WO2000076966A2 - Derives d'indolinylamide - Google Patents

Derives d'indolinylamide Download PDF

Info

Publication number
WO2000076966A2
WO2000076966A2 PCT/EP2000/005114 EP0005114W WO0076966A2 WO 2000076966 A2 WO2000076966 A2 WO 2000076966A2 EP 0005114 W EP0005114 W EP 0005114W WO 0076966 A2 WO0076966 A2 WO 0076966A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally
substituted
halogen
group
Prior art date
Application number
PCT/EP2000/005114
Other languages
German (de)
English (en)
Other versions
WO2000076966A3 (fr
Inventor
Gabriele Handke
Judith Baumeister
Wolfgang Bender
Ulrich Betz
Michael Brands
Peter Eckenberg
Rüdiger Fischer
Martin Hendrix
Kerstin Henninger
Axel Jensen
Jörg Keldenich
Gerald Kleymann
Jutta MÄSSEN
Udo Schneider
Olaf Weber
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 AU62623/00A priority Critical patent/AU6262300A/en
Publication of WO2000076966A2 publication Critical patent/WO2000076966A2/fr
Publication of WO2000076966A3 publication Critical patent/WO2000076966A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new compounds, a process for their preparation and their use as medicaments, in particular as antiviral medicaments.
  • US-A-4,428,881 discloses indolyl (alkyl) urea derivatives as herbicides.
  • WO97 / 24343 relates to phenylthiazole derivatives with anti-He ⁇ es virus properties.
  • WO99 / 42455 also relates to phenylthiazole derivatives with anti-He ⁇ es virus
  • WO 99/47507 relates to 1,3,4-thiadiazole derivatives with anti-He ⁇ es virus properties.
  • the object of the present invention is to provide new compounds which can serve as medicaments, preferably as antiviral agents.
  • the present invention relates to compounds of the general formula (I)
  • wo ⁇ n - is a single or a double bond
  • D is N or CH
  • R 1 is hydrogen or (-CC 6 ) alkyl
  • R 2 is hydrogen or (dC 6 ) alkyl
  • R 3 represents phenyl, which may optionally be substituted by one to two substituents selected from the group consisting of halogen, (C 6 -C ⁇ o) aryl, which may optionally be substituted by one to three substituents, from be selected from the group consisting of (-C-C ⁇ ) alkoxy carbonyl, halogen, (C ⁇ -C 6 ) alkyl, (C ⁇ -C 6 ) alkoxy, nitro, halogen (C ⁇ - C 6 ) alkyl and cyano , (C ⁇ -C6) alkanoyl, (C, -C 6) alkoxy, (C, -C 6) oxycarbonyl alk-, (C ⁇ -C6) alkylthio, hydroxyl, carboxyl, partially fluorinated (Ci-C6) alkoxy with up to 6 fluorine atoms, (-CC 6 ) -alkyl, which can optionally be substituted by 1 to 3 halogen atoms,
  • (-C-C ö ) alkyl, halogen (-C-C 6 ) alkyl and hydroxy (-C-C 6 ) alkyl may be substituted, and groups of the formulas -OR 6 , -NR 7 R 8 and -CO-NR 9 R 10 , in which R 6 is phenyl, optionally with 1 to 3 substituents selected from the group consisting of halogen,
  • R 'and R 8 are the same or different and are hydrogen, (-CC 6 ) alkyl, (-C-C ⁇ ) alkanoyl, and
  • R 9 and R 10 are the same or different and are hydrogen or (-CC 6 ) - alkyl, or
  • R 3 is (C ⁇ -C6) alkyl, which is substituted by (C 6 -C ⁇ 0) aryl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (C] -C 6 ) alkoxy, trifluoromethyl and phenyl, or
  • R 3 is (C 1 -C 6 ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 heteroatoms from the series S, N and O, or
  • R is a group of the following formula
  • R 4 is hydrogen, (-C 6 ) alkyl or (C 6 -C ⁇ o) aryl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen.
  • R 5 is hydrogen (-C-C h ) alkyl. or R 4 and R 5 together form a (C 2 -C) alkanedyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-ghed ⁇ gen ring, in which a methylene group can optionally be replaced by O or N - R u , wo ⁇ n R 11 is hydrogen, (C 1 -C 6 ) alkyl, which may optionally be substituted with ammo, mono (C 6 C) alkylam ⁇ no or D (C 6 C) alkylam ⁇ no, (C 6 C) alkanoyl, (-C-C ö ) alkoxycarbonyl, py ⁇ dyl or py ⁇ midmyl,
  • Physiologically acceptable, pharmaceutically acceptable salts of the compounds according to the invention can, depending on the functional group which they contain, be salts of the substances according to the invention with acids or bases
  • Salts of the substances according to the invention with acids can be salts with mineral acids,
  • Be carboxylic acids or sulfonic acids are particularly preferred. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, benzene acid, malic acid, malonic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, malic acid
  • Salts of the substances according to the invention with bases which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine ,
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine
  • the compounds according to the invention can be converted into stereoisomeric forms which are either like images and mirror images
