WO2007039578A1 - Composes d'azabenzophenone substitues par imidazolyle - Google Patents

Composes d'azabenzophenone substitues par imidazolyle Download PDF

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WO2007039578A1
WO2007039578A1 PCT/EP2006/066919 EP2006066919W WO2007039578A1 WO 2007039578 A1 WO2007039578 A1 WO 2007039578A1 EP 2006066919 W EP2006066919 W EP 2006066919W WO 2007039578 A1 WO2007039578 A1 WO 2007039578A1
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alkyl
alkylene
hydrogen
group
pyridin
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PCT/EP2006/066919
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English (en)
Inventor
Thomas Fuchss
Andreas Strub
Christian Hesslinger
Wolf-Rüdiger Ulrich
Martin Lehner
Céline ANÉZO
Rainer Boer
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Nycomed Gmbh
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Publication of WO2007039578A1 publication Critical patent/WO2007039578A1/fr

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

Definitions

  • the invention relates to imidazolyl-substituted azabenzophenone compounds, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
  • US 4,661 ,603 relates to imidazole derivatives having inhibitory activities on biosynthesis of thromboxane A 2 , inhibitory activities on platelet aggregation, vasodilative activities and protective effects against liver disorders.
  • the review of E. P. Erdal et al., Current Topics in Medicinal Chemistry, 2005, 5, 603-624 deals with selective neuronal nitric oxide synthase inhibitors.
  • the invention relates to compounds of formula (I)
  • X is N
  • Y is CH
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is selected from hydrogen and halogen;
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene, 2,5-pyridinylene and 2,5-pyrimidinylene;
  • R4 is selected from R5 and R6;
  • R5 is a group -NR51-A1-NR52R53;
  • R51 is selected from hydrogen and 1-3C-alkyl;
  • R52 is selected from hydrogen and 1-3C-alkyl;
  • R53 is selected from hydrogen and 1-3C-alkyl;
  • R6 is a monocyclic 5- to 7-membered heterocyclic group containing one or two heteroatoms selected from N and O, said group being optionally substituted by R7;
  • A1 is a 1-3C-alkylene group;
  • R7 is selected from 1-4C-alkyl, hydroxy- 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, -C(0)R8, -A2-
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 , -A7-O-R15, -A8-O-A9-O-R16 and -A10-Z3;
  • R17 is selected from hydrogen and 1-3C-alkyl
  • R18 is selected from hydrogen and 1-3C-alkyl
  • Het is a group of formula (II)
  • Q is selected from -NR19-, -CH 2 - and -O-;
  • R19 is selected from hydrogen and 1-3C-alkyl;
  • R20 is selected from hydrogen and 1-3C-alkyl;
  • R21 is selected from -C(O)R22, 1-3C-alkyl and 1-3C-alkylene-O-1-3C-alkyl;
  • R22 is selected from 1-3C-alkyl and 1-3C-alkylene-O-1-3C-alkyl; and the salts thereof.
  • Halogen includes fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.
  • 2,5-Pyridinylene is a group, to which the -SO 2 -R4 moiety is bonded in 2-position and to which the phenyl ring is bonded in 5-position.
  • 2,5-Pyrimidinylene is a group, to which the -SO 2 -R4 moiety is bonded in 2-position and to which the phenyl ring is bonded in 5-position.
  • the group -NR51-A1-NR52R53 includes, but is not limited to, -NH-CH 2 -NH 2 , -NH-CH 2 CH 2 -NH 2 , -NH-CH 2 CH 2 CH 2 -NH 2 , -NCH 3 -CH 2 -NH 2 , -NCH 3 -CH 2 CH 2 -NH 2 , -NCH 3 -CH 2 CH 2 CH 2 -NH 2 , -NH-CH 2 - N(CH 3 ) 2 , -NH-CH 2 CH 2 -N(CHa) 2 , -NH-CH 2 CH 2 -NHCH 3 , -NH-CH 2 CH 2 CH 2 -N(CH 3 ) 2 , -NCH 3 -CH 2 -N(CH 3 ) 2 , -NCH 3 -CH 2 CH 2 -N(CHa) 2 , -NCH 3 -CH 2 CH 2 -N(CHa) 2 , -NCH 3
  • the monocyclic 5- to 7-membered heterocyclic group containing one or two heteroatoms selected from N and O includes, but is not limited to, monocyclic 5- to 7-membered heterocyclic groups containing 1 nitrogen atom, monocyclic 5- to 7-membered heterocyclic groups containing 2 nitrogen atoms and monocyclic 5- to 7-membered heterocyclic groups containing 1 nitrogen atom and 1 oxygen atom.
  • a monocyclic 6- or 7-membered heterocyclic group containing 1 or 2 nitrogen atoms is preferred.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
  • the diazepanyl group includes all isomers regarding the position of the two ring nitrogen atoms, with 1 ,3-diazepanyl and 1 ,4- diazepanyl groups being preferred.
  • Specifically preferred isomeric forms include piperidin-1-yl, piperazin-1-yl, 1 ,4-diazepan-1-yl and pyridin-4-yl.
  • 1-6C-Alkylene is a straight-chain or branched alkylene group having 1 to 6 carbon atoms.
  • straight-chain alkylene group having 1 to 6 carbon atoms are methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), n-propylene (-CH 2 -CH 2 -CH 2 -), n-butylene (-CH 2 -CH 2 -CH 2 -CH 2 -), n-pentylene (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -) and n-hexylene (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -).
  • Examples of the branched alkylene group having 1 to 6 carbon atoms include, but are not limited to, the groups -CH(CH 3 )-, -CH 2 -CH(CH 3 )-, -C(CHa) 2 -, -CH 2 -C(CH 3 ) 2 -CH 2 - and -CH 2 -CH(C 2 H 5 )-CH 2 -CH 2 -.
  • the straight-chain alkylene groups having 1 to 4 carbon atoms are preferred.
  • 1-3C-alkylene is a straight-chain or branched alkylene group having 1 to 3 carbon atoms.
  • the straight-chain alkylene group having 1 to 3 carbon atoms are methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -) and n-propylene (-CH 2 -CH 2 -CH 2 -).
  • the branched alkylene group having 1 to 3 carbon atoms include the groups -CH(CH 3 )-, -CH 2 -CH(CH 3 )- and -C(CH 3 ) 2 -.
