WO2001007403A1 - Naphthyl-substituted sulfonamides - Google Patents

Naphthyl-substituted sulfonamides Download PDF

Info

Publication number
WO2001007403A1
WO2001007403A1 PCT/EP2000/006515 EP0006515W WO0107403A1 WO 2001007403 A1 WO2001007403 A1 WO 2001007403A1 EP 0006515 W EP0006515 W EP 0006515W WO 0107403 A1 WO0107403 A1 WO 0107403A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally
compounds
substituted
general formula
Prior art date
Application number
PCT/EP2000/006515
Other languages
German (de)
French (fr)
Inventor
Peter Eckenberg
Jürgen Reefschläger
Wolfgang Bender
Siegfried Goldmann
Michael Härter
Sabine Hallenberger
Jörg Keldenich
Olaf Weber
Kerstin Henninger
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU61570/00A priority Critical patent/AU6157000A/en
Publication of WO2001007403A1 publication Critical patent/WO2001007403A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to new naphthyl-substituted sulfonamides, processes for their preparation and their use as antiviral agents, in particular against cytomegaloviruses.
  • ⁇ , ⁇ -Naphthyl linked phenylsulfonamides are mainly known from phototechnical publications [cf. see JP-06 122 669-A2, EP-684 515-A1; JP-59 174 836-A2, DE-2 902 074, US-3 925 347, US-4 035 401, US-3 622 603, US-
  • WO 90/09 787 discloses sulfonamides as radio- or chemosensitizers and their use in the treatment of tumors.
  • the present invention relates to new compounds of the general formula (I)
  • R 1 represents hydrogen or (C, -C 6 ) alkanoyl
  • R 2 stands for (C ⁇ -C ö ) alkyl, which is formed by a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which may optionally also be bonded via the N atom, is substituted, or
  • R 4 for (-C-C ö ) alkyl optionally by amino, (-C-C 6 ) alkoxycarbonylamino, halogen or a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S or N, which can optionally also be bonded via the N atom, can be substituted, an aromatic 5- to 6-membered heterocyclic group having one to three heteroatoms from the series O, S or N, (C 3 -C 7 ) cycloalkyl , (CC 6 ) alkoxycarbonyl or
  • R and R are the same or different and each for
  • Hydrogen (-CC 6 ) alkyl, optionally selected from halogen, hydroxy by one to three substituents,
  • Carboxyl and (-C-C 6 ) alkoxy may be substituted, (C 7 -C 20 ) - alkyl or phenyl, which is optionally substituted by carboxyl, or
  • R 5 for (-CC 8 ) alkyl optionally with -CF 3 , -C 2 F 5 or with a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which may optionally also be bonded via the N atom, may be substituted, (C 3 -C 7 ) cycloalkyl or -NR 12 R ! 3 , in which
  • R 12 and R 13 are the same or different and each represent (d-C 6 ) alkyl, or
  • R 14 represents hydrogen, (-CC 6 ) alkyl, can be replaced,
  • R 7 represents (CC 6 ) alkyl
  • R 8 represents amino, mono- or di (-CC 6 ) alkylamino, or
  • R 1 and R 2 can both represent hydrogen if A or D represents (-C-C 6 ) alkylsulfonyl,
  • R 17 represents (C 1 -C 6 ) alkyl which is optionally substituted one to three times the same or different by hydroxy, halogen or (C 1 -C 4 ) alkoxycarbonyl,
  • A, D, E and G are identical or different and represent hydrogen, halogen, nitro, cyano, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or (Ci- C6) alkyl, (C ⁇ -C6) alkoxy, (C ⁇ -C 6 ) alkanoyloxy, (-C-C 6 ) alkoxycarbonyl or (C] -C 6 ) alkylsulfonyl, and their salts.
  • the substances according to the invention can also be present as salts.
  • Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid are preferred , Phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • metal or ammonium salts of the compounds according to the invention.
  • particular preference is given to Sodium-,
  • the compounds of the general formula (I) according to the invention can occur in various stereochemical forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers).
  • the invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • Invention includes. (CI -C ⁇ ) alkanoyl and (CI -C ⁇ ) alkanoyl in the definition (C ⁇ -Cg) alkanoyloxy stands for straight-chain or branched chain alkanoyl having 1 to 6 carbon atoms in the context of the invention. Examples include: formyl, acetyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl, pentanoyl and hexanoyl.
  • (-CC) alkyl generally stands for straight-chain or branched-chain hydrocarbon radicals having 1 to 6 carbon atoms.
  • (C 1 -C 4) alkyl or (C 3 -C 3) alkyl generally represent straight-chain or branched-chain hydrocarbon radicals having 1 to 4 or 1 to 3 carbon atoms. Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl and isohexyl.
  • (-C -Cs) alkyl reference is also made to straight-chain or branched-chain heptyl or octyl.
  • a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the O, S or N series, which can optionally also be bonded via the nitrogen atom includes, for example, pyrrolidinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl , Morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, tetrahydroognianyl, tetrahydrothienyl,
  • the (-C -C5) alkoxy group as used in the present invention, and as used in the definitions (C ⁇ -Cg) alkoxycarbonyl and (C ⁇ -C6) alkoxycarbonylamino, includes, for example, straight-chain or branched chain alkoxy groups with 1 to 6 A carbon atoms, particularly preferably alkoxy groups with 1 to 4 carbon atoms ((-C -C4) alkoxy), more preferably alkoxy groups with 1 to 3 carbon atoms ((C ⁇ -C3) alkoxy).
  • methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy can be mentioned.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine and fluorine are preferred.
  • An aromatic 5- to 6-membered heterocyclic group with one to three heteroatoms from the O, S or N series, which can optionally also be bonded via the nitrogen atom includes, for example: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.
  • Cycloalkyl stands for cycloalkyl groups with 3 to 7 carbon atoms and includes, for example: cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopropyl is preferred.
  • (C7-C2 ⁇ ) alkyl represents straight-chain or branched alkyl having 7 to 20
  • Carbon atoms e.g. Heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecy, octadecyl, nonadecyl and eicosanyl.
  • Saturated or unsaturated rings which form R 1 and R 2 , R 9 and R 10 or R 12 and R 13 together with the nitrogen atoms to which they are attached, with up to 7 C atoms, the ring carbon atoms of which may be 1 or 2 radicals selected from the group consisting of O, S, SO, CO and NR 11 or NR 14 or NR 16 , in which R 11 , R 14 and R 16 have the meaning given in claim 1, can be replaced, include, for example, the above-mentioned saturated 5 to
  • 6-membered heterocyclic groups which are bonded via the nitrogen atom, and, for example, morpholino, piperazinyl, piperidyl, which may optionally be mono- or di-unsaturated, 1-azacycloheptane, 1,4-diazacycloheptane, 1-azacyclooctane-1- yl, 1-azacycloheptan- 1-yl, 1,3-thiazole-idin-3-yl and dihydropyrrol-1-yl.
  • these rings can be fused with a phenyl ring.
  • Mono- or di (-C -Cg) alkylamino in the context of the invention includes those whose alkyl groups have 1 to 6 carbon atoms. This can be symmetrical or asymmetrical alkylamino groups, such as dimethylamino, diethylamino, methyl, ethylamino etc. This also applies to the
  • A, D, G and E in the general formula (I) are preferably hydrogen.
  • the compounds of general formula (I) of the invention basically include all positional isomers on the naphthyl and phenyl ring.
  • R 1 , R 2 , R 3 , A, D, E and G are as defined above, and their salts.
  • Another preferred embodiment relates to compounds of the formula (Ib)
  • R, ⁇ , R, R, A, D, E and G are as defined above, and their salts.
  • R 17 is (C 1 -C 6 ) alkyl which is optionally substituted one to three times the same or different by hydroxy, halogen or (C 1 -C 4 ) alkoxycarbonyl,
  • R 17 particularly preferred are compounds in which R is tert-butyl, which is optionally substituted by hydroxy, halogen or (-CC) alkoxycarbonyl.
  • the compounds of general formula (I) according to the invention can be prepared by:
  • A, D, E, G, R and R have the meaning given above, initially by catalytic hydrogenation on palladium / C or by reduction with SnCl 2 in inert solvents into the compounds of the general formula (III)
  • R, 17 has the meaning given above
  • T represents hydroxy, halogen, preferably chlorine
  • V represents halogen, preferably chlorine
  • the usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps.
  • These preferably include organic solvents such as ethers e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid triamidine, triamidine, triamidine, or trisaminophenamide,. It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, pyridine and dioxane are particularly preferred.
  • Suitable bases are organic amines, in particular trialkyl (C 1 -C 6 ) amines such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Pyridine, triethylamine and N-methylmorpholine are preferred.
  • the bases are generally used in an amount of 0.1 mol to 5 mol, preferably 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (III) and (IV).
  • Carbodiimides such as diisopropylcarbodimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l are suitable as auxiliaries.
  • the reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.
  • the reactions are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.
  • the reductions can generally by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides such as SnCl 2 , or boranes in inert solvents, optionally in the presence of a catalyst. Palladium on animal charcoal or SnCl 2 is preferred.
  • the reaction can be carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.
  • the reductions are generally carried out in a temperature range from 0 ° C. to + 60 ° C., preferably at + 10 ° C. to + 40 ° C.
  • Customary organic solvents which do not change under the reaction conditions are suitable as solvents for the acylation.
  • These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or chloro-benzene, chloro-benzene, chloro-benzene, chloro-benzene, chloro-benzene , Dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane and pyridine are preferred.
  • the ortho isomers can be prepared analogously.
  • Aniline 4 is prepared, for example, in accordance with US Pat. No. 3,979,202.
  • Aniline 6 is prepared, for example, according to S. Rajappa, R. Sreenivasan, A. Khalwadekar, J. Chem. Res. Miniprint 5, 1657 (1986).
  • the aniline 7 is produced e.g. according to WO 9631462.
  • the aniline 8 is produced e.g. according to R. W. Hartmann, M. Reichert, S. Goehring, Eur. J Med. Chem Chim. Ther. 29: 807 (1994).
  • Anilines 5 and 9 are prepared in an analogous manner.
  • the sulfonyl chlorides of Formula (VII) can be prepared in analogy to literature procedures, for example by acylation, sulfonation or Alkyliemng the corresponding Aminonaphtalinsulfonklaren by chlorination, for example with PC1 5 or SOCl 2, as shown in the following scheme.
  • the compounds of the general formula (I) according to the invention show an unforeseeable surprising spectrum of action. They show an antiviral effect against representatives of the group of herpes viridae, especially against that human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpes viruses, in particular diseases caused by human cytomegalovirus (HCMV).
  • the anti-HCMV activity was determined in a screening test system in 96-well microtiter plates with the aid of human embryonic pulmonary fibroblasts (HELF) cell cultures.
  • the influence of the substances on the spread of the cytopathogenic effect was determined in comparison to the reference substance ganciclovir (Cymevene R sodium), a clinically approved anti-HCMV chemotherapeutic.
  • the compounds according to the invention inhibit the multiplication of HCMV in HELF cells in concentrations which are in some cases 10-50 times lower than Cymeven R sodium and have a selectivity index which is several times higher.
  • the compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases which are triggered by human cytomegalovirus.
  • the following can be mentioned as indication areas:
  • HCMV infections Treatment and prophylaxis of HCMV infections in ATDS patients (retinitis, pneumonitis, gastrointestinal infections).
  • mice 5 week old male mice, strain NOD / LtSz-Prkdc (scid) / J, were obtained from a commercial breeder (The Jackson Lab., Bar Harbor). The animals were kept in isolators under sterile conditions (including bedding and feed). Virus / infection
  • Murine cytomegalovirus (MCMV), Smith strain, was passaged in vivo (BALB / c) and purified by fractional centrifugation. The titer was examined using a plaque assay on primary embryonic mouse fibroblasts. The mice were infected with a dose of 5x10 5 pfu in one
  • mice were treated with substance orally twice daily (morning and evening) over a period of 8 days.
  • the dose was 25 mg / kg body mass, the application volume 10 ml / kg body mass.
  • the substances were formulated in the form of a 0.5% tylose suspension. 16 hours after the last substance application, the animals were killed painlessly and the salivary gland, liver and kidney were removed.
  • the MCMV-DNA was quantified by means of DNA dot blot hybridization.
  • a digoxygenin-labeled (Boehringer-Mannheim, also listed buffer, unless otherwise described) 1.2 kb fragment from the MCMV range, Smith, Hindlll J, was used as the probe.
  • the signals were detected by means of chemiluminescence. For this, the membrane was washed for 3 minutes in 1 x digoxygenin wash buffer 1. The filters were then incubated for 30 minutes at room temperature with shaking in 1 x digoxygenin blocking solution.
  • the filters were then placed in 20 ml / 100 cm 2 for 30 minutes Incubate the membrane with the anti-DIG alkaline phosphatase conjugate solution (1: 20000 in 1 x digoxygenin blocking solution). 2 washing steps each lasting 15 minutes with 1 x digoxygenin washing buffer followed. This was followed by equilibration of the filters in 1 x digoxygenin detection buffer for 5 minutes and detection by means of 1 ml / 100 cm 2 membrane area 1: 100 diluted CDP-Star solution.
  • CDP-Star solution Spreading out the CDP-Star solution and incubating for 5 minutes in a dark box demonstrated the chemiluminescence or the evaluation using X-ray film (Kodak) or Lumilmager (Boehringer Mannheim).
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, parenterally or topically, in particular perlingually, intravenously or intravitreally, optionally as a depot in an implant.
  • solutions of the active ingredients can be used using suitable liquid carrier materials.
  • the organic phase is evaporated in a rotary evaporator and the residue is stirred well in 100 ml of diisopropyl ether for 2 hours, suction filtered, washed with diisopropyl ether and pentane and the residue is dried.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to compounds of general formula (I), to methods for preparing the same, to drugs containing said compounds as well as to the use thereof for treating viral infections and mainly cytomegalovirus infections.

