WO2007045622A1

WO2007045622A1 - Oxazolo [4 , 5-b] pyridine compounds as nitric oxide synthase inhibitors

Info

Publication number: WO2007045622A1
Application number: PCT/EP2006/067413
Authority: WO
Inventors: Thomas Martin; Wolf-Rüdiger Ulrich; Thomas Fuchss; Rainer Boer; Christian Hesslinger; Andreas Strub; Manfrid Eltze; Martin Lehner
Original assignee: Nycomed Gmbh
Priority date: 2005-10-18
Filing date: 2006-10-16
Publication date: 2007-04-26

Abstract

The compounds of formula (I) in which R1, R2, R3 and R4 have the meanings as given in the description, and the salts, N-oxides and salts of the N-oxide thereof are novel effective inhibitors of the inducible nitric oxide synthase.

Description

OXAZOLO [4, 5-B] PYRIDINE COMPOUNDS AS NITRIC OXIDE SYNTHASE INHIBITORS

Field of application of the invention

The invention relates to oxazolo[4,5-b]pyridine compounds, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.

Known technical background

WO 2005/030770 and WO 2005/030771 relate to imidazopyridines which are inhibitors of the inducible NO-snthase.

Description of the invention

It has now been found that the oxazolo[4,5-b]pyridine compounds, which are described in greater details below, have surprising and particularly advantageous properties.

The invention relates to compounds of formula (I)

in which

R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-

1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, and -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, phenyl, benzyl, =0, -C(O)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy;

R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy;

R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy; the salts, N-oxides and salts of the N-oxides thereof.

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.

Hydroxy- 1-4C-alkyl is a straight-chain alkyl group having 1 to 4 carbon atoms containing a terminal hydroxy group, such as hydroxy-n-butyl (-CH₂-CH₂-CH₂-CH₂-OH), hydroxy-n-propyl (-CH₂-CH₂-CH₂-OH), hydroxyethyl (-CH₂-CH₂-OH) and hydroxymethyl (-CH₂-OH), of which hydroxyethyl (-CH₂-CH₂-OH) is preferred.

1-4C-Alkoxy is a group which, in addition to the oxygen atom, contains a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Alkoxy groups having 1 to 4 carbon atoms include the n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-propoxy, iso-propoxy, ethoxy and methoxy group. As regards substituent R2, the 1-4C-alkoxy group is preferably selected from methoxy and ethoxy, more preferably R2 is methoxy.

Halogen includes fluorine, chlorine, bromine and iodine.

Examples of the group -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl include, but are not limited to, the groups -NH₂, -NHCH₃, -N(CH₃)₂, -NH(C₂H₅) and -N(C₂H₅)₂.

In the phenyl group substituted by one substituent, wherein said substituent is selected from 1-4C- alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, said substituent may be bonded to the phenyl ring in any position, i.e., in ortho, meta or para position. Ortho and para positions are preferred. Specific examples of the phenyl group substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C- alkyl, include, but are not limited to, methylphenyl, ethylphenyl, n-butylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl, aminophenyl and dimethylaminophenyl. The phenyl group substituted by one substituent includes preferably 4-methylphenyl, 2-methoxyphenyl, 4- dimethylaminophenyl and 4-chlorophenyl. Specific examples of R1 representing -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, include, but are not limited to, groups -NR10R11 with R10 and R11 being independently selected from hydrogen, methyl, hydroxyethyl, cyclohexyl, benzyl, phenyl and phenyl substituted by one substituent, wherein said substituent is selected from methyl, methoxy, chlorine and N,N-dimethylamino.

In a preferred embodiment, R1 is selected from an amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-(2-hydroxyethyl)amino, N,N-(di-2-hydroxyethyl)amino, N-cyclohexylamino, N-benzylamino, N-phenylamino, N-(4-methylphenyl)amino, N-(2-methoxyphenyl)amino, N-[4-(N,N-dimethylamino)-phenyl]amino and N-(4-chlorophenyl)amino group.

Examples of the 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen include, but are not limited to, 3- to 7-membered monocyclic saturated heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, 3- to 7-membered monocyclic aromatic heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, 8- to 12-membered bicyclic saturated heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, and 8- to 12-membered bicyclic partially aromatic heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen.

The term "bicyclic partially aromatic heterocyclic group" means any bicyclic group, wherein one aromatic ring and one non-aromatic ring are present. Non-limiting examples are indolin-1-yl, 1 ,2,3,4- tetrahydroisoquinolin-1-yl and 1 ,2,3,4-tetrahydroquinolin-1-yl.

Among the 3- to 7-membered monocyclic saturated heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, 3- to 7-membered monocyclic saturated heterocyclic groups comprising totally 1 or 2 heteroatoms selected from nitrogen and oxygen are preferred. Of these, 3- to 7-membered monocyclic saturated heterocyclic groups comprising one nitrogen atom, 3- to 7-membered monocyclic saturated heterocyclic groups comprising two nitrogen atoms and 3- to 7- membered monocyclic saturated heterocyclic groups comprising one nitrogen atom and one oxygen atom are preferred. Especially preferred are 4- to 7-membered monocyclic saturated heterocyclic groups comprising one nitrogen atom, 5- to 7-membered monocyclic saturated heterocyclic groups comprising two nitrogen atoms and 5- to 7-membered monocyclic saturated heterocyclic groups comprising one nitrogen atom and one oxygen atom. Specific examples of the 4- to 7-membered monocyclic saturated heterocyclic groups comprising one nitrogen atom include, but are not limited to, azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl and azepan-1- yl. Specific examples of the 5- to 7-membered monocyclic saturated heterocyclic groups comprising two nitrogen atoms include, but are not limited to, imidazolidin-1-yl, piperazin-1-yl and diazepan-1-yl. Specific examples of the 5- to 7-membered monocyclic saturated heterocyclic groups comprising one nitrogen atom and one oxygen atom include, but are not limited to, oxazolidin-3-yl, morpholin-4-yl and oxazepan-4-yl. Especially preferred are azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, diazepan-1-yl and morpholin-4-yl.

Among the 3- to 7-membered monocyclic aromatic heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, 5- to 6-membered monocyclic aromatic heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen are preferred. Of these, 5- to 6-membered monocyclic aromatic heterocyclic groups comprising one nitrogen atom, 5- to 6-membered monocyclic aromatic heterocyclic groups comprising two nitrogen atoms and 5-membered monocyclic aromatic heterocyclic groups comprising one nitrogen atom and one oxygen atom are preferred.

Specific examples of the 5- to 6-membered monocyclic aromatic heterocyclic groups comprising one nitrogen atom include pyrrol-1-yl and pyridin-1-yl. Specific examples of the 5- to 6-membered monocyclic aromatic heterocyclic groups comprising two nitrogen atoms include, but are not limited to, pyrazol-1-yl, imidazol-1-yl, pyrazin-1-yl and pyrimidin-1-yl. A specific example of the 5-membered monocyclic aromatic heterocyclic groups comprising one nitrogen atom and one oxygen atom is e.g. oxazol-3-yl. Especially preferred is pyrrol-1-yl.