  • the straight- chain alkylene groups having 1 to 3 carbon atoms are preferred. Methylene and ethylene are specifically preferred.
  • 1-4C-Alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples are n-butyl, iso-butyl, sec-butyl, tert-butyl, n-propyl, iso-propyl, ethyl and methyl.
  • 1-3C-alkyl is a straight-chain or branched alkyl group having 1 to 3 carbon atoms. Examples are n-propyl, iso-propyl, ethyl and methyl.
  • Hydroxy- 1-4C-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and containing a terminal hydroxy group.
  • Non-limiting examples include hydroxybutyl (e.g. -CH 2 -CH 2 -CH 2 - CH 2 -OH and -CH 2 -C(CH 3 ) 2 -OH), hydroxypropyl (e.g. -CH 2 -CH 2 -CH 2 -OH and -CH(CH 3 )-CH 2 -OH), hydroxyethyl (-CH 2 -CH 2 -OH and -CH(CH 3 )-0H) and hydroxymethyl (-CH 2 -OH).
  • Straight-chain hydroxy- 1-4C-alkyl groups are preferred, of which -CH 2 -CH 2 -OH is specifically preferred.
  • 1-4C-Alkoxy-1-4C-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which contains a terminal straight-chain or branched alkoxy group.
  • Examples thereof include, but are not limited to, a methoxybutyl (e.g. -CH 2 -CH 2 -CH 2 -CH 2 -O-CH 3 ), methoxypropyl (e.g.
  • -CH 2 -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 3 ethoxyethyl (e.g. -CH 2 -CH 2 -O-CH 2 -CH 3 ), ethoxymethyl (-CH 2 -O-CH 2 -CH 3 ) and butoxymethyl (e.g. -CH 2 -O-C(CH 3 ) 2 -CH 3 ) group.
  • 1-4C-Alkoxy-1-4C-alkyl groups wherein the alkoxy moiety and the alkyl moiety are each straight-chain groups, are preferred.
  • the -CH 2 -CH 2 -O-CH 3 group is specifically preferred.
  • the monocyclic or bicyclic group having 5 to 10 carbon atoms, wherein optionally 1 to 4 carbon atoms are replaced by identical or different heteroatoms selected from N, O and S includes, but is not limited to, 5- to 7-membered monocyclic and 8 to 10-membered bicyclic groups, wherein optionally 1 to 4 carbon atoms are replaced by identical or different heteroatoms selected from N, O and S.
  • a particularly preferred example is the hexahydro-1/-/-thieno[3,4-c/]imidazolyl group which is optionally substituted by the substituents mentioned.
  • the monocyclic or bicyclic group having 5 to 10 carbon atoms, wherein optionally 1 to 4 carbon atoms are replaced by identical or different heteroatoms selected from N, O and S, said group being substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, 0 and -NR17R18, includes, but is not limited to, phenyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, oxazolidinyl, thiolanyl, thiazolidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, piperidinyl, piperazinyl,
  • the group 1-3C-alkylene-O-1-3C-alkylene represents two 1-3C-alkylene groups bonded via an oxygen atom. Examples thereof include, but are not limited to, -CH 2 -O-CH 2 -, -CH 2 -O-CH 2 -CH 2 -, -CH 2 -U-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -U-CH 2 -CH 2 -, -CH 2 -CH 2 -U-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -, -CH(CHa)-O-CH 2 - and -CH 2 -O-C(CH 3 ) 2 -.
  • the group 1-3C-alkylene-O-1-3C-alkylene-O-1-3C-alkylene represents three 1-3C-alkylene groups bonded via oxygen atoms. Examples thereof include, but are not limited to, -CH 2 -O-CH 2 -O-CH 2 -, -CH 2 -O-CH 2 -O-CH 2 -CH 2 -, -CH 2 -O-CH 2 -O-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -O ⁇ 2 ⁇ O ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ O ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ , ⁇ C ⁇ 2 ⁇ O ⁇ 2 ⁇ O ⁇ C ⁇ 2 ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ , -CH 2 -O-CH(CHa)-O-CH 2 -,
  • the group -C(0)R8 with R8 being selected from hydrogen, 1-3C-alkyl, 3-6C-cycloalkyl, -A6-NH 2 , -A7-O-R15, -A8-O-A9-O-R16 and -A10-Z3 includes, but is not limited to, -C(O)H, -C(O)CH 3 ,
  • -C(O)CH 2 OCH 3 -C(O)CH 2 CH 2 OCH 3 , -C(O)CH 2 OCH 2 CH 2 OCH 3 and -C(O)CH 2 CH 2 CH 2 CH 2 -Z3.
  • Preferred examples include -C(O)H, -C(O)CH 3 , -C(O)cyclopropyl, -C(O)CH 2 NH 2 and -C(O)-(CH 2 ) 4 -2(3H)-oxo-tetrahydro-1H-thieno[3,4-c/]imidazol-4-yl.
  • Examples of the group -A2-NR9R10 include, but are not limited to, -NH 2 , -CH 2 -NH 2 , -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -CH 2 -NH 2 , -NHCH 3 , -CH 2 -NHCH 3 , -CH 2 -CH 2 -NHCH 3 , -CH 2 -CH 2 -NHCH 3 , -N(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -CH 2 -N(CH 3 ) 2 , -NH(C 2 H 5 ), -CH 2 -NH(C 2 H 5 ), -CH 2 -NH(C 2 H 5 ), -CH 2 -NH(C
  • a preferred example is -NH 2 .
  • Examples of the group -A3-C(O)-NR11 R12 include, but are not limited to, -CH 2 -C(O)-NH 2 , -CH 2 -CH 2 -C(O)-NH 2 , -CH 2 -CH 2 -CH 2 -C(O)-NH 2 , -CH 2 -C(O)-NHCH 3 , -CH 2 -CH 2 -C(O)-NHCH 3 , -CH 2 -CH 2 -CH 2 -C(O)-NHCH 3 , -CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 -CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 -CH 2 -CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 -CH 2 -CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 -C(O)-
  • Examples of the group -A4-Z1 include, but are not limited to, -CH 2 -phenyl, -CH 2 -CH 2 -phenyl,
  • the pyridinyl group may be bonded to the 1-3C- alkylene group in any position, i.e., in 2-, 3- or 4-position.
  • the morpholinyl group may be bonded to the 1-3C-alkylene group in any position, i.e., in 1-, 2-, 3- or 4-position.