  • the invention relates both to the enantiomers or diastereomers or to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • the scope of the invention also includes those compounds which are only converted into the actual active compounds of the formula (I) in the body (so-called produgs).
  • (CrC 6 ) -alkyl represents a straight-chain or branched alkyl radical with 1 to 6
  • a straight-chain or branched alkyl radical having 1 to 4 carbon atoms (C 1 -C 4 ) is preferred. Examples include: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. Particularly preferred is a straight-chain or branched alkyl radical having 1 to 3 carbon atoms ((C ⁇ - C 3) alkyl).
  • Halogen (-C-C ( ,) - alkyl represents a (-C-C 6 ) alkyl group, which can be as defined above, and which has 1 to 3 halogen atoms, namely F, Cl, Br and / or I, preferably chlorine or Fluorine, as a substituent, for example, trifluoromethyl, Fluo ⁇ nethvl etc.
  • Hydroxy (-C-C 6 ) alkyl represents a (-C-C 6 ) alkyl group, which can be as defined above, and which has 1 to 3 hydroxyl groups as substituents, for example hydroxymethyl etc.
  • (-C-C 6 ) alkoxy represents a straight-chain or branched alkoxy radical with 1 to
  • a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.
  • Partially fluorinated (Ci-C ⁇ alkoxy with up to 6 fluorine atoms stands for a straight-chain or branched alkoxy radical with 1 to 6 carbon atoms, which can be substituted with 1 to 6, preferably 1 to 4, more preferably 1 to 3, fluorine atoms.
  • a straight-chain is preferred or branched alkoxy radical having 1 to 4 carbon atoms and 1 to 4 fluorine atoms, for example: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy, each having one to 4 fluorine atoms, particularly preferred are (1,3-difluoroprop-2-yl) oxy and 1,1,2,2-tetrafluoroethoxy.
  • (CrC ⁇ VAlkylthio stands for a straight-chain or branched alkyl residue with 1 to 6 carbon atoms.
  • a straight-chain or branched alkylthio residue with 1 to 4 carbon atoms (C ⁇ -C) is preferred. Examples include: methylthio, ethylthio, n-propylthio , Isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • a straight-chain or branched alkylthio radical having 1 to 3 carbon atoms (C 1 -C 3 ) alkylthio is particularly preferred.
  • (-C 6 ) alkoxycarbonyl stands for a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms (-C-C) is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso- propoxycarbonyl and tert.butoxycarbonyl.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms (C 1 -C 3 ) is particularly preferred.
  • (C 6 -C ⁇ o) aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (Ci-C ⁇ VAlkanoyl in the context of the invention represents a straight-chain or branched alkanoyl radical having 1 to 6 carbon atoms. Examples include: formyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl.
  • (C -C 8 ) -cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. May be mentioned:
  • Halogen in the context of the invention generally represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.
  • a 5- to 6-membered aromatic heterocycle with up to 4 heteroatoms from the series S, O and / or N is, for example, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, N-triazolyl, tetrazolyl, oxazolyl or imidazolyl. Pyridyl, furyl and N-triazolyl are preferred.
  • the heterocycle can optionally be bound via a nitrogen atom (for example in the case of pyrrole). In the meaning of R 3 it can optionally be substituted by 1 to 3 halogen atoms.
  • a 3- to 8-membered or unsaturated, non-aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the S, N and / or O series includes, for example, 5- to 5 within the scope of the invention 6-membered saturated heterocycles bonded via a nitrogen atom, such as Mo ⁇ holinyl, Piperidinyl, Piperazinyl, Methylpiperazinyl, Thiomo ⁇ holinyl or Pyrrolidinyl. Mo ⁇ holinyl, piperidinyl, pyrrolidinyl and Thiomo ⁇ holinyl are particularly preferred.
  • 3-, 7- and 8-membered heterocycles such as, for example, aziridines (for example 1-azacyclopropan-l-yl), azetidines (for example 1-azacyclobutan-l-yl) and
  • Azepines e.g. 1-azepan-l-yl
  • the unsaturated representatives can contain 1 to 2 double bonds in the ring.
  • the ring can be substituted as indicated above.
  • Nitrogen atom to which it is bound forms a 3- to 8-membered ring, in which a methylene group can optionally be replaced by O or NR 1 ', where R 1 ' is hydrogen, (-C 6 ) alkyl, optionally with Amino, mono (-C-C6) alkylamino or di (-C-C 6 ) alkylamino can be substituted, (C ⁇ -C6) alkanoyl, (C ⁇ -C 6 ) alkoxycarbonyl, pyridyl or pyrimidinyl, for example, includes the above a nitrogen atom-bound 3- to 8-membered saturated heterocycles, which may be substituted on the nitrogen.