Among the 8- to 12-membered bicyclic saturated heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, 8- to 12-membered bicyclic saturated spiro groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen are preferred. Of these, 10- membered spiro groups comprising one 6-membered ring and one 5-membered ring which are bonded through a common carbon atom and comprise totally 1 to 3 heteroatoms selected from nitrogen and oxygen are preferred. A specific non-limiting example is 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl.

Among the 8- to 12-membered bicyclic partially aromatic heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, 8- to 12-membered bicyclic partially aromatic heterocyclic groups comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, wherein the two rings are anellated and one ring is aromatic while the other is saturated are preferred. Specific examples include, but are not limited to, indolin-1-yl, 1 ,2,3,4-tetrahydroisoquinolin-1-yl and 1 ,2,3,4- tetrahydroquinolin-1-yl. Of these, 1 ,2,3,4-tetrahydroisoquinolin-1-yl is preferred. The 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen is optionally substituted by one substituent selected from the substituents mentioned above. Specifically, said heterocyclic group can be substituted by said substituent in any position. Preferably, said substituent is bonded in 3-position, 4- position or 5-position with reference to the nitrogen atom bonded to the sulfur atom.

1-4C-Alkoxy-1-4C-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms containing a terminal straight chain or branched alkoxy group. Examples thereof include, but are not limited to, a methoxy-n-butyl (-CH₂-CH₂-CH₂-CH₂-O-CH₃), methoxy-n-propyl (-CH₂-CH₂-CH₂-O-CH₃), methoxy-iso-propyl (e.g. -CH₂-CH(CH₃)-O-CH₃ and -CH(CH₃)-CH₂-O-CH₃), methoxyethyl (e.g. -CH₂-CH₂-O-CH₃ and -CH(CH₃)-O-CH₃), methoxymethyl (-CH₂-O-CH₃), ethoxy-n-butyl (e.g. -CH₂-CH₂- CH₂-CH₂-O-CH₂-CH₃), ethoxy-n-propyl (e.g. -CH₂-CH₂-CH₂-O-CH₂-CH₃), ethoxyethyl (e.g. -CH₂-CH₂- 0-CH₂-CH₃), ethoxymethyl (-CH₂-O-CH₂-CH₃) and tert-butoxymethyl (-CH₂-O-C(CH₃)₂-CH₃) group. The -CH₂-CH₂-O-CH₃ group is preferred.

Specific examples of the group -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl include, but are not limited to, -C(O)CH₃, -C(O)CH₂CH₃, -C(O)CH₂CH₂CH₃, -C(O)CH₂CH₂CH₂CH₃ and -C(O)C₆H₅. Of these, -C(O)CH₃ and -C(O)C₆H₅ are preferred.

The phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano can be substituted by said substituents in any position, i.e., in ortho, meta and/or para position. Preferably, the phenyl moiety is substituted by one or two substituents. If one substituent is present, it is preferably present in para position. If two substituents are present, preferably one substituent is located in ortho position while the second substituent is located in para position or, alternatively, either substituents are located in meta position. Specifically preferred substituted phenyl groups include, but are not limited to, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dichlorophenyl and 4-cyanophenyl.

Specific examples of the substituents bonded to the 3- to 7-membered monocyclic or 8- to 12- membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen include, but are not limited to, methyl, ethyl, methoxy, ethoxy, methoxyethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, phenyl, benzyl, =0, methylphenyl, dimethylphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, and -C(O)RI 6 with R16 being methyl, ethyl or phenyl. Of these, methyl, methoxy, methoxyethyl, phenyl, benzyl, =0, 4-methylphenyl, 2,4-dimethylphenyl, 3,5- dichlorophenyl, 4-cyanophenyl, -C(O)RI 6 with R16 being methyl and -C(O)RI 6 with R16 being phenyl are preferred. 1-4C-Fluoroalkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, wherein one ore more hydrogen atoms are replaced by fluorine atoms. In particular, one hydrogen atom to three hydrogen atoms, if present, bonded to one carbon atom can be replaced by fluorine atoms. Non- limiting examples include trifluoromethyl, difluoromethyl, fluoromethyl, perfluoroethyl, 1 ,1 ,1 -trifl uoro-2- fluoroethyl, 1 ,1 ,1 -trifl uoroethyl , 1 ,1-difluoro-2,2-difluoroethyl, 1 ,1-difluoro-2-fluoroethyl, 1 ,1-difluoroethyl, 1-fluoro-2,2-difluoroethyl, 1-fluoro-2-fluoroethyl, 1 -fluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl and perfluoro-n-butyl.

Completely or predominantly fluorine-substituted 1-4C-alkoxy is a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, wherein more than half of the hydrogen atoms are replaced by fluorine atoms. Non-limiting examples are the 2,2,3,3,3-pentafluoro-n-propoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifl uoromethoxy and the difl uoromethoxy group, of which the difluoromethoxy group is preferred.

The -SO₂-RI moiety of formula (I) can be bonded to the phenyl moiety in any position, i.e., in ortho, meta or para position. Preferably, the -SO₂-RI moiety is bonded to the phenyl moiety in para position. Thus, the present invention preferably relates to compounds of formula (II)

in which

R1 is selected from

-NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy- 1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent selected from

1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, and

-NR10R1 1 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-

1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy;

In a further preferred embodiment, the present invention relates to compounds represented by formula (III)

in which

R1 is selected from

-NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy- 1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, and

-NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-

1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; the salts, N-oxides and salts of the N-oxides thereof.

