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WO2003104233A1 - Derives de 4,5-dihydro-imidazo (4,5,1-ij) quinoline-6-ones et utilisation de ceux-ci en tant qu'inhibiteurs de la poly (adp-ribosyl) transferase (parp) - Google Patents

Derives de 4,5-dihydro-imidazo (4,5,1-ij) quinoline-6-ones et utilisation de ceux-ci en tant qu'inhibiteurs de la poly (adp-ribosyl) transferase (parp) Download PDF

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Publication number
WO2003104233A1
WO2003104233A1 PCT/EP2003/005834 EP0305834W WO03104233A1 WO 2003104233 A1 WO2003104233 A1 WO 2003104233A1 EP 0305834 W EP0305834 W EP 0305834W WO 03104233 A1 WO03104233 A1 WO 03104233A1
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Prior art keywords
piperidin
dihydro
imidazo
formula
uinolin
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PCT/EP2003/005834
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English (en)
Inventor
Thomas Wagner
Steffen Weinbrenner
Rainer Boer
Frank Dullweber
Thomas Klein
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Takeda GmbH
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Altana Pharma AG
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Priority to AU2003240742A priority Critical patent/AU2003240742A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the invention relates to novel 4,5-Dihydro-imidazo[4,5,1-ij]quinolin-6-ones, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
  • PARP poly(ADP-ribosyl)transferase
  • the invention thus relates to compounds of formula 1,
  • A represents a radical of formulae (a), (b), (c) or (d),
  • R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group, or
  • R1 is hydrogen
  • R2 represents hydroxyethyl, di-1-4C-aikylaminocarbonyl, pyrrolidine-2-on-3-yl, 4-fluorophenylcarbon- yl, 4-methoxyphenyIcarbonyl or a thiophenyl, furanyl, benzimidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl or triazinyl group which is unsubstituted or substituted at one or more sites with 1-4C-alkyl, or a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-aikylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substitute
  • R1 is hydroxyl
  • R2 represents an alkynyl derivative of formula (e)
  • R3 is phenyl, pyridyl, hydroxymethyl, methoxym ethyl, phenoxymethyl, dimethylaminomethyl, tert-butyl, cyclopentylmethyl or 1-hydroxyeth-1-yl, or R1 is acetoxy and R2 a phenyl or benzyl group which is unsubstituted or substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycar- bonylamino, or
  • R1 is hydroxyl
  • R2 a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino,
  • R4 represents 4-fluorophenoxyethyl or a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl, hydroxymethyl hydroxyethyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino,
  • R5 is hydrogen or 1-4C-alkyl
  • R6 is hydrogen or 1-4C-alkyl
  • R7 is hydrogen, 1-4C-alkyl, cyclohexyl, cyclohexylmethyl, methoxymethyl, hydroxymethyl, 1-hydroxy- eth-1-yl, methylthioethyl, pyrid-4-yl, pyrid-3-yl, thiophen-2-yl, thiophen-3-yl, thiophen-2-ylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-yl methyl, indan-3-ylmethyl, aminocarbonylmethyl, hy- droxycarbonylmethyl, aminocarbonylethyl, hydroxycarbonylethyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, phenyl, benzyl, or benzyl substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of halogen, 1-4C-alkyl and 1-4C
  • R6 and R7 together with the nitrogen and the carbon atom to which they are attached form a pyrrolidine or a 3-hydroxypyrrolidine ring,
  • R8 is 1-4C-alkoxycarbonyl
  • R9 is hydrogen or
  • R8 is hydrogen
  • R9 is hydroxyl or hydroxymethyl, the salts, the N-oxides and the salts of the N-oxides of these compounds, and the following compounds
  • 1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radicals.
  • Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the above- mentioned 1-4C-aIkyl radicals.
  • Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, two of the abovementioned 1-4C-alkyl radicals. Preferred are the dimethylamino, the diethylamino and the diisopropylamino radical.
  • Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned di-1-4C-alkylamino radicals. Examples which may be mentioned are the N,N-dimethyl- and the N,N-diethyl-radical.
  • 1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, iso- propoxy, ethoxy and methoxy radicals.
  • 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3- pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluo- roethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred.