  • Preferred compounds of the general formula (I) are those in which
  • R 1 is hydrogen or (-CC 6 ) alkyl
  • R 2 is hydrogen or (C, -C 6 ) alkyl
  • R 3 represents phenyl, which can optionally be substituted by one or two substituents selected from the group consisting of halogen, (C 6 -C ⁇ o) aryl, which can optionally be substituted by one to three substituents, which are selected from the group consisting of (C 1 -C 6 ) alkoxycarbonyl, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, nitro, halogen (C 1 -C 6 ) alkyl and cyano exists, (-C-C 6 ) alkanoyl, (dC 6 ) alkoxy, (C : -C 6 ) alkoxycarbonyl, (C ⁇ -C ö ) alkylthio, hydroxy, carboxy, partially fluorinated (Q- C 6 ) alkoxy with up to 6 fluorine atoms, (-CC 6 ) -alkyl, which may optionally be substituted by 1 to 3 halogen
  • R 7 and R 8 are the same or different and are hydrogen, (C
  • R3 is (C ⁇ -C ⁇ ) alkyl, which is substituted by (C 6 -C ⁇ o) -aryl which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (C ⁇ -C 6) Alkoxy, trifluoromethyl and phenyl,
  • R 3 is (C 1 -C 6 ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 hetero atoms from the series S, N and O,
  • R is a group of the following formula
  • R 4 is hydrogen, (-CC 6 ) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of ammo, mono- or di (-CC 6 ) alkylam ⁇ no, (-C-C 6 ) alkoxy, t ⁇ azolyl, furyl, (Ci-C 6 ) cycloalkyl, pyrrolidino, optionally substituted with (C] -C 6 ) alkyl substituted pyrrolidinyl, Mo ⁇ holino, pyridyl, trifluoromethyl, (dC 6 ) alkoxy-carbonylamino and phenyl, or (C 3 -C 6 ) cycloalkyl,
  • R 5 is hydrogen, (-CC 6 ) alkyl, or R 4 and R 5 together form a (C 2 -C 7 ) alkanediyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-membered ring in which a methylene group can optionally be replaced by O or NR 1 1 , in which R u is hydrogen, (-CC 6 ) alkyl, which may optionally be substituted with amino, mono (-C 6 ) alkylamino or di (dC 6 ) alkylamino, (C] -C6) alkanoyl, (-C 6 ) alkoxycarbonyl, pyridyl or pyrimidinyl,
  • R 1 is hydrogen or (-CC 6 ) alkyl
  • R 2 is hydrogen or (C, -C 6 ) alkyl
  • R 3 represents phenyl which may be optionally substituted with one to two substituents selected from the group consisting of halogen, (C 6 -C ö) aryl which may be optionally substituted by one to three substituents can be selected from the group consisting of (-C 6 ) alkoxycarbonyl, halogen, (C 6 ) alkyl, (C 6 ) alkoxy.
  • R 7 and R 8 are the same or different and are hydrogen, (-CC 6 ) alkyl, (Q-
  • R 9 and R 10 are the same or different and are hydrogen or (-CC 6 ) alkyl
  • R3 is (C ⁇ -C ö) alkyl, which is substituted by (C 6 -C ⁇ 0) aryl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, (C ⁇ -C 6 ) There is alkoxy, trifluoromethyl and phenyl,
  • R 3 is (C 1 -C 6 ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 hetero atoms from the series S, N and O, or
  • R is a group of the following formula
  • R is hydrogen, (-CC 6 ) alkyl or (C 6 -C -o) aryl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, ammo, mono- or di (C ⁇ -C 6 ) alkylam ⁇ no, (C ⁇ -C ö ) alkoxy, T ⁇ azolyl, furyl, tetrahydrofuryl, (C 3 -C 6 ) cycloalkyl, pyrrodmo, optionally substituted with (C ⁇ -C 6 ) alkyl pyrrolidinyl, Mo ⁇ holomo, Py ⁇ dyl , (C ⁇ -C6) Alkoxycarbonylam ⁇ no and phenyl, trifluoromethyl, or (C 3 -C 6) cycloalkyl,
  • R 5 is hydrogen, (-CC 6 ) alkyl, or
  • R 4 and R 5 together form a (C 2 -C 7 ) alkanedyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-ghed ⁇ gen ring, in which a methylene group can optionally be replaced by O or N.
  • R 1 1 is hydrogen, (C 1 -C 6 ) alkyl, which can optionally be substituted with amino, mono (C 1 -C 6 ) alkylam ⁇ no or D (C 1 -C 6 ) alkylammo,
  • R 1 is (C, -C 6 ) alkyl.
  • R 2 is hydrogen
  • R 3 represents phenyl, which may optionally be substituted by a substituent selected from the group consisting of (C 6 -C ⁇ o) aryl and (Ci- C 6 ) alkoxycarbonyl,
  • R 4 is hydrogen, (C ⁇ -C6) alkyl or (C 6 -C ⁇ 0) aryl, which may be optionally substituted by a substituent which is selected from the group consisting of (C ⁇ -C6) alkoxy, and tetrahydrofuryl , or (C 3 - C 6 ) cycloalkyl,
  • R 5 is hydrogen, or
  • R 4 and R 5 together form a (C 2 -C 7 ) alkanedyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-ghed ⁇ gen ring in which a methylene group is replaced by NR 1 ' , where R is hydrogen or (-CC 6 ) alkyl,
  • the compounds of the general formula (I) for R 1 are hydrogen or methyl.
  • the compounds of the general formula (I) according to claim for R 3 have hydrogen or methyl.
  • the compounds of the formula (I) for R 4 have methyl, methoxyethyl, triazolylethyl, benzyl, cyclopropyl, furylmethyl, cyclopropylmethyl or sec-butyl.