Description

Naphthyl-substituierte SulfonamideNaphthyl substituted sulfonamides
Die vorliegende Erfindung betrifft neue Naphthyl-substituierte Sulfonamide, Verfahren zu ihrer Herstellung und ihre Verwendung als antivirale Mittel, insbesondere gegen Cytomegalieviren.The present invention relates to new naphthyl-substituted sulfonamides, processes for their preparation and their use as antiviral agents, in particular against cytomegaloviruses.
α,ß-Naphthyl verknüpfte Phenylsulfonamide sind überwiegend aus phototechnischen Publikationen bekannt [vgl. hierzu JP-06 122 669-A2, EP-684 515-A1; JP- 59 174 836-A2, DE-2 902 074, US-3 925 347, US-4 035 401, US-3 622 603, US-α, β-Naphthyl linked phenylsulfonamides are mainly known from phototechnical publications [cf. see JP-06 122 669-A2, EP-684 515-A1; JP-59 174 836-A2, DE-2 902 074, US-3 925 347, US-4 035 401, US-3 622 603, US-
3 482 971. EP-284 130].3,482,971. EP 284 130].
Die WO 90/09 787 offenbart Sulfonamide als Radio- oder Chemosensibilisie- rungsmittel und ihre Verwendung bei der Behandlung von Tumoren.WO 90/09 787 discloses sulfonamides as radio- or chemosensitizers and their use in the treatment of tumors.
Außerdem ist die Verbindung N-[4-[[[5-(Dimethylamino)-l-naphthalenyl]sulfonyl]- amino]phenyl]-acetamid bekannt (J. Inst. Chem. (India) (1976), 48, Pt 6, 280-5).In addition, the compound N- [4 - [[[5- (dimethylamino) -l-naphthalenyl] sulfonyl] amino] phenyl] acetamide is known (J. Inst. Chem. (India) (1976), 48, Pt 6 , 280-5).
Die vorliegende Erfindung betrifft neue Verbindungen der allgemeinen Formel (I),The present invention relates to new compounds of the general formula (I)
Figure imgf000002_0001
Figure imgf000002_0001
in welcherin which
R1 für Wasserstoff oder (C,-C6)Alkanoyl steht,R 1 represents hydrogen or (C, -C 6 ) alkanoyl,
R2 für (Cι-Cö)Alkyl steht, das durch eine gesättigte 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert ist, oderR 2 stands for (Cι-C ö ) alkyl, which is formed by a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which may optionally also be bonded via the N atom, is substituted, or
für eine Gruppe der Formelnfor a group of formulas
O 0 O O NHO 0 O O NH
II 5 II 7 -C-R< ■ — S-R5 ; ιι 6 ; — C-O-R6 ; S— R oder II 0 steht, worinII 5 II 7 -CR < ■ - SR 5 ; ιι 6; - COR 6 ; S— R or II 0, in which
R4 für (Cι-Cö)Alkyl, das gegebenenfalls durch Amino, (Cι-C6)Alkoxy- carbonylamino, Halogen oder eine gesättigte 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert sein kann, eine aromatische 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S oder N, (C3-C7)Cycloalkyl, (C C6)-Alkoxycarbonyl oderR 4 for (-C-C ö ) alkyl, optionally by amino, (-C-C 6 ) alkoxycarbonylamino, halogen or a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S or N, which can optionally also be bonded via the N atom, can be substituted, an aromatic 5- to 6-membered heterocyclic group having one to three heteroatoms from the series O, S or N, (C 3 -C 7 ) cycloalkyl , (CC 6 ) alkoxycarbonyl or
-NR9R10 steht,-NR 9 R 10 stands,
worin R und R gleich oder verschieden sind und jeweils fürwherein R and R are the same or different and each for
Wasserstoff, (Cι-C6)Alkyl, das gegebenenfalls durch ein bis drei Substituenten ausgewählt aus Halogen, Hydroxy,Hydrogen, (-CC 6 ) alkyl, optionally selected from halogen, hydroxy by one to three substituents,
Carboxyl und (Cι-C6)Alkoxy substituiert sein kann, (C7-C20)- Alkyl oder Phenyl, das gegebenenfalls durch Carboxyl substituiert ist, stehen, oderCarboxyl and (-C-C 6 ) alkoxy may be substituted, (C 7 -C 20 ) - alkyl or phenyl, which is optionally substituted by carboxyl, or
R9 und R10 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten Ring bilden mit bis zu 7 C-Atomen, dessen Ringkohlenstoffatome gegebenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, SO, C=O und N-R1 1 besteht, worin R1 ! für Wasserstoff oder (Cι-Cö)Alkyl steht, ersetzt sein können, R5 für (Cι-C8)Alkyl, das gegebenenfalls mit -CF3, -C2F5 oder mit einer gesättigten 5- bis 6-gliedrigen heterocychschen Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert sein kann, (C3-C7)Cycloalkyl oder -NR12R!3 steht, worinR 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring with up to 7 C atoms, the ring carbon atoms of which are optionally selected from the group consisting of O, S, SO and 1 or 2 radicals , C = O and NR 1 1 , where R 1! represents hydrogen or (-CC) alkyl, can be replaced, R 5 for (-CC 8 ) alkyl, optionally with -CF 3 , -C 2 F 5 or with a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which may optionally also be bonded via the N atom, may be substituted, (C 3 -C 7 ) cycloalkyl or -NR 12 R ! 3 , in which
R12 und R13 gleich oder verschieden sind und jeweils für (d- C6)Alkyl stehen, oderR 12 and R 13 are the same or different and each represent (d-C 6 ) alkyl, or
R12 und R13 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten Ring mit bis zu 7 Kohlenstoffatomen bilden, dessen Ringkohlenstoffatome gegebenenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, S=O, C=O und N-R14 besteht, worinR 12 and R 13 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring having up to 7 carbon atoms, the ring carbon atoms of which are optionally selected from the group consisting of O, S, S = O by 1 or 2 radicals , C = O and NR 14 , wherein
R14 für Wasserstoff, (Cι-C6)Alkyl steht, ersetzt sein können,R 14 represents hydrogen, (-CC 6 ) alkyl, can be replaced,
R6 für R15-OCH2CH2OCH2CH2-, worin R15 (Cι-C6)Alkyl ist, für eine gesättigte 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann und gegebenenfalls durch (Ci- C6)Alkyl substituiert ist, oder für (CrC6)Alkyl steht, das gegebenenfalls durch Hydroxy, (CrC6)Alkoxy, eine gesättigte, ungesättigte oder aromatische 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert sein kann,R 6 for R 15 -OCH 2 CH 2 OCH 2 CH 2 -, wherein R 15 is (-C-C 6 ) alkyl, for a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S , or N, which may optionally also be bonded via the N atom and is optionally substituted by (Ci-C 6 ) alkyl, or represents (CrC 6 ) alkyl, which may be saturated by hydroxy, (CrC 6 ) alkoxy , unsaturated or aromatic 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which can optionally also be bonded via the N atom, can be substituted,
R7 für (C C6)Alkyl steht,R 7 represents (CC 6 ) alkyl,
R8 für Amino, Mono- oder Di(Cι-C6)alkylamino steht, oderR 8 represents amino, mono- or di (-CC 6 ) alkylamino, or
R und R gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten Ring bilden mit bis zu 7 Kohlenstoffatomen, dessen Ringkohlenstoffatome gegebenenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, S=O, C=O und N-R16 besteht, worin R16 für Wasserstoff, (CrC6)Alkyl, das gegebenenfalls durch Halogen substituiert sein kann, oder für (Cι-C6)Alkanoyl, das gegebenenfalls durch 1 bis 3 Halogenatome substituiert sein kann, steht, ersetzt sein können, und wobei der Ring mit einem Phenylring kondensiert sein kann,R and R together with the nitrogen atom to which they are attached form a saturated or unsaturated ring having up to 7 carbon atoms, the ring carbon atoms of which are optionally selected by 1 or 2 radicals selected from the group consisting of O, S, S = O, C = O and NR 16 , in which R 16 represents hydrogen, (CrC 6 ) alkyl, which can optionally be substituted by halogen, or (C 1 -C 6 ) alkanoyl, which can optionally be substituted by 1 to 3 halogen atoms, can be replaced, and the ring can be fused with a phenyl ring,
oderor
R1 und R2 beide für Wasserstoff stehen können, wenn A oder D für (Cι-C6)Alkyl- sulfonyl steht,R 1 and R 2 can both represent hydrogen if A or D represents (-C-C 6 ) alkylsulfonyl,
RJ fürR J for
H H ι17 ι17H H ι17 ι17
-N~C°-R oder -CO-N-R' steht, worin- N ~ C ° - R or -CO-NR ' , in which
R17 für (Cι-C6)Alkyl steht, das gegebenenfalls ein- bis dreifach gleich oder verschieden durch Hydroxy, Halogen oder (Cι-C4)Alkoxycarbonyl substituiert ist,R 17 represents (C 1 -C 6 ) alkyl which is optionally substituted one to three times the same or different by hydroxy, halogen or (C 1 -C 4 ) alkoxycarbonyl,
A, D, E und G gleich oder verschieden sind und für Wasserstoff, Halogen, Nitro, Cyano, Hydroxy, Carboxyl, Trifluormethyl, Trifluormethoxy oder für (Ci- C6)Alkyl, (Cι-C6)Alkoxy, (Cι-C6)Alkanoyloxy, (Cι-C6)Alkoxycarbonyl oder (C]-C6)Alkylsulfonyl stehen, und deren Salze.A, D, E and G are identical or different and represent hydrogen, halogen, nitro, cyano, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or (Ci- C6) alkyl, (Cι-C6) alkoxy, (Cι-C 6 ) alkanoyloxy, (-C-C 6 ) alkoxycarbonyl or (C] -C 6 ) alkylsulfonyl, and their salts.
Die erfindungsgemäßen Stoffe können auch als Salze vorliegen. Im Rahmen der Erfindung sind physiologisch unbedenkliche Salze bevorzugt.The substances according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.
Physiologisch unbedenkliche Salze können Salze der erfmdungsgemäßen Verbindungen mit anorganischen oder organischen Säuren sein. Bevorzugt werden Salze mit anorganischen Säuren wie beispielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure oder Schwefelsäure, oder Salze mit organischen Carbon- oder Sulfon- säuren wie beispielsweise Essigsäure, Maleinsäure, Fumarsäure, Äpfelsäure, Zitronensäure, Weinsäure, Milchsäure, Benzoesäure, oder Methansulfonsäure, Ethansul- fonsäure, Phenylsulfonsäure, Toluolsulfonsäure oder Naphthalindisulfonsäure.Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid are preferred , Phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
Physiologisch unbedenkliche Salze können ebenso Metall- oder Ammoniumsalze der erfindungsgemäßen Verbindungen sein. Besonders bevorzugt sind z.B. Natrium-,Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. For example, particular preference is given to Sodium-,
Kalium-, Magnesium- oder Calciumsalze, sowie Ammoniumsalze, die abgeleitet sind von Ammoniak, oder organischen Aminen, wie beispielsweise Ethylamin, Di- bzw. Triethylamin, Di- bzw. Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Arginin, Lysin, Ethylendiamin oder 2-Phenylethylamin.Potassium, magnesium or calcium salts, and ammonium salts derived from ammonia, or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine ,
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) können in verschiedenen stereochemischen Formen auftreten, die sich entweder wie Bild und Spiegelbild (Enantiomere), oder die sich nicht wie Bild und Spiegelbild (Diastereo- mere) verhalten. Die Erfindung betrifft sowohl die Antipoden als auch die Racem- formen sowie die Diastereomerengemische. Die Racemformen lassen sich ebenso wie die Diastereomeren in bekannter Weise in die stereoisomer einheitlichen Bestandteile trennen.The compounds of the general formula (I) according to the invention can occur in various stereochemical forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers). The invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