  • Preferred groups -A4-Z1 include -CH 2 -pyridinyl and -CH 2 -CH 2 -morpholinyl.
  • the groups -CH 2 -pyridin-2-yl and -CH 2 -CH 2 -morpholin-4-yl are especially preferred.
  • Examples of the group -A5-C(O)-Z2 include, but are not limited to, -CH 2 -C(O)-phenyl, -CH 2 -CH 2 -C(O)-phenyl, -CH 2 -CH 2 -CH 2 -C(O)-phenyl, -CH 2 -C(O)-morpholinyl, -CH 2 -CH 2 -C(O)-morpholinyl and -CH 2 -CH 2 -CH 2 -C(O)-morpholinyl.
  • the morpholinyl group may be bonded to the 1-3C-alkylene group in any position, i.e., in 1-, 2-, 3- or 4-position.
  • a preferred group is -CH 2 -C(O)-morpholinyl, especially preferred is -CH 2 -C(O)-morpholin-4-yl.
  • Examples of the group -NH-C(0)R14 include, but are not limited to, -NH-C(O)CH 3 , -NH-C(O)CH 2 -CH 3 , -NH-C(O)CH 2 -CH 2 -CH 3 , of which -NH-C(O)CH 3 is preferred.
  • the substituent R7 may be bonded to the group R6 at any position.
  • R7 is bonded in 3- or 4- position, with reference to the bonding position of the -SO 2 - group at R6.
  • Preferred examples of the monocyclic 5- to 7-membered heterocyclic group containing one or two heteroatoms selected from N and O, which is substituted by R7 include, but are not limited to,
  • Examples of the group -NR19- include, but are not limited to, -NH-, -NCH 3 - and -NC 2 H 5 - with -NH- being preferred.
  • Examples of the group -C(O)R22 include, but are not limited to, -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 CH 2 CH 3 and -C(O)CH(CH 3 )CH 3 with -C(O)CH 3 being preferred.
  • the invention relates to compounds of formula (I), in which
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6;
  • R6 is a monocyclic 5- to 7-membered heterocyclic group containing one or two heteroatoms selected from N and O, said group being optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene;
  • A6 is 1-3C-alkylene;
  • A10 is selected from a single bond, 1-6C-alkylene, 1-3C-alkylene-O-1-3C-alkylene and 1-3C- alkylene-O-1-3C-alkylene-O-1-3C-alkylene;
  • R9 is selected from hydrogen and 1-3C-alkyl
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R13 is selected from 1-3C-alkyl and -NH 2 ;
  • R14 is 1-3C-alkyl
  • R17 is selected from hydrogen and 1-3C-alkyl
  • R18 is selected from hydrogen and 1-3C-alkyl
  • Het is a group of formula (II)
  • the invention relates to compounds of formula (I), in which X is N;
  • Y is CH
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6;
  • R6 is a monocyclic 5- to 7-membered heterocyclic group containing one or two heteroatoms selected from N and O, said group being optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene;
  • A6 is 1-3C-alkylene
  • A10 is 1-6C-alkylene
  • R9 is selected from hydrogen and 1-3C-alkyl
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R13 is selected from 1-3C-alkyl and -NH 2 ;
  • R14 is 1-3C-alkyl
  • Z3 is a bicyclic group having 8 to 10 carbon atoms, wherein optionally 1 to 4 carbon atoms are replaced by identical or different heteroatoms selected from N, O and S, said group being optionally substituted by one or more identical or different substituents selected from halogen, 1-
  • R17 is selected from hydrogen and 1-3C-alkyl
  • R18 is selected from hydrogen and 1-3C-alkyl
  • Het is a group of formula (II)
  • the invention relates to compounds of formula (I), in which
  • X is N
  • Y is CH
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6
  • R6 is a monocyclic 5- to 7-membered heterocyclic group containing one or two nitrogen atoms, said group being optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene
  • A6 is 1-3C-alkylene
  • A10 is selected from a single bond, 1-6C-alkylene, 1-3C-alkylene-O-1-3C-alkylene and 1-3C- alkylene-O-i-SC-alkylene-O-i-SC-alkylene;
  • R9 is selected from hydrogen and 1-3C-alkyl
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R13 is selected from 1-3C-alkyl and -NH 2 ;
  • R14 is 1-3C-alkyl
  • R17 is selected from hydrogen and 1-3C-alkyl
  • R18 is selected from hydrogen and 1-3C-alkyl
  • Het is a group of formula (II)
  • R20 is hydrogen
  • R21 is -C(O)R22
  • R22 is 1-3C-alkyl; and the salts thereof.
  • the invention relates to compounds of formula (I), in which
  • X is N
  • Y is CH;
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6
  • R6 is a monocyclic 5- to 7-membered heterocyclic group containing one or two nitrogen atoms, said group being optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene;
  • A6 is 1-3C-alkylene;
  • A10 is 1-6C-alkylene;
  • R9 is selected from hydrogen and 1-3C-alkyl
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R13 is selected from 1-3C-alkyl and -NH 2
  • R14 is 1-3C-alkyl
  • the invention relates to compounds of formula (I), in which
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6;
  • R6 is a monocyclic 6- or 7-membered heterocyclic group containing one or two nitrogen atoms, said group being optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene;
  • A6 is 1-3C-alkylene;
  • A10 is selected from a single bond, 1-6C-alkylene, 1-3C-alkylene-O-1-3C-alkylene and 1-3C- alkylene-O-1-3C-alkylene-O-1-3
  • R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
  • the invention relates to compounds of formula (I), in which X is N; Y is CH;
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen;
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6
  • R6 is a monocyclic 6- or 7-membered heterocyclic group containing one or two nitrogen atoms, said group being optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene;
  • A6 is 1-3C-alkylene;
  • A10 is 1-6C-alkylene;
  • R9 is selected from hydrogen and 1-3C-alkyl
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R13 is selected from 1-3C-alkyl and -NH 2
  • R14 is 1-3C-alkyl
  • R17 is selected from hydrogen and 1-3C-alkyl
  • R18 is selected from hydrogen and 1-3C-alkyl
  • Het is a group of formula (II)
  • R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
  • the invention relates to compounds of formula (I), in which X is N; Y is CH;
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen;
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R6 is a group selected from piperidinyl, piperazinyl, diazepanyl and pyridinyl, which is optionally substituted by R7;
  • R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH 2 and -A10-Z3;
  • A2 is selected from a single bond and 1-3C-alkylene
  • A6 is 1-3C-alkylene; A10 is 1-6C-alkylene;
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R17 is selected from hydrogen and 1-3C-alkyl
  • R18 is selected from hydrogen and 1-3C-alkyl
  • Het is a group of formula (II)
  • the invention relates to compounds of formula (I), in which X is N;
  • Y is CH
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R2 is hydrogen
  • A2 is selected from a single bond and 1-3C-alkylene
  • A6 is 1-3C-alkylene
  • R9 is selected from hydrogen and 1-3C-alkyl
  • R10 is selected from hydrogen and 1-3C-alkyl
  • R14 is 1-3C-alkyl
  • R20 is hydrogen
  • R22 is 1-3C-alkyl; and the salts thereof.