  • the compounds of the general formula (I) according to claim for R 4 and R 5 together with the nitrogen atom to which they are bonded have Mo ⁇ holino.
  • D is N or CH
  • R 1 is hydrogen or (-CC 3 ) alkyl
  • R 2 is hydrogen or (C, -C 3 ) alkyl
  • R 3 represents phenyl which may optionally be substituted with one to two substituents selected from the group consisting of halogen, phenyl which may optionally be substituted with one to three substituents selected from the group consisting of (-C-C 4 ) alkoxycarbonyl, halogen, (-C-C 3 ) -alkyl, (dC 3 ) alkoxy, nitro, halogen (C ⁇ -C 3 ) alkyl and cyano, (C ⁇ -C 3 ) alkanoyl, ( dC 4 ) alkoxy, (C ⁇ -C) alkoxycarbonyl, (C ⁇ -C 3 ) alkylfhio, hydroxy, carboxy, partially fluorinated (C ⁇ - C 3 ) alkoxy with up to 6 fluorine atoms, (C ⁇ -C 3 ) alkyl, if necessary by
  • 1 to 3 halogen atoms can be substituted, a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with 1 to 4 heteroatoms from the series S, N and O, which can optionally be substituted by 1 to 3 halogen atoms, optionally via one a nitrogen atom-bound 3- to 8-membered saturated or unsaturated non-aromatic heterocycle with up to three heteroatoms from the series S, N and O, optionally by 1 to 3 substituents, selected from oxo, halogen, hydroxy, (-C-C 4 ) alkoxycarbonyl, (-C-C 3 ) alkyl, halogen (-C-C 3 ) alkyl and hydroxy (Cj-C 3 ) alkyl may be substituted, and groups of the formulas -OR 6 , -NR 7 R 8 and -CO-NR 9 R 10 , wherein R 6 is phenyl, optionally selected from 1 to 3 substituents the group consisting
  • R 7 and R 8 are the same or different and are hydrogen, (-CC 3 ) alkyl, (-C-C 3 ) alkanoyl, and
  • R 9 and R 10 are the same or different and are hydrogen or (d-C 3 ) alkyl, or
  • R 3 is (C 1 -C 3 ) alkyl which is substituted by phenyl, which may optionally be substituted by 1 to 3 substituents, selected from the group consisting of halogen, (C 1 -C) alkoxy, trifluoromethyl and phenyl, or
  • R 3 is (C 1 -C 3 ) alkyl which is substituted by a 5- to 6-membered aromatic heterocycle optionally having a nitrogen atom and having 1 to 4 heteroatoms from the series S, N and O, or
  • R J is a group of the following formula
  • R 4 is hydrogen, (-CC) alkyl, which may optionally be substituted by 1 to 3 substituents selected from the group consisting of amino, Mono- or di (-C-C 3 ) alkylamino, (C ⁇ -C 3 ) alkoxy, triazolyl, furyl, (C 3 - C ö ) cycloalkyl, pyrrolidino, optionally substituted with (C ⁇ -C) alkyl pyrrolidinyl, Mo ⁇ holino, pyridyl, Trifluoromethyl, (-CC 4 ) alkoxy-carbonylamino and phenyl, or (C 3 -C 6 ) cycloalkyl,
  • R 5 is hydrogen, (-CC 3 ) alkyl, or
  • R 4 and R 5 together form a (C 2 -C 7) alkanediyl group which, together with the nitrogen atom to which it is attached, forms a 3- to 8-membered ring in which a methylene group can optionally be replaced by O or N -
  • R 11 in which R 1 1 is hydrogen, (C 1 -C 3 ) alkyl, which may optionally be substituted by amino, mono (C 1 -C 3 ) alkylamino or di (C 1 -C 3 ) alkylamino, (C] -C 3 ) Alkanoyl, (-C-C 3 ) alkoxycarbonyl, pyridyl or pyrimidinyl,
  • the invention further relates to processes for the preparation of the compounds of formula (I).
  • the reaction is preferably carried out in a solvent such as e.g. Ethyl acetate, dioxane, dichloroethane performed.
  • a solvent such as e.g. Ethyl acetate, dioxane, dichloroethane performed.
  • the reaction is preferably in a temperature range from room temperature to
  • the reaction is preferably carried out at normal pressure.
  • aminomethylpolystyrene resins are preferably used as scavenger reagents to trap the excess reactants.
  • reaction is preferably carried out in a solvent such as, for example, dioxane, tetrahydrofuran
  • the reaction is preferably carried out in a temperature range from room temperature to reflux of the solvents at normal pressure
  • the reaction is preferably carried out at normal pressure
  • the reaction is preferably carried out in the presence of a base such as, for example, T ⁇ (C 6 -C 6 ) alkylamine, such as T ⁇ ethylamine
  • ammomethylpolystyrene resins and / or methylsocyanate polystyrene resins are preferably used as scavenger reagents to trap the excess reactants
  • R 2 R 3 CHCOY (VI) where Y is an electronegative group such as halogen, for example chlorine, or the free acid is used in the presence of a coupling reagent, for example HOBt (N-hydroxybenzotriazole) and EDCI (l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide ⁇ Cl), and in which R 2 and R 3 have the meaning given above, to give compounds of the general formula (Ia):
  • a coupling reagent for example HOBt (N-hydroxybenzotriazole) and EDCI (l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide ⁇ Cl
  • the reaction is preferably carried out in a solvent such as e.g. Tetrahydrofuran, dioxane, dichloroethane performed.
  • a solvent such as e.g. Tetrahydrofuran, dioxane, dichloroethane performed.
  • the reaction is preferably carried out in a temperature range from room temperature to reflux of the solvents at atmospheric pressure.
  • the reaction is preferably carried out at normal pressure.
  • the reaction is preferably carried out in the presence of a base, e.g. N, N-diisopropylethylamine.
  • a base e.g. N, N-diisopropylethylamine.
  • the invention further relates to intermediates of formula (IV):
  • the compounds of general formulas (I) according to the invention show an unpredictable surprising spectrum of action. They show an antiviral activity against representatives of the He ⁇ es viridae group, especially against the He ⁇ es simplex virus (HSV). They are therefore suitable for the treatment and prophylaxis of diseases which are caused by He ⁇ es viruses, in particular diseases which are caused by He ⁇ es simplex viruses.
  • the invention further relates to the use of 6- (aminosulfonyl) -l-indolinecarboxamide derivatives or 6- (aminosulfonyl) -IH-indole-1-carboxamide derivatives for the production of medicaments, preferably for the production of medicaments for the treatment and or prevention of He ⁇ es Infections in humans or animals.
  • 6- (aminosulfonyl) -l-indolinecarboxamide derivatives or 6- (aminosulfonyl) -lH-indole-l-carboxamide derivatives in this context means those compounds which are substituted by at least one hydrogen atom from 6- (aminosulfonyl) - 1 - indoline carboxamide or ⁇ - (aminosulfonyl) - 1H-indole-1 - carboxamide emerge.
  • HSV HSV-1 walki, HSV-1F or HSV-2G
  • Vero cells ATCC CCL-
  • the cells were in M199 medium (5% fetal calf serum, 2 mM glutamine, 100 IU / ml penicillin, 100 ⁇ g / ml
  • Streptomycin grown in cell culture flasks at 37 ° C and 5% CO2.
  • the cells were split 1: 4 twice a week.
  • the medium was removed for the infection, the cells were washed with “Hank's solution”, detached with 0.05% trypsin, 0.02% EDTA (Seromed L2143) and incubated at a density of 4x10 3 cells per ml under the above-mentioned conditions for 24 hours.
  • the medium was then removed and the virus solution with a moi of ⁇ 0.05 in a volume of 2 ml per 175 cm surface was added. After incubation for one hour under the conditions mentioned, the medium was made up to a volume of 50 ml per 175 cm "bottle.
  • the cultures showed clear signs of a cytopathic effect.
  • the virus was released by freezing twice (-80 ° C) and thawing (37 ° C).
  • the cell debris was separated by centrifugation (300g, 10min, 4 ° C) and the supernatant was frozen away in aliquots at -80 ° C.
  • the virus titer was determined using a plaque assay. For this Vero cells with a density of 4xl0 3 cells per well were sown in 24 well plates and after 24 Hours of incubation (37 ° C, 5% CO 2 ) with dilutions of the virus stock from 10 "2 to 10 " 12 (100 ⁇ l inoculum) infected 1 hour after infection, the medium was removed and the cells were coated with 1 ml overlay medium (0 5% Methylcellulose, 0 225 sodium bicarbonate, 2mM glutamine, 100 IU / ml penicillin, 100 ⁇ g / ml streptomycin, 5% fetal calf serum in MEM-Eagle medium with Earl's salt) and coated for 3 days Fixed for 1 hour, washed with water, stained with Giemsa (Merck) for 30 min and then washed and dried. The virus titer was determined using a plaque viewer. The virus stocks used for the experiments had a titer of l
  • the anti-HSV effect was determined in a screening test system in 96-well microplates with the help of various cells of neuronal, lymphoid and epithal origin, such as Vero (kidney tame of the green sea cat), MEF (male embryonic fibroblasts) , HELP (human embryonic fibroblasts), NT2 (human neuronal cell) or Jurkat (human lymphoid T-cell elms) were determined.
  • Vero kidney tame of the green sea cat
  • MEF male embryonic fibroblasts
  • HELP human embryonic fibroblasts
  • NT2 human neuronal cell
  • Jurkat human lymphoid T-cell elms
  • the substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are measured on microplates (e.g. 96-well MTP) in final concentrations of 250 - 0.5 ⁇ M (micromolar) and 250 - 0.5 nM (nanomolar) in duplicate determinations (4th Substances / plate) examined Toxic and cytostatic substance effects are also recorded.
  • DMSO dimethyl sulfoxide
  • a suspension of cells (1x10 cells per well) such as Vero cells in MI 99 (medium 199) with 5 % fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 ⁇ g / ml streptomycin or MEF cells in EMEM (Eagle's Minimum Essential Medium) with 10% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 ⁇ g / ml streptomycin, or
  • the plates are then incubated at 37 ° C in a CO 2 incubator (5% CO 2 ) for several days. After this time, the cell lawn of, for example
  • the plates are first evaluated optically using a microscope and then analyzed using a fluorescent dye.
  • the cell culture supernatant from all the wells of the MTP is suctioned off and filled with 200 ⁇ l PBS washing solution.
  • the PBS is aspirated again and all wells with 200 ⁇ l
  • Fluorescent dye solution (fluorescein diacetate, 10 ⁇ g / ml in PBS) filled. After an incubation period of 30-90 min, the test plates are measured in a fluorescence measuring device at an excitation wavelength of 485 nm and an emission wavelength of 538 nm.
  • IC 50 here means the half-maximum fluorescence intensity with reference to the non-infected cell control
  • the 6- (aminosulfonyl) -l-indon carboxamid derivatives or 6- (aminosulfonyl) -lH-mdol-1-carboxamid derivatives of the invention preferably have an IC 50 (HSV-
  • the compounds according to the invention thus represent valuable active substances for the treatment and prophylaxis of diseases which are triggered by human He ⁇ es virus, in particular He ⁇ es simplex virus (HSV). Indications can be mentioned, for example
  • He ⁇ es infections especially HSV infections in patients with clinical pictures such as He ⁇ es labiahs, He ⁇ es genitahs, and HSV-related keratitis, encephalitis. Pneumomas, hepatitis etc
  • 6-week-old female mice strain BALB / cABom, were obtained from a commercial breeder (Bomholtgard Breeding and Research Center Ltd.).
  • the animals were anesthetized in a tight glass jar with diethyl ether (Merck). 50 ⁇ l of a dilution of the virus stock (infection dose 5 ⁇ 10 4 Pfu) was introduced into the nose of the anesthetized animals using an Eppendorf pipette. This infection dose leads to death in 90-100% of the animals due to a generalized infection with prominent respiratory and central nervous symptoms on average between 5 and 8 days.
  • the animals were treated with doses of 1-100 mg / kg body mass 3 times a day at 7:00 a.m., 2:00 p.m. and 7:00 p.m. over a period of 5 days.
  • the substances were pre-dissolved in DMSO and resuspended in Tylose / PBS (Hoechst) (final concentration 1.5% DMSO, 0.5% Tylose in PBS). After the last application, the animals were observed further and the times of death determined.
  • mice treated with Example 1 or Example 2 in the Lethal Challenge model (60 mg / kg, p.o., t.i.d., d0-d4 p.i.) showed an increased survival rate compared to animals treated with placebo.
  • the new active compounds can be converted into the customary formulations in a known manner, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients and 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 or intravenously.
  • oral Application is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg body weight.
  • the compound is prepared in analogy to literature P.R. Carlier, M.P. Lockshin, M.P. Filosa, J Org. Chem. 1994, 59, 3232-3236.
  • the product is dissolved in 2.50 ml of methanolic HCl solution without further purification and heated under reflux overnight.
  • the mixture is concentrated in vacuo, then saturated sodium bicarbonate solution is added and the mixture is stirred with ethyl acetate. After washing with water, the organic phase is dried with sodium sulfate. The solvent is removed in vacuo and the product is dried in a high vacuum. 0.282 g (85%) of a red oil is obtained.
  • the compound is prepared in analogy to literature P.R. Carlier, M.P. Lockshin, M.P. Filosa, J Org. Chem. 1994, 59, 3232-3236.
  • the crude product is dissolved in 2 50 ml of methanolic HCl solution and 5-16 hrs
  • indoline C 72 ⁇ l (0.299 mmol) of trichloromethyl chloroformate are added to a solution of 0.500 mmol of the indolines A or F prepared in accordance with working instructions A or F in 3 ml of tetrahydrofuran at room temperature. After stirring overnight at room temperature the solvent is removed in vacuo and the product is dried in a high vacuum (hereinafter referred to as indoline C).
  • indoline F 16.8 mmol of the indohn E prepared according to the general working procedure E are stirred in 50 ml HC1 saturated methanol overnight at room temperature. The solvent is then removed, the residue is taken up in 150 ml of water / ethyl acetate and the pH is adjusted to 8 using saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the solvent is removed. The product is called indoline F.
  • UV detector DAD 210 nm oven temp .: 40 ° C
  • UV detector DAD 210 nm oven temp .: 40 ° C

Landscapes

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

Abstract

L'invention concerne de nouveaux composés, un procédé pour leur préparation, ainsi que leur utilisation comme médicament, notamment comme médicament antiviral.
PCT/EP2000/005114 1999-06-16 2000-06-05 Derives d'indolinylamide WO2000076966A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62623/00A AU6262300A (en) 1999-06-16 2000-06-05 Indolinylamide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19927415A DE19927415A1 (de) 1999-06-16 1999-06-16 Indolinylharnstoffderivate
DE19927415.0 1999-06-16

Publications (2)

Publication Number Publication Date
WO2000076966A2 true WO2000076966A2 (fr) 2000-12-21
WO2000076966A3 WO2000076966A3 (fr) 2001-07-19

Family

ID=7911403

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/005114 WO2000076966A2 (fr) 1999-06-16 2000-06-05 Derives d'indolinylamide

Country Status (3)

Country Link
AU (1) AU6262300A (fr)
DE (1) DE19927415A1 (fr)
WO (1) WO2000076966A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2016097749A1 (fr) * 2014-12-19 2016-06-23 Cancer Research Technology Limited Composés inhibiteurs de parg
US10239843B2 (en) 2014-12-12 2019-03-26 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG
WO2019068817A1 (fr) 2017-10-05 2019-04-11 Innovative Molecules Gmbh Énantiomères de thiazoles substitués utilisés comme composés antiviraux
US10590094B2 (en) 2016-04-06 2020-03-17 Innovative Molecules Gmbh Aminothiazole derivatives useful as antiviral agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024343A1 (fr) * 1995-12-29 1997-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Derives de phenylthiazole dotes de proprietes anti virus de l'herpes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024343A1 (fr) * 1995-12-29 1997-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Derives de phenylthiazole dotes de proprietes anti virus de l'herpes

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
US10239843B2 (en) 2014-12-12 2019-03-26 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG
US10995073B2 (en) 2014-12-19 2021-05-04 Cancer Research Technology Limited PARG inhibitory compounds
CN107295799A (zh) * 2014-12-19 2017-10-24 癌症研究科技有限公司 Parg抑制化合物
US10508086B2 (en) 2014-12-19 2019-12-17 Cancer Research Technology Limited PARG inhibitory compounds
US20200165208A1 (en) * 2014-12-19 2020-05-28 Cancer Research Technology Limited Parg inhibitory compounds
CN107295799B (zh) * 2014-12-19 2021-03-16 癌症研究科技有限公司 Parg抑制化合物
WO2016097749A1 (fr) * 2014-12-19 2016-06-23 Cancer Research Technology Limited Composés inhibiteurs de parg
CN112979631A (zh) * 2014-12-19 2021-06-18 癌症研究科技有限公司 Parg抑制化合物
EP3907224A1 (fr) * 2014-12-19 2021-11-10 Cancer Research Technology Limited Composés inhibiteurs de parg
US10590094B2 (en) 2016-04-06 2020-03-17 Innovative Molecules Gmbh Aminothiazole derivatives useful as antiviral agents
WO2019068817A1 (fr) 2017-10-05 2019-04-11 Innovative Molecules Gmbh Énantiomères de thiazoles substitués utilisés comme composés antiviraux
US11278534B2 (en) 2017-10-05 2022-03-22 Innovative Molecules GmbG Enantiomers of substituted thiazoles as antiviral compounds
EP4209491A1 (fr) 2017-10-05 2023-07-12 Innovative Molecules GmbH Enantiometres d'une serie de composes antiviraux

Also Published As

Publication number Publication date
WO2000076966A3 (fr) 2001-07-19
AU6262300A (en) 2001-01-02
DE19927415A1 (de) 2000-12-21

Similar Documents

Publication Publication Date Title
EP1244641B1 (fr) Derives du type thiazolylamide
EP1161423B1 (fr) Derives de la thiazolyluree et leur utilisation comme antiviraux
DE19912638A1 (de) Naphthylcarbonsäureamid-substituierte Sulfonamide
DE69613377T4 (de) 2-(4-substituierte)-benzylamino-2-methyl-propanamid-derivate
CH671958A5 (fr)
DE19920790A1 (de) Bis-Sulfonamide mit anti-HCMV-Wirkung
DE2628189A1 (de) 3-phenylindoline, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
WO1999037609A1 (fr) Nouveaux sulfamides a substitution par naphtyle et anilide
DE19930075A1 (de) Neue Amino- und Amidosulfonamide als antivirale Mittel
WO2000076966A2 (fr) Derives d'indolinylamide
DE2129960A1 (de) Benzolderivate
WO2003007946A1 (fr) Derives secondaires de 1,3-thiazol-5-ylsulfonamides et leur utilisation en tant qu'agents antiviraux
DD245870A5 (de) Verfahren zur herstellung von triazoyl-chinolin-derivate
DE10210319A1 (de) Thiazolylcarbonyl-Derivate
DE3908298A1 (de) Substituierte (chinolin-2-yl-methoxy)phenyl-n,n'-sulfonylharnstoffe, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
EP0290958A2 (fr) Alkylamines substituées par des groupes diarylalkyles, leur procédé de préparation, leur utilisation ainsi que médicaments les contenant
DE19934321A1 (de) Naphthyl-substituierte Sulfonamide
EP0424722B1 (fr) (Quinolin-2-yl-méthoxy)phényl-thiourées substituées
DE10039265A1 (de) Thiazolylamid-Derivate
WO2002012211A1 (fr) Derives thiazolylamide inverses
DE10044328A1 (de) Thiazolylcarbonyl-Derivate
DE19959958A1 (de) Thiazolylharnstoff-Derivate
DE10129715A1 (de) Thiazolylamide
EP0108981B1 (fr) Semi-carbazides, leur préparation et utilisation
DE19919793A1 (de) Neue Sulfonamide

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY 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: A2

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)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY 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: A3

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

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