  • "Predominantly" in this connection means that more than the half of the hydrogen atoms of the 1-4C-alkoxy groups are replaced by fluorine atoms.
  • 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded.
  • Examples are the methoxycarbonyl [CH 3 0-C(0)-] and the ethoxycarbonyl [CH 3 CH 2 0-C(0)-] radical.
  • 1-4C-Alkoxycarbonylamino radicals may be mentioned, for example, the methoxycarbonylamino, the ethoxycarbonylamino and the t-butoxycarbonylamino radical.
  • 1-4C-Alkoxycarbonyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl radicals.
  • An example is the methoxy- carbonylmethyl radical [CH 3 OC(0)CH 2 -].
  • Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
  • R2 represents a thiophenyl, furanyl, benzimidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl or triazinyl group which is substituted at one or more sites with a 1-4C- alkyl group
  • the 1-4C-alkyl group can be bonded to a carbon atom or can replace the hydrogen atom of a >NH radical. Examples which may be mentioned are N-1-4C-alkyl-pyrrolyl or N-1-4C-alkyl-pyrazolyl.
  • N-oxides of these compounds stands for any single or multiple N-oxide(s) which can be formed starting from the compounds of formula 1. Preferred are the single N-oxides.
  • Possible salts for compounds of the formula 1 - depending on substitution - are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, tolue- nesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, it being possible to
  • salts with bases are also suitable.
  • salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
  • Pharmacologically intolerable salts which can initially be obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
  • One embodiment (embodiment A) of the invention are compounds of formula 1 in which in which
  • A represents a radical of formulae (a), (b), (c) or (d),
  • R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group, or
  • R1 is hydrogen
  • R2 represents hydroxyethyl, pyrrolidine-2-on-3-yl, 4-fluorophenylcarbonyl, 4-methoxyphenylcarbonyl or a thiophenyl, furanyl, benzimidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl or triazinyl group which is unsubstituted or substituted at one or more sites with 1-4C-alkyl, or a benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C ⁇ alkylamino, aminocarbonyl, 1 -4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-al
  • R1 is hydroxyl
  • R2 represents an alkynyl derivative of formula (e)
  • R3 is phenyl, pyridyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, tert-butyl, cyclopentylmethyl or 1-hydroxyeth-1-yl, or
  • R1 is acetoxy
  • R2 a phenyl or benzyl group which is unsubstituted or substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycar- bonylamino, or
  • R1 is hydroxyl
  • R2 a benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino,
  • R4 represents 4-fluorophenoxyethyl or a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl, hydroxymethyl hydroxyethyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino,
  • R5 is hydrogen or 1-4C-aIkyl
  • R6 is hydrogen or 1-4C-alkyl
  • R7 is hydrogen, 1-4C-aIkyl, cyclohexyl, cyclohexylmethyl, methoxymethyl, hydroxymethyl, 1-hydroxy- eth-1-yl, methylthioethyl, pyrid-4-yl, pyrid-3-yl, thiophen-2-yl, thiophen-3-yl, thiophen-2-ylmethyl, pyrid-2-ylmethyl, pyrid-3-yImethyl, pyrid-4-ylmethyl, indan-3-ylmethyl, aminocarbonylmethyl, hy- droxycarbonylmethyl, aminocarbonylethyl, hydroxycarbonylethyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, phenyl, benzyl, or benzyl substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of halogen, 1-4C-alkyl and 1-4C
  • R6 and R7 together with the nitrogen and the carbon atom to which they are attached form a pyrrolidine or a 3-hydroxypyrrolidine ring,
  • R8 is hydrogen
  • R9 is hydroxymethyl, the salts, the N-oxides and the salts of the N-oxides of these compounds, and the following compounds
  • R1 is hydrogen
  • R2 represents hydroxyethyl, di-1-4C-alkylaminocarbonyl, pyrrolidine-2-on-3-yl, 4-fluorophenylcarbonyl, 4-methoxyphenylcarbonyl or a thiophenyl, furanyl, benzimidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl or triazinyl group which is unsubstituted or substituted at one or more sites with 1-4C-alkyl, or a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluor
  • R1 is hydroxyl
  • R2 represents an alkynyl derivative of formula (e)
  • R3 is phenyl, pyridyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, tert-butyl, cyclopentylmethyl or 1-hydroxyeth-1-yl, or
  • R1 is acetoxy
  • R2 a phenyl or benzyl group which is unsubstituted or substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxy- carbonylamino, or
  • R1 is hydroxyl
  • R2 a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino,
  • R4 represents 4-fluorophenoxyethyl or a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl, hydroxymethyl hydroxyethyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino, R5 is hydrogen or 1-4C-alkyl,
  • R6 is hydrogen or 1-4C-alkyl
  • R7 is hydrogen, 1-4C-alkyl, cyclohexyl, cyclohexylmethyl, methoxymethyl, hydroxymethyl, 1-hydroxy- eth-1-yl, methylthioethyl, pyrid-4-yl, pyrid-3-yl, thiophen-2-yl, thiophen-3-yl, thiophen-2-ylmethyl, pyrid-2-yl methyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, indan-3-ylmethyl, aminocarbonylmethyl, hy- droxycarbonylmethyl, aminocarbonylethyl, hydroxycarbonylethyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, phenyl, benzyl, or benzyl substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of halogen, 1-4C-alkyl and 1-4C
  • R6 and R7 together with the nitrogen and the carbon atom to which they are attached form a pyrrolidine or a 3-hydroxypyrrolidine ring,
  • R8 is 1-4C-alkoxycarbonyl
  • R9 is hydrogen or
  • R8 is hydrogen
  • R9 is hydroxyl or hydroxymethyl, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group, or
  • R1 is hydrogen
  • R2 represents hydroxyethyl, pyrrol id ine-2-on-3-yl, 4-fluorophenylcarbonyl, 4-methoxyphenylcarbonyl or a thiophenyl, furanyl, benzimidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl or triazinyl group which is unsubstituted or substituted at one or more sites with 1-4C-alkyl, or a benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4
  • R1 is hydroxyl
  • R2 represents an alkynyl derivative of formula (e)
  • R3 is phenyl, pyridyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, tert-butyl, cyclopentylmethyl or 1-hydroxyeth-1-yl, or
  • R1 is acetoxy
  • R2 a phenyl or benzyl group which is unsubstituted or substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1 -4C-alkoxycarbonyl and 1-4C ⁇ alkoxycarb- onylamino, or
  • R1 is hydroxyl
  • R2 a benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of hydroxyl, hydroxymethyl, hydroxyethyl, mono- or di-1-4C-aIkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino,
  • R4 represents 4-fluorophenoxyethyl or a phenyl or benzyl group which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl, hydroxymethyl hydroxyethyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1 -4C-alkoxycarbonyl and 1-4C-alkoxycarbonylamino, R5 is hydrogen or 1-4C-alkyl,
  • R6 is hydrogen or 1-4C-alkyl
  • R7 is hydrogen, 1-4C-alkyl, cyclohexyl, cyclohexylmethyl, methoxymethyl, hydroxymethyl, 1-hydroxy- eth-1-yl, methylthioethyl, pyrid-4-yl, pyrid-3-yl, thiophen-2-yl, thiophen-3-yl, thiophen-2-ylmethyl, pyrid-2-yl methyl, pyrid-3-ylmethyl, pyrid-4-yl methyl, indan-3-ylmethyl, aminocarbonylmethyl, hy- droxycarbonylmethyl, aminocarbonylethyl, hydroxycarbonylethyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, phenyl, benzyl, or benzyl substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of halogen, 1-4C-alkyl and 1-4
  • R6 and R7 together with the nitrogen and the carbon atom to which they are attached form a pyrrolidine or a 3-hydroxypyrrolidine ring,
  • R8 is hydrogen
  • R9 is hydroxymethyl, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • R1 is hydrogen
  • R2 is hydroxyethyl, 3-methoxycarbonylbenzyl or thiophen-2-yl, or
  • R1 is hydroxyl
  • R2 represents an alkynyl derivative of formula (e)
  • R3 is methoxymethyl, phenoxymethyl or tert-butyl
  • R4 is 3-fluorobenzyl, 4-fluorophenoxyethyl, 4-trifluoromethylbenzyl, 3-trifluoromethylphenyl or
  • R7 is 1-4C-alkyl, 1-hydroxyeth-1-yl, phenyl or benzyl, or
  • R6 and R7 together with the nitrogen and the carbon atom to which they are attached form a pyrrolidine or a 3-hydroxypyrrolidine ring,
  • R8 is hydrogen