Weiterhin können bestimmte Verbindungen in tautomeren Formen vorliegen. Dies ist dem Fachmann bekannt, und derartige Verbindungen sind ebenfalls vom Umfang derFurthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art, and such connections are also within the scope of the
Erfindung umfaßt. (CI -CÖ) Alkanoyl sowie (CI -CÖ) Alkanoyl in der Definition (Cι -Cg)Alkanoyloxy steht im Rahmen der Erfindung für geradkettiges oder verzweigtkettiges Alkanoyl mit 1 bis 6 Kohlenstoffatomen. Beispielsweise seien erwähnt: Formyl, Acetyl, Propanoyl, Isopropanoyl, Butanoyl, Isobutanoyl, Pentanoyl und Hexanoyl.Invention includes. (CI -CÖ) alkanoyl and (CI -CÖ) alkanoyl in the definition (Cι -Cg) alkanoyloxy stands for straight-chain or branched chain alkanoyl having 1 to 6 carbon atoms in the context of the invention. Examples include: formyl, acetyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl, pentanoyl and hexanoyl.
(Cι -Cö)Alkyl steht im Rahmen der Erfindung im allgemeinen für geradkettige oder verzweigtkettige Kohlenwasserstoffreste mit 1 bis 6 Kohlenstoffatomen. Entsprechend stehen (Cι -C4)Alkyl bzw. (Cι -C3)Alkyl im Rahmen der Erfindung im allge- meinen für geradkettige oder verzweigtkettige Kohlenwasserstoffreste mit 1 bis 4, bzw. 1 bis 3 Kohlenstoffatomen. Es seien beispielsweise genannt: Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl, Pentyl, Isopentyl, Hexyl und Isohexyl. Bezüglich (Cι -Cs)Alkyl sei zusätzlich auf geradkettiges oder verzweigtkettiges Heptyl oder Octyl verwiesen.In the context of the invention, (-CC) alkyl generally stands for straight-chain or branched-chain hydrocarbon radicals having 1 to 6 carbon atoms. Accordingly, in the context of the invention, (C 1 -C 4) alkyl or (C 3 -C 3) alkyl generally represent straight-chain or branched-chain hydrocarbon radicals having 1 to 4 or 1 to 3 carbon atoms. Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl and isohexyl. With regard to (-C -Cs) alkyl, reference is also made to straight-chain or branched-chain heptyl or octyl.
Eine gesättigte 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S oder N, die gegebenenfalls auch über das Stickstoffatom gebunden sein kann, schließt beispielsweise ein Pyrrolidinyl, Pyrro- lidino, Piperidino, Piperidyl, Piperazino, Piperazinyl, Morpholino, Morpholinyl, Thiomorpholino, Thiomorpholinyl, Tetrahydrofüranyl, Tetrahydrothienyl,A saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the O, S or N series, which can optionally also be bonded via the nitrogen atom, includes, for example, pyrrolidinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl , Morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, tetrahydrofüranyl, tetrahydrothienyl,
Pyrazolidinyl, Imidazolidinyl, 1,3-Thiazolidinyl, 2,4-Dioxanyl etc.Pyrazolidinyl, imidazolidinyl, 1,3-thiazolidinyl, 2,4-dioxanyl etc.
Die (Cι -C5)Alkoxygruppe, wie sie in der vorliegenden Erfindung verwendet wird, und wie sie auch in den Definitionen (Cι -Cg)Alkoxycarbonyl und (Cι -C6)Alkoxycarbonylamino verwendet wird, schließt beispielsweise geradkettige oder verzweigtkettige Alkoxygruppen mit 1 bis 6 Kohlenstoffatomen ein, besonders bevorzugt Alkoxygruppen mit 1 bis 4 Kohlenstoffatomen ((Cι -C4)Alkoxy), noch bevorzugter Alkoxygruppen mit 1 bis 3 Kohlenstoffatomen ((Cι-C3)Alkoxy). Beispielsweise können erwähnt werden Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, Pentoxy, Isopentoxy, Hexoxy und Isohexoxy. Bevorzugt sindThe (-C -C5) alkoxy group, as used in the present invention, and as used in the definitions (Cι -Cg) alkoxycarbonyl and (Cι -C6) alkoxycarbonylamino, includes, for example, straight-chain or branched chain alkoxy groups with 1 to 6 A carbon atoms, particularly preferably alkoxy groups with 1 to 4 carbon atoms ((-C -C4) alkoxy), more preferably alkoxy groups with 1 to 3 carbon atoms ((Cι-C3) alkoxy). For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy can be mentioned. Are preferred
Methoxy, Ethoxy und Propoxy. Halogen schließt im Rahmen der Erfindung Fluor, Chlor, Brom und Iod ein. Bevorzugt sind Chlor und Fluor.Methoxy, ethoxy and propoxy. Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine and fluorine are preferred.
Eine aromatische 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S oder N, die gegebenenfalls auch über das Stickstoffatom gebunden sein kann, schließt beispielsweise ein: Pyridyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Thiazolyl, Isothiazolyl, Thiadiazolyl, Oxazolyl, Isoxazolyl, Pyrazolyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, etc.An aromatic 5- to 6-membered heterocyclic group with one to three heteroatoms from the O, S or N series, which can optionally also be bonded via the nitrogen atom, includes, for example: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.
(C3-C7)Cycloalkyl steht für Cycloalkylgruppen mit 3 bis 7 Kohlenstoffatomen und schließt beispielsweise ein: Cyclopropyl, Cyclopentyl, Cyclohexyl und Cycloheptyl. Bevorzugt ist Cyclopropyl.(C 3 -C 7 ) Cycloalkyl stands for cycloalkyl groups with 3 to 7 carbon atoms and includes, for example: cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopropyl is preferred.
(C7-C2θ)Alkyl steht für geradkettiges oder verzweigtes Alkyl mit 7 bis 20(C7-C2θ) alkyl represents straight-chain or branched alkyl having 7 to 20
Kohlenstoffatomen, wie z.B. Heptyl, Octyl, Nonyl, Decyl, Undecyl, Dodecyl, Tridecyl, Tetradecyl, Pentadecyl, Hexadecyl, Heptadecy, Octadecyl, Nonadecyl und Eicosanyl.Carbon atoms, e.g. Heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecy, octadecyl, nonadecyl and eicosanyl.
Gesättigte oder ungesättigte Ringe, die R1 und R2, R9 und R10 oder R12 und R13 gemeinsam mit den Stickstoffatomen, an das sie gebunden sind, bilden, mit bis zu 7 C-Atomen, deren Ringkohlenstoffatome gegebenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, SO, CO und N-R11 bzw. NR14 bzw. NR16 besteht, worin R11, R14 und R16 die im Anspruch 1 angegebene Bedeutung haben, ersetzt sein können, schließen beispielsweise die oben genannten gesättigten 5- bisSaturated or unsaturated rings, which form R 1 and R 2 , R 9 and R 10 or R 12 and R 13 together with the nitrogen atoms to which they are attached, with up to 7 C atoms, the ring carbon atoms of which may be 1 or 2 radicals selected from the group consisting of O, S, SO, CO and NR 11 or NR 14 or NR 16 , in which R 11 , R 14 and R 16 have the meaning given in claim 1, can be replaced, include, for example, the above-mentioned saturated 5 to
6-gliedrigen heterocychschen Gruppen ein, die über das Stickstoffatom gebunden sind, ein, sowie beispielsweise Morpholino, Piperazinyl, Piperidyl, das gegebenenfalls ein- oder zweifach ungesättigt sein kann, 1 -Azacycloheptan, 1,4-Diazacycloheptan, 1-Azacyclooctan-l-yl, 1 -Azacycloheptan- 1-yl, 1,3-Thiazol- idin-3-yl und Dihydropyrrol-1-yl. Im Falle von R1 und R" können diese Ringe mit einem Phenylring kondensiert sein. Mono- oder Di(Cι -Cg)Alkylamino schließt im Rahmen der Erfindung solche ein, deren Alkylgruppen 1 bis 6 Kohlenstoffatome aufweisen. Dabei kann es sich um symmetrische oder unsymmetrische Alkylaminogruppen handeln, wie beispielsweise Dimethylamino, Diethylamino, Methyl, Ethylamino usw. Dies gilt auch für den6-membered heterocyclic groups which are bonded via the nitrogen atom, and, for example, morpholino, piperazinyl, piperidyl, which may optionally be mono- or di-unsaturated, 1-azacycloheptane, 1,4-diazacycloheptane, 1-azacyclooctane-1- yl, 1-azacycloheptan- 1-yl, 1,3-thiazole-idin-3-yl and dihydropyrrol-1-yl. In the case of R 1 and R ", these rings can be fused with a phenyl ring. Mono- or di (-C -Cg) alkylamino in the context of the invention includes those whose alkyl groups have 1 to 6 carbon atoms. This can be symmetrical or asymmetrical alkylamino groups, such as dimethylamino, diethylamino, methyl, ethylamino etc. This also applies to the
Mono- oder Di(Cι -C6)Alkylamino-Teil in der Mono- oder Di(Cι-C6)-Alkylamino- carbonyl-Gruppe.Mono- or di (-CC6) alkylamino part in the mono- or di (-CC6) alkylamino carbonyl group.
Bezüglich (Cι-C6)Alkylsulfonyl sei auf die oben erwähnten Definitionen für (C 1 -Cß) Alkyl verwiesen.Regarding (-C-C6) alkylsulfonyl, reference is made to the above-mentioned definitions for (C 1 -C 6) alkyl.
Bevorzugt stehen A, D, G und E in der allgemeinen Formel (I) für Wasserstoff.A, D, G and E in the general formula (I) are preferably hydrogen.
Die Verbindungen der allgemeinen Formel (I) der Erfindung schließen grundsätzlich alle Positionsisomere am Naphthyl- und Phenylring ein.The compounds of general formula (I) of the invention basically include all positional isomers on the naphthyl and phenyl ring.
Eine bevorzugte Ausführungsform betrifft jedoch Verbindungen der Formel (Ia)However, a preferred embodiment relates to compounds of the formula (Ia)
Figure imgf000009_0001
Figure imgf000009_0001
worin R1, R2, R3, A, D, E und G wie oben definiert sind, und deren Salze.wherein R 1 , R 2 , R 3 , A, D, E and G are as defined above, and their salts.
Eine weitere bevorzugte Ausführungsform betrifft Verbindungen der Formel (Ib)
Figure imgf000010_0001
Another preferred embodiment relates to compounds of the formula (Ib)
Figure imgf000010_0001
worin R , ι , R , R , A, D, E und G wie oben definiert sind, und deren Salze.wherein R, ι, R, R, A, D, E and G are as defined above, and their salts.
Weiterhin sind Verbindungen der Erfindung bevorzugt, worinCompounds of the invention are further preferred, wherein
RJ fürR J for
HH
1717
-N— CO-R steht.-N— CO-R stands.
worin R17 für (Cι-C6)Alkyl steht, das gegebenenfalls ein- bis dreifach gleich oder verschieden durch Hydroxy, Halogen oder (Cι-C4)Alkoxycarbonyl substituiert ist,in which R 17 is (C 1 -C 6 ) alkyl which is optionally substituted one to three times the same or different by hydroxy, halogen or (C 1 -C 4 ) alkoxycarbonyl,
17 besonders bevorzugt sind dabei Verbindungen, worin R für tert.-Butyl steht, das gegebenenfalls durch Hydroxy, Halogen oder (Cι-C )Alkoxycarbonyl substituiert ist.17 particularly preferred are compounds in which R is tert-butyl, which is optionally substituted by hydroxy, halogen or (-CC) alkoxycarbonyl.
Die erfmdungsgemäßen Verbindungen der allgemeinen Formel (I) können hergestellt werden, indem manThe compounds of general formula (I) according to the invention can be prepared by:
[A] Verbindungen der allgemeinen Formel (II)[A] compounds of the general formula (II)
Figure imgf000010_0002
in welcher