A further preferred embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, R2 is 1-4C-alkoxy;

R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (II), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl,

R2 is 1-4C-alkoxy; R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy; R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen,

1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and

-NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, R2 is 1-4C-alkoxy; R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy; R4 is hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (II), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, R2 is 1-4C-alkoxy; R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy; R4 is hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from -NR10R11 with R10 and R1 1 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl;

R2 is 1-4C-alkoxy; R3 is hydrogen;

A further preferred embodiment of the present invention relates to a compound of formula (II), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl;

R2 is 1-4C-alkoxy; R3 is hydrogen;

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl;

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from -NR10R1 1 with R10 and R11 being independently selected from hydrogen, methyl, hydroxyethyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from methyl, methoxy, chlorine and -N(CH₃)₂; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, methyl, hydroxyethyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from methyl, methoxy, chlorine and -N(CH₃)₂; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from an amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-(2-hydroxyethyl)amino, N,N-(di-2-hydroxyethyl)amino, N-cydohexylamino, N-benzylamino, N-phenylamino, N-(4-methylphenyl)amino, N-(2-methoxyphenyl)amino, N-[4-(N,N- dimethylamino)-phenyl]amino and N-(4-chlorophenyl)amino group; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from an amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-(2-hydroxyethyl)amino, N,N-(di-2-hydroxyethyl)amino, N-cydohexylamino, N-benzylamino,

N-phenylamino, N-(4-methylphenyl)amino, N-(2-methoxyphenyl)amino, N-[4-(N,N- dimethylamino)-phenyl]amino and N-(4-chlorophenyl)amino group; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (I), in which

R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy,

1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(O)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is methoxy; R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy;

R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof. A further preferred embodiment of the present invention relates to a compound of formula (II), in which

R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy;

1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy;

R4 is hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; R3 is selected from hydrogen, halogen, 1-4C-alkyl, 1-4C-fluoroalkyl, 1-4C-alkoxy and completely or predominantly fluorine-substituted 1-4C-alkoxy; R4 is hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (II), in which

R4 is hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (II), in which R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy;

R4 is hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1 -4C-al koxy- 1 -4C-alkyl , phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; R3 is hydrogen;

A further preferred embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; R3 is hydrogen;

R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy;

R3 is hydrogen;

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 3- to 7-membered monocyclic saturated heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, a 3- to 7- membered monocyclic aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, a 8- to 12-membered bicyclic saturated heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, and a 8- to 12- membered bicyclic partially aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 3- to 7-membered monocyclic saturated heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, a 3- to 7- membered monocyclic aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, a 8- to 12-membered bicyclic saturated heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, and a 8- to 12- membered bicyclic partially aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to compounds of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic saturated heterocyclic group comprising totally

1 or 2 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

1 or 2 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 5- to 6-membered monocyclic aromatic heterocyclic group comprising totally

1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(O)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 5- to 6-membered monocyclic aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 8- to 12-membered bicyclic saturated spiro ring system comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said ring system being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 8- to 12-membered bicyclic partially aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, wherein two rings are anellated and one ring is aromatic while the other is saturated, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 8- to 12-membered bicyclic partially aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, wherein two rings are anellated and one ring is aromatic while the other is saturated, said group being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 3- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom, a 3- to 7-membered monocyclic saturated heterocyclic group comprising two nitrogen atoms and a 3- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom and one oxygen atom, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 3- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom, a 3- to 7-membered monocyclic saturated heterocyclic group comprising two nitrogen atoms and a 3- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom and one oxygen atom, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(O)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 4- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom, a 5- to 7-membered monocyclic saturated heterocyclic group comprising two nitrogen atoms and a 5- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom and one oxygen atom, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 4- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom, a 5- to 7-membered monocyclic saturated heterocyclic group comprising two nitrogen atoms and a 5- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom and one oxygen atom, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, azepan-1-yl, imidazolidin-1-yl, piperazin-1-yl, diazepan-1-yl, oxazolidin-3-yl, morpholin-4-yl and oxazepan-4-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from

1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C- alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, azepan-1-yl, imidazolidin-1-yl, piperazin-1-yl, diazepan-1-yl, oxazolidin-3-yl, morpholin-4-yl and oxazepan-4-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C- alkyl, halogen and cyano;

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 5- to 6-membered monocyclic aromatic heterocyclic group comprising one nitrogen atom, a 5- to 6-membered monocyclic aromatic heterocyclic group comprising two nitrogen atoms and a 5-membered monocyclic aromatic heterocyclic group comprising one nitrogen atom and one oxygen atom, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 5- to 6-membered monocyclic aromatic heterocyclic group comprising one nitrogen atom, a 5- to 6-membered monocyclic aromatic heterocyclic group comprising two nitrogen atoms and a 5-membered monocyclic aromatic heterocyclic group comprising one nitrogen atom and one oxygen atom, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from a pyrrol-1-yl, pyridin-1-yl, pyrazol-1-yl, imidazol-1-yl, pyrazin-1-yl, pyrimidin-1-yl and oxazol-3-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from a pyrrol-1-yl, pyridin-1-yl, pyrazol-1-yl, imidazol-1-yl, pyrazin-1-yl, pyrimidin-1-yl and oxazol-3-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 10-membered spiro ring system comprising one 6-membered ring and one 5- membered ring which are bonded through a common carbon atom and comprise totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said ring system being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl,

=0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 10-membered spiro ring system comprising one 6-membered ring and one 5- membered ring which are bonded through a common carbon atom and comprise totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said ring system being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an indolin-1-yl, 1 ,2,3,4-tetrahydroisoquinolin-1-yl and 1 ,2,3,4-tetrahydroquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, piperazin-1- yl, 1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4- tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, piperazin-1- yl, 1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4- tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(O)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, piperazin-1- yl, 1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4- tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from methyl, methoxy, methoxyethyl, phenyl, benzyl, =0, -C(O)RI 6 with R16 being selected from methyl and phenyl, and phenyl substituted by one or two substituents selected from methyl, chlorine and cyano;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, piperazin-1- yl, 1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4- tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from methyl, methoxy, methoxyethyl, phenyl, benzyl, =0, -C(O)RI 6 with R16 being selected from methyl and phenyl, and phenyl substituted by one or two substituents selected from methyl, chlorine and cyano; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, piperazin-1- yl, 1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4- tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from methyl, methoxy, methoxyethyl, phenyl, benzyl, =0, -C(O)RI 6 with R16 being methyl,

-C(O)RI 6 with R16 being phenyl, methylphenyl, dimethylphenyl, dichlorophenyl and cyanophenyl; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, piperazin-1- yl, 1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4- tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from methyl, methoxy, methoxyethyl, phenyl, benzyl, =0, -C(0)R16 with R16 being methyl, -C(O)RI 6 with R16 being phenyl, methylphenyl, dimethylphenyl, dichlorophenyl and cyanophenyl;

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, A- methylpiperidin-1-yl, 4-benzoylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, A- methoxyethylpiperazin-1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 4-acetylpiperazin-1- yl, 4-(4-methylphenyl)-piperazin-1-yl, 4-(2,4-dimethylphenyl)-piperazin-1-yl, 4-(3,5- dichlorophenyl)-piperazin-1-yl, 4-(4-cyanophenyl)-piperazin-1-yl, 1 ,4-diazepan-1-yl, 4-methyl-1 ,4- diazepan-1-yl, 5-oxo-1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 3-methylpyrrol-1-yl, 1 ,4- dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4-tetrahydroisoquinolin-1-yl; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrol id in-1-yl, piperidin-1-yl, A- methylpiperidin-1-yl, 4-benzoylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, A- methoxyethyl piperazin-1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 4-acetylpiperazin-1- yl, 4-(4-methylphenyl)-piperazin-1-yl, 4-(2,4-dimethylphenyl)-piperazin-1-yl, 4-(3,5- dichlorophenyl)-piperazin-1-yl, 4-(4-cyanophenyl)-piperazin-1-yl, 1 ,4-diazepan-1-yl, 4-methyl-1 ,A- diazepan-1-yl, 5-oxo-1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 3-methylpyrrol-1-yl, 1 ,4- dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4-tetrahydroisoquinolin-1-yl; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, methyl and phenyl, and -NR10R1 1 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl ring and a pyrrolidin-1- yl, said pyrrolidin-1-yl ring being optionally substituted by a methyl; R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

A further preferred embodiment of the present invention relates to a compound of formula (III), in which R1 is selected from -NR10R11 with R10 and R11 being independently selected from hydrogen, methyl and phenyl, and -NR10R1 1 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl ring and a pyrrolidin-1- yl, said pyrrolidin-1-yl ring being optionally substituted by a methyl; R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

R1 is selected from -NH(C₆H₅), -N(CH₃)₂, azetidin-1-yl, pyrrol-1-yl and 3-methylpyrrol-1-yl;

R2 is 1-4C-alkoxy; a salt, N-oxide or salt of an N-oxide thereof.

R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

Salts of the compounds according to the present invention include all acid addition salts and all salts with bases, specifically all pharmacologically acceptable inorganic and organic acid addition salts and salts with bases, more specifically all pharmacologically 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.

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 N-oxide denotes the N-oxide on the pyridine moiety which is substituted by R2.

The present invention further relates to compounds of formula (IV) shown below, which are intermediates in the process of producing the compounds of formula (I) according to the present invention as described hereinafter.

The compounds according to the present invention represented by formulas (I), (II) and (III) given above 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.

In general, a compound of formula (V)

in which

R2 and R4 are as defined above; and

Y is halogen;

is reacted with a compound of formula (Vl)

in which

R1 and R3 are as defined above; and X is halogen;

to give a compound of formula (IV)

in which R1 , R2, R3 and R4 have the meanings indicated above;

said compound (IV) being subsequently subjected to a hydrogenation reaction yielding a compound of formula (I)

in which R1 , R2, R3 and R4 have the meanings indicated above.

Above reaction of compounds (V) and (Vl) is preferably a two-step process, the first step thereof comprises reacting compound (Vl) with a boron compound, preferably a diboron compound, in the presence of a transition metal compound, preferably a palladium compound; and the second step thereof comprises reacting the product obtained in the first step with compound (V) in the presence of a transition metal compound, e.g. a nickel or palladium compound.

As the hydrogenation reaction mentioned above, any hydrogenation suitable for converting an ethenylene moiety into an ethylene moiety may be used. A hydrogenation in the presence of palladium on activated carbon is preferred.

X and Y in above formulas (V) and (Vl) are preferably independently selected from bromine and iodine, with bromine being most preferred.

In a preferred embodiment, starting compound (V) can be prepared, for example, as shown in scheme 1 below:

Scheme 1

Compound (XII), which is commercially available, can be used as starting material. Compound (Xl) can be prepared from said compound (XII) for example in accordance with J. Med. Chem. 1993, 36(4), 497-503 or in analogy thereto. Reaction of compound (Xl) e.g. according to Heterocydes 2001 , 55(7), 1329-1346 or in analogy thereto yields compound (X). As halogen, preferably bromine or iodine are present. Bromine is specifically preferred. Upon reaction of compound (X) e.g. in accordance with Heterocydes 2001 , 55(7), 1329-1346 or in analogy thereto, compound (IX) may be obtained. Then, for example, reaction of compound (IX) with p-toluenesulfonic acid monohydrate in triethyl orthoacetate ((C₂H₅O)₃CCH₃) at a temperature of from 100 to 15O⁰C for 0.5 to 2 h gives compound (VIII). Compound (V) may be obtained e.g. by reacting compound (VIII) with compound (VII), which is commercially available or can be prepared by methods known to a person skilled in the art, in an organic solvent (e.g. tert-butanol and tetrahydrofuran) at a temperature of from -20 to -7O⁰C, followed by addition of K- tert-butylate in an organic solvent (e.g. tetrahydrofuran).

Compound (Vl) is commercially available or can be prepared by methods known to a person skilled in the art, e.g. as described in J. Med. Chem. 2004, 47(21 ), 4979-4982; Chem. Ber. 1875, 8, 595; Synlett 1997, 4, 375-377; and WO 2005/030770; or in analogy thereto. Additionally, compound (Vl) can be prepared as follows: Compound R1 H is added to a mixture of sodium hydride in absolute tetrahydrofuran. After stirring at room temperature for 20 to 40 min, a solution of halobenzenesulfochloride in absolute tetrahydrofuran is dropped to the reaction mixture. The solution is stirred again for 20 to 40 min at room temperature to obtain compound (Vl). As mentioned above, the final compounds according to the present invention can be prepared, for example, as shown in scheme 2 below:

Scheme 2

In a preferred embodiment, compound (Vl) can be reacted in a first step with e.g. bis(pinacolato)- diboron in the presence of a palladium compound, for example PdCI₂(dppf)xCH₂Cl₂, PdCI₂ in admixture with 1 ,1'-bis(diphenylphosphino)ferrocene (dppf), or PdCI₂(dppf)xCH₂CI₂ in admixture with

1 ,1'-bis(diphenylphosphino)ferrocene, and an alkali acetate, e.g. sodium or potassium acetate, in an organic solvent. Examples of the solvent, which may be used, include alcohols (e.g. methanol, ethanol), toluene, benzene, N,N-dimethylformamide or ethereals (e.g. dimethoxyethane, dioxane) and mixtures thereof. The reaction is preferably conducted at a temperature in the range of from 120 to 18O⁰C for 30 to 60 min to give a boronic acid ester, which can be isolated or, preferably, is generated in situ and is used in the subsequent second reaction step without isolation. In a second step, preferably a Suzuki reaction is used to couple compound (V) to the boronic acid ester of compound (Vl), thus, obtaining compound (IV). Said reaction can be carried out in an organic solvent, for example an alcohol (e.g. methanol, ethanol), toluene, benzene, N,N-dimethylformamide or ethereal (e.g. dimethoxyethane, dioxane) or in a mixture thereof, or preferably in a mixture comprising an organic solvent (e.g. dioxane) and water, with an organic (e.g. triethylamine) or preferably inorganic base (e.g. potassium hydroxide, thallium hydroxide, sodium bicarbonate, caesium carbonate, caesium fluoride, sodium carbonate, potassium carbonate and mixtures thereof) in the presence of a transition metal catalyst, for example, a nickel or palladium catalyst (e.g. Pd(O(O)CCH₃)₂, PdCI₂(PPh₃)₂, Pd(PPh₃)₄ or PdCI₂(PcHeX)₃, with PPh₃ representing a triphenylphosphine ligand and PcHex representing a tricydohexylphosphine ligand) and, optionally, lithium chloride. The reaction is carried out at a temperature in the range from 20° to 16O⁰C, usually 60° to 14O⁰C for 10 min to 5 days, usually 30 minutes to 24 h. Advantageously, the solvents used are degassed and the reaction is carried out under protective gas.

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.

Compound (IV) is converted into final compound (I) preferably by hydrogenation over palladium on activated carbon (Pd/C) in an organic solvent, such as an alcohol (e.g. methanol or ethanol), for 30 min to 4 h at a temperature in the range of from 30 to 6O⁰C.

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.

The compounds of formulas (I), (II) and (III) according to the present invention can be converted into their N-oxides, for example with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxybenzoic acid in dichloromethane. The person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.

Salts of the compounds of formula (I), (II) and (III) 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, pharmacologically 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 pharmacologically acceptable salts by processes known to the person skilled in the art.

The person skilled in the art knows on the basis of his/her knowledge and on the basis of those synthesis routes, which are shown and described within the description of this invention, how to find other possible synthesis routes for compounds according to this invention. All these other possible synthesis routes are also part of this invention.

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, which are mentioned in the examples, their salts, N-oxides and salts of their N-oxides represent preferred embodiments of the present invention. Examples

Final products

The final products are prepared by the following general method:

A solution of each the compounds A5 to A9 in methanol (based on 1.0 mmol of the compound, 300 ml solvent is used) is hydrogenated over palladium on carbon (based on 1.0 mmol of the compound, 0.35 g of palladium on carbon (containing 10 wt% palladium) is used) until the starting material has disappeared (as can be determined by thin layer chromatography). Then, the catalyst is filtered off, and the solvent is removed in vacuo.

Example 1 : 6-[4-(N,N-Dimethylamino-1-sulfonyl)-phenyl]-2-[2-(4-methoxy-pyridin-2-yl)-ethyl]- oxazolo[4,5-b]pyridine

Compound A5 (0.15 g, 0.33 mmol) is reacted by the general method for 2.5 h at 4O⁰C. The title compound (0.14 g) is isolated as slightly grey crystals of m.p. 185-187⁰C.

Example 2: 6-[4-(Azetidine-1-sulfonyl)-phenyl]-2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-oxazolo[4,5- b]pyridine

Compound A6 (0.34 g, 0.75 mmol) is reacted by the general method for 3 h at 45⁰C. The title compound (0.14 g) is isolated after silica gel chromatography [CH₂CI₂ZCH₃OH (97/3 parts by volume)] as colorless crystals of m.p. 189.1⁰C.

Example 3: 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-6-[4-(pyrrole-1-sulfonyl)-phenyl]-oxazolo[4,5-b]pyridine

Compound A7 (0.19 g, 0.41 mmol) is reacted by the general method for 2 h at 45⁰C. The title compound (0.14 g) is isolated as colorless crystals of m.p. 179.5⁰C.

Example 4: 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-6-[4-(3-methyl-pyrrole-1-sulfonyl)-phenyl]-oxazolo[4,5- b]pyridine

Compound A8 (0.23 g, 0.48 mmol) is reacted by the general method for 45 min at 5O⁰C. The title compound (0.11 g) is isolated after silica gel chromatography [CH₂CI₂/ CH₃OH (98/2 parts by volume)] as colorless crystals of m.p. 155.2⁰C. Example 5: 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-6-[4-(N-phenylamino-1-sulfonyl)-phenyl]-oxazolo[4,5- b]pyridine

Compound A9 (0.24 g, 0.49 mmol) is reacted by the general method for 1.5 h at 45⁰C. The title compound (0.14 g) is isolated after silica gel chromatography [CH₂CI₂/ CH₃OH (98/2 parts by volume)] as colorless crystals of m. p. 194.8⁰C.

Starting materials:

Example A1 : 6-Bromo-2-methyl-oxazolo[4,5-b]pyridine

A solution of 20 g (106 mmol) 2-amino-6-bromo-3-hydroxy-pyridine and 0.05 g p-toluenesulfonic acid monohydrate in 22 ml triethyl orthoacetate is stirred at 13O⁰C for 1 h. After cooling to room temperature the reaction solution is diluted with ethyl acetate (150 ml) and extracted with water (3 x 150 ml). The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by crystallization from ethanol affords the title compound (19 g) as yellow-orange crystals. The mass spectrum shows the molecular peak MH⁺ at 213.2 and 215.2 Da.

Example A2: 6-Bromo-2-[2-(4-methoxy-pyridin-2-yl)-vinyl]-oxazolo[4,5-b]pyridine

A stirred solution of 1.46 g (10.6 mmol) 4-methoxy-pyridine-2-aldehyde and 6.0 g (28.3 mmol) 6- bromo-2-methyl-oxazolo[4,5-b]pyridine (starting compound A1 ) in 2.8 ml tert-butanol and 11 ml absolute tetrahydrofuran is cooled to -5O⁰C. A solution of 1.55 g K-tert-butylate in 10 ml absolute tetrahydrofuran is slowly added to the reaction solution under stirring. After further stirring for 1 h, the reaction mixture is warmed to room temperature. For workup, the mixture is poured into a saturated aqueous NaHCO₃ solution and then extracted three times with ethyl acetate. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [petrol ether/ethyl acetate (1/1 parts by volume)] affords the title compound (1.0 g) as yellow crystals of m.p. 159.8⁰C.

Example A3: 1-(4-Bromo-benzenesulfonyl)-1 H-pyrrole

To a stirred mixture of 235 mg (5.9 mmol) sodium hydride (60 wt%) in 10 ml absolute tetrahydrofuran 0.27 ml (3.9 mmol) pyrrole is slowly added. After stirring at room temperature for 30 min a solution of 1.0 g (3.9 mmol) 4-bromobenzenesulfochloride in 10 ml absolute tetrahydrofuran is dropped to the reaction mixture. The solution is stirred again for 30 min at room temperature. For workup, 25 ml water is slowly added and the mixture is then extracted three times with ethyl acetate. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [petrol ether/ethyl acetate (9/1 parts by volume)] affords the title compound (1.1 g) as colourless crystals. The mass spectrum shows the molecular peak [M⁺] at 286.9 Da.

Example A4: 1-(4-Bromo-benzenesulfonyl)-3-methyl-1H-pyrrole

To a stirred mixture of 370 mg (9.25 mmol) sodium hydride (60 wt%) in 10 ml absolute tetrahydrofuran 500 mg (6.2 mmol) 3-methylpyrrole is slowly added. After stirring at room temperature for 30 min a solution of 1.58 g (6.2 mmol) 4-bromobenzenesulfochloride in 13 ml absolute tetrahydrofuran is dropped to the reaction mixture. The solution is stirred again for 30 min at room temperature. For workup, 25 ml water is slowly added and the mixture is then extracted three times with ethyl acetate. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by crystallization with ethanol/ petrol ether affords the title compound (1.1 g) as colourless crystals. The mass spectrum shows the molecular peak [M-H⁺]^" at 221.0 and 219.0 Da.

Example A5: 6-[4-(N,N-Dimethylamino-1-sulfonyl)-phenyl]-2-[2-(4-methoxy-pyridin-2-yl)-vinyl]- oxazolo[4,5-b]pyridine

A stirred mixture of 0.13 g (0.50 mmol) 4-bromo-benzenedimethylsulfonarnide, 0.14 g (0.55 mmol) bis(pinacolato)-diboron, 8.3 mg (0.015 mmol) 1 ,1'-bis(diphenylphosphino)ferrocene (dppf), 11 mg (0.015 mmol) PdCI₂(dppf)xCH₂CI₂ and 0.15 g (1.50 mmol) potassium acetate in 3 ml absolute dioxane is heated to 16O⁰C for 40 min with a microwave equipment. After cooling to room temperature 0.11 g (0.33 mmol) 6-bromo-2-[2-(4-methoxy-pyridin-2-yl)-vinyl]-oxazolo[4,5-b]pyridine (starting compound A2), 15.0 mg (0.02 mmol) PdCI₂(PcHeX)₃ and 1 ml of a 2 N aqueous Na₂CO₃ solution are added to the reaction mixture. The suspension is heated again with a microwave equipment to 14O⁰C for 20 min. For workup, the mixture is poured into 100 ml water and then extracted three times with CH₂CI₂. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [CH₂CI₂/CH₃OH (98/2 parts by volume)] affords the title compound (0.17 g) as yellow crystals. The mass spectrum shows the molecular peak MH⁺ at 437.2 Da.

Example A6: 6-[4-(Azetidine-1-sulfonyl)-phenyl]-2-[2-(4-methoxy-pyridin-2-yl)-vinyl]-oxazolo[4,5- b]pyridine

A stirred mixture of 0.14 g (0.50 mmol) 1-(4-bromo-benzenesulfonyl)-azetidine, 0.14 g (0.55 mmol) bis(pinacolato)-diboron, 8.3 mg (0.015 mmol) 1 ,1'-bis(diphenylphosphino)ferrocene (dppf), 11 mg (0.015 mmol) PdCI₂(dppf)xCH₂CI₂ and 0.15 g (1.50 mmol) potassium acetate in 3 ml absolute dioxane is heated to 16O⁰C for 40 min with a microwave equipment. After cooling to room temperature 0.11 g (0.33 mmol) 6-bromo-2-[2-(4-methoxy-pyridin-2-yl)-vinyl]-oxazolo[4,5-b]pyridine (starting compound A2), 15.0 mg (0.02 mmol) PdCI₂(PcHeX)₃ and 1 ml of a 2 N aqueous Na₂CO₃ solution are added to the reaction mixture. The suspension is heated again with a microwave equipment to 14O⁰C for 20 min. For workup, the mixture is poured into 100 ml water and then extracted three times with CH₂CI₂- The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [CH₂CI₂/CH₃OH (98/2 parts by volume)] affords the title compound (0.34 g) as yellow crystals. The mass spectrum shows the molecular peak MH⁺ at 449.2 Da.

Example A7: 2-[2-(4-Methoxy-pyridin-2-yl)-vinyl]-6-[4-(pyrrole-1-sulfonyl)-phenyl]-oxazolo[4,5-b]pyridine

A stirred mixture of 0.14 g (0.50 mmol) 1-(4-bromo-benzenesulfonyl)-1 H-pyrrole (starting compound A3), 0.14 g (0.55 mmol) bis(pinacolato)-diboron, 8.3 mg (0.015 mmol)

1 ,1'-bis(diphenylphosphino)ferrocene (dppf), 1 1 mg (0.015 mmol) PdCI₂(dppf)xCH₂CI₂ and 0.15 g (1.50 mmol) potassium acetate in 3 ml absolute dioxane is heated to 16O⁰C for 40 min with a microwave equipment. After cooling to room temperature 0.11 g (0.33 mmol) 6-bromo-2-[2-(4-methoxy-pyridin-2- yl)-vinyl]-oxazolo[4,5-b]pyridine, 15.0 mg (0.02 mmol) PdCI₂(PcHeX)₃ and 1 ml of a 2 N aqueous Na₂CO₃ solution are added to the reaction mixture. The suspension is heated again with a microwave equipment to 14O⁰C for 20 min. For workup, the mixture is poured into 100 ml water and then extracted three times with CH₂CI₂. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [CH₂CI₂/CH₃OH (98/2 parts by volume)] affords the title compound (0.20 g) as yellow crystals. The mass spectrum shows the molecular peak MH⁺ at 459.2 Da.

Example A8: 2-[2-(4-Methoxy-pyridin-2-yl)-vinyl]-6-[4-(3-methyl-pyrrole-1-sulfonyl)-phenyl]-oxazolo[4,5- b]pyridine

A stirred mixture of 0.15 g (0.50 mmol) 1-(4-bromo-benzenesulfonyl)-3-methyl-1 H-pyrrole (starting compound A4), 0.14 g (0.55 mmol) bis(pinacolato)-diboron, 8.3 mg (0.015 mmol) 1 ,1'- bis(diphenylphosphino)ferrocene (dppf), 11 mg (0.015 mmol) PdCI₂(dppf)xCH₂CI₂ and 0.15 g (1.50 mmol) potassium acetate in 3 ml absolute dioxane is heated to 16O⁰C for 40 min with a microwave equipment. After cooling to room temperature 0.11 g (0.33 mmol) 6-bromo-2-[2-(4-methoxy-pyridin-2- yl)-vinyl]-oxazolo[4,5-b]pyridine, 15.0 mg (0.02 mmol) PdCI₂(PcHeX)₃ and 1 ml of a 2 N aqueous

Na₂CO₃ solution are added to the reaction mixture. The suspension is heated again with a microwave equipment to 14O⁰C for 20 min. For workup, the mixture is poured into 100 ml water and then extracted three times with CH₂CI₂. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [CH₂CI₂/CH₃OH (98/2 parts by volume)] affords the title compound (0.24 g) as yellow crystals. The mass spectrum shows the molecular peak MH⁺ at 473.2 Da. Example A9: 2-[2-(4-Methoxy-pyridin-2-yl)-vinyl]-6-[4-(N-phenylamino-1-sulfonyl)-phenyl]-oxazolo[4,5- b]pyridine

A stirred mixture of 0.16 g (0.50 mmol) 4-bromo-N-phenyl-benzenesulfonamide, 0.14 g (0.55 mmol) bis(pinacolato)-diboron, 8.3 mg (0.015 mmol) 1 ,1'-bis(diphenylphosphino)ferrocene (dppf), 11 mg

(0.015 mmol) PdCI₂(dppf)xCH₂CI₂ and 0.15 g (1.50 mmol) potassium acetate in 3 ml absolute dioxane is heated to 16O⁰C for 40 min with a microwave equipment. After cooling to room temperature 0.11 g (0.33 mmol) 6-bromo-2-[2-(4-methoxy-pyridin-2-yl)-vinyl]-oxazolo[4,5-b]pyridine, 15.0 mg (0.02 mmol) PdCI₂(PcHeX)₃ and 1 ml of a 2 N aqueous Na₂CO₃ solution are added to the reaction mixture. The suspension is heated again with a microwave equipment to 14O⁰C for 20 min. For workup, the mixture is poured into 100 ml water and then extracted three times with CH₂CI₂. The combined organic phases are dried over MgSO₄, filtered and concentrated in vacuo. Subsequent purification by silica gel chromatography [CH₂CI₂/CH₃OH (98/2 parts by volume)] affords the title compound (0.17 g) as yellow crystals. The mass spectrum shows the molecular peak MH⁺ at 485.2 Da.

Commercial applicability

The compounds according to the present invention have valuable pharmacological 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. 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 (septic, hemorrhagic and cytokine-induced).

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 gastrointestinal 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.

Increased iNOS expression has been found in the brains of AIDS (acquired immunodeficiency syndrome) patients and it is reasonable to assume a role of iNOS 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, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the present invention can be employed in human and veterinary medicine and therapeutics, 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 and 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, 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, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the present invention can also be useful in the treatment of cancers that express nitric oxide synthase.

Accordingly, the present invention further relates to a method of treating or preventing one of the above mentioned diseases in mammals, including humans. The method is characterized in that a pharmacologically effective amount of one or more of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention is administered to the mammal.

In particular, the present invention relates to a method of treating or preventing acute inflammatory diseases or chronic inflammatory diseases, especially chronic inflammatory diseases of peripheral organs and the central nervous system, in mammals, including humans, the method being characterized in that a pharmacologically effective amount of one or more of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention is administered to the mammal.

In the above methods, one or more of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention can be used. Preferably one or two of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides are used, more preferably, one of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides 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 mammals, including humans, comprise administering to said mammal a compound of the examples according to the present invention in a pharmacologically effective amount.

The invention further relates to the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention for use in the treatment or prophylaxis of diseases, especially the diseases exemplified above. The invention also relates to the use of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention in the manufacture of a pharmaceutical composition inhibiting the inducible nitric oxide synthase.

The invention also relates to the use of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention in the manufacture of a pharmaceutical composition 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 chronic inflammatory diseases of peripheral organs and the central nervous system.

The invention furthermore relates to a pharmaceutical composition, specifically for the treatment or prophylaxis of the diseases exemplified above, which comprises one or more of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention together with one or more pharmacologically acceptable auxiliaries.

Preferably, the pharmaceutical composition comprises one or two of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention. More preferably, the pharmaceutical composition comprises one of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention.

In a particularly preferred embodiment of the present invention, the pharmaceutical composition comprises a compound of the examples according to the present invention together with one or more pharmacologically acceptable auxiliaries.

The pharmaceutical compositions can be prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to the invention (the active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries, e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as transdermal therapeutic systems (TTS)), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 99 wt% and where, by the appropriate choice of the auxiliaries, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries which are suitable for the desired pharmaceutical formulations on account of his/her knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used. The administration of the pharmaceutical compositions according to the invention may be performed in any of the generally accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous delivery are preferred.

For the treatment of diseases of the respiratory tract, the active compounds according to the invention are preferably administered by inhalation in the form of an aerosol; the aerosol particles of solid, liquid or mixed composition preferably having a diameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant-driven metered aerosols or propel lant-free administration of micronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the active compounds, the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is as right as possible for the patient. In addition to the use of adaptors (spacers, expanders) and pear- shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhaler described in European Patent Application EP 0 505 321 ), using which an optimal administration of active compound can be achieved.

For the treatment of dermatoses, the active compounds according to the invention are in particular administered in the form of those pharmaceutical compositions which are suitable for topical application. For the production of the pharmaceutical compositions, the active compounds according to the invention are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels and solutions.

The pharmaceutical compositions according to the invention are prepared by processes known per se. The dosage of the active compounds is carried out in the order of magnitude customary for iNOS inhibitors. Topical application forms (such as ointments) for the treatment of dermatoses thus contain the active compounds in a concentration of, for example, 0.1 to 99 wt%. The dose for administration by inhalation is customarily in the range of from 0.1 to 10 mg/kg per day. The customary dose in the case of oral administration is e.g. in the range of from 0.3 to 30 mg/kg per day, in case of intravenous administration e.g. in the range of from 0.3 to 30 mg/kg/h.

Bioloqical 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 inhibitors were included into the incubation mixture. IC₅₀ 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 5 as described above, have -loglC₅₀ values of more than 6.50 (mol/l).

Claims

Patent claims

Compound of formula (I)

in which

R1 is selected from

-NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy- 1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, and -NR10R1 1 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C- alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano;

R2 is 1-4C-alkoxy;

Compound according to claim 1 represented by formula (II)

a salt, N-oxide or salt of an N-oxide thereof.

Compound according to claim 1 or 2, in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 3- to 7-membered monocyclic saturated heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, a 3- to 7-membered monocyclic aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, an 8- to 12-membered bicyclic saturated heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, and an 8- to 12-membered bicyclic partially aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; a salt, N-oxide or salt of an N-oxide thereof.

Compound according to any of claims 1 to 3, in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a group selected from a 4- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom, a 5- to 7-membered monocyclic saturated heterocyclic group comprising two nitrogen atoms, a 5- to 7-membered monocyclic saturated heterocyclic group comprising one nitrogen atom and one oxygen atom, a 5- to 6-membered monocyclic aromatic heterocyclic group comprising one nitrogen atom, a 5- to 6-membered monocyclic aromatic heterocyclic group comprising two nitrogen atoms, a 5-membered monocyclic aromatic heterocyclic group comprising one nitrogen atom and one oxygen atom, an 8- to 12-membered bicyclic saturated spiro group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, and an 8- to 12-membered bicyclic partially aromatic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, wherein the two rings are anellated and one ring is aromatic while the other is saturated, said groups being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; a salt, N-oxide or salt of an N-oxide thereof.

5. Compound according to any of claims 1 to 4, in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, imidazolidin-1-yl, piperazin-1-yl, diazepan-1-yl, oxazolidin-3-yl, morpholin-4-yl, oxazepan-4-yl, pyrrol-1-yl, pyridin-1-yl, pyrazol-1- yl, imidazol-1-yl, pyrazin-1-yl, pyrimidin-1-yl, oxazol-3-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl, indolin-1-yl, 1 ,2,3,4-tetrahydroisoquinolin-1-yl and 1 ,2,3,4-tetrahydroquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from 1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; a salt, N-oxide or salt of an N-oxide thereof.

6. Compound according to any of claims 1 to 5, in which R1 is -NR10R11 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a ring selected from an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 1 ,4-diazepan-1-yl, morpholin- 4-yl, pyrrol-1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4-tetrahydroisoquinolin-1-yl ring, said rings being optionally substituted by one substituent selected from methyl, methoxy, methoxyethyl, phenyl, benzyl, =0, -C(0)R16 with R16 being methyl, -C(0)R16 with R16 being phenyl, methylphenyl, dimethylphenyl, dichlorophenyl and cyanophenyl; a salt, N-oxide or salt of an N-oxide thereof.

7. Compound according to any of claims 1 to 6, in which R1 is selected from an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 4-benzoylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methoxyethyl piperazin-1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazin- 1-yl, 4-acetylpiperazin-1-yl, 4-(4-methylphenyl)-piperazin-1-yl, 4-(2,4-dimethylphenyl)-piperazin- 1-yl, 4-(3,5-dichlorophenyl)-piperazin-1-yl, 4-(4-cyanophenyl)-piperazin-1-yl, 1 ,4-diazepan-1-yl, 4-methyl-1 ,4-diazepan-1-yl, 5-oxo-1 ,4-diazepan-1-yl, morpholin-4-yl, pyrrol-1-yl, 3-m ethyl pyrrol-

1-yl, 1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl and 1 ,2,3,4-tetrahydroisoquinolin-1-yl; a salt, N-oxide or salt of an N-oxide thereof.

8. Compound according to claim 1 or 2, in which R1 is -NR10R11 with R10 and R1 1 being independently selected from hydrogen, methyl, hydroxyethyl, cyclohexyl, benzyl, phenyl and phenyl substituted by one substituent, wherein said substituent is selected from methyl, methoxy, chlorine and N,N-dimethylamino; a salt, N-oxide or salt of an N-oxide thereof.

9. Compound according to claim 1 , 2 or 8, in which R1 is selected from an amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-(2-hydroxyethyl)amino, N,N-(di-2- hydroxyethyl)amino, N-cydohexylamino, N-benzylamino, N-phenylamino, N-(4- methylphenyl)amino, N-(2-methoxyphenyl)amino, N-[4-(N,N-dimethylamino)-phenyl]amino and

N-(4-chlorophenyl)-N-methylamino group; a salt, N-oxide or salt of an N-oxide thereof.

10. Compound according to any of claims 1 to 9, in which R3 and R4 are hydrogen; a salt, N-oxide or salt of an N-oxide thereof.

11. Compound according to any of claims 1 to 10, in which R2 is methoxy; a salt, N-oxide or salt of an N-oxide thereof.

12. Compound according to any of claims 1 to 11 selected from the group consisting of 6-[4-(N, N- dimethylamino-1-sulfonyl)-phenyl]-2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-oxazolo[4,5-b]pyridine, 6- [4-(azetidine-1-sulfonyl)-phenyl]-2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-oxazolo[4,5-b]pyridine, 2-[2- (4-methoxy-pyridin-2-yl)-ethyl]-6-[4-(pyrrole-1-sulfonyl)-phenyl]-oxazolo[4,5-b]pyridine, 2-[2-(4- methoxy-pyridin-2-yl)-ethyl]-6-[4-(3-methyl-pyrrole-1-sulfonyl)-phenyl]-oxazolo[4,5-b]pyridine, 2- [2-(4-methoxy-pyridin-2-yl)-ethyl]-6-[4-(N-phenylamino-1-sulfonyl)-phenyl]-oxazolo[4,5-b]pyridine, a salt, an N-oxide and a salt of an N-oxide thereof.

13. Process for manufacturing a compound, salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 comprising

subjecting a compound of formula (IV)

in which

R1 is selected from

R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy;

to a hydrogenation reaction.

14. Process according to claim 13 further comprising a step of producing a compound of formula (IV), in which said step comprises

reacting a compound of formula (V)

in which

R2 is 1-4C-alkoxy;

R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy;

Y is halogen;

with a compound of formula (Vl)

(Vl)

in which

R1 is selected from

X is halogen.

15. Compound of formula (IV)

in which

R1 is selected from

-NR10R11 with R10 and R11 being independently selected from hydrogen, 1-4C-alkyl, hydroxy- 1-4C-alkyl, cyclohexyl, benzyl, phenyl, and phenyl substituted by one substituent, wherein said substituent is selected from 1-4C-alkyl, 1-4C-alkoxy, halogen and -NR12R13 with R12 and R13 being independently selected from hydrogen and 1-4C-alkyl, and -NR10R1 1 with R10 and R11 together and with inclusion of the nitrogen atom to which they are bonded form a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic heterocyclic group comprising totally 1 to 3 heteroatoms selected from nitrogen and oxygen, said group being optionally substituted by one substituent selected from 1-4C- alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, phenyl, benzyl, =0, -C(0)R16 with R16 being selected from 1-4C-alkyl and phenyl, and phenyl substituted by one to three substituents selected from 1-4C-alkyl, halogen and cyano; R2 is 1-4C-alkoxy;

R4 is selected from hydrogen, halogen, 1-4C-alkyl and 1-4C-alkoxy.

16. Compound, pharmacologically acceptable salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 for use in the treatment or prophylaxis of diseases.

17. Pharmaceutical composition comprising one or more of the compounds, pharmacologically acceptable salts, N-oxides and salts of N-oxides according to any of claims 1 to 12 together with one or more pharmacologically acceptable auxiliaries.

18. Use of a compound, pharmacologically acceptable salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 in the manufacture of a pharmaceutical composition inhibiting the inducible nitric oxide synthase.

19. Use of a compound, pharmacologically acceptable salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of acute or chronic inflammatory diseases.

20. Use of a compound, pharmacologically acceptable salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of chronic inflammatory diseases of peripheral organs and the central nervous system.

21. Use of a compound, pharmacologically acceptable salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 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.

22. Use of a compound, pharmacologically acceptable salt, N-oxide or salt of an N-oxide according to any of claims 1 to 12 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.

23. 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, pharmacologically acceptable salts, N-oxides or salts of an N-oxide according to any of claims 1 to 12.

24. 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, pharmacologically acceptable salts, N-oxides or salts of an N-oxide according to any of claims 1 to 12.

25. 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, pharmacologically acceptable salts, N-oxides or salts of an N-oxide according to any of claims 1 to 12.