  • R9 is hydroxyl or hydroxymethyl, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • R1 is hydrogen
  • R2 is hydroxyethyl, 3-methoxycarbonylbenzyl or thiophen-2-yl, or
  • R1 is hydroxyl
  • R2 represents an alkynyl derivative of formula (e)
  • R3 is methoxymethyl, phenoxymethyl or tert-butyl
  • R4 is 3-fluorobenzyl, 4-fluorophenoxyethyl, 4-trifluoromethylbenzyl, 3-trifluoromethylphenyl or
  • R7 is 1-4C-alkyl, 1-hydroxyeth-1-yl, phenyl or benzyl, or
  • R8 is hydrogen
  • R9 is hydroxymethyl, and the salts, the N-oxides and the salts of the N-oxides of these compounds
  • Preferred compounds of the formula 1 are those in which
  • A is 3-(3-fluoro-benzyl)-1 ,3,8-triaza-2,4-dioxo-spiro-[4.5]-decane-8-yl, 3-(4-trifluoromethylbenzyl) ⁇ 1 ,3,8-triaza-2,4-dioxo-spiro-[4.5]-decane-8-yl, 3-(3,5-dimethoxy-phenyl)-1 ,3,8-triaza-2,4-dioxo- spiro-[4.5]-decane-8-yl, 3-(4-fluoro-phenoxy-ethyl)-1 ,3,8-triaza-2,4-dioxo-spiro-[4.5]-decane-8-yl, 3-hydroxymethyl-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, 3-benzyl-1 ,4,9-triaza-2,5-dioxo-spiro- [5.5]undecan-9-yl
  • a special embodiment of the compounds according to the invention are compounds of formula 1, in which A represents a radical of formula (a).
  • Another special embodiment of the compounds according to the invention are compounds of formula 1 , in which A represents a radical of formula (b).
  • Still another special embodiment of the compounds according to the invention are compounds of formula 1 , in which A represents a radical of formula (c).
  • a further special embodiment of the compounds according to the invention are compounds of formula 1 , in which A represents a radical of formula (d).
  • reaction scheme 1 shows the preparation of the intermediate product A1.
  • intermediate product A4 is prepared by reacting 2-chloro-1 H-benzimidazole with 3-chloropropionic acid methyl ester.
  • the methyl ester of intermediate product A4 is then hydrolysed to give 3 ⁇ (2-chloro-benzimidazol-4-yl)-propionic acid (intermediate product A3).
  • Intermediate product A3 is then converted to the corresponding acid chloride A2.
  • intermediate product A2 is cyclocon- densed to give intermediate A1.
  • the starting compounds 2-chloro-1H-benzimidazole and 3-chloropropionic acid methyl ester are commercial available.
  • the reaction conditions which, for example, can be applied for the preparation of the intermediate product A1 are described in the paragraph starting compounds and intermediate products.
  • reaction scheme 2 the final step in the preparation of compounds of formula 1 , wherein A represents a radical of formulae (a), (b), (c) or (d) is shown.
  • Intermediate product A1 is reacted with compounds of the formulae (2a), (2b), (2c) or (2d) to give the compounds of formula 1.
  • Compounds of formulae (2a), (2b), (2c) or (2d) are known or can be prepared according to methods known to the person skilled in the art.
  • the compounds of formula 1 prepared by the processes described above can, if desired, be converted into their salts, or salts of the compounds of formula 1 obtained can, if desired, be converted into the free compounds.
  • Corresponding processes are known to the person skilled in the art.
  • the compounds of formula 1 can be converted by derivatisation into further compounds of formula 1.
  • compounds of formula 1 can be converted, if desired, into their N-oxides.
  • the N-oxidation is carried out in a manner which is known to the person skilled in the art, for example with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxybenzoic acid in dichloro- methane.
  • the person skilled in the art is familiar on the basis of his/her expert knowledge with the reaction conditions which are specifically necessary for carrying out the N-oxidation.
  • It is known to the person skilled in the art that in the case of a number of reactive centers on a starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center.
  • a detailed description of the use of a large number of proven protective groups is found, for example, in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the isolation and purification of the substances according to the invention is carried out in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.