Figure imgf000010_0002
in which
A, D, E, G, R und R die oben angegebene Bedeutung haben, zunächst durch katalytische Hydrierung an Palladium/C oder durch Reduktion mit SnCl2 in inerten Lösemitteln in die Verbindungen der allgemeinen Formel (III)A, D, E, G, R and R have the meaning given above, initially by catalytic hydrogenation on palladium / C or by reduction with SnCl 2 in inert solvents into the compounds of the general formula (III)
Figure imgf000011_0001
in welcher
Figure imgf000011_0001
in which
A, D, E, G, R und R die oben angegebene Bedeutung haben,A, D, E, G, R and R have the meaning given above,
überführt,convicted
und abschließend mit Verbindungen der allgemeinen Formel (IV)and finally with compounds of the general formula (IV)
T-CO-R17 (IV)T-CO-R 17 (IV)
in welcherin which
R , 17 die oben angegebene Bedeutung hatR, 17 has the meaning given above
undand
T für Hydroxy, Halogen, vorzugsweise für Chlor steht,T represents hydroxy, halogen, preferably chlorine,
in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels umsetzt,in inert solvents, optionally in the presence of a base and / or an auxiliary,
oderor
[B] Verbindungen der allgemeinen Formel (Va) oder (Vb)
Figure imgf000012_0001
[B] Compounds of the general formula (Va) or (Vb)
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0002
in welcherin which
E, G und R , 17 die oben angegebene Bedeutung haben,E, G and R, 17 have the meaning given above,
zunächst wie unter [A] beschrieben durch Hydrierung an Pd/C oder durch Reduktion mit SnCl2 in inerten Lösemitteln in die Verbindungen der allgemeinen Formel (Via) oder (VIb)initially as described under [A] by hydrogenation on Pd / C or by reduction with SnCl2 in inert solvents into the compounds of the general formula (Via) or (VIb)
Figure imgf000012_0003
Figure imgf000012_0003
Figure imgf000012_0004
Figure imgf000012_0004
in welcher E, G und R .17 die oben angegebene Bedeutung haben,in which E, G and R .17 have the meaning given above,
überführttransferred
und abschließend mit Verbindungen der allgemeinen Formel (VII)and finally with compounds of the general formula (VII)
Figure imgf000013_0001
Figure imgf000013_0001
in welcherin which
11
A, D, R und R die oben angegebene Bedeutung haben,A, D, R and R have the meaning given above,
undand
V für Halogen, vorzugsweise für Chlor steht,V represents halogen, preferably chlorine,
in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels umsetzt.in inert solvents, optionally in the presence of a base and / or an auxiliary.
Das erfindungsgemäße Verfahren kann durch folgende Formelschemata beispielhaft erläutert werden: The method according to the invention can be illustrated by the following formula schemes:
Figure imgf000014_0001
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0003
oder
Figure imgf000015_0001
or
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0002
Als Lösemittel eignen sich für alle Verfahrensschritte die üblichen inerten Lösemittel, die sich unter den Reaktionsbedingungen nicht verändern. Hierzu gehören bevorzugt organische Lösemittel wie Ether z.B. Diethylether, Glykolmono- oder -dimethylether, Dioxan oder Tetrahydrofuran, oder Kohlenwasserstoffe wie Benzol, Toluol, Xylol, Cyclohexan oder Erdölfraktionen oder Halogenkohlenwasserstoffe wie Methylenchlorid, Chloroform, Tetrachlorkohlenstoff, oder Dimethylsulfoxid, Dimethylformamid, Hexamethylphosphorsäuretriamid, Essigester, Pyridin, Triethylamin oder Picolin. Ebenso ist es möglich, Gemische der genannten Lösemittel, gegebenenfalls auch mit Wasser zu verwenden. Besonders bevorzugt sind Methylenchlorid, Tetrahydrofuran, Pyridin und Dioxan.The usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps. These preferably include organic solvents such as ethers e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid triamidine, triamidine, triamidine, or trisaminophenamide,. It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, pyridine and dioxane are particularly preferred.
Als Basen eignen sich organische Amine, insbesondere Trialkyl(Cι-C6)amine wie beispielsweise Triethylamin oder Heterocyclen wie Pyridin, Methylpiperidin, Piperidin oder N-Methylmorpholin. Bevorzugt sind Pyridin, Triethylamin und N- Methylmorpholin. Die Basen werden im allgemeinen in einer Menge von 0,1 mol bis 5 mol, bevorzugt von 1 mol bis 3 mol jeweils bezogen auf 1 mol der Verbindungen der allgemeinen Formeln (III) und (IV) eingesetzt.Suitable bases are organic amines, in particular trialkyl (C 1 -C 6 ) amines such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Pyridine, triethylamine and N-methylmorpholine are preferred. The bases are generally used in an amount of 0.1 mol to 5 mol, preferably 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (III) and (IV).
Als Hilfsmittel eignen sich Carbodiimide wie beispielsweise Diisopropylcarbodi- imid, Dicyclohexylcarbodiimid oder N-(3-Dimethylaminopropyl)-N'-ethylcarbodi- imid-Hydrochlorid oder Carbonylverbindungen wie Carbonyldiimidazol oder 1,2- Oxazoliumverbindungen wie 2-Ethyl-5-phenyl-l,2-oxazolium-3-sulfonat oder Pro- panphosphorsäureanhydrid oder Isobutylchloroformat oder Benzotriazolyloxy-tris-Carbodiimides such as diisopropylcarbodimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l are suitable as auxiliaries. 2-oxazolium-3-sulfonate or propane phosphoric anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-
(dimethylamino)phosphonium-hexafluorophosphat oder Phosphonsäurediphenyl- esteramid oder Methansulfonsäurechlorid, gegebenenfalls in Anwesenheit von Basen wie Triethylamin oder N-Ethylmorpholin oder N-Methylpiperidin oder Dicyclohexylcarbodiimid und N-Hydroxysuccinimid.(dimethylamino) phosphonium hexafluorophosphate or phosphonic acid diphenyl ester amide or methanesulfonic acid chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.
Die Umsetzungen können bei Normaldruck, aber auch bei erhöhtem oder erniedrigtem Druck (z.B. 0,5 bis 3 bar) durchgeführt werden. Im allgemeinen arbeitet man bei Normaldruck.The reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.
Die Reaktionen werden in einem Temperaturbereich von 0°C bis 100°C, vorzugsweise bei 0°C bis 30°C und bei Normaldruck durchgeführt.The reactions are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.
Die Reduktionen können im allgemeinen durch Wasserstoff in Wasser oder in inerten organischen Lösemitteln wie Alkoholen, Ethern oder Halogenkohlenwasserstoffen, oder deren Gemischen, mit Katalysatoren wie Raney-Nickel, Palladium, Palladium auf Tierkohle oder Platin, oder mit Hydriden wie SnCl2, oder Boranen in inerten Lösemitteln, gegebenenfalls in Anwesenheit eines Katalysators durchgeführt werden. Bevorzugt ist Palladium auf Tierkohle oder SnCl2.The reductions can generally by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides such as SnCl 2 , or boranes in inert solvents, optionally in the presence of a catalyst. Palladium on animal charcoal or SnCl 2 is preferred.
Die Umsetzung kann bei normalem, erhöhtem oder bei erniedrigtem Druck durchgeführt werden (z.B. 0,5 bis 5 bar). Im allgemeinen arbeitet man bei Normaldruck. Die Reduktionen werden im allgemeinen in einem Temperaturbereich von 0°C bis +60°C, vorzugsweise bei +10°C bis +40°C durchgeführt.The reaction can be carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure. The reductions are generally carried out in a temperature range from 0 ° C. to + 60 ° C., preferably at + 10 ° C. to + 40 ° C.
Als Lösemittel für die Acylierung eignen sich übliche organische Lösemittel, die sich unter den Reaktionsbedingungen nicht verändern. Hierzu gehören bevorzugt Ether wie Diethylether, Dioxan,Tetrahydrofuran, Glykoldimethylether, oder Kohlenwasserstoffe wie Benzol, Toluol, Xylol, Hexan, Cyclohexan oder Erdölfraktionen, oder Halogenkohlenwasserstoffe wie Dichlormethan, Trichlormethan, Tetrachlormethan, Dichlorethylen, Trichlorethylen oder Chlorbenzol, oder Essigester, oder Triethylamin, Pyridin, Dimethylsulfoxid, Dimethylformamid, Hexamethylphosphor- säuretriamid, Acetonitril, Aceton oder Nitromethan. Ebenso ist es möglich, Gemische der genannten Lösemittel zu verwenden. Bevorzugt sind Dichlormethan und Pyridin.Customary organic solvents which do not change under the reaction conditions are suitable as solvents for the acylation. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or chloro-benzene, chloro-benzene, chloro-benzene, chloro-benzene , Dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane and pyridine are preferred.
Die Herstellung der Verbindungen der allgemeinen Formel (Va) bzw. (Vb) wird beispielsweise anhand folgenden Reaktionsschemas erläutert:The preparation of the compounds of the general formula (Va) or (Vb) is explained, for example, using the following reaction schemes:
Figure imgf000017_0001
Figure imgf000017_0001
7 (m-, X=H)7 (m-, X = H)
8 (p-, X=H)8 (p-, X = H)
9 (P-, X=F)9 (P-, X = F)
Darin bedeutet Pyr. Pyridin.Therein means pyr. Pyridine.
Analog lassen sich die ortho-Isomere herstellen.The ortho isomers can be prepared analogously.
Die Herstellung des Anilins 4 erfolgt z.B. gemäß US-Patent Nr. 3979202. Die Herstellung des Anilins 6 erfolgt z.B. gemäß S. Rajappa, R. Sreenivasan, A. Khalwadekar, J. Chem. Res. Miniprint 5, 1657 (1986).Aniline 4 is prepared, for example, in accordance with US Pat. No. 3,979,202. Aniline 6 is prepared, for example, according to S. Rajappa, R. Sreenivasan, A. Khalwadekar, J. Chem. Res. Miniprint 5, 1657 (1986).
Die Herstellung des Anilins 7 erfolgt z.B. gemäß WO 9631462.The aniline 7 is produced e.g. according to WO 9631462.
Die Herstellung des Anilins 8 erfolgt z.B. gemäß R. W. Hartmann, M. Reichert, S. Goehring, Eur. J Med. Chem Chim. Ther. 29, 807 (1994).The aniline 8 is produced e.g. according to R. W. Hartmann, M. Reichert, S. Goehring, Eur. J Med. Chem Chim. Ther. 29: 807 (1994).
Die Herstellung der Aniline 5 und 9 erfolgt in analoger Weise.Anilines 5 and 9 are prepared in an analogous manner.
Bezüglich der genauen Reaktionsbedingungen sei auf die Beispiele und Ausgangsbeispiele verwiesen.With regard to the exact reaction conditions, reference is made to the examples and starting examples.
Die Sulfonylchloride der Formel (VII) werden in Analogie zu literaturbekannten Verfahren beispielsweise nach Acylierung, Sulfonierung oder Alkyliemng der entsprechenden Aminonaphtalinsulfonsäuren durch Chlorierung beispielsweise mit PC15 oder SOCl2 hergestellt, wie im nachfolgenden Schema dargestellt.The sulfonyl chlorides of Formula (VII) can be prepared in analogy to literature procedures, for example by acylation, sulfonation or Alkyliemng the corresponding Aminonaphtalinsulfonsäuren by chlorination, for example with PC1 5 or SOCl 2, as shown in the following scheme.
