, ( C6-C~2 ) -aryl, ( C7-Cl6 ) -aralkyl, (C3-C6) -alkenyl, ~C~-C8) - alkynyl, (Cl-C~,) -alkoxy, ( Cl-C~ alkoxy- ( Cl C8 ) oalkyl, ( C6-Cl2 ) ~aryloxy, ~ C7-C16)-aralkyloxy, (Cl-C8)-hydroxyalkyl, -O-~CH2 1xcfE~2s+l B)FU~

209a206 - ~5 -(Cl~Ca)-alkoxycarbonyl, (c6-C12)-aryloxyc~rbonyl/
~C7-C14)-aralkoxycarbonyl, ( C3_C~ ) -CYC1Oa1kOXY-carbonyl, (Cl-r8)-alkylcarbonyloxy, (C3-C8)-cyaloalkylcaro bonyloxy, (c6-cl2)-arylcarbonyloxy~ tC7-Cl83-aralkylcarbonyloxy, cinnamoylo~y, carbamoyl, N-~ C1_C12 )-alkylcarbamoyl, ~I~-di-~Cl-C~)-alkylcarbamo~l, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-Cl6)-arylcarbamoyl, N-(C7-C16)-aralkyl-carbamoyl, N-tcl-clo)-alkyl-N (C6-C~6)~
arylcar~amoyl, N-~cl-clo)-alkyl-N-~c7-cl6) : aralkylcarbamoyl, N-((cl-clo)-alkoxy-(cl-~lo) alkyl)carbamoyl~ N-~(c6-cl6~aryloxy~(cl~clo)-alkyljcarbamoyl, N-((C~-C16)-aralkyloXY-(cl-clO)-alkyl)carbamoyl, N-~cl-clo)-alkyl-N-((cl ClO)-XY~tCl-ClO)-alkyl)carbamoyl, N-(Cl-C10)-alkyl-(c6-cl6)-aryloxy-(cl-clo)-alk~l~carbamoyl, N (Cl-ClO)-alkyl-~ ((C7-Cl6)-aralkyloxy-(Cl-ClO)-alkyl) carbamoyl, amino, (Cl-C8~-alkylamino, di-(Cl -CB) -alkylamino, ~ C3-C~ ~ ~cycloalkylamino, N-(C6-Cl2)-arylamino, N-(C7-Cll)-aralkylamino,N-(Cl-C3)-alkyl-N-~C7-Cll) : aralkylamino, (Cl-ClD)-alkanoylamino, (C3-CB)-cycloalkanoylamino, (C6-Cl2)-aroylamino, ~C7-Cl6)-aralkanoylamino, (C~-ClO)-alkanoyl-N-(Cl-ClO)-alkylamino, (C3-C8)~cy~lo-alkanoyl-N-(Cl-C10)-alkylamino, (C~-Cl2)-aroyl-N-(Cl-C10)-alkylamino,(C7-Cll)-aralkanoyl-N-~Cl-ClO)-alkylamino, (C1-C~2) -a1kanOY1aminO- (C1-C6) -a1kY~ 3-CE~) -cycloalkanoylamino-(C1-C8)-alkyl, (C6-cl6~-aroylamino-(C1-C6)-alkyl, tC7-Cl6)~aralkanoy}amino-(Cl-C6)-alkyl, ~0~20~

~Cl-C"~-alkylmercapto, ~Cl-CD)-alkyl~ulfinyl, ~Cl-C8)-alkyl 8U1 fonyl, (c~-C~2)-arylmPr¢apto, (C~-C~2)-aryl~ulfinyl, ~C8-Cl2)-arylsulfonyl, (Cr~l4)-aralkylmercapto~ ~ C~-C14 ) -ara1kY1 5U1 finyl, ~C7-C14)-aralkyl~ulfo~yl, it b2ing possible for the radicals which ~ontain an aryl radical in turn to be sub~titut~d on the aryl by 1, 2, 3, 4 or 5 id~ntical or di~ferent ~ub~tituents select~d from th~ ~erie8 compri~ing hydroyen, hydroxyl/ halogen, cyano~ trifluoro~
methyl, nitro, carboxyl, (Cl-Ca)~alkYl, ( C3-l a)~
cycloalkyl, (C8-Cl2)-aryl, (C~-G16)-aralkyl, ~ C3-C12)-alkenyl, ~C3-C~2)-alkynyl, (Cl-C8)~alkoxy, ~C1 C6)-alkoxy-~cl-c6)-alky~ 6~~1a)-aryloX~ 7~
C~6~-aralkylOXy~ - [C~2~C~t2f+1-s)Fs~

(cl--cl2)-alkoxycarbonyl~ (C3-CB)~cycloalkoxy-carbonyl, (cl-cl2)-alkylcarbonyloxy~ (C3-C8)-aycloalkyl-carbonyloXY I

carbamoyl, N-(Cl-C~)-alkylcarbamoyl, N,~-di~lCl-Ca)-alkylcarbamoyl,N-( C3-C3 )-cycloalkylcarbamoyl, N- (CB_C16) _arY1CarbamGY1~ N- (C7 -C16) ~
aralkylcarbamoyl, N-(cl-c8)-alkyl-N-~c6-cl6) arylcarbamoyl, N-~ C1_CB )-alkyl-N-~C~-C6)-aralkyl-carbamoyl, N-((~1-C~)-alkoxy~ s) alkyl)carbamoyl, N-((C6-C6)-aryloxy-~Ct-C6)-alkyl)-carbamoyl, N-((C~-Cl6)-aralkyloxy-(Cl-C6)-alkyl~-carbamoyl, N-(Cl-Ca)-alkyl-N-((Cl C6)-alkoxy-(Cl-C6)-alkyl)carbamoyl, N~ ( C1_CB ) _alkyl-N-((C6_C16)_ aryloxy-(Cl-C6)-alkyl)carb~moyl, N-(C1-Ca)-alkyl-N~(~C7-C1~)-aralkyloxy-(C1-C6)-alkyl)carbamoyl, amino, tC1-C6)-alkylamino, di-(Cl-CB)-alkylamino, (c3-ca)-cycloalkylaminol N-(C6-C12)-arylamino, - 27 - 2 Q ~ 5 ~ ~ ~
N-(C7-C1l)-aralkylamlno, N-lCl-C3)-alkyl-(C7-c~
aralkylamlno, N-( Cl-c3 )-alkyl-(C~-C12~-aryl~mino, ~C,-C~)-alkoxyamlno, (Cl-CB)-alkanoylamino,~C3-C~)-cycloal~anoylamino, (C6-C~2)-aroylamino, (C~-C12)-aralkanoylaminQ, ~Cl-C8)~alkanoYl-N-~Cl-C6)-alkylamino, tC3-C8)-cyclo-alkanoyl-N~C1-C6)-alkylaminO, (C6-Cl2)-aroyl-~-(C1-ClQ)-alkylamino, (c7-C~ ralkanoYl-N-( Cl-C6 ) -alkylamino, ~cl-c~)-alkanoylamino-cl-c4)-alkyl~ (C3~Ca)-cycloalkanoylamino~(C1-C~) alkyl, (C6~cl2~~
aroylamino-(C1-C4)-alkyl, (C7-C12)-aralkanoylo amino-~Cl-C~)-alkyl, R9 i~ hydrogsn, (C1-C~)-alkyl or phenyl, unsubstituted or monosubstituted~ or R8 and R9 are bonded via (-C~2~)~, in which -NR~R8 may form a cyclic ~tructure and i may be 3, 4, 5 or 6, and ~C-U]r-D-W i3 not -SO2H, and R4 is methyl or -CH2oR5, in which R5 is hydrogen or the radical of a phy~iologically tolerated alcohol protective group which pre~erably can b~ elLminated in the liver under phy~iologi¢al conditions, and n is 0 or 1, f i~ 1 to 8, pre~erably 1 to 5, g is 0 or 1 to (2f+1) and x i~ 0 to 8, preferably 0 or 1.

Particularly preferred protective groups are the following:
(C1~Cla)~alkanYll (C1-Cl8)-alkenoyl, ~C1-C18)-alkylcar-bamoyl, di-(Cl-C8)-alkylc~rbamoyl, N-(C~-C8)-cycloalkyl~
~arbamoyl, (Cl-C18)-alkoxycarbonyl, (C6-Cl2~-aryloxy-2Q9~20~
_ 2~ -carbonyl, (C7-C~ aralkyloxycarbonyl, in particular ben~yloxycarbonyl, ~C6-Clz)-arylcarbonyl, ~C,-Cll)-aralkyl-carbonyl, (Cl-Cl2)-alkyl, (C1-C6)-alkoXy-~cl-c6)-al~Yl~
carbamoyl-(Cl-C~)-alkyl ester, (C1-C18)-acyloxy-(C~-C6)-alkyl, preferably (C1-Cl8)-alkanoyloxy-~C1-CB~-alkyl, benzyloxy-(Cl-C6)-alkyl, benzyloxycarbonyloxy-(cl-c6)-alkyl, (Cl~C6)-alkyl, tC1-C6~ alkoxycarbonyloxy-(C1-C6)-alkyl, i~ bein~ possible for these group~ to carry further ~ubstituent~, or amino acid e~ter or tetrahydropyranyl.

very particularly preferred compounds of the general formula I are those in which A is R3 and B is -~ NR6R7, X is a single bond and Y is -SO2- or X is -CO- and Y is -SO2- or -CONR9, Rl, R2 and R3 are hydrogen, R6 is hydrogen, (Cl-Cl2)~alkyl or an acyl group, such a~
~C1-C~8)-alkanoylt (C1~C~8)-alkenoyl, unfiubstituted or substituted ben~oyl or a monvalent, divalent or trivalent physiologically sui able cation, in particular Nai, K~, Mg2~, Ca2~ or an ammonium ion, un~ubstituted or monosubstituted to trisubstituted by (Cl-Cl2)-alkyl, (Cl-Cl2)-hydroxyalkyl, (C1-C4)-alkoxy-(Cl-C8)-alkyl, phenyl, benzyl or (Cl-Cl2) alkyl which may be monosubstituted to trisub~tituted by hydroxyl or (Cl-C4)-alkoxy, ~uch as, for example, NH3~
C(CH20H)3 or a cation of a basic amino acid derivative, R7 is a radical Y R8, with the exception of -SO2H, in which Y has the above meaning and R~ is lC-U]r-D-W, in which C i8 a bond or ~C1-C4)-alkanediyl, U i8 a bond, hydrogen or -O-, r is 1, D is a bond, hydrogen or (C1-C4)-alkanediyl, 20~206 ~9 W i~ hydrogen or a phenyl radical, at lea~t one of the variabl~
C or D or W not being a bond and U being -O- only when C 18 not a bond and W i~ subeti~uted by hydrogen, fluorine, chlorine, lCl-C~)-alkyl, ( C3_ C&)-cycloalkyl, ~ CB~C12 )~aryl, (C7~C1~) aralkyl, (C3-Cl2)-alkenyl/ phenyl, (C1-C6)-alkoxy, phenoxy or -O-[C~2~C~H(2f+,~,F~, car~amoyl, ~-(C~-C10)-alkylcarbamoyl, ~,N-di~C,-1 O C8 ) -a1kY1Carba~OY1~N-( C3-Ca )-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-(C7-C~ phenyl~lkyl-carbamoyl, N (cl-c9)-alky~ (c8-cl6)-phenyl-carbamoyl, N-(C1-C~)-alkyl N-~C7-Cl1)-phenyl-alkylcarbamoyl, N-((cl-clo~-alkoxy-icl-c8)-alk~l)carbamoyl/
N-(phenoxy-( C1-CB )-alkyl)carbamoyl, N-((C7-Cl6)-phenylalkyloxy-(Cl-C8)-alkyl)aarbamoyl, N-(cl-ca)-alkyl-N-((cl-c6)-alkoxy-(cl-c8)-alkyl) carbamoyl, : 20 N-(C1-C~)-alkyl-N-(( CB_C12 ~ _PhenOXY-(C1~C8)~a1kY1t carbamoyl, (cl-~8)-alkyl-N-~(c7-cl6)-ph~nylalkyloxy-(~l-c8) alkyl)carbamoyl, (Cl-C9)-alkanoylamino,(C3-C8)-cyc:loalkanoylamino, Z5 (C6-C12)-phenylamino,(C7-C11)-phenylalkanoylamino, (Cl-C8)-alkanoyl-N-(Cl-C1O)-alkylamino~ (C3-C8)-cycloalkanoyl-N-(C1-CB)-alkylamino,benzoyl-N-~Cl-Cl~)-alkylamino, (C~-Cll)-phenylalkanoyl-N-( C1_CB ) -alkylamino, (Cl-C1O)-alkanoylamino-(Cl-CO)-alkyl, (C3-C8)~
cycloalkanoylamino-(Cl-C~)-alkyl,phenylamino-(C1-C8)-alkyl, (C7-Cll), phenylalkanoylamino-(Cl-C8)-alkyl, 209~20~

it being po~ible for the radical3 whi~h contain an ~ryl radical in turn to be ~ub~tituted on the aryl by 1, 2, 3, 4 or 5 identical or differe~t ~ubstituents selected from the ~erie~ comprising hydroxyl, carboxyl, (C1-C4)-alkoxy, phenoxy, benzyloxy, fluorine, chlorine, trifluoromethyl, -O-[CH2]Xc E~Z~l~)Yg (C1-C~)-alkoxycarbonyl, phenoxycarbonyl, (C7-C~
phenylalkoxycarbonyl, lC3-C~ ~ cyc:loalkoxycarbonyl t 0 ( Cl-C12 ) - al~yl arbonyloxy~ (~3~Ca ) -cycloalkyl-carbonyloxy, benzoyloxy, (C7~C~ phenalky carbonyloxy, (C1-C8)-alkoxycarbonyloxy, ~C6-C12~-phenoxy-carbonyloxy, (C7-C11~-phenalkyloxycarbonyloxy, (C3-C~ ycloalkoxycarbonyloxy~

carbamoyl, N-(C1-C6)-alkylcarbamoyl~ N,N-di-(Cl-C6 )-alkylcarbamoyl~N-~C3-C8)-cycloalkylcarbamoyl, N phenylcarbamoyl; N-~C~-C11)-phenalkylcarbamoyl, hydroxy-(Cl-C4)-alkylcarbamoyl, acyloxy-(Cl-C4)-alkylcarbamoyl~

carbamoyloxy,N-(Cl-C6)-alkylcarbamoyloxy,N,N-di-(C1-C6)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyl, R~ is hydrogen, ~C1-C4)-alkyl or phenyl, R4 is -CH20 R5 ~ in which R5 i~ hydrogen, (C1-C12)-alkyl, un~ubstituted or substituted benzyl, (C1-C18)-alkanoyl, (C~~Cl6)~
alkenoyl or unsub3tituted or ~ubstituted benzoyl and n i~ 0, f is 1 to 5, g is 0 or 1 to (2~1) and x i~ O or 1.

2~9~2~6 Of the greatest importance ar~ compound~ oX the general formula I in which A is R3 and ~ X NR6R7, X i8 CO_, R1, R2 and R3 are hydrogen~
R6 is hydrogen, (C~ C8)-alkyl, (C1-C1a)-alkanoyl, (C1-C~ alkenoyl, benzoyl or a monovalent or divalent phy6iologically ~uitable cation, in particular Na~, R~, Mg2~ or Ca2~ ox an ammonium ion, un~ubstituted or monosubstituted to tri~ub~tituted by tC~-CB)-alkyl, (cl-c8)-hydroxyalkyl~ ~C~ C4 ) -a1kO~Y-(C~-C~-a1kY1~
phenyl, benzyl or (C~-Ca)-alkyl which may be monosubstituted to trisub~tituted by hydroxyl or ( C1_C4 ) -alkoxy~
R7 is a radical Y R8, with the exception of -SO2~, in which Y i~ -SO2- and Ra i8 lC~ UJr-D-W~ in which C 18 a bond ox lin~ar (~ 4 ) -alkanediyl~
V is a bond, hydrogen or -O-, ~ is 1, D i~ a bond, hydrogen or linear tC~ C4)-alkanediyl, W i~ hydrogen or a phenyl radicall at lea~t one of the variables C or D or W not being a bond and U being -O- only when C is not a bond and W being substituted by hydro~en, fluorine, chlorine, (C1-C6)-alkyl, ( C3_ CB ) -CYC1Oa1kY1~ ~C7-C~6)-phenylalkyl, phenyl, (cl-c6)-alkoxy~ phenoxy or --[CHZ]xcf~2f~ )Fg~

carbamoyl, N-(C1-C10)-alkylcarbamoyl, N,N-di-(C~-Ca)-alkylcarbamoyl,N-(C3-C8)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-(C~-C1~)-phenylalkylD
carbamoyl, N-(C1-C~)-alkyl-N-~C~-C1a)-phenyl-carbamoyl, N-(C~-C~)-alkyl-N-(C7-C~ phenylalkyl-carbamoyl, N-~( Cl-C3 ) -alkoxy-~cl-c4)-alkyl) carbamoyl, N~(phenoxy-(C~-C~-alkyl)carbamoyl, 2 0 9 ~ 2 0 ~

N-((C7~C18)-phenylalkyloxy-(C1-C4) alkyl)carbamoyl, N-(C1-C6)-alkyl~N-((C1-C3)-alkoxy-(C1-C4)-alkyl)-carbamoyl, N-(cl c6)-alkyl-~-((c6~ )-phenoxy~ c4)-alk~
carbamoyl, N-(Cl-C6)-alkyl-N-((C7-C16)-phenylalkyloxy-(Cl-C4)-alkyl~carbamoyl, (Cl~C6)~alkanoylam~no,(C3-C8)-cyc:loalkanoylamino, (c6-cl~)-phenylamino~(c7-c~ pheIlylalkanoylamino~
( Cl-C8 ) -alkanoyl-N-( Cl-C6 ) ~alkylamino, ( C3-c~ ) -cycloalkanoyl-N-(C~-C6)-alkylamino,b~nzoyl-N-(C1-C6)-alkylamino, (c7-cll)-phenylalkanoyl-N-(cl~c6) alkylamino, ~C1-C10)-alkanoylamino-~Cl-C2)-alkyl, ~C3-C8)~
cycloalkanoylamino-(C1-C2)-alkyl, benzoylamino-(Cl C2)-alkyl, (C7-C~ phenyl-alkanoylamino-(C1-Cz)-alkyl, : it being possible for the radical~ which contain an aryl radical in turn to be ~ub~tituted on the ~0 aryl by 1, 2, 3, 4 or 5 identical or different ~ubstituent~ selected from the serie~ compri~ing hydroxyl, carboxyl, ( C1_CB ) -alkoxy~ phenoxy~
benzyloxy, fluorine, chlorine, trifluoromethyl, (C1~Ca)-alkoxyaarbonyl, phenoxycarbonyl, (C7-C1l)-phenylalkoxycarbonyl, (C~-C~)-cycloalkoxycarbonyl, ~C~-Cl2)-alkylcarbo~yloxy, ~C3-c0 ) -cycloalkyl-carbonyloxy, benzoyloxy, (C7-Cll)~phenalkyl-carbonyloxy, carbamoyl, N-(Cl-C6)-alkylcarbamoyl, N,N-di-(Cl-C6)-alkylcarbamoyl~N-( C3-C~ ) -CyC loalkylcarbamoyl, N-phenylcarbamoyl, N-(C~-Cll)-phenalkylcarbamoyl, hydroxy-(Cl-C4)-alkylcarbamoyl, acyloxy-~Cl-C4)-33 209~23~
alkylcarbamoyl, carbamoyloxy,~-~C,-C6)-~lkylcarbamoyloxy,N-N~di-(cl-c~-alkylcarbamoyloxy~ N- ( C3_CB )-~y~loa~yl-carb~moyl;

R4 is -CH2O R5~ in which R5 iB hydrogen, (C1-C12)~alkyl, unsubstituted or substituted benzyl, (C1-C~ a}kanoyl, (C1 ~lB ) -alkenoyl, or un~ubstituted or ~ubstituted benzoyl and n is 0, f i~ 1 to 5, g iB O or 1 to (2f+1) and X i6 0 or 1.

The invention furthermore relates to the use of compounds lS of the formula I and their physiologically tolerated salte for the preparation of a medicament againat fibrotic diseasF~.

: Finally, the invention relates to the compound~ of the formula I for use as medicament.

The invention particularly relates to the compound~ of the formula I for use a8 fibro8uppreBsant8~

The invention furthermore relate3 to a process for the preparation of compounds of the formula I.

Compounds of the formula Ib in which X i8 a single bond and R4 is CHzoR5 were prepared by ~ method in which i) 2-methylpyridine N-oxide~ of the formula la~ were reacted with anhydrides in an acidic medium, or ii) 2-halomethy~pyridin2s of the formula 3 were reacted with reagents MoR5, or ~0~206 iii~ pyridine-2-carboxylic cid derivatives of fonmul~ 5 were raduced, or iv~ the 2-hydrox~methylpyridine dexivativ~e of the formula 4 were react~d with the ~ulonic acid S ~erivatiYe~ of the formula 2 (cf. Scheme 1~.