  • h stands for hour(s), RT for room temperature, calc. for calculated, fnd. for found.
  • APCI-MS Atmospheric Pressure Chemical lonisation Mass Spectrometry
  • El-MS Electron Impact Inoisation Mass Spectrometry
  • I I I I I I I i (Ikai et al., J. Histochem. Cytochem. 11: 1261-1264, 1983) a t a sc i tio al e latio . -1 is hi hly e esse i the clei o cells a is a mem e o the ase e cisio e ai com le ( -com le ).
  • oly - i osylatio is tho ht to sta Hi e the e io o the si le st a eak a to allo the e- c itme t o othe - e ai e ymes.
  • Co s me is e e e ate y the se o 4 -molec les o e e y molec le o . te i te se a to- - i osylatio -1 ecomes e ati elycha e a issociates om the
  • I a e o t to e ai these st a eaks -1 is o e acti ate , e- s Iti i cell la a e letio , cell eath a o a ama e. i isolate o a systems s ch as hea t o skeletal m scle i hi itio imi ishes ischemia e e sio i ce tiss e am- a e (Thiemerman et al. PNAS 94,: 679-683, 1997) an contractile ys notion (Docherty et al. Br. J. Pharmacol.
  • PA P me iate cell eath has een sho n in PA P-1 knock-o t mice in ario s in- i o mo els o cere ral an myocar ial ischemia re er sion inj ry.
  • a massi e re ction o the necrotic area in the CNS as re orte in PA P-1 -knock o tmice a ter transient occl sion o the mi le cere ral artery.
  • PA P inhi ition has een shown to re ce cell lar an or an ama e.
  • Con irmin res Its are a aila le rom small molec le inhi itors o PA Ps in mo els o transient cere ral ischemia an transient retinal ischemia (Lam, Res. Com. Mol. Pathol. Pharmacol. 95, 241-252, 1997).
  • ac te or chronic in lammation in enerai is characterise amon others y massi e enera- tion o reacti e o y en s ecies an nitric o i e.
  • reacti e o y en s ecies an nitric o i e.
  • PARP-1 o eracti ation an cell eath.
  • PARP acti ation plays a key role in lutamate-, NMDA-, N -, reacti e o y en species- an lucose epri ation in uce neuroto icity.
  • the use o PARP inhibitors was reporte to pre ent neuroto icity in cortical or cerebellar ranule cell cultures an in hippocampal slices (Wallis et al., NeuroReport, 5:3, 245-48. 1993; Cosi et al, J. Neurosci. Res 39: 38-46, 1994; Eliasson et al. Nature Med.
  • PARP-1 inhibition protects pancreatic islet cells rom NO or reacti e oxy- gene species induced damage (Uchigata et al. J. Biol. Chem. 257 6084- 6088, 1982).
  • PARP-1 inhibition reduced cellular damage and increased insulin production (Uchigata et al. Diabetes 32, 316-318, 1983)
  • PARP inhibitors ha e been reported to be e ecti e in radiosensitizing hypoxic tumor cells and in pre- enting tumor cells ro reco ering rom potentially lethal damage o DNA a ter radiation therapy, presumably by their ability to pre ent DNA repair (Griffin et al. J. Med. Chem. 41, 5247-5256, 1998).
  • the compounds according to the in ention can be employed in human and eterinary medicine and therapeutics, where they can be used for the treatment and prophylaxis of the following diseases: ascular stroke (cerebral stroke), myocardial infarction and other cardio ascular disorders (atherosclerosis), diabetes, head trauma, sepsis and septic shock; hemorrhagic shock, tissue damage resulting from PARP-1 mediated necrosis or apoptosis; any kind of reperfusion injury; especially neuronal (CNS), myocardial, retinal or other tissue damage resulting from ischemia and reperfusion; ischemia reperfusion injury during organ transplantation surgery, surgery with transient interruption of blood flow to organs or body areas, and surgery when heart-lung heart-circulation machines are used; renal failure due to ischemia or glomerulonephri- tis, retinal ischemia; neurological disorders and neurodegenerati e diseases
  • PARP-inhibitors can be used to extend the lifespan and proliferati e capacity of cells; to alter gene expression of senescent cells and to enhance the efficacy of chemo- or radiotherapy in cancers. PARP-inhibitors can also be used to potentiate cellular necrosis and or apoptosis by chemothera-plastic compounds of arious classes.
