WO2007039581A1 - Imidazolyl-substituted diazabenzophenone compounds - Google Patents
Imidazolyl-substituted diazabenzophenone compounds Download PDFInfo
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- WO2007039581A1 WO2007039581A1 PCT/EP2006/066923 EP2006066923W WO2007039581A1 WO 2007039581 A1 WO2007039581 A1 WO 2007039581A1 EP 2006066923 W EP2006066923 W EP 2006066923W WO 2007039581 A1 WO2007039581 A1 WO 2007039581A1
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- RTDYORLCSLRAJF-QXEWZRGKSA-N CCCCC[C@@H]([C@@]1(C)N2)SC[C@@H]1NC2=O Chemical compound CCCCC[C@@H]([C@@]1(C)N2)SC[C@@H]1NC2=O RTDYORLCSLRAJF-QXEWZRGKSA-N 0.000 description 1
- 0 Cc(cc1)cc(*C2(CCN(*)CC2)*2)c1S2(=O)=O Chemical compound Cc(cc1)cc(*C2(CCN(*)CC2)*2)c1S2(=O)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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]
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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
- C07D401/14—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
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- 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
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- 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 diazabenzophenone compounds, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
- the invention relates to compounds of formula (I)
- X is N
- Y is N
- 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-NR9R10,
- 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(CH 3 ) 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(CH 3 ) 2 , -NCH 3 -CH 2 CH 2 -NHCH 3 and -NCH 3 -CH 2 CH 2 CH 2 -N(CH 3 ) 2 .
- the group -NH-AI-NH 2 is preferred with -NH-CH 2 CH 2 -NH 2 being particularly preferred.
- 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.
- Non- limiting examples thereof include piperidinyl, piperazinyl, azepanyl, diazepanyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl groups. Of these, piperidinyl, piperazinyl, diazepanyl and pyridinyl groups are preferred. Piperazinyl and pyridinyl groups are particularly preferred. Said heterocyclic groups include all isomeric forms thereof, particularly all positional isomers. Thus, for example, 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. - A -
- Iy preferred isomeric forms include piperidin-1-yl, piperazin-1-yl, 1 ,4-diazepan-1-yl and pyridin-4-yl, of which piperazin-1-yl and pyridin-4-yl groups are even more preferred.
- 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 Hs)-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.
- 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 -, -C ⁇ 2 ⁇ O ⁇ C ⁇ 2 ⁇ C ⁇ 2 ⁇ C ⁇ 2 ⁇ , ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ O ⁇ C» ⁇ 2 ⁇ C» ⁇ 2 ⁇ , ⁇ C ⁇ 2 ⁇ C ⁇ 2 ⁇ O ⁇ C ⁇ 2 ⁇ C ⁇ 2 ⁇ 2 ⁇ , -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH(CHa)-O-CH 2 - and -CH 2 -O-C(CH 3 ) 2 -.
- the group i-SC-alkylene-O-i-SC-alkylene-O-i-SC-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-CH 2 -CH 2 -, -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -, -CH 2 -CH
- 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)-AI 0-Z3.
- Preferred examples include -C(O)H, -C(O)CH 3 , -C(O)cydopropyl, -C(O)CH 2 NH 2 , -C(O)CH 2 OCH 3 ,
- 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 , -NH(C 2 H 5 ), -CH 2 -NH(C 2 H 5 ), -CH 2 -CH 2 -NH(C 2 H 5 ), -CH 2 -CH 2 -NH(C 2 H 5 ), -CH 2 -CH 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 X is N; Y is N; R1 is selected from -R3-SO 2 -R4 and Het; R2 is hydrogen;
- R3 is selected from 1 ,4-phenylene 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;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(0)R8;
- R8 is 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 N
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen
- R3 is selected from 1 ,4-phenylene 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;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
- R8 is 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 N
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen;
- R3 is selected from 1 ,4-phenylene 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;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8; R8 is 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 N
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen
- R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene
- R4 is R6
- R6 is a monocyclic 6-membered heterocyclic group containing one or two nitrogen atoms, said group being optionally substituted by R7;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8; R8 is 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 N
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen
- R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene;
- R4 is R6;
- R6 is a group selected from piperazinyl and pyridinyl, which is optionally substituted by R7;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
- R8 is 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 N
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen;
- R3 is selected from 1 ,4-phenylene and 2, 5-pyridinylene;
- R4 is R6
- R6 is a group selected from piperazin-1-yl and pyridin-4-yl, which is optionally substituted by R7;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
- R8 is 1-3C-alkyl; Het is a group of formula (II)
- X is N
- Y is N
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen
- R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene
- R4 is R6
- R6 is a group selected from piperazin-1-yl substituted by R7 and pyridin-4-yl;
- R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
- R8 is 1-3C-alkyl
- Het is a group of formula (II)
- 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 N;
- R1 is selected from -R3-SO 2 -R4 and Het;
- R2 is hydrogen
- R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene
- R4 is R6
- R6 is a group selected from piperazin-1-yl substituted by R7 and pyridin-4-yl; R7 is selected from methyl, -CH 2 -CH 2 -O-CH 3 and -C(O)R8;
- R8 is methyl
- Het is a group of formula (II)
- Salts of the compounds according to the present invention include all acid addition salts and all salts with bases, specifically all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, more specifically all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
- 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.
- hydrochlorides, methanesulfonates and trifluoroacetates are preferred. Hydrochlorides and methanesulfonates are particularly 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 X is N; Y is N; R1 is -R3-SO 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
- R3 is selected from 1 ,4-phenylene 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;
- R7 is -C(0)R8
- R8 is -A10-Z3 having the formula (III); and the salts thereof.
- X is N
- Y is N
- R1 is selected from -R3-SO 2 -R4; R2 is hydrogen;
- R3 is selected from 1 ,4-phenylene 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.
- 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.
- Enantiomeric and diasteriomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, the mixtures are separated by chromatography or (fractional) crystallization.
- the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral bases for separating acids and chiral acids for separating enantiomeric mixtures of bases, subsequent resolution of the salts and release of the desired compound from the salt.
- derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group.
- enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
- 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.
- the present invention also relates to a compound of formula (Int1 )
- X is N
- Y is N
- R2 is selected from hydrogen and halogen
- Hal3 is halogen, which is an intermediate in the process of preparing the final compounds according to the present invention as explained below.
- 2,5-dihalo-pyrimidine which is commercially available or can be prepared by procedures known to the person skilled in the art, can be transformed into 5-halo-2-imidazol-1-yl- pyrimidine by nucleophilic displacement of HaM , thereby using imidazole and a strong base such as, for example, sodium hydride, in a suitable solvent, e.g. dimethylformamide or dimethylsulphoxide, at room temperature.
- a suitable reagent for metalation such as, for example, isopropylmagnesium chloride, in an appropriate solvent, e.g. tetrahydrofuran, at reduced temperatures, preferably at O 0 C.
- 4-halo-benzaldehyde which is commercially available or can be prepared by procedures known to the person skilled in the art, is added to the aforementioned reaction mixture to afford the desired intermediate precursor.
- said precursor is subjected to an oxidation reaction.
- This oxidation can be carried out in an art-known manner using a suitable oxidizing agent such as, for example, triacetoxy periodinane (Dess-Martin reagent) to obtain the desired intermediate of formula (Int1 ).
- 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 Lawessoris 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.
- a 1 ,4-dihalo-2- nitrobenzene e.g. 4-bromo-1-fluoro-2-nitrobenzene
- a 4-halo-2-nitrobenzenesulfonic acid by nudeophilic displacement of Hal9 using e.g. sodium sulfite, preferably at elevated temperatures, e.g. 7O 0 C.
- 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 Heterocycles 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.
- the substituent R7 which is optionally bonded to R6, may be introduced at the stage of preparing intermediate (Int2), (Int3), (Int4) or (Int6).
- each of which is already substituted by R7 can be used (compare reaction schemes 2, 3, 4 and 6) to obtain (Int2), (Int3), (Int4) or (Int6), each containing R7.
- 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 anhydrides, acid halides or amino acids
- R7 may be introduced after having obtained the final product containing R6 as shown exemplarily in reaction scheme 11.
- Az2 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.
- Az2 includes, but is not limited to, halogen, hydroxy, -O-1 -4C- alkyl, -O-R7 and pyrazol-1-yl).
- starting compounds as shown in reaction scheme 11 can be converted into compounds substituted by R7 by procedures known to the person skilled in the art, using e.g. a carboxylic anhydride, 1-3C-alkyl 1-3C-alkanimidoate or 1/-/-pyrazole-carboxamidine as R7- Az1.
- 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, repredpitating, 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.
- DPPF/dppf 1 ,1'- bis(diphenylphosphino)-ferrocene
- DMAP dimethylaminopyridine
- DMSO dimethyl sulphoxide
- DMF N,N-dimethylformamide
- DBU 1 ,8- diazabicyclo[5.4.0]undec-7-ene
- MS mass spectrometry
- ESI-MS elektrospray ionization mass spectrometry
- LC liquid chromatography
- TLC thin layer chromatography
- HPLC high performance liquid chromatography
- Cbz benzyloxycarbonyl
- Boc t-butyloxycarbonyl
- Ph phenyl.