  • the invention relates to compounds of formula (I), in which
  • Y is CH;
  • R1 is selected from -R3-SO 2 -R4 and Het;
  • R4 is R6
  • R8 is selected from hydrogen, methyl, cyclopropyl, -CH 2 -NH 2 and -A10-Z3;
  • A2 is a single bond;
  • A10 is n-butylene;
  • R10 is hydrogen
  • R13 is selected from methyl and -NH 2 ;
  • Het is a group of formula (II)
  • R20 is hydrogen
  • Acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, citrates, D-gluconates, benzoates, 2-(4-hydroxybenzoyl)benzoates, butyrates, subsalicylates, maleates, laurates, malates, fumarates, succinates, oxalates, tartarates, stearates, toluenesulfonates, methanesulfonates, 3-hydroxy-2-naphthoates and trifluoroacetates. Of these, hydrochlorides, methanesulfonates and trifluoroacetates are preferred.
  • salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • the compounds according to the present invention and their salts include chiral compounds.
  • Each of the chiral centers present in said compounds or salts may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog).
  • the present invention includes all conceivable pure diastereomers and pure enantiomers of the compounds and salts according to the present invention, and all mixtures thereof independent from the ratio, including the racemates.
  • Preferred stereoisomers include compounds of formula (I), in which
  • R1 is -R3-SC- 2 -R4;
  • R2 is selected from hydrogen and halogen
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene, 2,5-pyridinylene and 2,5-pyrimidinylene;
  • R4 is R6;
  • R6 is a monocyclic 5- to 7-membered heterocyclic group containing one or two heteroatoms selected from N and O, said group being optionally substituted by R7;
  • R7 is -C(O)R8
  • R8 is -A10-Z3 having the formula (III)
  • R1 is -R3-SO 2 -R4;
  • R2 is hydrogen
  • R7 is -C(O)R8
  • R8 is -A10-Z3 having the formula (III); and the salts thereof.
  • R1 is selected from -R3-SO 2 -R4;
  • R2 is hydrogen;
  • R3 is selected from 1 ,4-phenylene, 1 ,4-piperazinylene and 2,5-pyridinylene;
  • R4 is R6;
  • R6 is a 6- or 7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, said group being substituted by R7;
  • R7 is -C(O)R8;
  • R8 is -A10-Z3 having the formula (III) and the salts thereof.
  • R1 is selected from -R3-SO 2 -R4;
  • R2 is hydrogen
  • R3 is 1 ,4-phenylene
  • R4 is R6;
  • R6 is a 6- or 7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, said group being substituted by R7;
  • the pure diastereomers and pure enantiomers of the compounds and salts according to the present invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
  • the pure diastereomeric and pure enantiomeric compounds of the present invention are obtained by using chiral starting compounds.
  • the compounds according to the present invention can be prepared as described hereinafter and shown in the following reaction schemes, or as specified by way of example in the following examples or similarly or analogously thereto.
  • a compound of formula (Int1 ) can be obtained in a first step according to a procedure described in J. Med. Chem. 2003, 46(15), 3354-3370 to afford 1-(4-halophenyl)-1-(6-halo-pyridin-3-yl)- methanone from commercially available starting materials.
  • said compound can be transformed by nucleophilic displacement of HaH into the desired intermediate (Int1 ), thereby using imidazole and a strong base, e.g. sodium hydride, in a suitable solvent such as, for example, dimethylsulphoxide.
  • a compound of formula (Int2) can be obtained by reacting e.g. commercially available 4-halo-benzenesulphonyl chloride (e.g.
  • 4-bromo- benzenesulphonyl chloride with a compound HR4, preferably a compound HR6, which is either commercially available or can be prepared by procedures known to person skilled in the art, and an appropriate deprotonating agent, for example, ⁇ /, ⁇ /-diisopropylethylamine (H ⁇ nig's base), triethylamine or 1 ,8-diazabicydo[5.4.0]undec-7-ene (DBU) under Einhorn conditions in a suitable solvent, e.g. acetonitrile, tetrahydrofuran, toluene or dichloromethane.
  • a suitable solvent e.g. acetonitrile, tetrahydrofuran, toluene or dichloromethane.
  • a compound of formula (Int2) can also be prepared by using Schotten-Baumann conditions, thereby using a two-phase system, preferably consisting of a dichloromethane layer and an aqueous solution of sodium bicarbonate.
  • compound HR5 can be reacted in the said manner with 4-halo-benzenesulphonyl chloride (e.g. 4-bromo-benzenesulphonyl chloride) at room temperature for reaction times up to 42 hours to yield the corresponding intermediate (Int2).
  • 4-halo-benzenesulphonyl chloride e.g. 4-bromo-benzenesulphonyl chloride
  • a compound of formula (Int3) can be prepared by reacting, for example, commercially available 4-halo-thiophenol (e.g. 4-bromo-thiophenol) with R6-Hal6 in the presence of a base, preferably potassium hydroxide, and subsequent oxidation using, for example, potassium permanganate as described e.g. in WO 93/23358.
  • Reaction scheme 4 shows by way of example the synthesis of an intermediate of formula (Int4), in which R3 represents 2,5-pyridinylene or 2,5-pyrimidinylene and Hal7 is halogen, preferably bromine.
  • R3 represents 2,5-pyridinylene or 2,5-pyrimidinylene
  • Hal7 is halogen, preferably bromine.
  • commercially available 5-halopyridin-2(1/-/)-one e.g. 5-bromopyridin-2(1/-/)-one
  • 5-halopyrimidin-2(1/-/)-one e.g.