  • the in ention further relates to a method for the treatment of mammals, including humans, which are suffering from one of the abo ementioned illnesses.
  • the method is characterized in that a therapeuti- cally acti e and pharmacologically effecti e and tolerable amount of one or more of the compounds according to the in ention is administered to the ill mammal.
  • the in ention further relates to the compounds according to the in ention for use in the treatment and or prophylaxis of illnesses, especially the illnesses mentioned.
  • the in ention also relates to the use of the compounds according to the in ention for the production of pharmaceutical compositions which are employed for the treatment and or prophylaxis of the illnesses mentioned.
  • the in ention furthermore relates to pharmaceutical compositions for the treatment and or prophylaxis of the illnesses mentioned, which contain one or more of the compounds according to the in ention.
  • compositions are prepared by processes which are known perse and familiar to the person skilled in the art.
  • the compounds according to the in ention ( acti e compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and or excipients, e.g. in the form of tablets, coated tablets, capsules, cap- lets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the acti e compound content ad antageously being between 0.1 and 95 and where, by the appropriate choice of the auxiliaries and or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the acti e compound and or to the desired onset of action can be achie ed.
  • suitable pharmaceutical auxiliaries and or excipients e.g. in the form of tablets, coated tablets, capsules, cap- lets, suppositories, patches (e.g. as TTS),
  • auxiliaries or excipients which are suitable for the desired pharmaceutical formulations on account of his her expert knowledge.
  • gel formers, ointment bases and other acti e compound excipients for example antioxidants, dispersants, emulsifiers, preser ati es, solubilizers, colorants, complexing agents or permeation promoters, can be used.
  • the administration of the pharmaceutical compositions according to the in ention may be performed in any of the generally accepted modes of administration a ailable in the art.
  • Illustrati e examples of suitable modes of administration include intra enous, oral, nasal, parenteral, topical, transdermal and rectal deli ery. Oral and intra enous deli ery is preferred.
  • compositions according to the in ention are prepared by processes known perse. Dosage of the acti e compounds takes place in the order of magnitude customary for PARP inhibitors. Thus topical application forms (such as, for example, ointments) contain the acti e compounds in a concentration of, for example, 0.1-99 . or oral administration, e.g., the dosage that may be employed is from about 0.1 to about 100 mg kg body weight, with courses of treatment repeated at appropriate inter als.
  • T ⁇ e potency of the compounds according to the in ention to inhibit PARP-1 acti ity is tested by measuring the auto-ADP-ribosylation reaction at the le el of partially purified human PARP-1.
  • Cellular PARP- acti ity was measured by uantification of nuclear poly-ADP-ribose polymer.
  • Radiolabelled poly-ADP-ribose is measured by adding 50 to 500 ng of an anti polyADP-ribose antibody or an anti-PARP-1 antibody linked to scintillation proximity beads (Protein-A-beads, Amersham-Pharmacia). Bead bound radioacti ity is measured in a Wallac Trilux Microbeta counter. Inhibition of PARP acti ity by compounds is calculated from control alues in the absence of compounds and IC S0 - alues (concentration of compound yielding 50 inhibition are generated by nonlinear least s uare fitting.
  • the inhibitory alues measured as -loglC S0 ( ol I) determined for the compounds 1 to 27 were all greater than 5.
  • the number of the compounds correspond to the number of the examples.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule 1; dans cette formule, A est tel que défini dans la description. Les composés décrits dans cette invention sont des nouveaux inhibiteurs actifs de la PARP.