- the reaction mixture is heated at 11 O 0 C for 48 hours during which time the suspension becomes black (LC-MS monitoring for formation of boronic ester intermediate). Thereafter, 237 mg of 1-(5-bromo-pyridine-2-sulfonyl)-4-(2- methoxy-ethyl)-piperazine (compound B4), 180 mg of potassium carbonate, 55 mg of lithium chloride, 75 mg of Pd(PPh 3 ) 4 , 4.0 ml of oxygen-free dioxane, and 4.0 ml of water are added. The reaction mixture is heated at 11O 0 C and stirring is continued for 4 hours. Subsequently, the suspension is concentrated in vacuo and co-evaporated twice with 10 ml each of toluene.
- the title compound is synthesized according to a procedure described in WO 93/23358.
- 5-Bromo-2-imidazol-1-yl-pyrimidine 280 mg of sodium hydride (strength 60 Vol%) are suspended in 5.0 ml of DMSO under an atmosphere of dry nitrogen. Subsequently, a solution of 409 mg of imidazole in 5.0 ml of DMSO is added dropwise at room temperature. After the gas evolution has ceased, the reaction mixture is stirred for further 10 min. Thereafter, a solution of 987 mg of 5-bromo-2-chloro-pyrimidine in 10 ml of DMSO is added dropwise to the reaction mixture. The yellow suspension is stirred for 1 hour. For workup, the reaction mixture is poured into 150 ml of iced water and the suspension is filtered with suction.
- 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 6 as described above, show an inhibition of the inducible nitric oxide synthase (iNOS), measured as -loglC 50 (mol/l), in the range of from 6.28 to 7.16 and an inhibition of the constitutive nitric oxide synthases (eNOS and nNOS), measured as -loglC 50 (mol/l), of ⁇ 4.00.
- iNOS inducible nitric oxide synthase
- eNOS and nNOS constitutive nitric oxide synthases
Abstract
The compounds of formula (I) in which X, Y, R1 and R2 have the meanings as given in the description are novel effective inhibitors of the inducible nitric oxide synthase.
Description
Imidazolyl-substituted diazabenzophenone compounds
Field of application of the invention
The invention relates to imidazolyl-substituted diazabenzophenone compounds, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
Known technical background
The International Application WO 98/37079 describes imidazolyl-pyrimidine containing derivatives with inhibitory activity on iNOS dimerization. K. McMillan et al., Proceedings of the National Academy of Science of the Unites States of America, Vol. 97, No. 4, 1506-1511 (February 15, 2000) describes allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry.
Description of the invention
It has now been found that the imidazolyl-substituted diazabenzophenone compounds, which are described in detail below, have surprising and particularly advantageous properties.
The invention relates to compounds of formula (I)
in which
X is N;
Y is N;
R1 is selected from -R3-SO2-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-NR9R10,
-A3-C(O)-NR11 R12, =0, -A4-Z1 , -A5-C(O)-Z2, -C(=NH)R13 and -NH-C(0)R14; R8 is selected from hydrogen, 1-3C-alkyl, 3-6C-cydoalkyl, -A6-NH2, -A7-O-R15, -A8-O-A9-O-R16 and -A10-Z3;
A2 is selected from a single bond and 1-3C-alkylene; A3 is 1-3C-alkylene; A4 is 1-3C-alkylene; A5 is 1-3C-alkylene; A6 is 1-3C-alkylene; A7 is 1-3C-alkylene; A8 is 1-3C-alkylene; A9 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; R11 is selected from hydrogen and 1-3C-alkyl; R12 is selected from hydrogen and 1-3C-alkyl; R13 is selected from 1-3C-alkyl and -NH2; R14 is 1-3C-alkyl; R15 is 1-3C-alkyl; R16 is 1-3C-alkyl; Z1 is a 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18;
Z2 is a 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18; Z3 is a 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18; 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)
in which
Q is selected from -NR19-, -CH2- 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 -SO2-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 -SO2-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-CH2-NH2, -NH-CH2CH2-NH2, -NH-CH2CH2CH2-NH2, -NCH3-CH2-NH2, -NCH3-CH2CH2-NH2, -NCH3-CH2CH2CH2-NH2, -NH-CH2-
N(CH3)2, -NH-CH2CH2-N(CH3)2, -NH-CH2CH2-NHCH3, -NH-CH2CH2CH2-N(CH3)2, -NCH3-CH2-N(CH3)2, -NCH3-CH2CH2-N(CH3)2, -NCH3-CH2CH2-NHCH3 and -NCH3-CH2CH2CH2-N(CH3)2. The group -NH-AI-NH2 is preferred with -NH-CH2CH2-NH2 being particularly preferred.
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. Non- limiting examples thereof include piperidinyl, piperazinyl, azepanyl, diazepanyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl groups. Of these, piperidinyl, piperazinyl, diazepanyl and pyridinyl groups are preferred. Piperazinyl and pyridinyl groups are particularly preferred. Said heterocyclic groups include all isomeric forms thereof, particularly all positional isomers. Thus, for example, 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.
- A -
Specifical Iy preferred isomeric forms include piperidin-1-yl, piperazin-1-yl, 1 ,4-diazepan-1-yl and pyridin-4-yl, of which piperazin-1-yl and pyridin-4-yl groups are even more preferred.
1-6C-Alkylene is a straight-chain or branched alkylene group having 1 to 6 carbon atoms. Examples of the straight-chain alkylene group having 1 to 6 carbon atoms are methylene (-CH2-), ethylene (-CH2-CH2-), n-propylene (-CH2-CH2-CH2-), n-butylene (-CH2-CH2-CH2-CH2-), n-pentylene (-CH2-CH2-CH2-CH2-CH2-) and n-hexylene (-CH2-CH2-CH2-CH2-CH2-CH2-). Examples of the branched alkylene group having 1 to 6 carbon atoms include, but are not limited to, the groups -CH(CH3)-, -CH2-CH(CH3)-, -C(CHa)2-, -CH2-C(CH3)2-CH2- and -CH2-CH(C2Hs)-CH2-CH2-. The straight-chain alkylene groups having 1 to 4 carbon atoms are preferred.
Accordingly, 1-3C-alkylene is a straight-chain or branched alkylene group having 1 to 3 carbon atoms. Examples of the straight-chain alkylene group having 1 to 3 carbon atoms are methylene (-CH2-), ethylene (-CH2-CH2-) and n-propylene (-CH2-CH2-CH2-). Examples of the branched alkylene group having 1 to 3 carbon atoms include the groups -CH(CH3)-, -CH2-CH(CH3)- and -C(CH3)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.
Accordingly, 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. -CH2-CH2-CH2- CH2-OH and -CH2-C(CH3)2-OH), hydroxypropyl (e.g. -CH2-CH2-CH2-OH and -CH(CH3)-CH2-OH), hydroxyethyl (-CH2-CH2-OH and -CH(CH3)-0H) and hydroxymethyl (-CH2-OH). Straight-chain hydroxy- 1-4C-alkyl groups are preferred, of which -CH2-CH2-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. -CH2-CH2-CH2-CH2-O-CH3), methoxypropyl (e.g. -CH2-CH2-CH2-O-CH3, -CH2-CH(CHa)-O-CH3 and -CH(CH3)-CH2-O-CH3), methoxyethyl (-CH2-CH2-O-CH3 and -CH(CHa)-O-CH3), methoxymethyl (-CH2-O-CH3), ethoxybutyl (e.g. -CH2-CH2-CH2-CH2-O-CH2-CH3), ethoxypropyl (e.g. -CH2-CH2-CH2-O-CH2-CH3), ethoxyethyl (e.g. -CH2-CH2-O-CH2-CH3), ethoxymethyl (-CH2-O-CH2-CH3) and butoxymethyl (e.g. -CH2-O-C(CH3)2-CH3) group. 1-4C-Alkoxy-1-4C-alkyl groups, wherein the alkoxy moiety and the alkyl moiety are each straight-chain groups, are preferred. The -CH2-CH2-O-CH3 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. Specific examples thereof include, but are 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, morpholinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepanyl, diazepanyl, naphthyl, indolyl, indolizinyl, indazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl and hexahydro-1/-/-thieno[3,4- cφmidazolyl.
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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C- alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18, is preferably substituted by 1 to 3 identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18.
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, morpholinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepanyl, diazepanyl, naphthyl, indolyl, indolizinyl, indazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl and hexahydro-1/-/-thieno[3,4-c/]imidazolyl, substituted with 1 to 3 identical or different substituents selected from methyl, ethyl, hydroxy, methoxy, ethoxy, =0, -NH2, -NHCH3, -N(CH3)2, -NH(C2H5) and -N(C2H5)2.
Among 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C- alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18, the groups pyridinyl, morpholinyl and hexahydro-1/-/- thieno[3,4-c/]imidazolyl, said last group being substituted by the substituent =0, are preferred.
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, -CH2-O-CH2-, -CH2-O-CH2-CH2-,
-CΗ2~O~CΗ2~CΗ2~CΗ2~, ~C»Π2~C»Π2~O~C»Π2~C»Π2~, ~CΗ2~CΗ2~O~CΗ2~CΗ2~CΗ2~, -CH2-CH2-CH2-O-CH2-CH2-CH2-, -CH(CHa)-O-CH2- and -CH2-O-C(CH3)2-.
The group i-SC-alkylene-O-i-SC-alkylene-O-i-SC-alkylene represents three 1-3C-alkylene groups bonded via oxygen atoms. Examples thereof include, but are not limited to, -CH2-O-CH2-O-CH2-, -CH2-O-CH2-O-CH2-CH2-, -CH2-O-CH2-O-CH2-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-O-CH2-CH2-O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-CH2-CH2-CH2-O-CH2-CH2-CH2-, -CH2-O-CH(CHa)-O-CH2- and -CH2-O-CH2-O-C(CH3)2-.
The group -C(0)R8 with R8 being selected from hydrogen, 1-3C-alkyl, 3-6C-cycloalkyl, -A6-NH2, -A7-O-R15, -A8-O-A9-O-R16 and -A10-Z3 includes, but is not limited to, -C(O)H, -C(O)CH3,
-C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)CH3, -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O)cyclopentyl, -C(O)cyclohexyl, -C(O)CH2NH2, -C(O)CH2CH2NH2, -C(O)CH2CH2CH2NH2,
-C(O)CH2OCH3, -C(O)CH2CH2OCH3, -C(O)CH2OCH2CH2OCH3 and -C(O)-AI 0-Z3. Preferred examples include -C(O)H, -C(O)CH3, -C(O)cydopropyl, -C(O)CH2NH2, -C(O)CH2OCH3,
-C(O)CH2CH2OCH3, -C(O)CH2OCH2CH2OCH3, -C(O)CH2-phenyl, -C(O)CH2-pyridinyl, -C(O)CH2- morpholinyl, -C(O)CH2-quinolinyl and -C(O)CH2-naphthyridinyl. The group -C(O)CH3 is particularly preferred.
Examples of the group -A2-NR9R10 include, but are not limited to, -NH2, -CH2-NH2, -CH2-CH2-NH2, -CH2-CH2-CH2-NH2, -NHCH3, -CH2-NHCH3, -CH2-CH2-NHCH3, -CH2-CH2-CH2-NHCH3, -N(CH3)2, -CH2-N(CH3)2, -CH2-CH2-N(CH3)2, -CH2-CH2-CH2-N(CH3)2, -NH(C2H5), -CH2-NH(C2H5), -CH2-CH2-NH(C2H5), -CH2-CH2-CH2-NH(C2H5), -N(C2H5)2, -CH2-N(C2H5)2, -CH2-CH2-N(C2H5)2, -CH2-CH2-CH2-N(C2H5)2, -N(n-propyl)2, -CH2-N(n-propyl)2, -CH2-CH2-N(n-propyl)2 and -CH2-CH2-CH2-N(n-propyl)2.
Examples of the group -A3-C(O)-NR11 R12, include, but are not limited to, -CH2-C(O)-NH2, -CH2-CH2-C(O)-NH2, -CH2-CH2-CH2-C(O)-NH2, -CH2-C(O)-NHCH3, -CH2-CH2-C(O)-NHCH3, -CH2-CH2-CH2-C(O)-NHCH3, -CH2-C(O)-N(CH3)2, -CH2-CH2-C(O)-N(CH3)2, -CH2-CH2-CH2-C(O)-N(CH3)2, -CH2-C(O)-NH(C2H5), -CH2-CH2-C(O)-NH(C2H5), -CH2-CH2-CH2-C(O)-NH(C2H5), -CH2-C(O)-N(C2H5)2, -CH2-CH2-C(O)-N(C2H5)2, -CH2-CH2-CH2-C(O)-N(C2H5)2, -CH2-C(O)-N(n-propyl)2, -CH2-CH2-C(O)-N(n-propyl)2 and -CH2-CH2-CH2-C(O)-N(n-propyl)2. A preferred example is -CH2-C(O)-N(CH3)2.
Examples of the group -A4-Z1 include, but are not limited to, -CH2-phenyl, -CH2-CH2-phenyl,
-CH2-CH2-CH2-phenyl, -CH2-pyridinyl, -CH2-CH2-pyridinyl, -CH2-CH2-CH2-pyridinyl, -CH2-morpholinyl, -CH2-CH2-morpholinyl and -CH2-CH2-CH2-morpholinyl. 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 -CH2-pyridinyl and -CH2-CH2-morpholinyl. The groups -CH2-pyridin-2-yl and -CH2-CH2-morpholin-4-yl are especially preferred.
Examples of the group -A5-C(O)-Z2 include, but are not limited to, -CH2-C(O)-phenyl, -CH2-CH2-C(O)- phenyl, -CH2-CH2-CH2-C(O)-phenyl, -CH2-C(O)-morpholinyl, -CH2-CH2-C(O)-morpholinyl and -CH2-CH2-CH2-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 -CH2-C(O)-morpholinyl, especially preferred is -CH2-C(O)-morpholin-4-yl.
Examples of the group -C(=NH)R13 include, but are not limited to, -C(=NH)CH3, -C(=NH)CH2-CH3, -C(=NH)CH2-CH2-CH3 and -C(=NH)NH2. The groups -C(=NH)CH3 and -C(=NH)NH2 are preferred.
Examples of the group -NH-C(0)R14 include, but are not limited to, -NH-C(O)CH3, -NH-C(O)CH2-CH3, -NH-C(O)CH2-CH2-CH3, of which -NH-C(O)CH3 is preferred.
The substituent R7 may be bonded to the group R6 at any position. Preferably, R7 is bonded in 3- or 4- position, with reference to the bonding position of the -SO2- 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,
Of these, particularly preferred are
Examples of the group -NR19- include, but are not limited to, -NH-, -NCH3- and -NC2H5- with -NH- being preferred. Examples of the group -C(O)R22 include, but are not limited to, -C(O)CH3, -C(O)CH2CH3, -C(O)CH2CH2CH3 and -C(O)CH(CH3)CH3 with -C(O)CH3 being preferred.
In a preferred embodiment, the invention relates to compounds of formula (I), in which X is N; Y is N; R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene 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;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(0)R8;
R8 is 1-3C-alkyl;
Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene 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;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
R8 is 1-3C-alkyl; Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen; R3 is selected from 1 ,4-phenylene 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;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8; R8 is 1-3C-alkyl;
Het is a group of formula (II)
in which
Q is -NH-;
R20 is hydrogen;
R21 is -C(O)R22;
R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene;
R4 is R6;
R6 is a monocyclic 6-membered heterocyclic group containing one or two nitrogen atoms, said group being optionally substituted by R7;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8; R8 is 1-3C-alkyl; Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene; R4 is R6;
R6 is a group selected from piperazinyl and pyridinyl, which is optionally substituted by R7;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
R8 is 1-3C-alkyl;
Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen; R3 is selected from 1 ,4-phenylene and 2, 5-pyridinylene;
R4 is R6;
R6 is a group selected from piperazin-1-yl and pyridin-4-yl, which is optionally substituted by R7;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
R8 is 1-3C-alkyl; Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene;
R4 is R6;
R6 is a group selected from piperazin-1-yl substituted by R7 and pyridin-4-yl;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
R8 is 1-3C-alkyl;
Het is a group of formula (II)
in which
Q is -NH-;
R20 is hydrogen;
R21 is -C(O)R22;
R22 is 1-3C-alkyl; and the salts thereof.
In a further preferred embodiment, the invention relates to compounds of formula (I), in which
X is N;
Y is N; R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene and 2,5-pyridinylene;
R4 is R6;
R6 is a group selected from piperazin-1-yl substituted by R7 and pyridin-4-yl; R7 is selected from methyl, -CH2-CH2-O-CH3 and -C(O)R8;
R8 is methyl;
Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is methyl; and the salts thereof.
Salts of the compounds according to the present invention include all acid addition salts and all salts with bases, specifically all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, more specifically all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
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. Hydrochlorides and methanesulfonates are particularly preferred.
Examples of 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). Accordingly, 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 X is N; Y is N; R1 is -R3-SO2-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)
and the salts thereof.
Further preferred stereoisomers include compounds of formula (I), in which
X is N; Y is N;
R1 is -R3-SO2-R4;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene 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;
R7 is -C(0)R8;
R8 is -A10-Z3 having the formula (III); and the salts thereof.
Further preferred stereoisomers include compounds of formula (I), in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4; R2 is hydrogen;
R3 is selected from 1 ,4-phenylene 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.
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. Preferably, the pure diastereomeric and pure enantiomeric compounds of the present invention are obtained by using chiral starting compounds.
Enantiomeric and diasteriomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, the mixtures are separated by chromatography or (fractional) crystallization. For enantiomeric mixtures the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral bases for separating acids and chiral acids for separating enantiomeric mixtures of bases, subsequent resolution of the salts and release of the desired compound from the salt. Alternatively, derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group. Furthermore, enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
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.
The present invention also relates to a compound of formula (Int1 )
)
wherein X is N, Y is N, R2 is selected from hydrogen and halogen and Hal3 is halogen, which is an intermediate in the process of preparing the final compounds according to the present invention as explained below.
The intermediate (Int1 ) can be prepared as shown in reaction scheme 1 (Hall = halogen, preferably chlorine, Hal2 = halogen, preferably bromine or chlorine, Hal3 = halogen, preferably bromine or fluorine). In particular, 2,5-dihalo-pyrimidine, which is commercially available or can be prepared by procedures known to the person skilled in the art, can be transformed into 5-halo-2-imidazol-1-yl- pyrimidine by nucleophilic displacement of HaM , thereby using imidazole and a strong base such as, for example, sodium hydride, in a suitable solvent, e.g. dimethylformamide or dimethylsulphoxide, at room temperature. In a further step, said product is firstly reacted with a suitable reagent for metalation such as, for example, isopropylmagnesium chloride, in an appropriate solvent, e.g. tetrahydrofuran, at reduced temperatures, preferably at O0C. Secondly, 4-halo-benzaldehyde, which is commercially available or can be prepared by procedures known to the person skilled in the art, is added to the aforementioned reaction mixture to afford the desired intermediate precursor. In a last step, said precursor is subjected to an oxidation reaction. This oxidation can be carried out in an art-known manner using a suitable oxidizing agent such as, for example, triacetoxy periodinane (Dess-Martin reagent) to obtain the desired intermediate of formula (Int1 ).
Reaction scheme 1 :
An intermediate (Int2), in which R3 represents 1 ,4-phenylene, can be prepared as shown in reaction scheme 2 (Hal4 = halogen, preferably bromine). In particular, 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, Λ/,Λ/-diisopropylethylamine (Hϋnig'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. In an alternative, 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. For example, 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).
Reaction scheme 2:
(Int2)
An intermediate (Int3), in which R3 represents 1 ,4-phenylene and R4 represents R6, can additionally be prepared as shown in reaction scheme 3 (Hal5 = halogen, preferably bromine, Hal6 = halogen, preferably chlorine). In particular, 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 3:
Reaction scheme 4:
An intermediate (Int5), in which R1 represents Het, can be prepared as shown in reaction scheme 5 (Hal8 = halogen, preferably bromine, Hal9 = halogen, preferably fluorine). In particular, a 1 ,4-dihalo-2- nitrobenzene (e.g. 4-bromo-1-fluoro-2-nitrobenzene), which is commercially available or can be prepared by procedures known to the person skilled in the art, can be transformed in a first step into a 4-halo-2-nitrobenzenesulfonic acid by nudeophilic displacement of Hal9 using e.g. sodium sulfite, preferably at elevated temperatures, e.g. 7O0C. In a second step, 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, 9O0C and, in the second place, gaseous ammonia at reaction temperatures preferably below O0C. In a further step, the nitro group of said sulfonamide derivative (e.g. 4-bromo-2-nitrobenzenesulfonamide) can be reduced to an amine as is known to the person skilled in the art using selective reducing agents such as, for example, stannous chloride or hydriodic acid at elevated reactions temperatures, e.g. 9O0C. 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 1000C, optionally in the presence of an acid such as, for example, pyridinium p- toluenesulfonate.
Reaction scheme 5:
An intermediate (Int6), in which R3 represents 1 ,4-piperazinylene, can be prepared as shown in reaction scheme 6 (Cbz = benzyloxycarbonyl). In particular, 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. O0C, in a suitable solvent such as, for example, chloroform, acetonitrile or dichloromethane. The protective group of said piperazine sulfonamide derivative can be removed e.g. by hydrogenation using a hydrogenation catalyst, e.g. Adam's catalyst (PtO2), Perlmaris catalyst [Pd(OH)2] or palladium on charcoal to afford the compound of formula (Int6).
Reaction scheme 6:
The final compounds according to the present invention can be prepared as shown in reaction scheme 7. In particular, 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(CI2)(dppf) or Pd(PPh3)4 (dppf: 1 ,1'- bis(diphenylphosphino)-ferrocene, PPh3: triphenylphosphine), in a suitable solvent, e.g. dioxane, at elevated temperatures, preferably above 9O0C, and optionally in the presence of a base, e.g. potassium acetate, an alkali halide, e.g. lithium chloride, and water.
The Suzuki reaction is, for example, described in Tetrahedron Lett. 1998, 39, 4467; J. Org. Chem. 1999, 64, 1372; and Heterocycles 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.
Reaction scheme 7:
(lnt2-5) = (Int2), (Int3), (Int4) or (Int5)
Alternatively, the final compounds according to the present invention can be prepared as shown in reaction scheme 8. In particular, 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(CI2)(dppf) or Pd(PPh3)4, in a suitable solvent, e.g. dioxane, at elevated temperatures, preferably above 9O0C, and optionally in the presence of a base, e.g. potassium acetate, an alkali halide, e.g. lithium chloride, and water.
Reaction scheme 8:
(lnt2-5) = (Int2), (Int3), (Int4) or (Int5)
Reaction scheme 9:
The substituent R7, which is optionally bonded to R6, may be introduced at the stage of preparing intermediate (Int2), (Int3), (Int4) or (Int6). In a first alternative, HR6 or R6-Hal10 (HaIIO = halogen), each of which is already substituted by R7, can be used (compare reaction schemes 2, 3, 4 and 6) to obtain (Int2), (Int3), (Int4) or (Int6), each containing R7. In a second alternative, the R6 moiety is introduced first and subsequently (Int2), (Int3), (Int4) or (Int6) each containing R6 is substituted by R7 as shown exemplarily for (Int2) (with R4 = R6) in reaction scheme 10 below. 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. For example, an intermediate (Int2) (with R4 = R6, see reaction scheme 10) can be reacted, for example, with carboxylic acids or derivatives thereof (e.g. carboxylic anhydrides, acid halides or amino acids) by procedures known to the person skilled in the art, e.g. using Einhorn conditions, to afford the correspondingly substituted compounds (e.g. 1-3C- alkylcarbonyl, 3-6C-cydoalkylcarbonyl or ω-amino-1-3C-alkylenecarbonyl substituted compounds).
Reaction scheme 10:
Furthermore, R7 may be introduced after having obtained the final product containing R6 as shown exemplarily in reaction scheme 11. Az2 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. Az2 includes, but is not limited to, halogen, hydroxy, -O-1 -4C- alkyl, -O-R7 and pyrazol-1-yl). For example, starting compounds as shown in reaction scheme 11 can be converted into compounds substituted by R7 by procedures known to the person skilled in the art, using e.g. a carboxylic anhydride, 1-3C-alkyl 1-3C-alkanimidoate or 1/-/-pyrazole-carboxamidine as R7- Az1.
Reaction scheme 11 :
It is known to the person skilled in the art that, if there are 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 for 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, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000.
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. 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, repredpitating, 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. In this manner, 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.
Having described the invention in detail, the scope of the present invention is not limited only to those described characteristics or embodiments. As will be apparent to persons skilled in the art, modifications, analogies, variations, derivations, homologisations and adaptations to the described invention can be made on the basis of art-known knowledge and/or, particularly, on the basis of the disclosure (e.g. the explicit, implicit or inherent disclosure) of the present invention without departing from the spirit and scope of this invention.
The following examples illustrate the invention in greater detail, without restricting it. Additionally, further compounds according to the present invention, of which the preparation is explicitly not described, can be prepared in an analogous way.
The compounds according to the present invention, which are mentioned in the following examples, and the salts thereof represent preferred embodiments of the present invention.
Examples
The following abbreviations are used: DPPF/dppf: 1 ,1'- bis(diphenylphosphino)-ferrocene, DMAP: dimethylaminopyridine, DMSO: dimethyl sulphoxide, DMF: N,N-dimethylformamide, DBU: 1 ,8- diazabicyclo[5.4.0]undec-7-ene, MS: mass spectrometry, ESI-MS: elektrospray ionization mass spectrometry, LC: liquid chromatography, TLC: thin layer chromatography, HPLC: high performance liquid chromatography, Cbz: benzyloxycarbonyl, Boc: t-butyloxycarbonyl, Ph: phenyl.
1. 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-[4'-(4-methyl-piperazine-1-sulfonyl)-biphenyl-4-yl]- methanone
492 mg of 1-(4-Bromo-benzenesulfonyl)-4-methyl-piperazine (compound A1 ) are dissolved in 7 ml of oxygen-free dioxane under an atmosphere of dry nitrogen. Subsequently, 429 mg of bis(pinacolato)- diboron, 34 mg of Pd(CI)2(dppf) ' CH2CI2, 26 mg of DPPF (1 ,1'- bis(diphenylphosphino)-ferrocene), and 453 mg of potassium acetate are added. The reaction mixture is heated at 9O0C for 24 hours during which time the former yellowish suspension becomes black (LC-MS monitoring for formation of boronic ester intermediate). Thereafter, 329 mg of 1-(4-bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)- methanone (compound B1 ), 276 mg of potassium carbonate, 85 mg of lithium chloride, 1 16 mg of Pd(PPh3)4, 11 ml of oxygen-free dioxane, and 11 ml of water are added. The reaction mixture is heated at 9O0C and stirring is continued for 16 hours. Subsequently, the suspension is concentrated in vacuo and co-evaporated twice with 20 ml each of toluene. The resulting crude material is purified by chromatography (eluent: dichloromethane/ethanol 20:1 parts per volume) to afford 165 mg of the title compound as a colorless solid. M. p. 2520C. ESI-MS: 489.3 (MH+). TLC: Rf = 0.56 (dichloromethane/methanol 10:1 parts per volume).
2. 1-(4-{4'-[1-(2-lmidazol-1-yl-pyrimidin-5-yl)-methanoyl]-biphenyl-4-sulfonyl}-piperazin-1-yl)- ethanone hydrochloride
6.0 mg of 1-(4-{4'-[1-(2-lmidazol-1-yl-pyrimidin-5-yl)-methanoyl]-biphenyl-4-sulfonyl}-piperazin-1-yl)- ethanone (compound A2) are dissolved in each 1.0 ml dichloromethane and methanol. Subsequently, 6.0 μl of ethereal HCI (strength 2.0 M) are added. After stirring for 30 min, the clear solution is evaporated to dryness to yield 6.3 mg of title compound as a colorless solid. M. p. 2550C. ESI-MS: 517.2 (MH+). TLC: Rf = 0.70 (dichloromethane/ethanol 20:1 ).
3. 1'-Acetyl-6-{4-[1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanoyl]-phenyl}-4/-/-spiro[1 ,2,4- benzothiadiazine-3,4'-piperidine]-1 ,1 -dioxide
The title compound is synthesized as described for 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-[4'-(4-methyl- piperazine-1-sulfonyl)-biphenyl-4-yl]-methanone (compound 1 ) from 360 mg of 1'-acetyl-6-bromo-4/-/- spiro[1 ,2,4-benzothiadiazine-3,4'-piperidine]-1 ,1-dioxide (compound A3). Formation of boronic ester
intermediate is completed within 6 hours (LC-MS monitoring) at 11O0C. After addition of 206 mg of 1- (4-bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanone (compound B1 ) heating at 7O0C is continued for 18 hours. Purification by flash chromatography (eluent gradient: dichloromethane/ethanol 5.0-15.0 Vol%) yields 70 mg of the title compound as a light yellow solid. M. p. 2810C. ESI-MS: 544.1 (MH+). TLC: Rf = 0.58 (dichloromethane/ethanol 8:1 parts per volume).
4. 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-(4-{6-[4-(2-methoxy-ethyl)-piperazine-1-sulfonyl]-pyridin-3- yl}-phenyl)-methanone hydrochloride
The title compound is synthesized as described for 1-(4-{4'-[1-(2-imidazol-1-yl-pyrimidin-5-yl)- methanoyl]-biphenyl-4-sulfonyl}-piperazin-1-yl)-ethanone hydrochloride (compound 2) from 5.9 mg of 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-(4-{6-[4-(2-methoxy-ethyl)-piperazine-1-sulfonyl]-pyridin-3-yl}- phenyl)-methanone (compound A4) to yield 6.1 mg of title compound as a light yellow solid. M. p. 2780C. ESI-MS: 534.3 (MH+). TLC: Rf = 0.59 (dichloromethane/ethanol 10:1 parts per volume).
5. 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)-biphenyl-4-yl]-methanone hydrochloride
The title compound is synthesized as described for 1-(4-{4'-[1-(2-imidazol-1-yl-pyrimidin-5-yl)- methanoyl]-biphenyl-4-sulfonyl}-piperazin-1-yl)-ethanone hydrochloride (compound 2) from 20.1 mg of 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)-biphenyl-4-yl]-methanone (compound A5) to yield 21.4 mg of title compound as a colorless solid. M. p. 207°C. ESI-MS: 468.3 (MH+). TLC: Rf = 0.30 (dichloro-methane/ethanol 20:1 parts per volume).
6. 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)-biphenyl-4-yl]-methanone methanesulfonic acid
20.1 mg of 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)-biphenyl-4-yl]-methanone (compound A5) are dissolved in each 2.5 ml dichloromethane and methanol. Subsequently, 86 μl of methanesulfonic acid are added. After stirring for 30 min, the clear solution is evaporated to dryness to yield 23 mg of title compound as a colorless solid. M. p. 18O0C. ESI-MS: 468.2 (MH+). TLC: Rf = 0.30 (dichloromethane/ ethanol 20:1 parts per volume).
A1. 1-(4-Bromo-benzenesulfonyl)-4-methyl-piperazine
1.54 g of 4-Bromo-benzenesulphonyl chloride are dissolved in 35 ml of dichloromethane under an atmosphere of dry nitrogen. Subsequently, 691 mg of N-methyl-piperazine and 1.67 ml of triethylamine are added dropwise. The reaction mixture is stirred for 5 h at room temperature. The solution is diluted with 75 ml of water and extracted twice with each 75 ml of dichloromethane. The organic layer is dried using Na2SO4, filtered with suction and concentrated in vacuo to obtain 1.83 mg of the title compound
as a colorless solid. M.p. 154-1550C. ESI-MS: 319.1/321.1 (MH+). TLC: Rf = 0.33 (dichloromethane/ methanol 20:1 parts per volume).
A2. 1-(4-{4'-[1-(2-lmidazol-1-yl-pyrimidin-5-yl)-methanoyl]-biphenyl-4-sulfonyl}-piperazin-1-yl)- ethanone
The title compound is synthesized as described for 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-[4'-(4-methyl- piperazine-1-sulfonyl)-biphenyl-4-yl]-methanone (compound 1 ) from 500 mg of 1-[4-(4-bromo- benzenesulfonyl)-piperazin-1-yl]-ethanone (compound B2) . Formation of boronic ester intermediate is completed within 6 hours (LC-MS monitoring). After addition of 308 mg of 1-(4-bromo-phenyl)-1-(2- imidazol-1-yl-pyrimidin-5-yl)-methanone (compound B1 ) heating at 9O0C is continued for 24 hours. Purification by flash chromatography (eluent gradient: dichloromethane/ethanol 5.0-15.0 Vol%) yields 81 mg of the title compound as a light yellow solid. M.p. 2970C. ESI-MS: 517.3 (MH+). TLC: Rf = 0.70 (dichloromethane/ethanol 20:1 parts per volume).
A3. 1'-Acetyl-6-bromo-4/-/-spiro[1 ,2,4-benzothiadiazine-3,4'-piperidine]-1 ,1-dioxide
2.0 g of 2-Amino-4-bromobenzenesulfonamide (compound B3) are dissolved in 80 ml of toluene. 600 mg of pyridinium p-toluenesulfonate, 1.69 g of Na2SO4, and 980 μl of 1-N-acetyl-4-piperidone are added to the solution. Thereafter, the reaction mixture is stirred under reflux at 13O0C for 24 hours. Subsequently, the mixture is filtered with suction and the filtrate is evaporated to dryness. The remaining residue is purified by flash chromatography (eluent gradient: dichloromethane/ethanol 9:1- 4:1 parts per volume) to afford 2.86 g of the title compound as a colorless solid. M.p. 2520C. ESI-MS: 374.0/375.9 (MH+). TLC: Rf = 0.63 (dichloromethane/ethanol 10:1 parts per volume).
A4. 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-(4-{6-[4-(2-methoxy-ethyl)-piperazine-1-sulfonyl]-pyridin-3- yl}-phenyl)-methanone
329 mg of 1-(4-bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanone (compound B1 ) are dissolved in 4.0 ml of oxygen-free dioxane under an atmosphere of dry nitrogen. Subsequently, 279 mg of bis(pinacolato)-diboron, 22 mg of Pd(CI )2(dppf) CH2CI2, 17 mg of DPPF (1 ,1'- bis(diphenylphosphino)-ferrocene), and 294 mg of potassium acetate are added. The reaction mixture is heated at 11 O0C for 48 hours during which time the suspension becomes black (LC-MS monitoring for formation of boronic ester intermediate). Thereafter, 237 mg of 1-(5-bromo-pyridine-2-sulfonyl)-4-(2- methoxy-ethyl)-piperazine (compound B4), 180 mg of potassium carbonate, 55 mg of lithium chloride, 75 mg of Pd(PPh3)4, 4.0 ml of oxygen-free dioxane, and 4.0 ml of water are added. The reaction mixture is heated at 11O0C and stirring is continued for 4 hours. Subsequently, the suspension is concentrated in vacuo and co-evaporated twice with 10 ml each of toluene. The resulting crude material is purified by flash chromatography (eluent gradient: dichloromethane/ethanol 2.0-100 Vol%)
to afford 30 mg of the title compound as a light yellow solid. M. p. 2580C. ESI-MS: 534.3 (MH+). TLC: Rf = 0.59 (dichloromethane/ethanol 10:1 parts per volume).
A5. 1-(2-lmidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)-biphenyl-4-yl]-methanone
The title compound is synthesized as described for 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-(4-{6-[4-(2- methoxy-ethyl)-piperazine-1-sulfonyl]-pyridin-3-yl}-phenyl)-methanone (compound A4) from 494 mg of 1-(4-bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanone (compound B1 ). Formation of boronic ester intermediate is completed within 48 hours (LC-MS monitoring). After addition of 291 mg of 4-(4- pyridylsulfonyl)-bromobenzene (compound B5) heating at 11 O0C is continued for 90 hours. Purification by flash chromatography (eluent gradient: dichloromethane/ethanol 0-5.0 Vol%) yields 154 mg of the title compound as a colorless solid. M. p. 2750C. ESI-MS: 468.2 (MH+). TLC: Rf = 0.30 (dichloromethane/ethanol 20:1 parts per volume).
B1. 1-(4-Bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanone
10.93 g of 1-(4-bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanol (compound C1 ) are suspended in 150 ml of dichloromethane under an atmosphere of dry nitrogen. Subsequently, 14.0 g of Dess-Martin triacetoxy periodinane are added in portions. The reaction mixture is stirred for 18 hours at room temperature. Thereafter, the suspension is evaporated to dryness to afford a crude material, which is purified by recrystallization from 150 ml of ethanol to yield 8.54 g of the title compound as a colorless solid. M. p. 25O0C. ESI-MS: 329.3/331.3 (MH+). TLC: Rf = 0.47 (dichloromethane/ethanol 20:1 parts per volume).
B2. 1-[4-(4-Bromo-benzenesulfonyl)-piperazin-1-yl]-ethanone
2.13 g of 1-(4-Bromo-benzenesulfonyl)-piperazine (compound C2) are dissolved in 100 ml of pyridine and 75 of acetic anhydride under an atmosphere of dry nitrogen. 213 mg of 4-(N,N-dimethylamino)- pyridine are added to the solution. The reaction mixture is stirred for 18 hours at room temperature. Subsequently, the solution is concentrated in vacuo. The remaining residue is purified by flash chromatography (eluent: cyclohexane/ethyl acetate 1 :2 parts per volume) to yield 2.18 g of the title compound as a solid. M.p. 1740C. ESI-MS: 347.0/349.0 (MH+). TLC: Rf = 0.75 (dichloromethane/ethanol 10:1 parts per volume).
B3. 2-Amino-4-bromobenzenesulfonamide
14.0 g of 4-bromo-2-nitrobenzenesulfonamide (compound C3) are dissolved in 130 ml of hydriodic acid (strength 57 Vol%). The solution is heated at 9O0C under reflux for 24 hours. After cooling to room temperature, 200 ml of ethyl acetate are added. Thereafter, the solution is cooled in an ice bath and Na2S2O3 (solid) is added under stirring until decolorization of the solution occurs. Subsequently,
portions of Na2CO3 (solid) are carefully added to neutralize the mixture. The layers are separated, the aqueous layer is extracted with 20 ml of ethyl acetate, and the combined organic layers are dried, using Na2SO4. After filtration and concentration in vacuo the crude product is purified by flash chromatography (eluent: dichloromethane/ ethanol 10:1 parts per volume) to yield 8.03 g of the title compound as a colorless, amorphous solid. M. p. 1440C. ESI-MS: 250.8/252.8 (MH+). TLC: Rf = 0.52 (dichloromethane/ethanol 10:1 parts per volume).
B4. 1-(5-Bromo-pyridine-2-sulfonyl)-4-(2-methoxy-ethyl)-piperazine
809 mg of 1-(2-methoxyethyl)-piperazine are dissolved in 9.0 ml of dichloromethane and 9.0 ml of an aqueous K2CO3 solution (strength 4.0 M). Subsequently, the reaction mixture is cooled in an ice bath and a solution of 1.20 g of 5-bromo-pyridine-2-sulfonyl chloride (compound C4) in 2.0 ml of dichloromethane is added dropwise. Thereafter, the reaction mixture is allowed to warm up to room temperature during which time the two-phase system is vigorously stirred for 1 hour. For workup, the organic layer is separated and the aqueous layer is extracted once with 10 ml of dichloromethane. The combined organic layers are dried, using Na2SO4, filtered with suction and evaporated to dryness to yield 1.70 g of the title compound as yellow oil, which crystallizes at room temperature. M. p. 940C. ESI- MS: 364.3/366.1 (MH+). TLC: Rf = 0.40 (dichloromethane/ethanol 20:1 parts per volume).
B5. 4-(4-Pyridylsulfonyl)bromobenzene
The title compound is synthesized according to a procedure described in WO 93/23358 from 4-(4- pyridylthio)bromobenzene (compound C5).
C1. 1-(4-Bromo-phenyl)-1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanol
22.5 g of 5-bromo-2-imidazol-1-yl-pyrimidine (compound D1 ) are dissolved in 250 ml of tetrahydrofuran under an atmosphere of dry nitrogen. Subsequently, the reaction mixture is cooled in an ice bath and 70 ml of isopropylmagnesium chloride (strength 2.0 M in tetrahydrofurane) are added dropwise. Thereafter, the solution is allowed to warm up to room temperature and stirred for 30 min.
Subsequently, a solution of 14.8 g of 4-bromo-benzaldehyde in 50 ml of tetrahydrofurane is added dropwise and stirring is continued for 48 hours. For workup, the reaction mixture is poured into 300 ml of water. The solution is subsequently acidified to pH 5 using hydrochloric acid (strength 1.0 N), extracted three times with each 100 ml of dichloromethane, dried using Na2SO4, filtered with suction, and evaporated to dryness. The remaining crude material is purified by flash chromatography (eluent gradient: dichloromethane/ethanol 0.0-5.0 Vol%) to afford 11.19 g of the title compound as a colorless solid. M. p. 2270C. ESI-MS: 331.3/333.2 (MH+). TLC: Rf = 0.29 (dichloromethane/ethanol 20:1 ).
C2. 1-(4-Bromo-benzenesulfonyl)-piperazine
1.89 g of piperazine are dissolved in 70 ml of dichloromethane under an atmosphere of dry nitrogen. 6.09 g of DBU are added to the solution. 5.11 g of 4-bromo-benzenesulphonyl chloride are dissolved in 30 ml of dichloromethane and added dropwise to the reaction mixture. Thereafter, the reaction mixture is stirred at room temperature for 2 hours. Subsequently, the mixture is diluted with 200 ml of water and extracted with 100 ml of dichloromethane. The organic layer is dried using Na2SO4, filtered with suction and concentrated in vacuo. The crude material is purified by flash chromatography (eluent: dichloromethane/ethanol 15:1 parts per volume) to obtain 3.81 g of the title compound as a colorless solid. M. p. 1180C. ESI-MS: 304.9/307.0 (MH+). TLC: Rf = 0.45 (dichloromethane/methanol 10:1 parts per volume).
C3. 4-Bromo-2-nitrobenzenesulfonamide
25.0 g of 4-Bromo-2-nitrobenzenesulfonic acid (compound D2) are dissolved in 130 ml of thionyl chloride and 2.5 ml of DMF. The solution is heated at 9O0C for 2 hours. Subsequently, excess thionyl chloride is distilled off under reduced pressure. The residue is co-evaporated twice with 20 ml each of chloroform. Thereafter, the 4-bromo-2-nitrobenzenesulfonyl chloride intermediate is re-dissolved in 550 ml of chloroform. The solution is cooled to -50C and ammonia is passed through the reaction mixture for 15 min. After excess ammonia has been swept out by passing dry nitrogen through the mixture, the solution is acidified with 5 ml of concentrated HCI to adjust pH 2. Subsequently, the mixture is concentrated in vacuo and the residue is recrystallized from 1500 ml of water and 300 ml of ethanol. The precipitate is collected by filtration and dried under high vacuum to yield 14.14 g of the title compound as a light yellow, crystalline solid. MS: 278.9, 280.9 (M-H+). TLC: Rf = 0.82 (dichloromethane/ethanol 10:1 parts per volume).
C4. 5-Bromo-pyridine-2-sulfonyl chloride
2.0 g of 5-Bromo-pyridine-2-thiol (compound D3) are dissolved in 40 ml of carbon tetrachloride and 8 ml of water. Subsequently, the suspension is cooled in an ice bath and chlorine gas is passed into the reaction mixture for 20 min (flow: 35 ml/min). Thereafter, nitrogen is passed into the yellow solution to remove excess chlorine. Subsequently, the mixture is diluted with 150 ml of dichloromethane and extracted with 50 ml of brine (saturated aqueous NaCI solution). The organic layer is separated, dried using Na2SO4, filtered with suction, and evaporated to dryness to afford 2.70 g of the title compound as light yellow needles. M.p. 8O0C. GC-MS: 254.8/256.8/258.8 (77:100:25; M+). TLC: Rf = 0.84 (dichloromethane/ethanol 20:1 parts per volume).
C5. 4-(4-Pyridylthio)bromobenzene
The title compound is synthesized according to a procedure described in WO 93/23358.
D1. 5-Bromo-2-imidazol-1-yl-pyrimidine
280 mg of sodium hydride (strength 60 Vol%) are suspended in 5.0 ml of DMSO under an atmosphere of dry nitrogen. Subsequently, a solution of 409 mg of imidazole in 5.0 ml of DMSO is added dropwise at room temperature. After the gas evolution has ceased, the reaction mixture is stirred for further 10 min. Thereafter, a solution of 987 mg of 5-bromo-2-chloro-pyrimidine in 10 ml of DMSO is added dropwise to the reaction mixture. The yellow suspension is stirred for 1 hour. For workup, the reaction mixture is poured into 150 ml of iced water and the suspension is filtered with suction. The residue is rinsed with water and dried to yield 1.11 g of the title compound as a colorless solid. M. p. 2260C. ESI- MS: 225.2/227.2 (MH+). TLC: Rf = 0.50 (dichloromethane/methanol 20:1 parts per volume).
D2. 4-Bromo-2-nitrobenzenesulfonic acid
25 g of 4-Bromo-1-fluoro-2-nitrobenzene are dissolved in 300 ml of ethanol. Subsequently, a suspension of 31.5 g of Na2SO3 in 500 ml of ethanol and 625 ml of water are added. The suspension is stirred at 7O0C for 24 hours. Thereafter, the reaction mixture is acidified to pH 2 at room temperature using 15 ml of concentrated HCI. The mixture is filtered and the filtrate is concentrated in vacuo. The remaining residue is dissolved under reflux in 500 ml of brine (saturated aqueous NaCI solution). Subsequently, 50 ml of water are added and the solution is cooled in an ice bath. The precipitate is collected by filtration and dried under high vacuum to yield 28.2 g of the title compound as a light yellow, crystalline solid. M. p. >400°C. MS: 280.1 , 282.0 (M-H+). TLC: Rf = 0.70 (dichloromethane/ethanol 8:1 parts per volume).
D3. 5-Bromo-pyridine-2-thiol
8.97 g of of 5-Bromopyridin-2(1/-/)-one are suspended in 250 ml of toluene under an atmosphere of dry nitrogen. Subsequently, 10.42 g of 2,4-bis-(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4- disulfide (Lawesson's reagent) are added and the solution is heated at 12O0C under reflux for 1 hour. After cooling to room temperature, the product precipitates. The precipitate is collected by filtration and dried under high vacuum to yield 8.08 g of the title compound as a yellow solid. M. p. 1980C. ESI-MS: 190.2/192.2 (MH+). TLC: Rf = 0.50 (dichloromethane/ethanol 20:1 parts per volume).
Commercial applicability
The compounds and their pharmaceutically acceptable salts according to the present invention have valuable pharmaceutical properties which make them commercially utilizable. In particular, they are selective inhibitors of the enzyme inducible nitric oxide synthase. Nitric oxide synthases (NO- synthases, NOSs) are enzymes that generate NO and citrulline from the amino acid arginine. In certain pathophysiological situations, such as arginine depletion or tetrahydrobiopterin depletion, the generation of O2 " 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. The most prominent action of NO is it's smooth muscle relaxing activity, which is caused on the molecular level by the activation of soluble guanylate cyclase. In the last years, numerous other enzymes have been shown to be regulated by NO or to be reaction products of NO.
There exist three isoforms of NO-synthases which fall into two classes and differ in their physiologic functions and molecular properties. The first class, known as constitutive NO-synthases, 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). Activation of these two enzymes is dependent on Ca27calmodulin which is generated by transient increases of the intracellular free Ca2+ 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).
In contrast to the constitutive isoforms, the activation of inducible NO-synthase (iNOS, NOS-II), the sole member of the second class, is performed by transcriptional activation of the iNOS-promoter. For example, proinflammatory stimuli lead to transcription of the gene for inducible NO-synthase, which is catalytically active without increases in the intracellular Ca2+-concentration. Due to the long half life of the inducible NO-synthase and the unregulated activity of the enzyme, 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 O2 ' 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.
There are a number of pathophysiological situations which among others are characterized by the high expression of inducible NO-synthase and concomitant high NO or O2 " 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. As 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).
It is clear that nonselective NO-synthase inhibitors will lead to cardiovascular and neuronal side effects due to concomitant inhibition of constitutive NO-synthase isoforms.
It has been shown in in-vivo animal models of septic shock that reduction of circulating plasma NO- levels by NO-scavenger or inhibition of inducible NO-synthase restores systemic blood pressure, reduces organ damage and increases survival (deAngelo Exp. Opin. Pharmacother. 19-29, 1999; Redl et al. Shock 8, Suppl. 51 , 1997; Strand et al. Crit. Care Med. 26, 1490-1499, 1998). It has also been shown that increased NO production during septic shock contributes to cardiac depression and myocardial dysfunction (Sun et al. J. MoI. Cell Cardiol. 30, 989-997, 1998). Furthermore there are also reports showing reduced infarct size after occlusion of the left anterior coronary artery in the presence of NO-synthase inhibitors (Wang et al. Am. J. Hyperttens. 12, 174-182, 1999). Considerable inducible NO-synthase activity is found in human cardiomyopathy and myocarditis, supporting the hypothesis that NO accounts at least in part for the dilatation and impaired contractility in these pathophysiologies (de Belder et al. Br. Heart. J. 4, 426-430, 1995).
In animal models of acute or chronic inflammation, blockade of inducible NO-synthase by isoform- selective or nonselective inhibitors or genetic knock out improves therapeutic outcome. It is reported that experimental arthritis (Connor et al. Eur. J. Pharmacol. 273, 15-24, 1995) and osteoarthritis (Pelletier et al. Arthritis & Rheum. 41 , 1275-1286, 1998), experimental inflammations of the gastro- intestinal tract (Zingarelli et al. Gut 45, 199-209, 1999), experimental glomerulonephritis (Narita et al. Lab. Invest. 72, 17-24, 1995), experimental diabetes (Corbett et al. PNAS 90, 8992-8995, 1993), and lipopolysaccharide-induced experimental lung injury is reduced by inhibition of inducible NO-synthase or in iNOS-knock out mice (Kristof et al. Am. J. Crit. Care. Med. 158, 1883-1889, 1998). A pathophysiological role of inducible NO-synthase derived NO or O2 " is also discussed in chronic inflammatory diseases, such as asthma, bronchitis and chronic obstructive pulmonary disease (COPD).
Furthermore, in models of neurodegenerative diseases of the central nervous system such as MPTP- induced parkinsonism (MPTP = 1-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine), 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) and experimental encephalitis (Parkinson et al. J. MoI. Med. 75, 174-186, 1997) a causal participation of NO and inducible NO-synthase has been shown.
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).
Other studies implicated 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).
An inflammatory reaction with concomitant expression of inducible NO-synthase also takes place during cerebral ischemia and reperfusion (ladecola et al. Stroke 27, 1373-1380, 1996). Resulting NO together with O2 ' from infiltrating neutrophils is thought to be responsible for cellular and organ damage.
Also, in models of traumatic brain injury (Mesenge et al. J. Neurotrauma 13, 209-214, 1996; Wada et al. Neurosurgery 43, 1427-1436, 1998), 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).
On account of their inducible NO-synthase-inhibiting properties, 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 O2 " due to increases in the activity of inducible NO-synthase is involved. In particular, 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 vasculitides such as polyarteritis nodosa, serum sickness, Wegener's granulomatosis, Kawasaki's syndrome; headaches
such as migraine, chronic tension headaches, cluster and vascular headaches, post-traumatic stress disorders; pain disorders such as neuropathic pain; myocardial and cerebral ischemia/reperfusion injury.
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.
In the context of their properties, functions and usabilities mentioned herein, 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.
Accordingly, 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.
In particular, 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.
Especially, 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.
Furthermore, 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.
In the above methods, one or more of the compounds and pharmaceutically acceptable salts according to the invention can be used. Preferably one or two of the compounds and pharmaceutically acceptable salts are used, more preferably, one of the compounds and pharmaceutically acceptable salts is used.
In a particularly preferred embodiment of the present invention, 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.
Preferably, 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.
In a particularly preferred embodiment of the present 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.
The pharmaceutical 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%.
As pharmaceutically acceptable 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. In particular, 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). Additionally, 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).
The pharmaceutical 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.
Specifically, tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, 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. Depending on the kind of active compound to be administered, 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. Examples of carriers include, but are not limited to, saccharides, e.g. lactose and glucose. Examples of 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 (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably it is in the range of from 0.5 to 10 μm, in particular in the range of from 2 to 6 μm (D50 value, measured by laser diffraction).
Specific 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.
In case of topical administration suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g. transdermal therapeutic systems).
For 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.
In case of intranasal administration, for example, sprays and solutions to be applied in drop form are preferred formulations.
For intraocular administration, solutions to be applied in drop form, gels and ointments are exemplified formulations.
Generally, 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. In particular, 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. In this respect, it is to be noted that 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. Furthermore, 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.
Biological investigations
Measurement of inducible NO-synthase activity:
The assay is performed in 96-well microtiter F-plates (Greiner, Frickenhausen, FRG) in a total volume of 100 μl in the presence of 100 nM calmodulin, 226 μM CaCI2, 477 μM MgCI2, 5 μM flavin-adenine- dinudeotide (FAD), 5 μM flavin mononucleotide (FMN), 0.1 mM nicotinamide adenine dinucleotide phosphate (NADPH), 7 mM glutathione, 10 μM tetrahydrobiopterine (BH4) and 100 mM 4-(2- hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), pH 7.2. Arginine concentrations are 0.1 μM for enzyme inhibition experiments. 150000 dpm of [3H]arginine are added to the assay mixture. Enzyme reaction is started by the addition of 4 μg of a crude cytosolic fraction containing human inducible NO-synthase and the reaction mixture is incubated for 45 to 60 min at 370C. Enzyme reaction is stopped by adding 10 μl of 2M 2-morpholinoethane sulfonic acid buffer (MES-buffer) pH 5.0. 50 μl of the incubation mixture are transferred into a MADP N65 filtration microtiter plate (Millipore, Eschborn, FRG) containing already 50 μl of AG-50W-X8 cation exchange resin (Biorad, Munich, FRG). The resin in the Na loaded form is pre-equilibrated in water and 70 μl (corresponding to 50 μl dry beads) are pipetted under heavy stirring with a 8 channel pipette into the filtration plate. After pipetting 50 μl of the enzyme reaction mixture onto the filtration plates, the plates are placed on a filtration manifold (Porvair, Shepperton, UK) and the flow through is collected in Pico scintillation plates (Packard, Meriden, USA). The resin in the filtration plates is washed with 75 μl of water (1x50 μl and 1x 25 μl) which is also collected in the same plate as the sample. The total flow through of 125 μl is mixed with 175 μl 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.
For the measurement of inducible NO-synthase-inhibiting potencies of the tested compounds, increasing concentrations of said compounds were included into the incubation mixture. IC50 values were calculated from the percent inhibition at given concentrations by nonlinear least square fitting.
Measurement of the inhibiting potencies of the tested compounds regarding the constitutive NO- synthases [endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS)] was identical with the method used for determination of iNOS inhibitory activity, except for using crude cellular fractions containing 5 μg human endothelial NO synthase or 2 μg human neuronal NO synthase, respectively, for starting the enzyme reaction. Incubation of the reaction mixture was 60 min at 370C. All other steps and assay components were identical as was the calculation of IC50 values.
The compounds according to the present invention, which are prepared according to examples 1 to 6 as described above, show an inhibition of the inducible nitric oxide synthase (iNOS), measured as -loglC50 (mol/l), in the range of from 6.28 to 7.16 and an inhibition of the constitutive nitric oxide synthases (eNOS and nNOS), measured as -loglC50 (mol/l), of < 4.00.
Claims
1. Compound of formula (I)
in which
X is N; Y is N;
R1 is selected from -R3-SO2-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(O)R8,
-A2-NR9R10, -A3-C(O)-NR11 R12, =0, -A4-Z1 , -A5-C(O)-Z2, -C(=NH)R13 and -NH-C(O)R14;
R8 is selected from hydrogen, 1-3C-alkyl,
3-6C-cydoalkyl, -A6-NH2, -A7-O-R15, -A8-O-A9-O-R16 and -A10-Z3;
A2 is selected from a single bond and 1-3C-alkylene;
A3 is 1-3C-alkylene; A4 is 1-3C-alkylene;
A5 is 1-3C-alkylene;
A6 is 1-3C-alkylene;
A7 is 1-3C-alkylene;
A8 is 1-3C-alkylene; A9 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; R11 is selected from hydrogen and 1-3C-alkyl;
R12 is selected from hydrogen and 1-3C-alkyl;
R13 is selected from 1-3C-alkyl and -NH2;
R14 is 1-3C-alkyl;
R15 is 1-3C-alkyl; R16 is 1-3C-alkyl;
Z1 is a 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18; Z2 is a 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18;
Z3 is a 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 optionally substituted by one or more identical or different substituents selected from halogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, =0 and -NR17R18;
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)
in which Q is selected from -NR19-, -CH2- 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; or a salt thereof. Compound according to claim 1 , in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene 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; R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8; R8 is 1-3C-alkyl; Het is a group of formula (II)
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; or a salt thereof.
Compound according to claim 1 or 2, in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,4-phenylene 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; R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8; R8 is 1-3C-alkyl; Het is a group of formula (II) 
in which Q is -NH-; R20 is hydrogen; R21 is -C(O)R22; R22 is 1-3C-alkyl; or a salt thereof.
Compound according to any of claims 1 to 3, in which
X is N;
Y is N;
R1 is selected from -R3-SO2-R4 and Het;
R2 is hydrogen;
R3 is selected from 1 ,
4-phenylene and 2,5-pyridinylene;
R4 is R6;
R6 is a group selected from piperazinyl and pyridinyl, which is optionally substituted by R7;
R7 is selected from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl and -C(O)R8;
R8 is 1-3C-alkyl;
Het is a group of formula (II)
n which
Q is -NH-;
R20 is hydrogen;
R21 is -C(O)R22;
R22 is 1-3C-alkyl; or a salt thereof.
5. Compound according to any of claims 1 to 4 selected from the group consisting of 1-(2- imidazol-1-yl-pyrimidin-5-yl)-1-[4'-(4-methyl-piperazine-1-sulfonyl)-biphenyl-4-yl]-methanone, 1- (4-{4'-[1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanoyl]-biphenyl-4-sulfonyl}-piperazin-1-yl)- ethanone hydrochloride, 1'-acetyl-6-{4-[1-(2-imidazol-1-yl-pyrimidin-5-yl)-methanoyl]-phenyl}-
4/-/-spiro[1 , 2, 4-benzothiadiazine-3,4'-piperidine]-1 ,1 -dioxide, 1-(2-imidazol-1-yl-pyrimidin-5-yl)- 1-(4-{6-[4-(2-methoxy-ethyl)-piperazine-1-sulfonyl]-pyridin-3-yl}-phenyl)-m ethanone hydrochloride, 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)-biphenyl-4-yl]- methanone hydrochloride, and 1-(2-imidazol-1-yl-pyrimidin-5-yl)-1-[4'-(pyridine-4-sulfonyl)- biphenyl-4-yl]-methanone methanesulfonic acid.
6. Compound of formula (Int1 )
)
in which X is N; Y is N;
R2 is selected from hydrogen and halogen; and Hal3 is halogen.
7. Compound or pharmaceutically acceptable salt according to any of claims 1 to 5 for the treatment or prophylaxis of diseases.
8. Compound or pharmaceutically acceptable salt according to any of claims 1 to 5 for the treatment or prophylaxis of diseases alleviated by inhibition of inducible nitric oxide synthase.
9. Pharmaceutical composition comprising one or more of the compounds and pharmaceutically acceptable salts according to any of claims 1 to 5 together with one or more pharmaceutically acceptable auxiliaries.
10. Use of a compound or pharmaceutically acceptable salt according to any of claims 1 to 5 in the manufacture of a pharmaceutical composition inhibiting the inducible nitric oxide synthase.
11. Use of a compound or pharmaceutically acceptable salt according to any of claims 1 to 5 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of acute or chronic inflammatory diseases.
12. Use of a compound or pharmaceutically acceptable salt according to any of claims 1 to 5 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of acute or chronic inflammatory diseases of peripheral organs or the central nervous system.
13. Use of a compound or pharmaceutically acceptable salt according to any of claims 1 to 5 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of sepsis, septic shock, systemic inflammatory response syndrome, hemorrhagic shock and shock states induced by cytokine therapy.
14. Use of a compound or pharmaceutically acceptable salt according to any of claims 1 to 5 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of asthma, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, allergic rhinitis, cardiomyopathy and myocarditis.
15. Method of treating or preventing a disease in a mammal in need thereof comprising administering a therapeutically effective amount of at least one of the compounds and pharmaceutically acceptable salts according to any of claims 1 to 5.
16. Method of treating or preventing an acute or chronic inflammatory disease in a mammal in need thereof comprising administering a therapeutically effective amount of at least one of the compounds and pharmaceutically acceptable salts according to any of claims 1 to 5.
17. Method of treating or preventing sepsis, septic shock, systemic inflammatory response syndrome, hemorrhagic shock, shock states induced by cytokine therapy, asthma, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, allergic rhinitis, cardiomyopathy or myocarditis in a mammal in need thereof comprising administering a therapeutically effective amount of at least one of the compounds and pharmaceutically acceptable salts according to any of claims 1 to 5.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05109256 | 2005-10-05 | ||
| EP05109256.7 | 2005-10-05 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110194744A (en) * | 2018-02-26 | 2019-09-03 | 云南大学 | A kind of compound and its preparation method and application for inhibiting beta-amyloid protein to generate |
| CN110194743A (en) * | 2018-02-26 | 2019-09-03 | 云南大学 | Phenyl (3- methoxyl group -4- (4- methyl-1 H-imidazole-1-group) phenyl) first ketone compounds |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037079A1 (en) * | 1997-02-19 | 1998-08-27 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as nos inhibitors |
-
2006
- 2006-09-29 WO PCT/EP2006/066923 patent/WO2007039581A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037079A1 (en) * | 1997-02-19 | 1998-08-27 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as nos inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| MCMILLAN K ET AL: "Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 15 FEB 2000, vol. 97, no. 4, 15 February 2000 (2000-02-15), pages 1506 - 1511, XP002361624, ISSN: 0027-8424 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110194744A (en) * | 2018-02-26 | 2019-09-03 | 云南大学 | A kind of compound and its preparation method and application for inhibiting beta-amyloid protein to generate |
| CN110194743A (en) * | 2018-02-26 | 2019-09-03 | 云南大学 | Phenyl (3- methoxyl group -4- (4- methyl-1 H-imidazole-1-group) phenyl) first ketone compounds |
| CN110194744B (en) * | 2018-02-26 | 2022-11-11 | 云南大学 | Compound for inhibiting beta-amyloid protein generation and preparation method and application thereof |
| CN110194743B (en) * | 2018-02-26 | 2022-11-11 | 云南大学 | Phenyl (3-methoxy-4- (4-methyl-1H-imidazole-1-yl) phenyl) ketone compound |
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