2. BnOCOCI
Figure imgf000018_0002
Figure imgf000018_0001
2. BnOCOCI
Figure imgf000018_0002
Figure imgf000018_0001
Beispielsweise erwähnt seien Vorschriften von R.H. Bradbury, C. Bath, Rj. Butlin, M. Dennis, C. Heys et al., J. Med. Chem., 40, 6, 1997, 996-1004; A.A. Nedospasov und LG. Sharina, Synlett, 1992, 661-662 und P.D. Stein, LT. Hunt, D. M. Floyd, S. Moreland, K.E.J. Dickinson et al., J.Med.Chem., 37, 3, 1994, 329-331.For example, regulations by R.H. Bradbury, C. Bath, R. Butlin, M. Dennis, C. Heys et al., J. Med. Chem., 40, 6, 1997, 996-1004; A.A. Nedospasov and LG. Sharina, Synlett, 1992, 661-662 and P.D. Stein, LT. Hunt, D.M. Floyd, S. Moreland, K.E.J. Dickinson et al., J.Med.Chem., 37, 3, 1994, 329-331.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) zeigen ein nicht vorhersehbares überraschendes Wirkspektrum. Sie zeigen eine antivirale Wirkung gegenüber Vertretern der Gruppe der Herpes viridae, besonders gegenüber dem humanen Cytomegalievirus (HCMV). Sie eignen sich somit zur Behandlung und Prophylaxe von Erkrankungen, die durch Herpes- Viren, insbesondere Erkrankungen, die durch humanes Cytomegalievirus (HCMV) hervorgerufen werden.The compounds of the general formula (I) according to the invention show an unforeseeable surprising spectrum of action. They show an antiviral effect against representatives of the group of herpes viridae, especially against that human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpes viruses, in particular diseases caused by human cytomegalovirus (HCMV).
Die Anti-HCMV- Wirkung wurde in einem Screening-Testsystem in 96-Well-Mikro- titerplatten unter Zuhilfenahme von humanen embryonalen Lungenfibroblasten (HELF)-Zellkulturen bestimmt. Der Einfluß der Substanzen auf die Ausbreitung des cytopathogenen Effektes wurde im Vergleich zu der Referenzsubstanz Ganciclovir (CymeveneR-Natrium), einem klinisch zugelassenen anti-HCMV-Chemotherapeuti- kum, bestimmt.The anti-HCMV activity was determined in a screening test system in 96-well microtiter plates with the aid of human embryonic pulmonary fibroblasts (HELF) cell cultures. The influence of the substances on the spread of the cytopathogenic effect was determined in comparison to the reference substance ganciclovir (Cymevene R sodium), a clinically approved anti-HCMV chemotherapeutic.
Die in DMSO (Dimethylsulfoxid) gelösten Substanzen (50 mM) werden auf Mikro- titerplatten (96-Well) in Doppelbestimmungen (4 Substanzen/Platte) untersucht. Toxische und cytostatische Substanzwirkungen werden dabei miterfaßt. Nach den entsprechenden Substanzverdünnungen (1:2) auf der Mikrotiterplatte wird eine Suspension von 50 - 100 HCMV-infizierten HELF-Zellen und 30 x 105 nicht- infizierten HELF-Zellen in Eagle's MEM mit 10% fötalem Kälberserum in jedes Näpfchen gegeben, und die Platten bei 37°C in einem CO2-Brutschrank über mehrere Tage inkubiert. Nach dieser Zeit ist der Zellrasen in den substanzfreien Viruskontrollen, ausgehend von 50 - 100 infektiösen Zentren, durch den cytopathogenen Effekt des HCMV völlig zerstört (100% CPE). Nach einer Anfärbung mit Neutralrot und Fixierung mit Formalin / Methanol werden die Platten mit Hilfe eines Projektions-Mikroskopes (Plaque-Viewer) ausgewertet. Die Ergebnisse sind für einige Verbindungen in der folgenden Tabelle zusammengefaßt:The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (96-well) in duplicate (4 substances / plate). Toxic and cytostatic effects are also included. After the corresponding substance dilutions (1: 2) on the microtiter plate, a suspension of 50-100 HCMV-infected HELF cells and 30 × 10 5 non-infected HELF cells in Eagle's MEM with 10% fetal calf serum is added to each well, and the plates are incubated at 37 ° C in a CO 2 incubator for several days. After this time, the cell lawn in the substance-free virus controls, starting from 50 - 100 infectious centers, is completely destroyed by the cytopathogenic effect of HCMV (100% CPE). After staining with neutral red and fixation with formalin / methanol, the plates are evaluated using a projection microscope (plaque viewer). The results for some compounds are summarized in the following table:
Tabelle:Table:
Figure imgf000019_0001
Es wurde nun gefunden, daß die erfindungsgemäßen Verbindungen, die Vermehrung des HCMV in HELF-Zellen in z.T. 10-50fach niedrigeren Konzentrationen als CymevenR-Natrium hemmen und einen mehrfach höheren Selektivitätsindex aufweisen.
Figure imgf000019_0001
It has now been found that the compounds according to the invention inhibit the multiplication of HCMV in HELF cells in concentrations which are in some cases 10-50 times lower than Cymeven R sodium and have a selectivity index which is several times higher.
Die erfindungsgemäßen Verbindungen stellen somit wertvolle Wirkstoffe zur Behandlung und Prophylaxe von Erkrankungen dar, die durch humanes Cytomegalievirus ausgelöst werden. Als Indikationsgebiete können beispielsweise genannt werden:The compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases which are triggered by human cytomegalovirus. The following can be mentioned as indication areas:
1) Behandlung und Prophylaxe von HCMV-Infektionen bei ATDS-Patienten (Retinitis, Pneumonitis, gastrointestinale Infektionen).1) Treatment and prophylaxis of HCMV infections in ATDS patients (retinitis, pneumonitis, gastrointestinal infections).
2) Behandlung und Prophylaxe von Cytomegalievirus-Infektionen bei Knochen- mark- und Organtransplantationspatienten, die an einer HCMV-Pneumonitis,2) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients suffering from HCMV pneumonitis,
-Enzephalitis, sowie an gastrointestinalen und systemischen HCMV-Infektionen oft lebensbedrohlich erkranken.-Encephalitis, as well as gastrointestinal and systemic HCMV infections, often life-threatening.
3) Behandlung und Prophylaxe von HCMV-Infektionen bei Neugeborenen und Kleinkindern.3) Treatment and prophylaxis of HCMV infections in newborns and young children.
4) Behandlung einer akuten HCMV-Infektion bei Schwangeren.4) Treatment of acute HCMV infection in pregnant women.
In vivo-WirkungIn vivo effect
Tiereanimals
5 Wochen alte männliche Mäuse, Stamm NOD/LtSz-Prkdc(scid)/J, wurden von einem kommerziellen Züchter (The Jackson Lab., Bar Harbor) bezogen. Die Tiere wurden unter sterilen Bedingungen (einschließlich Einstreu und Futter) in Isolatoren gehalten. Virus/Infektion5 week old male mice, strain NOD / LtSz-Prkdc (scid) / J, were obtained from a commercial breeder (The Jackson Lab., Bar Harbor). The animals were kept in isolators under sterile conditions (including bedding and feed). Virus / infection
Murines Cytomegalievirus (MCMV), Stamm Smith, wurde in vivo (BALB/c) passagiert und über eine fraktionierte Zentrifugation aufgereinigt. Der Titer wurde mit Hilfe eines Plaqueassays auf primären embryonalen Mäusefibroblasten unter- sucht. Die Infektion der Mäuse erfolgte mit einer Dosis von 5x105 pfu in einemMurine cytomegalovirus (MCMV), Smith strain, was passaged in vivo (BALB / c) and purified by fractional centrifugation. The titer was examined using a plaque assay on primary embryonic mouse fibroblasts. The mice were infected with a dose of 5x10 5 pfu in one
Gesamtvolumen von 0,2 ml intraperitoneal. Diese Dosis führt bei 100% der infizierten Tiere nach ca. 11 Tagen zum Tode.Total volume of 0.2 ml intraperitoneally. This dose leads to death in 100% of the infected animals after approx. 11 days.
B ehandlung/ Aus Wertung 24 Stunden nach der Infektion wurden die Mäuse über einen Zeitraum von 8 Tagen zweimal täglich (morgens und abends) per os mit Substanz behandelt. Die Dosis betrug 25 mg/kg Körpermasse, das Applikationsvolumen 10 ml/kg Körpermasse. Die Formulierung der Substanzen erfolgte in Form einer 0,5%igen Tylosesuspension. 16 Stunden nach der letzten Substanzapplikation wurden die Tiere schmerzlos getötet und Speicheldrüse, Leber und Niere entnommen.Treatment / From evaluation 24 hours after infection, the mice were treated with substance orally twice daily (morning and evening) over a period of 8 days. The dose was 25 mg / kg body mass, the application volume 10 ml / kg body mass. The substances were formulated in the form of a 0.5% tylose suspension. 16 hours after the last substance application, the animals were killed painlessly and the salivary gland, liver and kidney were removed.
Aus 25 mg der Gewebe wurde über Phenol/Chloroform-Extraktion genomische DNA aufgereinigt. Die Quantifizierung der DNA erfolgte photometrisch und mit Hilfe der Formel OD26ox50=mg/ml.Genomic DNA was purified from 25 mg of the tissue by phenol / chloroform extraction. The DNA was quantified photometrically and using the formula OD 26 ox50 = mg / ml.
Die Reinheit der DNA wurde über den Quotienten OD260/OD28o kontrolliert und die DNA anschließend mit Tris-EDTA pH = 8,0 eingestellt.The purity of the DNA was checked using the quotient OD 260 / OD 28 o and the DNA was then adjusted to pH = 8.0 with Tris-EDTA.
Die Quantifizierung der MCMV-DNA erfolgte mittels DNA-Dot-Blot-Hybridisie- rung. Als Sonde wurde ein Digoxygenin-gelabeltes (Boehringer-Mannheim, ebenfalls aufgeführte Puffer, wenn nicht anders beschrieben) 1,2 kb Fragment aus dem Bereich MCMV, Smith, Hindlll J, verwendet. Die Detektion der Signale erfolgte mittels Chemolumineszenz. Dafür wurde die Membran für 3 Minuten in 1 x Digoxygenin-Waschpuffer 1 gewaschen. Im Anschluß wurden die Filter für 30 Minuten bei Raumtemperatur unter Schütteln in 1 x Digoxygenin Blockierungslösung inkubiert. Die Filter wurden danach für 30 Minuten in 20 ml/ 100 cm2 Membran mit der Anti-DIG-Alkalische-Phosphatase-Konjugatlösung (1:20000 in 1 x Digoxygenin Blockierungslösung) inkubiert. 2 je 15 Minuten dauernde Waschschritte mit 1 x Digoxygenin- Waschpuffer schlössen sich an. Es folgten 5 Minuten Äquilibrierung der Filter in 1 x Digoxygenin-Detektionspuffer und die Detektion mittels 1 ml / 100 cm2 Membranfläche 1:100 verdünnte CDP-Star-Lösung. NachThe MCMV-DNA was quantified by means of DNA dot blot hybridization. A digoxygenin-labeled (Boehringer-Mannheim, also listed buffer, unless otherwise described) 1.2 kb fragment from the MCMV range, Smith, Hindlll J, was used as the probe. The signals were detected by means of chemiluminescence. For this, the membrane was washed for 3 minutes in 1 x digoxygenin wash buffer 1. The filters were then incubated for 30 minutes at room temperature with shaking in 1 x digoxygenin blocking solution. The filters were then placed in 20 ml / 100 cm 2 for 30 minutes Incubate the membrane with the anti-DIG alkaline phosphatase conjugate solution (1: 20000 in 1 x digoxygenin blocking solution). 2 washing steps each lasting 15 minutes with 1 x digoxygenin washing buffer followed. This was followed by equilibration of the filters in 1 x digoxygenin detection buffer for 5 minutes and detection by means of 1 ml / 100 cm 2 membrane area 1: 100 diluted CDP-Star solution. To