  • 5-bromopyrimidin-2(1/-/)-one) can be transformed to a thiol in an art- known manner using a thionating reagent, preferably Lawesson's reagent [2,4-bis-(4-methoxyphenyl)- 1 ,3-dithia-2,4-diphosphetane-2,4-disulfide], at elevated temperatures, e.g. 12O 0 C.
  • said thiol can be subjected to an oxidation reaction. This oxidation can be carried out by treating a solution of said thiol intermediate in a two-phase system of a halocarbon, preferably carbon tetrachloride, and water with chlorine gas.
  • the sulfochloride obtained can be converted in an art-known manner into the corresponding sulfonamide of formula (Int4) by reacting said sulfochloride according to procedures described with regard to reaction scheme 2, preferably using Schotten-Baumann reaction conditions.
  • said sulfonic acid can be converted into the corresponding sulfonamide in a one-pot procedure, thereby using first a chlorinating agent, preferably thionyl chloride, at elevated temperatures such as, for example, 9O 0 C and, in the second place, gaseous ammonia at reaction temperatures preferably below O 0 C.
  • first a chlorinating agent preferably thionyl chloride
  • gaseous ammonia at reaction temperatures preferably below O 0 C.
  • the nitro group of said sulfonamide derivative e.g. 4-bromo-2-nitrobenzenesulfonamide
  • selective reducing agents such as, for example, stannous chloride or hydriodic acid at elevated reactions temperatures, e.g. 9O 0 C.
  • the compound of formula (Int5) can be obtained by condensation of said amine derivative (e.g. 2-amino-4- bromobenzenesulfonamide) with a piperidone derivative, which is either commercially available or can be prepared by procedures known to the person skilled in the art, in a suitable solvent, e.g. toluene, at temperatures above 100 0 C, optionally in the presence of an acid such as, for example, pyridinium p- toluenesulfonate.
  • a suitable solvent e.g. toluene
  • benzyl-1-piperazine-carboxylate which is commercially available or can be prepared by procedures known to the person skilled in the art, can be transformed into a piperazine sulfonamide derivative as outlined in reaction scheme 6 by a two step procedure, thereby using first sulfuryl chloride, followed by a compound of formula HR4 to obtain the piperazine sulfonamide derivative.
  • the reaction can be carried out at reduced temperatures, e.g.
  • the protective group of said piperazine sulfonamide derivative can be removed e.g. by hydrogenation using a hydrogenation catalyst, e.g. Adam's catalyst (PtO 2 ), Perlmaris catalyst [Pd(OH) 2 ] or palladium on charcoal to afford the compound of formula (Int6).
  • a hydrogenation catalyst e.g. Adam's catalyst (PtO 2 ), Perlmaris catalyst [Pd(OH) 2 ] or palladium on charcoal to afford the compound of formula (Int6).
  • the final compounds according to the present invention can be prepared as shown in reaction scheme 7.
  • compounds of formula (lnt2-5) can be reacted with bis(pinacolato)diboron, which is commercially available or can be prepared by procedures known to the person skilled in the art, to afford boronic acids or derivatives thereof, especially boronic acid esters.
  • Said boronic acid esters can be transformed into final compounds using compounds of formula (Int1 ) under conditions appropriate for a Suzuki cross coupling reaction to occur, thereby using palladium catalysts such as, for example, Pd(CI 2 )(dppf) or Pd(PPh 3 ) 4 (dppf: 1 ,1'- bis(diphenylphosphino)-ferrocene, PPh 3 : triphenylphosphine), in a suitable solvent, e.g. dioxane, at elevated temperatures, preferably above 9O 0 C, and optionally in the presence of a base, e.g. potassium acetate, an alkali halide, e.g. lithium chloride, and water.
  • a base e.g. potassium acetate
  • an alkali halide e.g. lithium chloride
  • Suzuki reaction is, for example, described in Tetrahedron Lett. 1998, 39, 4467; J. Org. Chem. 1999, 64, 1372; and Heterocydes 1992, 34, 1395.
  • a general review of Suzuki cross-couplings between boronic acids and aryl halides can be found in A. Chem. Rev. 1995, 95, 2457.
  • the final compounds according to the present invention can be prepared as shown in reaction scheme 8.
  • compounds of formula (Int1 ) can be reacted with bis(pinacolato)diboron, which is commercially available or can be prepared by procedures known to the person skilled in the art, to afford boronic acids or derivatives thereof, especially boronic acid esters.
  • Said boronic acid esters can be transformed into final compounds using compounds of formula (lnt2-5) under conditions appropriate for a Suzuki cross coupling reaction to occur, thereby using palladium catalysts such as, for example, Pd(CI 2 )(dppf) or Pd(PPh 3 ) 4 , in a suitable solvent, e.g. dioxane, at elevated temperatures, preferably above 9O 0 C, and optionally in the presence of a base, e.g. potassium acetate, an alkali halide, e.g. lithium chloride, and water.
  • a base e.g. potassium acetate
  • Final compounds according to the present invention in which R3 is 1 ,4-piperazinylene, can be prepared, for example, as shown in reaction scheme 9 using intermediate (Int6).
  • intermediate (Int6) compounds of formula (Int1 ) and (Int6) can be converted into the desired final compounds under conditions suitable for a Buchwald-Hartwig type reaction.
  • Buchwald-Hartwig type reactions are known to the person skilled in the art.
  • said reaction is carried out using palladium catalysts such as, for example, Pd 2 (dba) 3 (dba: dibenzylideneacetone) and a base, e.g. caesium carbonate, in a suitable inert solvent such as, e.g.
  • toluene at elevated temperatures, preferably above 100 0 C, optionally in the presence of an auxiliary such as ( ⁇ )-(1 ,1'-binaphthalene-2,2'-diyl)bis(diphenylphosphine) (BINAP) for prolonged reaction times up to 5 days.
  • an auxiliary such as ( ⁇ )-(1 ,1'-binaphthalene-2,2'-diyl)bis(diphenylphosphine) (BINAP) for prolonged reaction times up to 5 days.
  • Az1 is a group which is reacting with a carbon atom or a heteroatom, for example, a nitrogen atom, thereby replacing a hydrogen or halogen atom of R6 and enabling R7 to become bonded to R6.
