WO2008113760A2 - Arylsulphonyglycine derivatives as suppressors of the interaction of glycogen phosphorylase a with the gl subunit of glycogen-associated protein phosphatase 1 (ppl) for the treatment of metabolic disorders, particulary diabetes - Google Patents

Arylsulphonyglycine derivatives as suppressors of the interaction of glycogen phosphorylase a with the gl subunit of glycogen-associated protein phosphatase 1 (ppl) for the treatment of metabolic disorders, particulary diabetes Download PDF

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WO2008113760A2
WO2008113760A2 PCT/EP2008/053087 EP2008053087W WO2008113760A2 WO 2008113760 A2 WO2008113760 A2 WO 2008113760A2 EP 2008053087 W EP2008053087 W EP 2008053087W WO 2008113760 A2 WO2008113760 A2 WO 2008113760A2
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carbonyl
alkyl
amino
aminocarbonyl
dichloro
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PCT/EP2008/053087
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French (fr)
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WO2008113760A3 (en
Inventor
Holger Wagner
Elke Langkopf
Matthias Eckhardt
Rüdiger STREICHER
Corinna Schoelch
Annette Schuler-Metz
Alexander Pautsch
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Boehringer Ingelheim International Gmbh
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Priority to DE602008002567T priority Critical patent/DE602008002567D1/en
Priority to CA002681124A priority patent/CA2681124A1/en
Priority to AT08735421T priority patent/ATE481382T1/en
Priority to US12/530,507 priority patent/US8232312B2/en
Priority to EP08735421A priority patent/EP2125718B1/en
Priority to JP2009554009A priority patent/JP2010521515A/en
Publication of WO2008113760A2 publication Critical patent/WO2008113760A2/en
Publication of WO2008113760A3 publication Critical patent/WO2008113760A3/en

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Definitions

  • New substituted arylsulphonylglycines the preparation thereof and the use thereof as pharmaceutical compositions
  • the present invention relates to substituted arylsulphonylglycines of general formula I
  • This invention further relates to pharmaceutical compositions containing a compound of formula I according to the invention as well as the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment of metabolic disorders, particularly type 1 or type 2 diabetes mellitus.
  • the invention also relates to processes for preparing a pharmaceutical composition as well as a compound according to the invention.
  • Compounds of formula I are suitable for preventing the inhibiting effect of glycogen phosphorylase on the activity of glycogen synthase by stopping the interaction of glycogen phosphorylase a with the G ⁇ _ subunit of glycogen- associated protein phosphatase 1 (PP1 ). Compounds with these properties stimulate glycogen synthesis and are proposed for the treatment of metabolic disorders, particularly diabetes (P. Cohen, Nature Reviews Molecular Cell Biology 2006, 7, 867-874). Aim of the invention
  • the aim of the present invention is to provide new arylsulphonylglycines that suppress the interaction of glycogen phosphorylase a with the G ⁇ _ subunit of glycogen-associated protein phosphatase 1 (PP1 ).
  • a further aim of the present invention is to provide new pharmaceutical compositions that are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.
  • Another aim of this invention is to provide a process for preparing the compounds according to the invention.
  • the present invention relates to new substituted arylsulphonylglycines of general formula
  • R denotes a group of formula
  • R 1 denotes H, Ci-6-alkyl or a group of formula
  • Ci-6-alkyl group mentioned for R 1 hereinbefore may be substituted by Ci -6 -alkyl-carbonyloxy, Ci -6 -alkoxy- carbonyloxy, Ci-6-alkoxy, hydroxy, amino, Ci-3-alkyl-amino, di- (Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci- 3 -alkyl)-piperazin-1-yl, aminocarbonyl, C 1 .
  • R 2 and R 3 independently of one another denote halogen, C 1.3- alkyl, C2 -4 -alkynyl, Ci-3-perfluoroalkyl, Ci- 3 -perfluoroalkoxy, C 1 . 3 - alkoxy, cyano, nitro or hydroxy, and
  • A denotes CH or N
  • the heterocyclic group denotes a group of formula
  • heterocycles of formulae (Ia), (Ib), (Ic), (Ie), (If), (Ig), (Ii) and (In) may each optionally be substituted at the carbon atoms of the 5-ring by one or two groups selected from among Ci- 3 -alkyl, amino-Ci -3 -alkyl, hydroxy-Ci -3 -alkyl, cyano, Ci -3 - perfluoroalkyl, C 3-6 -cycloalkyl, C 2-4 -alkynyl, C 2-4 -alkenyl, Ci -3 -alkyl- carbonyl, Ci-s-perfluoroalkyl-carbonyl, carboxyl, Ci- 3 -alkyloxy-carbonyl, carboxy-Ci-3-alkyl, aminocarbonyl, Ci-3-alkyl-aminocarbonyl or di-(Ci -3 - alkyl)-aminocarbonyl, wherein the
  • heterocyclic group of formula (Ib) may optionally be substituted at the nitrogen atom of the 5-ring by methyl or hydroxycarbonylmethyl, and wherein
  • Ci- 6 -alkyl-carbonyl carboxyl, Ci- 6 -alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci- 6 -alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
  • Ci -6 -alkyl-aminocarbonyl di-(Ci -6 -alkyl)-aminocarbonyl, Cs-e-cycloalkyl-aminocarbonyl, N-(C 3 -6-cycloalkyl)-N-(Ci-6-alkyl)-amino- carbonyl, aryl-amino-carbonyl, N-oxy-pyridylamino-carbonyl,
  • aminocarbonyl-carbonyl Ci-s-alkylanninocarbonyl-carbonyl, di-(Ci -3 - alkyl)-aminocarbonyl-carbonyl, pyrrolidin-i -ylcarbonyl-carbonyl, piperidin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl, piperazin-1 -ylcarbonyl-carbonyl, 4-methyl-piperazin-1 -ylcarbonyl- carbonyl,
  • Ci- 6 -alkyl-aminocarbonyl, di-(Ci- 6 -alkyl)- aminocarbonyl and N-(C3-6-cycloalkyl)-N-(Ci-6-alkyl)-amino- carbonyl group mentioned above in the definition of R 4 may each be substituted in the alkyl moiety by aryl, Ci-3-alkyl-amino, di-(Ci- 3-alkyl)-amino, Cs-e-cycloalkyl-amino, N-(C 3 -6-cycloalkyl)-N-(Ci-6- alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1 -yl, 4-methyl-piperazin-1 -yl or Ci -3 - alkylaminocarbonyl, and
  • aryl group mentioned above in the definition of R 4 is a 6-membered aromatic system that may contain 0 to 3 nitrogen atoms and may be substituted by nitro.
  • the invention also relates to the tautomers, stereoisomers, mixtures and salts, particularly the physiologically acceptable salts, of the compounds according to the invention.
  • the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, in particular they suppress the interaction of glycogen phosphorylase a with the G ⁇ _-subunit of glycogen-associated protein phosphatase 1 (PP1 ).
  • this invention also relates to the use of the compounds according to the invention, including the physiologically acceptable salts, as pharmaceutical compositions.
  • prodrugs compounds that are not active per se but are converted into the corresponding active compound in vivo, cleaving the prodrug group.
  • This invention further relates to pharmaceutical compositions containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
  • a further object of this invention is the use of at least one compound according to the invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition that is suitable for the treatment or prevention of diseases or conditions that can be influenced by suppressing the interaction of glycogen phosphorylase a with the d-subunit of glycogen-associated protein phosphatase 1 (PP1 ).
  • the invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders, for example type I or Il diabetes mellitus.
  • the invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition for suppressing the interaction of glycogen phosphorylase a with the G ⁇ _-subunit of glycogen- associated protein phosphatase 1 (PP1 ).
  • a further object of this invention is a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
  • the present invention also relates to a process for preparing the compounds of general formula I according to the invention.
  • R denotes a group of the above-mentioned formula wherein
  • R 1 denotes H, Ci-6-alkyl or a group of formula
  • Ci-6-alkyl group mentioned for R 1 hereinbefore may be substituted by Ci-6-alkyl-carbonyloxy, Ci-6-alkoxy- carbonyloxy, Ci -6 -alkoxy, hydroxy, amino, Ci -3 -alkyl-amino, di- (Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci -3 -alkyl)-piperazin-1-yl, aminocarbonyl, Ci -3 - alkyl-aminocarbonyl, di-(Ci- 3 -alkyl)-aminocarbonyl, pyrrolidin-1- yl-carbonyl, pipehdin-1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl or 4-(Ci- 3 -alkyl)--
  • R 2 and R 3 independently of one another denote halogen, Ci-3-alkyl, C 2 - 4-alkynyl, Ci -3 -perfluoroalkyl, Ci -2 -alkoxy or cyano and
  • heterocycles of formulae (Ia), (Ib), (Ic), (Ie), (If), (Ig), (Ii) and (In) may each optionally be substituted at the carbon atoms of the 5-ring by one or two groups selected from among Ci- 3 -alkyl, amino-Ci -3 -alkyl, hydroxy-Ci -3 -alkyl, cyano, C 3-6 -cycloalkyl, Ci- 3 -alkyl-carbonyl, Ci- 3 -perfluoroalkyl-carbonyl, carboxyl, Ci -2 -alkyloxy- carbonyl, carboxy-Ci -2 -alkyl, aminocarbonyl, Ci- 3 -alkyl-aminocarbonyl or di-(Ci- 3 -alkyl)-aminocarbonyl, wherein the groups may be identical or different and each carbon atom may carry only one group, and
  • heterocyclic group of formula (Ib) may optionally be substituted at the nitrogen atom of the 5-ring by methyl or hydroxycarbonylmethyl, and wherein
  • Ci -4 -alkyl-carbonyl carboxyl
  • Ci -4 -alkoxy-carbonyl phenylcarbonyl
  • phenyl-Ci -4 -alkyl-carbonyl 5-chloro-1 H-indol-2-yl-carbonyl
  • Ci -4 -alkyl-aminocarbonyl di-(Ci -4 -alkyl)-aminocarbonyl, Cs- ⁇ -cycloalkyl-aminocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci -4 -alkyl)-annino- carbonyl, [N.N-dKCi ⁇ -alkylJ-aminol-Ci-s-alkyl-amino-carbonyl, 1 - (methylanninocarbonyl)-ethyl-annino-carbonyl, aryl-amino-carbonyl, aryl- Ci- 3 -alkyl-annino-carbonyl, N-oxy-pyridylamino-carbonyl,
  • aminocarbonyl-carbonyl Ci ⁇ -alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl, pipehdin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl,
  • R 4 is a 6-membered aromatic system that may contain 0 to 2 nitrogen atoms and may be substituted by nitro.
  • R denotes a group of the above-mentioned formula wherein
  • R 1 denotes H, Ci -4 -alkyl or a group of formula
  • Ci -4 -alkyl group mentioned for R 1 hereinbefore may be substituted by Ci -4 -alkoxy, hydroxy, di-(Ci -3 -alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1-yl or 4- (methyl)-piperazin-i -yl,
  • R 2 and R 3 independently of one another denote chlorine, bromine, Ci-2- alkoxy, C 2 - 3 -alkynyl or Ci- 2 -alkyl and
  • A denotes CH or N
  • heterocycles of formulae (Ia1 ), (Ia2) and (Ie1 ) may each optionally be substituted at the carbon atoms of the 5 ring by a group selected from among Ci- 2 -alkyl, methylcarbonyl, trifluoromethylcarbonyl, carboxyl, methoxy-carbonyl, aminocarbonyl, methyl-aminocarbonyl, dimethyl-aminocarbonyl, aminomethyl or hydroxymethyl, and
  • heterocyclic group of formula (Ib1 ) may optionally be substituted at the nitrogen atom of the 5 ring by methyl or hydroxycarbonylmethyl, and wherein R 4 denotes H, cyano, Ci -4 -alkyl, phenyl-Ci -4 -alkyl, phenylsulphonyl-Ci -4 - alkyl,
  • Ci -4 -alkyl-carbonyl carboxyl
  • Ci -4 -alkoxy-carbonyl phenylcarbonyl
  • phenyl-Ci -4 -alkyl-carbonyl 5-chloro-1 H-indol-2-yl-carbonyl
  • Ci -4 -alkyl-aminocarbonyl di-(Ci -4 -alkyl)-aminocarbonyl, C3-6-cycloalkyl-anninocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci -4 -alkyl)-annino- carbonyl, N.N-dKCi-s-alkylJ-amino-Ci-s-alkyl-amino-carbonyl, 1 - (methylanninocarbonyl)-ethyl-annino-carbonyl, phenylamino-carbonyl, (nitrophenyl)-amino-carbonyl, phenyl-Ci- 2 -alkyl-annino-carbonyl, pyridinylamino-carbonyl, pyrazinylamino-carbonyl, N-oxy-pyridylamino- carbonyl,
  • aminocarbonyl-carbonyl Ci ⁇ -alkylaminocarbonyl-carbonyl, di-(Ci- 2 - alkylj-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl, pipehdin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl,
  • R denotes a group of the above-mentioned formula wherein
  • R 1 denotes H or a Ci -3 -alkyl group optionally substituted by a di-(Ci-
  • R 2 and R 3 independently of one another represent chlorine, ethynyl, methoxy, methyl or ethyl and denotes CH or N, and the heterocyclic group denotes a group of formula
  • heterocycles of formulae (Ia1 ) and (Ie1 ) may each optionally be substituted at the carbon atoms of the 5-ring by a group selected from among thfluoromethylcarbonyl, carboxyl, aminocarbonyl or hydroxy methyl, and
  • heterocyclic group of formula (Ib1 ) may optionally be substituted at the nitrogen atom of the 5-ring by methyl or hydroxycarbonylmethyl, and wherein
  • aminocarbonyl Ci- 3 -alkyl-aminocarbonyl, di-(Ci- 3 -alkyl)-aminocarbonyl, cyclopropyl-aminocarbonyl, N-(cyclopropyl)-N-(Ci-2-alkyl)-amino- carbonyl, (N,N-dimethyl-amino)-ethyl-amino-carbonyl, 1- (methylaminocarbonyl)-ethyl-amino-carbonyl, phenylamino-carbonyl, (nitrophenyl)-amino-carbonyl, phenyl-Ci -3 -alkyl-carbonyl, phenyl-Ci -2 - alkyl-amino-carbonyl, pyhdinylamino-carbonyl, pyrazinylamino- carbonyl, N-oxy-pyridin-3-ylamino-carbonyl,
  • azetidin-1-yl-carbonyl pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylaminocarbonyl)-pyrrolidin-1 -yl-carbonyl, pipehdin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl,
  • aminocarbonyl-carbonyl Ci ⁇ -alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-i -ylcarbonyl-carbonyl,
  • R denotes a group of the above-mentioned formula wherein
  • R 1 denotes H, methyl, ethyl or 2-dimethylamino-ethyl
  • R ⁇ 2 a _ ,n_d _j n R3 independently of one another denote chlorine, ethynyl, methoxy, methyl or ethyl and
  • A denotes CH or N
  • heterocyclic group of formula (Ia1 ) may optionally be substituted by trifluoromethylcarbonyl at the carbon atom of the 5-ring adjacent to the phenyl ring, and
  • heterocyclic group of formula (Ie1 ) may optionally be substituted by carboxyl, amino-carbonyl or hydroxymethyl at the carbon atom of the 5-ring adjacent to the phenyl ring, and
  • heterocyclic group of formula (Ib1 ) may optionally be substituted by methyl or hydroxycarbonylmethyl at the nitrogen atom of the 5 ring, and wherein
  • aminocarbonyl methyl-aminocarbonyl, dimethyl-aminocarbonyl, cyclopropyl-aminocarbonyl, N-(cyclopropyl)-N-(methyl)-anninocarbonyl, (N,N-dimethyl-annino)-ethyl-annino-carbonyl, i -(methylanninocarbonyl)- ethyl-amino-carbonyl, phenylamino-carbonyl, benzylamino-carbonyl, 3- nitro-phenylamino-carbonyl, 2-nitro-phenylamino-carbonyl, pyridin-3- ylamino-carbonyl, pyridin-4-ylannino-carbonyl, pyrazinylamino-carbonyl, N-oxy-pyridin-3-ylamino-carbonyl,
  • azetidin-1-yl-carbonyl pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylanninocarbonyl)-pyrrolidin-1 -yl-carbonyl, piperidin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
  • aminocarbonyl-carbonyl methylaminocarbonyl-carbonyl, dimethyl- aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl,
  • halogen denotes an atom selected from among F, Cl, Br and I, particularly F, Cl and Br.
  • Ci -n -alkyl wherein n may have a value as defined hereinbefore or hereinafter, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms.
  • examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo- pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • C2 -n -alkynyl wherein n has a value as defined hereinbefore, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C ⁇ C triple bond.
  • groups include ethynyl, 1 -propynyl, 2-propynyl, iso-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 2-methyl-1 -propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc..
  • groups include ethenyl, 1-propenyl, 2- propenyl, iso-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 -propenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc..
  • Ci -n -alkoxy or Ci -n -alkyloxy denotes a Ci -n -alkyl-O group, wherein
  • Ci-n-alkyl is as hereinbefore defined.
  • examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso- hexoxy etc.
  • groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n- butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n- pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n- hexylcarbonyl, iso-hexylcarbonyl, etc..
  • C3 -n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.
  • the term C 3-7 -cycloalkyl includes saturated monocyclic groups.
  • Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc..
  • Ci -n -alkyl-amino and di-(Ci -n -alkyl)-amino denote a Ci -n -alkyl-NH- or a di-(Ci -n -alkyl)-N group, respectively, wherein Ci -n -alkyl is as hereinbefore defined.
  • Cs-n-cycloalkyl-amino denotes a Cs-n-cycloalkyl-NH group, wherein £.
  • C3- n -cycloalkyl is as hereinbefore defined.
  • N-(C3-n-cycloalkyl)-N-(Ci-n-alkyl)-amino denotes an N-(C3 -n - cycloalkyl)-N-(Ci- n -alkyl)-N group, wherein C 3-n -cycloalkyl and Ci -n -alkyl are as hereinbefore defined.
  • Ci -n -perfluoroalkyl denotes a F-(CF2) n group.
  • groups include trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-iso-propyl etc., but preferably trifluoromethyl, pentafluoroethyl.
  • Ci -n -perfluoroalkoxy denotes a F-(CF2) n -O group.
  • examples of such groups include trifluoromethoxy, pentafluoroethoxy, heptafluoro-n-propoxy, heptafluoro-iso-propoxy etc., but preferably trifluoromethoxy, pentafluoroethoxy.
  • the compounds according to the invention may be obtained using methods of synthesis that are known in principle. Preferably the compounds are obtained by methods of preparation according to the invention that are described more fully hereinafter.
  • Diagram 1 Process a
  • compounds of general formula III are obtained by reacting a compound of general formula Il with a reducing agent.
  • the starting compounds of general formula Il or III are either commercially obtainable or may be prepared by synthesising the heterocyclic group and/or nitrogenation (Houben-Weyl, Methoden der organischen Chemie, Volume X/1 , 463-890) using methods known per se starting from commercially obtainable compounds.
  • a suitable reducing agent is for example hydrogen in the presence of a catalyst, such as palladium on charcoal, palladium hydroxide on charcoal or Raney nickel, while palladium on charcoal is particularly suitable.
  • the hydrogenation is carried out in a suitable solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane or ethyl acetate, but preferably methanol, ethanol or tetrahydrofuran, at a pressure between 0.5 and 7 bar, but preferably at a pressure between 0.5 and 3 bar, and at a temperature between 0 0 C and 60 0 C, but preferably at a temperature between 15°C and 40 0 C.
  • a suitable solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane or ethyl acetate, but preferably methanol, ethanol or tetrahydrofuran, at a pressure between 0.5 and 7 bar
  • tin dichloride hydrate in lower alcoholic solvents such as methanol or ethanol at a temperature between ambient temperature and 80 0 C.
  • titanium trichloride may be used as reducing agent.
  • Suitable solvents are mixtures of acetone and water. The reaction is carried out between 0°C and 60°C, but preferably between 15°C and 40 0 C and in the presence of ammonium acetate.
  • the sulphonylation is carried out with aromatic sulphonyl chlorides in the presence of a base, such as thethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine, or 4-dimethylamino-pyhdine, but preferably pyridine.
  • a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine, or 4-dimethylamino-pyhdine, but preferably pyridine.
  • the reaction may be carried out in suitable solvents, such as diethyl ether, tetrahydrofuran, toluene, pyridine, dichloromethane, or chloroform, but preferably dichloromethane.
  • the temperature may be between 0°C and 60 0 C, but preferably between 15°C and 40°C.
  • Suitable alkylating agents are acetic acid derivatives that contain a leaving group such as chlorine, bromine, iodine, p-tolylsulphonate, methylsulphonate, or trifluoromethylsulphonate in the 2-position.
  • the alkylation is carried out in a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, and at a temperature between 0 0 C and 100 0 C, but preferably between 15°C and 50°C.
  • a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate
  • the cleaving of the tert.-butyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • R, R , R and A are as hereinbefore defined.
  • Acyl groups may be introduced by reacting a compound of general formula V with an acylating reagent such as for example an acid chloride or acid anhydride.
  • the reaction may be carried out in the presence of a base such as sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, caesium carbonate, thethylamine or N,N-diisopropyl-N-ethyl-amine as well as in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide at temperatures between -30 0 C and 200 0 C, but preferably between 0°C and 160 0 C.
  • the reaction may be carried out by acylation with an acid.
  • the acid is activated in situ by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'- tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)- N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzotriazol-1- yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), (benzotriazol
  • Sulphonyl groups may be introduced by reacting with a sulphonyl chloride in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl- amine, but preferably potassium carbonate, in a solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylformamide at temperatures between -30°C and 100°C, but preferably between 0 0 C and 60 0 C.
  • a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl- amine, but preferably potassium carbonate
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylformamide at temperatures between -30°C and 100°
  • Alkoxycarbonyl groups may be introduced by reacting with an alkyl chloroformate in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N 1 N- diisopropyl-N-ethyl-amine, but preferably potassium carbonate, in a solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylfornnannide at temperatures between -30 0 C and 100 0 C, but preferably between 0°C and 60 0 C.
  • a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N 1 N- diisopropyl-N-ethyl-amine, but preferably potassium carbonate
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylfornnannide at temperatures between -30 0 C
  • alkoxycarbonyl groups are obtained by reacting a compound of general formula V with phosgene in a solvent such as dichloromethane, tetrahydrofuran or dioxane in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably thethylamine or N,N-diisopropyl-N-ethyl-amine, and subsequently treating with an alcohol at temperatures between -20°C and 100°C, but preferably between 0 0 C and 50 0 C.
  • a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably thethylamine or N,N-diisopropyl-N-ethyl-amine
  • Aminocarbonyl groups may be introduced by reacting with an isocyanate, optionally in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N- ethyl-amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide at temperatures between -30°C and 150°C, but preferably between 0 0 C and 100 0 C.
  • a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N- ethyl-amine
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide
  • aminocarbonyl groups are obtained by reacting a compound of general formula V with phosgene in a solvent such as dichloromethane, tetrahydrofuran or dioxane in the presence of a base such as for example sodium hydride, sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably sodium hydride, triethylamine or N,N-diisopropyl-N-ethyl-amine and subsequently treating with an amine at temperatures between -20°C and 100°C, but preferably between 0 0 C and 50 0 C.
  • a base such as for example sodium hydride, sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably sodium hydride, triethylamine or N,N-
  • the compounds of general formula V are reacted with a base such as for example sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyldisilazide and an alkylating agent.
  • a base such as for example sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyldisilazide and an alkylating agent.
  • the reaction is carried out in a solvent such as for example tetrahydrofuran, 1 ,4-dioxane, dimethylformamide, dimethylacetamide, N- methyl pyrrol idone or acetonitrile at temperatures between -40°C and 120°C, but preferably between -10 0 C and 100
  • the transformation may be carried out by first converting the acid into an acid chloride.
  • a compound of general formula VII is combined with thionyl chloride, optionally in the presence of a solvent such as toluene or benzene heating it to temperatures between 50 0 C and 150 0 C, but preferably between 80°C and 120 0 C.
  • a solvent such as toluene or benzene heating it to temperatures between 50 0 C and 150 0 C, but preferably between 80°C and 120 0 C.
  • the acid chloride thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but o
  • tetrahydrofuran at temperatures between -30 0 C and 150 0 C, but preferably between 0°C and 80 0 C and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine.
  • a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine.
  • the acid may be converted into an acid imidazolide.
  • a compound of general formula VII is reacted with carbonyldiimidazole in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 20°C and 100°C.
  • the acid imidazolide thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran, at temperatures between -30 0 C and 150°C, but preferably between 0°C and 80 0 C, and optionally in the presence of a base such as thethylamine, N 1 N- diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine.
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran, at temperatures between -30 0 C and 150°C, but preferably between 0°C and 80 0 C, and optionally in the presence of a base such as thethylamine, N 1 N- diisopropyl-
  • the acid is activated by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'- tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)- N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzotriazol-1- yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), (benzotriazol-i
  • Compounds of general formula VIII wherein R 4 denotes alkoxy-carbonyl may also be prepared by alkylating carboxylic acids of general formula VII. For this, the carboxylic acid is reacted with an alkylating agent.
  • Suitable alkylating agents are alkyl derivatives that contain a leaving group such as chlorine, bromine, iodine, p-tolylsulphonate, methylsulphonate or thfluoromethylsulphonate.
  • the alkylation is carried out in a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, at a temperature between 0 0 C and 100 0 C, but preferably between 15°C and 50 0 C.
  • a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, at a temperature between 0 0 C and 100 0 C, but preferably between 15°C and 50 0 C.
  • the reaction may be carried out without a solvent or with a solvent such as for example dichloromethane, 1 ,2-dichloroethane, toluene, tetrahydrofuran, 1 ,4- dioxane, dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone and optionally in the presence of a catalyst such as for example aluminium trichloride or boron trifluohde etherate and at temperatures between -10 0 C and 180°C, but preferably between 0°C and 120 0 C.
  • a catalyst such as for example aluminium trichloride or boron trifluohde etherate
  • carboxylic acid obtained as described hereinbefore may be combined with thionyl chloride, optionally in the presence of a solvent such as toluene or benzene, and heated to temperatures between 50°C and 150 0 C, but preferably between 80°C and 120°C.
  • a solvent such as toluene or benzene
  • the acid chloride thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran at temperatures between - 30 0 C and 150°C, but preferably between 0°C and 80 0 C and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyhdine.
  • the acid may be converted into an acid imidazolide.
  • the acid imidazolide thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformannide, but preferably tetrahydrofuran, at temperatures between -30 0 C and 150 0 C, but preferably between 0°C and 80 0 C, and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethylamine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine.
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformannide, but preferably tetrahydrofuran
  • the acid is activated by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium- hexafluorophosphate (HATU), (benzotriazol-1 -yloxy)-ths-(dimethylamino)- phosphonium-hexafluorophosphate (BOP), (benzotriazol-1 -
  • the alkylation is carried out in a solvent such as dimethylfornnannide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, at a temperature between O 0 C and 100 0 C, but preferably between 15°C and 50 0 C.
  • a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate
  • R 2 , R 3 and A are as hereinbefore defined.
  • Diagram 4 Process f
  • compounds of general formula IX are converted into the chloro- carbonyl-carbonyl derivatives by reaction with oxalyl chloride in a solvent such as dichloromethane, diethyl ether, tetrahydrofuran, dioxane or toluene, but preferably diethyl ether, at temperatures between -20 0 C and 80 0 C, but preferably between 0°C and 50°C.
  • a solvent such as dichloromethane, diethyl ether, tetrahydrofuran, dioxane or toluene, but preferably diethyl ether, at temperatures between -20 0 C and 80 0 C, but preferably between 0°C and 50°C.
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran, at temperatures between -30 0 C and 70°C, but preferably between 0 0 C and 50 0 C and optionally in the presence of a base such as triethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine to form the compounds of general formula X.
  • a base such as triethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine to form the compounds of general formula X.
  • Cyano functionalities may in each case be prepared from primary amides obtained in the syntheses. Suitable methods for this transformation are, for example, reaction with thionyl chloride and optionally catalytic amounts of dimethylformamide in a solvent such as dichloromethane, 1 ,2-dichloroethane, toluene or acetone at temperatures between 0°C and 100°C, reaction with trifluoroacetic anhydride or trichloroacetic anhydride, a base such as for example pyridine, triethylamine or N,N-diisopropyl-N-ethyl-amine in a solvent such as for example dichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, 1 ,4-dioxane or toluene at temperatures between -10 0 C and 100 0 C, as well as reaction with phosphorus oxychlohde and optionally a base such as pyridine or
  • Sulphonyl chlorides may be prepared from anilines.
  • the aniline is first diazotised by reacting with sodium nitrite in hydrochloric acid at temperatures between - 30 0 C and 10 0 C.