2~9~206 Equation 1 illu~tratec the preparation of compounda of the formulae Ia, Ia~, Ib and Ib', in which X i~ a ~ingle bond:

R~ R~
R1~NHR~ 2-R7 R1~ R7 CH~)"N R2 ~H~ R2 1 O

/ Halogenation w 3 R3 OK I ~a t t on R t ~- R 7 O
la' A~2O2ACO~ 0R

P 6 ~ 7 Reduction ~ Rs Q S O - H ~ i R _ ~R 2 R 2 C~N~ R 2 4 (41ky 1 ) ¦ 5 Ox i d~ t I on 2-R7 - H ~ 7 ~ ~N H 1 20~1~20~

Compounds of the formula 1 are reacted with ~ulfonic acid derivatives or carboxylic acid derivatives of the formula 2 in which Z is a leaving group which can be detached nuclaophilically and i8, in particular, F, Cl, Br, I or to ylate, to give compounds of the formula Ia in which R4 i~ methyl. This reaction i~ carried ou- in a dipolar aprotic organic solvent or a ~olvent mixtur2. The follow-ing ~olvents may be mentioned in particular: methyle~e chloride, carbon tetrachloride, butyl acetate, ethyl cetate, toluene, tetrahydrofuran, dimethoxyeth~ne, 1,4 dioxane, acetonitrile, ~,N-dimethylfonmamide, N,N-dimethylacetamide, dimethyl ~ulfoxide, nitromethane and/or pyridine, if appropriate with addition of an a~id-~inding agent, ~uch as ammonia, triethylamine or txi-butylamine, at a reaction $emperature of 0 to 180C,preferably 0 to 80C.

If appropriate, oxidation to give the pyridine N-oxides of the formula Ia' then al80 follow~.

General instructions on this oxidation method are also deccribed, for example, in "~. Rlinsberg, Pyridine and its Derivative~, Interscience Publishers, New York, 1961, Part 2~ 93". Oxidation with hydrogen peroxide i~ des-cribed, for example, in "E. Ochiai, J. Org. Chem. 18, 534 ~1953)". The process conditions can be found in detail in German Patent Application P 38 ~6 471.4, 38 28 140.6, 39 24 093.2 and 40 01 002.3, and DE-A-37 03 959, 37 03 962 and 37 03 963.

If compounds o~ the formula I in which R4 i8 -cHzoR5 ( in this case compounds Ib or Ib') are to be prepared, com-pounds of the formula Ia ~2-picolines) are halogenated with N-halogenoamides, such as ~-bromo~uccinimide or N-chlorophthalimide, or with trichloroisocyanuric acid (Chem. ~er. 120, 649 - 651 (1987)).

_ 37 _ 209~20~

The reaction of ~he 2-picolyl halides of the formula 3 with base~ of the formula ~VR5 i8 carried out by method3 familiar to the expert and leads to compound~ o the formula Ib. ~he preparation proce~s moreover iB de3cribed in P 41 3~ 346~9O Thi~ can be followed by oxidation to give the corresponding pyridine N oxides of the ~ormul~
Ib' (see oxidation to give compounds of the formula Ia').

If sppropriate, the compounds of the formula Ib can also be prepared by conver~ion of pyridine N-oxide~ of the formula Ia' (proces~ i~, equation 1~. Th~ conver~ion i~
carried out with trifluoroacetic anhydride at 0~ or with acetic anhydride, if appropriate in the preçence of an acid, ~uch as glacial acetic acid, at 80 - }20C to give acetakes (formula Ib, in which R5 ~ Ac). The conversio~ i~
also described by Katritzky, A.R~, Lagowski, J,M. in:
Chemi~try of ~he Heterocyclic ~-Oxides"/ Academic Pres~, New York, 1972l IV. 2, pages 352 - 365. Subseqllent hydrolysis to give compound~ o~ the formula Ib in which R5 = H is carried out by known methods. Alkali metal hydroxide~ or carbonates in methanol, ethanol, water or the like are used in particular for ~his purpo~e.

The reaction sequence according to equation 1 described above for the preparation o~ compunds of the formulae Ia, Ia', Ib and Ib' which contain an NR6YRB group in the 5-po~ition can al~o be u6ed for the preparation of thosecompound~ which contain this group in the 4-position. The sequence is then started with compound~ of the general formula 1':

R l~R 3 CH3/~N R2 - 2~952~6 Equation 2 illu~trates the preparation of eompound~ of the formulae Ic or Ic~ in which X is -CO-:
R~ Ri R~ ~ C02H HNR6R7 R1 ~ N-R7 l ~ _I ~ I R6 R ~ /~'N~ ~ R 2 5 ~ ~ /~N~R 2 I s 4 1 OX I d~ t ~ 011 R 1 ~--N - R 7 R 4 ~¦~ R 2 I C ' Compounds of the formula 4 in which R4 iB methyl or -CH2 oR5 are known from T. Su~iyama et al., Chem. Lett.
1982, 917 - 920 and 3.K. Seydel et al., J.Med.Chem. 1~76, 19, 483 - 4g3~

The reaction of compounds of the formula 4 with amides of the formula 5 is carried out in accordance with the information from Houben-Weyl: Methoden der organi~chen Chemie (Method of Organic Chemi~try), Yolume IX, Chapter 19, page~ 636 - 637. It may be expedient here to activate both reactants with auxiliary reagent~.

The ~ubstance~ known to the expert can be used a~ auxili-ary reagents for carboxylic acid activation, ~uch asthionyl chloride, oxalyl chloride, pivaloyl chloride, N,N'-carbonyldiimidaæole or chloroformic acid ester derivativeq. It i~ not always nece~sary to isolate these activated derivatives of the compounds of the formula 4.
It is ueually expedient to react them with the ~mid~ of the formula 5 after preparation in situ or a~ the crude product.

The compounds of the fo~mula S are expediently fir~t reacted with an inorganic or organic ba~e, ~uch a , for ~Q~52~

example, ~odium hydroxide or potassium hydroxide, pota~sium tert-butylate, carbonate, alkoxide, hydride or amide, potas~ium hydroxide, carbonate, alkoxide, hydride or amide, ammonia, triethyl~mi~e, tributylamine or pyridine, at -20 to +150C, preferably at 0 - ~09C, and this reaction mixture i~ reacted with iq compound of the formula ~ or an activa~ed form thereof. Tha reactio~ i8 carried out în an inert solvent, su~h as, for example, methylene chloride, msthanol, ethanol, acetone, ethyl acetate, tolue~e, tetrahydrofuran, acetonitrile, ~,N-dimethylformamide, ~,N-dimethylacetamide, ~itromethane~
dimethyl ~ulfoxide or mixture~ of the~e solvent~.

Another method which can be used for preparation of the compounds of the formula Ic according to the invention i~
conden~ation of compou~ds of the formula 4 with the ~ulfonamide or carboxylic acid ~mide derivative~ of the formula 5 by means of N,N~-dicyclohexylcarbodiimide and 4-N,N-dimethylaminopyridine, A8 desaribed in J.Med.Chem.
1992, 35, 800-804 for the preparation of 5-sulfonylimide~
of pyridine 2,5-di~arboxylic acid 2-methyl ester.

The other condensation methods and oondensation reagent~
known from peptide chemistry can likewise be used.

Compounds of the formula I in which R4 is -CH2oR5, X i~ -CO- and Y is SO2 were prepared by a method in which i) the 6-halomethylpyridine derivatives of the formula 12 were reacted with the reagent~ MoR5, or li) the 6-hydroxymethylpyridine derivatve~ of the formula 13 were reacted with the ~ulfonamide derivatives of the formula 9, or iii) the 6-hydroxymethylpyridine-3-carboxamide derivative~ of the formula 15 were reacted with the sulfonic acid derivatives of the ~ormu}a 2, or ~ 40 - 2Q9~206 iv) pyridine-2 carboxylic acids or pyridine-2-carboxylate~ of the formula 14 were reduced ~cf.
Scheme 3~, the compounds of the formulae 13 and 15 in turn being prepared from the compound~ of the formula 6 by the known methods~

Scheme 3 illustr~tes the preparation of compound6 of the formula ld or ld~, in whi~h X ia -CO- and Y i~ SO2:

~952~

5chem~ 3 R3 R~
Rl~,,~,C02R (R lower alkYl ) ~ C02H
H 3 C~Nf~ R 2 Halogenating WH 2 C R 2 0 6 agent 7 ~ W-Ho I ogon, OAcy I
H2NR,~
1~,/ RSHN-R7 9 Z2R 7R 1 ll R 7 ~/
'~`N'- R2 ~6 WH2C/ ~`N ~ R2R6 1 1 ~oR5 /
R H, / ; ) lower alkyl ~ 5 #~ o R~ o 2 ~ t 2 r~ Q ~I H ~ 5 ~,~ R O ; ~ ) 0,~ ~N~ 2 ; i ) Id ~ 3 /,~ O R
R~2 ' 2 ~i O~ i d5 ~ i oo , ' ( '; ) ~ (R ~ ~, lower alky~
R S o ~
~ IJ R R O
~S 1 ' 2 0 9 ~ 2 0 6 Further reaction to give the pyridine N-oxides of the formula Ia~ has already been explained in connection with equation 1.

~ he reaction seguence acc:ording to eguation 2 deacribed 5 above for preparation of compound~ of the formulae Ic and Ic~ which contain a -CO-~R6- YRB group in the 5 ~po~ition can also be used for the preparation oiE tho~e c:ompounds which contain this group in the 4-po~ition. The ~equence is then started with compound~ of the general formula 4' o Rl ~3 R4 R~
~o prepare compound~ of the formula I (Ia, Ia', Ib, Ib', Ic, Ic') according to the invention by equaltions 1 and 2, compounds in which R6 is hydro~n are employed. The ~alt formation~ after which R6 i8 a physiolo~ically u~able 15 cation, is preferably carried out thereafter. Preferred salt-f orming agents are N alkylamine~, ~ hydroxyalkyl ) amines and (alkoxyalkyl)amines, such as, for example, 2-ethanolamine, 3-propanolamine, ~-methoxyethylamine, 2-ethoxyethylamine and ~ tris-20 (hydroxymethyl)methylamine ~- Tri~ buffer, Tromethamine) or basic amino acids, ~uch as ~ for example, histidine, arginine and lysine.

Scheme 4 illustrate~ the prepa:ration of the compound3 of the formula ld in which 25 X is CO and Y i~ CONR~.

3 2Q9520~

Scheme 4 O R ~N~NHRg 0 R ~ o~[~ ~ r R 5 0 J J~ I H 2 N R_ 5 ;~ N~c~

I S t 0 ~ C ~ N - R 9 I d 1 7 t 6 Their synthesis i~ effected i) by reacting the amides of the formula 15 with corresponding isocyanates 0~ the fonmula 16, or ii) by reacting the carbonyl i~ocyanats~ of the formula 17 with the amines ~2NR9 and if neces~ary carrying out aub~equent oxidation to the N-oxide (ldi).

The compounds of the formula I aocording to the invention have useful pharmacological properties and exhibit an antifibrotic activity, in particular in the liver.

The antifibrotic action can be determined in the model of carbon tetrachloride-induced fibrosis of the liver. For this, rats are treated twice weekly with CCl4 (1 ml/kg) -dissolved in olive oil. The test ~ubstance i~ adminis-tered daily; if appropriate even twice daily, orally or intraperitonea}ly - di~olved in a suitable tolerated ~olventO The extent of the liver fibrosis i8 determlned histologically and the content of collagen in the liver is analyzed by hydroxyproline determination - as de~-cribed by Kivirikko et al. (Anal. Biochem. 19, 249 et seq. (1967)). The fibrogenesis activity can be determined by radioimmunological ~ssay of collagen fragment~ and procollagen peptides in the serum. In this model, the compound~ according to the invention are active in 2~9~0~

concentration~ of 1 - }00 mg/kg.

The fibrogenesis activity ~an be determined by radio-immunological a~say of the N-terminal propeptide of collagen type III or of the N- or C-terminal crosslinking domains of collagen type IV (7~-collagen or ~ype IV
collage~ NC1) in the serum.

For this purpose, the hydroxyproline, procollagen III
peptide, 7s-collagen and type IV collayen ~C concentra-tions in the liver of a) untreated rats ~ coRtrol ~
b) rats to which carbon tetrachloride was administered (CCl4 control) c) rats to which first CC14 and then a compound acsord-ing to the invention were admini~tered were measured (this te~t me~hod is described by Rouiller, C., Experimental Toxic Injury of the ~iver; in The Liver, C. Rouiller, Volume 2, 5. 335-476, New York, Academic Press, 1964).

The compounds of the formula I can be used as medicament~
in the form of pharma~eutical preparations which comprise them, if appropriate together with tolerated pharmace~ti-cal excipients. The compound6 can be used as medicines, for examplP in the form of pharmaceutical preparations, which comprise these compounds ac a mixture with a pharmaceutical, organic or inorganic excipient suitable for enteral, percutaneoue or parenteral admini~tration, such as, for examplel water, gum arabic, gelatin, lac-tose, star~h, magne~ium stearater talc, veyetable oils, polyalkylene glycols, petroleum jelly and the like.

For this purpose, they can be administered orally in dose~ of 0.1 - 25 mg/kg/day, preferably 1 - 5 mg/kg/day, or parenterally in dose~ of 0.01 - 5 mg/kg/day, prefer-ably 0.01 ~ 2.5 mg/kg/day, in particular 0.5 - 1.0 mg/kg/
day. In serious cases, the dosage can ~l~o be increased.

20~2a6 In many ca3es, however, lower doee~ are also ~ufficient.
These data relate to an adult weighing about 75 kg.

The invention furthermore relate~ to the u~e of the compounds a~cording to the invention in the preparation of medicament~ which are employed for the treatment and prophylaxi~ of the a~ovemen~ioned metabolic di~turbances.

The invention furthermore relate~ to medicaments which comprise one or more compounds of the ~ormula I according to the invention and/nr physiologically tolerated ~alts thereof.

The medicaments are prepared by proces~e~ which are known per se and are familiar to the expert. As medicament~, the pharmacologically active compounds ~ active compound) acoording to the invention are employed either a~ such or, preferably, in combination with ~uitable pharmaceutical auxiliaries or excipients, in the form of tablets, coated tablets, capsule~, 6uppositories, emulsions, ~u6pensions or solutions, the active compound content being up to about 95~, ~nd advantageously between 10 and 75%.

Suitable auxiliariec or excipients for the desired medicament formulation are, for example, in addition to 501vent~ gel-forming agent~, suppo~itory bases, tablet-ing auxiliaries and other active compound excipient~, also antioxidant~, disper~ing agent6, emulsifier~, foam suppressants, flavour correctant~, preservative~, ~olubi-lizing agents or dyestuff~.

$he following examples are intended to illu~trate the invention.

~09~20~
- ~6 -Example 1 5-[(4-Fluorophenyl~ulfonyl)amino]-2-hydroxymethyl-pyridine a) Methyl 5-~(4-fluorophenylsulfonyl)amino]-pyridine-2-carboxylate 3.8 g (25 mmol) of methyl 5-amino-pyrid;ne-2-carboxylate are di~solved in 75 ml of anhydrou~ pyritine, and 5.8 g (30 mmol) o~ 4-fluorobenzenesulfonyl chloride are added in portion~ the temperature of the reaction ~olution increasing to 35C. A~ter 1 hour, the mixture i6 concen-trated in vacuo, and the residue i~ triturated with water, filtared off with ~uotion, wash~d with water and dried, ~his give~ 7.3 g o~ product, melting point 183-185C.

b~ 2.6 g ~8.4 mmoll of the above compound ar~ di6~01ved in 100 ml of anhydrou~ 1,4-dioxane, and 20 ml o~ a 1 M
solution of lithium aluminum hydride in tetrahydrofuran are added at 15 - 20C, while stirring. Ethyl acetate i~
~lowly added to the reaction mixture, saturated aqueou~
~H4Cl ~olution i8 then added, and the solution i8 brought to pH 3. The organic phase i~ decanted o~f, the re~idue is washed eeveral times with ethyl acetate, the combin~d organic phase~ are dried and concentrated, and the oily crude product is chromatographed over silica gel (70 -200 ~) using ethyl acetate/methanol l}9:1). The corres-ponding fractions give 1.6 g of the title compound in the form of colorles~ cry~tal~, melting point B8 - 90CO

Example 2 4-[((Phenylsulfonyl)amino)carbonyl]-6-ben~yloxymethyl-pyridine a) Methyl 6-chloromethylpyridine-4~carboxylate hydro-chloride 209~20~
- ~7 -ml o~ thionyl chloride, di~olved in 70 ml of methylene chloride, are added dropwi~e to a ~olution of 16.7 g (O.01 mol) of me~hyl 2-hydroxymethylpyridine-4-carboxylate in 500 ml of methylene chloride, while cooling with ice and stirring. After the mixture has been warmed to room temperature, it i8 stirred for 1 hour and concentrated in vacuo, ~he re~idue i~ treated with diethyl ether, and 23 g of the produc~ are obtained in the form of colorles~ cry~tals, melting point 116 -118C.

b) 6-Benzyloxymethylpyridine-4-carboxylic acid 14.4 g (about 0.5 mol) of 80% ~trength ~odium hydride are added in portion~ to 60 ml (0.6 mol) of benzyl alcohol in 500 ml of N,N-dimethylacetamide. ~he mixture is stirred at 60C for 30 minutes and cooled to 20C, 23 g (Q.l mol) of the compound from Example 2a are added in portion~, and the mixture is stirred at 75C for 2 hour~. 300 ml of water are then added, the dark ~olution ic concentrated in vacuo, a further 100 ml of water are added, 2N NaOH iB
added until a clear solution i6 obtained, the ~olution i8 filtered, the filtrate î~ brought to pH 4 with 2~ ~Cl, and the precipitate i~ filtered off with ~uction, rinsed with water and dried to give 10.8 g of product, melting point 173 - ~75C.

c) 2.4 g (lD mmol) o~ the above compound are ~uepended in 50 ml of anhydrou~ tetrahydrofuran, and 1.5 ml (1.1 g, 11 mmol) of triethylamine are added at 0C. After 30 minutes, 1.35 ml (1.32 g, 11 mmol) of pivaloyl chloride are added dropwise at 0C, and the mixture is stirred at 0C for 2 hour~.

In a second reaction ve~sel, 1.4 g (11 mmol) of potassium tert-butylate are added to 1.7 g (11 mmol) of benzene-sulfonamide in 50 ml of anhydrous tetrahydrofuran. The mixture is heated to 50C, stirred at thi~ temperature - 4~ 20g for 30 minutes, and cooled to 20C. This su~pen~ion i~
added to the above reaction ~olution via a dropping funnel, and the mixture i~ ~tirred at 20C for 1 hour, at 50C for 2 hours and at 794C for 2 hours. The solvent i~
distilled off in vacuo, saturated a~ueous Na~CO3 ~olution i5 added to the residue, and the ~ixture i~ extracted with methylene chloride 0.4 g of educt are recovered from the aqueou9 phase after acidification. The organic phase is concentrated, and the residue i8 chromatographed 10 over silica gel U8ing ethyl aeetate/methanol. The re~idue of corresponding fxactions i~ crystall.ized with diethyl ether to give 1.7 g of the kitle compound a~ a cry~tal-line substance, melting point about 80C.

Example 3 5-~4-(Chlorophenylsulfonyl)~mino]-2-methylpyridine 11.4 g (54 mmol) of 4-chlorobenzene~ulfonyl chloride, dissolved in 15 ml of pyridine, are added dropwise to 4.5 g (41.7 mmol) of 5-amino-2-methylpyridine in 40 ml of anhydrous pyridine, while ~tirring, the temperature rising to 35 - 40C. After 30 minute6, the mixture i~
concentxated in vacuo, the residue i8 treated with water, and the cry~talline product is filtered off with ~uction and recrystallized from ethanol/water t2 : 1). Thi~ give~
10.2 g of the title compound. Melting point 158 - 160C.

Example 4 5-~(4-Chlorophenylsulfonyl)amino]-2-hydroxymethyl-pyridine 9.4 g (39 mmol) of 3-chloroperbenzoic acid are added in portions to 9.9 g (35 mmol) of the compound from Example 30 3 in 400 ml of methylene chloride, while stirring. After 30 minutes at 20C, ammonia ga~ i~ passed in, and 5-~4-chlorophenyl~ulfonyl)amino]-2-methylpyridine N-oxide i8 ~09~20~
- 49 ~
obtained in crystalline form, aq a mixture with ammonium 3-chlorobenzoate, and i8 fil~ered off with suction and dried.