  • Az1 includes, but is not limited to, halogen, hydroxy, -O-1-4C-alkyl and -O-R7.
  • carboxylic acids or derivatives thereof e.g. carboxylic an
  • the compounds according to the present invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts of the compounds according to the present invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone, such as acetone, methylethylketone or methylisobutylketone, 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 methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone, such as acetone, methylethylketone or methylisobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight ali
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts.
  • pharmaceutically unacceptable salts which can be obtained, for example, as process products during the preparation of the compounds according to the present invention on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • the reaction mixture is heated at 1 1O 0 C for 24 hours during which time the suspension becomes black (LC-MS monitoring for formation of boronic ester intermediate). Thereafter, 365 mg of 1'-acetyl-6-bromo-4/-/-spiro[1 ,2,4-benzothiadiazine-3,4'- piperidine]-1 ,1-dioxide (compound A13) 270 mg of potassium carbonate, 83 mg of lithium chloride, 113 mg of Pd(PPh 3 ) 4 , 7.0 ml of oxygen-free dioxane, and 7.0 ml of water are added. The reaction mixture is heated at 1 1O 0 C and stirring is continued for 48 hours.
  • the title compound is synthesized according to a procedure described in WO 93/23358.
  • the title compound is synthesized according to a procedure described in WO 93/23358.
  • Nitric oxide synthases are enzymes that generate NO and citrulline from the amino acid arginine.
  • NO-synthases In certain pathophysiological situations, such as arginine depletion or tetrahydrobiopterin depletion, the generation of O 2 " from NO-synthases instead or together with NO has been reported.
  • NO is long known as a signalling molecule in most living organisms including mammals and humans.
  • NO soluble guanylate cyclase
  • the first class comprises of the endothelial NO-synthase and the neuronal NO-synthase. Both isoenzymes are expressed constitutively in various cell types, but are most prominent in endothelial cells of blood vessel walls (therefore called endothelial NO-synthase, eNOS or NOS-III) and in neuronal cells (therefore called neuronal NO-synthase, nNOS or NOS-I).
  • endothelial NO-synthase eNOS or NOS-III
  • neuronal NO-synthase nNOS or NOS-I
  • Activation of these two enzymes is dependent on Ca 2 7calmodulin which is generated by transient increases of the intracellular free Ca 2+ concentration.
  • Activation of constitutive isoforms leads to transient bursts of nitric oxide resulting in nanomolar cellular or tissue NO concentrations.
  • the endothelial isoform is involved in the physiologic regulation of blood pressure. NO generated by the neuronal isoform seems to have neurotransmitter function and the neuronal isoform is among other regulatory processes involved in memory function (long term potentiation).
  • inducible NO-synthase the sole member of the second class
  • the activation of inducible NO-synthase is performed by transcriptional activation of the iNOS-promoter.
  • proinflammatory stimuli lead to transcription of the gene for inducible NO-synthase, which is catalytically active without increases in the intracellular Ca 2+ -concentration.
  • high micromolar concentrations of NO are generated over longer time periods.
  • These high NO-concentrations alone or in cooperation with other reactive radicals such as O 2 ' are cytotoxic. Therefore, in situations of microbial infections, iNOS is involved in cell killing by macrophages and other immune cells during early nonspecific immune responses.
  • pathophysiological situations which among others are characterized by the high expression of inducible NO-synthase and concomitant high NO or O 2 " concentrations. It has been shown that these high NO concentrations alone or in combination with other radical species lead to tissue and organ damage and are causally involved in these pathophysiologies.
  • inflammation is characterized by the expression of proinflammatory enzymes, including inducible NO-synthase, selective inhibitors of inducible NO-synthase can be used as therapeutics for diseases involving acute and chronic inflammatory processes.
  • Other pathophysiologies with high NO-production from inducible NO-synthase are several forms of shock (e.g. septic, hemorrhagic and cytokine-induced shock).
  • MPTP MPTP- induced parkinsonism
  • amyloid peptide induced Alzheimer's disease Ishii et al., FASEB J. 14, 1485-1489, 2000
  • malonate induced Huntington's disease Connop et al. Neuropharmacol. 35, 459-465, 1996)
  • experimental meningitis Korytko & Boje Neuropharmacol. 35, 231-237, 1996)
  • experimental encephalitis Parkinson et al. J. MoI. Med.
  • iNOS lncreased iNOS expression has been found in the brains of AIDS (acquired immunodeficiency syndrome) patients and it is therefore assumed that iNOS plays a role in AIDS related dementia (Bagasra et al. J. Neurovirol. 3 153-167, 1997).
  • nitric oxide as a potential mediator of microglia dependent primary demyelination, a hallmark of multiple sclerosis (Parkinson et al. J. MoI. Med. 75, 174-186, 1997).
  • NO-synthase inhibitors have been shown to possess protective properties.
  • a regulatory role for inducible NO-synthase has been reported in various tumor cell lines (Tozer & Everett Clin Oncol. 9. 357-264, 1997).
  • the compounds and pharmaceutically acceptable salts according to the present invention can be employed in human and veterinary medicine, where an excess of NO or O 2 " due to increases in the activity of inducible NO-synthase is involved.
  • they can be used without limitation for the treatment and prophylaxis of the following diseases:
  • Acute inflammatory diseases Septic shock, sepsis, systemic inflammatory response syndrome (SIRS), hemorrhagic shock, shock states induced by cytokine therapy (interleukin-2, tumor necrosis factor), organ transplantation and transplant rejection, head trauma, acute lung injury, acute respiratory distress syndrome (ARDS), inflammatory skin conditions such as sunburn, inflammatory eye conditions such as uveitis, glaucoma and conjunctivitis.
  • Chronic inflammatory diseases of peripheral organs or the central nervous system gastrointestinal inflammatory diseases such as Crohn's disease, inflammatory bowel disease, ulcerative colitis, lung inflammatory diseases such as asthma, chronic bronchitis, emphysema and COPD, inflammatory diseases of the upper respiratory tract such as allergic rhinitis and allergic sinusitis, inflammatory eye conditions such as allergic conjunctivitis, arthritic disorders such as rheumatoid arthritis, osteoarthritis and gouty arthritis, heart disorders such as cardiomyopathy and myocarditis, artherosclerosis, neurogenic inflammation, skin diseases such as psoriasis, dermatitis and eczema, diabetes, glomerulonephritis; dementias such as dementias of the Alzheimer's type, vascular dementia, dementia due to a general medical condition such as AIDS, Parkinson's disease, Huntington's induced dementias, amyotrophic lateral sclerosis (ALS), multiple sclerosis; necrotizing vascul
  • the compounds and pharmaceutically acceptable salts according to the present invention can also be useful in the treatment of cancers that express nitric oxide synthase.
  • the compounds and pharmaceutically acceptable salts according to the present invention are distinguished by valuable and desirable effects related therewith, such as for example by low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, absence of significant side effects and further beneficial effects related with their therapeutic and pharmaceutical suitability.
  • the present invention further relates to a method of treating or preventing one of the above mentioned diseases in a mammal, including a human, comprising administering a therapeutically effective amount of one or more of the compounds and pharmaceutically acceptable salts according to the present invention.
  • the present invention relates to a method of treating or preventing a disease which is alleviated by inhibition of inducible nitric oxide synthase in a mammal, including a human, comprising administering a therapeutically effective amount of one or more of the compounds and pharmaceutically acceptable salts according to the present invention.
  • the present invention relates to a method of treating or preventing acute or chronic inflammatory diseases, especially acute or chronic inflammatory diseases of peripheral organs or the central nervous system, in a mammal, including a human, comprising administering a therapeutically effective amount of one or more of the compounds and pharmaceutically acceptable salts according to the present invention.
  • the present invention relates to a method of treating or preventing shock-type diseases, gastrointestinal inflammatory diseases, nephritic inflammatory diseases, lung inflammatory diseases, inflammatory diseases of the upper respiratory tract, arthritic disorders, inflammatory skin diseases, inflammatory eye diseases, diabetes, neurodegenerative diseases, pain disorders, heart disorders and cancer, in a mammal, including a human, comprising administering a therapeutically effective amount of one or more of the compounds and pharmaceutically acceptable salts according to the present invention.
  • one or more of the compounds and pharmaceutically acceptable salts according to the invention can be used.
  • one or two of the compounds and pharmaceutically acceptable salts are used, more preferably, one of the compounds and pharmaceutically acceptable salts is used.
  • the above methods of treating or preventing one of the above mentioned diseases in a mammal, including a human comprise administering a therapeutically effective amount of one compound of the examples according to the present invention.
  • the invention further relates to the compounds and pharmaceutically acceptable salts according to the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of inducible nitric oxide synthase, in particular the diseases exemplified above.
  • the invention also relates to the use of the compounds and pharmaceutically acceptable salts according to the invention in the manufacture of pharmaceutical compositions inhibiting the inducible nitric oxide synthase, in particular pharmaceutical compositions for the treatment or prophylaxis of diseases alleviated by inhibition of inducible nitric oxide synthase.
  • the invention also relates to the use of the compounds and pharmaceutically acceptable salts according to the invention in the manufacture of pharmaceutical compositions for the treatment or prophylaxis of the diseases exemplified above, specifically for the treatment or prophylaxis of acute and chronic inflammatory diseases, more specifically for the treatment or prophylaxis of acute and chronic inflammatory diseases of peripheral organs or the central nervous system, in particular shock- type diseases, gastrointestinal inflammatory diseases, nephritic inflammatory diseases, lung inflammatory diseases, inflammatory diseases of the upper respiratory tract, arthritic disorders, inflammatory skin diseases, inflammatory eye diseases, diabetes, neurodegenerative diseases, pain disorders, heart disorders and cancer.
  • the invention furthermore relates to pharmaceutical compositions, in particular for the treatment or prophylaxis of the diseases exemplified above, which comprise one or more of the compounds and pharmaceutically acceptable salts according to the invention together with one or more pharmaceutically acceptable auxiliaries.
  • the pharmaceutical compositions comprise one or two of the compounds and pharmaceutically acceptable salts according to the invention. More preferably, the pharmaceutical compositions comprise one of the compounds and pharmaceutically acceptable salts according to the invention.
  • the pharmaceutical compositions comprise a compound of the examples according to the present invention together with one or more pharmaceutically acceptable auxiliaries.
  • the present invention furthermore relates to pharmaceutical compositions according to this invention inhibiting the inducible nitric oxide synthase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of inducible nitric oxide synthase, in particular for the treatment or prophylaxis of the diseases exemplified above.
  • compositions can contain one or more of the compounds and pharmaceutically acceptable salts according to the invention (hereinafter referred to as "the active compound”) in a total amount of from 0.1 to 99.9 wt%, preferably 5 to 95 wt%, more preferably 20 to 80 wt%.
  • auxiliaries any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.
  • auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
  • the pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g. sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g. transdermal therapeutic systems).
  • the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the active compound is coupled to monoclonal antibodies and systems in which the active compound is coupled to polymers (e.g. soluble or biodegradable polymers).
  • compositions comprising the active compound and one or more auxiliaries can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the selected formulation depends inter alia on the route of administering the pharmaceutical composition.
  • the pharmaceutical compositions of the present invention can be administered by any suitable route, for example by the oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraocular, intaperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal administration, by inhalation or by insufflation. Oral administration is preferred.
  • tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration.
  • said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form or a sustained release form.
  • Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the active compound to a biodegradable polymer.
  • Administration by inhalation is preferably made by using an aerosol.
  • the aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
  • the aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers.
  • the aerosol-producing device can contain the active compound in form of a powder, a solution or a dispersion.
  • the powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers.
  • the solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings.
  • the dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings.
  • auxiliaries include, but are not limited to, saccharides, e.g. lactose and glucose.
  • propellants include, but are not limited to, fluorohydrocarbons, e.g. 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the particle size of the aerosol particles is preferably less than 100 ⁇ m, more preferably it is in the range of from 0.5 to 10 ⁇ m, in particular in the range of from 2 to 6 ⁇ m (D50 value, measured by laser diffraction).
  • Aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Turbohaler®, Novolizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers.
  • the aerosol- producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
  • suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g. transdermal therapeutic systems).
  • parenteral modes of administration such as, for example, intravenous, intramuscular, subcutaneous, intracutaneous, intaperitoneal and intrasternal administration, preferably solutions (e.g. sterile solutions, isotonic solutions) are used. They are preferably administered by injection or infusion techniques.
  • solutions e.g. sterile solutions, isotonic solutions
  • intranasal administration for example, sprays and solutions to be applied in drop form are preferred formulations.
  • solutions to be applied in drop form gels and ointments are exemplified formulations.
  • the pharmaceutical compositions according to the invention can be administered such that the dose of the active compound is in the range customary for inducible nitric oxide synthase inhibitors.
  • a dose in the range of from 0.01 to 4000 mg of the active compound per day is preferred for an average adult patient having a body weight of 70 kg.
  • the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination.
  • the pharmaceutical composition can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day.
  • a single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the active compound.
  • the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the active compound in form of a sparingly soluble salt or by using the active compound coupled to a polymer.
  • the assay is performed in 96-well microtiter F-plates (Greiner, Frickenhausen, FRG) in a total volume of 100 ⁇ l in the presence of 100 nM calmodulin, 226 ⁇ M CaCI 2 , 477 ⁇ M MgCI 2 , 5 ⁇ M flavin-adenine- dinudeotide (FAD), 5 ⁇ M flavin mononucleotide (FMN), 0.1 mM nicotinamide adenine dinucleotide phosphate (NADPH), 7 mM glutathione, 10 ⁇ M tetrahydrobiopterine (BH4) and 100 mM 4-(2- hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), pH 7.2.
  • Greiner Frickenhausen, FRG
  • Arginine concentrations are 0.1 ⁇ M for enzyme inhibition experiments. 150000 dpm of [ 3 H]arginine are added to the assay mixture. Enzyme reaction is started by the addition of 4 ⁇ g of a crude cytosolic fraction containing human inducible NO-synthase and the reaction mixture is incubated for 45 to 60 min at 37 0 C. Enzyme reaction is stopped by adding 10 ⁇ l of 2M 2-morpholinoethane sulfonic acid buffer (MES-buffer) pH 5.0.
  • MES-buffer 2-morpholinoethane sulfonic acid buffer
  • the resin in the filtration plates is washed with 75 ⁇ l of water (1x50 ⁇ l and 1x 25 ⁇ l) which is also collected in the same plate as the sample.
  • the total flow through of 125 ⁇ l is mixed with 175 ⁇ l of Microscint-40 scintillation cocktail (Packard) and the scintillation plate is sealed with TopSeal P-foil (Packard). Scintillation plates are counted in a szintillation counter.
  • IC 50 values were calculated from the percent inhibition at given concentrations by nonlinear least square fitting.
  • the compounds according to the present invention which are prepared according to examples 1 to 19 as described above, show an inhibition of the inducible nitric oxide synthase (iNOS), measured as -loglC 50 (mol/l), in the range of from 6.17 to 7.25 and an inhibition of the constitutive nitric oxide synthases (eNOS and nNOS), measured as -loglC 50 (mol/l), of ⁇ 3.50 to 4.86.
  • iNOS inducible nitric oxide synthase
  • eNOS and nNOS constitutive nitric oxide synthases

Abstract

Selon l'invention, les composés de formule (I), dans laquelle X, Y, R1 and R2 possèdent les significations données dans la description, constituent de nouveaux inhibiteurs efficaces de la synthase inductible de l'oxyde nitrique.
PCT/EP2006/066919 2005-10-05 2006-09-29 Composes d'azabenzophenone substitues par imidazolyle WO2007039578A1 (fr)

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WO2012013643A1 (fr) 2010-07-26 2012-02-02 Tibotec Pharmaceuticals Dérivés hétéro-bicycliques en tant qu'inhibiteurs du vhc
WO2012168162A1 (fr) 2011-06-06 2012-12-13 F. Hoffmann-La Roche Ag Acide acétique de benzocylcoheptène
WO2013098313A1 (fr) 2011-12-28 2013-07-04 Janssen R&D Ireland Dérivés hétérobicycliques en tant qu'inhibiteurs de vhc
WO2017013410A1 (fr) 2015-07-17 2017-01-26 Ucl Business Plc Inhibiteurs sélectifs de i-no pour utilisation contre une infection virale
CN110194743A (zh) * 2018-02-26 2019-09-03 云南大学 苯基(3-甲氧基-4-(4-甲基-1h-咪唑-1-基)苯基)甲酮类化合物
CN110194746A (zh) * 2018-02-26 2019-09-03 云南大学 用于治疗阿尔茨海默症的化合物，其制备方法和用途
CN110194744A (zh) * 2018-02-26 2019-09-03 云南大学 一种抑制β-淀粉样蛋白生成的化合物及其制备方法和用途

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013643A1 (fr) 2010-07-26 2012-02-02 Tibotec Pharmaceuticals Dérivés hétéro-bicycliques en tant qu'inhibiteurs du vhc
US8815849B2 (en) 2010-07-26 2014-08-26 Janssen R&D Ireland Hetero-bicyclic derivatives as HCV inhibitors
WO2012168162A1 (fr) 2011-06-06 2012-12-13 F. Hoffmann-La Roche Ag Acide acétique de benzocylcoheptène
WO2013098313A1 (fr) 2011-12-28 2013-07-04 Janssen R&D Ireland Dérivés hétérobicycliques en tant qu'inhibiteurs de vhc
US9126986B2 (en) 2011-12-28 2015-09-08 Janssen Sciences Ireland Uc Hetero-bicyclic derivatives as HCV inhibitors
WO2017013410A1 (fr) 2015-07-17 2017-01-26 Ucl Business Plc Inhibiteurs sélectifs de i-no pour utilisation contre une infection virale
CN110194743A (zh) * 2018-02-26 2019-09-03 云南大学 苯基(3-甲氧基-4-(4-甲基-1h-咪唑-1-基)苯基)甲酮类化合物
CN110194746A (zh) * 2018-02-26 2019-09-03 云南大学 用于治疗阿尔茨海默症的化合物，其制备方法和用途
CN110194744A (zh) * 2018-02-26 2019-09-03 云南大学 一种抑制β-淀粉样蛋白生成的化合物及其制备方法和用途
CN110194744B (zh) * 2018-02-26 2022-11-11 云南大学 一种抑制β-淀粉样蛋白生成的化合物及其制备方法和用途
CN110194743B (zh) * 2018-02-26 2022-11-11 云南大学 苯基(3-甲氧基-4-(4-甲基-1h-咪唑-1-基)苯基)甲酮类化合物
CN110194746B (zh) * 2018-02-26 2022-11-18 云南大学 用于治疗阿尔茨海默症的化合物，其制备方法和用途

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