WO2001007403A1 - Sulfonamides a substitution naphtyle - Google Patents

Sulfonamides a substitution naphtyle Download PDF

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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
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Prior art keywords
alkyl
optionally
compounds
substituted
general formula
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PCT/EP2000/006515
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German (de)
English (en)
Inventor
Peter Eckenberg
Jürgen Reefschläger
Wolfgang Bender
Siegfried Goldmann
Michael Härter
Sabine Hallenberger
Jörg Keldenich
Olaf Weber
Kerstin Henninger
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Bayer Aktiengesellschaft
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Priority to AU61570/00A priority Critical patent/AU6157000A/en
Publication of WO2001007403A1 publication Critical patent/WO2001007403A1/fr

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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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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.

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Abstract

L'invention concerne des composés de formule générale (I), des procédés pour leur préparation, des médicaments les contenant, ainsi que leur utilisation pour traiter des infections virales, notamment des infections aux cytomégalovirus.
PCT/EP2000/006515 1999-07-21 2000-07-10 Sulfonamides a substitution naphtyle WO2001007403A1 (fr)

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AU61570/00A AU6157000A (en) 1999-07-21 2000-07-10 Naphthyl-substituted sulfonamides

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DE19934321.7 1999-07-21
DE19934321A DE19934321A1 (de) 1999-07-21 1999-07-21 Naphthyl-substituierte Sulfonamide

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058709A1 (fr) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Inhibiteurs du ccr8
WO2004058736A1 (fr) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Inhibiteurs de ccr8
JP2004536080A (ja) * 2001-06-11 2004-12-02 ビオヴィトルム・アクチボラゲット 置換スルホンアミド化合物、ｃｎｓ障害、肥満およびｉｉ型糖尿病の処置のための医薬としてのそれらの使用方法
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 (de) * 1993-09-14 1995-03-16 Bayer Ag Neue antiviral wirksame Pseudopeptide
WO1999037609A1 (fr) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Nouveaux sulfamides a substitution par naphtyle et anilide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4331134A1 (de) * 1993-09-14 1995-03-16 Bayer Ag Neue antiviral wirksame Pseudopeptide
WO1999037609A1 (fr) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Nouveaux sulfamides a substitution par naphtyle et anilide

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 (fr) * 1999-11-16 2007-10-10 Boehringer Ingelheim Pharmaceuticals Inc. Derives d'uree utilises comme agents anti-inflammatoires
JP2004536080A (ja) * 2001-06-11 2004-12-02 ビオヴィトルム・アクチボラゲット 置換スルホンアミド化合物、ｃｎｓ障害、肥満およびｉｉ型糖尿病の処置のための医薬としてのそれらの使用方法
KR100888906B1 (ko) * 2001-06-11 2009-03-16 바이오비트럼 에이비(피유비엘) 치환 술폰아미드 화합물, ｃｎｓ 장애, 비만 및 ⅱ 형당뇨병 치료용 약제로서의 이들의 사용 방법
JP4731114B2 (ja) * 2001-06-11 2011-07-20 プロキシマゲン・リミテッド 置換スルホンアミド化合物、ｃｎｓ障害、肥満およびｉｉ型糖尿病の処置のための医薬としてのそれらの使用方法
WO2004058709A1 (fr) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Inhibiteurs du ccr8
WO2004058736A1 (fr) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Inhibiteurs de ccr8
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

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DE19934321A1 (de) 2001-01-25
GT200000119A (es) 2002-01-10

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