Thi~ residue i8 di~solved in 60 ml of glacial acetic acid, 70 ml of acetic anhydride are added dropwi~e at 80C, while stirring, ~he mixture ia ~tirred at 100 -105C for 1 hour and cooled to 80C, 100 ml of metha~ol are added dropwi~e, the mixture i8 conce~rated in vacuo, the residue i8 di~solved in a little methanol, and the solution is poured into 250 ml of 1.5 N methanolic ~odium hydroxide ~olution. The mixture i~ then oonoentrated in vacuo, 200 ml of water are added, the mixture i~ acidi-fied to pH 6 with aqueous HCl~ re6inous by-products are removed, and the mixture is extracted with methylene chloride. The re~idue of the organic pha~e ~about 4 g~ i~
chromatographed over ~ilica gel u~ing ethyl acetate/
methanol (10 s 1). The product i~ cry~tallized from corresponding fractions wi~h ethyl acetate. Thi~ gives 2.2 g of the product, melting point 156 - 157C.

~xample 5 5-~N-(4-Chlorophenylsulfonyl)-N-~2-methylbenzoyl)amino]
2-(2-methylbenzoyloxymethyl)pyridine 0.22 ml (1.65 ~mol) of triethylamine and 0.1 g of 4-N,~-dimethylaminopyridine are added to 0.45 g ~15 mmol) of the title compound from Example 4 in 100 ml of anhydrou~
methylene chloride at 209C~ while stirri~g. After 15 minutes, 0.4 ml ~465 mg; 3.0 mmol) o~ 2-methylbenzoyl chloride i6 added dropwise, the mixture i8 ~tirred for 30 minute~ and concentrated, the residue i~ treated with water, the mixture is takan up in ethyl acetate, dried and concentrated, the re~idue i~ chromatographed over silica gel u~ing ethyl acetate, and the residue of corresponding fractions is crystallized with diisopropyl ether/petroleum ether. This gives 600 mg of tbe title _ 5~ _ 20~206 compound, meltirlg point 113 ~ C.

~xample 6 5- [ ( 4-Fluorophenyl3ulfonyl ) amino~-2-methylpyridirle is obtained analogously to Ex~nple 3, melting poi~t 175 -5 180C ~from water).

Example 7 5-[(4-Fluorophenyl~ulfonyl3 unino ~ -2 -me~hylpyridine N-oxide is obtained from the compound of Example 6 and m-chloro-perbenzoic acid, melting point 123 - 124C ~from diethyl ether).

Example 8 5-[(4-Methoxyphenylsulfonyl)amino~-2-methyl~pyridine is obtained analogously to Example 3, melting point 112 -114C (from water).

Example 9 5-~4-Methoxyphenylsulfonyl)amino~-2-hydroxymethyl-pyridine is obtained analogously to Example 4 from the compound described in Example 8, melting point 119 - 121C.

Examples 10 - 15 are obtained analogously to ~xample 3 from 5-amino-2-methylpyxidine and the corresponding sulfonyl chlorides. The products are in each case i~o-lated from water:

- 51 - ~ ~9~20~
Example 10 5-[(4 Trifluoromethylphenylsulfonyl)amino]-2-msthyl pyridine, melting point 131 - 133C

Example 11 5-[(4-Trifluoromethoxyphenylsulfonyl)amino]-2-methyl pyr~dine, melting point 68 - 70C

Example 12 5-~(4-(2,2,2-Trifluoroethyloxy)phenyl-sul~onyl)amino]-2-methylpyridine, melting point 116 - 118C

Example 13 5-[~3-Flllorophenyl~ulfonyl)amino]-2-methylpyri.dine, melting point 146 - 148C

Example 14 5-[t3,5-bis~Trifluoromethyl]phenyl~ulfonyl)amino]-2-methylpyridine, melting point 194 - 197C

Example 15 5-[(3-Trifluoromethylphenylaulfonyl)amino]-2-methyl-pyridine, melting point 95 - 97C

Example~ 16 - 20 are obtained analogou~ly to Example 4 from the compound~ of Examples 10 - 12 t 14 and 15.

- 52 - 2 ~ 9 ~ 2 0 6 Example 16 5-~(4~Trifluoromethylphenyl~ulfonyl)amino]-2-hydroxy-methylpyridine, melting point 156 - 158C; from diethyl ~ther Example 17 5-[(4-Trifluoromethoxyphenyl~ulfonyl)amino~-2~hydroxy-methylpyridine, meltiny point 115 - 117C7 from diethyl ether Example 18 5-[(4-(2,2,2~Trifluoro~thyloxy)phenyl~ulfonyl)aminol-2 hydroxymethylpyridine, melting point 122 - 123C; from diethyl ether Example 19 5-[~3,5-bis~Tri~luoromethyl]phenylsul~onyl)amino]-2-hydroxymethylpyridine, melting point 173 - 174C; ~rom diethyl ether Example 20 5-[(3-Trifluoromethylphenylsulfonyl]amino~-2-hydroxy-methylpyridine, melting point 115 - 116C; from diethyl ether The followi~g compound~ of the formula I in which X is -C0- are prepared analogously to the examples mentioned and in accordance with equations 2 and 3.

Example 21 3 ~(Phenylsulfonyl)amino)carbonyl~-6~benzyloxymethyl-pyridine 2Q9~206 a) 6-Benzyloxymethylpyridine-3~carboxylic acid 0.93 g (40.5 mmol) of sodium i~ di~solved in 60 ml of benzyl alcohol at 50C under a nitrogen atmo~pher~O ~he 801ution i5 allowed to cool to 0C, 3.0 g (16~2 mmol) of methyl 6-chloromethyl-pyridine-3-carboxylate tprepared by chlorination of methyl 6-methyl-pyridine-3-carboxylate with trichloroisocyanuric acid), di~solved in 20 ~l of benzyl alcohol, are added, 0.243 g (1.62 mmol) of ~odium iodide i~ added, and the mlxture i~ heated at 80 - 90C
for 8 houxs.
After cooling, the mixture is poured onto water and stirred at 50C for 8 hourR, 200 ml of ethyl acetate are added, and the organic phase i8 extracted 2x with dilute NaOH. The combined ~queous pha6e is acidified with concentrated ~Cl at 0C, and the product i~ filtered nff with ~uction, washed with wa~er and dried at 60C in vacuo. 1.4 g of the compound (melting point 121 - 122C) are obtained.

b) 0.79 g (5 mmol) o~ benzenesulfonamide, 1.03 g ~5 mmol) of N,N~-dicyclohexylcarbodiimide and 0.61 g (5 mmol~ of 4-N,N-dimethylaminopyridine are added ~o 1.22 g (5 mmol~
of the above compound in 100 ml of anhydrous methylene chloride, and the mixture i~ ~tirred at 2CC for 20 hours. The solid i~ then removed, the filtrate is treated with aqueou~ NaHCO3 solutio~, and the aqueou6 phase is washed 2x with diethyl ether and bro~ght to p~ 2 - 3 with concentrated aqueou~ HCl. After filtration with 6uction, washing with water and drying, O.9 g of the title compound are obtained, melting point 178 o 179C~

Example 22 3-[((Phenyl~ulfonyl)amino)carbonyl]-6-acetoxymethyl-pyridine ~s~

Example 23 3-[((PhenylsulfGnyl)amino)car~onyl]-6-(2-methylpropion-yl)oxymethyl-pyxidine Example 24 3-[((Phenylsulfonyl)amino)carbonyl]-6-cyclohexanoyloxy-methyl-pyridine Example 25 3-~((Phenylsulfonyl~amino)carbonyl]-6-bsnzoyloxymethyl~
pyridine Example 26 3-t((Phenyl~ulfonyl)amino)carbonyll-6-hydroxymethyl-pyridine Example 27 3-[((Phenyl~ulfonyl)amino)carbo~yl]-6~2-methylbenzoyl)-oxymethyl-pyridine Example 28 3-[((Methylsulfonyl)amino~carbonyl] 6-hydroxymethyl-pyridine Example 29 3 [((Methylsul~onyl)amino)carbonyl]-6-methoxymethyl-pyridine ~Q95206 2xample 30 3-[((Methylsulfonyl)amino)carbonyl]-6-ethyloxymethyl-pyrldlne Example 31 3-[t(Methyl8ulfonyl)amino)carbonyl]-6-benzoyloxymethyl-pyridine Example 32 3-[((Methylsulfonyl)amino)carbonyl]-6-(2-methylbenzoyl~-oxymethyl-pyridine lQ Example 33 3-r((n-Butyl~ulfonyl)amlno)carbonyl]-6-(2-methylbenzoyl) oxymethyl-pyridine Example 34 3-[((n-B-ltyl6ulfonyl)amino)carbonyl]-6-acetoxymethyl-pyridine Example 35 3-~(~4-[2,2,2-Trifluoroethyloxy]phenylsulfonyl)amino)~
carbonyl]-6-hydroxymethyl-pyridine Example 36 3~~((4-[2,2,2-Trifluoroethyloxy]phenylsulfonyl)amino)-carbonyl]-6-methoxymethyl-pyridine Example 37 3-[((4-[2,2,2-Trifluoroethyloxylphenylsulfonyl)amino)-carbonyl]-6-ethyloxymethyl-pyridine - 56 - ~ ~9~2~
Example 3~

3-[((4-[2,2,2-TrifluoroethyloxyJphenyl~ul~onyl)~mino)-carbonyl]-6-benzyloxymethyl-pyridine ~xample 39 3-[~(4-[2,2,2-Trifluoroethyloxy}phenylsulfonyl)amino~-carbonyl]-6-isopropyloxymethyl-pyridine Example 40 3-[((4-[2,2,2-Tri~luoroethyloxy]phenyl~ulfonyl)a~ino)-carbonyl]-6-acetoxymethyl-pyridine Example 41 3-[((~-[2,~,3,3,4,4,4-~eptafluorobutyloxy]phenyl~ulfon-yl)amino)carbonyll-6-hydroxymethyl-pyridine Example 42 3-[((4-[2,2,3,3,4,4,4-~eptafluorobutyloxy]phenylsulfon-yl)amino~carbonyl]o6-ethyloxymethyl-pyridine Example 43 3-[((4-Methoxyphenyl~ulfonyl)amino)carbonyl~-6-ethyloxy-methyl-pyridine Example 44 3-~((4-Methoxyphenyl~ul~onyl)amino)carbonyl] 6-benzyloxy-methyl-pyridine _ 57 _ 2 Q ~ ~ 2 0 ~

Example 45 3-[((4-Methoxyphenyl~ulfonyl)amino)aarbonyl]-6-acetoxy-methyl-pyxidine Example 46 3-[((4-Methoxyphenyleulfonyl)am1no)carbonyl]-6-ben~yl-oxymethyl-pyridine Example 47 3-[((4-[2,2,3,3,4,4,4-~epta~luorobutyloxy]phenyl~ulfon-yl)amlno)carbvnyl]-6 (2~methylbenzoyl)oxymethyl-pyridine l~ Example 48 3-[((4-[2,2,3,3,4,4,4-~eptafluorobutyloxy~phenylsul~on-yl)amino)carbonyl]-6-isopropyloxymethyl-pyridine Example 49 3-[(~4-Phenoxy-phenylsul~onyl)amino~carbonyl]-6-hydroxy-methyl-pyridine a) 6-Chloromethyl-pyridine-3 carboxylic acid 1.28 g ~32 mmol) of ~olid ~odium hydroxide lozenge~ are dissolved in 250 ml of methanol at 0C, and 5.92 g (32 mmol) of methyl 6-chloromethyl-pyridine-3 carbox~late (prepared by chlorination of methyl 6 methyl-pyridine-3-carboxylate with trichloroisocyanuric acid) are added.
After the mixture has been ~tirred for 18 hours, it i~
concentrated, the re~idue i~ taken up in ~aturated, aqueous Na bicarbonate solution, the mixture i8 extracted with ethyl acetate, the aqueous phase i~ acidi~ied with concentrated hydrochloric acid, and 2.43 g are filtered off with suction as the ~irst product ~raction.

209~

Melting point = lS7 - 159C.
The a~ueous phaee i~ extracted three time~ wi h ethyl acetate, the organic pha~e i~ dried and concentrated, and 0.9 g of further product i8 isolated, melting point 159-1~1C.
Yield: 3.33 g b) ~he title compound i8 obtained analo~ou~ly to Example 92.

1~5 g (8.8 mmol) of the above compound were stirred in 300 ml of methylene chloride with 2~19 g (B.8 mmol) of 4-phenoxybenzenesulfonamide, 1.81 g ~8.8 mmol) of N,~'-dicyclohexylcarbodiimide and 1.07 g (8.8 mmol) of 4 ~,N-dimethylaminopyridine at 20C for 24 hours under an N2 atmosphere. The solld was filtered off, the filtrate was washed with 2 ~ aqueous HCl, the organic ph~se was concentrated, and the re~idue wa~ heated at 80~C in a mixtur~ of 200 ml of 1,4-dioxane and 200 ml of lN agueous NaOH solution for 5 hours, while stirring (control by thin layer chromatography).
The mixture was then concentrated, the residue waa taken up in water, and the mixture was washed with diethyl ether and acidified with concentrated aqueous ~Cl. ~he resulting crude product wa~ chromatographed over ~ilica gel using ethyl acetate/n-heptanetMeOH = 5:3:2, to give, from corresponding fractions, 0.8 g of the title compound as colorle~s crys~al~, melting point 253-254C.

Example 50 3-[~(n-Butylsulfonyl)amino)carbonyl]~6-hydroxymethyl-pyridine Example 51 3~[((n-Butylsulfonyl)amino)carbonyl]-6-ethylOxymeth pyridine 2~5206 Example 52 3-E(~n-Buty1~lfonyl)amino)carbonyl~-6-ben7yloxymethyl-pyridine The following compounds, in which X i a æingle bond, are prepared analogously to equation 1.

Example 53 5-((Phenylsulfonyl)~mino)-2-acetox~methyl-pyridine Example 54 5-((Phenylsulfonyl)amlno3-2-~2-methylpropionyl)oxymsthyl-pyridine Example 55 5-((Phenylsulfonyllamino)-2-cyclohexanoyloxymethyl-pyridine Example 56 5-((Phenylsulfonyl)amino)-2-benzoyloxymethyl-pyridine Example 57 5-((Phenylsulfonyl~mino)-2-benzylox~methyl-pyridine Example 58 5-((Phenylsulfonyllamino)-2-(2-methylbenzoyl)oxymethyl-pyridine Example 59 5-((Methyl~ulfonyl)amino)-2-hydroxymethyl-pyridine 2~2~6 Example S0 5-((Methylsulfonyl)amino)-2-methoxymethyl-pyridine Example 61 5-((Methylsulfonyl)amino)-2-ethyloxymethyl-pyridine Example 62 5-((Methylsulfonyl)amino)-2-benzoyloxymethyl-pyridine Example 63 5-(~Methylsulfonyl)amino)-2 (2-methylbenzoyl)oxymethyl-pyridine Example 64 5-((n-Butylsulfonyl)amino)-2-t2-methylbenzoyl)oxymethyl-pyridine Example 65 5-(~n-Butyl~ulfonyl)amino)-2-acetoxymethyl-pyridine Compounds in which X i5 -CO- and Y i6 -CONR9- are summar-ized below. These compounds are prepared by a proces~
analogous to that in J. Agr. Food Chem. Volume 21, No. 3, 1973, page 348 and the literature cited therein for the preparation of benzoyl-3-phenylureas from the corre~-ponding6-hydroxymethyl-pyridine 4(5)~carboxamidedexiva-tives.

Example 66 3- [~((N-Phenylamino)carbonyl)amino~carbonyl]-6-methoxy-methyl-pyridine 20~2~6 a) Methyl 6-methoxymethylpyridine-3-carboxylate 54 ml (about 0.3 mol) of 30~ atrength sodium methylate 801ution and 4.5 g of aodium iodide a:re added to 52 g (0.28 mol) of methyl 6-chloromethyl-pyridine-3-carboxy 5 late in 590 ml of methanol, and the reaction mixture i~
heated under reflux or 3 hours. It i8 conccntrated in vacuo, and the residue i~ extracted with warm diisopropyl ether and chromatographed over silica gel u~ing n-hept-ane/ethyl acetate (2:}~. 42.8 g of product, melting point 34-36C (from petroleum ether~
b) 6-Methoxymethyl pyridine-3-csrboxamide 13.6 9 (75 mmol) of the above ester are ~tirred in lO0 ml of concentrated aqueou~ ammonia:~olution at 25C for 1 houx. The mixture is ~hen neutralized with concentrated aqueous hydrochloric acid, while cooling with ice, ~nd concentrated until crystallization start~, 6.7 g of product, melting point 150-15~C (from water) c) 2.5 g (15 mmol) of 6-methoxymethyl~pyridine-3-carbox-amide are Ruspended in 50 ml Gf anhydrou~ xylene, 2.0 g (1.85 ml; 17 ~mol) of phenyl isocyanate are added, and the reaction mixture is heated at 130C for 18 hours, while stirring. It i~ then cooled, the dark resin is decanted off, 10 ml of methanol are added, the mlxture i9 concentrated, and the residue i~ crystallized with ethyl acetate. The crude product thus obtained is chromato-graphed over ~ilica gel (70 - 200 ~m~ u8ing methylene chloride - up to 10% methanol content in th~ coursa of the chromatography. The title compound i8 crystallized from corresponding fraction~ with methylene chloride, 2.3 g of product, melting point 194-196C.

2~9~20~

Example Ç7 3-~(((N-Phenylamino)carbonyl)amino)carbonyl~-S-~thyloxy-~ethyl-pyridine Example 68 3-lt((N-n-ButYlamino)carbonyl)amino)carbonyll~6-meth methyl-pyridine 3.3 g (20 mmol) of 6-metboxymethylpyridine;3-carboxamide (for the prPparation, cf. Example 66 b)~ are heated at 130C in 100 ml of anhydrous xylene with 2.5 g (2.~ ml, 25 mmol) of n-butyl isocyanate analogou~ly to ~xa~lple 66 c) for 8 hours. A~ter thin layer chromatography control, a further 1 ~1 of n-butyl i60cyanate is added, and the mixture i8 heated for a further 2 hours. The undis~olved material i8 filtered off hot, the filtr~te i~
concentrated, and the re~idue iB crystallized with diisopropyl ether. This crude product i8 chromat~graphed over æilica gel using ethyl acetate~ Corresponding fractions are concentrated, and cry~tallized with diiso-propyl ether. This ~ives 2.3 g of the title compound, melting point 116-118~C.

Example 69 3-[(((N-Propylamino~carbonyl)amlno)carbonyl]-6-benzyloxy-methyl-pyridine Example 70 3-t((~N-Phenyl-N-methylamino)carbonyl~amino)carbonyl]-fi-methoxymethyl-pyridine 20~20~

Example 71 3-[(((N-Phenyl-N-ethyl~mino)carbonyl)a~ino)carbonyl]-6-ethyloxymethyl-pyridine Example 72 3-l(t(N-cYclohexylamino)carbonyl)amino~carbonyl]-6 ethyloxymethyl-pyridine Example 73 3-[((tN-Cyclohexyl-N-ethylam1no)carbonyl)amino)carbonyl]-6-ethyloxymethyl-pyridine Example 74 3-[(((N-n-Butylamino)carbonyl)amino)carbonyl]-6-acetoxy~
methyl-pyridine Example 75 3-~(((N-n-Butylamino)carbonyl)amino)carbonyl]-6-hydroxy-methyl-pyridine Example 76 3-~(((N-Ethylamino)carbonyl)amino)carbonyl]-6-acetoxy-methyl-pyridine Example 77 3-[((~N-Ethylamino)carbonyl)amino)carbonyl] ~-hydroxy-methyl-pyridine ~9~
- ~4 -Example 78 3-[(((N-[4-F}uorophenyl]amino)carbonyl)amino)carbonyl]-5-hydroxymethyl-pyridine Ex~mple 79 3-[((~N-[4-Fluorophenyl~amino~carbonyl)amino)carbonyl3 6-ethyloxymethyl~pyridine Example 80 3-[(((N-[4-Fluorophenyl]-N methylamino)carbonyl)amino)-carbonyl]-6-hydroxymethyl-pyridine Example 81 3-[(((N-[4-Methoxyphenyl]amino)aarbonyl)amino)carbonyl~-6-ethyloxymethyl-pyridine Example 82 3-[(((N-~4-Fluorophenyl]amino)carbonyl)amino)carbonyl]-6-benzyloxymethyl-pyridine Example 83 3-~(((N-Ethylamino)carbonyl)amino)carbonyl]-6-benzyloxy-methyl-pyridine Example 84 3-[(((N-Phenylamino)carbonyl)amino)carbonyl]-6-acetoxy-methyl-pyridine ~Q9~20~

Example 85 3-[((~N-Phenylamino)carbonyl~amino)carbonyl~-6-hydroxy-methyl-pyridine Example 86 3-[(~N-Phenylamino)carbonyl)amlno)carbonyl]-6-~2-methyl-benzoyl)methyl-pyridine Example 87 3-[(((N-Cyclohexylamino)carbonyl)amino)carbonyl]-6-acetoxymethyl-pyridine Example 88 3 ~(((N-Cyclohexylamino)carbonyl)amino)carbonyl~-6-hydroxymethyl-pyridine Example 89 3-r(((N-4-Fluorophenylamino)carbonyl)amino)carbonyl]-6 methoxymethyl-pyridine 1.7 g (10 mmol) of 6-methoxymethylpyridine-3-carboxamide are reacted with 1.8 g (13 mmol) of 4-fluorophenyl isocyanate at 120C for 8 hours analogously to Example~
66 and 68. Yellow crystals which have precipitated out on ~0 cooling are ~iltered off with ~uction, heated with 50 ml of methanol, filtered off with ~uction at 20 4C / wa6hed and dried. Thi~ gives 2.6 g of product, melting point 222-224C ~from methanol).