  • the diazonium salt solution thus prepared is then added dropwise to copper-ll-chlohde and water in a 30% sulphur dioxide solution in glacial acetic acid at temperatures between - 30°C and 10 0 C. Then it is left to warm up to temperatures between 5°C and 50°C.
  • the sulphonyl chlorides may be prepared from aryl metal compounds such as aryl lithium or aryl magnesium chloride compounds.
  • Aryl lithium compounds are obtained from the aryl bromides or aryl iodides by reacting with n-butyllithium, sec-butyllithium or tert.-butyllithium in a solvent such as diethyl ether or tetrahydrofuran at temperatures between - 60 0 C and - 85°C.
  • Arylmagnesium chloride compounds are obtained by a process as described in Angew. Chem. 2006, 118, 3024-3027.
  • the aryl metal compounds thus obtained are further reacted at temperatures between -78°C and -20 0 C by piping sulphur dioxide through. This produces metal sulphinates, which can optionally be precipitated by the addition of hexane.
  • the metal sulphinates are dissolved in dichloromethane and combined with N-chlorosuccinimide at temperatures between -20°C and 30°C. After the reaction the solid is filtered off, to obtain a dichloromethane solution of the sulphonyl chloride.
  • any reactive groups present such as carboxy, hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a protecting group for a carboxy group may be a methyl, ethyl, tert.butyl or benzyl group.
  • a protecting group for a hydroxy group may be an acetyl, benzyl or tetrahydropyranyl group.
  • Protecting groups for an amino or alkylamino may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
  • a carboxymethyl or carboxyethyl unit is cleaved for example by hydrolysis in an aqueous solvent, e.g. In water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, but preferably in methanol/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically, e.g. In the presence of iodothmethylsilane, at temperatures between 0 and 120 0 C, preferably at temperatures between 10 and 100 0 C.
  • an aqueous solvent e.g. In water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or di
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 100°C, but preferably at temperatures between 20 and 60 0 C, and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 3 bar.
  • a 2,4-dimethoxy- benzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert. -butyl or tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • the compounds of general formula I obtained, or intermediate products from the synthesis of compounds of general formula I, as already mentioned hereinbefore, may be resolved into their enantiomers and/or diastereomers.
  • cis/trans mixtures may be resolved into O
  • the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained, or intermediate products from the synthesis of compounds of general formula I, which occur as racemates may be separated by methods known per se (cf. Allinger N. L. And ENeI E. L. In “Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I, or intermediate products from the synthesis of compounds of general formula I, with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • the enantiomers are preferably separated by chromatography on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. Esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomehc mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomehc salts or derivatives by the action of suitable agents.
  • Optically active acids in common use are e.g.
  • An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl.
  • the compounds of formula I obtained, or intermediate products from the synthesis of compounds of general formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of general formula I obtained, or intermediate products from the synthesis of compounds of general formula I, if they contain a carboxy group, may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
  • Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compounds of general formula I are inhibitors of the interaction between human liver glycogen phosphorylase (HLGP) and protein PPP1 R3 (G L - subunit of glycogen-associated protein phosphatase 1 (PP1 )).
  • HLGP human liver glycogen phosphorylase
  • protein PPP1 R3 G L - subunit of glycogen-associated protein phosphatase 1 (PP1 )
  • the effect of the compounds on the binding of the protein PPP1 R3 and the glycogen phosphorylase activated by phosphorylation is determined in a binding test based on SPA technology (Amersham Pharmacia).
  • the binding of the substances inhibits the interaction of the glycogen phosphorylase with the protein PPP1 R3B. All measurements were made in triplicate in the 384-well format (Optiplate, Perkin Elmer).
  • Human glycogen phosphorylase is recombinantly expressed in E. CoIi and purified.
  • the isolated non-phosphorylated HLGP is radioactively labelled in a marking reaction with phosphorylase kinase (200-500 U/ mg, P2014, Sigma) and 33 P-gamma ATP (110 TBq/ mmol, Hartmann Analytic) (Ref.: Cohen et al., Methods Enzymol. 1988, VoI 159 pp 390).
  • test buffer 50 mM Tris/HCI pH 7.0, 0.1 mM EGTA, 0.1 % mercapto- ethanol
  • test buffer 50 mM Tris/HCI pH 7.0, 0.1 mM EGTA, 0.1 % mercapto- ethanol
  • different amounts of a test substance final concentration: 1 nM to 30 ⁇ M
  • 100000 cpm of labelled HLGP, 375 ⁇ g streptavidin-SPA Beads RPNQ 0007, Amersham Pharmacia
  • 0.1 ⁇ g GL-peptide Biotin-FPEWPSYLGYEKLGPYY
  • After centrifuging for 5 minutes at 500 g the plate is measured (Topcount, Packard).
  • the cpm values measured are used to calculate the IC 5 O values specified.
  • the basal value is determined in the absence of the peptide and the maximum value is determined in the absence of the test substance.
  • the compounds of general formula I have IC 5 O values in the range from 100 nM to 15 ⁇ M.
  • the compounds of general formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for treating and/or preventatively treating all those conditions or diseases that can be influenced by inhibiting the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1 ). Therefore the compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g.
  • retinopathy retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies
  • metabolic acidosis or ketosis reactive hypoglycaemia, hypehnsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuhcaemia.
  • beta-cell degeneration such as e.g. Apoptosis or necrosis of pancreatic beta cells.
  • the substances are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells.
  • the compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
  • the compounds according to the invention are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
  • the dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide.
  • the dosage may be from 0.1 to 1000 mg, preferably 0.5 to 500 mg, by intravenous route, and 1 to 1000 mg, preferably 10 to 500 mg, by oral route, in each case administered 1 to 4 times a day.
  • the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g.
  • the compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above.
  • Other active substances which are suitable for such combinations include in particular those which potentiate the therapeutic effect of an inhibitor of the interaction of glycogen phosphorylase a with the G L subunit of glycogen-associated protein phosphatase 1 (PP1 ) according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an an inhibitor of the interaction of glycogen phosphorylase a with the GL subunit of glycogen- associated protein phosphatase 1 (PP1 ) according to the invention to be reduced.
  • Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. Gl 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g.
  • antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PP
  • miglitol miglitol, acarbose, voglibose
  • DPPIV inhibitors e.g. sitagliptine, vildagliptine
  • SGLT2-inhibitors alpha2- antagonists
  • insulin and insulin analogues GLP-1 and GLP-1 analogues (e.g. Exendin-4) or amylin.
  • Other active substances suitable as combination partners are inhibitors of protein tyrosinephosphatase 1 , substances that affect deregulated glucose production in the liver, such as e.g.
  • Avasimibe or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ⁇ 3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
  • bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport
  • HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin
  • drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-Il antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ -blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
  • drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-Il antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ -blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
  • angiotensin Il receptor antagonists examples include candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671 , GA-0113, RU-64276, EMD- 90423, BR-9701 , etc.
  • Angiotensin Il receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
  • a combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
  • a combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
  • the dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
  • this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the interaction of glycogen phosphorylase a with the G L subunit of glycogen-associated protein phosphatase 1 (PP1 ).
  • diseases or conditions which can be affected by inhibiting the interaction of glycogen phosphorylase a with the G L subunit of glycogen-associated protein phosphatase 1 (PP1 ).
  • PP1 glycogen-associated protein phosphatase 1
  • the use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
  • this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
  • a pharmaceutical composition according to the invention comprises a combination of a compound of formula I according to the invention or a physiologically acceptable salt of such a compound and at least one angiotensin Il receptor antagonist optionally together with one or more inert carriers and/or diluents.
  • the compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so- called kit-of-parts.
  • the mother liquor is evaporated down in vacuo, and the residue is purified by chromatography on silica gel.
  • 4-Pyridylamine is used instead of N,N-dimethylethylenediamine. Carried out overnight at ambient temperature. Then the solvents are eliminated in vacuo, the residue is taken up in methanol and purified by chromatography on silica gel.
  • Example 1 The product is further reacted directly in Example 1 (3).
  • Example 6 The product is further reacted directly in Example 6.
  • Phenylmethanesulphonyl chloride is used instead of benzoyl chloride.
  • Example Vl (24) The product is further reacted directly in Example Vl (24).
  • the product additionally contains 3,5-dichloro-N-[1 -(3,5-dichloro- phenylsulphonyl)-3-methyl-1 H-indazol-5-yl]-phenylsulphonamide.
  • Tetrahydrofuran is used as solvent.
  • the product is further reacted directly in XVII (2).
  • Tetrahydrofuran is used as solvent.
  • Rf value 0.42 (silica gel: petroleum ether/ethyl acetate 2:1 )
  • a 3:2:2 mixture of ethyl acetate, methanol and tetrahydrofuran is used as solvent.
  • Tetrahydrofuran is used as solvent.
  • Tetrahydrofuran is used as solvent.
  • Rf value 0.33 (silica gel: petroleum ether/ethyl acetate 1 :1 )
  • Tetrahydrofuran is used as solvent.
  • Tetrahydrofuran is used as solvent.
  • Tetrahydrofuran is used as solvent.
  • Rf value 0.45 (silica gel: petroleum ether/ethyl acetate 2:1 )
  • Tetrahydrofuran/methanol 2:1 is used as solvent.
  • the crude product is further reacted directly in Xl (29).
  • Tetrahydrofuran/methanol 2:1 is used as solvent.
  • the crude product is further reacted directly in Xl (30).
  • Tetrahydrofuran is used as solvent.
  • Rf value 0.54 (silica gel: petroleum ether/ethyl acetate 1 :1 )
  • Tetrahydrofuran is used as solvent.
  • Rf value 0.46 (silica gel: dichloromethane/methanol 5:1 )
  • Tetrahydrofuran is used as solvent.
  • Tetrahydrofuran is used as solvent.
  • Example IXXX (9) Obtained as a mixture from the reaction of a mixture of 6-nitro- benzo[b]thiophene-3-carboxylic acid-amide and 5-nitro-benzo[b]thiophene-3- carboxylic acid-amide.
  • the crude product is further reacted directly in Example Xl (42).
  • Example XIII
  • 2,3-dihydro-1 H-indol-5-yl]-amino ⁇ -acetate are dissolved in 3 ml dichloromethane and 100 mg 3-chloro-perbenzoic acid are added. The mixture is stirred overnight at ambient temperature, diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 99:1 to 4:1 ).
  • the aqueous phase is twice extracted with ethyl acetate.
  • the combined organic phases are dried on magnesium sulphate and the solvent is eliminated in vacuo.
  • Example XVIII The product is further reacted directly in Example Xl(14) without any further purification.
  • Example XVIII
  • rO-chloro- ⁇ -t ⁇ iinethylsilylethvnyl-phenylsulphonvD-O-ethyl-QH-carbazol-S-yl)- aminoi-acetic acid 180 mg tert-butyl [(3-chloro-5-trinnethylsilylethynyl-phenylsulphonyl)-(9-ethyl- 9H-carbazol-3-yl)-amino]-acetate are dissolved in 5 ml dichloromethane. 1 ml of trifluoroacetic acid is added with stirring. The mixture is stirred overnight at ambient temperature and then the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
  • tert-butyl [(3-chloro-5-thfluoromethylsulphonyloxy-phenylsulphonyl)- (9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 4 ml dimethylformamide.
  • 20 mg copper-l-iodide, 40 mg bis-triphenylphosphine- palladium-dichloride and 210 ⁇ l thmethylsilylacetylene are added under argon. Then the mixture is heated to 60 0 C for 6 hours and then stirred overnight at ambient temperature. The mixture is then divided between saturated potassium carbonate solution and ethyl acetate. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to
  • 3-chloro-5-nitro-phenyl trifluoromethanesulphonate 2.2 g 3-chloro-5-nitrophenol are dissolved in 30 ml dichloromethane, combined with 1.1 ml of pyridine and cooled to -10 0 C. A solution of 2.2 ml trifluoromethanesulphonic acid anhydride in 5 ml dichloromethane is added thereto, the mixture is left overnight to warm up to ambient temperature and then divided between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvent is eliminated in vacuo.
  • 3-chloro-5-nitrophenol 1.65 g 3-chloro-5-nitroanisole are combined with 20.3 g pyridinium hydrochloride and heated to 200 0 C for 1 hour. Then the mixture is left overnight to come up to ambient temperature, 200 ml of water are added, the precipitated solid is suction filtered and dried in vacuo.
  • the reaction is carried out in the presence of a catalytic amount of 4-N.N- dimethylamino-pyridine at 60 0 C.
  • the product is obtained in admixture with 3- (bis-tert.-butoxycarbonyl)-aminocarbonyl-6-nitro-1 H-indole.
  • Rf value 0.50 (silica gel; petroleum ether/ethyl acetate 4:1 )
  • the reaction is carried out in the presence of a catalytic amount of 4-N,N- dimethylamino-pyridine at 60 0 C.
  • the crude product is chromatographed on silica gel (cyclohexane/ethyl acetate 40:60 to 0:100).
  • Example XLV 6-nitro-benzo[b]- thiophene-3-carboxylic acid and 5-nitro-benzo[b]thiophene-3-carboxylic acid
  • 3-nitro-9H-carbazole 2.2 g 9-(2-phenylsulphonyl-ethyl)-3-nitro-9H-carbazole are dissolved in 40 ml of tetrahydrofuran, combined with 700 mg potassium-tert.-butoxide and stirred for 2 hours at ambient temperature. A further 100 mg potassium-tert.- butoxide are added and the mixture is stirred for 4 hours at ambient temperature. Then another 100 mg potassium-tert.-butoxide are added. The mixture is heated for 2 hours to 50 0 C, divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is washed with saturated sodium chloride solution and dried with magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 80:20).
  • G-O. ⁇ -dichloro-phenylsulphonylanninoM -methyl-1 H-indole-3-carboxylic acid- dimethylamide 300 mg 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3- carboxylic acid are dissolved in 2 ml dimethylformamide, combined with 319 ⁇ l N,N-diisopropyl-N-ethyl-amine and 241 mg O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU) and stirred for 15 minutes at ambient temperature.
  • TBTU O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate

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Abstract

The present invention relates to substituted arylsulphonylglycines of general formula (I) wherein R denotes a group of formula (A) wherein X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof, which have valuable pharmacological properties, particularly the suppression of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1 ), and their use as pharmaceutical compositions.

Description

New substituted arylsulphonylglycines, the preparation thereof and the use thereof as pharmaceutical compositions
The present invention relates to substituted arylsulphonylglycines of general formula I
Figure imgf000002_0001
wherein the groups R, X, Y and Z are defined as hereinafter, including the tautomers, stereoisomers, mixtures thereof and salts thereof. This invention further relates to pharmaceutical compositions containing a compound of formula I according to the invention as well as the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment of metabolic disorders, particularly type 1 or type 2 diabetes mellitus. The invention also relates to processes for preparing a pharmaceutical composition as well as a compound according to the invention.
Compounds of formula I are suitable for preventing the inhibiting effect of glycogen phosphorylase on the activity of glycogen synthase by stopping the interaction of glycogen phosphorylase a with the Gι_ subunit of glycogen- associated protein phosphatase 1 (PP1 ). Compounds with these properties stimulate glycogen synthesis and are proposed for the treatment of metabolic disorders, particularly diabetes (P. Cohen, Nature Reviews Molecular Cell Biology 2006, 7, 867-874). Aim of the invention
The aim of the present invention is to provide new arylsulphonylglycines that suppress the interaction of glycogen phosphorylase a with the Gι_ subunit of glycogen-associated protein phosphatase 1 (PP1 ).
A further aim of the present invention is to provide new pharmaceutical compositions that are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.
Another aim of this invention is to provide a process for preparing the compounds according to the invention.
Other aims of the present invention will become directly apparent to the skilled man from the foregoing remarks and those that follow.
Object of the invention
In a first aspect the present invention relates to new substituted arylsulphonylglycines of general formula
Figure imgf000003_0001
wherein
R denotes a group of formula
Figure imgf000004_0001
wherein
R1 denotes H, Ci-6-alkyl or a group of formula
Figure imgf000004_0002
wherein the Ci-6-alkyl group mentioned for R1 hereinbefore may be substituted by Ci-6-alkyl-carbonyloxy, Ci-6-alkoxy- carbonyloxy, Ci-6-alkoxy, hydroxy, amino, Ci-3-alkyl-amino, di- (Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci-3-alkyl)-piperazin-1-yl, aminocarbonyl, C 1.3- alkyl-aminocarbonyl, di-(Ci-3-alkyl)-aminocarbonyl, pyrrolidin-1- yl-carbonyl, pipehdin-1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-(Ci-3-alkyl)-piperazin-1 -yl-carbonyl, tetrahydrofuran-3-yl-oxy, Ci-s-alkylamino-Ci-s-alkyloxy, di-(Ci-3- alkyl)-amino-Ci-3-alkyloxy, pyrrolidin-1 -yl-Ci-3-alkyloxy, piperidin- 1 -yl-Ci-3-alkyloxy, morpholin-4-yl-Ci-3-alkyloxy, piperazin-1 -yl-Ci- 3-alkyloxy or 4-(Ci-3-alkyl)-piperazin-1 -yl-Ci-3-alkyloxy,
R2 and R3 independently of one another denote halogen, C 1.3- alkyl, C2-4-alkynyl, Ci-3-perfluoroalkyl, Ci-3-perfluoroalkoxy, C 1.3- alkoxy, cyano, nitro or hydroxy, and
A denotes CH or N, and the heterocyclic group
Figure imgf000005_0001
denotes a group of formula
Figure imgf000005_0002
or
Figure imgf000006_0001
wherein the above-mentioned heterocycles of formulae (Ia), (Ib), (Ic), (Ie), (If), (Ig), (Ii) and (In) may each optionally be substituted at the carbon atoms of the 5-ring by one or two groups selected from among Ci-3-alkyl, amino-Ci-3-alkyl, hydroxy-Ci-3-alkyl, cyano, Ci-3- perfluoroalkyl, C3-6-cycloalkyl, C2-4-alkynyl, C2-4-alkenyl, Ci-3-alkyl- carbonyl, Ci-s-perfluoroalkyl-carbonyl, carboxyl, Ci-3-alkyloxy-carbonyl, carboxy-Ci-3-alkyl, aminocarbonyl, Ci-3-alkyl-aminocarbonyl or di-(Ci-3- alkyl)-aminocarbonyl, wherein the groups may be identical or different and each carbon atom may carry only one group, and
wherein the above-mentioned heterocyclic group of formula (Ib) may optionally be substituted at the nitrogen atom of the 5-ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-6-alkyl, phenyl-Ci-6-alkyl, phenylsulphonyl-Ci-6- alkyl,
Ci-6-alkyl-carbonyl, carboxyl, Ci-6-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-6-alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-6-alkyl-aminocarbonyl, di-(Ci-6-alkyl)-aminocarbonyl, Cs-e-cycloalkyl-aminocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci-6-alkyl)-amino- carbonyl, aryl-amino-carbonyl, N-oxy-pyridylamino-carbonyl,
4- to 7-membered cycloalkyleneimino-carbonyl optionally substituted by hydroxy or Ci-3-alkyl-aminocarbonyl,
morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-(Ci-3-alkyl)- piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, Ci-s-alkylanninocarbonyl-carbonyl, di-(Ci-3- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-i -ylcarbonyl-carbonyl, piperidin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl, piperazin-1 -ylcarbonyl-carbonyl, 4-methyl-piperazin-1 -ylcarbonyl- carbonyl,
Ci-3-alkyl-sulphonyl, phenyl-Ci-3-alkylsulphonyl or phenylsulphonyl optionally substituted in the phenyl moiety by one or two chlorine atoms,
wherein the Ci-6-alkyl-aminocarbonyl, di-(Ci-6-alkyl)- aminocarbonyl and N-(C3-6-cycloalkyl)-N-(Ci-6-alkyl)-amino- carbonyl group mentioned above in the definition of R4 may each be substituted in the alkyl moiety by aryl, Ci-3-alkyl-amino, di-(Ci- 3-alkyl)-amino, Cs-e-cycloalkyl-amino, N-(C3-6-cycloalkyl)-N-(Ci-6- alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1 -yl, 4-methyl-piperazin-1 -yl or Ci-3- alkylaminocarbonyl, and
wherein the aryl group mentioned above in the definition of R4 is a 6-membered aromatic system that may contain 0 to 3 nitrogen atoms and may be substituted by nitro.
The invention also relates to the tautomers, stereoisomers, mixtures and salts, particularly the physiologically acceptable salts, of the compounds according to the invention. The compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, in particular they suppress the interaction of glycogen phosphorylase a with the Gι_-subunit of glycogen-associated protein phosphatase 1 (PP1 ).
Therefore this invention also relates to the use of the compounds according to the invention, including the physiologically acceptable salts, as pharmaceutical compositions.
The compounds of the above general formula I, wherein R1 does not represent hydrogen, but denotes one of the other groups specified, are so- called prodrugs. By prodrugs are meant compounds that are not active per se but are converted into the corresponding active compound in vivo, cleaving the prodrug group.
This invention further relates to pharmaceutical compositions containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
A further object of this invention is the use of at least one compound according to the invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition that is suitable for the treatment or prevention of diseases or conditions that can be influenced by suppressing the interaction of glycogen phosphorylase a with the d-subunit of glycogen-associated protein phosphatase 1 (PP1 ).
The invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders, for example type I or Il diabetes mellitus. The invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition for suppressing the interaction of glycogen phosphorylase a with the Gι_-subunit of glycogen- associated protein phosphatase 1 (PP1 ).
A further object of this invention is a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
The present invention also relates to a process for preparing the compounds of general formula I according to the invention.
Detailed description of the invention Unless stated otherwise, the groups, radicals and substituents, particularly R, R1 to R4, X, Y, Z and A have the meanings given hereinbefore and hereinafter.
If groups, substituents or radicals occur more than once in a compound, they may have the same or different meanings.
Preferred compounds of the above general formula I are those wherein
R denotes a group of the above-mentioned formula wherein
R1 denotes H, Ci-6-alkyl or a group of formula
Figure imgf000009_0001
wherein the Ci-6-alkyl group mentioned for R1 hereinbefore may be substituted by Ci-6-alkyl-carbonyloxy, Ci-6-alkoxy- carbonyloxy, Ci-6-alkoxy, hydroxy, amino, Ci-3-alkyl-amino, di- (Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci-3-alkyl)-piperazin-1-yl, aminocarbonyl, Ci-3- alkyl-aminocarbonyl, di-(Ci-3-alkyl)-aminocarbonyl, pyrrolidin-1- yl-carbonyl, pipehdin-1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl or 4-(Ci-3-alkyl)-piperazin-1 -yl-carbonyl,
R2 and R3 independently of one another denote halogen, Ci-3-alkyl, C2- 4-alkynyl, Ci-3-perfluoroalkyl, Ci-2-alkoxy or cyano and
denotes CH or N,
and the heterocyclic group
Figure imgf000010_0001
denotes a group of formula
Figure imgf000010_0002
Figure imgf000011_0001
wherein the above-mentioned heterocycles of formulae (Ia), (Ib), (Ic), (Ie), (If), (Ig), (Ii) and (In) may each optionally be substituted at the carbon atoms of the 5-ring by one or two groups selected from among Ci-3-alkyl, amino-Ci-3-alkyl, hydroxy-Ci-3-alkyl, cyano, C3-6-cycloalkyl, Ci-3-alkyl-carbonyl, Ci-3-perfluoroalkyl-carbonyl, carboxyl, Ci-2-alkyloxy- carbonyl, carboxy-Ci-2-alkyl, aminocarbonyl, Ci-3-alkyl-aminocarbonyl or di-(Ci-3-alkyl)-aminocarbonyl, wherein the groups may be identical or different and each carbon atom may carry only one group, and
wherein the above-mentioned heterocyclic group of formula (Ib) may optionally be substituted at the nitrogen atom of the 5-ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-4-alkyl, phenyl-Ci-4-alkyl, phenylsulphonyl-Ci-4- alkyl,
Ci-4-alkyl-carbonyl, carboxyl, Ci-4-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-4-alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-4-alkyl-aminocarbonyl, di-(Ci-4-alkyl)-aminocarbonyl, Cs-θ-cycloalkyl-aminocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci-4-alkyl)-annino- carbonyl, [N.N-dKCi^-alkylJ-aminol-Ci-s-alkyl-amino-carbonyl, 1 - (methylanninocarbonyl)-ethyl-annino-carbonyl, aryl-amino-carbonyl, aryl- Ci-3-alkyl-annino-carbonyl, N-oxy-pyridylamino-carbonyl,
4- to 7-nnennbered cycloalkyleneimino-carbonyl optionally substituted by hydroxy or methylaminocarbonyl,
morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-(methyl)-piperazin- 1 -yl-carbonyl, (piperazin-2-on-4-y)l-carbonyl,
aminocarbonyl-carbonyl, Ci^-alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl, pipehdin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl,
Ci-2-alkyl-sulphonyl, phenyl-Ci-2-alkyl-sulphonyl or phenylsulphonyl optionally substituted in the phenyl moiety by one or two chlorine atoms,
while the aryl group mentioned above in the definition of R4 is a 6-membered aromatic system that may contain 0 to 2 nitrogen atoms and may be substituted by nitro.
Particularly preferred are those compounds of the above general formula I, wherein
R denotes a group of the above-mentioned formula wherein
R1 denotes H, Ci-4-alkyl or a group of formula
Figure imgf000013_0001
wherein the Ci-4-alkyl group mentioned for R1 hereinbefore may be substituted by Ci-4-alkoxy, hydroxy, di-(Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1-yl or 4- (methyl)-piperazin-i -yl,
R2 and R3 independently of one another denote chlorine, bromine, Ci-2- alkoxy, C2-3-alkynyl or Ci-2-alkyl and
A denotes CH or N,
and the heterocyclic group
Figure imgf000013_0002
denotes a group of formula
Figure imgf000013_0003
Figure imgf000014_0001
wherein the above-mentioned heterocycles of formulae (Ia1 ), (Ia2) and (Ie1 ) may each optionally be substituted at the carbon atoms of the 5 ring by a group selected from among Ci-2-alkyl, methylcarbonyl, trifluoromethylcarbonyl, carboxyl, methoxy-carbonyl, aminocarbonyl, methyl-aminocarbonyl, dimethyl-aminocarbonyl, aminomethyl or hydroxymethyl, and
wherein the above-mentioned heterocyclic group of formula (Ib1 ) may optionally be substituted at the nitrogen atom of the 5 ring by methyl or hydroxycarbonylmethyl, and wherein R4 denotes H, cyano, Ci-4-alkyl, phenyl-Ci-4-alkyl, phenylsulphonyl-Ci-4- alkyl,
Ci-4-alkyl-carbonyl, carboxyl, Ci-4-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-4-alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-4-alkyl-aminocarbonyl, di-(Ci-4-alkyl)-aminocarbonyl, C3-6-cycloalkyl-anninocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci-4-alkyl)-annino- carbonyl, N.N-dKCi-s-alkylJ-amino-Ci-s-alkyl-amino-carbonyl, 1 - (methylanninocarbonyl)-ethyl-annino-carbonyl, phenylamino-carbonyl, (nitrophenyl)-amino-carbonyl, phenyl-Ci-2-alkyl-annino-carbonyl, pyridinylamino-carbonyl, pyrazinylamino-carbonyl, N-oxy-pyridylamino- carbonyl,
azetidin-1 -yl-carbonyl, pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylanninocarbonyl)-pyrrolidin-1 -yl-carbonyl, piperidin-
1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, Ci^-alkylaminocarbonyl-carbonyl, di-(Ci-2- alkylj-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl, pipehdin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl,
benzyl-sulphonyl, phenylsulphonyl or 3.5-dichloro-phenyl-sulphonyl,
but particularly those compounds of the above general formula I, wherein
R denotes a group of the above-mentioned formula wherein
R1 denotes H or a Ci-3-alkyl group optionally substituted by a di-(Ci-
3-alkyl)-amino group, R2 and R3 independently of one another represent chlorine, ethynyl, methoxy, methyl or ethyl and denotes CH or N, and the heterocyclic group
Figure imgf000016_0001
denotes a group of formula
Figure imgf000016_0002
Figure imgf000017_0001
wherein the above-mentioned heterocycles of formulae (Ia1 ) and (Ie1 ) may each optionally be substituted at the carbon atoms of the 5-ring by a group selected from among
Figure imgf000017_0002
thfluoromethylcarbonyl, carboxyl, aminocarbonyl or hydroxy methyl, and
wherein the above-mentioned heterocyclic group of formula (Ib1 ) may optionally be substituted at the nitrogen atom of the 5-ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-3-alkyl, phenyl-Ci-2-alkyl, phenylsulphonyl-Ci-2- alkyl,
Ci-3-alkyl-carbonyl, Ci-2-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-2- alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-3-alkyl-aminocarbonyl, di-(Ci-3-alkyl)-aminocarbonyl, cyclopropyl-aminocarbonyl, N-(cyclopropyl)-N-(Ci-2-alkyl)-amino- carbonyl, (N,N-dimethyl-amino)-ethyl-amino-carbonyl, 1- (methylaminocarbonyl)-ethyl-amino-carbonyl, phenylamino-carbonyl, (nitrophenyl)-amino-carbonyl, phenyl-Ci-3-alkyl-carbonyl, phenyl-Ci-2- alkyl-amino-carbonyl, pyhdinylamino-carbonyl, pyrazinylamino- carbonyl, N-oxy-pyridin-3-ylamino-carbonyl,
azetidin-1-yl-carbonyl, pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylaminocarbonyl)-pyrrolidin-1 -yl-carbonyl, pipehdin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl,
(piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, Ci^-alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-i -ylcarbonyl-carbonyl,
benzyl-sulphonyl or phenyl-sulphonyl.