Ausstreichen der CDP-Star-Lösung und 5 minütiger Inkubation in einer dunklen Box erfolgte der Nachweis der Chemolumineszenz bzw. die Auswertung mittels Röntgenfilm (Kodak) oder Lumilmager (Boehringer Mannheim).Spreading out the CDP-Star solution and incubating for 5 minutes in a dark box demonstrated the chemiluminescence or the evaluation using X-ray film (Kodak) or Lumilmager (Boehringer Mannheim).
Alle Ergebnisse wurden statistisch gesichert (Varianzanalyse mittels Statistika;All results were backed up statistically (analysis of variance using statistics;
StatSoft Inc.).StatSoft Inc.).
Die neuen Wirkstoffe können in bekannter Weise in die üblichen Formulierungen überführt werden, wie Tabletten, Dragees, Pillen, Granulate, Aerosole, Sirupe, Emul- sionen, Suspensionen und Lösungen, unter Verwendung inerter, nicht-toxischer, pharmazeutisch geeigneter Trägerstoffe oder Lösemittel. Hierbei soll die therapeutisch wirksame Verbindung jeweils in einer Konzentration von etwa 0,5 bis 90 Gew.-% der Gesamtmischung vorhanden sein, d.h. in Mengen, die ausreichend sind, um den angegebenen Dosierungsspielraum zu erreichen.The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
Die Formulierungen werden beispielsweise hergestellt durch Verstrecken der Wirkstoffe mit Lösemitteln und/oder Trägerstoffen, gegebenenfalls unter Verwendung von Emulgiermitteln und/oder Dispergiermitteln, wobei z.B. im Fall der Benutzung von Wasser als Verdünnungsmittel gegebenenfalls organische Lösemittel als Hilfs- lösemittel verwendet werden können.The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
Die Applikation erfolgt in üblicher Weise, vorzugsweise oral, parenteral oder topisch, insbesondere perlingual, intravenös oder intravitreal gegebenenfalls als Depot in einem Implantat. Für den Fall der parenteralen Anwendung können Lösungen der Wirkstoffe unter Verwendung geeigneter flüssiger Trägermaterialien eingesetzt werden.The application is carried out in the usual way, preferably orally, parenterally or topically, in particular perlingually, intravenously or intravitreally, optionally as a depot in an implant. In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials.
Im allgemeinen hat es sich als vorteilhaft erwiesen, bei intravenöser Applikation Mengen von etwa 0,001 bis 10 mg/kg, vorzugsweise etwa 0,01 bis 5 mg/kg Körpergewicht zur Erzielung wirksamer Ergebnisse zu verabreichen, und bei oraler Applikation beträgt die Dosierung etwa 0,01 bis 25 mg/kg, vorzugsweise 0,1 bis 10 mg/kg Körpergewicht.In general, it has proven to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight in the case of intravenous administration, in order to achieve effective results, and in the case of oral administration the dosage is approximately 01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit vom Körpergewicht bzw. der Art des Applikationsweges, vom individuellen Verhalten gegenüber dem Medikament, der Art von dessen Formulierung und dem Zeitpunkt bzw. Intervall, zu welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muß. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen.Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place , In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.
Gegebenenfalls kann es sinnvoll sein, die erfindungsgemäßen Verbindungen mit anderen Wirkstoffen zu kombinieren. It may make sense to combine the compounds according to the invention with other active ingredients.
Laufmittelgemische:Eluent mixtures:
A Methylenchlorid : Methanol 100:0A methylene chloride: methanol 100: 0
B Methylenchlorid : Methanol 100: 1 C Methylenchlorid : Methanol 100:2B methylene chloride: methanol 100: 1 C methylene chloride: methanol 100: 2
D Methylenchlorid : Methanol 100:3D methylene chloride: methanol 100: 3
E Methylenchlorid : Methanol 100:5E methylene chloride: methanol 100: 5
F Methylenchlorid : Methanol 10:1F methylene chloride: methanol 10: 1
G Methylenchlorid : Methanol : Ammoniak 10:1 :0,1 H Methylenchlorid : Cyclohexan 1:1G methylene chloride: methanol: ammonia 10: 1: 0.1 H methylene chloride: cyclohexane 1: 1
I Cyclohexan : Essigester 95:5I cyclohexane: ethyl acetate 95: 5
K Cyclohexan : Essigester 90:10K Cyclohexane: ethyl acetate 90:10
L Cyclohexan : Essigester 85:15L Cyclohexane: ethyl acetate 85:15
M Cyclohexan : Essigester 80:20 N Cyclohexan : Essigester 75:25M cyclohexane: ethyl acetate 80:20 N cyclohexane: ethyl acetate 75:25
O Cyclohexan : Essigester 70:30O cyclohexane: ethyl acetate 70:30
P Cyclohexan : Essigester 60:40P Cyclohexane: ethyl acetate 60:40
Q Cyclohexan : Essigester 50:50Q Cyclohexane: ethyl acetate 50:50
R Cyclohexan : Essigester 40:60 S Cyclohexan : Essigester 30:70R cyclohexane: ethyl acetate 40:60 S cyclohexane: ethyl acetate 30:70
T Butanol : Eisessig : Wasser 4:1:1T butanol: glacial acetic acid: water 4: 1: 1
U Methylenchlorid : Methanol 9: 1U methylene chloride: methanol 9: 1
V Acetonitril : Wasser 9:1V acetonitrile: water 9: 1
W Cyclohexan : Essigester 1:10 X Acetonitril : Wasser 95:5W cyclohexane: ethyl acetate 1:10 X acetonitrile: water 95: 5
Y Methylenchlorid : Methanol 95:5 Z Petrolether : Essigester 1 : 1Y methylene chloride: methanol 95: 5 Z petroleum ether: ethyl acetate 1: 1
ZA Petrolether : Essigester 1 :2ZA petroleum ether: ethyl acetate 1: 2
ZB Petrolether : Essigester 1 :3 AusgangsverbindungenEg petroleum ether: ethyl acetate 1: 3 starting compounds
Beispiel IExample I
N-(4-Nitrophenyl)-pivaloylamidN- (4-nitrophenyl) -pivaloylamid
Figure imgf000025_0001
Figure imgf000025_0001
20 g (0,14 mol) 4-Nitroanilin werden im 1 1 Dreihalskolben in 400 ml Methylenchlorid und 100 ml Dioxan gelöst. Anschließend wird mit 23,4 ml Pyridin versetzt. Unter Eiskühlung werden 19,2 g (0,16 mol) Pivalinsäurechlorid zugetropft. Es wird 24 h bei RT gerührt. Danach wird 3 x mit 200 ml Wasser ausgeschüttelt und die organische Phase mit Natriumsulfat getrocknet. Die organische Phase wird einrotiert und der Rückstand in 100 ml Diisopropyl ether 2 h gut gerührt, abgesaugt, mit Diisopropylether und Pentan gewaschen und der Rückstand getrocknet.20 g (0.14 mol) of 4-nitroaniline are dissolved in 1 1 three-necked flask in 400 ml of methylene chloride and 100 ml of dioxane. Then 23.4 ml of pyridine are added. 19.2 g (0.16 mol) of pivalic acid chloride are added dropwise with ice cooling. The mixture is stirred at RT for 24 h. Then it is shaken 3 times with 200 ml of water and the organic phase is dried with sodium sulfate. The organic phase is evaporated in a rotary evaporator and the residue is stirred well in 100 ml of diisopropyl ether for 2 hours, suction filtered, washed with diisopropyl ether and pentane and the residue is dried.
Ausbeute: 30 g (93% d.Th.)Yield: 30 g (93% of theory)
Beispiel IIExample II
N-(4-Aminophenyl)-pivaloylamidN- (4-Aminophenyl) -pivaloylamid
Figure imgf000025_0002
Figure imgf000025_0002
25 g (0,11 mol) der Verbindung aus Beispiel III werden im 1 1 Rundkolben in 500 ml25 g (0.11 mol) of the compound from Example III are in 1 1 round-bottom flasks in 500 ml
Dioxan unter Rühren gelöst. Anschließend wird mit Argon überschichtet und 5 g 10% Pd auf Aktivkohle zugegeben. Es wird bei Raumtemperatur und Normaldruck 20 h hydriert. Der Katalysator wird über Kieselgur abgesaugt und die Mutterlauge einrotiert. Der Rückstand wird in 200 ml Heptan 2 h gut verrührt, abgesaugt und mit Heptan gewaschen, die Kristalle werden getrocknet.Dioxane dissolved with stirring. The mixture is then covered with argon and 5 g of 10% Pd on activated carbon are added. It is at room temperature and normal pressure Hydrogenated for 20 h. The catalyst is suctioned off through kieselguhr and the mother liquor is spun in. The residue is stirred well in 200 ml of heptane for 2 hours, suction filtered and washed with heptane, the crystals are dried.
Ausbeute: 19,6 g (90,6%) Yield: 19.6 g (90.6%)
BeispieleExamples
Beispiel 77Example 77
3-Fluor-2,2-dimethyl-N-{4-[({5-[(3-moφholinopropanoyl)amino]-l- naphthyl} sulfonyl)amino]phenyl}propanamid (77)3-fluoro-2,2-dimethyl-N- {4 - [({5 - [(3-moφholinopropanoyl) amino] -l-naphthyl} sulfonyl) amino] phenyl} propanamide (77)
Figure imgf000027_0001
Figure imgf000027_0001
0.30 g [1.4 mmol] N-(4-Aminophenyl)-3-fluor-2,2-dimethylpropanamid und 0.23 g0.30 g [1.4 mmol] N- (4-aminophenyl) -3-fluoro-2,2-dimethylpropanamide and 0.23 g
[2.9 mmol] Pyridin werden in 7 ml Dioxan vorgelegt und mit 0.66 g [1.7 mmol] 5-[(3-Morpholinopropanoyl)amino]- 1 -naphthalinsulfonyl chlorid versetzt.[2.9 mmol] pyridine are placed in 7 ml of dioxane, and 0.66 g [1.7 mmol] of 5 - [(3-morpholinopropanoyl) amino] - 1 -naphthalenesulfonyl chloride are added.
Nach Rühren bei Raumtemperatur für 18 h wird zur Aufarbeitung 40 ml Wasser zugesetzt und kräftig gerührt. Nach abdekantieren des Wassers wird diese Prozedur dreimal wiederholt, die Kristalle aus der wässrigen Phase abgenutscht, mit Wasser und Pentan nachgewaschen und im Hochvakuum getrocknet.After stirring at room temperature for 18 h, 40 ml of water are added for working up and the mixture is stirred vigorously. After decanting off the water, this procedure is repeated three times, the crystals are filtered off from the aqueous phase, washed with water and pentane and dried in a high vacuum.
Man erhält 0.21 g [26% d. Th.] des Herstellbeispiels 77 als Feststoff.0.21 g [26% of theory] is obtained. Th.] Of Preparation 77 as a solid.
Rf-Wert: = 0.01 (Z).Rf value: = 0.01 (Z).
MS (ESI): (m/z) = 557 (100 %, [M+H]+). 1H-NMR (300 MHz, d6-DMSO, TMS): δ = 1.14 (s; 6H), 2.49 (s, breit, teils von DMSO verdeckt; 4H), 2.68 (s, breit; 4H), 3.64 (s, breit; 4H), 4.41 (d, J = 48 Hz; 2H), 6.92 (d, J = 9 Hz; 2H), 7.34 (d, J = 9 Hz; 2H), 7.70 (t, J = 7.5 Hz; IH), 7.75 (t, J = 7.5 Hz; IH), 7.96 (d, J = 7.5 Hz; IH), 8.14 (d, J = 7.5 Hz; IH), 8.28 (d, J = 7.5 Hz; IH), 8.75 (d, J = 7.5 Hz; IH), 9.14 (s; IH), 10.42 (s; 2H).MS (ESI): (m / z) = 557 (100%, [M + H] + ). 1H-NMR (300 MHz, d6-DMSO, TMS): δ = 1.14 (s; 6H), 2.49 (s, broad, partly covered by DMSO; 4H), 2.68 (s, broad; 4H), 3.64 (s, broad; 4H), 4.41 (d, J = 48 Hz; 2H), 6.92 (d, J = 9 Hz; 2H), 7.34 (d, J = 9 Hz; 2H), 7.70 (t, J = 7.5 Hz; IH), 7.75 (t, J = 7.5 Hz; IH), 7.96 (d, J = 7.5 Hz; IH), 8.14 (d, J = 7.5 Hz; IH), 8.28 (d, J = 7.5 Hz; IH) , 8.75 (d, J = 7.5 Hz; IH), 9.14 (s; IH), 10.42 (s; 2H).
Analog wurden die Beispiele in den folgenden Tabellen hergestellt. The examples in the following tables were prepared analogously.
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000052_0001