Example 90 3~ Phenylsulfonyl)amino)carbonyl]-6-ethyloxymethyl-pyridine ~9~20~

- ~6 -a) 6-Ethyloxymethyl-pyridine-3-carboxylic acid The compound i~ obtained analogously to ~xample 21a) from sodium, ethanol, 5 g (27 mmol) of methyl 6-chloromethyl-pyridine-3-carboxylate and 0.4 g (2.7 mmol) of ~odium S iodide. Thi~ give~ 4.8 g of product, ~e}ting point 95-96C (from ethyl acetate).

b) Analogously to Example 49), 1.09 g (6 mmol) of 6-ethyloxymethyl-pyridine-3-~arboxylic acid are ~tirred in 100 ml o~ anhydrous methylene chloride with 0~94 g (6 mmol) of benzenesulfonamide, 1.24 g (6 mmol) of N,N'-dicyclohexylcarbodiimide and 0.73 g (6 mmol) of 4-~oN~
dimet~ylaminopyridine at 20C for 20 hour~. The ~,N'-dicyclohexylurea formed is filtered off~ the mixture is concentrated, the residue i~ taken up in aqueous Na bicarbonate ~olution, the undi~olved material i5 filtered off, and the re~idue i8 acidified with concen-trated hydrochloric acid. After filtration with ~uction, rinsing with wa~er and drying, 1.51 g of the title compound are obtained, melting point 180-182C.

Example 91 3-[((4-n-~utyloxyphenylsulfonyl)amino)carbonyl]-6 methoxymethyl pyridine 1.2 g (5.26 mmo}) o~ 4-n-butyloxybenzene~ulfonamide, 1.09 g (5.26 mmol) of N,N'-dicyclohexylcarbodiimide and 0.64 g (5.2~ mmol) of 4-N,N-dimethylaminopyridine were added to 0.9 g ~5.26 mmol~ of 6-chloromethyl-pyridine-3-carboxylic acid (for the preparation, c~. Example 49 a)) in 200 ml of methylene chloride under an N2 atmo~phere r and the mixture was ~kirred at 20C for 20 hour~. The N,N'-dicyclohexylurea i~ filtered off, the filtrate i8 concentrated in vacuo, the residue i8 treated with hot methanol for 15 minutes, the mixture i8 concentrated, and the re6idue i8 chromatoyraphed over silica gel u8ing ethyl a~etate/methanol (9:1). 0.88 g of the title ~095~01~

compound i8 obtained a~ cry~tala from corre~ponding frac-tions, melting point 21B-220C.

Example 92 3-E((4-n-Butyloxyphenyl~u}fonyl)amino~carbonyl]-6 hydroxymethyl-pyridine O.9 g (5.26 mmol) of 6-chloromethyl-pyridine-3-carboxylic acid (for the prepara-ion, cf. ~xample 49 a)) wa~ ~u~pen-ded in 200 ml of methylene ~hloride under an N2 atmoB-phere, and 1.2 g (5.26 mmol~ of 4 n-butyloxybenzene-sulfonamide, 1.09 g ~5.26 mmol) of N,N~-dicyclohexyl-carbodiimide and 0.64 g (5.26 mmol) of 4-~,N-dimethy}-~minopyridine were added. After 10 mi~ute~, a cle r ~olution i8 formed, which becomes cloudy after 1 hour.
The reaction mixture i8 stirred at 20C for a further 19 15 hours. The N,N'-dicyclohexylurea which ha~ precipitated i6 filtered off, the filtrate iB ~oncentx~ted, and the residue i8 ~tirred in 100 ml of 1 N aqueous ~odium hydroxide solution at 50C for 4 hours and ~t 80C for 2 hours~ The mixture i3 concentrated in vacuo, water i~
added, and the mixture i8 extracted twice with diethyl ether. The aqueous phase i8 then acidified with concen-trated aqueous HC} and concentrated, toluene i~ added, the mixture i~ concentrated i~ vacuo, and the reRidu~ i~
chromatographed over ~ilica gel using ethyl acetate/
methanol (1:1, 0.75 ml of acetic a~id added per liter)~
0.8~ ~ of the title compound, which i8 crystallized with ethyl acetate, i~ obtained from corre~ponding fractions, melting point 178-179C.

The following example~ are prep2red analogou~ly to Examples 49 and 9~:

2~206 - ~8 Example 93 3-[((4-Methoxyph2nylqulfonyl)amino)carbonylj~6-hydr4xy-methyl-pyridine Example 94 3-[((4-Ethyloxyphenylsulfonyl)amino)car'bonyl]-6-hydroxy-methyl-pyridine Example 95 3-t(~4-i-Propyloxyphenylsulfonyl)amino)carbony~l-6-hydroxymethyl-pyridine Example 96 3-[((4-n-Pentyloxyphenylsul~onyl)amino)aarbonyl]-6-hydroxymethyl-pyridine Example 97 3-[((4-n-Hexyoxyphenylsulfonyl)amlno)carbonyl]-6-hydroxy-methyl-pyridine Example 98 3-[((4 -n-Octyloxyphenyl6ulfonyljamino)carbonyl~-6-hy~roxymethyl-pyridine Example 9g 3-~((4-n-Hexyloxyphenyl~ul~onyl) amino)carbonyl]-6-hydroxymethyl-pyridine 2~2~
~9 Example 100 3-[t(4-l~-Hexylmethyloxy)phenyl~ulfonyl)amino)carbon 6-hydroxymethyl-pyridine Example 101 3-[((4-Methylphenyl~ulfonyl)amino)carbonyl]-6-hydroxy-methyl-pyridi~e Example 102 3-[((4-Ethylphenylsulfonyl)amino)carbonyl]-6-hydroxy-methyl-pyridine Example 103 3-[((4-n-Propylphenyl~ulfonyl)amino)carbonyl]~6-hydroxy-methyl-pyridine Example 104 3-[~t4-Biphenylsulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 105 3-[((2-~iphenyl~ulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 106 3-~((4-(4-Fluorophenoxy)phenylsulfonyl)amino)carbonyl]-fi-hydroxymethyl-pyridine 21~9~0~
- 7~ -Example 107 3-[((4-~3-Fluorophenoxy)phenyl~ulfonyl)amino)carbonyl]
6-hydroxymethyl-pyridine Example 108 3-[((4-(4-Chlorophenoxy)phenyl~ul~onyl)amino~carbonyl3-6-hydroxymethyl-pyridine Example 109 3-[((4-(3,5-Dichloxophenoxy)phenylsulfonyl)amino)carbon-yl]-6-hydroxymethyl pyridine Example 110 3-[((4-(3 Trifluoromethylphenoxy)phenylsulfonyl)amino)D
carbonyl]-6-hydroxymethyl-pyridine Example 111 3-[((4-(4-Trifluoromethylphenyloxy)phenyl~ulfonyl)amlno)-carbonyl]-6-hydroxymethyl-pyxidine Example 112 3-[((3-(4-Fluorophenoxy)phenylsulfonyl)amino)carbonylJ-6-hydroxymethyl-pyridine Example 113 3-[((3-(3-Fluorophenoxy)phenylsul~onyl)amino)carbonyl~-6-hydroxymethyl-pyridine - 71 - 2~952~
Example 114 3-[((3~(4-Chlorophenoxy)phenyl~ulfonyl)amino)carbonyl~-6-hydroxymethyl-pyridine Example 115 3~t(l3~(3,5-Dichlorophenoxy)phenylsulfonyl)amino)oarbon-yl]-6-hydroxymethyl-pyridine Example 116 3-t((4-(2-(Phenyloxy)ethyloxy)phenylsulfonyl)amino)car-bonyl]-6~hydroxymethyl-pyridine Example 117 3-[((4-(2-(n-Butyloxy)ethyloxy)phenyl~ulfonyl)amino)car-bonyl~-6-hydroxymethyl-pyridine Ex~mple 118 3-[((4-((4-Phenyl n-butyl)aminocarbonyl)phenylsulfonyl~-amino)carbonyl~-6-hydroxymethyl-pyridine Example 119 3-~(4-(Ethylaminocarbonyl)phenylsulfonyl)amir.o)carbon-yl]-~-hydroxymethyl-pyridine Example 120 3~-[((4-(n-Propylaminocarbonyl)phenylsulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine 2i~9~20~

Example 121 3-[((4-(n-Hexylaminocarbonyl~phenyl ulfonyl)amlno)carbon~
yl]-6-hydroxymethyl-pyridine Example 122 5 3-[((4-(N,N-Di-n-butylaminocarbonyl)phenyl3ulfonyl)-amino)carbonyl]-6-hydroxymethyl pyridine Example 123 3~ 4-(Cyclohexylaminocarbonyl)phenyl~ulfonyl)amino3-carbonyl3-6-hydroxymethyl-pyridine Example 124 3-[((4-(~enzyl~minocarbonyl)phenyl~ulfonyl)amino~carbon-yl]-6-hydroxymethyl-pyridine Example 125 ~mmonium ~alt of 3-~((4-((2-phenylethyl)amino~arbonyl)-phenyl 6U lfcnyl)amino)carbonyl]-6-hydroxymethyl-pyridine 6.1 g (20 mmol) of 4-(~2-phenylethyl)aminocarbonyl)-benzane~ulfonamide, 2.45 q (20 mmol) of 4-N,N-dimethyl-aminopyridine and 4.12 g (20 mmol) of N,N'-dicyclohexyl-carbodiimi~e were added ~o 3.42 g (20 mmol) of 6-chloro-meth~lpyridine-3-carboxylic acid under an N2 atmo~phere in 200 ml of dichloromethane, and stirring wa~ carried out for 20 h at 20C. Thereafter, the N,N'-dicyclohexylurea wa~ fi.ltered off and wa~hed with dichloromethane, the filtrate wa~ evaporated down, 200 ml of lN HC} were added and the precipitated product was filtered off under ~uction and washed with water. The intermediate thu~
obtained (13 g) was stirxed in 200 ml of 1,4-dioxane and 300 ml o~ lN NaOH for 5 h at 80C. The mixture wa3 then 2~9~20~

evaporated down, the residue wa~ taken up with water, the solution wa~ extra~ted with diethyl ether and the aqueou~
phase was acidified with concentxated aqueou~ ~Cl.

The precipitated product wa~ filtered off under ~uction and then dissolved in methanol, and m~thanoli~ ammonia solution wa~ added.

After the addi~ion of diethyl ether, cry~t~lline product was filtered off under suction and wa3hed with ether, and 350 mg of the title compound of m.p. 188-190C were obtained. Further product could be i olated from the mother liquor ~7 g) after chromatography.

Example 126 3-[((4-((3-Phenylpropyl)aminocarbo~yl)phenylsulfonyl)-amino)carbonyll 6-hydroxymethyl-pyridine Example 127 3-[(~4-~(2-Methoxyethyl)aminocarbonyl)phenylsulfonyl)-amino)carbonyl3 6-hydroxymethyl~pyridine Exa~ple 128 3-[~(4-((2-Ethoxyethyl)aminocarbonyl)phenylsulfonyl)-amino)carbonyl]-6-hydroxymethyl-pyridine Example 129 3-[((4-((3-Ethoxypropyl)aminooarbonyl)phenyl~ulfonyl)-amino)carbonyl~-6-hydroxymethyl-pyridine Example 130 ~5 3-~((3-(4-Phenyl-n-butyl)aminocarbonyl)phenyl~ulfonyl)-amino)carbonyll-6-hydroxymethyl-pyridine ~Q9~206 Example 131 3 [((3-(Ethylaminocarbonyl)phenylsulfonyl)amino)carbon-yl~-6-hydroxymethyl-pyridine Example 132 3-[~(3-(n-Propylaminocarbonyl)phenyl~ulfonyl)amino)car bonyl] 6-hydroxymethyl-pyridine Example 133 3-~((3-~n-Hexylaminocarbonyl~phenylsulfonyl)amino)carbon-yl]-6-hydroxymethyl-pyridine Example 134 3-[((3-(N,N-Di-n-butylaminocarbonyl)phenylsulfonyl)-amino)carbonylJ~6-hydroxymethyl-pyridlne Example 135 3-[~(3-(Cyclohexylaminocarbonyl)phenyl~ulfonyllamino)-carbonyl]-6-hydroxymethyl-pyridi~e Example 136 3-[(~3-~Benzylaminocarbonyl)phenylsulfonyl)amino)~arbon-yl~-6-hydroxymethyl-pyridine Example 137 3-[((~3-(2-Phenylethyl)aminocarbonyl)phenylsulfonyl)-amino)carbonyl]-6-hydroxymethyl-pyridine 2 0 ~

Example 138 3-[t((3-(3-phenylpropyl)aminocarbonyl)phenyl~ulfonyl) amino)carbonyl~-6-hydroxymethyl-pyridine Example 139 S 3-[(((3-~2-Methoxyethyl)aminocarbonyl)phenyl~ulfonyl3-amino)carbonyl~-6-hydroxymethyl-pyridine Example 140 3-[(((3-(2-Ethoxyethyl)aminocarbonyl)phenyl~ulfonyl)-amino)carbonyl]-~-hydroxymethyl-pyridine Example 141 3-[(((3~(3-Ethoxypropyl)aminocarbonyl)phenylsulfonyl)-~mino)carbonyl]-6-hydroxymethyl-pyridine Example 142 3-[((4-(4-Phenyl-n-butanoylamino)phenylsulfonyl)amino)-carbonyl]-k-hydroxymethyl-pyridina Example 143 3-~(4-[Acetylamino)phenyl~ulfonyl)amino~carbonyl]-6-hydroxymethyl-pyridine Example 144 ~0 3~ 4-(n-Propionylamino)phenylsul~onyl~amino)carbonyl]-~-hydroxymethyl-pyridine ~ ~ 9 ~ 2 0 6 Example 145 3 - r ~ ( n-Hexanoylamino ) phenyl ~ul~onyl ) an~ino ) cQrbollyl ] -6-hydroxymethyl pyridine Example 14S

5 3-[((4-(Benzoylamino)phenyl~ulfonyl)amino3carbonyl] 6-hydroxymethyl-pyridine Example 147 3-[((4-(3-Phenylpropionylamino~phenyl~ulfQnyl)~mino)car-bonyl]-6-hydroxymethyl-pyridine Example 148 3-~((4-(2-Pheny}acetylamino)phenylsulfonyl)amino~carbon-yl~-6-hydroxymethyl-pyridine Example 149 3-[(~4-(2-(Acetylamino) ethyl)phenylsulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine Example 150 3-E( (4-(2-(Butanoylamino)ethyl)phenylsul~onyl~amino)aar-bonyl]-6-hydroxymethyl-pyridine Example 151 3-[((4-~2-~enzoylamino)ethyl)phenylsulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine ~09~2~G

Example 152 Sodium ~alt of 3-[((4-(2-((2-chloro-5-methoxybenzoyl)~
amino)ethyl~phenyl~ulfonyl)amino)carbonyl]-6-chloro-methylpyridine S a) sodium ~alt of 3-~((4~ ((2-chloro-5-methoxy-benzoyl)aminc:>)ethyl)phenylsulfonyl)~nino)caxbonyll-6-chloromethylpyridine 1.85 g (16.5 ~mol) of pota~sium tert-butylate wexe added to 5.5 g ~15 mmol) of ~-(2-((2-chloro-5-methoxybenzoyl)-amino)ethyl)benzenesul~onamide in 300 ml of tetrahydro-furan while ~tirring at 20C, and stirriny was continued for 30 min at 50C. A ~olution of 2.57 g of 6-chlor-omethylpyridine 3-carboxylic acid and 2.7 g ~16.5 ~nol) of N,N'-carbonyldiimidaæole in 70 ml of anhydrou~ tetra-hydro~uran, which ~olution had likewise been ~tirredbeforshand for 30 min at 50C, wa~ added dropwi~e to this ~olution after cooling. The reaction mixture wa~ ~tirred for 2 h at 40-50C, cooled and then evaporated down in vacuo, the ~olid xe~idue wa~ treated with water, with 200 ml of saturated aqueous sodium bicarbonate ~olution and with 200 ml of dichloromethane, and 7.3 g of product of m.p. 192-193C were obtainedO

b) 2.7 g t5 mmol) of the above compound were 6usp~nded in 60 ml of lN NaOH and 30 ml of 1,4-dioxane were added while ~tirring at 80C until a cl~ar solution had formed.
After 1 h at 80C (TLC check), the mixture was cooled and was evaporated down in vacuo, 30 ml of water were added, extraction was effected once with 100 ml o~ dichloro-methane and the aqueou~ phase wa6 adjusted to p~ 1 with concentrated aqueous ~Cl. The ~emicrystalline product thus obtained was dissolved in methanol, aqueou~ sodium bicarbonate solution was added, the mixture wa~
evaporated down and the residue was chromatographed with ethyl acetate/methanol (5:1) on ~ilica gel.

2~9~20~

0044 g of the colorle~ cry~talline title compound (mOp.
from 120C, with foamlng) was obtained from corre~ponding fraction3 after treatment with ethyl acetate~

Example 153 3~[((3-~4-Phenyl-n-but~noylamino)phenylsulfonyl)amino)-carbonyl]~6-hydrox~methyl-pyridine Example 154 3-[((3-(Acetylamino)phenyl~ulfonyl~amino)~arbonyl]-6-hydroxymethyl-pyridine Example 155 3-[((3-~Propionylamino)phenyl~ulfonyl)amino)carbonyl~-6-hydroxymethyl-pyridine Example 156 3-[((3-(n-Hexanoylamino)phenylsulfonyl)amino)carbonyll-6-hydroxymethyl-pyridine Example 157 3-[((3-(Benzoylamino)phenylsulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 158 3-[((3-~3-Phenylpropionylamino)phenylsulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine Example 159 3-~((2-(2-Phenylacetylamino)phenyl~ulfonyl)amino)carbon-yl]-6-hydrox~methyl-pyridine 2 0 9 ~ 2 0 ~
- 7g -Example 160 3-[~((3-(2-Acetylamino)ethyl)phenyl~ulfonyl)amino)carbon-yl]-6-hydroxymethyl-pyridine Example 161 5 3-[((~3-(2-Butanoylamlno)ethyl)phenyl~ulfvnyl)amino~aar bonyl]-6-hydroxymethyl-pyridine Example 162 3-[(((3-(2-3enzoylamino)ethyl)phenylsulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine Example 163 3-[((3-(2-((2-Chloro-5-methoxy-benzoyl)amino~ethyl~-phenylsulfonyl)amino3caxbonyl]-6-hydroxymethyl-pyridine Example 164 3-E((((4-Fluorophenyl)-2-oxyethyl)sulfonyl)amino~carbon-yl]-6-hydroxymethyl-pyridine Example 165 3-~(((3-Fluorophenyl)-~-oxyethyl)6ulfonyl)amino)carbon-yl]-6-hydroxymethy~-pyridine ~xample 166 3-[~(((2,4-Difluorophenyl)-2-oxyethy~)sulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine ~0~5~0~

Example 167 3-[~(((4~Chlorophenyl)-2-oxyethyl~sulfonyl)aminv~carbon-yl]-6-hydroxymethyl-pyridine Example 16~

3-~(((t3,5-Dichlorophenyl)-2-oxyethyl~Yulfonyl)amino~car-bonyl]-6-hydroxymethyl-pyridine Example 169 3-t((((3-Trifluoromethylphenyl)-2-oxyethyl)sulfonyl)-amino)carbonyl]~6-hydroxymethyl-pyridine Example 170 3-[((((4-Trifluoromethylphenyl)-2-oxyethyl) 8ul fonyl)-amino)carbonyl]-6-hydroxymethyl-pyridine Example 171 3-~((((4-n-~utyloxyphenyl)-2-oxyethyl)~ulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridine Example 172 3-[((((2-Ethyloxyphenyl)-2-oxyethyl)~ulfonyl)amino)car-bonyl]-6-hydroxymethyl-pyridi~e Example 173 3-~ 2-Methoxyethyl)sulfonyl)amino)carbonyl]-6-hydroxy-methyl-pyridine 20~206 Example 174 3 [(((2-Ethyloxyethyl)~ulf4nyl)am1no)carbonyll-6-hydroxymethyl-pyridine Example 175 3-[(((2-Isopropyloxyethyl)~ulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine ~xample 176 3-[(((2-n-Butyloxyethyl)~ulfonyl)amino)carbonyl]-5-hydroxymethyl-pyridine Example 177 3-~(((2-Benzyloxyethyl)~ulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 178 3-[((((2-Phenylethyl)-2-oxyethyl)~ulfonyl)amino)carbon-yl1-6-hydxoxymethyl-pyridine Example 179 3-~((1-Naphthylsulfonyl)amino)~arbonyl]-6~hydroxymethyl-pyridine Example 180 3-[((~4-Methoxy-l-naphthyl)sulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine ~V9~ 6 Example 181 3-[(((5-Eth~xy-1 naphthyl)~ulfonyl)amino~carbonyl]~6-hydroxymethyl-pyridine Example 182 3-[~2-Biphenyl~ulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 183 3-E(~(4-Methoxy-2-biphenyl~ulfonyl)amino)carbonyl]-6 hydroxymethyl-pyridine Example 184 3-~((((4-Fluorophenyl)-3~oxypropyl)sulfonyl)amlno~carbon-yl]-6-hydroxymethyl-pyridine Example 185 3-~(([(3-Fluorophenyl)-3-oxyprop~1)3ulfonyl)amino)carbon-yl]-6-hydroxymethyl-pyridine Example 186 3-C((((2,4-Difluorophenyl)-3-oxypropyl)sulfonyl)amino)-carbonyl]-6-hydroxymethyl-pyridine Example 187 3-[((((4-Chlorophenyl)-3-oxypropyl)~ulfonyl)amino)carbon yl]-6-hydroxymethyl-pyridine ~9~

Exampl0 188 3-[((((3,5-Dichlorophenyl)-3 oxypropyl)sulfonyl)amino)-carbonyl]-6-hydroxymethyl-pyridine Example 189 3-[((((3-Trifluoromethylphenyl)-3-oxypropyl)sulfonyl)-amino~carbonyl]-6-hydroxymethyl-pyridine Example l90 3-[((((4-Trifluoromethylphenyl)-3-oxypropyl)~ul~onyl)-amino)carbonyl]-fi hydroxymethyl~pyridine Example 191 3-[~(((2-Phenylethyl)-2-oxypropyl)sulfonyl)amino)carbon-yl]-6-hydroxymethyl-pyridine Example 192 3-[((t(4-Fluorophenyl)-4-oxy-n-butyl)sulfonyl)amlno)carb onyl]-6-hydroxymethyl-pyridine Example lg3 3-[~(((3-Fluorophenyl~-4-oxy-n-butyl)sulfonyl)amino)carb-onyl~-6-hydroxymethyl-pyridine ~xample 194 3-~((((2,4-Difluorophenyll-4-oxy-n-butyl)8ulfonyl)amino)-carbonyl]-6-hydroxymethyl-pyridine 2~2as Example 195 3-[t(((4-Chlorophenyl)-4-oxy-n-butyl~ulfonyl)amino)carb onyl]-6-hydroxymethyl-pyridine Example 196 3-[((((3,5-Dichlorophenyl)-4~oxy-n-butyl)~ulfQnyl)~miAo)-carbonyl]-6-hydroxymethyl-pyridine ~xample 197 3-~((((3-Trifluoromethylphenyl)-4-oxy-n-butyl)sulfonyl~-amino)carbonyl~-6-hydroxymethyl-pyridine Exampls 198 3-[(~((4-Trifluoromethylphenyl)-4~oxy-n-butyl)~ulonyl)-amino)carbonyl]-6-hydroxymethyl-pyridine Example 199 3-[((((4-n-Butyloxyphenyl)-4-oxy-n-butyl)sulfonyl)amino)-carbonyl]-6-hydroxymethyl-pyridine Example 200 3-[((((2-Ethyloxyphenyl)-4-oxy-n-butyl)sulfonyl)amiho)-carbonyl]-6-hydroxymethyl-pyridine Example 201 3-~(((4-Methoxy-n-butyl) 8ul fonyl)amino)carbonyl]-6-hydroxymethyl-pyridine ~09~206 Example 202 3-[(((4-Ethyloxy-n-butyl)sulfonyl)ami~o)carbonyl]-6-hydroxymethyl-pyridine Example 203 5 3-[((~4-Isopropyloxy-n-butyl)sulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 204 3-[(((4-n-Butyloxy-n-butyl)sulfonyl)amino)carbonyl~ 6 hydroxymethyl-pyridine Example 205 3-[(~(4-Benzyloxy-n-butyl)sulfonyl~amino)carbonyl]-6-hydroxymethyl-pyridine Example 206 3-[(~((2-Phenylethyl)-4-oxy-n-butyl)sulfonyl)amino)carb-onylJ~fi-hydroxymethyl-pyridine Example 207 3-[~(2-Naphthyl~ulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine Example 208 3-~ 4-Methoxy-2-naphthyl)sulfonyl)amino~arbonyl]-6-hydroxymethyl-pyridine ~09~20~

Example 209 3-[((((4-Fluorophenyl)-2-oxyethyl)sul~onyl~mino)carbon-yl]-6-ethyloxymethyl-pyridine Example 210 3-[((((3-Fluorophenyl)-2-oxyethyl)sulfonyl)amino)carbo~-yl]-6-ethyloxymethyl-pyridine Example 211 3~ (2,4-Difluorophenyl)-2-oxyethyl~ulfonyl~amino)car-bonyl}-6-ethyloxymethyl-pyridine Example 213 3-[((((4-Chlorophenyl)-2-oxyethyl)sulfonyl)amino)carbon~
yl]-6-ethyloxymethyl-pyridine Example 214 3-t(t((3,5-Dichlorophenyl)-2-oxyethyl)sulfonyl)am1no)car-bonyl]-6-ethyloxymethyl-pyridine Example 215 3~ r ( ~ ( I 3-Trifluoromethylphenyl)-2 oxyethyl)sulfonyl)-amino~carbonyl]-6-ethyloxymethyl-pyridine Example 216 3-[((((4-Trifluoromethylphenyl)-2-oxyethyl)sul~onyl)-amino)carbonyl~-6-ethyloxymethyl-pyridine ~095206 Example 217 3 [((((4-n-Butyloxyphenyl)-~-oxyethyl)sulfonyl)amino)car-bonyl]-6-ethyloxymethyl-pyridine Example 218 3-[((((2-~thyloxyphenyl)-2-oxyethyl)~ulfonyl)amino)carb-onyl]-6-ethyloxymethyl-pyridine Example 219 3~ (2-Methoxyethyl~sulfonyl)am~no~carbonyl]-6-ethyloxy-methyl-pyridine Example 220 3--[(((2-Ethyloxyethyl)~ulfonyl)amino)carbonyl]-6-ethyl-oxymethyl-pyridine Example 221 3-[(((2 Isopropyloxyethyl)~ulfonyl)amino)carbonyl] 6-1~ ethyloxymethyl-pyridine Example 222 3-[(~(2-n-Butyloxyethyl~6ulfonyl)amino)carbonyll-6-ethyloxymethyl-pyridine Example 223 3-[(((2-Benzyloxyethyl)sulfonyl)amino)carbonyl]-6-ethyl-oxymethyl-pyridine ~9~20~

Example 224 3-[((((2-Phenylethyl) 2-oxyethyl)sulfonyl)amino)carbon-yl}-6~ethyloxymethyl-pyridine Example 225 3-[((1-Naphthylsulfonyl)amino)carbonyl3-6-0thylQ~ymethyl-pyridine Example 226 3-[(((4-Methoxy-1-naphthyl)sulfonyl)amino)carbonyl~-6-ethyloxymethyl-pyridine Example 227 3-[(((5-Ethoxy-1-naphthyl~ulfonyl)amino)carbonyl3-6 ethyloxymethyl-pyridine Example 228 3-[((2-Biphenyl~ulfonyl)amino)carbonyl] 6-ethyloxymethyl-pyridine Example 229 3-[(((4-Methoxy 2-biphenyl)sulfonyl)amino)carbonyl~-6-ethyloxymethyl-pyridine Example 230 3-~((4-(4-Fluorophenoxy)phenylsulfonyl)amino)carbonyl]-6-ethylox~methyl-pyridine 2~20~

Example 231 3-[((4-(~-Fluorophenoxy~phenyl~ulfonyl)amino)carbonyl~
6-ethyloxymethyl-pyridine Example 232 3-[((4-(4-Chlorophenoxy)phenyl~ulfonyl)amino)car~onyl~-6-ethyloxymethyl-pyridine Example 233 3-[((4-~3,5-Dichlorophenoxy)phenyl~ulfonyl)amino)carbon yll-6-ethyloxymethyl-p~rridine Example 234 3-[(((~4-Fluorophenyl)-2-oxyethyl)Rulfonyl)amino)carbon-yl]-6-acetoxymethyl-pyridi~e Example 235 3-[(~((3-Fluorophenyl)-2-oxyethyl)sulfonyl)amino)carbon-yl]-6-acetoxymethyl-pyridine Example 236 3-[((((2,4-Difluorophenyl)-~-oxyethyl)sulfonyl)amino)car-~onyl]-6-acetoxymethyl-pyridine Ex~nple 237 3-[((((4-Chlorophenyl)-2-oxyethyl)sulfonyl)~mino)carbon-yl]-6-acetox~nethyl-pyridine 2~20~

Example ~38 3-[((((3,5-Dichlorophenyl)-2-o~yethyl)~ul~onyl3amino3car-bonyl]-6-acetoxymethyl-pyridine Example 239 3-[((((3~Trifluoromethylphenyl)-2-oxyethyl)~ulfonyl)-amino)carbonyl~-6-acetoxymethyl-pyridine Example 240 3-[((((4-Trifluoromethylphenyl)-2-oxyethyl)~ulfonylj-amino)carbonyl]-6-acetoxymethyl-pyridine Example 241 3-r ( ( ( (4-n-Butyloxypheny~ oxyethyl)8ul~onyl)amino)car bonyl~-6-acetoxymethyl-pyridine - Example 242 3-[((~(2-Ethyloxyphenyl)~2-oxyethyl)~ulfonyl)amino)carb-onyl]-6-acetoxymethyl-pyridine Example 243 3-~(((2-Methoxyethyl) 8ul fonyl)amino)carbonyl3-6-acetoxy-methyl-pyridine Example 244 3-[(((2-Ethyloxyethyl)sulfonyl)amlno)carbonyl]-6-acetoxy-methyl-pyridine ~09~206 Example 245 3-[t((2-I~opropyloxyethyl)sulfonyl)amino)carbonyl]-fi~
acetoxymethyl-pyridine Example 246 3-[~((2-n-~utyloxyethyl)~ulfonyl)amino)carbonyl]-6-acetoxymethyl-pyridine Example 247 3-[(((2-Benzyloxyethyl)~ulfonyl)amino)carbonyl]-6~acet-oxymethyl~pyridine Example 248 3-~((((2-Phenylethyl)-2-oxyethyl)~ulfonyl)amino)carbon-yl]-6-acetoxymethyl-pyridine Example 249 3 [((1-Naphthyl~ulfonyl)amino)carbonyl]-6-acetoxymethyl-pyridine Example 250 3-[(((4-Methoxy-1-naphthyl)s~lfonyl)amino)oaxbonyl]-6-acetoxymethyl-pyridine Example 251 3-[(((5-~thoxy-1-naphthyl)sul~onyl)amino)carbonyl]-6-acetoxymethyl-pyridine ~9~20~

Example 252 3-[~2-Biphenylsulfonyl)amino)carbonyl]-6~acetoxymethyl-py.ridine Example 253 3-[~4-Methoxy-2 biphenyl)~ulfonyl)amino)carbonyl]-6-acetoxymethyl-pyridine Example 254 3-[~(4-(4-Phenyl-n-butylaminocarbonyl)phenylsulfonyl)-amino)carbonyl~-6-acetoxymethyl-pyridine Example 255 3-[(~4-~2-Phenylethylaminocarbonyl)phenylsulfonyl~amino)-carbonyl]~6-acetoxymethyl-pyridine Example 256 3-[~(4-(3-Phenylpropylaminocarbonyl)phenylsulfonyl)-amino)carbonyl]-6-acetoxymethyl-pyridine Example 257 3~ 4-(2-Methoxyethylaminocarbonyl)phenylsulfonyl)-amino)carbonyl3-6-acetox~methyl-pyridine Example 258 20 3-L ~ (4-(2-Ethoxyethylaminocarbonyl)phenylsulfonyl)amino)-carbonyl]-6-acetoxymethyl-pyridine 2~206 Example 259 3-[([4-(3-Ethoxypropylaminocarbonyl~phenyl~ulfonyl~-amino)carbonyl~-6-~cetoxymethyl-pyridine Example 260 3-[~4-(Ethylaminocarbonyl)phenyl~ulfonyl)amino)carbon-yl3-6-benzyloxymethyl-pyridine Example 261 3-~((4-(n-Propylaminocarbonyl)phenyl~ulfonyl)amino)~arb-onyl~-6-benzyloxymethyl-pyridine Exampl~ 262 3-[~4~(n-Hexylaminocarbonyl)phenylsulfonyl)amino)carbon-yl]-6-n-butanoyloxymethyl-pyridine Example ~63 3-[~t4-(N,N-Di-n-butylaminocarbonyl~phenylsul$onyl)-amino)carbonyl]-6-benzoyloxymethyl-pyridine Example 264 3-[((4-~Cyclohexylaminocarbonyl)phenylsulfonyl)amino)c:ar-bonyl]~6-a~etoxymethyl-pyridine Example 265 ~0 3-[((4-(~enzylaminocarbonyl)phenylsulfonyl)amino)carbon-yl]-6-acetoxymethyl-pyridine 2(3952~

Example 266 3-[~(4-(4-Phenylbutanoylamino)phenylsulfony}~amino)carb-onyl~-6-acetoxymethyl-pyridine Example 267 3-~(((4-[2-Acetylamino~ethyl)phenyl~ulfonyl)amino)carbon-yl~-6~benzyloxymethyl-pyridine Example 268 3-[(((4-[2-Butanoylamino]ethyl)phenyl)sulfonyl)amino)car-bonyl]~6-(2-methylpropionyl)oxymethyl-pyridine Example 269 3-r ( ( ~4-~ enzoy~ n~]ethyl)phenyl)~ulfony~ no)car-bonyl]-6 benzoyloxymethyl~pyridine Example 270 3-[~((4-[2-~2-Chloro-~-methoxy-benzoyl)amino]ethyl)-phenylsulfonyl)amino)carbonyl]-6-n-butanoyloxymethyl-pyridine Example 271 3-t(((4-Acetylamino)phenylsulfonyl)amino~carbonyl]-6-ethyloxymethyl-pyridine Example 272 3-[(((4-Propionylamino)phenyl~ulfonyl)amino)carbonyll-6-ethyloxymekhyl-pyridine 209~6 ~xample 273 3-[(((4-n-Hexanoylamino)phenyl~ulfonyl~amino)carbonyl}~
6-ethyloxymethyl-pyridine Example 274 3-[(((4-Benzoylamino)phenyl~ulfonyl)amino)carbonyl]-6-ethyloxymethyl-pyridine Example 275 3-[((4-[3-Phenylpropionylamlno~phenyl~ulfonyl)amino)carb-onyll-6-ethyloxymethyl-pyridine Example 276 3~[((4-(2-Phenylacetylamino)phenyl~ulfonyl)amino)carbon-yl]-6~benzyloxymethyl-pyridine Example 277 3-[((((4-Fluorophenyl)-2-oxyethyl)~ulfonyl)amino)carbon-yl]-6-benzoyloxymethyl-pyridine Example 278 3-[((((3-Fluorophenyl)-2-oxyethyl)~ulfonyl)amino)carbon-yl~-6-(2-methylbenzoyl)oxymethyl-pyridine Example 279 3-[((((2~4-Difluorophenyl)-2-oxyethyl)sulfonyl)amlno)car bonyl~-6-(2-methylpropionyl)oxymethyl-pyridine ~09~2~6 Example 280 3-[((((4-Chlorophenyl)-2-oxyethyl)sulfonyl~amino)carbon-yl]-6-benæyloxymethyl-pyridins Example 281 3-[((((3,5-Dichlorophenyl)-2~oxyethyl)sulfonyl)aminolaar-bonyl~-6-benzyloxymethyl-pyridine Example 282 3-[((((3-~rifluoromethylphenyl)-2-oxyethyl)sulfonyl)-amino)carbonyl]-6-benzyloxymethyl-pyridine Example 283 3-[((t(4-Trifluoromethylphenyl)-2-oxyethyl)~ulfonyl)-amino)carbonyl]-6-benzyloxymethyl-pyridine Example 284 3-[((((4-n-Butyloxyphenyl)-2-oxyethyl)~ulfonyl)amino)car-bonyl]-6-(2-methylpropionyl)oxymethyl-pyridine Example 2B5 3-[((((2-Ethyloxyphenyl)-2-oxyethyl)sulfonyl)amlno)carb-onyl]-6-propionyloxymethyl-pyridine Example 286 3-[((~2~Methoxyethyl)sulfonyl)amino)carbonyl~-6-benzyl oxymethyl-pyridine 2~206 Example 287 3-~(((2-Ethyloxyethyl)~ulfonyl)~nino)carbonyl~-6-benzyl-oxymethyl-pyridine Example 288 3-[(tt2-I8Opropyloxye hyl~ulfonyl~am:ino)carbonyl]-6-benzoyloxymethyl-pyridine Example 289 3-~tt(2-n-Butyloxyethyl)sulfonyl)amino)carbonyl]-6-~2-methylpropionyl)oxymethyl-pyridine 10 ExalTIplo 2 9 0 3-[((t2-Benzyloxyethyl~sulfonyl~amino)carbonyl]-6-n-butanoylox~methyl-pyridine Example 291 3-[((t(2-Phenylethyl)-2-oxyethyl)sulfonyl)amino)carbon yll-6-benzyloxymethyl-pyridine Example 292 3-[((1-Naphthylsulfonyl)amino)carbonyl]-6-~2-methylpropi-onyl)oxymethyl-pyridine Example 293 3-[((~4-Methoxy-l-naphthyl)~ulfonyl)amino)carbonyl]-6-benzoyloxymethyl~pyridine ~9a206 Example 294 3-[(((5-Ethoxy-l-naphthyl)~ulfonyl)amino)carbonylJ-6-(2-methylpropionyl)oxymethyl-pyrid.ine Example 295 3-[((2-Biphenylsulfonyl)amino~carbonyl]-6-methoxymethyl-pyridine Example 296 3-~(((4-Methoxy-2-biphenyl) 6ulf onyl)amino)carbonyl] 6-methoxymethyl-pyridine Example 297 3-[(~t4-n-Butyloxyphenyl) 3-oxypropyl)~ulfonyl)amino~-carbonyl]-6-ethyloxymethyl-pyridine Example 298 3-r ( ( ( (2-Ethyloxyphenyl)-3-oxypropyl)~ulfonyl)amino)carb-onylJ-6-ethyloxymethyl-pyridine Example 299 3-[~'3-Methoxypropyl)sulfonyl)amino)carbonyl}-6-acetoxy-methyl~pyridine Example 300 3-[(((3-Ethyloxypropyl)sulfonyl)amino)carbonyl~-6-acet-oxymethyl-pyri~ine 21~2~6 ~9 Example 301 3-[(((3-I~opropyloxypropyl)~ulfonyl)amino)carbonyl]-6-ethyloxymethyl-pyridine Example 302 5 3-[(((3-n-~utyloxypropyl)~ulfonyl)amino)carbonyl~-6-(2-methylpropionyl)oxymethyl-pyri~ine ~xample 303 3-[~((3-Benzyloxypropyl)~ulfonyl)amino3carbonyl]-6-acetoxymethyl-pyridine Example 304 3-[((1-Naphthyl~ulfonyl)amino)carbonyl~-6-methoxymethyl-pyrid ine Example 305 3-~t(4-Methoxy-1-naphthyl)sulfonyl)amino)carbonyl]-6-methoxymethyl-pyridine Example 306 3-[((~S-Ethoxy-1-naphthyl)6ulfonyl)amino)carbonyl]-6-methoxymethyl-pyridine Example 307 3-[~(2-Biphenyl~ulfonyl)amino)carbonyl]-6~(2-methylpropi-onyl)oxymethyl-pyridine 2~2~

- 10~ -Example 308 3-[~((4-Methoxy-2-biphenyl)sulfonyl)amino)carbonyl]-fi-benzyloxymethyl-pyrid~ne ~ he following examples 309 318 were prepared from 6-benzyloxymethylpyridine-3-carboxylic acid ~cf. ~xample 21a)) or 6-ethoxymethylpyridine 3-carboxylic acid (cf.
Example 90a)~ and th~ corre~pcnding ~ulfona~ide derivativ~ by the method de3cr~b2d in Examples 21h) ~nd 90b).

Example 309 3-[((4-((n-Butylamino)carbonyl)phenylsulfonyl)ami3no)-carbonyl~-6-benzyloxymethylpyridine m.p. 189-191C ~from methanol) Example 310 3-[((4-(2-((2-Methylpropionyl~mino)ethyl)phenyl~ul~onyl)-amino)carbonyl]-6-benzyloxymethylpyridine m.p. 156-158C (after chromatography with 5:3:2 ethyl acetate/n-heptane/methanol over ~ilia gel~

Example 311 3-[((4-(2-((4 -Methylpentanoyl) amino ) ethyl)phenyl-8ul fonyl)amino)carbonyll-6-benzyloxymethylpyridine m.p. 109-111C ~after chromatography with 5:3:2 ethyl acetatetn-heptane/methanol over ~ilica ~el) 209~0~

- ~01 -Example 312 3-[((4-(2-(~2-Phenylethyl)am~no3caxbonyl)phenyl~ulfony~-~nino)carbonyl]-6-benzyloxymethylpyridine m.p. 175-176C (from methanol) S Example 313 3-[((4-~(2-Phenylethyl)amino)carbonyl)phenylsulfonyl)-amino)carbonyl~-6-ethoxymethylpyridine m.p. 190-191C (from methanol) Example 314 3-[((4~ ((Cyclohexylacetyl~amino)ethyl)phenylsulfonyl)-amino)carbonyl3-6-ethyloxymethylpyridine m.p. 201-202C (from methanol/diisopropyl ether) Example 315 3-r((4-(2-(Hexanoylamino)ethyl)phenyl~ulfonyl)amino)-carbonylJ-6-ethyloxymethylpyridina m.p. 175-177C (from aqueous hydrochloric acid) Example 316 3-~((4-(2~((4-Methylpentanoyl)amino)ethyl)phenylsul fonyl)~nino)carbony~-6-ethyloxymethylpyridine m.p. 156-158C (from aqueous hydrochloria acid) Example 317 3-[((4-((n-~utylamino)carbonyl)phenyl~ulfonyl)amino)-carbonyl]-6-ethyloxymethylpyridine 2 ~ 2 0 6 m.p. 206-20B~C (from aqueou~ hydrochloric acid) Example ~lB

3-[(t3-(~n-Butylamino)carbonyl)phenylsulfonyl)amino~-carbonyll-6-ethyloxymethylpyridine m.p. 214-216C ~after chromatography with 5:3:2 ethyl acetate/n-heptans/methanol ovex ~ilica gel) Example 319 Ammonium salt of 3-[((2-chloro-5-t((2-(4-fluorophenyl)-ethyl)amino)carbonyl)phenylsulfonyl)amino)carbonylJ-6-hydroxymethylpyridine pale browni h amorphous sub~tan~e ~fter chromatography with dichloromethane/methanol/a~uaous ammonia (10:4:0.25);

Preparation analogou~ to Example 125.

Example 320 3-[l(4-((2-(4-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl]-6-hydroxymethylpyridine Example 321 3- E ~ ( 4-(t2-(3,4-~imethoxyphenyl)ethyl3aminocarbonyl)-phenylsulfonyl)amino)carbonyl]-6-hydroxymethylpyridine Example 322 3-[((4-((2-~2-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl]-6-hydroxymethylpyridine 2~g~20~

Example 323 3-[((4-~(2-(4-Fluorophenyl)ethyllaminocarbonyl)phenyl-8ul fonyl)~mino)oarbonylJ-6-hydroxymethylpyridine Example 324 3~[~4-t(2-(4-Chlorophenyltethyl)aminocarbonyl)phenyl-~ulfonyl)amino)carbonyll-6-hydroxymethylpyridine Example 325 3-[((4-(2-((5-Chloro-2-methoxybenæoyl)amino)ethyl)phenyl-sulfonyl)aminQ)carbonylJ-6~hydroxymethylpyridine Example 326 3~[t(4-(2-((3,4-Dimethoxyphenylpropionyl)amino)ethyl)-phenylsulfonyl)amino)carbonyl]-6-hydroxymethylpyri~ine Example 327 3-[((4-~2-((2-Phenylacetyl)amino)ethyl)phenylsulfonyl)-amino)carbonylJ-6-hydroxymethylpyridine Example 328 3-[((4-(2-((Phenoxyacetyl)amino)ethyl)phenyl~ulfonyl)-amino)carbonyl]-6-hydroxymethylpyridine Example 329 3-[((4-~2-((4 Fluorobenzoyl)amino)ethyl)phenyl~ulfonyl)-amino)carbonylJ-6-hydroxymethylpyridine 2 0 ~

Example 330 3-~((4-( 2-((4-Methylpentanoyl~amino)ethyl)phenyl-sulfonyl)amino)carbonyll-6-hydroxymethylpyridine Example 331 3-[((4-(2-((Cyclohexanoyl)amino~ethyl)phenyl~ulfonyl)-amino~carbonyl~-6-hydroxymethylpyridine Example 332 Ammonium 6alt of 3-[t~4-(2-((cyclohexylacetyl~amino)-ethyl)phenylsulfonyl)amino)carbt)rlyl~-6-hydroxymeth pyridine 1 9 7 3 g o~ the title compsund were obtained ~rom ~.46 g (14.4 mmol) of 6-chloromethylpyridine-3-carboxylic aci~
analogously to Example 125.

m.p. 140-142C; after chxomatography with dichloro-methane/methanol/aqueous ammonia (10:4:0.2) over ~ilica gel.

Example 333 Ammonium salt of 3-[((4-(2-~(2-Methylpropionyl)amino)-ethyl)phenylsulfonyl)amino)carbonyl]-6-hydroxymethyl-pyridine 2.48 g of the title compound were obtained from 2.46 g(14.4 mmol) o~ 6-chloromethylpyridine-3-carboxylic acid analogou~ly to Example 125.

m.p. 178-180C; a~ter chromatography analogously to Example 332.

20~201~

Example 334 3-[((4-(2-((3,4-Dimethoxybenzoyl)amino)~thyl)phenyl-eulfonyl)amino~carbonyl3-6-hydroxymethylpyridine Example 335 3~[((4-t2-((3,4-Diethoxybenzoyl)amino)ethyl)phenyl-sulfonyllamino)carbonyl~-6-hydroxymethylpyridine Example 336 3-[~4-(2-((4-n-Butyloxybenzoyl)aminojethyljphenyl-sulfonyl)amino3carbonyl]-6-hydroxymethylpyridine Example 337 3-[(~4 ((5-Chloro-2-methoxybenzoyl)amino)methyl)phenyl-~ulfonyl)~mino)carbonyll-6 hydroxymethylpyridine Example 338 3-[((4-((3,4-Dimethoxyphenylpropionyl)amino)methyl)-phenyl 8ul fonyl)amino)carbonyl]-6-hydroxymethylpyridine ~xample 339 3~[((4-((2-Phenylacetyl)amino)methyl)phenylsulfonyl)-amino )carbonyll-6-hydroxymethylpyridine Example 340 ~0 3-~((4-((Phenoxyacetyl)amino)methyl)phenyl~ul~onyl)-carbonyl]-G-hydroxymethylpyridine ~09~206 Example 341 3-[((4-((4-Fl~orobenzoyl~smino)methyl)phenyl~ulfonyl)-amino)carbonyl]-6-hydroxymethylpyridine Example 342 3-E((4-((4-Methylpentanoyl)amino)methyl)phenylsulfonyl) amino)carbonyl]-6-hydroxymethylpyridine Example 343 3-[(~4-((Cyclohexanoyl)amino)methyl)phenyl~ulfonyl)-amino)carbonyl]-6-hydroxymethylpyridine Example 344 3-[((4-((Cyclohexylacetyl)amino)methyl)phenylsulfonyl)-amino)carbonyl]-6 hydroxymethylpyr}dine Example 345 3-[(t4-t(2-Methylpropionyl)amino)methyl)phenylaulfonyl~-amino)~arbonyl] 6-hydroxymethylpyridine Example 346 3-E~(4-((3,4-Dimethoxybenzoyl)amino)methyl)phenyl-sulfonyl)amino)carbonyl~-6-hydroxymethylpyridine Example 347 3-~((4-((3,4~Diethoxybenzoyl~amino)methyl)phenyl-8ul fonyl)amino)carbonyl]-6-hydroxymethylpyridine 2~2~

Example 348 3-~((4-((4-n-~utyloxybenzoyl)amino) methyl ) phenyl-sulfonyl)amino)carbonyl}-6 hydroxymethylpyridine Example 349 3-[((4-((2-Phenylethyl)aminocarbonyl~phenyl~ulfonyl)-amino~carbonyl~-6-caproyloxym~thylpyridine Example 350 3-~((4-([2-(4-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-sulfonyl)amino~carbonyl]-6-caproyloxymethylpyridine Example 351 3-[(~4-((2-(3,4-Dimethoxyphenyl)ethyl)aminocarbonyl)-phenyl~ulfonyl)amino)carbonyl]-6-capr~yloxymethylpyridine Example 352 3-1((4-((2-(2-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-sul~onyl~amino)carbonyl~-6-caproyloxymethylpyridine Example 353 3-[((4-((2-(4-Fluorophenyl)ethyl)aminocarbonyl~ph~y}-~ulfonyl~amino)carbonyl]-6-caproyloxymethylpyridine Example 354 3-[~(4-(~2-(4 ChlorophenylJethyl)amlnocarbonyl)phenyl-sulfonyl)amino)carbonyl]-6-caproyloxymethylpyridine ~9~0~
- 10~ --~xample 355 3-[((4-~(2-(4-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl]-6-lauroyloxymethylpyridin~

Example 356 3-[(~4-((2-(3,4-Dimethox~phenylpropionyl)amino)ethyl)-phenyl~ulfonyl)amino)carbonyl]-6-lauroyloxyme~hylpyridine Example 357 3 [((4-((2-(2-Methoxyphenyl)ethyl)aminocarbonyl~phe~yl-5U lfonyl)amino)carbonyl]-6 lauroyloxymethylpyridine Example 358 3-[((4-((2-(4-Fluorophenyl)ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl]-6-lauroyloxymethylpyridine Example 359 3-[(~4-~(2-(4-Chlorophenyl)ethyl)~minocarbonyl)phenyl-~ulfonyl)amino)carbonyl~-6-lauroyloxymethylpyridine Example 360 3-[((4-((2-(Cyclohexy}acetyl~dmino)ethyl)phenylsulfonyl)-amino) carbonyl]-6-lauroyloxymethylpyridine Example 361 3-[((4-(2-((2-Methylpropionyl3amino)ethyl~phenyl-sulfonyl)amino)carbonyl]-6-lauroyloxymethylpyridina ~9~

Example 3~2 3-[((4-(2-(~3,4-Dimethoxybenzoyl)amino3ethyl)phenyl sulfonyl)amino)carbonyl]-6-lauroyloxymethylpyridine Example 363 3-[((4-(2-((3,4-Diethoxybenzoyl)amino)ethyl)phenyl-sulfonyl)amino)carbonyl]-6-lauroyloxymethylpyxidine Exampl~ 364 3-[((4-(2-((4-n-Butyloxybenzoyl~amino)ethyl)phenyl-~ulfonyl)amino)carbonyl]-6-lauroyloxymethylpyridine Example 365 3-[((4-((2-~4~Methoxyphenyl)ethyl)aminocarbonyl)phenyl sulfonyl)amino)carbonyl]-6-palmitoyloxymethylpyridine Example 366 3-[((4-t(2-(3,4-Dimethoxyphenyl)ethyl)aminocarbonyl)-phenylsulfonyl)amino)carbonyl]-6-palmitoyloxy-methylpyridine Example 367 3-[(~4-((2-(2-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-5ul fonyl)amino)carbonyl]-6-palmitoyloxymethylpyridine Example 368 3~ 4-((2-~4-Fluorophenyl) ethyl) aminocarbonyl)phenyl-sulfonyl)amino)carbonyl~-6-palmitoyloxymethylpyridine llO- ~95206 Exampl~ 363 3-[((4-~(2-(4-Chlorophenyl~ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl~-6-palmitoyloxymsthylpyridine Example 370 3-~((4-(2-(tCyclohexylacetyl)amino)ethyl)phenyl~ulfonyl)-amino)carbonyl~ ~-palmitoyloxymethylpyridine Example 371 3-[((4-t2-((2 Methylpropionyl)amino3~thyl)phenyl-sulfonyl)amino)carbonyl]-6-palmitoyloxymethylpyridine Example 372 3-[((4-(2-((3r4-Dimethoxybenzoyl)amino)ethyl~phen sulfonyl)amino~carbonylJ-6-palmitoylo~ymethylpyridine Example 373 3-[((4-(2~((3,4-Diekho~ybenzoyl)amino)ethyl)phenyl-sulfonyl)amino)carbonylJ-6-palmitoyloxymethylpyridine Example 374 3-[((4-(2-((4-n-Bu~yloxybenzoyl)amino)ethyl)phenyl-sulfony~)amino)carbonyl]-6-palmitoyloxymethylpyridine Example 375 3-[((4-((2-(4-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-~ulfonyl)amino)carbonyl]-6-stearoyloxymethylpyridine 2~20~

Example 376 3-[(~4-(~2-(3,4-Dimetho~yphenyl)ethyl)aminocarbonyl)-phenylsulfonyl)amino)carbonyl]-6-stearoyloxymeth pyridine S Example 377 3-[t(4-((2-Phenylethyl)aminocarbonyl~phenylsulfonyl)-amino)carbonyl]-6-stearoyloxymethylpyridine Example 378 3-E((4-((2-(4-Fluorophenyl3ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl]-~-stearoyloxymethylpyridine Example 379 3-~(4-((2-(4-Chlorophenyl)ethyl)2minocarbonyl)phenyl-sulfonyl~amino)carbonyl]-6-steaxoylnxymethylpyridine Example 380 3-[((4-(2-((Cyclohexylacetyl)amino)ethyl)phenyl6ulfonyl)-amino)carbonyl]-6-stearoyloxymethylpyridine Example 381 3-[((4-(2-~(2-Methylpropionyl)amino)ethyl)phenyl-~ulfonyl~amino)carbonyl]-6-~tearoyloxymethylpyridine Example 382 : 3-~((4-(2-((3,4-Dimethoxybenzoyl)amino)e~hyl)phenyl-sulfonyl)amino)carbonyl]-6-stearoyloxymethylpyridine 209~206 Example 383 3-[((4-(2-((3,4-Diethoxybenzoyl)amino)ethyl)phenyl-sulfonyl)amino)carbonyl]-6-stearoyloxyme~hylpyridine Example 384 S 3-[~(4-(2~((4-n-Butyloxybenzoyl)amino)ethyl)phenyl-sulfonyl)amino)carbonylJ-6-stearoyloxymethylpyridine Example 385 3-[~(4-(2-((2-Chloro-5-methoxybenzoyl)amino)methyl~-phenylsulfonyl)amino)carbonyl]-6-linoyloxymethyIpyridine Example 386 3-[((4-(2-((3,4-Dimethoxyphenylpropionyl)amino)ethyl)-phenyl~ulfonyl)amino)carbonyl]-6-linoyloxymethylpyridine Example 387 3-[((4-(2-((2-Phenylacetyl)amino)ethyl)phenylsulfonyl)-amino)carbonyl]-6-linoyloxymethylpyridine Example 388 3-[((4-(2-((Phenoxyacetyl)amino)ethyl)phenyl~ulfonyl~-amino)carbonyl]-6-linoyloxymethylpyridine Example 389 3-[((4-(2-((4-Fluorobenzoyl)amino~ethyl)phenylsulfonyl)-amino)carbonyl]-6-linoyloxymethylpyridine 2~9~6 Exa~ple 390 3-[((4-(~-Phenylethyl]aminocarbonyl)phenyl~ulfonyl)-amino)carbonyl3-6-(2-ethylbutyryl)oxymethylpyridine Example 391 3-t((4-~(2-(4-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-~ulfonyl)amino~carbonyl]-6-(2-et~ylbutyryl)ox~methylpyridine Example 392 3-[~(4-((2-(3,4-Dimethoxyphenyl)ethyl)aminocarbonyl)-phenylsulfonyl)~mino)carbonyl]-6-(2-ethylbutyryl)oxy-methylpyridine Example 393 3-[((4-((2-(2-Methoxyphenyl)ethyl)aminocarbonyl)phenyl-sulfonyl)amino)carbonyl3-6-(2-ethy}butyrylJoxymethyl-pyridine Example 394 3-[(~4-((2-(4-Fluorophenyl3ethyl~aminocarbonyl)phenyl-sulfonyl)amino]carbonyl]-6-(2-ethylbutyryl)oxy-methylpyridine Example 395 3-[((4~ (4-Chlorophenyl)ethyl)aminocarbonyl)phenyl ~ulfonyl~amino)carbonyl]-6-(2-ethylbutyryl)oxymethyl-pyridine Example 396 3-~((4-(2-((Cyclohexylwetyl)Emino)ethyl)phenylsulfonyl)-amino)carbonyl3-6-(2-methylbenzoyl)oxymethylpyridine ~9~2~6 Example 397 3-E((4-(2-~(2-Methylpropionyl)amino)ethyl)phen sulfonyl~amino)carbonyl]-6-~2-methylbenzoyl)oxymethyl~
pyridine Example 398 3-[((4-~2-((3,4 Dimethoxybenzoyl)amino)ethyl)p~enyl-æulfonyl)amino)carbonyl] 6-(2-methylbenxoyl)oxymethyl-pyridine Example 399 3-~(4-(2-~(3,4-Diethoxybenzoyl)amino)ethyl)phenyl-sulfonyl)amino)carbonyl]-6-(2-methylbenzoyl)oxymethyl-pyridine Example 400 3-[((4-(2~(4-n-Butyloxyb~nzoyl)amino)ethyl)phenyl-sulfonyl)amino)carbonylJ-6-(2-methylbenzoyl)oxymethyl-pyridine Example 401 3-[((4-((n-Butylamino)carbonyl)phenyl~ulfonyl)-~-acetyl-amino)carbonyl]-6-ethyloxymethylpyridine, prepared by reacting Example 317 with sodium hydride in te~rahydro-furan and acetyl chloride.

Example 402 3-[((4-(2~((2-Chloro-5-methoxybenzoyl)amino~ethyl)phenyl-sulfonyl)-N-acetylamino)carbonyl]-6-acet~x~methylpyridine m.p. 235C (with decomposition) from diethyl ether ~95~

Exampl~ 403 3-E((4-(2~((Cyclohexylacetyl)amino)ethyl)phenyl~ulfon~
N-lauroylamino)carbonyl]-6-hydroxymethylpyridine Example 404 3~[((4-(2-((Cyclohexylacetyl)amino)ethyl)phenylsulfonyl)-N-caproylamino)c~rbonyl]-6-caproyloxymethylpyridine Example 405 3-~((4-(~-((2-Chloro-5-methoxybenzoyl)amino)ethyl)-phenylsulfonyl)-N-stearoylamino~carbonyl3-6-hydrQxy-10 methylpyridine Example 496 3-~((4-((2-Phenylethyl)aminocarbonyl)phenylsulfonyl)-N-lauroylamino)carbonyl]-6-hydroxymethylpyridine Examp}e 407 3-~((4-((2-Phenylethyl)aminocarbonyl)phenylsulfonyl)-N-palmitoylamino)carbonyll-6-hyd~oxymethylpyridine Example 408 3-[((4-((2-Phenylethyl)aminocarbonyl)phenylsulfonyl)-N-lauroylamino)carbonyl]-6 acetoxymethylpyridine Example 409 3-C~(4~((2~Phenylethyl)aminocarbonyl)phenylsulfonyl)-N-~tearoylamino)carbonyl]-6-hydroxymethylpyridine

Claims (17)

1. A 4- or 5-(sulf)imido or (sulfon)amidopyrldine or a related compound or its pyridine N-oxides of the formula I

I

in which A is R3 and B is -XNR8R7 or B is R3 and A is -XNR8R7 and X is single bond or -CO-, and R1, R2 and R3 are identical or different and are hydrogen, unsubstituted or substituted (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, in particular fluorine, chlorine or bromine, nitrile, hydroxyl or amino, R6 is hydrogen, (C1-20)-alkyl or a N protective group, such as acyl, (C1-C20)-alkanoyl, (C1-C20)-alkenoyl, (C1-C20)-alkynoyl, (C7-C20)-aralkanoyl, (C6-C18)-aroyl, (C1-C6)-alkylcarbamoyl, (C1-C6)-alkoxycarbonyl, benzyloxycarbonyl, (C1-C10)-acyloxy-(C1-C6)-alkyl, preferably (C1-C10) -alkanoyloxy-(C1-C6)-alkyl, benzoyloxy-(C1-C6)-alkyl, benzyloxycarbonyloxy (C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkyl, a physiologically suitable cation, such as Na?, X?, Mg2?, Ca2?, Al3? or an ammonium ion, if desired monosubstituted to trisubstitutod by (C1-C16)-alkyl, (C1-C16)-hydroxyalkyl, (C1-C8)-alkoxy-(C1-C16)-alkyl, phenyl, benzyl or (C1-C16)-alkyl which may be monosubstituted to trisubstituted by hydroxyl or (C1-C8)-alkoxy, or a cation of a basic amino acid derivative, where any aryl moiety present may be substituted, R7 is a radical Y R8, in which Y is -SO2-, -CO-, -CONR9 or SO2NR9 and R8 and R9 are [C-U]r-D-W, in which C is a bond or a branched or straight-chain aliphatic (C1-C16)-alkanediyl or cycloaliphatic (C3-C10)-alkanediyl radical or a branched or straight-chain a (C2-C16)-alkenediyl or cycloalenediyl radical or a (C2-Cl6)-alkynediyl radical or a (C2-Cl6)-alkenynediyl radical, each of which may contain one or more C-C multiple bonds, U is a bond or hydrogen or a radical selected from the series comprising the following heteroatom groups: -CO-, -O-(CO)-, -(CO)-O-, -(CO)NR-, NR(CO)-, -O--SO , -SO2- or -NR, in which R is (C1-C3)-alkyl, (C1-C6)-alkanoyl, (C7-Cl6)-aralkanoyl/ (C8-C12)-aroyl or hydrogen, r is 1, 2, 3 or 4, D is a bond or hydrogen or a branched or straight chain aliphatic (C1-C10)-alkanediyl radical or a branched or straight-chain (C1-C10)-alkenediyl radical, a (C2-C10)-alkynediyl radical or a (C2-C10)-alkenynediyl radical, each of which may contain one or more C-C multiple bonds, W is a bond or hydrogen or a (C3-C10) cycloaliphatic alkyl, alkenyl, alkynyl or alkenynyl radical or a (C6-Cl6)-aryl radical or a 5-membered or 6-membered heteroaryl radical, at least one of the variables C or D or W not being a bond and U being a heteroatom group only when C is not a bond, and C, D and/or W, where they are not a bond or hydrogen, and are preferably in turn substituted, or R8 and R9 are furthennore boncled via 3-6 carbon atoms, -NR8R9 forming heterocyclic ring, with N as a heteroatom, or R9 is R6 and [C-U]r-D-W is not -SO2H, and R4 is a radical whicb can be converted physiologically, in particular in the liver, into a carboxylate group or salts thereof, esters and amides being excepted, and n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0 or 1 to (2f+1) and x is 0 to 8, preferably 0 or 1.
2. A compound of the formula I as claimed in claim 1, in which X is a single bond or -CO-, R1, R2 and R3 are identical or different and are hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, in particular fluorine, chlorine or bromine, nitrile, hydroxyl, amino, unsubstituted or mono-or disubstituted by (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl or (C1-C8)-alkylcarbonyloxy, R8 is hydrogen, (C1-C20)-alkyl or an N protective group, such as acyl, (C1-C20)-alkanoyl, (C1-C20)-alkenoyl, (C1-C20)-alkynoyl, (C7-C20)-aralkanoyl, (C6-C18)-aroyl, (C1-C6)-alkylcarbamoyl, (Cl-C6)-alkoxycarbonyl, benzyloxycarbonyl, (C1-C10)-acyloxy-(C1-C5)-alkyl, preferably (C1-C10)-alkanoyloxy-(C1-C6)-alkyl, benzoyloxy-(C1-C6) alkyl, benzyloxycarbonyloxy-(C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C1-C8)-alkyl, a physiologically suitab1e cation, such as Na?, K?, Mg2?, Ca2?, Al3? or an ammonium ion, unsubstituted or monosubstituted to trisubstituted by (C1-C15)-alkyl, (C1-C16)-hydroxyalkyl, (C1-C8)-alkoxy-(C1-C16)-alkyl, phenyl, banzyl or (C1-C18)-alkyl which may be monosubstituted to trisubstituted by hydroxyl or (C1-C8)-alkoxy, or a cation of a basic amino acid derivative, where any aryl moiety present may be substituted, and R7 is a radical Y R8, in which Y is -SO2-, -CO , -CONR9 or -SO2NR8 and R8 and R9 are [C-U]r-D-W, in which C is a bond or a branched or straight-chain aliphatic (C1-C16)-alkanediyl or cycloaliphatic (C3-C10)-alkanediyl radical or a branched or straight-chain (C2-C16)-alkenediyl or cycloalkenediyl radical or a (C2-C16)-alkynediyl radical or a (C2-C16)-alkenynediyl radical, each of which may contain one or more C-C multiple bond, U is a bond or hydrogen or a radical selected from the series comprising the following heteroatom groups: -CO-, -O-(CO)- -(CO)-O-, -(CO)NR-, -NR(CO)-, -O-, -SO-, -SO2-, -NR, in which R is (C1-C3)-alkyl, (C1-C8)-alkanoyl, (C7-C16)-aralkanoyl, (C6-C12)-aroyl or hydrogen, r is 1, 2, 3 or 4, D is a bond or hydrogen or a branched or straight-chain aliphatic (C1-C10)-alkanediyl radical or a branched or straight-chain (C1-C10)-alkenediyl radical, a (C2-C10)-alkynediyl radical or a (C2-C10)-alkenynediyl radical, each of which may contain one or more C-C multiple bonds, W is hydrogen or a (C3-C10) cycloaliphatic alkyl, alkenyl, alkynyl or alkenynyl radical or a (C6-C16)-aryl radical or a 5-membered or 6 membered heteroaryl radical, at least one of the variables C or D or W not being a bond and U being a heteroatom group only when C is not a bond, and C, D and/or W, where they are not a bond or hydrogen, are pxeferably in turn substituted by accommodation of up to 5 identical or different substituents selected from the series comprising hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, (C7-C16)-aralkyl, (C3-C12)-alkenyl, (C3-C12)-alkyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C6-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy,(C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C1-C8)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl,-OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkyl-carbonyl, (C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl, cinnamoyl, (C3-C12)-alkenylcarbonyl, (C3-C12)-alkynylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C3-C12)-alkenyloxycarbonyl, (C3-C12)-alkynyloxy-carbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, (C3-C12)-alkenylcarbonyloxy, (C3-C12)-alkynylcarbonyloxy, (C1-C12) -alkoxycarbony, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalk-oxycarbonyloxy, (C3-C12)-alkenyloxycarbonyl, (C3-C12)-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C16)-arylcarbamoyl, N-(C7-C18)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl, N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)alkyl)carbamoyl, (C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyl, N((C1-C10)-alkyl-N-((C6-C16)-aryloxy-(C1-C10)alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)alkyl-carbamoyl, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-Di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkylcarbamoyloxy, N-(C6-C16)-arylcarbamoyl-oxy, N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C6-C12)arylcarbamoyloxy,N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcabamoyloxy, N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyloxy, N-((C6-C16)-aryloxy-(C1-C10)alkyl)carbamoyloxy,N-((C7-C16)-aralkyloxy-(C1-C10)alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C6-C16)-aryloxy-(C1-C10)alkyl)-carbamoyloxy, N-(C1-C10)-alkyl N-((C7-C18)-aralkyloxy-(C1-C10)alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)alkynylamino, N-(C8-C12)-arylamino, N-(C7-C111)-aralklamino, N-(C1-C10)alkyl-(C7-C10)aralkylamino, N-(C1-C10)-alkyl-N-(C8-C12)-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-Cl2)-aroylamino, (C7-C16-aralkanoylamino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cycloalkanoyl-N (C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C,-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)alkyl, (C7-C16)-arolkanoylamino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(c1-C10)alkylamino-(C1-C10)alkyl, N,N-di(C1-C10)alkylamino-(C1-C10)alkyl, (C3-C8)-cycloalkylamino-(C1-C10)alkyl, (C1-C12)-alkylmercapto,(C1-C12)-alkylsulfinyl,(C1-C12)-alkylsulfonyl,(C1-C16)-arylmercapto,(C6-C16)-aroylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-aralksulfonyl, sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(C1-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C16)-arylsulfamoyl, N-(C7-C16)-aralkyl-sulfamoyl, N-(C1-C10)-alkyl-N-(C6-C16) arylsulfamoyl, N-(C1-C10)-alkyl-N-(C7-C16) aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, N-((C1-C10)alkyl)-(C1-C10)alkylsulfonamido, (C7-C16)-aralkylsulfonamido, N-((C1-C10)alkyl)-(C7-C16)-aralkylsulfonamido, where the radicals which contain an aryl radical may in turn be substituted on the aryl by 1, 2, 3, 4 or 5 identical substituents selected from the series comprising hydroxyl, halogen, cyano, trifluoro-methyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, (C7-C16)-aralkyl, (C3-C12)-alkenyl, (C3-C12)-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkyl,(C1-C12)-alkoxy-(C1-C12)-alkoxy, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C1-C8)-hydroxyalkyl, -O-[CH2-]XCfH(2f+1-g)Fg, -OCF2Cl.
-OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12) arylcarbonyl, (C7-C16)-aralkylcarbonyl, cinnamoyl, (C3-C12) alkenylcarbonyl, (C3-C12)-alkynylcarbonyl, (C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy-carbonyl,(C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkyloxycarbonyl, (C3-C12)-alkenyl-oxycarbonyl, (C3-C12)-alkynylcarbonyl, ( C 1- C 12 ) - a l k y l c a r b o n y l o x y , ( C 3 - C 8 ) -cycloalkylcarbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, (C3-C12)-alkenylcarbonyloxy, (C3-C12)-alkynylcarbonyloxy, (C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkyloxycarbonyloxy, (C3-C12)-alkenyloxy-carbonyloxy, (C3-C12)-alkynyloxycarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbo=amoyl, N,N-di-(C1-C12)-alkylcarbonyl, N-(C3-C8)-cycloalkylcarbamoyl, N-(C6-C16)arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)arylcarbamyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl,N-((C1-C10)-alkoxy-(C1-C10)alkyl)-carbamoyl, N-((C6-C18)-(C1-C10)alKyl)carbamoYl, N-((C7-C16)-aralkyloxy-(C1-C10)alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyl, n-(C1-C10)-alkyl-N-(C6-C16)-aryloxy-(C1-C10)alkyl)carbamoyl, N-(C1-C10-alkyl-N-((C7-C16)-aralkyloXy-(C1-C10)alkyl)-carbamoyl, carbamoyloxy, N-(C1-C12)-alkylcarbamoyloXy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-carbamoyloxy, N-(C6-C16)-arylcarbamoyloxy, N-(C7-C16)-aralkylcarbamoyl-oxy, N-(C1-C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyloxy N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyloxy, N-((C6-C16)-aryloxy-(C1-C10)alKyl)-carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)alkyl)-carbamoyloxy, N-(C1-C10) alkyl-N-((C1-C10)-alkoxy-(C1-C10)alkyl)-carbamoyloxy, N-(C1-C10)-alkyl N-((C6-C16)-aryloxy-(C1-C10)alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralklyloxy(C1-C10)alkyl)carbamoyloxy, amino, (C1-C12)-alkylamino, di-(C1-C12)alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12) alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylamino, N-(C1-C10)-alkyl-N-(C6-C12)-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)-alkanyly-N-(C1-C10)-alkylamino, (C3-C8)-cycloalkanoyl-N-(C1-C10)-alkylamino,(C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10) alkylamino, C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)ocyclo-alkanoylamino-(C1-C8)alkyl, (C6-C16)-aroylamino-(C1-C8)alkyl, (C7-C16)-aralkanoylamino-(C1-C8)-alkyl, amino (C1-C1O)-alkyl, N-(C1-C10)alkylamino-(C1-C10)alkyl, N,N-di-(C1-C10)alkylamino-(C1-C10alkyl, (C3-C8)cycloalkylamino-(C1-C10)alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12) alkylsulfonyl, (C6-C16)arylmercapto, (C6-C15)-aryllsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aralkyl-mercapto, (C7-C16)-aralkylsulfinyl, (C7-C16)-aralkyl-sulfonyl, sulfamoyl,N-(C1-C10)-alkylsulfamoyl,N,N-di-(C1-C10)-alkylsulfamoyl, (C3-C6)-cycloalkylsulfamoyl, N-(C6-C16)-arylsulfamoyl, N-(C7-C16)-aralkylsulfamoyl, N-(C1-C10)-alkyl-N-(C5-C6)-arylsulfamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, N-((C1-C10)alkyl)-(C1-C10)-alkylsulfonamido, (C7-C16)-aralkylsulfonamido, N-((C1-C10)alkyl)-(C7-C16) aralkylsulfonamido, or R8 and R9 are furthermore bonded via 3-6 carbon atoms, -NR8R9 form in a heterocyclic ring, with N
as a heteroatom, or R9 is R6 and [C-U]r-D-W is not not -SO2H, and R4 is a (C1-C10)-alkyl group which may be substituted by hydroxyl or (C1-C6)-alkoky, or is an aldehyde, imino, N-(C1-C8)-alkylimino, acetal, thioacetal or cyclic acetal group, a cyclic thioacetal group or another group equivalent to the aldehyde group or -CH2OR5, in which R5 is hydrogen or the radical of a physilogically tolerated alcohol protected group which preferably can be eliminated in the liver under physiological conditions, and n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0 or 1 to (2f+1) and x is 0 to 8, preferably 0 or 1.
3. Compound of formula I as claimed in claim 1 or 2, in which X is a single bond and Y is -SO2- or -CO- or X is -CO- and Y is -SO2-, -CO- or -CONR9, in which R1, R2 and R3 are identical or different and are hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, in particular fluorine and chlorine, hydroxyl, amino or hydroxy-(C1-C4)-alkyl, R6 is hydrogen, (C1-C20)-alkyl or an N protective group, such as acyl, (C1-C20)-alkanoyl, (C1-C20)-alkenoyl, (C1-C20)-alkynoyl, (C7-C20)-aralkanoyl, (C6-C18)-aroyl, (C1-C6)-alkylcarbamoyl, (C1-C6)-alkoxycarbonyl, benzyloxycarbonyl, (C1-C10)-acyloxy-(C1-C6)-alkyl, preferably (C1-C10)-alkanoyloxy-(C1-C6)-alkyl, benzoyloxy-(C1-C6)-alkyl, benzyloxycarbonyloxy-(C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkyl, a physiologically suitable cation, such as Na?, K?, Mg2?, Ca2?, Al3? or an ammonium ion, unsubstituted or monosubstituted to trisubstituted by (C1-C16)-alkyl, (C1-C16) hydroxyalkyl, (C1-C8)-alkoxy-(C1-C16)-alkyl, phenyl, benzyl or (C1-C16)-alkyl which may be monosubstituted to trisubstituted by hydroxyl or (C1-C8)-alkoxy, or a cation of a basic amino acid derivative, it being possible for any aryl moiety present to be substituted, R7 is a radical Y R6, in which Y has the abovementioned meaning and R8 and R9 are [C-U]r-D-W, in which C is a bond or a branched or straight-chain aliphatic (C1-C12)-alkanediyl radical or a branched or straight-chain (C2-C12)-alkanediyl radical, a (C2-C12)-alkynediyl radical or a (C2-C12) alkenynediyl radical which may contain one or more C C multiple bonds, U is a bond or hydrogen or a radical selected from the series comprising the following heteroatom groups:
-(CO)NR-, -NR(CO)-, -O-, -SO- or -SO2-, in which R is (C1-C3)-alkyl, (C1-C8)-alkanoyl, (C7-C10) -aralkanoyl, (C6-C12)-aroyl or hydrogen, r is 1 or 2, D is a bond or hydrogen or a branched or straight-chain aliphatic (C1-C8)-alkanediyl radical or a branched or straight-chain (C2-C8)-alkenediyl radical or (C2-C8-alkynyldiyl radical and W is hydrogen or a (C3-C10)-cycloaliphatic alkyl, alkenyl, alkynyl or alkenynyl radical or a (C8-C16)-aryl radical or a 5-membered or 6-membered heteroaryl radical, at least one of the variables C or D or W not being a bond and U being a heteroatom group only when C is not a bond and C, D and/or W, where they are not a bond or hydrogen, are preferably in turn substituted by a combination of up to 5 identical or different substituents selected from the series comprising hydroxyl, halogen, cyano, trifluoxomethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl,(C7-C16)-aralkyl, (C3-C12)-alkenyl, (C3-C12-alkynyl, (C1-C12)-alkoxy, (C1-C12)-alkoxy- (C1-C12)alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C1-C6)-hydroxyalkyl, -O-[CH2-]xCfH(2f=1-8F8, -OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkyl-carbonyl, (C8-C12)-arycarbonyl, (C7-C16)-aralkylcarbonyl, cinnamoyl, (C3-C12)-alkenyl-carboinyl, (C3-C12)-alkynylcarbonyl, (C1-C12)-alkoxycarbonyl,(C1-c12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxy-carbonyl, (C3-C12)-alkenyloxycarbonyl, (C3-C12)-alkynyloxy-carbonyl, (C1-C12-alkylcarbonyloxy, (C3-C8)-cycloaklyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, (C3-C12)-alkenylcarbonyloxy, (C3-C12)-alkynylcarbonyloxy, carbamoyal, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-(C6-C16)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C8-C15)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carboymoyl, N-((C1-C10-alkoxy-(C1-C10)alkyl)-carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)alkyl)-carbamoyl,N-((C7-C16)-aralkyloxy-(C1-C10)alkyl)-carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C16)-aryloxy-(C1-C10)alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-atalkyloxy-(C1-C10)alkyl)carbamoyl.
amino, (C1-C12)-alkylamino, di0(C1-C12)-alkyl-amino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6 C12)-arylamino, N-(C7-C11)-aralkylamino, N-(C1-C5)-alkyl-N-(C7-C10)-aralkylamino, N-(C1-C5)-alkyl-N-(C6-C12)-arylamino, (C1-12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoyl-amino, (C6-C12)-aroylamino, (C7-C15)-aralkanoyl-amino, (C1-C12)-alkanoyl-N-(C1-C10)-alkylamino (C3-C8)-cycloalkanoyl-N-C1-C10)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, (C6-C16) aroylamino-(C1-C80-alkyl, (C7-C16)-aralkanoyl-amino-(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-Cycloalkyl-amino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-arylsulfinyl, (C6-Cl6)-arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkyl-sulfinyl, (C7-C16)-aralkylsulfonyl, it being possible for the radicals which contain an aryl radical in turn to be substituted on the aryl by 1, 2, 3, 4 or 5 identical or different substituents selected from tha series comprising hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C12)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, (C7-C16)-aralkyl, (C3-C12) -alkenyl, (C3-C12)-alkynyl, (C1,-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-(C1-C12)-alkoxy, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C1-C8)-hydroxyalkyl, -O-[CH2]xCfH(2f+1-g)Fg, -OCF2Cl, -OCF2-CHFCl, (C1-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)arylcarbonyl, (C7-C16)-aralkylcarbonyl, cinnamoyl, (C3-C12)-alkenylcarbonyl, (C3-C12)-alkynylcarbonyl, (C1-C12)-alkoxycarbonyl,(C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8) -cycloalkoxy-carbonyl, (C3-C12)-alkenyloxycarbonyl, (C3-C12)-alkynyloxy-carbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, (C3-C12)-alkenylcarbonyloxy,(C3-C12)-alkynylcarbonyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-(C6-C16)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkyl-carbamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)-carbamoyl, N-((C8-C18)-aryloxy-(C1-10)-alkyl)-carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl-carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C8-C16)-aryloxy-(C1-C10)-alkyl)-carbamoyl, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino, (C3-C12)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino, N-(C1-C5)-alkyl-(C7-C10 )-aralkylamino,N-(C1-C5)-alkyl-(C6-C12)-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(C1-C1O)-alkylamino, (C1-C12 )-alkanoylamino, (C3-C8)-cyloalkanoyl-amino, (C6-C12)-aroylamino, (C7-C18)-aralkanoyl-amino, (C1-C12)-alkanoyl-N- C1-C10)-alkylamino, (C3-C8)- cyclo-alkanoyl-N-(C1-C1O)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8) -cycloalkanoylamino-(C1-C8)-alkyl, ( C8-C16)-aroylamino (C1-C8)-alkyl, (C7-C16)-aralkanoyl amino-(C1-C8)-alkyl, amino-(C1-C1O)-alkyl,N-(C1-C10)-alkylamino-(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-alkyl, (C3-C8)-cycloalkyl-amino-(C1-C10)-alkyl, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl, (C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto, (C6-C16)-arylsulfinyl, (C6-C16)-arylsulfonyl, (C7-C16)-aralkylmercspto, (C7-C16)-aralkyl-sulfinyl, (C7-C16)-aralkylsulfonyl, or R8 and R9 are furthermore bonded via 3-6 carbon atoms, -NR8R9 forming a heterocyclic ring, with N as a heteroatom, or R9 is R6 and [C-U]r-D-W is not -SO2H, and R4 is a methyl group or -CH2OR5, in which R5 is hydrogen or the radical of a physiologically tolerated alcohol protective group which preferably can be eliminated in the liver under physiological conditions, and n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0 or 1 to (2f+1) and x is 0 to 8, in particular 0 or 1.
4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which A is R3 and B is -XNR6R7, X is a single bond and Y is -SO2- or CO, or X is CO and Y is -SO2 or -CONR9, and R1, R2 and R3 are identical or different and are hydrogen or (C1-C3)-alkyl, (C1-C3)-alkoxy, hydroxyl, fluorine or chlorine, R6 is hydrogen, (C1-C12)-alkyl or an N protective group, such as acyl, (C1-C18)-alkanoyl, (C1-C18)-alkenoyl, unsubstituted or substituted benzoyl, a monovalent, divalent, trivalent or tetravalent physiologically suitable cation, in particular Na?, K?, Ca2?, Mg2?, Al3? or an ammonium ion, unsubstituted or monosubstituted to trisubstituted by (C1-C12)-alkyl, (C1-C12)-hydtroxyalkyl, (C1-C4)-alkoxy-(C1-C10)-alkyl, phenyl, benzyl or (C1-C12)-alkyl which may be monosubstituted to trisubstituted by hydroxyl or (C1-C8)-alkoxy, it being possible for an aryl radical to be substituted, or a cation of a basic amino acid derivative, R7 is a radical Y R8, in which Y has the above meaning and R8 is [C-U]r-D-W, in which C is a bond or a (C1-C6)-alkanediyl radical, U is a bond or hydrogen or -O-, r is 1, D is a bond or hydrogen or a straight-chain aliphatic (C1-C8)-alkanediyl radical and W is hydrogen, a (C8-C12)-aryl radical or a 5-membered or 6-membered heteroaryl radical, at least one of the variables C or D or W not being a bond and U being a heteroatom group only when C is not a bond and W, if it is not hydrogen, is preferably in turn substituted by up to 3 identical or different substituents selected from the series comprising hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, (C7-C16)-aralkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, (C1-C8)-alkoxy, (C1-C8)-alkoxy (C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, (C1-C8)-hydroxyalkyl, -O-[CH2-]xCfH(2f+1-g)Fg, (C1-C8)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C14)-aralkoxycarbonyl, (C3-C8)-cycloalkoxy-carbonyl, (C1-C8)-alkylcarbonyloxy,(C3-C8)-cycloalklcar-bonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-aralkylcarbonyloxy, cinnamoyloxy, carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-(C6-C16)-arylcarbamoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-Cl0)-alkyl-N-(C6-C16)-arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl, N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl,N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-Cl6)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C7-Cl6)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, amino, (C1-C8)-alkylamino, di-(C1-C8)-alkylamino, (C3-C8)-cycloalkylamino, N-(C6-Cl2)-arylamino, N-(C7-C11)-aralkylamino, N-(C1-C3)-alkyl-N-(C7-C11)-aralkylamino, (C1-C10)-alkanoylamino, (C3-C8)-cycloalkanoyl-amino, (C6-C12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C10)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cycloalkanoyl-N-(C1-C10)-alkylamino,(C6-C12)-aroyl-N-(C1-C10)-alkyamino, (C7-C11)-aralkanoyl-N-(C1-C10)-alkylamino, (C1-C12)-alkanoylamino-(C1-C6)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, (C6-C16)-aroylamino-(C1-C6)-alkyl, (C7-C16)-aralkanoyl-amino-(C1-C6)-alkyl, (C1-C8)-alkylmercapto, (C1-C8)-alkylsulfinyl, (C1-C8)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C12)-arylsulfinyl, (C6-C12)-arylsulfonyl, (C7-C14)-aralkylmercapto, (C7-C14)-aralkylsulfinyl, (C7-C14)-aralkylsulfonyl, it being possible for the radicals which contain an aryl radical in turn to be substituted on the aryl by 1, 2, 3, 4 or 5 identical or different substituents selected from the series comprising hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, (C1-C16)-aralkyl, (C3-C12)-alkenyl, (C3-C12)-alkynyl, (C1-C8)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy, -O-[CH2]xCfH(2f+1-g)Fg, (C1-C12)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-carbinyl, (C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, carbamoyl,N-(C1-C8)-alkylcarbamoyl,N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-(C6-C16)-arylcarbomoyl, N-(C7-C16)-aralkylcarbamoyl, N-(C1-C8)-alkyl-N-(C8-C16)-arylcarbamoyl,N-(C1-C8)-alkyl-N-(C7-C8)-aralkyl-carbamoyl, N-((C1-C6)-alkoxy-(C1-C6)-alkyl)carbamoyl, N-((C6-C6)-aryloxy-(C1-C6)-alkyl)carbamoyl,N-((C7-C16)-aralkyloxy-(C1-C6)-alkyl)carbamoyl, N-(C1-C8)-alkyl-N-((C1-C6)-alkoxy-(C1-C6)-alkyl)carbamoyl,N-(C1-C8)-alkyl-N-((C6-C16)-aryloxy-(C1-C6)-alkyl)carbamoyl, N-(C1-C8)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C6)-alkyl)carbamoyl, amino, (C1-C6)-alkylamino, di-(C1-C8)-alkylamino, (C3-C8)-cycloalkylamino, N-(C6-C12)-arylamino, N-(C7-C11)-aralkylamino,N-(C1-C8)-alkyl-(C7-C11)-aralkylamino, N-(C1-C3)-alkyl-(C6-C12)-arylamino, (C1-C8)-alkoxyamino, (C1-C8)-alkanoylamino, (C3-C8)-cycloalkanoyl-amino, (C6-C12)-aroylamino, (C7-C12)-aralkanoyl-amino, (C1-C8)-alkanoyl-N-(C1-C8)-alkylamino, (C3-C8)-cycloalkanoyl-N-(C1-C8)-alkylamino, (C6-C12)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C6)-alkylamino, (C1-C8)-alkanoylamino-C1-C4)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C4)-alkyl, (C6-C12)-aroylamino-(C1-C4)-alkyl, (C7-C12)-aralkanoyl-amino-(C1-C4)-alkyl, R9 is hydrogen, (C1-C6)-alkyl or phenyl, unsubstituted or monosubstituted, or R8 and R9 are bonded via (-CH2-)1, in which -NR8R9 may form a cyclic structure and i may be 3, 4,
5 or 6, and [C-U]r-D-W is not -SO2H, and R4 is methyl or -CH2OR5, in which R5 is hydrogen or the radical of a physiologically tolerated alcohol protective group which preferably can be eliminated in the liver under physiological conditions, and n is 0 or 1, f is 1 to 8, preferably 1 to 5, g is 0 or 1 to (2f+1) and x is 0 to 8, preferably 0 or 1 5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which A is R3 and B is -X NR6R7, X is a single bond and Y is -SO2- or X is -CO- and Y is -SO2- or -CONR9, R1, R2 and R3 are hydrogen, R6 is hydrogen, (C1-C12)-alkyl or an acyl group, such as (C1-C18)-alkanoyl, (C1-C18)-alkenoyl, unsub-stituted or substituted benzoyl or a monvalent, divalent or trivalent physiologically suitable cation, in particular Na?, K?, Mg2?, Ca2? or an ammonium ion, unsubstituted or monosubstituted to trisubstituted by (C1-C12)-alkyl, (C1-C12)-hydroxyalkyl, (C1-C4)-alkoxy-(C1-C8) alkyl, phenyl, benzyl or (C1-C12)-alkyl which may be monosubstituted to trisubstituted by hydroxyl or (C1-C4)-alkoxy, such as, for example, NH3?C(CH20H)3 or a cation of a basic amino acid derivative, R7 is a radical Y R8, with the exception of -SO2H, in which Y has the above meaning and R6 is [C-U]r-D-W, in which C is a bond or (C1-C4)-alkanediyl, U is a bond, hydrogen or -O-, r is 1, D is a bond, hydrogen or (C1-C4)-alkansdiyl, W is hydrogen or a phenyl radical, at least one of the variables C or D or W not being a bond and U being -O-only when C is not a bond and W is substituted by hydrogen, fluorine, chlorine, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C6-C12)-aryl, (C7-C16)-aralkyl, (C3-C12)-alkenyl, phenyl, (C1-C6)-alkoxy, phenoxy or -O-[CH2]xCfH(2f+1-g)Fg, carbamoyl, N-(C1-C10)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-phenylcarbamoyl, N-(C7-C11)-phenylalkylcarbamoyl, N-(C1-C8)-alkyl-N-(C6-C16)-phenylcarbamoyl,N-(C1-C8)-alkyl-N-(C7-C11)-phenylalkylcarbamoyl, N-((C1-C10)-alkoxy-(C1-C8)-alkyl)carbamoyl, N-(phenoxy-(C1-C8)-alkyl)carbamoyl, N-((C7-C16)-phenylalkyloxy-(C1-C8)-alkyl)carhamoyl, N-(C1-C8)-alkyl-N-((C1-C6)-alkoxy-(C1-C8)-alkyl)-carbamoyl, N-(C1-C8)-alkyl-N-((C6-C12)-phenoxy-(C1-C8)-alkyl)carbamoyl, N-(C1-C8)-alkyl-N-((C6-C12)-phenoxy-(C1-C8)-alkyl)-carbamoyl, (C1-C8)-alkanoylamino, (C3-C8) -cycloalkanoyl-amino, (C6-C12)-phenylamino, (C7-C11)-phenyl-alkanoylamino, (C1-C8)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cycloalkanoyl-N-(C1-C6)-alkylamino, benzoyl-N-(C1-C10)-alkylamino, (C7-C11)-phenylalkanoyl-N-(C1-C6)-alkylamino, (C1-C10)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C8)-alkyl, phenylamino-(C1-C8)-alkyl, (C7-C11), phenylalkanoylamino-(C1-C8)-alkyl, it being possible for the radicals which con-tain an aryl radical in turn to be substituted on the aryl by 1, 2, 3, 4 or 5 identical or different substituents selected from the series comprising hydroxyl, carboxyl, (C1-C4)-alkoxy, phenoxy, benzyloxy, fluorine, chlorine, tri-fluoromethyl, -O-[CH2]xCfH(2f+1-g)Fg (C1-C9)-alkoxycarbonyl, phenoxycarbonyl, (C7-C11) phenylalkoxycarbonyl, (C3-C8)-cyclo-alkoxycarbonyl, (C1-C12)-alkylcarbonyloxy, (C3-C8 )-cycloalkyl-carbonyloxy, benzoyloxy, (C7-C11)-phenalkyl-carbonyloxy, (C1-C8)-alkoxycarbonyloxy, (C6-C12)-phenoxy-carbonyloxy, (C7-C11) phenalkyloxycarbonyloxy, (C3-C8)-cycloalkoxycarbonyloxy, carbamoyl,N-(C1-C6)-alkylcarbamoyl,N,N-di-(C1-C6) - a l k y l c a r b a m o y l , N-(C3-C8)-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-(C7-C11)-phenalkylcarbamoyl, hydroxy-(C1-C4)-alkylcarbamoyl,acyloxy-(C1-C4)-alkylcarbamoyl, carbamoyloxy, N-(C1-C6)-alkylcarbamoyloxy, N,N-di-(C1-C6)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkylcarbamoyl, R9 is hydrogen, (C1-C4)-alkyl or phenyl, R4 is -CH2O R5, in which R5 is hydrogen, (C1-C12)-alkyl, unsubstituted or substituted benzyl, (C1-C18)-alkanoyl, (C1-C18)-alkenoyl or unsubstituted or substituted benzoyl and n is 0, f is 1 to 5, g is 0 or 1 to (2f+1) and x is 0 or 1.
6. A compound of the formula I as claimed in one or more of claims 1 to 5, in which A is R3 and B is -X NR6R7, X is -CO-, R1, R2 and R3 are hydrogen, R6 is hydrogen, (C1-C6)-alkyl, (C1-C18)-alkanoyl, (C1-C18)-alkenoyl, benzoyl or 2 monovalent or divalent physiologically suitable cation, in particular Na?, K?, Mg2? or Ca2? or an ammonium ion, unsubstituted or monosubstituted to trisubstituted by (C1-C8)-alkyl, (C1-C8)-hydroxyalkyl, (C1-C4)-alkoxy-(C1-C8)-alkyl, phenyl, benzyl or (C1-C8)-alkyl which may be monosubstituted to trisubstituted by hydxoxyl or (C1-C4)-alkoxy, R7 is a radical Y R8, with the exception of -SO2H, in which Y is -SO2- and R8 is [C-U]r-D-W- in which C is a bond or linear (C1-C4)-alkanediyl, U is a bond, hydrogen or -O-, r is 1, D is a bond, hydrogen or linear (C1-C4)-alkanediyl, W is hydrogen or a phenyl radical, at least one of the variables C or D or W not being a bond and U being -O-only when C is not a bond and W being substituted by hydrogen, fluorine, chlorine, (C1-C6)-alkyl, (C3-C6) cycloalkyl, (C7-C16)-phenylalkyl, phenyl, (C1-C6)-alkoxy, phenoxy or -O-[CH2]xCfH(2f+l-g)Fg, carbamoyl, N-(C1-C10)-alkylcarbamoyl, N,N-di-(C1-C8)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-phenylcarbamoyl, N-(C7-C11)-phenylalkylcarbamoyl, N-(C1-C8)-alkyl-N-(C6-C16)-phenylcarbamoyl, N-(C1-C8)-alkyl-N-(C7-C11)-phenylalkylcarbamoyl,N-(C1-C3)-alkoxy-(C2-C4)-alkyl)carbamoyl, N-(phenoxy-(C1-C8)-alkyl)carbamoyl, N-((C7-C16)-phenylalkyloxy-(C1-C4)-alkyl)-carbamoyl, N-(C1-C6)-alkyl-N-((C1-C3)-alkoxy-(C1-C4)-alkyl)-carbamoyl, N-(C1-C6)-alkyl-N-((C6-C12)-phenoxy-(C1-C4) alkyl)carbamoyl, N-(C1-C6)-alkyl-N-((C7-C16)-phenylalkyloxy-(C1-C4)-alkyl)carbamoyl, (C1-C8)-alkanoylamino, (C3-C8)-cycloalkanoyl-amino, (C6-C12)-phenylamino, (C7-C11)-phenyl-alkanoylamino, (C1-C8)-alkanoyl-N-(C1-C6) alkylamino, (C3-C8)-cycloalkanoyl-N-(C1-C6)-alkylamino, benzoyl-N-(C1-C6)-alkylamino, (C7-C11)-phenylalkanoyl-N-(C1-C6)-alkylamino, (C1-C10)-alkanoylamino (C1-C2)-alkyl, (C3-C8)-cycloalkanoylamino-(C1-C2)-alkyl, benzoylamino-(C1-C2)-alkyl, (C7-C11)-phenylalkanoylamino-(C1-C2)-alkyl, it being possible for the radicals which con-tain an aryl radical is turn to be substituted on the aryl by 1, 2, 3; 4 or 5 identical or different substituents selected from the series comprising hydroxyl, carboxyl, (C1-C6)-alkoxy, phenoxy, benzyloxy, fluorine, chlorine, trifluoromethyl, (C1-C8)-alkoxycarbonyl, phenoxycarbonyl, (C7-11) phenylalkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C1-C12) alkylcarbonyloxy, (C3-C8)-cycloalkyl-carbonyloxy, benzoyloxy, (C7-C11)-phenalkyl-carbonyloxy, carbamoyl, N-(C1-C6)-alkylcarbamoyl,N,N-di-(C1-C6)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-carbamoyl, N-phenylcarbamoyl, N-(C7-C11)-phenalkylcarbamoyl, hydroxy-(C1-C4)-alkylcarbamoyl, acyloxy (C1-C4)-alkylcarbamoyl, carbamoyloxy, N-(C1-C6)-alkylcarbamoyloxy, N,N-di-(C1-C6)-alkylcarbamoyloxy, N-C3-C8)-cycloalkylcarbamoyl, R4 is -CH2O R5, in which R5 is hydrogen, (C1-C12) alkyl, unsubstituted or substituted benzyl, (C1-C18)-alkanoyl, (C1-C18)-alkenoyl, or unsubstituted or substituted benzoyl and n is 0, f is 1 to 5, g is 0 or 1 to (2f+1) and x is 0 or 1.
7. A compound as claimed in any of claims 1 to 6, which comprises a physiologically suitable salt, salt formation being effected via R5.
8. A compound as claimed in any of claims 1 to 7 against fibrotic diseases.
9. A compound as claimed in any of claims 1 to 7 for use as a fibrosuppressant.
10. A medicament comprising at least one compound of the formula I as claimed in any of claims 1 to 7 and if appropriate a tolerated pharmaceutical excipient.
11. The use of a compound of the formula I 6 claimed in any of claims 1 to 7 for the treatment of disturbances in the metabolism of collagen and collagen-like substances.
12. The use of a compound of the formula I as claimed in any of claims 1 to 7 for the treatment of fibrotic diseases.
13. The use of a compound of the formula I as claimed in any of claims 1 to 7 for the treatment of fibrosis of the liver.
14. A process for the prep ration of medicaments for the treatment of fibrotic diseases, wherein the medicament comprises a compound of the formula I as claimed in any of claims 1 to 7.
15. A process for the preparation of compounds as claimed in one or more of claims 1 to 7, in which, according to formula I, X is a single bond and R1 to R9 have the meaning as claimed in any of claims 1 to 6, wherein a compound of the formula I

I

in which A' is R3 and B' is NHR6 or A' is NHR6 and B' is R3, is reacted with a sulfonic acid derivative of the formula 2 in which Z is a leaving group to give a compound of the formula Ia Ia in which A is R3 and B is -NHR6R7 or A is -NHR6R7 and B is R3, and, if required, this compound is oxidized to a compound of the formula Ia' Ia' or the compound of the formula Ia is monohalogenated at the methyl group and then reacted with HOR5 to give a compound of the formula Ib Ib which, if required, is then oxidized to its pyridine N-oxide of the formula Ib' Ib' or the compound of the formula Ia' is reacted with an anhydride in the acidic pH range to give a compound of the formula Ib.
16. A process for the preparation of compounds as claimed in one or more of claims 1 to 7, in which, according to formula I, X is -CO- and R1 to R7 have the meanings as claimed in any of claims 1 to 3, wherein a compound of the formula 4 4 in which A" is R3 and B" is -CO2H or A" is -CO2H and B" is R3, is reacted with a compound of formula 5 to give a compound Ic Ic in which A is R3 and B is -CO-NR6R7 or A is -CO-NHR6R7 and B is R3, if required, this compound is oxidized to its pyridine N-oxide of the formula Ic' Ic'
17. A process for the preparation of compounds as claimed in one or more of claims 1 to 7, in which, according to formula I, X is -CO and Y is SO2 and to R9 have the meaning as claimed in any of claims 1 to 6, wherein a compound of the formula 6 6 in which A" is R3 and B" is -CO2R or A" is -CO2R and B" is R3, R being hydrogen or (C1-C5)-alkyl, is reacted with a halogenating agent 7 for the methyl group, the halogenated compound is reacted with an amine of the formula H2NR5 and when with a sulfonic acid derivative of the formula 2, in which Z is a leaving group, and then with MOR5 to give a compound of the formula Id Id in which A''' is R3 and B''' i3 -CONHR6R7 or A''' is -CONHR6R7 and B''' is R3, and, if required, this compound is oxidized to a compound of the formula Id' Id' or, after the halogenation, the compound of the formula 6 is reacted first with MOR5, then with an amine of the formulae R6NH2 or HNR6R7 and then with a compound of the formula 2 to give a compound of the formula Id Id and, if required, the latter is then oxidized to its pyridine N-oxide of the formula Ib' Ib'
CA002095206A 1992-04-30 1993-04-29 4- or 5-(sulf)imido- and -(sulfon)amidopyridines and their pyridine n-oxides, processes for their preparation, and their use as medicaments Abandoned CA2095206A1 (en)

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