Most particularly preferred are those compounds of the above general formula I, wherein
R denotes a group of the above-mentioned formula wherein
R1 denotes H, methyl, ethyl or 2-dimethylamino-ethyl,
R }2 a _ ,n_d _j n R3 independently of one another denote chlorine, ethynyl, methoxy, methyl or ethyl and
A denotes CH or N,
and the heterocyclic group
Figure imgf000018_0001
which may be substituted by R4 as hereinbefore described, denotes a group of formula
Figure imgf000019_0001
wherein the above-mentioned heterocyclic group of formula (Ia1 ) may optionally be substituted by trifluoromethylcarbonyl at the carbon atom of the 5-ring adjacent to the phenyl ring, and
wherein the above-mentioned heterocyclic group of formula (Ie1 ) may optionally be substituted by carboxyl, amino-carbonyl or hydroxymethyl at the carbon atom of the 5-ring adjacent to the phenyl ring, and
wherein the above-mentioned heterocyclic group of formula (Ib1 ) may optionally be substituted by methyl or hydroxycarbonylmethyl at the nitrogen atom of the 5 ring, and wherein
denotes H, cyano, ethyl, phenyl-ethyl, phenylsulphonyl-ethyl,
methyl-carbonyl, methoxy-carbonyl, phenylcarbonyl, benzylcarbonyl, 5- chloro-I H-indol-2-yl-carbonyl,
aminocarbonyl, methyl-aminocarbonyl, dimethyl-aminocarbonyl, cyclopropyl-aminocarbonyl, N-(cyclopropyl)-N-(methyl)-anninocarbonyl, (N,N-dimethyl-annino)-ethyl-annino-carbonyl, i -(methylanninocarbonyl)- ethyl-amino-carbonyl, phenylamino-carbonyl, benzylamino-carbonyl, 3- nitro-phenylamino-carbonyl, 2-nitro-phenylamino-carbonyl, pyridin-3- ylamino-carbonyl, pyridin-4-ylannino-carbonyl, pyrazinylamino-carbonyl, N-oxy-pyridin-3-ylamino-carbonyl,
azetidin-1-yl-carbonyl, pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylanninocarbonyl)-pyrrolidin-1 -yl-carbonyl, piperidin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, methylaminocarbonyl-carbonyl, dimethyl- aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl,
benzyl-sulphonyl or phenyl-sulphonyl.
The following preferred compounds may be mentioned by way of example:
(4-}(1 ) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylcarbamoyl-1 H-indol-5-yl)- amino]-acetic acid, (2)(2) [(3,5-dichloro-phenylsulphonyl)-(1-phenylcarbamoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetic acid,
(S)(3) {(3,5-dichloro-phenylsulphonyl)-[1-(3-nitro-phenylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetic acid,
(4)(4) {(3,5-dichloro-phenylsulphonyl)-[1-(pyridin-3-ylcarbamoyl)-2,3-dihydro- 1 H-indol-5-yl]-amino}-acetic acid,
(§1(5) {(3,5-dichloro-phenylsulphonyl)-[1-(2-nitro-phenylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetic acid,
(€-}(6) [(1 -acetyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid,
(-7-)(7) [(3,5-dichloro-phenylsulphonyl)-(1 -methylcarbannoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetic acid, t#)(8) {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-4-ylcarbamoyl)-2,3-dihydro-
1 H-indol-5-yl]-amino}-acetic acid,
(9)(9) [(2,6-dichloro-pyridine-4-sulphonyl)-(9-ethyl-9H-carbazol-3-yl)-annino]- acetic acid,
(4-9)(10) {(3,5-dichloro-phenylsulphonyl)-[3-(morpholine-4-carbonyl)-1 H- indol-6-yl]-amino}-acetic acid, f14)(11 ) [(3,5-dichloro-phenylsulphonyl)-(3-dimethylcarbannoyl-1 -methyl-
1 H-indol-6-yl)-amino]-acetic acid,
(4-2-)(12) [(3,5-dichloro-phenylsulphonyl)-(3-methylcarbannoyl- benzo[b]thiophen-6-yl)-amino]-acetic acid, (4-34(13) {(3,5-dichloro-phenylsulphonyl)-[1-methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetic acid,
(44-}(14) [(3,5-dimethyl-phenylsulphonyl)-(1-nnethylcarbannoyl-2,3-dihydro-
1 H-indol-5-yl)-amino]-acetic acid, f-!-§)(15) [[3-(azetidine-1 -carbonyl)-1 -methyl-1 H-indol-6-yl]-(3,5-dichlorc- phenylsulphonyl)-amino]-acetic acid,
(4€)(16) {(3,5-dichloro-phenylsulphonyl)-[3-(3-hydroxy-pyrrolidine-1 - carbonyl)-1 -methyl-1 H-indol-6-yl]-amino}-acetic acid,
(4-7-}(17) [^-(cyclopropyl-methyl-carbamoyO-i -methyl-1 H-indol-6-yl]-(3,5- dichloro-phenylsulphonyl)-amino]-acetic acid, (4li}(18) {(3-chloro-5-methyl-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetic acid,
(4-9-)(19) {(3,5-dimethyl-phenylsulphonyl)-[1-methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetic acid and
(2OK20) [(3,5-dichloro-phenylsulphonyl)-(3-hydroxymethyl-1 - methylcarbamoyl-2,3-dihydro-1 H-indol-5-yl)-amino]-acetic acid, the enantiomers, the mixtures and the salts thereof.
Some terms used hereinbefore and hereinafter to describe the compounds according to the invention are defined more specifically below.
The term halogen denotes an atom selected from among F, Cl, Br and I, particularly F, Cl and Br.
The term Ci-n-alkyl, wherein n may have a value as defined hereinbefore or hereinafter, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo- pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc..
The term C2-n-alkynyl, wherein n has a value as defined hereinbefore, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C≡C triple bond. Examples of such groups include ethynyl, 1 -propynyl, 2-propynyl, iso-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 2-methyl-1 -propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc..
The term C2-n-alkenyl, wherein n has a value as defined hereinbefore, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C=C double bond. Examples of such groups include ethenyl, 1-propenyl, 2- propenyl, iso-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 -propenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc..
The term Ci-n-alkoxy or Ci-n-alkyloxy denotes a Ci-n-alkyl-O group, wherein
Ci-n-alkyl is as hereinbefore defined. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso- hexoxy etc.
The term Ci-n-alkyl-carbonyl denotes a Ci-n-alkyl-C(=O) group, wherein Ci-n- alkyl is as hereinbefore defined. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n- butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n- pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n- hexylcarbonyl, iso-hexylcarbonyl, etc..
The term C3-n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.. Preferably the term C3-7-cycloalkyl includes saturated monocyclic groups.
The term Cs-n-cycloalkyloxy or C3-n-cycloalkoxy d a C3-n-cycloalkyl-O group, wherein C3-n-cycloalkyl is as hereinbefore defined. Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc..
The term Ci-n-alkoxy-carbonyl denotes a Ci-n-alkyl-O-C(=O) group, wherein Ci-n-alkyl is as hereinbefore defined.
The term C3-n-cycloalkyl-carbonyl denotes a C3-n-cycloalkyl-C(=O) group, wherein C3-n-cycloalkyl is as hereinbefore defined.
The terms Ci-n-alkyl-amino and di-(Ci-n-alkyl)-amino denote a Ci-n-alkyl-NH- or a di-(Ci-n-alkyl)-N group, respectively, wherein Ci-n-alkyl is as hereinbefore defined.
The term Cs-n-cycloalkyl-amino denotes a Cs-n-cycloalkyl-NH group, wherein £.
C3-n-cycloalkyl is as hereinbefore defined.
The term N-(C3-n-cycloalkyl)-N-(Ci-n-alkyl)-amino denotes an N-(C3-n- cycloalkyl)-N-(Ci-n-alkyl)-N group, wherein C3-n-cycloalkyl and Ci-n-alkyl are as hereinbefore defined.
The terms Ci-n-alkyl-aminocarbonyl and di-(Ci-n-alkyl)-aminocarbonyl denote a Ci-n-alkyl-NH-C(=O)- or a di-(Ci-n-alkyl)-N-C(=O) group, respectively, wherein Ci-n-alkyl is as hereinbefore defined.
The term Cs-n-cycloalkyl-aminocarbonyl denotes a C3-n-cycloalkyl-NH-C(=O) group, wherein C3-n-cycloalkyl is as hereinbefore defined.
The term N-(C3-n-cycloalkyl)-N-(Ci-n-alkyl)-amino denotes an N-(C3-n- cycloalkyl)-N-(Ci-n-alkyl)-N-C(=O) group, wherein C3-n-cycloalkyl and Ci-n-alkyl are as hereinbefore defined.
The terms di-(Ci-n-alkyl)amino and di-(Ci-n-alkyl)aminocarbonyl, wherein n has a value as defined hereinbefore, encompass amino groups which have the same or two different alkyl groups.
The term Ci-n-perfluoroalkyl denotes a F-(CF2)n group. Examples of such groups include trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-iso-propyl etc., but preferably trifluoromethyl, pentafluoroethyl.
The term Ci-n-perfluoroalkoxy denotes a F-(CF2)n-O group. Examples of such groups include trifluoromethoxy, pentafluoroethoxy, heptafluoro-n-propoxy, heptafluoro-iso-propoxy etc., but preferably trifluoromethoxy, pentafluoroethoxy.
The term Ci-n-alkylsulphonyl denotes a Ci-n-alkyl-S(=O)2 group, wherein Ci-n- alkyl is as hereinbefore defined. The compounds according to the invention may be obtained using methods of synthesis that are known in principle. Preferably the compounds are obtained by methods of preparation according to the invention that are described more fully hereinafter.
The preparation of compounds of general formula I may be carried out according to Process a) according to the invention shown in Scheme 1 , wherein X, Y, Z, R1, R2, R3 and A are as hereinbefore defined, starting from a compound of general formula II.
Figure imgf000025_0001
Diagram 1 : Process a
Here, compounds of general formula III are obtained by reacting a compound of general formula Il with a reducing agent. The starting compounds of general formula Il or III are either commercially obtainable or may be prepared by synthesising the heterocyclic group and/or nitrogenation (Houben-Weyl, Methoden der organischen Chemie, Volume X/1 , 463-890) using methods known per se starting from commercially obtainable compounds.
A suitable reducing agent is for example hydrogen in the presence of a catalyst, such as palladium on charcoal, palladium hydroxide on charcoal or Raney nickel, while palladium on charcoal is particularly suitable. The hydrogenation is carried out in a suitable solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane or ethyl acetate, but preferably methanol, ethanol or tetrahydrofuran, at a pressure between 0.5 and 7 bar, but preferably at a pressure between 0.5 and 3 bar, and at a temperature between 00C and 600C, but preferably at a temperature between 15°C and 400C.
Also suitable for the reduction is tin dichloride hydrate in lower alcoholic solvents such as methanol or ethanol at a temperature between ambient temperature and 800C. Alternatively titanium trichloride may be used as reducing agent. Suitable solvents are mixtures of acetone and water. The reaction is carried out between 0°C and 60°C, but preferably between 15°C and 400C and in the presence of ammonium acetate.
Compounds of general formula IV are obtained by sulphonylation of compounds of general formula III.
The sulphonylation is carried out with aromatic sulphonyl chlorides in the presence of a base, such as thethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine, or 4-dimethylamino-pyhdine, but preferably pyridine. The reaction may be carried out in suitable solvents, such as diethyl ether, tetrahydrofuran, toluene, pyridine, dichloromethane, or chloroform, but preferably dichloromethane. The temperature may be between 0°C and 600C, but preferably between 15°C and 40°C.
Compounds of general formula I are obtained from compounds of general formula IV by alkylation.
Suitable alkylating agents are acetic acid derivatives that contain a leaving group such as chlorine, bromine, iodine, p-tolylsulphonate, methylsulphonate, or trifluoromethylsulphonate in the 2-position. The alkylation is carried out in a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, and at a temperature between 00C and 1000C, but preferably between 15°C and 50°C.
If acetic acid derivatives with a tert. -butyl ester unit are used as alkylating agents, compounds of general formula I are obtained wherein R1 = tert.-butyl. The cleaving of the tert.-butyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
b) Compounds of general formula Vl, wherein R4 is bound to X and X denotes nitrogen, may be obtained by Process b) according to the invention shown in Scheme 2 from compounds of general formula V, wherein -Y "Z→ has the meaning -CH=CH→, -CH2-CH2→ or -N=CH→, but preferably has the meaning -CH=CH→ or -CH2-CH2→, while the carbon atoms therein may be substituted as hereinbefore defined and R4 denotes an acyl, sulphonyl, alkoxy-carbonyl, substituted amino-carbonyl or optionally substituted alkyl group denotes and R5 denotes the group R defined as hereinbefore, a nitro group or a group of formula
Figure imgf000027_0001
wherein R, R , R and A are as hereinbefore defined.
Figure imgf000027_0002
Diagram 2: Process b
Acyl groups may be introduced by reacting a compound of general formula V with an acylating reagent such as for example an acid chloride or acid anhydride. The reaction may be carried out in the presence of a base such as sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, caesium carbonate, thethylamine or N,N-diisopropyl-N-ethyl-amine as well as in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide at temperatures between -300C and 2000C, but preferably between 0°C and 1600C. Alternatively the reaction may be carried out by acylation with an acid. For this, the acid is activated in situ by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'- tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)- N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzotriazol-1- yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), (benzotriazol-i-yloxy)-tripyrrolidinophosphonium-hexafluorophosphate (PyBOP) and reacted in a dipolar aprotic solvent such as for example N1N- dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in N1N- dimethylformamide or N-methylpyrrolidone with a compound of general formula V in the presence of a base such as triethylamine, N,N-diisopropyl-N- ethyl-amine and optionally a catalyst such as 4-N,N-dimethylaminopyridine at temperatures between -20°C and 80°C, but preferably between 00C and 500C.
Sulphonyl groups may be introduced by reacting with a sulphonyl chloride in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl- amine, but preferably potassium carbonate, in a solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylformamide at temperatures between -30°C and 100°C, but preferably between 00C and 600C.
Alkoxycarbonyl groups may be introduced by reacting with an alkyl chloroformate in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N1N- diisopropyl-N-ethyl-amine, but preferably potassium carbonate, in a solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylfornnannide at temperatures between -300C and 1000C, but preferably between 0°C and 600C. Alternatively, alkoxycarbonyl groups are obtained by reacting a compound of general formula V with phosgene in a solvent such as dichloromethane, tetrahydrofuran or dioxane in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably thethylamine or N,N-diisopropyl-N-ethyl-amine, and subsequently treating with an alcohol at temperatures between -20°C and 100°C, but preferably between 00C and 500C. Aminocarbonyl groups may be introduced by reacting with an isocyanate, optionally in the presence of a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N- ethyl-amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide at temperatures between -30°C and 150°C, but preferably between 00C and 1000C. Alternatively aminocarbonyl groups are obtained by reacting a compound of general formula V with phosgene in a solvent such as dichloromethane, tetrahydrofuran or dioxane in the presence of a base such as for example sodium hydride, sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably sodium hydride, triethylamine or N,N-diisopropyl-N-ethyl-amine and subsequently treating with an amine at temperatures between -20°C and 100°C, but preferably between 00C and 500C.
In order to introduce alkyl groups the compounds of general formula V are reacted with a base such as for example sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyldisilazide and an alkylating agent. The reaction is carried out in a solvent such as for example tetrahydrofuran, 1 ,4-dioxane, dimethylformamide, dimethylacetamide, N- methyl pyrrol idone or acetonitrile at temperatures between -40°C and 120°C, but preferably between -100C and 1000C.
The compounds of general formula Vl thus obtained correspond to intermediates from Scheme 1 and may be converted into the end compounds of general formula I according to Process a).
c) Compounds of general formula VIII, wherein R4 is bound to X and X denotes a carbon atom or CH, may be obtained according to Process c) according to the invention shown in Scheme 3 from compounds of general formula VII wherein -γ-Z→ denotes =CH-N(H)→, =CH-N(Me)→, =N- N(Me)→ or =CH-S→, while the carbon atoms therein may be substituted as hereinbefore defined and R4 denotes an optionally substituted amino-carbonyl or an alkoxy-carbonyl group and R6 denotes nitro or
Figure imgf000030_0001
wherein R , R and A are as hereinbefore defined.
Figure imgf000030_0002
Scheme 3: Process c
The transformation may be carried out by first converting the acid into an acid chloride. For this, a compound of general formula VII is combined with thionyl chloride, optionally in the presence of a solvent such as toluene or benzene heating it to temperatures between 500C and 1500C, but preferably between 80°C and 1200C. After the elimination of the volatile constituents the acid chloride thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but o
preferably tetrahydrofuran at temperatures between -300C and 1500C, but preferably between 0°C and 800C and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine. Alternatively the acid may be converted into an acid imidazolide. For this a compound of general formula VII is reacted with carbonyldiimidazole in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 20°C and 100°C. The acid imidazolide thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran, at temperatures between -300C and 150°C, but preferably between 0°C and 800C, and optionally in the presence of a base such as thethylamine, N1N- diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine. Moreover, compounds of general formula VIII may be prepared by in situ activation of the carboxylic acid. For this, the acid is activated by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'- tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)- N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzotriazol-1- yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), (benzotriazol-i-yloxy)-tripyrrolidinophosphonium-hexafluorophosphate (PyBOP) and reacted in a dipolar aprotic solvent such as for example dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in dimethylformamide or N-methylpyrrolidone, with an alcohol or an amine in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally a catalyst such as 4-N,N-dimethylaminopyridine at temperatures between -20°C and 80°C, but preferably between 00C and 500C. Compounds of general formula VIII wherein R4 denotes alkoxy-carbonyl may also be prepared by alkylating carboxylic acids of general formula VII. For this, the carboxylic acid is reacted with an alkylating agent. Suitable alkylating agents are alkyl derivatives that contain a leaving group such as chlorine, bromine, iodine, p-tolylsulphonate, methylsulphonate or thfluoromethylsulphonate. The alkylation is carried out in a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, at a temperature between 00C and 1000C, but preferably between 15°C and 500C. The compounds of general formula VIII thus obtained correspond to inter- mediates from Scheme 1 and may be converted into the end compounds of general formula I according to Process a).
d) Compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(R4)=, wherein R4 is an alkylcarbonyl or arylcarbonyl group optionally substituted as mentioned hereinbefore, may be obtained by Process d) from compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -CH=.
For this a compound of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -CH=, is reacted with an acid chloride or an acid anhydride, but preferably an acid anhydride. The reaction may be carried out without a solvent or with a solvent such as for example dichloromethane, 1 ,2-dichloroethane, toluene, tetrahydrofuran, 1 ,4- dioxane, dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone and optionally in the presence of a catalyst such as for example aluminium trichloride or boron trifluohde etherate and at temperatures between -100C and 180°C, but preferably between 0°C and 1200C. The compounds thus obtained correspond to intermediates from Scheme 1 and and may be converted into the end compounds of general formula I according to Process a). e) Compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(R4)=, wherein R4 denotes an aminocarbonyl or alkoxycarbonyl group optionally substituted as mentioned hereinbefore, may be obtained by Process e) from compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(CF3)=.
The compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(CF3)=, are reacted with 5 to 50 %, but preferably 40 % sodium hydroxide solution or potassium hydroxide solution at temperatures between 00C and 2000C, but preferably between ambient temperature and 1500C. The carboxylic acids of general formula III thus obtained, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(COOH)=, may for example be converted into an acid chloride.
For this the carboxylic acid obtained as described hereinbefore may be combined with thionyl chloride, optionally in the presence of a solvent such as toluene or benzene, and heated to temperatures between 50°C and 1500C, but preferably between 80°C and 120°C. After elimination of the volatile constituents the acid chloride thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran at temperatures between - 300C and 150°C, but preferably between 0°C and 800C and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyhdine. Alternatively the acid may be converted into an acid imidazolide. For this a compound of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(COOH)= is reacted with carbonyldiimidazole in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 20°C and 100°C. The acid imidazolide thus obtained is reacted with the alcohol or amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformannide, but preferably tetrahydrofuran, at temperatures between -300C and 1500C, but preferably between 0°C and 800C, and optionally in the presence of a base such as thethylamine, N,N-diisopropyl-N-ethylamine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine. Moreover, compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(R4)=, where R4 denotes an aminocarbonyl or alkoxycarbonyl group optionally substituted as mentioned hereinbefore, are prepared by in situ activation of the carboxylic acid. For this the acid is activated by the addition of diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide, O-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), O-(benzothazol-1 -yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium- hexafluorophosphate (HATU), (benzotriazol-1 -yloxy)-ths-(dimethylamino)- phosphonium-hexafluorophosphate (BOP), (benzotriazol-1 -yloxy)- tripyrrolidinophosphonium-hexafluorophosphate (PyBOP) and reacted in a dipolar aprotic solvent such as for example dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, but preferably in dimethylformamide or N- methylpyrrolidone, with an alcohol or amine in the presence of a base such as triethylamine, N,N-diisopropyl-N-ethyl-amine and optionally a catalyst such as 4-N,N-dimethylaminopyridine at temperatures between -20°C and 80°C, but preferably between 00C and 500C. Compounds of general formula III, wherein Y and Z are as hereinbefore defined and X denotes a group of formula -C(R4)=, where R4 denotes an alkoxycarbonyl group optionally substituted as mentioned hereinbefore, may also be prepared by alkylation of carboxylic acids of general formula VII. For this the carboxylic acid is reacted with an alkylating agent. Suitable alkylating agents are alkyl derivatives that contain a leaving group such as chlorine, bromine, iodine, p-tolylsulphonate, methylsulphonate or thfluoromethylsulphonate. The alkylation is carried out in a solvent such as dimethylfornnannide, dimethylacetamide, tetrahydrofuran, acetonitrile, N- methyl pyrrol idone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, at a temperature between O0C and 1000C, but preferably between 15°C and 500C. The compounds thus obtained correspond to intermediates from Scheme 1 and may be converted into the end compounds of general formula I according to Process a).
Compounds of general formula X wherein X and Y are defined as stated hereinafter and R4 denotes an aminocarbonyl-carbonyl group, may be obtained by Process f) shown in Scheme 4 from compounds of general formula IX wherein -γ-Z→ has the meaning =CH-N(H)→, =CH-N(Me)→, =N- N(Me)→ or =CH-S→ where the carbon atoms therein may be substituted as hereinbefore defined, and R denotes nitro or
Figure imgf000035_0001
wherein R2, R3 and A are as hereinbefore defined.
Figure imgf000035_0002
Diagram 4: Process f In this, compounds of general formula IX are converted into the chloro- carbonyl-carbonyl derivatives by reaction with oxalyl chloride in a solvent such as dichloromethane, diethyl ether, tetrahydrofuran, dioxane or toluene, but preferably diethyl ether, at temperatures between -200C and 800C, but preferably between 0°C and 50°C. After elimination of the volatile constituents they are reacted with an amine in a solvent such as dichloromethane, tetrahydrofuran, dioxane or dimethylformamide, but preferably tetrahydrofuran, at temperatures between -300C and 70°C, but preferably between 00C and 500C and optionally in the presence of a base such as triethylamine, N,N-diisopropyl-N-ethyl-amine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine to form the compounds of general formula X.
The compounds of general formula X thus obtained correspond to intermediates from Scheme 1 and may be converted according to Process a) into the end compounds of general formula I.
Cyano functionalities may in each case be prepared from primary amides obtained in the syntheses. Suitable methods for this transformation are, for example, reaction with thionyl chloride and optionally catalytic amounts of dimethylformamide in a solvent such as dichloromethane, 1 ,2-dichloroethane, toluene or acetone at temperatures between 0°C and 100°C, reaction with trifluoroacetic anhydride or trichloroacetic anhydride, a base such as for example pyridine, triethylamine or N,N-diisopropyl-N-ethyl-amine in a solvent such as for example dichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, 1 ,4-dioxane or toluene at temperatures between -100C and 1000C, as well as reaction with phosphorus oxychlohde and optionally a base such as pyridine or N,N-dimethylaniline in the presence or absence of a solvent such as for example dichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, 1 ,4-dioxane or toluene, at temperatures between -10°C and 120°C.
Sulphonyl chlorides may be prepared from anilines. For this, the aniline is first diazotised by reacting with sodium nitrite in hydrochloric acid at temperatures between - 300C and 100C. The diazonium salt solution thus prepared is then added dropwise to copper-ll-chlohde and water in a 30% sulphur dioxide solution in glacial acetic acid at temperatures between - 30°C and 100C. Then it is left to warm up to temperatures between 5°C and 50°C. Alternatively the sulphonyl chlorides may be prepared from aryl metal compounds such as aryl lithium or aryl magnesium chloride compounds. Aryl lithium compounds are obtained from the aryl bromides or aryl iodides by reacting with n-butyllithium, sec-butyllithium or tert.-butyllithium in a solvent such as diethyl ether or tetrahydrofuran at temperatures between - 600C and - 85°C. Arylmagnesium chloride compounds are obtained by a process as described in Angew. Chem. 2006, 118, 3024-3027. The aryl metal compounds thus obtained are further reacted at temperatures between -78°C and -200C by piping sulphur dioxide through. This produces metal sulphinates, which can optionally be precipitated by the addition of hexane. The metal sulphinates are dissolved in dichloromethane and combined with N-chlorosuccinimide at temperatures between -20°C and 30°C. After the reaction the solid is filtered off, to obtain a dichloromethane solution of the sulphonyl chloride.
In the reactions described hereinbefore, any reactive groups present such as carboxy, hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a carboxy group may be a methyl, ethyl, tert.butyl or benzyl group.
For example, a protecting group for a hydroxy group may be an acetyl, benzyl or tetrahydropyranyl group.
Protecting groups for an amino or alkylamino may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
A carboxymethyl or carboxyethyl unit is cleaved for example by hydrolysis in an aqueous solvent, e.g. In water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, but preferably in methanol/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically, e.g. In the presence of iodothmethylsilane, at temperatures between 0 and 1200C, preferably at temperatures between 10 and 1000C.
A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 100°C, but preferably at temperatures between 20 and 600C, and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 3 bar. However, a 2,4-dimethoxy- benzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert. -butyl or tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Moreover, the compounds of general formula I obtained, or intermediate products from the synthesis of compounds of general formula I, as already mentioned hereinbefore, may be resolved into their enantiomers and/or diastereomers. Thus, for example, cis/trans mixtures may be resolved into O
their cis and trans isomers, and compounds with at least one stereocentre may be resolved into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained, or intermediate products from the synthesis of compounds of general formula I, which occur as racemates may be separated by methods known per se (cf. Allinger N. L. And ENeI E. L. In "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I, or intermediate products from the synthesis of compounds of general formula I, with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by chromatography on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. Esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomehc mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomehc salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. The D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-O-p-toluoyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl. Furthermore, the compounds of formula I obtained, or intermediate products from the synthesis of compounds of general formula I, may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, the new compounds of general formula I obtained, or intermediate products from the synthesis of compounds of general formula I, if they contain a carboxy group, may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formula I are inhibitors of the interaction between human liver glycogen phosphorylase (HLGP) and protein PPP1 R3 (GL- subunit of glycogen-associated protein phosphatase 1 (PP1 )). The effect of the compounds on the binding of the protein PPP1 R3 and the glycogen phosphorylase activated by phosphorylation is determined in a binding test based on SPA technology (Amersham Pharmacia). The binding of the substances inhibits the interaction of the glycogen phosphorylase with the protein PPP1 R3B. All measurements were made in triplicate in the 384-well format (Optiplate, Perkin Elmer).