Claims

Patentansprücheclaims
1 Verbindungen der allgemeinen Formel (I),1 compounds of the general formula (I),
Figure imgf000053_0001
Figure imgf000053_0001
in welcherin which
R1 für Wasserstoff oder (Cι-C6) Alkanoyl steht,R 1 represents hydrogen or (-C-C 6 ) alkanoyl,
R2 für (Cι-C6)Alkyl steht, das durch eine gesattigte 5- bis 6-ghedπge heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert ist, oderR 2 stands for (-C-C 6 ) alkyl, which is saturated by a saturated 5- to 6-ghedπge heterocyclic group with one to three heteroatoms from the series O, S, or N, which may optionally also be bonded via the N atom , is substituted, or
R2 für eine Gruppe der FormelnR 2 for a group of the formulas
O O O O NHO O O O NH
-C-R4 , -S-R5 , -C-O-R6 , -S-R7 H 8 oder —C-R8 O-CR 4 , -SR 5 , -COR 6 , -SR 7 H 8 or -CR 8 O
steht, woπnstands where
R4 für (Cι-Cö)Alkyl, das gegebenenfalls durch Ammo, (Cι-C6)Alkoxy- carbonylamino, Halogen oder eine gesattigte 5- bis 6-ghedπge heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert sein kann, eine aromatische 5- bis 6-ghedπge heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S oder N, (C3-C7)Cycloalkyl, (C C6)-Alkoxycarbonyl oder -NR9R10 steht,R 4 for (-C-C ö ) alkyl, optionally by Ammo, (-C-C 6 ) alkoxycarbonylamino, halogen or a saturated 5- to 6-ghedπge heterocyclic group with one to three heteroatoms from the series O, S or N, which may also be bonded via the N atom, may be substituted, an aromatic 5- to 6-ghedπge heterocyclic group with one to three heteroatoms from the series O, S or N, (C 3 -C 7 ) cycloalkyl, (CC 6 ) alkoxycarbonyl or -NR 9 R 10 ,
worin R9 und R10 gleich oder verschieden sind und jeweils fürwherein R 9 and R 10 are the same or different and each for
Wasserstoff, (Cι-C6)Alkyl, das gegebenenfalls durch ein bis drei Substituenten ausgewählt aus Halogen, Hydroxy, Carboxyl und (Cι-C6)Alkoxy substituiert sein kann, (C -C20)- Alkyl oder Phenyl, das gegebenenfalls durch Carboxyl substituiert ist, stehen, oderHydrogen, (-CC 6 ) alkyl, which may optionally be substituted by one to three substituents selected from halogen, hydroxy, carboxyl and (-C-C 6 ) alkoxy, (C -C 20 ) - alkyl or phenyl, which may be substituted by Carboxyl is substituted, stand, or
R9 und R10 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten Ring bilden mit bis zu 7 C-Atomen, dessen Ringkohlenstoffatome gegebenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, S=O, C=O und N-R11 besteht, worin R11 für Wasserstoff oder (C]-C6)Alkyl steht, ersetzt sein können,R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring with up to 7 carbon atoms, the ring carbon atoms of which are optionally selected from the group consisting of O, S, S and 1 or 2 radicals = O, C = O and NR 11 , where R 11 is hydrogen or (C] -C 6 ) alkyl, can be replaced,
R5 für (Cι-C8)Alkyl, das gegebenenfalls mit -CF3, -C2F5 oder mit einer gesättigten 5- bis 6-gliedrigen heterocychschen Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert sein kann, (C3-C7)Cycloalkyl oder -NR12R13 steht, woπnR 5 for (-CC 8 ) alkyl, optionally with -CF 3 , -C 2 F 5 or with a saturated 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which may also be bonded via the N atom, may be substituted, (C 3 -C 7 ) cycloalkyl or -NR 12 R 13 , where
1 7 11 7 1
R und R gleich oder verschieden sind und jeweils für (Cι-C6)Alkyl stehen, oderR and R are the same or different and each represent (-CC 6 ) alkyl, or
R und R gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigtenR and R together with the nitrogen atom to which they are attached are saturated or unsaturated
Ring mit bis zu 6 Kohlenstoffatomen bilden, dessen Ringkohlenstoffatome gegebenenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, S=O, C=O und N-R14 besteht, worin R14 für Wasserstoff, ( -C^Alkyl steht, ersetzt sein können,Form ring with up to 6 carbon atoms, the Ring carbon atoms optionally substituted by 1 or 2 radicals selected from the group consisting of O, S, S = O, C = O and NR 14 , in which R 14 represents hydrogen, (-C ^ alkyl),
R6 für R15-OCH2CH2OCH2CH2-, worin R15 (d-C6)Alkyl ist, für eine gesättigte 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis dreiR 6 for R 15 -OCH 2 CH 2 OCH 2 CH 2 -, wherein R 15 is (dC 6 ) alkyl, for a saturated 5- to 6-membered heterocyclic group with one to three
Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann und gegebenenfalls durch (Ci- C6)Alkyl substituiert ist, oder für (d-C6)Alkyl steht, das gegebenenfalls durch Hydroxy, (Cι-C6)Alkoxy, eine gesättigte, ungesättigte oder aromatische 5- bis 6-gliedrige heterocyclische Gruppe mit ein bis drei Heteroatomen aus der Reihe O, S, oder N, die gegebenenfalls auch über das N-Atom gebunden sein kann, substituiert sein kann,Heteroatoms from the series O, S, or N, which can optionally also be bonded via the N atom and is optionally substituted by (C 1 -C 6 ) alkyl, or represents (dC 6 ) alkyl, which is optionally substituted by hydroxy, ( Cι-C 6 ) alkoxy, a saturated, unsaturated or aromatic 5- to 6-membered heterocyclic group with one to three heteroatoms from the series O, S, or N, which may also be bound via the N atom, may be substituted can
R7 für (C,-C6)Alkyl steht,R 7 represents (C, -C 6 ) alkyl,
R8 für Amino, Mono- oder Di(Cι-C6)alkylamino steht,R 8 represents amino, mono- or di (-CC 6 ) alkylamino,
oder R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten Ring bilden mit bis zu 6 Kohlenstoffatomen, dessen Ringkohlenstoffatome gegebenenfalls durch 1 oder 2 Reste ausgewählt aus der Gruppe, die aus O, S, S=O, C=O und N-R16 besteht, worin R16 für Wasserstoff, (C]-C6)Alkyl, das gegebenenfalls durchor R 1 and R 2 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring having up to 6 carbon atoms, the ring carbon atoms of which are optionally selected by 1 or 2 radicals selected from the group consisting of O, S, S = O, C = O and NR 16 , where R 16 is hydrogen, (C] -C 6 ) alkyl, optionally by
Halogen substituiert sein kann, oder (Cι-C6) Alkanoyl, das gegebenenfalls durch 1 bis 3 Halogenatome substituiert sein kann, steht, ersetzt sein können, und wobei der Ring mit einem Phenylring kondensiert sein kann,Halogen can be substituted, or (-C-C 6 ) alkanoyl, which may optionally be substituted by 1 to 3 halogen atoms, can be replaced, and wherein the ring can be fused with a phenyl ring,
oder 1 7or 1 7
R und R beide für Wasserstoff stehen können, wenn A oder D für ( - C6)Alkylsulfonyl steht,R and R can both be hydrogen if A or D is (- C 6 ) alkylsulfonyl,
R3 fürR 3 for
H H — N-CO-R17 Qder -CO-N-R17 ^ worinHH - N-CO-R 17 Qder -CO-NR 17 ^ where
R17 für (C]-C6)Alkyl steht, das gegebenenfalls ein- bis dreifach gleich oder verschieden durch Hydroxy, Halogen oder (Ci- C )Alkoxycarbonyl substituiert ist,R 17 represents (C) -C 6 ) alkyl which is optionally substituted one to three times in the same or different manner by hydroxyl, halogen or (Ci-C) alkoxycarbonyl,
A, D, E und G gleich oder verschieden sind und für Wasserstoff, Halogen, Nitro, Cyano, Hydroxy, Carboxyl, Trifluormethyl, Trifluormethoxy oder für (Cι-C6)Alkyl, (C,-C6)Alkoxy, (Cι-C6)Alkanoyloxy, (Cι-C6)Alkoxy-carbonyl oder (C]-C6)Alkylsulfonyl stehen,A, D, E and G are the same or different and are for hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, trifluoromethyl, trifluoromethoxy or for (Cι-C 6 ) alkyl, (C, -C 6 ) alkoxy, (Cι- C 6 ) alkanoyloxy, (-C-C 6 ) alkoxy-carbonyl or (C] -C 6 ) alkylsulfonyl,
und deren Salze.and their salts.
2. Verbindungen nach Anspruch 1, worin A, D, G und E für Wasserstoff stehen.2. Compounds according to claim 1, wherein A, D, G and E are hydrogen.
3. Verbindungen nach Anspruch 1 der Formel (Ia)3. Compounds according to claim 1 of formula (Ia)
Figure imgf000056_0001
Figure imgf000056_0001
1 1 worin R , R , R , A, D, E und G wie oben definiert sind, und deren Salze. 1 1 wherein R, R, R, A, D, E and G are as defined above, and their salts.
4. Verbindungen nach Anspruch 1 der Formel4. Compounds according to claim 1 of the formula
Figure imgf000057_0001
Figure imgf000057_0001
worin R1, R2, R3, A, D, E und G wie oben definiert sind, und deren Salze.wherein R 1 , R 2 , R 3 , A, D, E and G are as defined above, and their salts.
5. Verbindungen nach Anspruch 1, worin5. Compounds according to claim 1, wherein
R3 fürR 3 for
H — N-co-R17 steht, worinH - N-co-R 17 is where
R17 für (Cι-C6)Alkyl steht, das gegebenenfalls ein- bis dreifach gleich oder verschieden durch Hydroxy, Halogen oder (d- C4)Alkoxycarbonyl substituiert ist.R 17 represents (-CC 6 ) alkyl, which is optionally substituted one to three times the same or different by hydroxy, halogen or (d-C 4 ) alkoxycarbonyl.
6. Verbindungen nach Anspruch 6, worin R17 für tert.-Butyl steht, das gegebenenfalls durch Hydroxy, Halogen oder (C]-C4)Alkoxycarbonyl substituiert ist.6. Compounds according to claim 6, wherein R 17 is tert-butyl which is optionally substituted by hydroxy, halogen or (C] -C 4 ) alkoxycarbonyl.
7. Verfahren zur Herstellung von Verbindungen der obigen allgemeinen Formel7. Process for the preparation of compounds of the general formula above
(I), das dadurch gekennzeichnet ist, daß man(I), which is characterized in that one
[A] Verbindungen der allgemeinen Formel (II)
Figure imgf000058_0001
in welcher[A] compounds of the general formula (II)
Figure imgf000058_0001
in which
A, D, E, G, R1 und R2 die oben angegebene Bedeutung haben,A, D, E, G, R 1 and R 2 have the meaning given above,
zunächst durch katalytische Hydrierung an Palladium/C oder durch Reduktion mit SnCl2 in inerten Lösemitteln in die Verbindungen der allgemeinen Formel (III)initially by catalytic hydrogenation on palladium / C or by reduction with SnCl 2 in inert solvents into the compounds of the general formula (III)
Figure imgf000058_0002
in welcher
Figure imgf000058_0002
in which
1 71 7
A, D, E, G, R und R die oben angegebene Bedeutung haben, überführt,A, D, E, G, R and R have the meaning given above,
und abschließend mit Verbindungen der allgemeinen Formel (IV)and finally with compounds of the general formula (IV)
T-CO-R 17 (IV)T-CO-R 17 (IV)
in welcherin which
R , 17 die oben angegebene Bedeutung hatR, 17 has the meaning given above
undand
für Hydroxy, Halogen, vorzugsweise für Chlor steht, in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels umsetzt,represents hydroxy, halogen, preferably chlorine, in inert solvents, optionally in the presence of a base and / or an auxiliary,
oderor
[B] Verbindungen der allgemeinen Formel (Va) oder (Vb)[B] Compounds of the general formula (Va) or (Vb)
Figure imgf000059_0001
Figure imgf000059_0001
Figure imgf000059_0002
in welcher
Figure imgf000059_0002
in which
E, G und R » 17 die oben angegebene Bedeutung haben,E, G and R »17 have the meaning given above,
zunächst wie unter [A] beschrieben durch Hydrierung an Pd/C oder durch Reduktion mit SnCl2 in inerten Lösemitteln in die Verbindungen der allgemeinen Formel (Via) oder (VIb)initially as described under [A] by hydrogenation on Pd / C or by reduction with SnCl2 in inert solvents into the compounds of the general formula (Via) or (VIb)
Figure imgf000059_0003
Figure imgf000060_0001
Figure imgf000059_0003
Figure imgf000060_0001
in welcherin which
E, G und R . 17 die oben angegebene Bedeutung haben,E, G and R. 17 have the meaning given above,
überführttransferred
und abschließend mit Verbindungen der allgemeinen Formel (VII)and finally with compounds of the general formula (VII)
Figure imgf000060_0002
Figure imgf000060_0002
in welcherin which
1 71 7
A, D, R und R die oben angegebene Bedeutung haben,A, D, R and R have the meaning given above,
undand
V für Halogen, vorzugsweise für Chlor steht,V represents halogen, preferably chlorine,
in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels umsetzt.in inert solvents, optionally in the presence of a base and / or an auxiliary.
Verbindungen nach Anspruch 1, zur Verwendung als Arzneimittel. Compounds according to claim 1, for use as medicaments.
9. Pharmazeutische Zusammensetzung, die eine Verbindung der allgemeinen Formel (I) nach Anspruch 1 in Mischung mit mindestens einem pharmazeutisch verträglichen Träger oder Exzipienten umfaßt.9. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 in admixture with at least one pharmaceutically acceptable carrier or excipient.
10. Verwendung der Verbindung der allgemeinen Formel (I) nach Anspruch 1 zur10. Use of the compound of general formula (I) according to claim 1 for
Herstellung eines Arzneimittels.Manufacture of a drug.
11. Verwendung einer Verbindung der allgemeinen Formel (I) nach Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von viralen Infektionen, insbesondere Infektionen durch Cytomegalieviren. 11. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections, in particular infections by cytomegaloviruses.
PCT/EP2000/006515 1999-07-21 2000-07-10 Naphthyl-substituted sulfonamides WO2001007403A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61570/00A AU6157000A (en) 1999-07-21 2000-07-10 Naphthyl-substituted sulfonamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19934321A DE19934321A1 (en) 1999-07-21 1999-07-21 New N-phenyl-naphthalenesulfonamide derivatives are antiviral agents especially useful for treating cytomegalovirus infections
DE19934321.7 1999-07-21