PCT/EP2003/005834 2002-06-07 2003-06-04 Derives de 4,5-dihydro-imidazo (4,5,1-ij) quinoline-6-ones et utilisation de ceux-ci en tant qu'inhibiteurs de la poly (adp-ribosyl) transferase (parp) Ceased WO2003104233A1 (fr)

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AU2003240742A AU2003240742A1 (en) 2002-06-07 2003-06-04 4,5-dihydro-imidazo (4,5,1-ij) quinolin-6-ones derivatives and their use as poly (adp-ribosyl) transferase (parp) inhibitors

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EP02012704.9 2002-06-07

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099943A1 (fr) * 2005-03-19 2006-09-28 Sanofi-Aventis 8-n-benzimidazoles a substitution amide, leur procede de production, et leur utilisation en tant que medicaments
EP1541574A4 (fr) * 2002-09-18 2007-06-20 Ono Pharmaceutical Co Derives triazaspiro 5.5|undecanes et medicaments les contenant en tant que principe actif
WO2006099942A3 (fr) * 2005-03-19 2007-06-21 Sanofi Aventis Deutschland Utilisation de 8-n-benzimidazoles a substitution amino
WO2007067504A3 (fr) * 2005-12-05 2007-11-08 Incyte Corp Composes lactames et procedes d'utilisation de ceux-ci
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
JP2016503408A (ja) * 2012-11-08 2016-02-04 セルビタ エス．エー． キナーゼ阻害剤としての置換三環式ベンゾイミダゾール
CN111349094A (zh) * 2020-04-23 2020-06-30 杭州师范大学 一种6H-咪唑[4,5,1-ij]并喹诺酮及其合成方法和应用
WO2022226166A1 (fr) * 2021-04-22 2022-10-27 Protego Biopharma, Inc. Imidazolidinediones et imidazolidinones spirocycliques pour le traitement d'une amylose à chaîne légère

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EP0646583A1 (fr) * 1993-10-04 1995-04-05 Synthelabo Dérivés d'imidazol-4-yl-pipéridine, leur préparation et leur application en thérapeutique
WO2002012239A1 (fr) * 2000-08-08 2002-02-14 Sanofi-Synthelabo Derives de benzimidazole, leur preparation et leur application en therapeutique
DE10039610A1 (de) * 2000-08-09 2002-02-28 Basf Ag Azepinoindol-Derivate, deren Herstellung und Anwendung

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0646583A1 (fr) * 1993-10-04 1995-04-05 Synthelabo Dérivés d'imidazol-4-yl-pipéridine, leur préparation et leur application en thérapeutique
WO2002012239A1 (fr) * 2000-08-08 2002-02-14 Sanofi-Synthelabo Derives de benzimidazole, leur preparation et leur application en therapeutique
DE10039610A1 (de) * 2000-08-09 2002-02-28 Basf Ag Azepinoindol-Derivate, deren Herstellung und Anwendung

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1541574A4 (fr) * 2002-09-18 2007-06-20 Ono Pharmaceutical Co Derives triazaspiro 5.5|undecanes et medicaments les contenant en tant que principe actif
WO2006099943A1 (fr) * 2005-03-19 2006-09-28 Sanofi-Aventis 8-n-benzimidazoles a substitution amide, leur procede de production, et leur utilisation en tant que medicaments
WO2006099942A3 (fr) * 2005-03-19 2007-06-21 Sanofi Aventis Deutschland Utilisation de 8-n-benzimidazoles a substitution amino
US8003668B2 (en) 2005-03-19 2011-08-23 Sanofi-Aventis Amino-substituted 8-N-benzimidazoles and methods for their use in blood sugar disorders
US8163774B2 (en) 2005-03-19 2012-04-24 Sanofi-Aventis Amide-substituted 8-N-benzimidazoles, method for the production thereof, and use of the same as medicaments
WO2007067504A3 (fr) * 2005-12-05 2007-11-08 Incyte Corp Composes lactames et procedes d'utilisation de ceux-ci
US8193207B2 (en) 2005-12-05 2012-06-05 Incyte Corporation Lactam compounds and methods of using the same
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US8614213B2 (en) 2008-08-07 2013-12-24 Novartis Ag Cyclohexyl amide derivatives and their use as CRF-1 receptor antagonists
JP2016503408A (ja) * 2012-11-08 2016-02-04 セルビタ エス．エー． キナーゼ阻害剤としての置換三環式ベンゾイミダゾール
CN111349094A (zh) * 2020-04-23 2020-06-30 杭州师范大学 一种6H-咪唑[4,5,1-ij]并喹诺酮及其合成方法和应用
WO2022226166A1 (fr) * 2021-04-22 2022-10-27 Protego Biopharma, Inc. Imidazolidinediones et imidazolidinones spirocycliques pour le traitement d'une amylose à chaîne légère

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