Human glycogen phosphorylase is recombinantly expressed in E. CoIi and purified. The isolated non-phosphorylated HLGP is radioactively labelled in a marking reaction with phosphorylase kinase (200-500 U/ mg, P2014, Sigma) and 33P-gamma ATP (110 TBq/ mmol, Hartmann Analytic) (Ref.: Cohen et al., Methods Enzymol. 1988, VoI 159 pp 390). In a binding test, in a volume of 100 μl (test buffer: 50 mM Tris/HCI pH 7.0, 0.1 mM EGTA, 0.1 % mercapto- ethanol), different amounts of a test substance (final concentration: 1 nM to 30 μM) are incubated at ambient temperature for 16 hours with 100000 cpm of labelled HLGP, 375 μg streptavidin-SPA Beads (RPNQ 0007, Amersham Pharmacia), 0.1 μg GL-peptide (Biotin-FPEWPSYLGYEKLGPYY). After centrifuging for 5 minutes at 500 g the plate is measured (Topcount, Packard). The cpm values measured are used to calculate the IC5O values specified. The basal value is determined in the absence of the peptide and the maximum value is determined in the absence of the test substance.
The compounds of general formula I have IC5O values in the range from 100 nM to 15 μM.
In view of their ability to suppress the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1 ), the compounds of general formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for treating and/or preventatively treating all those conditions or diseases that can be influenced by inhibiting the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1 ). Therefore the compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hypehnsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuhcaemia. These substances are also suitable for preventing beta-cell degeneration such as e.g. Apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 0.1 to 1000 mg, preferably 0.5 to 500 mg, by intravenous route, and 1 to 1000 mg, preferably 10 to 500 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include in particular those which potentiate the therapeutic effect of an inhibitor of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1 ) according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an an inhibitor of the interaction of glycogen phosphorylase a with the GL subunit of glycogen- associated protein phosphatase 1 (PP1 ) according to the invention to be reduced. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. Gl 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. miglitol, acarbose, voglibose), DPPIV inhibitors (e.g. sitagliptine, vildagliptine), SGLT2-inhibitors, alpha2- antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. Exendin-4) or amylin. Other active substances suitable as combination partners are inhibitors of protein tyrosinephosphatase 1 , substances that affect deregulated glucose production in the liver, such as e.g. Inhibitors of glucose-6-phosphatase, or fructose-1 ,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA- reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. Avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor. Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-Il antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Examples of angiotensin Il receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671 , GA-0113, RU-64276, EMD- 90423, BR-9701 , etc. Angiotensin Il receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1 ). These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabetes or diabetic complications.
The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
Thus, for example, a pharmaceutical composition according to the invention comprises a combination of a compound of formula I according to the invention or a physiologically acceptable salt of such a compound and at least one angiotensin Il receptor antagonist optionally together with one or more inert carriers and/or diluents.
The compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so- called kit-of-parts.
In the foregoing and following text, H atoms of oxygen and nitrogen atoms are not explicitly shown in every case in structural formulae. The Examples that follow are intended to illustrate the present invention without restricting it: Preparation of the starting compounds:
Example I
Figure imgf000046_0001
tert. butyl [(3.5-dichloro-phenylsulphonyl)-(1-phenylcarbannoyl-2.3-dihvdro-1 H- indol-5-yl)-amino1-acetate
990 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)- amino]-acetate are dissolved in 10 ml dichloromethane. 598 mg potassium carbonate and 247 μl phenylisocyanate are added. After stirring overnight the solid is filtered off and washed twice with dichloromethane. The combined organic phases are evaporated down in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :2). Yield: 1.24 g (99 % of theory) Mass spectrum (ESI+): m/z = 576 [M+H]+
The following compounds are obtained analogously to Example I:
(1 ) tert. butyl [(1-benzylcarbamoyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000046_0002
Carried out without potassium carbonate for 3 hours. Mass spectrum (ESI+): m/z = 589 [M+H]+ (2) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(3-nitro-phenylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetate
Figure imgf000047_0001
Carried out for 3 hours. Then the mixture is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried on sodium sulphate, the solvents are eliminated in vacuo, and the residue is extracted from diisopropylether. Mass spectrum (ESI+): m/z = 621 [IvRH]+
(3) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(2-nitro-phenylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetate
Figure imgf000047_0002
Carried out for 3 hours. The mixture is diluted with ethyl acetate and washed successively with dilute citric acid solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is extracted from diethyl ether. The solid is filtered off.
The mother liquor is evaporated down in vacuo, and the residue is purified by chromatography on silica gel.
Mass spectrum (ESI+): m/z = 621 [M+H]+
(4) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-3-ylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetate
Figure imgf000048_0001
Carried out for 3 hours. The mixture is diluted with ethyl acetate and washed successively with dilute citric acid solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo. Mass spectrum (ESI+): m/z = 577 [M+H]+
(5) 4-nitro-2,3-dihydro-indole-1 -carboxylic acid-phenylamide
Figure imgf000048_0002
After the reaction the mixture is diluted with dichloromethane and washed twice with saturated sodium chloride solution. Then it is dried on magnesium sulphate, the solvents are eliminated in vacuo and the residue is extracted from diisopropylether. Mass spectrum (ESI+): m/z = 284 [M+H]+
(6) 4-nitro-2,3-dihydro-indole-1 -carboxylic acid-pyridin-3-ylamide
After the reaction the mixture is diluted with dichloromethane and washed twice with saturated sodium chloride solution. Then it is dried on magnesium sulphate and the solvent is eliminated in vacuo. Mass spectrum (ESI+): m/z = 285 [M+H]+ (7) 6-nitro-2,3-dihydro-indole-1 -carboxylic acid-phenylamide
Figure imgf000049_0001
After the reaction the mixture is diluted with dichloromethane and washed with semi-saturated sodium chloride solution. Then it is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel.
Mass spectrum (ESI+): m/z = 284 [M+H]+
Example Il
Figure imgf000049_0002
5-(3.5-dichloro-DhenylsulDhonylamino)-indole-1 -carboxylic acid-benzylamide 130 mg 3,5-dichloro-N-(1 H-indol-5-yl)-phenylsulphonamide are dissolved in 5 ml dichloromethane and 14 mg dimethylaminopyridine and 56 μl benzyl isocyanate are added. The mixture is stirred overnight at ambient temperature, divided between 1 N HCI and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :3). Yield: 152 mg (84 % of theory)
Mass spectrum (ESI+): m/z = 474 [M+H]+
The following compounds are obtained analogously to Example II:
(1 ) 4-(3,5-dichloro-phenylsulphonylamino)-indole-1 -carboxylic acid- benzylamide
Figure imgf000050_0001
Mass spectrum (ESI+): m/z = 474 [M+H]+
Example III
Figure imgf000050_0002
5-(3.5-dichloro-DhenylsulDhonylamino)-indole-1 -carboxylic acid-Dhenylamide 100 mg 3,5-dichloro-N-(1 H-indol-5-yl)-phenylsulphonamide are dissolved in 3 ml dimethylformamide. 38 μl phenyl isocyanate and 10 dimethylaminopyridine are added and the mixture is heated to 800C for 5 minutes in the microwave. Then another 30 μl phenylisocyanate are added and the mixture is heated to 1000C for 15 minutes in the microwave. The solvent is then eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :3). Yield: 124 mg ( the product also contains 3,5-dichloro-N-(1 H-indol-5-yl)- phenylsulphonamide and diphenylurea) Mass spectrum (ESI"): m/z = 458 [M-H]" Example IV
Figure imgf000051_0001
tert. butyl K3.5-dichloro-phenylsulphonylH1 -(pyridin-4-ylcarbamoyl)-2.3- dihvdro-1 H-indol-5-yl1-anninol-acetate 215 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)- amino]-acetate are dissolved in 10 ml dichloromethane. For this 75 μl diisopropylethylamine and 1 ml of a 20 % solution of phosgene in toluene are added. The mixture is stirred for another 2 hours and then the solvents are eliminated in a nitrogen current. The residue is taken up in 10 ml of tetrahydrofuran. To this is added a solution prepared by the addition of 75 mg 4-aminopyridine to a solution of 30 mg sodium hydride (60 % suspension in mineral oil) in 10 ml of tetrahydrofuran and 30 minutes' stirring. The mixture is stirred overnight at ambient temperature and then refluxed for 24 hours. The solvents are eliminated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :3). Yield: 190 mg (70 % of theory) Mass spectrum (ESI+): m/z = 577 [M+H]+
The following compounds are obtained analogously to Example IV:
(1 ) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(pyrazin-2-ylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetate
Figure imgf000052_0001
Carried out for 2 hours at ambient temperature. Mass spectrum (ESI+): m/z = 578 [M+H]+
Example V
Figure imgf000052_0002
ethylcarbamoyl)-2.3-dihvdro-1 H-indol-5-yl1-aminol-acetate
800 μl of a 20 % solution of phosgene in toluene are dissolved in 10 ml dichloromethane and cooled to 00C . To this are added 35 μl diisopropylethylamine and 100 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)- (2,3-dihydro-1 H-indol-5-yl)-amino]-acetate. The mixture is stirred for a further 1 hour and then the solvents are eliminated in a nitrogen current. The residue is taken up in 10 ml of tetrahydrofuran, 200 μl N,N-dimethylethylenediamine are added and the mixture is stirred for 3 hours at ambient temperature. Then it is diluted with ethyl acetate and washed with semi-saturated sodium chloride solution. The organic phase is dried on magnesium sulphate, the solvents are eliminated in vacuo and the residue is purified by chromatography on aluminium oxide (cyclohexane/ethyl acetate 3:7 to ethyl acetate).
Yield: 75 mg (60 % of theory)
Mass spectrum (ESI+): m/z = 571 [M+H]+ The following compounds are obtained analogously to Example V:
(1 ) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -dimethylcarbamoyl^.S- dihydro-1 H-indol-5-yl)-amino]-acetate
Figure imgf000053_0001
Carried out for 3 hours at 600C.
Mass spectrum (ESI+): m/z = 528 [M+H]+
(2) methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-2,3-dihydro-indole-1 -carboxylate
Figure imgf000053_0002
4-Pyridylamine is used instead of N,N-dimethylethylenediamine. Carried out overnight at ambient temperature. Then the solvents are eliminated in vacuo, the residue is taken up in methanol and purified by chromatography on silica gel. It is not the desired product 5-[tert-butoxycarbonylmethyl-(3,5-dichloro- phenylsulphonyl)-amino]-2,3-dihydro-indole-1 -carboxylic acid-pyridin-3-yl- amide, but methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro- phenylsulphonyl)-amino]-2,3-dihydro-indole-1 -carboxylate that is isolated. Mass spectrum (ESI+): m/z = 532 [M+NH4]+
(3) 5-nitro-2,3-dihydro-indole-1 -carboxylic acid-methylamide
Figure imgf000054_0001
The crude product is extracted from 1 N HCI. Mass spectrum (ESI+): m/z = 222 [M+H]+
(4) 4-nitro-2,3-dihydro-indole-1 -carboxylic acid-methylamide
Figure imgf000054_0002
Mass spectrum (ESI+): m/z = 222 [M+H]+
(5) tert. butyl (3,5-dichloro-phenylsulphonyl)-[1-(3-oxo-piperazin-1 -carbonyl)- 2,3-dihydro-1 H-indol-5-yl]-amino}-acetate
Figure imgf000054_0003
Mass spectrum (ESI+): m/z = 600 [M+NH4]+
(6) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(1 -methylcarbamoyl- ethylcarbamoyl)-2,3-dihydro-1 H-indol-5-yl]-amino}-acetate
Figure imgf000054_0004
Mass spectrum (ESI+): m/z = 585 [M+H]+
(7) methyl 5-(3,5-dichloro-phenylsulphonylamino)-1 -methylcarbamoyl-2,3- dihydro-1 H-indole-3-carboxylate
Figure imgf000055_0001
Mass spectrum (ESI+): m/z = 458 [M+H]+
(8) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(2-methylcarbannoyl- pyrrolidine-1 -carbonyl)-2,3-dihydro-1 H-indol-5-yl]-annino}-acetate
Figure imgf000055_0002
Mass spectrum (ESI+): m/z = 611 [M+H]+
Example Vl
Figure imgf000055_0003
tert. butyl [(1-benzylcarbamoyl-i H-indol-5-ylH3.5-dichloro-phenylsulphonyl)- aminoi-acetate
150 mg 5-(3,5-dichloro-phenylsulphonylamino)-indole-1 -carboxylic acid- benzylamide are dissolved in 5 ml dimethylformamide. 109 mg potassium carbonate and 51 μl tert. butyl bromoacetate are added thereto. The mixture is stirred for 4 hours at ambient temperature, the solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :3). Yield: 127 mg (68 % of theory) Mass spectrum (ESI"): m/z = 586 [M-H]"
The following compounds are obtained analogously to Example Vl:
(1 ) tert. butyl [(1-benzylcarbamoyl-1 H-indol-4-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000056_0001
Mass spectrum (ESI"): m/z = 586 [M-H]"
(2) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -phenylcarbamoyl-I H-indol-δ- yl)-amino]-acetate
Figure imgf000056_0002
The product is further reacted directly in Example 1 (3).
(3) tert. butyl [(3,δ-dichloro-phenylsulphonyl)-(1 -phenylacetyl-1 H-indol-δ-yl)- amino]-acetate
Figure imgf000057_0001
Mass spectrum (ESI+): m/z = 590 [M+NH4]+
(4) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -phenylacetyl^.S-dihydro-I H- indol-5-yl)-amino]-acetate
Figure imgf000057_0002
Mass spectrum (ESI+): m/z = 575 [M+H]+
(5) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1-(phenylethyl)-1 H-indol-5-yl]-amino}-acetate
Figure imgf000057_0003
Mass spectrum (ESI+): m/z = 576 [M+NH4]+
(6) tert. butyl [(S.δ-dichloro-phenylsulphonylHI H-indol-δ-yO-aminol-acetate
Figure imgf000058_0001
Mass spectrum (ESI+): m/z = 472 [M+NH4]+
(7) tert. butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)- amino]-acetate
Figure imgf000058_0002
Mass spectrum (ESI+): m/z = 455 [M-H]+
(8) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -methylcarbamoyl^.S-dihydro- 1 H-indol-5-yl)-amino]-acetate
Figure imgf000058_0003
Mass spectrum (ESI+): m/z = 514 [M+H]+
(9) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -methylcarbamoyl^.S-dihydro- 1 H-indol-4-yl)-amino]-acetate
Figure imgf000059_0001
Mass spectrum (ESI+): m/z = 514 [M+H]+
(10) ethyl [(3,5-dichloro-phenylsulphonyl)-(1 H-indol-5-yl)-amino]-acetate
Figure imgf000059_0002
Mass spectrum (ESI+): m/z = 427 [M+H]+
(11 ) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -phenylcarbamoyl^.S- dihydro-1 H-indol-4-yl)-amino]-acetate
Figure imgf000059_0003
Mass spectrum (ESI+): m/z = 576 [M+H]+
(12) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-3-ylcarbamoyl)-2,3- dihydro-1 H-indol-4-yl]-amino}-acetate
Figure imgf000059_0004
Mass spectrum (ESI+): m/z = 577 [M+H]+
(13) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -phenylcarbamoyl^S- dihydro-1 H-indol-6-yl)-amino]-acetate
Figure imgf000060_0001
Mass spectrum (ESI+): m/z = 576 [M+H]+
(14) tert-butyl 5-[(3,5-dichloro-phenylsulphonyl)-methoxycarbonylmethyl- amino]-2,3-dihydro-indole-1 -carboxylate
Figure imgf000060_0002
Mass spectrum (ESI+): m/z = 532 [M+NH4]+
(15) tert. butyl [(3,5-dichloro-phenylsulphonyl)-(2-methyl-benzothiazole-5-yl)- amino]-acetate
Figure imgf000060_0003
Mass spectrum (ESI+): m/z = 487 [M+H]+
(16) methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-benzo[b]thiophen-2-carboxylate
Figure imgf000061_0001
Mass spectrum (ESI+): m/z = 547 [M+NH4]+
(17) tert. butyl [(3-chloro-5-methoxy-phenylsulphonyl)-(9-ethyl-9H-carbazol-3- yl)-amino]-acetate
Figure imgf000061_0002
Mass spectrum (ESI+): m/z = 529 [M+H]+
(18) tert. butyl [(2,6-dichloro-pyridine-4-sulphonyl)-(9-ethyl-9H-carbazol-3-yl)- amino]-acetate
Figure imgf000061_0003
Mass spectrum (ESI+): m/z = 534 [M+H]+
(19) tert. butyl [(3,5-dichloro-phenylsulphonyl)-(1 H-indazol-5-yl)-amino]- acetate
Mass spectrum (ESI+): m/z = 294 [M+H]+
Rf value: 0.53 (silica gel: ethyl acetate/petroleum ether 1 :1 )
(20) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(3,5-dichloro- phenylsulphonyl)-3-methyl-1 H-indazol-5-yl]-amino}-acetate
Figure imgf000062_0001
This is isolated as a by-product of the formation of Vl (21 ) from Xl (13).
Mass spectrum (ESI+): m/z = 678 [M+H]+
Rf value: 0.80 (silica gel: petroleum ether/ethyl acetate 2:1 )
(21 ) tert. butyl [(3,5-dichloro-phenylsulphonyl)-(3-methyl-1 H-indazol-5-yl)- amino]-acetate
Figure imgf000062_0002
Mass spectrum (ESI+): m/z = 470 [M+H]+ Rf value: 0.32 (silica gel: petroleum ether/ethyl acetate 2:1 )
(22) tert-butyl [(3-chloro-5-trifluoromethylsulphonyloxy-phenylsulphonyl)-(9- ethyl-9H-carbazol-3-yl)-amino]-acetate
Figure imgf000063_0001
Mass spectrum (ESI+): m/z = 664 [M+NH4]+
(23) tert-butyl 3-(tert-butoxycarbonyl-methyl-aminocarbonyl)-6-[tert- butoxycarbonylnnethyl-(3,5-dichloro-phenylsulphonyl)-annino]-indole-1 - carboxylate
Figure imgf000063_0002
Mass spectrum (ESI+): m/z = 712 [M+H]+
(24) methyl [(3,5-dichloro-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]- acetate
Figure imgf000063_0003
The product is further reacted directly in Example 6.
(25) tert. butyl [[9-(2-phenylsulphonyl-ethyl)-9H-carbazol-3-yl]-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000063_0004
Mass spectrum (ESI+): m/z = 690 [M+NH4]+
(26) methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-benzo[b]thiophen-2-carboxylate
Figure imgf000064_0001
Mass spectrum (ESI+): m/z = 547 [M+NH4]+
(27) tert. butyl [(9H-carbazol-3-yl)-(3,5-dichloro-phenylsulphonyl)-amino]- acetate
Figure imgf000064_0002
Mass spectrum (ESI"): m/z = 503 [M-H]"
(28) tert. butyl {6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-3-phenylcarbamoyl-indol-1-yl}-acetate
Figure imgf000064_0003
Obtained from the reaction of 6-(3,5-dichloro-phenylsulphonylamino)-1 H- indole-3-carboxylic acid-phenylamide. The product is further reacted directly in 1 (38).
(29) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(phenylethyl)-1 H- benzoimidazol-5-yl]-amino}-acetate
Figure imgf000065_0001
and tert. butyl {(3,5-dichloro-phenylsulphonyl)-[3-(phenylethyl)-3H-benzoimidazol-
5-yl]-amino}-acetate
Figure imgf000065_0002
Obtained from the reaction of a mixture of 3,5-dichloro-N-(1 -phenylethyl-1 H- benzoimidazol-5-yl)-phenylsulphonamide and 3,5-dichloro-N-[3-(phenylethyl)- 3H-benzoimidazol-5-yl]-phenylsulphonamide. The products may be separated by chromatography on silica gel. Mass spectrum (ESI+): m/z = 560 [M+H]+ tert. butyl {(3,5-dichloro- phenylsulphonyl)-[1 -(phenylethyl)-i H-benzoimidazol-5-yl]-amino}-acetate and Mass spectrum (ESI+): m/z = 560 [M+H]+ tert. butyl {(3,5-dichloro- phenylsulphonyl)-[3-(phenylethyl)-3H-benzoimidazol-5-yl]-amino}-acetate
(30) tert. butyl [(S.δ-dichloro-phenylsulphonylJ^-dimethylcarbamoyl-I H-indol- 5-yl)-amino]-acetate
Figure imgf000065_0003
Mass spectrum (ESI+): m/z = 526 [M+H]+ (31 ) tert-butyl 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- annino]-3-(nnorpholine-4-carbonyl)-indole-1 -carboxylate
Figure imgf000066_0001
Mass spectrum (ESI+): m/z = 668 [M+H]+
(32) tert-butyl 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-3-(4-tert-butoxycarbonyl-piperazin-1 -carbonyl)-indole-1 -carboxylate
Figure imgf000066_0002
Mass spectrum (ESI+): m/z = 767 [M+H]+
(33) tert-butyl 3-(benzyl-tert-butoxycarbonyl-aminocarbonyl)-6-[tert- butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-indole-1 - carboxylate
Figure imgf000066_0003
Mass spectrum (ESI+): m/z = 788 [M+H]+
(34) tert-butyl 3-(bis-tert-butoxycarbonyl)-aminocarbonyl-6-[tert- butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-indole-1 - carboxylate
Figure imgf000067_0001
Mass spectrum (ESI+): m/z = 798 [M+H]+
(35) tert-butyl 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- anninol-S-^ert-butoxycarbonyl-phenyl-anninocarbonylJ-indole-i -carboxylate
Figure imgf000067_0002
Mass spectrum (ESI+): m/z = 774 [M+H]+
(36) tert. butyl [(3-cyano-1 -methyl-1 H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000067_0003
Mass spectrum (ESI+): m/z = 511 [M+NH4]+
(37) tert. butyl [(S.δ-dichloro-phenylsulphonylHS-dimethylcarbamoyl-i -methyl- 1 H-indol-6-yl)-amino]-acetate
Figure imgf000067_0004
Mass spectrum (ESI+): m/z = 540 [M+H]+ (38) tert. butyl [(3-carbamoyl-1 -methyl-1 H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000068_0001
Mass spectrum (ESI+): m/z = 512 [M+H]+
(39) tert. butyl [(S.δ-dichloro-phenylsulphonylHS-nnethylcarbannoyl- benzo[b]thiophen-5-yl)-amino]-acetate
Figure imgf000068_0002
Mass spectrum (ESI+): m/z = 546 [M+NH4]+
(40) tert. butyl [(S.δ-dichloro-phenylsulphonylHS-methylcarbamoyl- benzo[b]thiophen-6-yl)-amino]-acetate
Figure imgf000068_0003
Mass spectrum (ESI+): m/z = 529 [M+H]+
(41 ) tert-butyl 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-3-(4-tert-butoxycarbonyl-3-oxo-piperazin-1 -carbonyl)-indole-1 - carboxylate
Figure imgf000069_0001
Mass spectrum (ESI+): m/z = 798 [M+NH4]+
(42) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[3-(1 -methylcarbannoyl- ethylcarbamoyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000069_0002
Mass spectrum (ESI"): m/z = 581 [M-H]"
(43) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(morpholine-4- carbonyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000069_0003
Mass spectrum (ESI"): m/z = 582 [M-H]"
(44) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -methyl-S-methylcarbamoyl- 1 H-indol-6-yl)-amino]-acetate
Figure imgf000069_0004
Mass spectrum (ESI+): m/z = 526 [M+H]+ (45) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -nnethyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000070_0001
Mass spectrum (ESI+): m/z = 566 [M+H]+
(46) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(piperidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000070_0002
Mass spectrum (ESI+): m/z = 580 [M+H]+
(47) tert. butyl (S.δ-dichloro-phenylsulphonylHI -methyl-S-phenylcarbamoyl- 1 H-indol-6-yl)-amino]-acetate
Figure imgf000070_0003
Mass spectrum (ESI+): m/z = 588 [M+H]+
(48) tert. butyl [(3-benzylcarbamoyl-i-methyl-i H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000071_0001
Mass spectrum (ESI+): m/z = 602 [M+H]+
(49) tert. butyl [(3,5-dimethyl-phenylsulphonyl)-(1 -methylcarbamoyl-2,3- dihydro-1 H-indol-5-yl)-amino]-acetate
Figure imgf000071_0002
Mass spectrum (ESI+): m/z = 474 [M+H]+
(50) tert-butyl 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-3-dimethylcarbamoyl-indole-1 -carboxylate
Figure imgf000071_0003
Mass spectrum (ESI+): m/z = 626 [M+H]+
(51 ) tert. butyl [(3-aminooxalyl-1-methyl-1 H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000071_0004
Mass spectrum (ESI+): m/z = 540 [M+H]+ (52) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -nnethyl-S-nnethylanninooxalyl- 1 H-indol-6-yl)-amino]-acetate
Figure imgf000072_0001
Mass spectrum (ESI+): m/z = 554 [M+H]+
(53) tert. butyl [(S.S-dichloro-phenylsulphonylHS-dinnethylanninooxalyl-i- methyl-1 H-indol-6-yl)-amino]-acetate
Figure imgf000072_0002
Mass spectrum (ESI+): m/z = 568 [M+H]+
(54) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(2-oxo-2-pyrrolidin- 1 -yl-acetyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000072_0003
Mass spectrum (ESI+): m/z = 594 [M+H]+
(55) tert. butyl [[3-(azetidine-1 -carbonyl)-1 -methyl-1 H-indol-6-yl]-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000073_0001
Mass spectrum (ESI+): m/z = 552 [M+H]+
(56) tert. butyl [(3,5-dichloro-phenylsulphonyl)-(1 ,3-dimethyl-2-oxo-2,3- dihydro-1 H-benzoimidazol-5-yl)-annino]-acetate
Figure imgf000073_0002
Mass spectrum (ESI+): m/z = 500 [M+H]+
(57) methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-1 -methylcarbamoyl-2,3-dihydro-1 H-indole-3-carboxylate
Figure imgf000073_0003
Mass spectrum (ESI+): m/z = 572 [M+H]+
(58) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[3-(3-hydroxy-pyrrolidine-1 - carbonyl)-1 -methyl-1 H-indol-6-yl]-amino}-acetate H
Figure imgf000073_0004
Rf value: 0.27 (silica gel: dichloromethane/methanol 9:1 )
(59) tert. butyl [(3-cyclopropylcarbamoyl-1 -methyl-1 H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000074_0001
Rf value: 0.39 (silica gel: petroleum ether/ethyl acetate 1 :2)
(60) tert. butyl [^-(cyclopropyl-methyl-carbamoyO-i -nnethyl-I H-indol-G-yl]- (3,5-dichloro-phenylsulphonyl)-amino]-acetate
Figure imgf000074_0002
Rf value: 0.34 (silica gel: petroleum ether/ethyl acetate 1 :2)
(61 ) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(2- methylcarbamoyl-pyrrolidine-i-carbonylJ-I H-indol-θ-yll-aminoϊ-acetate
Figure imgf000074_0003
Rf value: 0.44 (silica gel: dichloromethane/methanol 9:1 )
(62) tert. butyl {(3-chloro-5-methyl-phenylsulphonyl)-[1-methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000075_0001
Mass spectrum (ESI+): m/z = 546 [M+H]+
(63) tert. butyl {(3,5-dinnethyl-phenylsulphonyl)-[1 -nnethyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetate
Figure imgf000075_0002
Mass spectrum (ESI+): m/z = 526 [M+H]+
(64) tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indazol-6-yl]-amino}-acetate
Figure imgf000075_0003
Mass spectrum (ESI+): m/z = 567 [M+H]+
(65) tert. butyl [(S.δ-dichloro-phenylsulphonylHI -methyl-S-methylcarbamoyl- 1 H-indazol-6-yl)-amino]-acetate
Figure imgf000075_0004
Mass spectrum (ESI+): m/z = 527 [M+H]+ (66) tert. butyl [(3-carbamoyl-benzo[b]thiophen-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000076_0001
Mass spectrum (ESI+): m/z = 532 [M+NH4]+
(67) tert. butyl [(3-carbamoyl-benzo[b]thiophen-5-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000076_0002
Mass spectrum (ESI+): m/z = 532 [M+NH4]+
Example VII
Figure imgf000076_0003
tert. butyl f(1-benzoyl-1 H-indol-5-ylH3.5-dichloro-phenylsulphonyl)-aminol- acetate
50 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(1 H-indol-5-yl)-amino]- acetate are dissolved in 2 ml dichloromethane. 5 mg powdered sodium hydroxide and 19 μl benzoyl chloride are added. Then the mixture is stirred for 4 hours at ambient temperature, divided between 1 N sodium hydroxide solution and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :2).
Yield: 15 mg (24 % of theory)
Mass spectrum (ESI+): m/z = 576 [M+NH4]+
Example VIII
Figure imgf000077_0001
1 -(5-nitro-indol-1 -yl)-2-phenyl-ethanone
300 mg 5-nitroindole are dissolved in 10 ml of tetrahydrofuran. 81 mg sodium hydride (60 % in mineral oil) are added and the mixture is stirred for 1 hour at ambient temperature. Then 294 μl phenylacetic acid chloride are added dropwise and the mixture is stirred for another 3 hours. It is divided between saturated ammonium chloride solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :3). Yield: 250 mg (48 % of theory) Mass spectrum (ESI+): m/z = 281 [M+H]+
The following compounds are obtained analogously to Example VIII:
(1 ) 5-nitro-1 -(phenylethyl)-i H-indole
Figure imgf000077_0002
Dimethylformamide is used instead of tetrahydrofuran. Mass spectrum (ESI+): m/z = 267 [M+H]+
(2) 5-nitro-1 -(phenylethyl)-i H-benzimidazole
Figure imgf000078_0001
and 6-nitro-1 -(phenylethyl)-i H-benzimidazole
Figure imgf000078_0002
Dimethylformamide is used instead of tetrahydrofuran. The compounds are obtained as a mixture of regioisomers. Mass spectrum (ESI+): m/z = 268 [M+H]+
Example IX
Figure imgf000078_0003
DhenylsulphonvD-aminoi-acetate
150 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)- amino]-acetate are dissolved in 5 ml dichloromethane. 110 mg potassium carbonate and 45 μl benzoyl chloride are added, the mixture is stirred for 3 hours at ambient temperature and then divided between dichloromethane and water. The organic phase is washed with water and then dried on magnesium sulphate. The solvents are eliminated in vacuo. Yield: 170 mg (92 % of theory) Mass spectrum (ESI+): m/z = 561 [M+H]+
The following compounds are obtained analogously to Example IX:
(1 ) tert. butyl [(1-phenylsulphonyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetate
Figure imgf000079_0001
Phenylsulphonyl chloride is used instead of benzoyl chloride. Mass spectrum (ESI+): m/z = 614 [M+NH4]+
(2) tert. butyl [(3,5-dichloro-phenylsulphonyl)-(1 -phenylmethanesulphonyl-2,3- dihydro-1 H-indol-5-yl)-amino]-acetate
Figure imgf000079_0002
Phenylmethanesulphonyl chloride is used instead of benzoyl chloride. Mass spectrum (ESI+): m/z = 628 [M+NH4]+
Example X
Figure imgf000080_0001
tert. butyl rπ-(5-chloro-1 H-indol-2-carbonyl)-2.3-dihvdro-1 H-indol-5-yll-(3.5- dichloro-DhenylsulDhonvD-anninoi-acetate
55 mg δ-chloro-I H-indol^-carboxylic acid are dissolved in 2 ml of thionyl chloride and heated to 800C for 1 hour. The solvent is eliminated in vacuo and the residue is twice combined with dichloromethane and the latter is eliminated again in vacuo. The residue is taken up in 5 ml dichloromethane and the solution is added dropwise to a mixture of 100 mg tert. butyl [(3,5- dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)-amino]-acetate and 60 mg potassium carbonate in 2 ml dimethylformamide. The mixture is stirred for 2 hours at ambient temperature, diluted with ethyl acetate and washed with 1 N HCI and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :2). Yield: 60 mg (43 % of theory) Mass spectrum (ESI+): m/z = 634 [M+H]+
Example Xl
Figure imgf000080_0002
S.δ-dichloro-N-d H-indol-δ-vD-DhenylsulDhonamide
100 mg 5-aminoindole are dissolved in 10 ml of pyridine. 186 mg 3,5- dichlorophenylsulphonyl chloride are added thereto and the mixture is stirred for 4 hours at ambient temperature. The solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :5). Yield: 240 mg (93 % of theory)
Mass spectrum (ESI+): m/z = 341 [M+H]+
The following compounds are obtained analogously to Example Xl:
(1 ) 3,5-dichloro-N-(1 H-indol-4-yl)-phenylsulphonamide
Figure imgf000081_0001
Mass spectrum (ESI+): m/z = 341 [M+H]+
(2) tert-butyl 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1 ■ carboxylate
Figure imgf000081_0002
Mass spectrum (ESI+): m/z = 460 [M+NH4]+
(3) 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1 -carboxylic acid-methylamide
Figure imgf000082_0001
The crude product is extracted from diisopropylether. Mass spectrum (ESI+): m/z = 400 [M+H]+
(4) 4-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1 -carboxylic acid-methylamide
Figure imgf000082_0002
Mass spectrum (ESI+): m/z = 400 [M+H]+
(5) 4-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1 -carboxylic acid-phenylamide
Figure imgf000082_0003
Mass spectrum (ESI+): m/z = 462 [M+H]+
(6) 4-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1 -carboxylic acid-pyridin-3-ylamide
Figure imgf000082_0004
Mass spectrum (ESI+): m/z = 463 [M+H]+ (7) 3,5-dichloro-N-[4-ethyl-3-(1 -methyl-3-phenyl-ureido)-phenyl]- phenylsulphonamide
Figure imgf000083_0001
The reaction is carried out in dichloromethane/pyridine 2:1. The crude product is extracted from diisopropylether. Mass spectrum (ESI+): m/z = 462 [M+H]+
(8) 3,5-dichloro-N-(2-methyl-benzothiazole-5-yl)-phenylsulphonamide
Figure imgf000083_0002
The reaction is carried out in dichloromethane with 2 equivalents of triethylamine. Mass spectrum (ESI+): m/z = 373 [M+H]+
(9) methyl 5-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophen-2- carboxylate
Figure imgf000083_0003
Mass spectrum (ESI"): m/z = 414 [M-H]"
(10) 3,5-dichloro-N-(9-ethyl-9H-carbazol-3-yl)-phenylsulphonamide
Figure imgf000083_0004
The reaction is carried out in dichloromethane/pyridine 5:1. o
The product is further reacted directly in Example Vl (24).
(11 ) N-(9H-carbazol-3-yl)-3,5-dichloro-phenylsulphonamide
Figure imgf000084_0001
The reaction is carried out in dichloromethane/pyridine 5:1. Mass spectrum (ESI+): m/z = 389 [M+H]+
(12) S-chloro-N^Θ-ethyl-ΘH-carbazol-S-yO-δ-methoxy-phenylsulphonamide
Figure imgf000084_0002
Mass spectrum (ESI+): m/z = 415 [M+H]+
(13) 3,5-dichloro-N-(1 H-indazol-5-yl)-phenylsulphonamide
Figure imgf000084_0003
The product additionally contains 3,5-dichloro-N-[1 -(3,5-dichloro- phenylsulphonyl)-3-methyl-1 H-indazol-5-yl]-phenylsulphonamide. Mass spectrum (ESI"): m/z = 340 [M-H]"
Rf value: 0.60 (silica gel: ethyl acetate/petroleum ether 2:1 )
(14) 3-chloro-N-(9-ethyl-9H-carbazol-3-yl)-5-thfluoromethylsulphonyloxy- phenylsulphonamide
Figure imgf000085_0001
Mass spectrum (ESI+): m/z = 533 [M+H]+
(15) tert-butyl 3-(tert-butoxycarbonyl-nnethyl-anninocarbonyl)-6-(3,5-dichloro- phenylsulphonylamino)-indole-1 -carboxylate
Figure imgf000085_0002
Rf value: 0.63 (silica gel: petroleum ether/ethyl acetate 2:1 )
(16) 3,5-dichloro-N-(9-ethyl-9H-carbazol-3-yl)-phenylsulphonamide
Figure imgf000085_0003
Mass spectrum (ESI+): m/z = 533 [M+H]+
(17) N-[9-(2-phenylsulphonyl-ethyl)-9H-carbazol-3-yl]-3,5-dichloro- phenylsulphonamide
Figure imgf000085_0004
Mass spectrum (ESI+): m/z = 576 [M+NH4]+ (18) methyl 5-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophen-2- carboxylate
Figure imgf000086_0001
Mass spectrum (ESI+): m/z = 433 [M+NH4]+
(19) N-(9H-carbazol-3-yl)-3,5-dichloro-phenylsulphonamide
Figure imgf000086_0002
Mass spectrum (ESI"): m/z = 389 [M-H]"
(20) methyl 6-(3,5-dichloro-phenylsulphonylamino)-1 H-indole-3-carboxylate
Figure imgf000086_0003
Mass spectrum (ESI+): m/z = 399 [M+H]+
(21 ) 3,5-dichloro-N-[1 -(phenylethyl)-i H-benzimidazol-5-yl]- phenylsulphonamide
Figure imgf000086_0004
and 3,5-dichloro-N-[3-(phenylethyl)-3H-benzinnidazol-5-yl]-phenylsulphonannide
Figure imgf000087_0001
are obtained as a mixture and used as such in Vl (29). Mass spectrum (ESI+): m/z = 446 [M+H]+
(22) ethyl δ^S.δ-dichloro-phenylsulphonylaminoJ-I H-indole^-carboxylate
Figure imgf000087_0002
The reaction is carried out in dichloromethane. 1.4 equivalents 2,6-lutidine are used as the base.
Mass spectrum (ESI"): m/z = 411 [M-H]"
(23) tert-butyl 6-(3,5-dichloro-phenylsulphonylamino)-3-(morpholine-4- carbonyl)-indole-1 -carboxylate
Figure imgf000087_0003
Rf value: 0.41 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(24) tert-butyl 3-(4-tert-butoxycarbonyl-piperazin-1 -carbonyl)-6-(3,5-dichloro- phenylsulphonylamino)-indole-1 -carboxylate
Figure imgf000087_0004
Rf value: 0.63 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(25) tert-butyl 3-(benzyl-tert-butoxycarbonyl-aminocarbonyl)-6-(3,5-dichloro- phenylsulphonylamino)-indole-1 -carboxylate
Figure imgf000088_0001
Rf value: 0.65 (silica gel: petroleum ether/ethyl acetate 2:1 )
(26) tert-butyl 3-(bis-tert.-butyloxycarbonyl)-aminocarbonyl-6-(3,5-dichloro- phenylsulphonylamino)-indole-1 -carboxylate
Figure imgf000088_0002
Rf value: 0.67 (silica gel: petroleum ether/ethyl acetate 2:1 )
(27) tert-butyl 3-(tert-butoxycarbonyl-phenyl-aminocarbonyl)-6-(3,5-dichloro- phenylsulphonylamino)-indole-1 -carboxylate
Figure imgf000088_0003
Rf value: 0.74 (silica gel: petroleum ether/ethyl acetate 2:1 )
(28) 3,5-dichloro-N-(3-cyano-1 -methyl-1 H-indol-6-yl)-phenylsulphonamide
Figure imgf000089_0001
Mass spectrum (ESI"): m/z = 378 [M-H]"
(29) 5-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophen-3-carboxylic acid-methylamide
Figure imgf000089_0002
Mass spectrum (ESI"): m/z = 413 [M-H]"
(30) 6-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophen-3-carboxylic acid-methylamide
Figure imgf000089_0003
Mass spectrum (ESI+): m/z = 415 [M+H]+
(31 ) tert-butyl 3-(4-tert-butoxycarbonyl-3-oxo-piperazin-1 -carbonyl)-6-(3,5- dichloro-phenylsulphonylamino)-indole-1-carboxylate
Figure imgf000089_0004
Rf value: 0.73 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(32) 6-(3,5-dichloro-phenylsulphonylamino)-1 H-indole-3-carboxylic acid-(1 - methylcarbamoyl-ethyl)-amide
Figure imgf000090_0001
Rf value: 0.35 (silica gel: dichloromethane/methanol 9:1 )
(33) 5-(3,5-dinnethyl-phenylsulphonylannino)-2,3-dihydro-indole-1 -carboxylic acid-methylamide H
Figure imgf000090_0002
Mass spectrum (ESI+): m/z = 360 [M+H]+
(34) tert-butyl Θ^S.S-dichloro-phenylsulphonylaminoJ-S-dimethylcarbamoyl- indole-1 -carboxylate
Figure imgf000090_0003
Rf value: 0.60 (silica gel: petroleum ether/ethyl acetate 1 :2)
(35) 3,5-dichloro-N-(1 -methyl-1 H-indol-6-yl)-phenylsulphonamide
Figure imgf000090_0004
Mass spectrum (ESI+): m/z = 355 [M+H]+
(36) 3,5-dichloro-N-(1 ,3-dimethyl-2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)- phenylsulphonamide
Figure imgf000091_0001
Mass spectrum (ESI+): m/z = 386 [M+H]+
(37) 1 -tert-butyl-3-methyl 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro- indole-1 ,3-dicarboxylate
Figure imgf000091_0002
Rf value: 0.30 (silica gel: petroleum ether/ethyl acetate 3:1 )
(38) 3-chloro-5-methyl-N-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H-indol-6-yl]- phenylsulphonamide
Figure imgf000091_0003
Mass spectrum (ESI+): m/z = 432 [M+H]+
(39) 3,5-dimethyl-N-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H-indol-6-yl]- phenylsulphonamide
Figure imgf000091_0004
Mass spectrum (ESI+): m/z = 412 [M+H]+ (40) 3,5-dichloro-N-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H-indazol-6-yl]- phenylsulphonamide
Figure imgf000092_0001
Mass spectrum (ESI+): m/z = 453 [M+H]+
(41 ) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indazol-3-carboxylic acid-methylamide
Figure imgf000092_0002
Mass spectrum (ESI+): m/z = 413 [M+H]+
(42) 6-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophen-3-carboxylic acid-amide
Figure imgf000092_0003
and
5-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophen-3-carboxylic acid- amide
Figure imgf000092_0004
Obtained from the reaction of a mixture of 6-amino-benzo[b]thiophene-3- carboxylic acid-amide and 5-amino-benzo[b]thiophene-3-carboxylic acid- amide (Example XII (30)). The crude product is dissolved in hot ethyl acetate. After cooling to ambient temperature the precipitated solid (5-(3,5-dichloro- phenylsulphonylamino)-benzo[b]thiophene-3-carboxylic acid-amide) is filtered off. The mother liquor is freed from the solvents in vacuo and the residue is chromatographed on silica gel, to obtain 6-(3,5-dichloro- phenylsulphonylamino)-benzo[b]thiophene-3-carboxylic acid-amide. Mass spectrum (ESI+): m/z = 401 [M+H]+
6-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophene-3-carboxylic acid- amide and 5-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophene-3- carboxylic acid-amide
Example XII
Figure imgf000093_0001
tert-butyl 5-amino-2,3-dihvdro-indole-1 -carboxylate 6.8 g tert-butyl 5-nitro-indole-1 -carboxylate are dissolved in 120 ml of methanol. 600 mg palladium on charcoal (10%) are added thereto and the mixture is hydrogenated for 1.5 hours at ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo. Yield: 6 g (100 % of theory) Mass spectrum (ESI+): m/z = 235 [M+H]+
The following compounds are obtained analogously to Example XII:
(1 ) 5-amino-2,3-dihydro-indole-1 -carboxylic acid-methylamide
Figure imgf000093_0002
Mass spectrum (ESI+): m/z = 192 [M+H]+ (2) 4-amino-2,3-dihydro-indole-1 -carboxylic acid-methylamide
Figure imgf000094_0001
Mass spectrum (ESI+): m/z = 192 [M+H]+
(3) 4-amino-2,3-dihydro-indole-1 -carboxylic acid-phenylamide
Figure imgf000094_0002
Mass spectrum (ESI+): m/z = 254 [M+H]+
(4) 4-amino-2,3-dihydro-indole-1 -carboxylic acid-pyridin-3-ylamide
Figure imgf000094_0003
Mass spectrum (ESI+): m/z = 255 [M+H]+
(5) 1 -(5-amino-2-ethyl-phenyl)-1 -methyl-3-phenyl-urea
Figure imgf000094_0004
The crude product is extracted from diisopropylether. Mass spectrum (ESI+): m/z = 254 [M+H]+
(6) 9H-carbazol-3-ylamine
Figure imgf000094_0005
Tetrahydrofuran is used as solvent. Mass spectrum (ESI+): m/z = 183 [M+H]+ (7) 1 -chloro-S-methoxy-δ-annirio-benzene
Figure imgf000095_0001
Tetrahydrofuran is used as solvent. Mass spectrum (ESI+): m/z = 158 [M+H]+
(8) 3-amino-5-chloro-phenyl trifluoromethanesulphonate
Figure imgf000095_0002
Tetrahydrofuran is used as solvent. The product is further reacted directly in XVII (2).
(9) tert-butyl 6-amino-3-(tert-butoxycarbonyl-methyl-aminocarbonyl)-indole-1 ■ carboxylate
Figure imgf000095_0003
Tetrahydrofuran is used as solvent. Rf value: 0.42 (silica gel: petroleum ether/ethyl acetate 2:1 )
(10) 9-(2-phenylsulphonyl-ethyl)-9H-carbazol-3-ylamine
Figure imgf000095_0004
Mass spectrum (ESI+): m/z = 351 [M+H]+ (11 ) 9H-carbazol-3-ylamine
Figure imgf000096_0001
Mass spectrum (ESI+): m/z = 183 [M+H]+
(12) ethyl δ-amino-I H-indole^-carboxylate
Figure imgf000096_0002
A 3:2:2 mixture of ethyl acetate, methanol and tetrahydrofuran is used as solvent.
Mass spectrum (ESI+): m/z = 205 [M+H]+
(13) tert-butyl 6-amino-3-(morpholine-4-carbonyl)-indole-1 -carboxylate
Figure imgf000096_0003
Tetrahydrofuran is used as solvent.
Rf value: 0.21 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(14) tert-butyl 6-amino-3-(4-tert-butoxycarbonyl-piperazin-1 -carbonyl)-indole- 1 -carboxylate
Figure imgf000096_0004
Tetrahydrofuran is used as solvent. Rf value: 0.33 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(15) tert-butyl 6-amino-3-(benzyl-tert-butoxycarbonyl-aminocarbonyl)-indole-1 ■ carboxylate
Figure imgf000097_0001
Tetrahydrofuran is used as solvent.
Rf value: 0.44 (silica gel: petroleum ether/ethyl acetate 2:1 )
(16) tert-butyl 6-amino-3-(bis-tert-butoxycarbonyl)-anninocarbonyl-indole-1 - carboxylate
Figure imgf000097_0002
Tetrahydrofuran is used as solvent.
Rf value: 0.62 (silica gel: petroleum ether/ethyl acetate 2:1 )
(17) tert-butyl θ-amino-S-^ert-butoxycarbonyl-phenyl-aminocarbonylJ-indole-i - carboxylate
Figure imgf000097_0003
Tetrahydrofuran is used as solvent. Rf value: 0.45 (silica gel: petroleum ether/ethyl acetate 2:1 )
(18) 6-amino-1 -methyl-1 H-indole-3-carbonithle
Figure imgf000097_0004
The crude product is crystallised from isopropanol. Mass spectrum (ESI+): m/z = 172 [M+H]+ (19) 5-amino-benzo[b]thiophene-3-carboxylic acid-methylamide
Figure imgf000098_0001
Tetrahydrofuran/methanol 2:1 is used as solvent. The crude product is further reacted directly in Xl (29).
(20) 6-amino-benzo[b]thiophene-3-carboxylic acid-methylamide
Figure imgf000098_0002
Tetrahydrofuran/methanol 2:1 is used as solvent. The crude product is further reacted directly in Xl (30).
(21 ) tert-butyl 6-amino-3-(4-tert-butoxycarbonyl-3-oxo-piperazin-1-carbonyl)- indole-1 -carboxylate
Figure imgf000098_0003
Tetrahydrofuran is used as solvent. Rf value: 0.54 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(22) 6-amino-1 H-indole-3-carboxylic acid-(1 -methylcarbamoyl-ethyl)-amide
Figure imgf000098_0004
Tetrahydrofuran is used as solvent. Rf value: 0.46 (silica gel: dichloromethane/methanol 5:1 )
(23) tert-butyl θ-amino-S-dimethylcarbamoyl-indole-i -carboxylate
Figure imgf000099_0001
Tetrahydrofuran is used as solvent.
Rf value: 0.32 (silica gel: petroleum ether/ethyl acetate 1 :2)
(24) 1-methyl-1 H-indol-6-ylamine
Figure imgf000099_0002
Tetrahydrofuran is used as solvent.
Mass spectrum (ESI+): m/z = 147 [M+H]+
(25) 5-amino-1 ,3-dimethyl-1 ,3-dihydro-benzimidazol-2-one
Figure imgf000099_0003
Tetrahydrofuran is used as solvent. Mass spectrum (ESI+): m/z = 178 [M+H]+
(26) 1 -tert-butyl-3-methyl 5-amino-2,3-dihydro-indole-1 ,3-dicarboxylate
Figure imgf000099_0004
Obtained from the hydrogenation of 1 -tert-butyl-3-methyl 5-nitro-indole-1 ,3- dicarboxylate in ethyl acetate/methanol/tetrahydrofuran 10:7:7. It is hydrogenated at 500C and 15 bar.
Rf value: 0.30 (silica gel: petroleum ether/ethyl acetate 1 :1 )
(27) (6-amino-1 -methyl-1 H-indol-3-yl)-pyrrolidin-1 -yl-methanone
Figure imgf000100_0001
Mass spectrum (ESI+): m/z = 244 [M+H]+
(28) (6-amino-1-methyl-1 H-indazol-3-yl)-pyrrolidin-1 -yl-methanone
Figure imgf000100_0002
Rf value: 0.40 (silica gel: dichloromethane/methanol 95:5)
(29) θ-amino-i -methyl-I H-indazol-S-carboxylic acid-methylamide
Figure imgf000100_0003
Rf value: 0.40 (silica gel: dichloromethane/methanol 95:5)
(30) 6-amino-benzo[b]thiophene-3-carboxylic acid-amide
Figure imgf000100_0004
and
5-amino-benzo[b]thiophene-3-carboxylic acid-amide
Figure imgf000100_0005
Obtained as a mixture from the reaction of a mixture of 6-nitro- benzo[b]thiophene-3-carboxylic acid-amide and 5-nitro-benzo[b]thiophene-3- carboxylic acid-amide (Example IXXX (9)). The crude product is further reacted directly in Example Xl (42). Example XIII
Figure imgf000101_0001
carboxylate 6.6 g tert-butyl 5-nitro-2,3-dihydro-indole-1 -carboxylate are dissolved in 120 ml of methanol. 600 mg palladium on charcoal (10%) are added and the mixture is hydrogenated until no more educt can be detected by thin layer chromatography. The catalyst is suction filtered and washed with methanol. The solvent is eliminated in vacuo and the residue is taken up in 30 ml of pyridine. 6.1 g of 3,5-dichlorophenylsulphonyl chloride are added and the mixture is stirred for 5 hours at ambient temperature. Then the pyridine is eliminated in vacuo and the residue is divided between 1 N HCI and ethyl acetate. The organic phase is washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo. Yield: 11 g (99 % of theory) Mass spectrum (ESI"): m/z = 441 [M-H]"
The following compounds are obtained analogously to Example XIII:
(1 ) 3,5-dichloro-N-(1 -phenylacetyl-1 H-indol-5-yl)-phenylsulphonamide
Figure imgf000101_0002
and 3,5-dichloro-N-(1 -phenylacetyl-2,3-dihydro-1 H-indol-5-yl)- phenylsulphonamide
Figure imgf000102_0001
The hydrogenation is carried out in the presence of 1.2 equivalents of 1 N
HCI. The crude product is chromatographed on silica gel.
Mass spectrum (ESI"): m/z = 457 [M-H]" (3,5-dichloro-N-(1 -phenylacetyl-1 H- indol-5-yl)-phenylsulphonamide)
Mass spectrum (ESI"): m/z = 459 [M-H]" (3,5-dichloro-N-(1 -phenylacetyl-2,3- dihydro-1 H-indol-5-yl)-phenylsulphonamide)
(2) 3,5-dichloro-N-[1 -(phenylethyl)-i H-indol-5-yl]-phenylsulphonamide
Figure imgf000102_0002
Mass spectrum (ESI+): m/z = 445 [M+H]+
Example XIV
Figure imgf000102_0003
tert-butyl 5-nitro-2.3-dihvdro-indole-1 -carboxylate
5 g 5-nitro-2,3-dihydro-1 H-indole are dissolved in 70 ml acetonithle. 7.3 g di- tert-butyl-dicarbonate and 900 mg 4-dimethylaminopyridine are added thereto. After stirring for 24 hours at ambient temperature the mixture is divided between 1 N HCI and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution.
After drying with magnesium sulphate the solvents are eliminated in vacuo.
The residue is extracted from diisopropylether/petroleum ether.
Yield: 6.6 g (82 % of theory) Mass spectrum (ESI+): m/z = 265 [M+H]+
Example XV
3.5-dichloro-N-(2.3-dihvdro-1 H-indol-5-yl)-indolsulphonamide
4.08 g tert-butyl 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1 - carboxylate are dissolved in 70 ml dichloromethane. To this are added 25 ml trifluoroacetic acid and the solution is stirred for 2 hours at ambient temperature. The solvents are eliminated in vacuo and the residue is divided between saturated sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo. Yield: 3.O g (97 % of theory) Mass spectrum (ESI"): m/z = 341 [M-H]"
The following compounds are obtained analogously to Example XV:
(1 ) methyl 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-1 H-indole-3- carboxylate
Figure imgf000104_0001
Rf value: 0.50 (silica gel: petroleum ether/ethyl acetate 1 :1 )
Example XVI
Figure imgf000104_0002
tert. butyl ((3.5-dichloro-DhenylsulDhonvh-ri -d -oxy-Dvπdin-3-ylcarbamovh-
2.3-dihvdro-1 H-indol-5-yl1-aminol-acetate
85 mg tert. butyl {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-3-ylcarbamoyl)-
2,3-dihydro-1 H-indol-5-yl]-amino}-acetate are dissolved in 3 ml dichloromethane and 100 mg 3-chloro-perbenzoic acid are added. The mixture is stirred overnight at ambient temperature, diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 99:1 to 4:1 ).
Yield: 75 mg (86 % of theory)
Mass spectrum (ESI"): m/z = 591 [M-H]"
Example XVII
Figure imgf000104_0003
S-chloro-δ-methyl-phenylsulphonyl-chloride
300 mg S-chloro-δ-nnethyl-phenylannine are dissolved in 1 ml concentrated HCI and cooled to 00C . A solution of 170 mg sodium nitrite in 0.3 ml of water is added dropwise thereto. The solution thus prepared is added dropwise at 00C to a solution of 85 mg copper-ll-chlohde, 0.3 ml of water and 7 ml sulphur dioxide in glacial acetic acid (30%). The cooling bath is removed and the mixture is stirred for another 20 minutes at ambient temperature. Then it is heated to 400C for 10 minutes. It is then diluted with ice water, the solid is suction filtered and dried in the desiccator. The product is further reacted directly in Example Xl without any further purification. Yield: 370 mg (78 % of theory)
The following compounds are obtained analogously to Example XVII:
(1 ) 3-chloro-5-methoxy-phenylsulphonyl chloride
Figure imgf000105_0001
The aqueous phase is twice extracted with ethyl acetate. The combined organic phases are dried on magnesium sulphate and the solvent is eliminated in vacuo.
Rf value: 0.95 (silica gel; dichloromethane)
(2) S-chloro-δ-chlorosulphonyl-phenyl trifluoromethanesulphonate
Figure imgf000105_0002
The product is further reacted directly in Example Xl(14) without any further purification. Example XVIII
Figure imgf000106_0001
tert. butyl [(2-carbannoyl-benzorb1thiophene-5-yl)-(3,5-dichloro- phenylsulphonvD-aminoi-acetate
250 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-benzo[b]thiophen-2-carboxylate are dissolved in 30 ml ammonia- saturated methanol and stirred for 24 hours at ambient temperature. Then the solution is heated to 800C in a pressurised vessel for 8 hours. Then the solvent is eliminated in vacuo and the residue is extracted from diisopropylether. The product thus obtained is chromatographed on silica gel with cyclohexane/ethyl acetate (9:1 to 1 :4).
Yield: 141 mg (58 % of theory)
Mass spectrum (ESI+): m/z = 515 [M+H]+
Example IXX
Figure imgf000106_0002
1 -chloro-3-methoxy-5-nitro-benzene
10 g 3-chloro-5-nitrophenol are dissolved in 250 ml of ethanol. 11.9 g potassium carbonate and 6 ml dimethylsulphate are added and the mixture is stirred for 12 hours at ambient temperature. Then 3 ml of a 33 % ammonia solution are added and then the ethanol is eliminated in vacuo. The residue is taken up in water and the precipitated solid is suction filtered and dried. Yield: 10.37 g (96% of theory) Mass spectrum (El): m/z = 187 [M]+
Example XX
Figure imgf000107_0001
2,6-dichloro-pyhdine-4-sulphonic acid-O-ethyl-QH-carbazol-S-vD-amide
2 g 4-amino-2,6-dichloropyridine are dissolved in 8 ml concentrated HCI and cooled to 00C . A solution of 900 mg sodium nitrite in 2 ml of water is added dropwise thereto. The solution thus prepared is added dropwise at 00C to a solution of 550 mg copper-ll-chlohde, 1 ml of water and 10 ml sulphur dioxide in glacial acetic acid (30%). The cooling bath is removed and the mixture is stirred for 15 minutes at ambient temperature. Then it is diluted with ice water and the solid is suction filtered. The aqueous phase is extracted with ethyl acetate. The solid filtered off is dissolved in ethyl acetate. The combined ethyl acetate phases are dried on magnesium sulphate and the solvent is eliminated in vacuo. 1.2 g of (9-ethyl-9H-carbazol-3-yl)-methyl-amine and 15 ml of pyridine are added to the residue. The mixture is stirred for 12 hours at ambient temperature, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel with dichloromethane. Yield: 210 mg (10% of theory) Mass spectrum (ESI"): m/z = 418 [M-H]" Example XXI
Figure imgf000108_0001
rO-chloro-δ-tπiinethylsilylethvnyl-phenylsulphonvD-O-ethyl-QH-carbazol-S-yl)- aminoi-acetic acid 180 mg tert-butyl [(3-chloro-5-trinnethylsilylethynyl-phenylsulphonyl)-(9-ethyl- 9H-carbazol-3-yl)-amino]-acetate are dissolved in 5 ml dichloromethane. 1 ml of trifluoroacetic acid is added with stirring. The mixture is stirred overnight at ambient temperature and then the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Yield: 134 mg (74 % of theory)
Mass spectrum (ESI"): m/z = 537 [M-H]"
Example XXII
Figure imgf000108_0002
tert-butyl rO-chloro-δ-trimethylsilylethvnyl-phenylsulphonvD-O-ethyl-gH- carbazol-3-yl)-amino1-acetate
320 mg tert-butyl [(3-chloro-5-thfluoromethylsulphonyloxy-phenylsulphonyl)- (9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 4 ml dimethylformamide. 20 mg copper-l-iodide, 40 mg bis-triphenylphosphine- palladium-dichloride and 210 μl thmethylsilylacetylene are added under argon. Then the mixture is heated to 600C for 6 hours and then stirred overnight at ambient temperature. The mixture is then divided between saturated potassium carbonate solution and ethyl acetate. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to
95:5).
Yield: 223 mg (76 % of theory)
Mass spectrum (ESI+): m/z = 595 [M+H]+
Example XXIII
Figure imgf000109_0001
3-chloro-5-nitro-phenyl trifluoromethanesulphonate 2.2 g 3-chloro-5-nitrophenol are dissolved in 30 ml dichloromethane, combined with 1.1 ml of pyridine and cooled to -100C. A solution of 2.2 ml trifluoromethanesulphonic acid anhydride in 5 ml dichloromethane is added thereto, the mixture is left overnight to warm up to ambient temperature and then divided between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvent is eliminated in vacuo.
Yield: 3.5 g (81 % of theory)
Rf value: 0.90 (silica gel: dichloromethane)
Example XXIV
Figure imgf000109_0002
3-chloro-5-nitrophenol 1.65 g 3-chloro-5-nitroanisole are combined with 20.3 g pyridinium hydrochloride and heated to 2000C for 1 hour. Then the mixture is left overnight to come up to ambient temperature, 200 ml of water are added, the precipitated solid is suction filtered and dried in vacuo.
Yield: 860 mg (56 % of theory)
Mass spectrum (ESI"): m/z = 162 [M-H]"
Example XXV
Figure imgf000110_0001
3-chloro-5-nitroanisol 11.1 g 1-chloro-3,5-dinitrobenzene are dissolved in 100 ml of methanol and combined with 3 g sodium methoxide. Then the mixture is refluxed for 48 hours, cooled to ambient temperature and the solid is suction filtered.
Yield: 2.27 g (22 % of theory)
Mass spectrum (El): m/z = 187 [M]+
Example XXVI
Figure imgf000110_0002
1 -chloro-3,5-dinitrobenzene 18 g 3,5-dinitroaniline are suspended in 45 ml concentrated hydrochloric acid and 15 ml of water and cooled to 00C . A solution of 7.6 g sodium nitrite in 25 ml of water is added dropwise thereto. Then the diazonium salt solution thus obtained is added dropwise at 00C to a solution of 13 g of copper-l-chloride in 45 ml concentrated hydrochloric acid. Then the mixture is refluxed for 10 minutes. After cooling to ambient temperature it is extracted 3 times with 150 ml of ethyl acetate and the combined organic phases are washed with water. Then the mixture is dried on magnesium sulphate, the solvents are eliminated in vacuo and the residue is chromatographed on silica gel with petroleum ether/ ethyl acetate.
Yield: 11.15 g (58 % of theory)
Mass spectrum (El): m/z = 202 [M]+
Example XXVII
Figure imgf000111_0001
tert-butyl S-ftert-butoxycarbonyl-methyl-aminocarbonvD-G-nitro-indole-i- carboxylate
220 mg of θ-nitro-I H-indole-S-carboxylic acid-methylamide are dissolved in 10 ml of tetrahydrofuran. 350 mg di-tert.-butyl-dicarbonate are added thereto and the mixture is stirred for 3 hours at ambient temperature. Then the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 20:80) Yield: 95 mg (23 % of theory) Mass spectrum (ESI+): m/z = 420 [M+H]+
The following compounds are obtained analogously to Example XXVII:
(1 ) tert-butyl 3-(morpholine-4-carbonyl)-6-nitro-indole-1 -carboxylate
Figure imgf000111_0002
Mass spectrum (ESI+): m/z = 376 [M+H]+
(2) tert-butyl 3-(4-tert-butoxycarbonyl-piperazine-1 -carbonyl)-6-nitro-indole-1 - carboxylate
Figure imgf000112_0001
Mass spectrum (ESI+): m/z = 475 [M+H]+
(3) tert-butyl 3-(benzyl-tert-butoxycarbonyl-aminocarbonyl)-6-nitro-indole-1 - carboxylate
Figure imgf000112_0002
Mass spectrum (ESI+): m/z = 496 [M+H]+
(4) tert-butyl 3-(bis-tert.-butoxycarbonyl)-aminocarbonyl-6-nitro-indole-1 - carboxylate
Figure imgf000112_0003
The reaction is carried out in the presence of a catalytic amount of 4-N.N- dimethylamino-pyridine at 600C. The product is obtained in admixture with 3- (bis-tert.-butoxycarbonyl)-aminocarbonyl-6-nitro-1 H-indole. Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate 4:1 )
(5) tert-butyl 3-(tert-butoxycarbonyl-phenyl-aminocarbonyl)-6-nitro-indole-1 - carboxylate
Figure imgf000112_0004
The reaction is carried out in the presence of a catalytic amount of 4-N,N- dimethylamino-pyridine at 600C.
Rf value: 0.39 (silica gel; petroleum ether/ethyl acetate 4:1 ) Mass spectrum (ESI+): m/z = 482 [M+H]+
(6) tert-butyl 3-(4-tert-butoxycarbonyl-3-oxo-piperazine-1 -carbonyl)-6-nitro- indole-1 -carboxylate
Figure imgf000113_0001
The reaction is carried out in the presence of a catalytic amount of 4-N,N- dimethylamino-pyhdine at 600C. Mass spectrum (ESI+): m/z = 489 [M+H]+
(7) tert-butyl S-dimethylcarbamoyl-e-nitro-indole-i -carboxylate
Figure imgf000113_0002
The reaction is carried out in the presence of a catalytic amount of 4-N,N- dimethylamino-pyhdine. Mass spectrum (ESI+): m/z = 334 [M+H]+
Example XXVIII
Figure imgf000113_0003
6-nitro-1 H-indole-3-carboxylic acid-methylamide
250 mg θ-nitro-I H-indole-S-carboxylic acid are dissolved in 10 ml of tetrahydrofuran, combined with 240 mg carbonyl-diimidazole and stirred for 30 minutes at 60°C. Then 750 μl of a 2 M solution of methylamine in tetrahydrofuran is added and the mixture is stirred overnight at 600C. Then 1 N hydrochloric acid is added and the precipitated solid is suction filtered. Then the solid is extracted from ethyl acetate, suction filtered and dried. Yield: 225 mg (82 % of theory) Mass spectrum (ESI+): m/z = 220 [M+H]+
The following compounds are obtained analogously to Example XXVIII:
(1 ) morpholin-4-yl-(6-nitro-1 H-indol-3-yl)-methanone
Figure imgf000114_0001
Mass spectrum (ESI+): m/z = 276 [M+H]+
(2) tert-butyl 4-(6-nitro-1 H-indole-3-carbonyl)-piperazine-1 -carboxylate
Figure imgf000114_0002
Mass spectrum (ESI"): m/z = 373 [M-H]"
(3) 6-nitro-1 H-indole-3-carboxylic acid-benzylamide
Figure imgf000114_0003
Mass spectrum (ESI+): m/z = 296 [M+H]+
(4) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3-carboxylic acid-amide
Figure imgf000114_0004
The crude product is chromatographed on silica gel (cyclohexane/ethyl acetate 40:60 to 0:100).
Mass spectrum (ESI+): m/z = 398 [M+H]+
(5) 5-nitro-benzo[b]thiophene-3-carboxylic acid-methylamide
Figure imgf000115_0001
Mass spectrum (ESI+): m/z = 237 [M+H]+
(6) 6-nitro-benzo[b]thiophene-3-carboxylic acid-methylamide
Figure imgf000115_0002
Mass spectrum (ESI+): m/z = 237 [M+H]+
(7) tert. butyl (i -methylcarbamoyl-ethylj-carbamate
Figure imgf000115_0003
After the reaction has ended the mixture is diluted with ethyl acetate, washed with 1 M phosphoric acid solution and dried on magnesium sulphate. The solvents are then eliminated in vacuo. Mass spectrum (ESI+): m/z = 203 [M+H]+
(8) tert-butyl 2-methylcarbamoyl-pyrrolidine-1 -carboxylate
Figure imgf000115_0004
After the reaction has ended the mixture is divided between ethyl acetate and 1 M phosphoric acid solution. The organic phase is washed with 1 M sodium hydroxide solution and dried on magnesium sulphate. The solvents are eliminated in vacuo. Mass spectrum (ESI+): m/z = 229 [M+H]+
(9) 6-nitro-benzo[b]thiophene-3-carboxylic acid-amide
Figure imgf000116_0001
and 5-nitro-benzo[b]thiophene-3-carboxylic acid-amide
Figure imgf000116_0002
are obtained as a mixture during the reaction of a mixture of 6-nitro-benzo[b]- thiophene-3-carboxylic acid and 5-nitro-benzo[b]thiophene-3-carboxylic acid (Example XLV). The crude product is chromatographed on silica gel, while the two products are obtained as a mixture and further reacted directly in Example XII (30).
Example XXIX
Figure imgf000116_0003
6-nitro-1 H-indole-3-carboxylic acid
3.7 g 2,2,2-trifluoro-1 -(6-nitro-1 H-indol-3-yl)-ethanone are combined with 20 ml of a 40 % sodium hydroxide solution solution and refluxed for 4 hours.
After cooling to 00C the mixture is diluted with a little water and adjusted to pH 1 by the careful addition of concentrated hydrochloric acid. The precipitated solid is suction filtered and dissolved in dichloromethane/methanol 10:1. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is extracted from diethyl ether.
Yield: 3 g (100 % of theory) Mass spectrum (ESI"): m/z = 205 [M-H]" The following compounds are obtained analogously to Example XXIX:
(1 ) i-methyl-θ-nitro-I H-indole-S-carboxylic acid
Figure imgf000117_0001
Mass spectrum (ESI"): m/z = 219 [M-H]"
(2) 5-nitro-1 H-indole-3-carboxylic acid
Figure imgf000117_0002
Rf value: 0.30 (silica gel: dichloromethane/methanol 10:1 )
Example XXX
Figure imgf000117_0003
2,2,2-trifluoro-1 -(6-nitro-1 H-indol-3-yl)-ethanone 2.5 g 6-nitro-1 H-indole are dissolved in 10 ml dimethylformamide. 5 ml trifluoroacetic anhydride are added thereto and the mixture is heated to 600C for 3 hours. Then the mixture is diluted with ethyl acetate and the organic phase is washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is extracted from dichloromethane. Yield: 3.7 g (96 % of theory) Mass spectrum (ESI"): m/z = 257 [M-H]"
The following compounds are obtained analogously to Example XXX: (1 ) 2,2,2-trifluoro-i -(1 -methyl-6-nitro-1 H-indol-3-yl)-ethanone
Figure imgf000118_0001
Tetrahydrofuran is used as solvent. Mass spectrum (ESI"): m/z = 317 [M-HCOO]"
(2) 2,2,2-trifluoro-i -(5-nitro-1 H-indol-3-yl)-ethanone
Figure imgf000118_0002
The reaction is carried out overnight at ambient temperature. The product is extracted from ethyl acetate. Rf value: 0.50 (silica gel: petroleum ether/ethyl acetate 1 :1 )
Example XXXI
Figure imgf000118_0003
9-(2-phenylsulphonyl-ethyl)-3-nitro-9H-carbazole
3.39 g 9-(2-phenylsulphonyl-ethyl)-9H-carbazole are dissolved in 120 ml acetonitrile, and combined with 6.4 g ammonium-cerium-nitrate and 5 g silica gel. Then the mixture is heated to 700C for 4 hours, filtered hot and the solid is washed with hot acetonitrile. The mother liquor is freed from the solvent in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 98:2). Yield: 1.53 g (40 % of theory) Mass spectrum (ESI+): m/z = 381 [M+H]+
Example XXXII
Figure imgf000119_0001
9-(2-phenylsulphonyl-ethyl)-9H-carbazole
1.8 g 9H-carbazole and 9.8 g phenylvinylsulphone are suspended in 3 ml of tetrahydrofuran, cooled to 00C, combined with 60 μl benzyltrimethylammonium hydroxide (40 % solution in water) and stirred for
20 minutes. Then the mixture is heated to 115°C for 7 hours. Then it is divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1 ).
Yield: 2.35 g (65 % of theory)
Mass spectrum (ESI+): m/z = 336 [M+H]+
Example XXXIII
Figure imgf000119_0002
3-nitro-9H-carbazole 2.2 g 9-(2-phenylsulphonyl-ethyl)-3-nitro-9H-carbazole are dissolved in 40 ml of tetrahydrofuran, combined with 700 mg potassium-tert.-butoxide and stirred for 2 hours at ambient temperature. A further 100 mg potassium-tert.- butoxide are added and the mixture is stirred for 4 hours at ambient temperature. Then another 100 mg potassium-tert.-butoxide are added. The mixture is heated for 2 hours to 500C, divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is washed with saturated sodium chloride solution and dried with magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 80:20).
Yield: 900 mg (73 % of theory)
Mass spectrum (ESI+): m/z = 213 [M+H]+
Example XXXIV
Figure imgf000120_0001
G-O.δ-dichloro-phenylsulphonylaminoM H-indole-S-carboxylic acid- phenylamide
100 mg methyl 6-(3,5-dichloro-phenylsulphonylamino)-1 H-indole-3- carboxylate are dissolved in 5 ml of methanol, combined with 2 ml 1 N sodium hydroxide solution and stirred for 2 hours at ambient temperature. Then the mixture is divided between ethyl acetate and 2 N hydrochloric acid, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried on sodium sulphate. The solvents are eliminated in vacuo and the residue is taken up in 3 ml dimethylformamide. 114 mg O-(7- azabenzothazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU) and 65 μl N,N-diisopropyl-N-ethyl-amine are added and the mixture is stirred for 3 hours at 500C. Then it is divided between water and ethyl acetate, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried on sodium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 20:80). The product thus obtained is further reacted directly in Vl (28). Example XXXV
Figure imgf000121_0001
methyl 6-nitro-1 H-indole-3-carboxylate
1 g methyl 1 H-indole-3-carboxylate is dissolved in 5 ml acetic acid, combined with 500 μl concentrated nitric acid (>90%) and heated to 600C for 1 hour. The mixture is divided between water and dichloromethane and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried on sodium sulphate, freed from the solvent in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 40:60).
Yield: 290 mg (23 % of theory)
Mass spectrum (ESI"): m/z = 219 [M-H]"
In addition 275 mg of methyl 4-nitro-1 H-indole-3-carboxylate are obtained.
Example XXXVI
Figure imgf000121_0002
5-nitro-1 -(phenylethvD-1 H-benzimidazole
and
Figure imgf000121_0003
6-nitro-1 -(phenylethvD-1 H-benzimidazole
1 g 5-nitro-1 H-benzimidazole is dissolved in 10 ml dimethylformamide and combined with 270 mg NaH (60 % in mineral oil). The mixture is left for 1 hour with stirring and 1 ml phenylethylbromide is added. Then the mixture is stirred for 3 hours at ambient temperature and divided between saturated ammonium chloride solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 820 mg (50 % of theory) as an isomer mixture of 5-nitro-1-(phenylethyl)- 1 H-benzimidazole and 6-nitro-1 -(phenylethyl)-1 H-benzimidazole Mass spectrum (ESI+): m/z = 268 [M+H]+
Example XXXVII
Figure imgf000122_0001
δ-O.δ-dichloro-phenylsulphonylaminoM H-indol^-carboxylic acid- dimethylamide 55 mg 5-(3,5-dichloro-phenylsulphonylamino)-1 H-indole-2-carboxylic acid are dissolved in 2 ml of tetrahydrofuran, combined with 25 mg carbonyldiimidazole, stirred for 3 hours at ambient temperature and for 1 hour at 400C. Then the mixture is combined with 300 μl dimethylamine (2 M in tetrahydrofuran) and stirred overnight. The solvent is eliminated in vacuo and the residue is divided between ethyl acetate and 0.5 N hydrochloric acid. The organic phase is washed with water and saturated sodium chloride solution and dried on magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 30:70). Yield: 26 mg (44 % of theory)
Mass spectrum (ESI"): m/z = 410 [M-H]"
The following compounds are obtained analogously to Example XXXVII: (1 ) tert. butyl [(3-carbamoyl-1-methylcarbamoyl-2,3-dihydro-1 H-indol-5-yl)- (3,5-dichloro-phenylsulphonyl)-amino]-acetate
Figure imgf000123_0001
To form the imidazolide the mixture is heated to 600C for 1 hour. To form the methylamide the mixture is heated to 600C overnight. After the reaction has ended the mixture is divided between ethyl acetate and water and the organic phase is washed with saturated sodium chloride solution. Mass spectrum (ESI+): m/z = 557 [M+H]+
Example XXXVIII
Figure imgf000123_0002
δ-O.δ-dichloro-phenylsulphonylaminoM H-indol^-carboxylic acid
100 mg ethyl 5-(3,5-dichloro-phenylsulphonylamino)-1 H-indole-2-carboxylate are dissolved in 2 ml of tetrahydrofuran and combined with 2 ml of 1 N sodium hydroxide solution. The mixture is stirred for 48 hours at ambient temperature, the tetrahydrofuran is eliminated in vacuo, the residue is diluted with water, and 1 N hydrochloric acid is added until the pH is 2. The precipitated solid is suction filtered, washed with water and dried in vacuo. Yield: 60 mg (64 % of theory)
Mass spectrum (ESI"): m/z = 383 [M-H]" Example XXXIX
Figure imgf000124_0001
6-nitro-1 H-indole-3-carboxylic acid-amide
250 mg 6-nitro-1 H-indole-3-carboxylic acid are dissolved in 10 ml of toluene, combined with 3 ml of thionyl chloride and refluxed for 1 hour. Then the volatile constituents are eliminated in vacuo, the residue is taken up in dichloromethane and this is in turn eliminated in vacuo. Then it is taken up in 10 ml of tetrahydrofuran, combined with 6 ml of a 0.5 M solution of ammonia in dioxane and heated to 600C for 12 hours. The solvents are eliminated in vacuo, the residue is extracted from 1 N hydrochloric acid and the solid obtained is suction filtered and dried in vacuo. Yield: 230 mg (92 % of theory) Mass spectrum (ESI+): m/z = 206 [M+H]+
The following compounds are obtained analogously to Example XXXIX:
(1 ) 6-nitro-1 H-indole-3-carboxylic acid-phenylamide
Figure imgf000124_0002
Mass spectrum (ESI+): m/z = 282 [M+H]+
(2) 4-(6-nitro-1 H-indole-3-carbonyl)-piperazin-2-one
Figure imgf000124_0003
The acid chloride formed is reacted in dichloromethane with 2-oxo-piperazine in the presence of 1 equivalent of pyridine. Mass spectrum (ESI"): m/z = 287 [M-H]" (3) 6-nitro-1 H-indole-3-carboxylic acid-(1 -nnethylcarbannoyl-ethyl)-annide
Figure imgf000125_0001
The acid chloride formed is reacted in dichloromethane with 2-oxo-piperazine in the presence of 1 equivalent of pyridine. Mass spectrum (ESI+): m/z = 291 [M+H]+
(4) 6-nitro-1 H-indole-3-carboxylic acid-dimethylamide
Figure imgf000125_0002
The acid chloride formed is reacted in dichloromethane with dimethylamine (2M in tetrahydrofuran) in the presence of 1 equivalent of pyridine. Mass spectrum (ESI+): m/z = 234 [M+H]+
(5) methyl 5-nitro-1 H-indole-3-carboxylate
Figure imgf000125_0003
During the formation of the acid chloride, 2 drops of dimethylformamide are added and the mixture is refluxed for 5 hours. To form the methylester the mixture is refluxed in methanol for 5 hours. After cooling to ambient temperature the precipitated solid is suction filtered and dried in vacuo. Rf value: 0.40 (silica gel: dichloromethane/methanol 40:1 )
Example XL
Figure imgf000125_0004
1 -methyl-6-nitro-1 H-indole-3-carbonitrile
1.6 g 6-nitro-1 H-indole-3-carbonitrile are dissolved in 45 ml of tetrahydrofuran, combined with 1 g potassium-tert.-butoxide and stirred for 30 minutes. Then a solution of 560 μl methyl iodide in 5 ml of tetrahydrofuran is slowly added dropwise and the mixture is stirred for 5 hours. The solvents are eliminated in vacuo, water is added and the pH is adjusted to 4 by the addition of citric acid. The solid is suction filtered and washed with water and some cold methanol. Yield: 1.59 g (65 % of theory) Mass spectrum (ESI+): m/z = 219 [M+NH4]+
Example XLI
Figure imgf000126_0001
6-nitro-1 H-indole-3-carbonitrile
6.1 g 6-nitro-1 H-indole are dissolved in 100 ml acetonitrile and cooled to 00C . A solution of 3.2 ml chlorosulphonyl isocyanate in 25 ml acetonitrile is added dropwise and the mixture is stirred for 2 hours. Then a solution of 5 ml triethylamine in 25 ml acetonitrile is added dropwise. The mixture is stirred for
1 hour at ambient temperature and for 50 minutes at 800C. Then the solvents are eliminated in vacuo, the residue is extracted from cold water, the solid is suction filtered and washed successively with water, saturated sodium hydrogen carbonate solution and water. The solid thus obtained is dried in the desiccator. Then the solid is taken up in 500 ml dichloromethane/methanol 95:5 and stirred with some aluminium oxide. It is suction filtered through a thin layer of aluminium oxide and washed with 400 ml dichloromethane/methanol 95:5. The filtrate is evaporated down in vacuo and the residue is dried in vacuo.
Yield: 2.76 g (40 % of theory)
Mass spectrum (ESI"): m/z = 186 [M-H]" Example XLII
Figure imgf000127_0001
G-O.δ-dichloro-phenylsulphonylanninoM -methyl-1 H-indole-3-carboxylic acid- dimethylamide 300 mg 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3- carboxylic acid are dissolved in 2 ml dimethylformamide, combined with 319 μl N,N-diisopropyl-N-ethyl-amine and 241 mg O-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU) and stirred for 15 minutes at ambient temperature. 751 μl of a 2 M solution of dimethylamine in tetrahydrofuran are added and the mixture is stirred overnight at ambient temperature. Then it is divided between water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo. Yield: 360 mg (112 % of theory) Mass spectrum (ESI"): m/z = 424 [M-H]"
The following compounds are obtained analogously to Example XLII:
(1 ) 3,5-dichloro-N-[1 -methyl-3-(morpholine-4-carbonyl)-1 H-indol-6-yl]- phenylsulphonamide
Figure imgf000127_0002
Mass spectrum (ESI"): m/z = 466 [M-H]" (2) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3-carboxylic acid-methylamide
Figure imgf000128_0001
Mass spectrum (ESI"): m/z = 410 [M-H]"
(3) 3,5-dichloro-N-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H-indol-6-yl]- phenylsulphonamide
Figure imgf000128_0002
Mass spectrum (ESI"): m/z = 450 [M-H]"
(4) 3,5-dichloro-N-[1 -methyl-3-(piperidine-1 -carbonyl)-1 H-indol-6-yl]- phenylsulphonamide
Figure imgf000128_0003
Mass spectrum (ESI"): m/z = 464 [M-H]"
(5) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3-carboxylic acid-phenylamide
Figure imgf000129_0001
Mass spectrum (ESI"): m/z = 472 [M-H]"
(6) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3-carboxylic acid-benzylamide
Figure imgf000129_0002
Mass spectrum (ESI"): m/z = 486 [M-H]"
(7) N-[3-(azetidine-1 -carbonyl)-1 -methyl-1 H-indol-6-yl]-3,5-dichloro- phenylsulphonamide
Figure imgf000129_0003
Mass spectrum (ESI+): m/z = 438 [M+H]+
(8) 3,5-dichloro-N-[3-(3-hydroxy-pyrrolidine-1 -carbonyl)-1 -methyl-1 H-indol-6- yl]-phenylsulphonamide
Figure imgf000129_0004
Mass spectrum (ESI+): m/z = 468 [M+H]+ (9) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3-carboxylic acid-cyclopropylamide
Figure imgf000130_0001
Rf value: 0.34 (silica gel: petroleum ether/ethyl acetate 1 :2)
(10) 6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3-carboxylic acid-cyclopropyl-methyl-amide
Figure imgf000130_0002
Mass spectrum (ESI+): m/z = 452 [M+H]+
(11 ) 1 -[6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indole-3- carbonyl]-pyrrolidin-2-carboxylic acid-methylamide
Figure imgf000130_0003
Mass spectrum (ESI+): m/z = 509 [M+H]+
(12) (1 -methyl-6-nitro-1 H-indol-3-yl)-pyrrolidin-1 -yl-methanone
Figure imgf000130_0004
o
Mass spectrum (ESI+): m/z = 274 [M+H]+
(13) (1 -methyl -6-nitro-1 H-indazol-3-yl)-pyrrolidin-1 -yl-methanone
Figure imgf000131_0001
Obtained during the reaction of a mixture of 1 -methyl-6-nitro-1 H-indazole-3- carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid. The product is purified by chromatography on silica gel. Mass spectrum (ESI+): m/z = 275 [M+H]+
(14) i-methyl-θ-nitro-I H-indazole-S-carboxylic acid-methylamide
Figure imgf000131_0002
Obtained during the reaction of a mixture of 1 -methyl-6-nitro-1 H-indazole-3- carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid. The product is purified by chromatography on silica gel.
Mass spectrum (ESI+): m/z = 235 [M+H]+
Example XLIII
Figure imgf000131_0003
6-amino-1 -methyl-1 H-indole-3-carboxylic acid 12 g 6-nitro-1 -methyl-1 H-indole-3-carboxylic acid are dissolved in 500 ml of water, 60 ml 1 N sodium hydroxide solution and 30 ml of methanol. 1.2 g Raney nickel are added and the mixture is hydrogenated for 26 hours at 1.5 bar. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is suspended in 100 ml of pyridine. 16.3 g 3,5- dichlorophenylsulphonyl chloride are added and the mixture is stirred overnight at ambient temperature. The pyridine is eliminated in vacuo. The residue is divided between water and ethyl acetate and the pH is adjusted to 5 by the addition of citric acid. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are dried on magnesium sulphate. After elimination of the solvents the residue is chromatographed on silica gel (dichloromethane/methanol/acetic acid 95:5:1 to 89:10:1 ) Yield: 2.5 g (9 % of theory) Mass spectrum (ESI"): m/z = 397 [M-H]"
Example XLIV
Figure imgf000132_0001
1 -methyl-6-nitro-1 H-indole
4 g of 6-nitro-1 H-indole are added batchwise at 00C to 800 mg sodium hydride
(60 % in mineral oil) in 20 mg dimethylformamide. The mixture is stirred for 10 minutes, then 1.86 ml methyl iodide are added dropwise and the mixture is left overnight to come up to ambient temperature. Then it is divided between water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo.
Yield: 4.54 g (104 % of theory)
Mass spectrum (ESI+): m/z = 177 [M+H]+
The following compounds are obtained analogously to Example XLIV:
(1 ) 1 ,3-dimethyl-5-nitro-1 ,3-dihydro-benzimidazol-2-one
Figure imgf000132_0002
The product is extracted from ethyl acetate/methanol 95:5. Mass spectrum (ESI+): m/z = 208 [M+H]+
Example XLV
Figure imgf000133_0001
δ-nitro-benzorbithiophene-S-carboxylic acid
and
Figure imgf000133_0002
G-nitro-benzoFbithiophene-S-carboxylic acid
2 g benzo[b]thiophene-3-carboxylic acid are dissolved in 11 ml acetic anhydride and cooled to 00C. A solution of 4.4 ml concentrated nitric acid in 10 ml acetic acid is added dropwise, while not allowing the temperature to rise above 5°C. Then the mixture is stirred for 1.5 hours and then combined with 200 ml ice water. The solid is suction filtered and dried in vacuo. Then it is dissolved in hot ethanol. After cooling to ambient temperature the solid (5- nitro-benzo[b]thiophene-3-carboxylic acid, approximately 80 %) is suction filtered. By elimination of the solvent in vacuo, 6-nitro-benzo[b]thiophene-3- carboxylic acid (approx. 66 %) is obtained from the mother liquor. Yield: 250 mg (10 % of theory, about 80 %) 5-nitro-benzo[b]thiophene-3- carboxylic acid
Mass spectrum (ESI"): m/z = 222 [M-H]"
Yield: 624 mg (25 % of theory, about 66 %) 6-nitro-benzo[b]thiophene-3- carboxylic acid Mass spectrum (ESI"): m/z = 222 [M-H]"
Example XLVI
Figure imgf000134_0001
2-amino-N-nnethyl-propionannide
2 g tert. butyl (i -methylcarbannoyl-ethyl)-carbannate are dissolved in 20 ml dichloromethane, combined with 3.7 ml of a 4 M solution of hydrogen chloride in dioxane and stirred for 24 hours at ambient temperature. The solvents are eliminated in vacuo and the residue is divided between 10 ml 1 N sodium hydroxide solution and dichloromethane. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo. Yield: 400 mg (40 % of theory)
Mass spectrum (ESI+): m/z = 103 [M+H]+
Example XLVII
Figure imgf000134_0002
2-[6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indol-3-vπ-2-oxo- acetamide
400 mg [6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indol-3-yl]-oxo- acetyl-chloride are dissolved in 1.5 ml tetrahydroduran, combined with 550 μl concentrated ammonia (32 % solution in water) and stirred for 3.5 hours. The solvent is eliminated in vacuo and the residue is extracted from a little methanol. The solid is suction filtered and dried in vacuo.
Yield: 140 mg (37 % of theory)
Mass spectrum (ESI+): m/z = 426 [M+H]+
The following compounds are obtained analogously to Example XLVII: (1 ) 2-[6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indol-3-yl]-N- nnethyl-2-oxo-acetannide
Figure imgf000135_0001
Mass spectrum (ESI"): m/z = 438 [M-H]"
(2) 2-[6-(3,5-dichloro-phenylsulphonylamino)-1 -methyl-1 H-indol-3-yl]-N,N- dimethyl-2-oxo-acetamide
Figure imgf000135_0002
Mass spectrum (ESI+): m/z = 454 [M+H]+
(3) 3,5-dichloro-N-[1 -methyl-3-(2-oxo-2-pyrrolidin-1 -yl-acetyl)-1 H-indol-6-yl]- phenylsulphonamide
Figure imgf000135_0003
Mass spectrum (ESI+): m/z = 480 [M+H]+ Example XLVIII
Figure imgf000136_0001
rG-O.δ-dichloro-phenylsulphonylanninoM-iinethyl-I H-indol-S-yli-oxo-acetyl- chloride 1.1 g 3,5-dichloro-N-(1 -methyl-1 H-indol-6-yl)-phenylsulphonannide are dissolved in 15 ml diethyl ether, cooled to 00C and combined with 296 μl oxalyl chloride. Then the mixture is stirred for 2 hours at 00C and for 12 hours at ambient temp. The solvents are distilled off at 500C. The crude product thus obtained is further reacted directly (XLVII). Yield: 1.34 g (96 % of theory)
Example XLIX
Figure imgf000136_0002
δ-rtert-butoxycarbonylmethyl-O.δ-dichloro-phenylsulphonvD-aminoi-i- methylcarbamoyl-2,3-dihvdro-1 H-indole-3-carboxylic acid 100 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-1 -methylcarbamoyl-2,3-dihydro-1 H-indole-3-carboxylate are dissolved in 1.2 ml of tetrahydrofuran, combined with 349 μl of a 1 M solution of lithium hydroxide in water and stirred overnight at ambient temperature. Then the mixture is cooled to 00C, combined with 350 μl 1 M hydrochloric acid and divided between ethyl acetate and saturated sodium chloride solution. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 20:1 ). Yield: 40 mg (41 % of theory) Mass spectrum (ESI+): m/z = 558 [M+H]+
Example L
Figure imgf000137_0001
1 -tert-butyl-3-methyl 5-nitro-indole-1 ,3-dicarboxylate
5.9 g methyl 5-nitro-1 H-indole-3-carboxylate are dissolved in 100 ml acetonitrile, combined with 100 mg N,N-dimethylamino-pyhdine and a solution of 6.4 g di-tert.-butyl-dicarbonate in 20 ml of tetrahydrofuran is added dropwise thereto. The mixture is stirred overnight at ambient temperature, then heated to 300C for 30 minutes and cooled to 00C. The solid thus precipitated is suction filtered. The mother liquor is freed from the solvents in vacuo and the residue is extracted from petroleum ether/ethyl acetate. Yield: 7.4 g (86 % of theory) Rf value: 0.50 (silica gel: petroleum ether/ethyl acetate 3:1 )
Example LI
Figure imgf000137_0002
pyrrol id ine-2-carboxylic acid-methylamide * CF3CO?!-! 200 mg tert-butyl 2-methylcarbamoyl-pyrrolidine-1 -carboxylate are dissolved in 2 ml dichloromethane, combined with 1 ml trifluoroacetic acid and stirred for 2 hours at ambient temperature. Then the volatile constituents are eliminated in vacuo, the residue is dissolved in dichloromethane and diethyl ether and combined with some activated charcoal. Then the solution is filtered, evaporated down in vacuo and the residue is dried in vacuo. The product thus obtained is further reacted directly in V (8).
Example LII
Figure imgf000138_0001
3-chloro-5-methyl-aniline
2.4 g of 3-chloro-5-nitro-toluene are dissolved in 35 ml of ethanol, combined with 15.8 g tin dichloride-dihydrate and refluxed for 3 hours. The solvent is eliminated in vacuo, the residue is taken up in 4 M sodium hydroxide solution and filtered through kieselguhr. The filter cake is washed thoroughly with ethyl acetate. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 81 :15 to 70:30). Yield: 1.59 g (80 % of theory) Mass spectrum (ESI+): m/z = 142 [M+H]+
Example LIII
Figure imgf000138_0002
1 -methyl-6-nitro-1 H-indazole-3-carboxylic acid and o
Figure imgf000139_0001
2-methyl-6-nitro-2H-indazole-3-carboxylic acid
670 mg of a mixture of methyl 1 -methyl -6-nitro-1 H-indazole-3-carboxylate and methyl 2-methyl-6-nitro-2H-indazole-3-carboxylate (Example LV) are dissolved in 20 ml of ethanol, combined with 10 ml of 1 M sodium hydroxide solution and stirred for 2 hours. Then 10 ml of 1 M hydrochloric acid are added, the mixture is diluted with water and the precipitated solid is suction filtered. Then the solid is dissolved in dichloromethane/methanol 90:10. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is dried in vacuo. 640 mg of a mixture of 1 -methyl-6-nitro-1 H- indazole-3-carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid is obtained, which is further reacted directly in Example XLII (13) or in XLII (14).
Example LIV
Figure imgf000139_0002
methyl 1 -methyl-6-nitro-1 H-indazole-3-carboxylate and
Figure imgf000139_0003
methyl 2-methyl-6-nitro-2H-indazole-3-carboxylate
830 mg of e-nitro-I H-indazole-S-carboxylic acid are dissolved in 16 ml dimethylformamide, combined with 1.66 g potassium carbonate and 823 μl methyl iodide and stirred for 4 hours at 500C. After cooling to ambient temperature the mixture is divided between water and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo. The residue is dissolved in hot dimethylformamide and after cooling to ambient temperature the precipitated solid is suction filtered and washed with diethyl ether. 670 mg of a mixture of methyl i -methyl-θ-nitro-I H-indazole-S-carboxylate and methyl 2-methyl-6-nitro-2H-indazole-3-carboxylate is obtained, which is further reacted directly in Example LIII.
Example LV
Figure imgf000140_0001
tert. butyl [(3,5-dichloro-phenylsulphonyl)-(3-hvdroxymethyl-1 - methylcarbamoyl-2,3-dihvdro-1 H-indol-5-yl)-amino1-acetate 110 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)- amino]-1 -methylcarbamoyl-2,3-dihydro-1 H-indole-3-carboxylate are dissolved in 3 ml of tetrahydrofuran, cooled to 00C, combined with 4.2 mg lithium borohydride and stirred for 1 hour. Then the mixture is allowed to come up to ambient temperature and stirred overnight. Then it is divided between ethyl acetate and ice water, the pH is adjusted to 4 by the addition of citric acid and the phases are separated. The organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulphate and freed from the solvents in vacuo. The residue is chromatographed on silica gel (ethyl acetate). Yield: 43 mg (41 % of theory)
Mass spectrum (ESI+): m/z = 544 [M+H]+ Preparation of the end compounds:
Example 1
Figure imgf000141_0001
[O.δ-dichloro-phenylsulphonvD-d-phenylcarbannoyl^.S-dihvdro-I H-indol-δ- vD-aminoi-acetic acid
1.24 g tert. butyl [(3,5-dichloro-phenylsulphonyl)-(1-phenylcarbamoyl-2,3- dihydro-1 H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 5 ml of trifluoroacetic acid is added with stirring. The mixture is stirred for 2 hours at ambient temperature and then the solvents are eliminated in vacuo.
The residue is extracted from diisopropylether and cyclohexane.
Yield: 1.09 g (97 % of theory)
Mass spectrum (ESI+): m/z = 520 [M+H]+
The following compounds are obtained analogously to Example 1 :
(1 ) [(1 -benzylcarbamoyl-1 H-indol-5-yl)-(3,5-dichloro-phenylsulphonyl)-amino]- acetic acid
Figure imgf000141_0002
Mass spectrum (ESI+): m/z = 532 [M+H]+
(2) [(1 -benzylcarbamoyl-1 H-indol-4-yl)-(3,5-dichloro-phenylsulphonyl)-amino]- acetic acid
Figure imgf000142_0001
Mass spectrum (ESI+): m/z = 532 [M+H]+
(3) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylcarbamoyl-1 H-indol-5-yl)-amino]- acetic acid
Figure imgf000142_0002
Mass spectrum (ESI+): m/z = 518 [M+H]+
(4) [(1 -benzoyl-1 H-indol-δ-ylHS.δ-dichloro-phenylsulphonyO-aminol-acetic acid
Figure imgf000142_0003
Mass spectrum (ESI"): m/z = 501 [M-H]"
(5) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylacetyl-1 H-indol-5-yl)-amino]- acetic acid
Figure imgf000143_0001
Mass spectrum (ESI+): m/z = 517 [M+H]+
(6) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylacetyl-2,3-dihydro-1 H-indol-5-yl)- amino]-acetic acid
Figure imgf000143_0002
Mass spectrum (ESI+): m/z = 519 [M+H]+
(7) {(3,5-dichloro-phenylsulphonyl)-[1 -(phenylethyl)-i H-indol-5-yl]-amino}- acetic acid
Figure imgf000143_0003
Mass spectrum (ESI+): m/z = 503 [M+H]+
(8) {(3,5-dichloro-phenylsulphonyl)-[1-(phenylethyl)-3-(2,2,2-trifluoro-acetyl)- 1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000143_0004
Obtained as a by-product of the cleaving of tert. butyl {(3,5-dichloro- phenylsulphonyl)-[1-(phenylethyl)-1 H-indol-5-yl]-amino}-acetate to form {(3,5- dichloro-phenylsulphonyl)-[1 -(phenylethyl)-i H-indol-5-yl]-amino}-acetic acid. The products are separated by preparative HPLC. Mass spectrum (ESI"): m/z = 597 [M-H]"
(9) [(1 -benzoyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000144_0001
Mass spectrum (ESI+): m/z = 505 [M+H]+
(10) [(1 -phenylsulphonyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000144_0002
Mass spectrum (ESI"): m/z = 539 [M-H]"
(11 ) [(1 -benzylcarbamoyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000144_0003
Mass spectrum (ESI*): m/z = 534 [M+H]* (12) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylmethanesulphonyl-2,3-dihydro- 1 H-indol-5-yl)-amino]-acetic acid
Figure imgf000145_0001
Mass spectrum (ESI"): m/z = 553 [M-H]"
(13) {(3,5-dichloro-phenylsulphonyl)-[1 -(3-nitro-phenylcarbamoyl)-2,3-dihydro- 1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000145_0002
Mass spectrum (ESI+): m/z = 565 [M+H]+
(14) {(3,5-dichloro-phenylsulphonyl)-[1 -(2-nitro-phenylcarbamoyl)-2,3-dihydro- 1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000145_0003
Mass spectrum (ESI+): m/z = 565 [M+H]+
(15) {(3,5-dichloro-phenylsulphonyl)-[1 -(pyrazin-2-ylcarbamoyl)-2,3-dihydro- 1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000146_0001
Mass spectrum (ESI"): m/z = 520 [M-H]"
(16) {(3,5-dichloro-phenylsulphonyl)-[1 -(1 -oxy-pyridin-3-ylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000146_0002
Mass spectrum (ESI+): m/z = 537 [M+H]+
(17) [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)-amino]-acetic acid * CF3CO2H
Figure imgf000146_0003
Mass spectrum (ESI+): m/z = 401 [M+H]+
(18) [(3,5-dichloro-phenylsulphonyl)-(1 -methylcarbamoyl-2,3-dihydro-1 H-indol- 5-yl)-amino]-acetic acid
Figure imgf000146_0004
Mass spectrum (ESI+): m/z = 458 [M+H]+
(19) [N-(3,5-dichloro-phenyl-sulphonyl)-N-(1 -dimethylcarbamoyl-2,3-dihydro- 1 H-indol-5-yl)-amino]-acetic acid
Figure imgf000147_0001
Mass spectrum (ESI+): m/z = 472 [M+H]+
(20) {N-(3,5-dichloro-phenylsulphonyl)-N-[1 -(2-dimethylannino- ethylcarbamoyl^S-dihydro-I H-indol-S-yll-aminoJ-acetic acid * CF3CO2H
Figure imgf000147_0002
Mass spectrum (ESI+): m/z = 515 [M+H]+
(21 ) [[1 -(5-chloro-1 H-indol-2-carbonyl)-2,3-dihydro-1 H-indol-5-yl]-(3,5- dichloro-phenylsulphonyl)-amino]-acetic acid
Figure imgf000147_0003
Mass spectrum (ESI+): m/z = 578 [M+H]+
(22) methyl 5-[carboxymethyl-(3,5-dichloro-phenylsulphonyl)-amino]- benzo[b]thiophene-2-carboxylate
Figure imgf000147_0004
Mass spectrum (ESI"): m/z = 472 [M-H]" (23) [(2-carbamoyl-benzo[b]thiophene-5-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000148_0001
Mass spectrum (ESI+): m/z = 459 [M+H]+
(24) {(3,5-dichloro-phenylsulphonyl)-[1 -(phenylethyl)-i H-benzimidazol-5-yl]- amino}-acetic acid * CF3CO2H
Figure imgf000148_0002
Mass spectrum (ESI+): m/z = 504 [M+H]+
(25) {(3,5-dichloro-phenylsulphonyl)-[3-(phenylethyl)-3H-benzimidazol-5-yl)]- amino}-acetic acid * CF3CO2H
Figure imgf000148_0003
Mass spectrum (ESI+): m/z = 504 [M+H]+
(26) [(9H-carbazol-3-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid
Figure imgf000148_0004
The crude product is chromatographed on silica gel. Mass spectrum (ESI+): m/z = 449 [M+H]+
(27) [(3-chloro-5-methoxy-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-annino]- acetic acid
Figure imgf000149_0001
The crude product is chromatographed on silica gel. Mass spectrum (ESI+): m/z = 473 [M+H]+
(28) [(2,6-dichloro-pyridine-4-sulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]- acetic acid
Figure imgf000149_0002
Mass spectrum (ESI+): m/z = 478 [M+H]+
(29) {(3,5-dichloro-phenylsulphonyl)-[1-(3,5-dichloro-phenylsulphonyl)-3- methyl-1 H-indazol-5-yl]-amino}-acetic acid
Figure imgf000149_0003
Mass spectrum (ESI"): m/z = 620 [M-H]"
Rf value: 0.30 (silica gel: dichloromethane/methanol 95:5) (30) {(3,5-dichloro-phenylsulphonyl)-[3-(morpholine-4-carbonyl)-1 H-indol-6-yl]- amino}-acetic acid
Figure imgf000150_0001
Mass spectrum (ESI+): m/z = 512 [M+H]+
(31 ) {(3,5-dichloro-phenylsulphonyl)-[3-(piperazine-1 -carbonyl)-1 H-indol-6-yl]- amino}-acetic acid * CF3CO2H
Figure imgf000150_0002
Mass spectrum (ESI+): m/z = 511 [M+H]+
(32) [(3,5-dichloro-phenylsulphonyl)-(3-methylcarbamoyl-1 H-indol-6-yl)- amino]-acetic acid
Figure imgf000150_0003
Mass spectrum (ESI"): m/z = 454 [M-H]"
(33) [(3-benzylcarbamoyl-1 H-indol-6-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000150_0004
Mass spectrum (ESI+): m/z = 532 [M+H]+
(34) [(3,5-dichloro-phenylsulphonyl)-(3-phenylcarbamoyl-1 H-indol-6-yl)- amino]-acetic acid
Figure imgf000151_0001
Mass spectrum (ESI+): m/z = 518 [M+H]+
(35) [(3-carbamoyl-1 H-indol-6-yl)-(3,5-dichloro-phenylsulphonyl)-annino]-acetic acid
Figure imgf000151_0002
Mass spectrum (ESI+): m/z = 442 [M+H]+
(36) {(3,5-dichloro-phenylsulphonyl)-[1 -(3-oxo-piperazine-1 -carbonyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000151_0003
Mass spectrum (ESI+): m/z = 527 [M+H]+
(37) [[9-(2-phenylsulphonyl-ethyl)-9H-carbazol-3-yl]-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000151_0004
Mass spectrum (ESI"): m/z = 615 [M-H]" (38) {θ-tcarboxynnethyl^S.S-clichloro-phenylsulphonylJ-anninol-S- phenylcarbamoyl-indol-1 -yl}-acetic acid
Figure imgf000152_0001
Mass spectrum (ESI"): m/z = 574 [M-H]"
(39) [(3,5-dichloro-phenylsulphonyl)-(2-dimethylcarbannoyl-1 H-indol-5-yl)- amino]-acetic acid
Figure imgf000152_0002
Mass spectrum (ESI+): m/z = 470 [M+H]+
(40) [(3-cyano-1-methyl-1 H-indol-6-yl)-(3,5-dichloro-phenylsulphonyl)-amino]- acetic acid
Figure imgf000152_0003
Mass spectrum (ESI+): m/z = 438 [M+H]+
(41 ) [(3,5-dichloro-phenylsulphonyl)-(3-dimethylcarbamoyl-1 -methyl-1 H-indol- 6-yl)-amino]-acetic acid
Figure imgf000152_0004
Mass spectrum (ESI+): m/z = 484 [M+H]+
(42) [(3-carbamoyl-1 -methyl-1 H-indol-6-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000153_0001
Mass spectrum (ESI+): m/z = 456 [M+H]+
(43) [(3,5-dichloro-phenylsulphonyl)-(3-methylcarbamoyl-benzo[b]thiophene- 5-yl)-amino]-acetic acid
Figure imgf000153_0002
Mass spectrum (ESI"): m/z = 471 [M-H]"
(44) [(3,5-dichloro-phenylsulphonyl)-(3-methylcarbamoyl-benzo[b]thiophene- 6-yl)-amino]-acetic acid
Figure imgf000153_0003
Mass spectrum (ESI"): m/z = 471 [M-H]"
(45) {(3,5-dichloro-phenylsulphonyl)-[1 -(1 -methylcarbamoyl-ethylcarbamoyl)- 2,3-dihydro-1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000154_0001
Mass spectrum (ESI"): m/z = 527 [M-H]"
(46) {(3,5-dichloro-phenylsulphonyl)-[3-(3-oxo-piperazine-1 -carbonyl)-1 H- indol-6-yl]-amino}-acetic acid
Figure imgf000154_0002
Mass spectrum (ESI+): m/z = 525 [M+H]+
(47) {(3,5-dichloro-phenylsulphonyl)-[3-(1-methylcarbamoyl-ethylcarbamoyl)- 1 H-indol-6-yl]-amino}-acetic acid
Figure imgf000154_0003
Mass spectrum (ESI+): m/z = 527 [M+H]+
(48) {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(morpholine-4-carbonyl)-1 H- indol-6-yl]-amino}-acetic acid
Figure imgf000154_0004
Mass spectrum (ESI+): m/z = 526 [M+H]+
(49) [(3,5-dichloro-phenylsulphonyl)-(1 -methyl-3-methylcarbamoyl-i H-indol-6- yl)-amino]-acetic acid
Figure imgf000155_0001
Mass spectrum (ESI+): m/z = 470 [M+H]+
(50) {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H- indol-6-yl]-amino}-acetic acid
Figure imgf000155_0002
Mass spectrum (ESI+): m/z = 510 [M+H]+
(51 ) {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(piperidine-1 -carbonyl)-1 H- indol-6-yl]-amino}-acetic acid
Figure imgf000155_0003
Mass spectrum (ESI+): m/z = 524 [M+H]+
(52) [(3,5-dichloro-phenylsulphonyl)-(1 -methyl-3-phenylcarbamoyl-i H-indol-6- yl)-amino]-acetic acid
Figure imgf000155_0004
Mass spectrum (ESI+): m/z = 532 [M+H]+
(53) [(3-benzylcarbamoyl-1 -methyl-1 H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000156_0001
Mass spectrum (ESI"): m/z = 544 [M-H]"
(54) [(3,5-dimethyl-phenylsulphonyl)-(1 -methylcarbamoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetic acid
Figure imgf000156_0002
Mass spectrum (ESI+): m/z = 418 [M+H]+
(55) [(3,5-dichloro-phenylsulphonyl)-(3-dimethylcarbamoyl-1 H-indol-6-yl)- amino]-acetic acid
Figure imgf000156_0003
Mass spectrum (ESI+): m/z = 470 [M+H]+
(56) [(3-aminooxalyl-1 -methyl-1 H-indol-6-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000157_0001
Mass spectrum (ESI"): m/z = 482 [M-H]"
(57) [(3,5-dichloro-phenylsulphonyl)-(1 -methyl-3-methylaminooxalyl-i H-indol- 6-yl)-amino]-acetic acid
Figure imgf000157_0002
Mass spectrum (ESI+): m/z = 498 [M+H]+
(58) [(3,5-dichloro-phenylsulphonyl)-(3-dimethylaminooxalyl-1 -methyl-1 H- indol-6-yl)-amino]-acetic acid
Figure imgf000157_0003
Mass spectrum (ESI+): m/z = 512 [M+H]+
(59) {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(2-oxo-2-pyrrolidin-1 -yl- acetyl)-1 H-indol-6-yl]-amino}-acetic acid
Figure imgf000158_0001
Mass spectrum (ESI"): m/z = 536 [M-H]"
(60) [[3-(azetidine-1 -carbonyl)-1 -methyl-1 H-indol-6-yl]-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000158_0002
Mass spectrum (ESI+): m/z = 496 [M+H]+
(61 ) [(3,5-dichloro-phenylsulphonyl)-(1 ,3-dimethyl-2-oxo-2,3-dihydro-1 H- benzimidazol-5-yl)-amino]-acetic acid
Figure imgf000158_0003
Mass spectrum (ESI+): m/z = 444 [M+H]+
(62) 5-[carboxymethyl-(3,5-dichloro-phenylsulphonyl)-amino]-1 ■ methylcarbamoyl-2,3-dihydro-1 H-indole-3-carboxylic acid
Figure imgf000158_0004
Mass spectrum (ESI"): m/z = 500 [M-H]" (63) {(3,5-dichloro-phenylsulphonyl)-[1 -(2-nnethylcarbannoyl-pyrrolidine-1 - carbonyl)-2,3-dihydro-1 H-indol-5-yl]-amino}-acetic acid
Figure imgf000159_0001
Mass spectrum (ESI+): m/z = 555 [M+H]+
(64) [(3-carbamoyl-1 -methylcarbamoyl-2,3-dihydro-1 H-indol-5-yl)-(3,5- dichloro-phenylsulphonyl)-amino]-acetic acid
Figure imgf000159_0002
Mass spectrum (ESI+): m/z = 501 [M+H]+
(65) {(3,5-dichloro-phenylsulphonyl)-[3-(3-hydroxy-pyrrolidine-1 -carbonyl)-1 ■ methyl-1 H-indol-6-yl]-amino}-acetic acid
Figure imgf000159_0003
Mass spectrum (ESI+): m/z = 526 [M+H]+
(66) [(S-cyclopropylcarbamoyl-i -methyl-1 H-indol-6-yl)-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000160_0001
Mass spectrum (ESI+): m/z = 496 [M+H]+
(67) [[3-(cyclopropyl-methyl-carbamoyl)-1 -methyl-1 H-indol-6-yl]-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid
Figure imgf000160_0002
Mass spectrum (ESI+): m/z = 510 [M+H]+
(68) {(3,5-dichloro-phenylsulphonyl)-[1-methyl-3-(2-methylcarbamoyl- pyrrolidine-1 -carbonyl)-1 H-indol-6-yl]-amino}-acetic acid
Figure imgf000160_0003
Mass spectrum (ESI+): m/z = 567 [M+H]+
(69) {(3-chloro-5-methyl-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 ■ carbonyl)-1 H-indol-6-yl]-amino}-acetic acid
Figure imgf000160_0004
Mass spectrum (ESI+): m/z = 490 [M+H]+ (70) {(3,5-dimethyl-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H- indol-6-yl]-amino}-acetic acid
Figure imgf000161_0001
Mass spectrum (ESI+): m/z = 470 [M+H]+
(71 ) {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 -carbonyl)-1 H- indazol-6-yl]-amino}-acetic acid
Figure imgf000161_0002
Mass spectrum (ESI+): m/z = 511 [M+H]+
(72) [(3,5-dichloro-phenylsulphonyl)-(1 -methyl-3-methylcarbamoyl-i H-indazol- 6-yl)-amino]-acetic acid
Figure imgf000161_0003
Mass spectrum (ESI+): m/z = 471 [M+H]+
(73) [(3-carbamoyl-benzo[b]thiophene-6-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000162_0001
Mass spectrum (ESI+): m/z = 476 [M+NH4]+
(74) [(3-carbamoyl-benzo[b]thiophene-5-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid
Figure imgf000162_0002
Mass spectrum (ESI"): m/z = 457 [M-H]"
(75) [(3,5-dichloro-phenylsulphonyl)-(3-hydroxymethyl-1-methylcarbamoyl-2,3- dihydro-1 H-indol-5-yl)-amino]-acetic acid
Figure imgf000162_0003
Mass spectrum (ESI+): m/z = 488 [M+H]+
Example 2
Figure imgf000162_0004
Methyl lO.δ-dichloro-DhenylsulDhonvD-fi -fDyridin-S-ylcarbamovD^.S-dihvdro- 1 H-indol-5-yli-anninol-acetate
610 mg tert-butyl S-^S-dichloro-phenylsulphonylJ-methoxycarbonylmethyl- amino]-2,3-dihydro-indole-1 -carboxylate are dissolved in 8 ml dichloromethane. 4 ml of trifluoroacetic acid are added with stirring. The mixture is stirred for 2 hours at ambient temperature and then the solvents are eliminated in vacuo. The residue is divided between saturated sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried on sodium sulphate. The solvents are eliminated in vacuo and the residue is taken up in 10 ml dichloromethane. 245 mg potassium carbonate and 150 mg 3-pyhdylisocyanate are added and the mixture is stirred overnight at ambient temperature. The solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. A solid is precipitated which is suction filtered and dried in vacuo. Yield: 340 mg (54 % of theory) Mass spectrum (ESI+): m/z = 535 [M+H]+
Example 3
Figure imgf000163_0001
(O.δ-dichloro-DhenylsulDhonvπ-ri-fDyridin-S-ylcarbamovh^.S-dihvdro-I H- indol-5-yli-aminol-acetic acid
220 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)- amino]-acetate are dissolved in 10 ml dichloromethane. 166 mg potassium carbonate and 121 mg 3-pyhdylisocyanate are added and the mixture is stirred overnight at ambient temperature. The reaction mixture is divided between water and dichloromethane. The aqueous phase is extracted twice with dichloromethane and the combined organic phases are dried on sodium sulphate. The solvent is eliminated in vacuo and the residue is taken up in 8 ml dichloromethane. 4 ml trifluoroacetic acid are added and the mixture is stirred for 2 hours at ambient temperature. The solvents are eliminated in vacuo and the residue is extracted from diisopropylether and petroleum ether. The solid is suction filtered and dried in vacuo. Mass spectrum (ESI+): m/z = 521 [M+H]+
Example 4
Figure imgf000164_0001
[(i -acetyl^.S-dihvdro-I H-indol-δ-vD-O.δ-dichloro-DhenylsulDhonvD-aminoi- acetic acid
40 mg [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)-amino]- acetic acid are dissolved in 2 ml dichloromethane. 100 μl acetic anhydride are added and the mixture is stirred overnight at ambient temperature. The volatile constituents are eliminated in vacuo and the residue is purified by chromatography on silica gel with dichloromethane/methanol (99:1 to 85:15).
The product thus obtained is extracted from diethyl ether/diisopropylether.
The solid is suction filtered and dried in vacuo.
Yield: 15 mg (34 % of theory) Mass spectrum (ESI+): m/z = 443 [M+H]+
Example 5
Figure imgf000165_0001
[O.δ-dichloro-phenylsulphonvD-d-iinethylcarbannoyl^.S-dihvdro-I H-indol^- vh-aminoi-acetic acid 300 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(1-methylcarbannoyl-2,3- dihydro-1 H-indol-4-yl)-amino]-acetate are dissolved in 4 ml of a 4 N solution of HCI in dioxane. The mixture is stirred overnight at RT and the solvents are then eliminated in vacuo. The residue is extracted from dichloromethane. Yield: 155 mg (58 % of theory) Mass spectrum (ESI+): m/z = 458 [M+H]+
The following compounds are obtained analogously to Example 5:
(1 ) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylcarbamoyl-2,3-dihydro-1 H-indol- 4-yl)-amino]-acetic acid
Figure imgf000165_0002
Mass spectrum (ESI+): m/z = 520 [M+H]+
(2) {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-3-ylcarbamoyl)-2,3-dihydro-1 H- indol-4-yl]-amino}-acetic acid * HCI
Figure imgf000165_0003
The crude product is extracted from diethyl ether. Mass spectrum (ESI+): m/z = 521 [M+H]+
(3) methyl 5-[carboxymethyl-(3,5-dichloro-phenylsulphonyl)-amino]-2,3- dihydro-indole-1 -carboxylate
Figure imgf000166_0001
After the end of the reaction the dioxane is eliminated in vacuo. The residue is taken up in diethyl ether and the solid is filtered off. The solvent is eliminated in vacuo and the residue is purified by chromatography on silica gel. The product thus obtained is extracted from diisopropylether. Mass spectrum (ESI+): m/z = 476 [M+H]+
(4) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylcarbamoyl-2,3-dihydro-1 H-indol- 6-yl)-amino]-acetic acid
Figure imgf000166_0002
The crude product is extracted from diethyl ether. Mass spectrum (ESI+): m/z = 520 [M+H]+
(5) {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-4-ylcarbamoyl)-2,3-dihydro-1 H- indol-5-yl]-amino}-acetic acid * HCI
Figure imgf000166_0003
Mass spectrum (ESI+): m/z = 521 [M+H]+
(6) [(3,5-dichloro-phenylsulphonyl)-(1 H-indol-5-yl]-acetic acid
Figure imgf000167_0001
The crude product is extracted from diethyl ether. Mass spectrum (El): m/z = 398 [M]+
Example 6
Figure imgf000167_0002
r(3,5-dichloro-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino1-acetic acid 512 mg methyl [(3,5-dichloro-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)- amino]-acetate are dissolved in 5 ml of tetrahydrofuran. 3 ml 1 N sodium hydroxide solution are added and the mixture is stirred for 3 hours at ambient temperature. It is diluted with ice water and the precipitated solid is suction filtered. The solid is taken up in 15 ml dichloromethane and the organic phase is dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on silica gel with dichloromethane/methanol (10:0 to 9:1 ). Yield: 24 mg (5 % of theory) Mass spectrum (ESI"): m/z = 475 [M-H]"
Example 7
Figure imgf000167_0003
[(3-chloro-5-ethyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino1-acetic acid
104 mg [(3-chloro-5-ethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)- amino]-acetic acid are dissolved in 5 ml of ethyl acetate. 30 mg of platinum dioxide are added and the mixture is hydrogenated for 5.5 hours at 3 bar hydrogen pressure. Then the catalyst is removed by suction filtering, the solvent is eliminated in vacuo and the residue is purified by preparative HPLC. Yield: 38 mg (36 % of theory) Mass spectrum (ESI"): m/z = 469 [M-H]"
Example 8
Figure imgf000168_0001
rO.δ-dichloro-phenylsulphonvD-d-methylcarbamoyl^.S-dihvdro-I H-indol-δ- vD-aminoi-acetic acid-2-dimethylamino-ethylester * HCI
115 mg [(3,5-dichloro-phenylsulphonyl)-(1 -methylcarbamoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetic acid are dissolved in 5 ml of tetrahydrofuran. 90 mg carbonyldiimidazole are added thereto and the mixture is refluxed for 1 hour. After another hour's stirring at ambient temperature 56 μl of 2-dimethylamine- ethanol are added. The mixture is refluxed for 2 hours and stirred for 1 hour at ambient temperature. Then the solvent is eliminated in vacuo and the residue is divided between ethyl acetate and 1 N sodium hydroxide solution. The organic phase is washed once with water and once with saturated sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is taken up in 4 ml dichloromethane. 100 μl of a 4 N solution of hydrogen chloride in dioxane are added dropwise thereto. The solvent is then eliminated in vacuo and the residue is taken up twice in toluene and the latter is again eliminated in vacuo. Yield : 105 mg (74 % of theory)
Mass spectrum (ESI+): m/z = 529 [M+H]+
(1 ) ethyl [(3,5-dichloro-phenylsulphonyl)-(1 -methylcarbamoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetate
Figure imgf000169_0001
After the aqueous working up the crude product is extracted from ethyl acetate, diisopropylether and petroleum ether. Mass spectrum (ESI+): m/z = 486 [M+H]+
Example 9
Figure imgf000169_0002
r(3-chloro-5-ethvnyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino1-acetic acid 134 mg [(3-chloro-5-thmethylsilylethynyl-phenylsulphonyl)-(9-ethyl-9H- carbazol-3-yl)-amino]-acetic acid are dissolved in 2 ml of methanol, combined with 50 mg potassium carbonate and stirred for 2 hours at ambient temperature. Then the mixture is diluted with dichloromethane and washed with 4 M hydrochloric acid. The organic phase is dried on magnesium sulphate and the solvent is then eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Yield: 108 mg (93 % of theory)
Mass spectrum (ESI"): m/z = 465 [M-H]" Example 10
Coated tablets containing 75 mg of active substance
1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg
230.0 mg
Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin- ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet- making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape. Weight of core: 230 mg die: 9 mm, convex
The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg. Example 11
Tablets containing 100 mg of active substance
Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg
Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack- type drier at 500C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
Example 12
Tablets containing 150 mg of active substance
Composition: 1 tablet contains: active substance 50.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg
300.0 mg
Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Weight of tablet: 300 mg die: 10 mm, flat
Example 13
Hard gelatine capsules containing 150 mg of active substance
1 capsule contains: active substance 50.0 mg corn starch (dried approx. 80.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg
Preparation:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Example 14
Suppositories containing 150 mg of active substance
1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg
Preparation:
After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds. Example 15
Suspension containing 50 mg of active substance
100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g
70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml
Preparation:
The distilled water is heated to 700C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air. 5 ml of suspension contain 50 mg of active substance. Example 16
Ampoules containing 10 mg active substance
Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 ml
Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Example 17
Ampoules containing 50 mg of active substance
Composition: active substance 50.0 mg
0.01 N hydrochloric acid q.s. double-distilled water ad 10.0 ml
Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Claims

Patent Claims
1. Compounds of general formula (I)
Figure imgf000176_0001
wherein
R denotes a group of formula
Figure imgf000176_0002
wherein
R1 denotes H, Ci-6-alkyl or a group of formula
Figure imgf000176_0003
wherein the Ci-6-alkyl group mentioned for R1 hereinbefore may be substituted by Ci-6-alkyl-carbonyloxy, Ci-6-alkoxy- carbonyloxy, Ci-6-alkoxy, hydroxy, amino, Ci-3-alkyl-amino, di- (Ci-3-alkyl)-annino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci-3-alkyl)-piperazin-1-yl, aminocarbonyl, Ci-3- alkyl-aminocarbonyl, di-(Ci-3-alkyl)-anninocarbonyl, pyrrolidin-1 - yl-carbonyl, piperidin-1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-(Ci-3-alkyl)-piperazin-1 -yl-carbonyl, tetrahydrofuran-3-yl-oxy, Ci-s-alkylannino-Ci-s-alkyloxy, di-(Ci-3- alkyl)-amino-Ci-3-alkyloxy, pyrrolidin-1 -yl-Ci-3-alkyloxy, piperidin- 1 -yl-Ci-3-alkyloxy, morpholin-4-yl-Ci-3-alkyloxy, piperazin-1 -yl-Ci- 3-alkyloxy or 4-(Ci-3-alkyl)-piperazin-1 -yl-Ci-3-alkyloxy,
R2 and R3 independently of one another denote halogen, Ci-3- alkyl, C2-4-alkynyl, Ci-3-perfluoroalkyl, Ci-3-perfluoroalkoxy, Ci-3- alkoxy, cyano, nitro or hydroxy,
and
A denotes CH or N,
and the heterocyclic group
Figure imgf000177_0001
denotes a group of formula
Figure imgf000177_0002
Figure imgf000178_0001
wherein the above-mentioned heterocycles of formulae (Ia), (Ib), (Ic), (Ie), (If), (Ig), (Ii) and (In) may each optionally be substituted at the carbon atoms of the 5 ring by one or two groups selected from among Ci-3-alkyl, amino-Ci-3-alkyl, hydroxy-Ci-3-alkyl, cyano, Ci-3- perfluoroalkyl, C3-6-cycloalkyl, C2-4-alkynyl, C2-4-alkenyl, Ci-3-alkyl- carbonyl, Ci-s-perfluoroalkyl-carbonyl, carboxyl, Ci-3-alkyloxy-carbonyl, carboxy-Ci-3-alkyl, aminocarbonyl, Ci-3-alkyl-aminocarbonyl or di-(Ci-3- alkyl)-aminocarbonyl, wherein the groups may be identical or different and each carbon atom may carry only one group, and
wherein the above-mentioned heterocyclic group of formula (Ib) may optionally be substituted at the nitrogen atom of the 5 ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-6-alkyl, phenyl-Ci-6-alkyl, phenylsulphonyl-Ci-6- alkyl,
Ci-6-alkyl-carbonyl, carboxyl, Ci-6-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-6-alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-6-alkyl-aminocarbonyl, di-(Ci-6-alkyl)-aminocarbonyl, Cs-β-cycloalkyl-aminocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci-6-alkyl)-amino- carbonyl, aryl-amino-carbonyl, N-oxy-pyridylamino-carbonyl,
4- to 7-membered cycloalkyleneimino-carbonyl optionally substituted by hydroxy or Ci-3-alkyl-aminocarbonyl,
morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-(Ci-3-alkyl)- piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, Ci-s-alkylaminocarbonyl-carbonyl, di-(Ci-3- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl, piperidin-1 -ylcarbonyl-carbonyl, morpholin-4-ylcarbonyl-carbonyl, piperazin-1 -ylcarbonyl-carbonyl, 4-methyl-piperazin-1 -ylcarbonyl- carbonyl,
Ci-3-alkyl-sulphonyl, phenyl-Ci-3-alkylsulphonyl or phenylsulphonyl optionally substituted in the phenyl moiety by one or two chlorine atoms,
wherein the Ci-6-alkyl-aminocarbonyl, di-(Ci-6-alkyl)- aminocarbonyl and N-(C3-6-cycloalkyl)-N-(Ci-6-alkyl)-amino- carbonyl group mentioned above in the definition of R4 may each be substituted in the alkyl moiety by aryl, Ci-3-alkyl-annino, di-(Ci-
3-alkyl)-amino, Cs-e-cycloalkyl-amino, N-(C3-6-cycloalkyl)-N-(Ci-6- alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1 -yl, 4-methyl-piperazin-1 -yl or Ci-3- alkylaminocarbonyl, and
wherein the aryl group mentioned above in the definition of R4 is a 6-membered aromatic system that may contain 0 to 3 nitrogen atoms and may be substituted by nitro.
and the tautomers, stereoisomers, mixtures thereof and the salts thereof.
2. Compounds of general formula (I) according to claim 1 , wherein
R denotes a group of the formula given in claim 1 , wherein
R1 denotes H, Ci-6-alkyl or a group of formula
Figure imgf000180_0001
wherein the Ci-6-alkyl group mentioned for R1 hereinbefore may be substituted by Ci-6-alkyl-carbonyloxy, Ci-6-alkoxy- carbonyloxy, Ci-6-alkoxy, hydroxy, amino, Ci-3-alkyl-amino, di- (Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci-3-alkyl)-piperazin-1-yl, aminocarbonyl, C 1.3- alkyl-aminocarbonyl, di-(Ci-3-alkyl)-aminocarbonyl, pyrrolidin-1- yl-carbonyl, pipehdin-1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl or 4-(Ci-3-alkyl)-piperazin-1 -yl-carbonyl, R2 and R3 independently of one another denote halogen, Ci-3-alkyl, C2- 4-alkynyl, Ci-3-perfluoroalkyl, Ci-2-alkoxy or cyano and
A denotes CH or N, and the heterocyclic group
Figure imgf000181_0001
denotes a group of formula
Figure imgf000181_0002
wherein the above-mentioned heterocycles of formulae (Ia), (Ib), (Ic), (Ie), (If), (Ig), (Ii) and (In) may each optionally be substituted at the carbon atoms of the 5 ring by one or two groups selected from among Ci-3-alkyl, amino-Ci-3-alkyl, hydroxy-Ci-3-alkyl, cyano, C3-6-cycloalkyl, Ci-3-alkyl-carbonyl, Ci-3-perfluoroalkyl-carbonyl, carboxyl, Ci-2-alkyloxy- carbonyl, carboxy-Ci-2-alkyl, aminocarbonyl, Ci-3-alkyl-aminocarbonyl or di-(Ci-3-alkyl)-aminocarbonyl, wherein the groups may be identical or different and each carbon atom may carry only one group, and
wherein the above-mentioned heterocyclic group of formula (Ib) may optionally be substituted at the nitrogen atom of the 5 ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-4-alkyl, phenyl-Ci-4-alkyl, phenylsulphonyl-Ci-4- alkyl,
Ci-4-alkyl-carbonyl, carboxyl, Ci-4-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-4-alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-4-alkyl-aminocarbonyl, di-(Ci-4-alkyl)-aminocarbonyl,
C3-6-cycloalkyl-aminocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci-4-alkyl)-amino- carbonyl, [N,N-di-(Ci-4-alkyl)-amino]-Ci-3-alkyl-amino-carbonyl, 1 - (methylaminocarbonylj-ethyl-amino-carbonyl, aryl-amino-carbonyl, aryl- Ci-3-alkyl-amino-carbonyl, N-oxy-pyhdylamino-carbonyl,
4- to 7-membered cycloalkyleneimino-carbonyl optionally substituted by hydroxy or methylaminocarbonyl,
morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-(methyl)-piperazin- 1 -yl-carbonyl, (piperazin-2-on-4-y)l-carbonyl, aminocarbonyl-carbonyl, Ci^-alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-i -ylcarbonyl-carbonyl, piperidin-i -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl,
Ci-2-alkyl-sulphonyl, phenyl-Ci-2-alkyl-sulphonyl or phenylsulphonyl optionally substituted in the phenyl moiety by one or two chlorine atoms,
while the aryl group mentioned above in the definition of R4 is a 6-membered aromatic system that may contain 0 to 2 nitrogen atoms and may be substituted by nitro,
the tautomers, stereoisomers, mixtures thereof and the salts thereof.
3. Compounds of general formula (I) according to claim 2, wherein
R denotes a group of the formula given in claim 1 , wherein
R1 denotes H, Ci-4-alkyl or a group of formula
Figure imgf000183_0001
wherein the Ci-4-alkyl group mentioned for R1 hereinbefore may be substituted by Ci-4-alkoxy, hydroxy, di-(Ci-3-alkyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1-yl or 4- (methyl)-piperazin-i-yl,
R2 and R3 independently of one another denote chlorine, bromine, Ci-2- alkoxy, C2-3-alkynyl or Ci-2-alkyl and denotes CH or N, and the heterocyclic group
Figure imgf000184_0001
denotes a group of formula
Figure imgf000184_0002
Figure imgf000185_0001
wherein the above-mentioned heterocycles of formulae (Ia1 ), (Ia2) and (Ie1 ) may each optionally be substituted at the carbon atoms of the 5 ring by a group selected from among Ci-2-alkyl, methylcarbonyl, trifluoromethylcarbonyl, carboxyl, methoxy-carbonyl, aminocarbonyl, methyl-aminocarbonyl, dimethyl-aminocarbonyl, aminomethyl or hydroxymethyl, and
wherein the above-mentioned heterocyclic group of formula (Ib1 ) may optionally be substituted at the nitrogen atom of the 5 ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-4-alkyl, phenyl-Ci-4-alkyl, phenylsulphonyl-Ci-4- alkyl,
Ci-4-alkyl-carbonyl, carboxyl, Ci-4-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-4-alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-4-alkyl-aminocarbonyl, di-(Ci-4-alkyl)-aminocarbonyl, C3-6-cycloalkyl-aminocarbonyl, N-(C3-6-cycloalkyl)-N-(Ci-4-alkyl)-amino- carbonyl, N,N-di-(Ci-3-alkyl)-amino-Ci-3-alkyl-amino-carbonyl, 1 - (methylanninocarbonyl)-ethyl-annino-carbonyl, phenylamino-carbonyl,
(nitrophenyl)-amino-carbonyl, phenyl-Ci-2-alkyl-annino-carbonyl, pyridinylamino-carbonyl, pyrazinylamino-carbonyl, N-oxy-pyridylamino- carbonyl,
azetidin-1-yl-carbonyl, pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylanninocarbonyl)-pyrrolidin-1 -yl-carbonyl, piperidin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, Ci^-alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl, piperidin-1 -ylcarbonyl-carbonyl, nnorpholin-4-ylcarbonyl-carbonyl,
benzyl-sulphonyl, phenylsulphonyl or 3.5-dichloro-phenyl-sulphonyl,
the tautomers, stereoisomers, mixtures thereof and the salts thereof.
4. Compounds of general formula (I) according to claim 3, wherein
R denotes a group of the formula given in claim 1 , wherein
R1 denotes H or a Ci-3-alkyl group optionally substituted by a di-(Ci-
3-alkyl)-amino group,
R2 and R3 independently of one another represent chlorine, ethynyl, methoxy, methyl or ethyl and
A denotes CH or N,
and the heterocyclic group
Figure imgf000187_0001
denotes a group of formula
Figure imgf000187_0002
wherein the above-mentioned heterocycles of formulae (Ia1 ) and (Ie1) may each optionally be substituted at the carbon atoms of the 5 ring by a group selected from among trifluoromethylcarbonyl, carboxyl, hydroxycarbonylmethyl, aminocarbonyl or hydroxymethyl, and
wherein the above-mentioned heterocyclic group of formula (Ib1 ) may optionally be substituted at the nitrogen atom of the 5 ring by methyl or hydroxycarbonylmethyl, and wherein
denotes H, cyano, Ci-3-alkyl, phenyl-Ci-2-alkyl, phenylsulphonyl-Ci-2- alkyl,
Ci-3-alkyl-carbonyl, Ci-2-alkoxy-carbonyl, phenylcarbonyl, phenyl-Ci-2- alkyl-carbonyl, 5-chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, Ci-3-alkyl-aminocarbonyl, di-(Ci-3-alkyl)-aminocarbonyl, cyclopropyl-aminocarbonyl, N-(cyclopropyl)-N-(Ci-2-alkyl)-amino- carbonyl, (N,N-dimethyl-amino)-ethyl-amino-carbonyl, 1 - (methylaminocarbonyl)-ethyl-amino-carbonyl, phenylamino-carbonyl, (nitrophenyl)-amino-carbonyl, phenyl-Ci-3-alkyl-carbonyl, phenyl-Ci-2- alkyl-amino-carbonyl, pyhdinylamino-carbonyl, pyrazinylamino- carbonyl, N-oxy-pyridin-3-ylamino-carbonyl,
azetidin-1 -yl-carbonyl, pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylaminocarbonyl)-pyrrolidin-1 -yl-carbonyl, piperidin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, Ci-2-alkylaminocarbonyl-carbonyl, di-(Ci-2- alkyl)-aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl,
benzyl-sulphonyl or phenyl-sulphonyl, the tautomers, stereoisomers, mixtures thereof and the salts thereof.
5. Compounds of general formula (I) according to claim 4, wherein
R denotes a group of the formula given in claim 1 , wherein
R1 denotes H, methyl, ethyl or 2-dimethylamino-ethyl,
R2 and R3 independently of one another denote chlorine, ethynyl, methoxy, methyl or ethyl and
denotes CH or N,
and the heterocyclic group
Figure imgf000189_0001
which may be substituted by R as hereinbefore described, denotes a group of formula
Figure imgf000189_0002
or
Figure imgf000190_0001
wherein the above-mentioned heterocyclic group of formula (Ia1 ) may optionally be substituted by thfluoromethylcarbonyl at the carbon atom of the 5 ring adjacent to the phenyl ring, and
wherein the above-mentioned heterocyclic group of formula (Ie1 ) may optionally be substituted by carboxyl, amino-carbonyl or hydroxymethyl at the carbon atom of the 5 ring adjacent to the phenyl ring, and
wherein the above-mentioned heterocyclic group of formula (Ib1 ) may optionally be substituted by methyl or hydroxycarbonylmethyl at the nitrogen atom of the 5 ring, and wherein
denotes H, cyano, ethyl, phenyl-ethyl, phenylsulphonyl-ethyl,
methyl-carbonyl, methoxy-carbonyl, phenylcarbonyl, benzylcarbonyl, 5- chloro-1 H-indol-2-yl-carbonyl,
aminocarbonyl, methyl-aminocarbonyl, dimethyl-aminocarbonyl, cyclopropyl-aminocarbonyl, N-(cyclopropyl)-N-(methyl)-aminocarbonyl, (N,N-dimethyl-amino)-ethyl-amino-carbonyl, i -(methylaminocarbonyl)- ethyl-amino-carbonyl, phenylamino-carbonyl, benzylamino-carbonyl, 3- nitro-phenylamino-carbonyl, 2-nitro-phenylamino-carbonyl, pyridin-3- ylamino-carbonyl, pyridin-4-ylamino-carbonyl, pyrazinylamino-carbonyl, N-oxy-pyridin-3-ylamino-carbonyl, azetidin-1-yl-carbonyl, pyrrolidin-1 -yl-carbonyl, 3-hydroxy-pyrrolidin-1 - yl-carbonyl, 2-(methylanninocarbonyl)-pyrrolidin-1 -yl-carbonyl, piperidin- 1 -yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1 -yl-carbonyl, (piperazin-2-on-4-yl)-carbonyl,
aminocarbonyl-carbonyl, methylaminocarbonyl-carbonyl, dimethyl- aminocarbonyl-carbonyl, pyrrolidin-1 -ylcarbonyl-carbonyl,
benzyl-sulphonyl or phenyl-sulphonyl,
the tautomers, stereoisomers, mixtures thereof and the salts thereof.
6. The following compounds according to claim 1 :
f4-)(1 ) [(3,5-dichloro-phenylsulphonyl)-(1 -phenylcarbamoyl-1 H-indol-5-yl)- amino]-acetic acid,
(2)(2) [(3,5-dichloro-phenylsulphonyl)-(1-phenylcarbamoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetic acid, f^}(3) {(3,5-dichloro-phenylsulphonyl)-[1-(3-nitro-phenylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetic acid, (4-)(4) {(3,5-dichloro-phenylsulphonyl)-[1 -(pyridin-3-ylcarbamoyl)-2,3-dihydro-
1 H-indol-5-yl]-amino}-acetic acid,
(§)(5) {(3,5-dichloro-phenylsulphonyl)-[1-(2-nitro-phenylcarbamoyl)-2,3- dihydro-1 H-indol-5-yl]-amino}-acetic acid,
(€-}(6) [(1 -acetyl-2,3-dihydro-1 H-indol-5-yl)-(3,5-dichloro-phenylsulphonyl)- amino]-acetic acid,
(7-}(7) [(3,5-dichloro-phenylsulphonyl)-(1 -methylcarbamoyl-2,3-dihydro-1 H- indol-5-yl)-amino]-acetic acid, t#)(8) {(3,5-dichloro-phenylsulphonyl)-[1-(pyridin-4-ylcarbamoyl)-2,3-dihydro-
1 H-indol-5-yl]-amino}-acetic acid, i~9)(9) [(2,6-dichloro-pyhdine-4-sulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]- acetic acid, (4-9)(10) {(3,5-dichloro-phenylsulphonyl)-[3-(morpholine-4-carbonyl)-1 H- indol-6-yl]-amino}-acetic acid,
(44-}(11 ) [(3,5-dichloro-phenylsulphonyl)-(3-dimethylcarbannoyl-1 -methyl-
1 H-indol-6-yl)-amino]-acetic acid,
(4-2--)(12) [(3,5-dichloro-phenylsulphonyl)-(3-methylcarbannoyl- benzo[b]thiophen-6-yl)-amino]-acetic acid,
(43-X13) {(3,5-dichloro-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetic acid,
(44-}(14) [(3,5-dimethyl-phenylsulphonyl)-(1-methylcarbamoyl-2,3-dihydro-
1 H-indol-5-yl)-amino]-acetic acid, f4-§)(15) [[3-(azetidine-1 -carbonyl)-1 -methyl-1 H-indol-6-yl]-(3,5-dichloro- phenylsulphonyl)-amino]-acetic acid,
(4€)(16) {(3,5-dichloro-phenylsulphonyl)-[3-(3-hydroxy-pyrrolidine-1 - carbonyl)-1 -methyl-1 H-indol-6-yl]-amino}-acetic acid, f4-7)(17) [[3-(cyclopropyl-methyl-carbamoyl)-1 -methyl-1 H-indol-6-yl]-(3,5- dichloro-phenylsulphonylj-anninol-acetic acid,
I4β)(18) {(3-chloro-5-methyl-phenylsulphonyl)-[1 -methyl-3-(pyrrolidine-1 - carbonyl)-1 H-indol-6-yl]-amino}-acetic acid,
(4#}(1 9) {(3,5-dimethyl-phenylsulphonyl)-[1-nnethyl-3-(pyrrolidine-1 - carbonylJ-I H-indol-θ-yll-anninoϊ-acetic acid and (20X20) [(3,5-dichloro-phenylsulphonyl)-(3-hydroxymethyl-1 - methylcarbannoyl-2,3-dihydro-1 H-indol-5-yl)-amino]-acetic acid,
the enantiomers, the mixtures and the salts thereof.
7. Physiologically acceptable salts of the compounds according to claims 1 to 6 with inorganic or organic acids or bases.
8. Pharmaceutical compositions, containing a compound according to at least one of claims 1 to 6 or a salt according to claim 7 optionally together with one or more inert carriers and/or diluents.
9. Use of a compound according to at least one of claims 1 to 6 or a salt according to claim 7 for preparing a pharmaceutical composition that is suitable for the treatment of type I and type Il diabetes mellitus.
10. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 6 or a salt according to claim 7 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
11. Process for preparing the compounds of general formula I according to claims 1 to 7, characterised in that
a) a compound of general formula (IV)
Figure imgf000193_0001
(IV)
wherein R2 R3, X, Y, Z and A are defined as in claim 1 , is alkylated and
b) if desired any protective group used to protect reactive groups during the reactions is cleaved afterwards or simultaneously and/or
c) a compound of general formula I thus obtained is resolved into its stereoisomers and/or
d) a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
PCT/EP2008/053087 2007-03-16 2008-03-14 Arylsulphonyglycine derivatives as suppressors of the interaction of glycogen phosphorylase a with the gl subunit of glycogen-associated protein phosphatase 1 (ppl) for the treatment of metabolic disorders, particulary diabetes WO2008113760A2 (en)

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WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors

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WO2008113760A3 (en) 2008-11-13
US8232312B2 (en) 2012-07-31
EP2125718B1 (en) 2010-09-15
US20100130557A1 (en) 2010-05-27
CA2681124A1 (en) 2008-09-25
ES2349331T3 (en) 2010-12-30
ATE481382T1 (en) 2010-10-15

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