Publications (1)

Publication Number Publication Date
WO2001007403A1 true WO2001007403A1 (en) 2001-02-01

Family

ID=7915624

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/006515 WO2001007403A1 (en) 1999-07-21 2000-07-10 Naphthyl-substituted sulfonamides

Country Status (7)

Country Link
AU (1) AU6157000A (en)
CO (1) CO5180634A1 (en)
DE (1) DE19934321A1 (en)
GT (1) GT200000119A (en)
PE (1) PE20010549A1 (en)
UY (1) UY26250A1 (en)
WO (1) WO2001007403A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058709A1 (en) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2004058736A1 (en) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
JP2004536080A (en) * 2001-06-11 2004-12-02 ビオヴィトルム・アクチボラゲット Substituted sulfonamide compounds, their use as medicaments for the treatment of CNS disorders, obesity and type II diabetes
US7241758B2 (en) 1999-11-16 2007-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US7491827B2 (en) 2002-12-23 2009-02-17 Millennium Pharmaceuticals, Inc. Aryl sulfonamides useful as inhibitors of chemokine receptor activity

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4331134A1 (en) * 1993-09-14 1995-03-16 Bayer Ag New antiviral pseudopeptides
WO1999037609A1 (en) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Novel naphthyl-substituted and anilide-substituted sulfonamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4331134A1 (en) * 1993-09-14 1995-03-16 Bayer Ag New antiviral pseudopeptides
WO1999037609A1 (en) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Novel naphthyl-substituted and anilide-substituted sulfonamides

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7241758B2 (en) 1999-11-16 2007-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
EP1232150B1 (en) * 1999-11-16 2007-10-10 Boehringer Ingelheim Pharmaceuticals Inc. Urea derivatives as anti-inflammatory agents
JP2004536080A (en) * 2001-06-11 2004-12-02 ビオヴィトルム・アクチボラゲット Substituted sulfonamide compounds, their use as medicaments for the treatment of CNS disorders, obesity and type II diabetes
KR100888906B1 (en) * 2001-06-11 2009-03-16 바이오비트럼 에이비(피유비엘) Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ⅱ diabetes
JP4731114B2 (en) * 2001-06-11 2011-07-20 プロキシマゲン・リミテッド Substituted sulfonamide compounds, methods for their use as medicaments for the treatment of CNS disorders, obesity and type II diabetes
WO2004058709A1 (en) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2004058736A1 (en) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
US7329755B2 (en) 2002-12-23 2008-02-12 Millennium Pharmaceuticals, Inc. CCR8 inhibitors
US7378525B2 (en) 2002-12-23 2008-05-27 Millennium Pharmaceuticals, Inc. CCR8 inhibitors
US7491827B2 (en) 2002-12-23 2009-02-17 Millennium Pharmaceuticals, Inc. Aryl sulfonamides useful as inhibitors of chemokine receptor activity
US8063222B2 (en) 2002-12-23 2011-11-22 Millennium Pharmaceuticals, Inc. Aryl sulfonamides useful as inhibitors of chemokine receptor activity

Also Published As

Publication number Publication date
PE20010549A1 (en) 2001-01-01
AU6157000A (en) 2001-02-13
CO5180634A1 (en) 2002-07-30
DE19934321A1 (en) 2001-01-25
UY26250A1 (en) 2001-01-31
GT200000119A (en) 2002-01-10

Similar Documents

Publication Publication Date Title
DE19912638A1 (en) Naphthylcarboxamide substituted sulfonamides
WO2000068186A1 (en) Bis-sulfonamide with anti-hcmv effect
AT393507B (en) NEW PURINYL RIBOFURANURONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR THERAPEUTIC PREPARATIONS
EP1049666B1 (en) Novel naphthyl-substituted and anilide-substituted sulfonamides
DE4331135A1 (en) New antiviral valine-containing pseudopeptides
DE4331134A1 (en) New antiviral pseudopeptides
WO1999037291A2 (en) Utilization of substituted sulfonamides as antiviral agents and novel substances
WO2001002350A2 (en) Novel amino sulfonamides and amido sulfonamides as antiviral agents
DE2231067C2 (en) Phenoxathiine derivatives, processes for their production and pharmaceutical preparations containing phenoxathiine derivatives for combating viral infections
WO2001007403A1 (en) Naphthyl-substituted sulfonamides
DE10053813A1 (en) New use of sulfonamides
EP0725064A1 (en) Use of phenylcyclohexylcarboxylic amides
DE2144683A1 (en) Virustatic 4-phenyl-thiazoles - active against dna and rna viruses
DE4027052C2 (en)
EP0086453B1 (en) Thiazaspiro derivatives, process for their preparation and pharmaceutical composition
DE10053796A1 (en) Aminonaphthalene N-phenylsulfonamide derivatives, useful for treating central nervous system disorders, e.g. Alzheimer&#39;s disease, dementia, Parkinson&#39;s disease, are 5-HT6 receptor antagonists
WO2000066553A1 (en) Substituted indole sulfonamides as antiviral agents
DE19802436A1 (en) New N-aryl sulfonamides as antiviral agents, particularly against cytomegalovirus, e.g. in patients with acquired immune deficiency syndrome
DE19927415A1 (en) Indolinyl urea derivatives
WO2001007412A1 (en) Antiviral tetrahydroisichinolinsulfonamides
DE2654888A1 (en) DIPHENYL ACETAMIDES, THE METHOD OF MANUFACTURING THEM AND THE MEDICINAL PRODUCTS CONTAINING THEM
WO2001007402A1 (en) Antiviral agents
DE10053794A1 (en) Amino- or amido-benzene N-phenylsulfonamide derivatives, useful for treating central nervous system disorders e.g. Alzheimer&#39;s disease, dementia, depression, are 5-HT6 receptor antagonists
DE2827454A1 (en) 4-HOMOISOTWISTAN DERIVATIVES, METHOD FOR MANUFACTURING THEM, USE OF THE SAME AND MEDICINAL PRODUCTS CONTAINING THEM
EP0462150B1 (en) Novel aryloxy alkyl amines, their production and medicaments containing them

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP