Patent Application
20070032482
The present invention relates to benzoxazinone-derived sulphonamide compounds of general formula (I),
a process for their preparation, a medicament comprising these compounds and the use of benzoxazinone-derived sulphonamide compounds for the preparation of medicaments for 5-HT6 receptor regulation as well as for the treatment of disorders related thereto.
The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT1-5-HT7) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419]. The 5-HT6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [F. J. Monsma, et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen, et al., J. Neurochem., 1996, 66, 47]. Compounds with 5-HT6 receptor affinity are useful for the treatment of various disorders of the Central Nervous System and of the gastrointestinal tract, such as irritable intestine syndrome. Compounds with 5-HT6 receptor affinity are also useful in the treatment of anxiety, depression and cognitive memory disorders [M. Yoshioka, et al., Ann. NY Acad. Sci., 1998, 861, 244; A. Bourson, et al., Br. J. Pharmacol., 1998, 125, 1562; D. C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp. Ther., 1995, 274, 173; A. J. Sleight, et al., Behav. Brain Res., 1996, 73, 245; T. A. Branchek, et al., Annu. Rev. Pharmacol. Toxicol., 2000, 40, 319; C. Routledge, et al., Br. J. Pharmacol., 2000, 130, 1606]. It has been shown that typical and atypical antipsychotic drugs for treating schizophrenia have a high affinity for 5-HT6 receptors [B. L. Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403; C. E. Glaft, et al., Mol. Med., 1995, 1, 398; F. J. Mosma, et al., Mol. Pharmacol., 1993, 43, 320; T. Shinkai, et al., Am. J. Med. Genet., 1999, 88, 120]. Compounds with 5-HT6 receptor affinity are useful for treating infant hyperkinesia (ADHD, attention deficit/hyperactivity disorder) [W. D. Hirst, et al., Br. J. Pharmacol., 2000, 130, 1597; C. Gérard, et al., Brain Research,1997, 746, 207; M. R. Pranzatelli, Drugs of Today, 1997, 33, 379].
Moreover, it has been shown that the 5-HT6 receptor also plays a role in food ingestion [Neuropharmacology, 41, 2001, 210-219].
Food ingestion disorders, particularly obesity, are a serious, fast growing threat to the health of humans of all age groups, since they increase the risk of developing other serious, even life-threatening diseases such as diabetes or coronary diseases.
Thus, it was an object of the present invention to provide novel compounds that are suitable in particular as active substances in medicaments, preferably in medicaments for the regulation of 5-HT6 receptors, for cognitive enhancement, for the prophylaxis and/or treatment of food-intake related disorders, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrom, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus Huntington, schizophrenia, psychosis, infantile hyperkinesia, ADHC (attention deficit, hyperactivity disorders) and other 5-HT6 mediated disorders particularly in mammals, including humans.
It has been found that the benzoxazinone-derived sulphonamide compounds of general formulas (I), (Ia) and (Ib) given below show affinity for the 5-HT6-receptor. These compounds are therefore also suitable for the manufacture of a medicament for cognitive enhancement, for the prophylaxis and/or treatment of food ingestion (food intake) disorders, particularly for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (Non-insulin Dependent Diabetes Mellitus), preferably type II diabetes, which is caused by obesity, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrome anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus Huntington, schizophrenia, psychosis, infantile hyperkinesia, ADHC (attention deficit, hyperactivity disorders) and other 5-HT6 mediated disorders particularly in mammals, including man.
Thus, one aspect of the present invention are benzoxazinone-derived sulfonamide compounds of general formula (I),
wherein
R1, R2, R3, R4 are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR10, —OC(═O)R11, —(C═O)O—R11, —SR12, —SOR12, —SO2R12, —NH—SO2R12, —SO2NH2 and a —NR13R14 moiety,
R5 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6, R7, R8, R9 are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a —COOR15 moiety,
W represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted heteroaryl radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
an optionally at least mono-substituted, monocyclic aryl radical, which is condensed with an optionally at least mono-substituted mono- or polycyclic ring-system and which may be bonded via an optionally at least mono-substituted alkylene group,
a NR16R17-moiety,
a COR18-moiety,
or a phenyl radical, which is at least mono-substituted with one of the substituents selected from the group consisting of:
with the proviso that W does not represent unsubstituted furyl-, unsubstituted thienyl- or thienyl substituted with a substituent selected from the group consisting of C1-5-alkoxycarbonyl, C1-5-alkylcarbonyl, carboxyl and pyridyl, unsubstituted pyrrolyl-, unsubstituted naphthyl, unsubstituted indolyl, unsubstituted tetrahydronaphthyl, substituted or unsubstituted pyridyl, unsubstituted pyrazinyl, unsubstituted quinolinyl-, C1-5-alkylsubstituted pyrrolyl-, and unsubstituted cyclohexyl or cyclohexyl substituted with one or two members selected from the group consisting of oxo, hydroxyl, C1-5-alkoxyl, C1-5-alkoxy-carbonylamino-C1-5 alkyl and amino-C1-5 alkyl,
R10 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R11 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R12 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R13 and R14 each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R13 and R14 together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
R15 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R16 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R17 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, and
R18 represents an optionally at least mono-substituted aryl radical, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate.
A mono- or polycyclic ring-system according to the present invention means a mono- or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or polycyclic ring system may contain one or more heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S. Preferably the polycyclic ring-system may comprise two rings that are condensed. The rings of the mono- or polycyclic ring-system are prefarably 5- or 6-membered.
If one or more of the residues R1—R17 and W represents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl , wherein the C1-4-alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1—R15 represents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, benzoyl, phenoxy, cyclohexyl, —CF3, —CO—CH3, —CO—OCH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1—R4, R10—R15 and W comprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1—R4 and R10—R15 comprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—Cl1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF3, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1—R4, R10—R15 and R18 represents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SOC1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, —CO—CH3, —CO—OCH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1—R4 and R10—R15 represents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, nitro, —CH(OH)(phenyl), —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, SO—C1-4-alkyl, SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, —CH(OH)(phenyl), —CO—CH3, —CO—OCH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R13 and R14 form a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R13 and R14 form a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.
If one or more of the residues R1—R15 and W represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If one or more of the residues R1—R4, R10—R15 and W represents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If W represents or comprises a cycloaliphatic radical, a heteroaryl radical, an aryl radical and/or a mono- or polycyclic ring system, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, C1-20-alkyl, partially fluorinated C1-4 alkyl, partially chlorinated C1-4 alkyl, partially brominated C1-4 alkyl, C1-5-alkoxy, partially fluorinated C1-4 alkoxy, partially chlorinated C1-4 alkoxy, partially brominated C1-4 alkoxy, C2-6-alkenyl, SO2—C1-4-alkyl, —(C═O)—C1-5-alkyl, —(C═O)—O—C1-5-alkyl, —(C═O)—Cl, —S—C1-4-alkyl-, —(C═O)—H, —NH—(C═O)—NH—C1-5-alkyl, —(C═O)—C1-4-perfluoroalkyl, —NRARB, wherein RA and RB are independently selected from the group consisting of H, C1-4-alkyl and phenyl, NH—(C═O)—C1-5-alkyl, —C1-5-alkylen-(C═O)—C1-5-alkyl, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO2-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH2-thiazolyl-, NH-phenyl, and —C1-4-Alkylen-NH—(C═O)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C1-12-alkyl, CH2F, CHF2, CF3, CH2Cl, CH2Cl2, CCl3, CH2Br, CHBr2, CBr3, OCF3, OCHF2, OCH2F, O—CH2—CF3, vinyl, SO2—CH3, —(C═O)—CH3, —(C═O)C2H5, —(C═O)—O—CH3, —(C═O)—O—C2CH5, —(C═O)—Cl, —S—CH3—, —(C═O)H, —NH—(C═O)—NH—CH3, —(C═O)—CF3, dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butyamino, NH—(C═O)—CH3, —CH2—(C═O)—CH3, —CH2—(C═O)—C2H5, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO2-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH2-thiazolyl-, NH-phenyl, and —CH2—NH—(C═O)-phenyl.
If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, —(C═O)—C1-4-alkyl, C1-4-alkyl, at least partially fluorinated C1-4-alkyl, at least partially chlorinated C1-4-alkyl, at least partially brominated C1-4-alkyl, —S—C1-4-alkyl, —C(═O)—O—C1-5-alkyl, —(C═O)—CH2—F, —(C═O)—CH2—Cl, —(C═O)—CH2—Br, preferably from the group consisting of F, Cl, Br, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3, nitro, cyano, hydroxy, —(C═O)—CH3, CH3, C2H5, —S—CH3, —C(═O)—O—CH3, —C(═O)—O—C2H5, —(C═O)—CH2—F, —(C═O)—CH2—Cl and —(C═O)—CH2—Br.
Preferred compounds of general formula (I) are those, wherein R1, R2, R3, R4 are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR10, —OC(═O)R11, —SR12, —SOR12, —SO2R12, —NH—SO2R12, —SO2NH2 and a —NR13R14 moiety,
preferably selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C1-3-aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C5- or C6-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1- or C2-alkylene group, a nitro group, a cyano group, —OR10, —OC(═O)R11, —SR12 and —NR13R14 moiety,
more preferably selected from the group consisting of H, F, Cl, —CH3, —CH2CH3, —CF3, —CF2CF3, cyclopentyl, cyclohexyl, a nitro group, a cyano group and —OR10,
and R5—R18 and W have the meaning as defined above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of generals formula (I), wherein R5 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical,
preferably represents H or a branched or unbranched C1-3-alkyl radical,
more preferably H, CH3 or CH2CH3,
and R1—R4, R6—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Preferred compounds of general formula (I) are also those, wherein R6, R7, R8, R9 are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, a cyano group and a —COOR15 moiety,
preferably selected from the group consisting of H, a branched or unbranched C1-3-alkyl radical, a cyano group and a —COOR15 group,
more preferably from the group consisting of H, —CH3, —CH2CH3 and a cyano moiety,
and R1—R5, R10—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (I), wherein W represents an unbranched or branched, optionally at least mono-substituted C11-20-alkyl radical, a napthyl group, which is at least mono substituted, a quinolinyl group, which is at least mono-substituted, a pyrrolyl group, which is at least mono-substituted by a substituent other than C1-5-alkyl, an optionally at least mono-substituted thiazolyl-, benzo[b]-thiophenyl-, benzo[b]-furanyl-, isoquinolinyl-, tetrahydroisoquinolinyl-, pyrazolyl-, isoazolyl-, chromanyl-, benzothiadiazolyl-, imidazolyl-, benzofurazanyl-, dibenzo[b,d]-furanyl-, benzoxadiazolyl-, imidazo[2,1-b]-thiazolyl-, anthracenyl-, coumarinyl-, 2,3-Dihydro-1,4-benzodioxinyl-, 2,3-Dihydrobenzo[b]furanyl-, 3,4-Dihydro-2H-1,4-Benzoxazinyl-, 3,4-Dihydro-2H-1,5-Benzodioxepinyl-, Benzothiazolyl-, Imidazo[1,2-a]-pyridinyl-, a chromonyl-group, an isatinyl group, a pentamethyldihydrobenzofuranyl group, an optionally at least mono-substituted cyclopropyl- or cyclopentyl-group, a 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl-)ethyl, a thienyl group, which is at least mono-substituted by one or more substituents independently selected from the group consisting of F, Cl, Br, C1-5-alkoxy-, CF3, —SO2—C1-5-alkyl and optionally at least mono substituted benzoylaminomethyl-, phenylsulfonyl-, isoxazolyl-, benzamidomethyl-, pyrimidyl-, thiazolyl-, pyrazolyl-, phenyl-, 1,2,4-thiadiazolyl-, 1,3-oxazolyl- or 1,2,4-oxadiazolyl-, a furyl group, which is at least mono-substituted by one or more subsitutents independently selected from the group consisting of a C1-5-alkyl radical, which may be at least partially fluorinated or chlorinated, an optionally at least mono-substituted phenyl and a —(C═O)—O—C1-5-alkyl group,
a NR16R17-moiety,
a COR18-moiety,
or a phenyl radical, which is at least mono-substituted with one of the substituents selected from the group consisting of:
2,2,2,-Trifluoroethoxy-, C2-6-Alkenyl-, 1,3-Dihydro-1-oxo-2H-isoindol-2-yl-, N-Phthalimidinyl-, [(2-chloro-1,3-thiazolyl-5-yl)-methoxy, Ethyl-5-yl-2-methyl-3-furoate, C11-20-alkyl-, 1,3-Dioxo-2-azaspiro[4,4]non-2-yl-, pyrazolyl-, (1,3-oxazol-5-yl)-, (5-Methyl-1,3,4-oxadiazol-2-yl)-, difluoromethoxy, dichloromethoxy, 1-pyrrolidinylsulfonyl, morpholinosulfonyl, 2-methyl-pyrimidinyl-, a phenoxy group, which is at least mono-substituted with C1-5-alkoxy, a phenyl group, which is at least mono-substituted with one of the substituents selected from the group consisting of nitro, C1-5-alkoxy, F, Cl, Br, at least partially fluorinated C1-5-alkyl, at least partially chlorinated C1-5-alkyl, [(2-Chloro-1,3-thiazol-5-yl)methoxy]-, —(C═O)—H and —(C═O)—C1-5-alkyl, a pyridinyl group, which is at least mono-substituted with C1-5-alkoxy, a pyridinyloxy group, which is at least mono-substituted with C1-5-alkoxy, a phenoxy group, which is at least di-substituted and a pyridinyloxy group, which is at least di-subsituted,
more preferably W represents a moiety selected from the group consisting of 5-Dimethylamino-napth-1-yl, 2-Acetamido-4-methyl-5-thiazolyl-, Trifluoromethyl-, Trichloromethyl-, Isopropyl-, Methyl-, 2,2,2-Trifluoroethyl-, Ethyl-, Hexadecyl-, 2-Chloroethyl-, n-Propyl-, 3-Chloro-propyl-, n-Butyl-, Dichloromethyl-, Chloromethyl-, Dodecyl-, 1-Octyl-, 6-(p-toluidino)-naphth-2-yl-, 4,5-Dibromo-thiophene-2-yl-,Benzoylchloride-2-yl-, 1-Octadecyl-, 4-Bromo-2,5-dichloro-thiophene-3-yl-, 2,5-Dichloro-thiophene-3-yl-, 5-Chloro-thiophene-2-yl-, 1-Decyl-, 3,5-Dichloro-4-(2chloro-4-nitrophenoxy)-phenyl-, 2,3-Dichlorothiophene-5-yl-, 3-Bromo-2-chloro-thiophene-5-yl-, 3-Bromo-5-chloro-thiophene-2-yl-, 2-Benzoylaminomethyl)-thiophene-5-yl-, 4-(Phenyl-sulphonyl)-thiophene-2-yl-, 2-Phenyl-sulphonyl-thiophene-5-yl-, 2-[1-Methyl-5-(trifluoromethyl)pyrazol-3-yl]-thiophene-5-yl-, 5-Chloro-1,3-dimethylpyrazole-4-yl-, 3,5-Dimethylisoxazole-4-yl-, 2-(2,4-Dichlorophenoxy)-phenyl, 4-(2-Chloro-6-nitro-phenoxy)-phenyl-, 4-(3-chloro-2-cyanophenoxy)-phenyl, 2,4-Dimethyl-1,3-thiazole-5-yl-, Methyl-methane-sulfonyl-, 2,5-Bis-(2,2,2-Trifluoroethoxy)phenyl-, 5-(Di-n-propylamino)-naphth-1-yl-, 2,2,5,7,8-Pentamethyl-chroman-6-yl-, 5-Chloro-4-nitro-thiophene-2-yl-, 2,1,3-Benzothiadiazole-4-yl-, 1-Methyl-imidazole-4-yl-, Benzofurazan-4-yl-, 5-(Isoxazol-3-yl)-thiophene-2-yl-, Vinyl-phenyl-4-yl-, 5-Dichloro-methyl-furan-2-yl-, 5-Bromo-thiophene-2-yl-, 5-(4-Chlorobenzamidomethyl)-thiophene-2-yl-, Dibenzo[b,d]-furan-2-yl-, 5-Chloro-3-methylbenzo[b]-thiophene-2-yl-, 3-Methoxy-4-(methoxycarbonyl)-thiophene-2-yl-, 5-[2-(Methylthio)-pyrimidin-4-yl-]-thiophene-2-yl-, 4-Chloro-2,1,3-Benzoxadiazole-7-yl-, 5-Chloro-2,1,3-Benzoxadiazole-4-yl-, 6-Chloro-imidazo(2,1-B)thiazole-5-yl-, 3-Methyl-benzo[b]-thiophene-2-yl-, 4-[[3-Chloro-5-(Trifluoromethyl)-2-pyridyl]oxy-phenyl-, 5-Chloro-naphth-1-yl-, 5-Chloro-naphth-2-yl-, 9,10-Dibromoanthracene-2-yl-, Isoquinoline-5-yl-, 4-Methoxy-2,3,6-trimethylbenzoyl-, 4′-Nitro-biphenyl-4yl-, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl-)-4-phenyl-, 5-(2-Methyl-1,3-thiazole-4-yl)-thiophene-2-yl-, 5-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl-]-thiophene-2-yl-, 5-[5-Trifluoromethyl)-isoxazol-3-yl]-thiophene-2-yl-, p-Dodecyl-phenyl-, 4-[(3-Cyano-4-methoxy-2-pyridinyl)oxy]-phenyl-, 4-(N-phthalimidinyl)-phenyl-, 1,2,3,4-Tetrahydro-2-(trifluoroacetyl)-isoquinoline-7-yl-, 1,2-Dimethylimidazole-4-yl-, 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-yl-, 4-Chloro-naphth-1-yl-, 2,5-Dichloro-4-nitro-thiophene-3-yl-, 4-(4-Methoxy-phenoxy)-phenyl-, [4-(3,5-Dichlorophenoxy)phenyl]-, [4-(3,4-Dichlorophenoxy)phenyl]-, [4-(3,5)-Bis(trifluoromethylphenoxy)phenyl]-, 3-(2-Methoxy-phenoxy)-phenyl, 3-(4-Methoxy-phenyl)-phenyl-, 3-(4-Chloro-phenyl)-phenyl-, 3-(3,5-Dichloro-phenyl)-phenyl-, 3-(3,4-Dichloro-phenyl)-phenyl-, 3-(4-Fluorophenyl)-phenyl-, 3-[4-(Trifluoromethyl)-phenyl]-phenyl-, 3-[3,5-Bis-(Trifluoromethyl)-phenyl]-phenyl-, 4-(2-Methoxy-phenoxy)-phenyl-, 4-(2-Methyl-phenoxy)-phenyl-, 4-(4-Methoxy-phenoxy)-phenyl-, 4-(4-Chlorophenyl)-phenyl-, 4-(3,5-Dichlorophenyl)-phenyl-, 4-(3,4-Dichlorophenyl)-phenyl-, 4-(4-Fluorophenyl)-phenyl-, 4-[4-(Trifluormethyl)-phenyl]-phenyl-, 4-[3,5-Bis-(Trifluoromethyl)-phenyl]-phenyl-, Cyclopropyl-, 2-(2-Chlorophenyl)-2-Phenylethyl-, 2-(2-Trifluoromethylphenyl)-2-phenylethyl-, 5-[4-Cyano-1-methyl-5-(methylthio)-1H-pyrazol-3-yl-thiophene-2-yl-, 3-Cyano-2,4-bis-(2,2,2-Trifluorothoxy)-phenyl-, 4-[(2-Chloro-1,3-Thiazol-5-yl)-methoxy]-phenyl-, 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl-, 5-Iodo-naphth-1-yl-, Ethyl-2,5-dimethyl-1-phenylpyrrole-4-carboxylate-3-yl-, Ethyl-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate-4-yl-, Ethyl-5-(4-chlorophenyl)-2-methyl-3-furoate-4-yl, Ethyl-5-(4-chlorophenyl)-2-methyl-1-phenyl-3-carboxylate-4-yl-, Ethyl-2,5-dimethyl-3-furoate-4-yl-, 3-Chloro-4-(1,3-dioxo-2-Azaspiro[4,4]non-2-yl)-phenyl-, Coumarin-6-yl, 3-(4-Methoxy-phenoxy)-phenyl-, [3-(3,5-Dichlorophenoxy)]-phenyl-, [3-(3,4 Dichlorophenoxy)]-phenyl-, 3,5-Bis(Trifluoromethyl)phenoxyphenyl-, 2,2-Diphenylethyl-, 4-Phenyl-5-(trifluoromethyl)-thiophene-3-yl-, Methyl-4-Phenyl-5-(Trifluoromethyl)-thiophene-2-carboxylate-3-yl-, Methyl-1,2,5-trimethylpyrrole-3-Carboxylate-4-yl-, 4-Fluoro-naphth-1-yl-, 5-Fluoro-3-methylbenzo[b]-thiophene-2-yl-, Methyl-2,5-dimethyl-3-furoate-4-yl-, Methyl-2-furoate-5-yl-, Methyl-2-methyl-3-furoate-5-yl-, Methyl-1-methyl-1H-pyrrole-2-Carboxylate-5-yl-, 2-(5-Chloro-1,2,4-Thiadiazol-3-yl)-thiophene-5-yl-, 1,3,5-Trimethyl-1H-pyrazole-4-yl-, Pentafluoroethoxytetrafluoroethyl-, 5-(5-Isoxazyl)-thiophene-2-yl-, 5-(5-Isoxazol-yl)-2-furyl-, 5-Methyl-2,1,3-benzothiadiazole-4-yl-, 2,3-Dihydro-1,4-benzodioxine-6-yl-, 4-Methyl-Naphth-1-yl-, 5-Methyl-2-(Trifluormethyl)-3-Furyl-, 2,3-Dihydrobenzo[b]furan-5-yl-, 1-Benzothiophene-3-yl-, 4-Methyl-3,4-dihydro-2H-1,4-Benzoxazine-7-yl-, 5-Methyl-1-phenyl-1H-pyrazole-4-yl-, 6-Morpholino-3-Pyridinyl-, 4-(1H-Pyrazol-1-yl)-phenyl-, 6-Phenoxy-3-Pyridyl-, 3,4-Dihydro-2H-1,5-benzodioxepine-7-yl-, 5-(1,3-Oxazol-5-yl)-2-thienyl-, 4-(1,3-Oxazol-5-yl)-phenyl-, 5-Methyl-4-isoxazolyl, 2,1,3-Benzothiadiazole-5-yl-, 5-Acetamido-naphth-1-yl-, 3-Methyl-8-Quinolinyl-, 1,3-Benzothiazole-6-yl-, 2-Morpholino-3-Pyridyl-, 2,5-Dimethyl-3-thienyl-, 5-[5-(Chloromethyl)-1,2,4-oxadiazol-3-yl]-2-thienyl-, Ethyl-3-[5-yl-2-thienyl-]1,2,4-oxadiazole-5-carboxylate-, 3-(5-Methyl-1,3,4-oxadiazol-2-yl)-phenyl-, 4-(Difluoromethoxy)-phenyl-, 3-(Difluoromethoxy)-phenyl-, 2,2-Dimethyl-6-Chromanyl-, Ethyl-3,5-dimethyl-1H-pyrrole-2-carboxylate-4-yl-, Imidazo[1,2-A]pyridine-3-yl-, 3-(1,3-Oxazol-5-yl)-phenyl-, Ethyl-5-[4-yl)-phenyl]-2-methyl-3-furoate, 1-Pyrrolidinylphenylsulfonyl-, Methyl-5-yl-4-methyl-2-thiophene-carboxylate, Methyl-3-yl-4-(isopropylsulfonyl)-2-thiophene, 7-Chlorochromone-3-yl-, 4′-Bromobiphenyl-4-yl-, 4′-Acetyl-biphenyl-4-yl-, 4′-Bromo-2′-fluoro-biphenyl-4-yl-, 1-Methyl-5-isatinyl-, 2-Chloro-3-thiophenecarboxylic-acid-5-yl-, 2-Methoxy-5-(N-phthalimidinyl)-phenyl-, 1-Benzothiophene-2-yl-, Morpholinophenylsulfonyl- and 3-(2-Methyl-4-pyrimidinyl)-phenyl- and R1—R18 have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Furthermore, compounds of general formula (I) are preferred, wherein R10 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical,
more preferably H, —CH3, —C2H5 or phenyl,
and R1—R9, R12—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Moreover, compounds of general formula (I) are preferred, wherein R11 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, more preferably H, —CH3, —C2H5 or phenyl,
and R1—R10, R12—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Preference is also given to compounds of general formula (I), wherein R12 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably represents H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical,
more preferably H, —CH3, —C2H5 or phenyl,
and R1—R11, R13—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (I), wherein R13 and R14 are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably are each independently selected from the group consisting of H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical and a phenyl radical,
more preferably are each independently selected from the group consisting of H, CH3, C2H5 and phenyl,
and R1—R12, R15—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Furthermore, compounds of general formula I are preferred, wherein R13 and R14 together with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
preferably form an unsubstituted piperidin or morpholine group,
and R1—R12, R15—R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (I), wherein R15 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably represents H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical,
more preferably represents H, —CH3, —C2H5 or phenyl,
and R1—R14, R16, R17, R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (I), wherein R16 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical,
preferably an unbranched or branched, saturated, unsubstituted C1-3 alkyl radical,
more preferably a methyl radical,
and R1—R15, R17, R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (I), wherein R17 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical,
preferably an unbranched or branched, saturated, unsubstituted C1-3 alkyl radical,
more preferably a methyl radical, and R1—R16, R18 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (I), wherein R18 represents a phenyl radical, which is optionally at least mono-substituted by a C1-6 aliphatic radical, more preferably a phenyl radical, which is optionally at least mono-substituted by a methyl group,
and R1—R17 and W have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Particularly preferred are compounds of general formula (I) selected from the following list A:
More particularly preferred are compounds of general formula (I) selected from the group consisting of
1-[1-(5-Chloro-3-methyl-benzo[b]thiophenyl-2-sulfonyl)-piperidine-4-yl]-1,4dihydro-benzo[d][1,3]oxazin-2-one,
1-[1-(5-Dimethylamino-naphthyl-1-sulfonyl)-piperidine-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
1-[1-(5-Dimethylamino-naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
and corresponding salts thereof, and corresponding solvates.
In a further aspect the present invention also provides a process for the preparation of benzoxazinone-derived sulphonamide compounds of general formula (I), wherein R1—R9 and W have the meaning given above, comprising reacting at least one piperidine compound of general formula (II) and/or a corresponding salt thereof, preferably a hydrochloride salt,
wherein R1 to R9 have the meaning given above, with at least one compound of general formula (III),
wherein W has the meaning given above, in a suitable reaction medium, optionally in the presence of at least one base and/or at least one auxiliary agent, to yield a compound of general formula (I).
Suitable reaction media include e.g. organic solvents, such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene, chlorobenzene or/and other solvents, preferably ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, diemthylformamide, hexamethylphosphoramide, acetonitril, acetone or nitromethane, are included. Mixtures based one or more of the afore mentioned solvents may also be used.
Bases that may be used in the processes according to the present invention are generally organic or inorganic bases, preferably alkali metal hydroxides, e.g. sodium hydroxyde or potassium hydroxyde, or obtained from other metals such as barium hydroxyde or different carbonates, preferably potassium carbonate, sodium carbonate, calcium carbonate, or alkoxides, e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, preferably triethylamine, diisopropyethylamine or heterocycles, e.g. 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene pyridine, diamino pyridine, dimethylaminopyridine, methylpiperidine or morpholine.
Alkali metals such as sodium or ist hydrides, e.g. sodium hydride, may also be used. Mixtures based one or more of the afore mentioned bases may also be used.
During the synthetic reactions described above or while preparing the compounds of general formulas (II) or (III) the protection of sensitive groups or of reagents may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in the literature [Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991. Said literature description is hereby incorporated by reference as part of the disclosure. The protective groups may also be eliminated as convenient by means well-known to those skilled in the art.
The compounds of general formulas (II) and (III) are either commercially available or can be produced according to methods known to those skilled in the art. The reaction of compounds of general formulas (II) and (III) to yield benzoxazinone-derived sulphonamide compounds of general formula (I) may also be facilitated by conventional methods known to those skilled in the art.
The substituted benzoxazinone compounds of general formula (II), wherein R5 represents H, are preferably synthesized from substituted anthranilic acid or a corresponding ester via the corresponding substituted benzylalcohol (see scheme 1, method A). By reductive amination with 1-Boc-(tert.-Butylcarbonyloxy)-4-piperidone the Boc-piperidin-moiety is introduced into the substituted benzylalcohol. The benzoxazinone-ring is formed by cyclisation with triphosgene. The elimination of the Boc-protecting group is carried out by treatment in acidic media according to the method described in Williams et al., J. Med. Chem. 1995 38, 4634 and later by Bell et al., J. Med. Chem., 1998, 41, 2146 which are hereby incorporated by reference and form part of the disclosure. By reacting such a substituted benzoxazinone compound of general formula (II) with a substituted sulfuryl chloride of general formula (III) compounds of general formula (I) are obtained.
By reduction of the corresponding ketones via conventional methods known to those skilled in the art, e.g. by reduction with sodium borohydride (see scheme 1, method B, R5=Z) benzoxazinone derived sulphonamide compounds of general formula (I), wherein R5 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical (denoted by Z in method B) can be obtained.
The respective reagents used in said process for the preparation of benzoxazinone derived sulphonamide compounds of general formula (I) are either commercially available or can be obtained by methods well known to those skilled in the art.
In a further aspect the present invention also provides a process for the preparation of salts of benzoxazinone-derived sulphonamide compounds of general formula (I), wherein at least one compound of general formula (I) having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media are, for example, the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
In yet a further aspect the present invention also provides a process for the preparation of salts of benzoxazinone-derived sulphonamide compounds of general formula (I), wherein at least one compound of general formula (I) having at least one acidic group is reacted with one or more suitable bases, preferably in the-presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NHnR4-n]+, wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched C1-4-alkyl-radical. Suitable reaction media are, for example, the ones given above.
Solvates, preferably hydrates, of the Benzoxazinone-derived sulphonamide compounds of general formula (I) or of the salts thereof may also be obtained by standard procedures known to those skilled in the art.
If the Benzoxazinone-derived compounds of general formula (I) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.
The purification and isolation of the Benzoxazinone-derived sulphonamide compounds of general formula (I) or a corresponding stereoisomer, or salt, or solvate respectively, if required, may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
The Benzoxazinone-derived sulphonamide compounds of general formula (I), their stereoisomers, the corresponding salts and the corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
The present invention therefore also provides for a medicament comprising at least one benzoxazinone-derived sulphonamide compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate, and optionally one or more pharmaceutically acceptable adjuvants.
Furthermore, the present invention also provides for a pharmaceutical composition comprising at least one benzoxazinone-derived sulphonamide compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate and optionally one or more pharmaceutically acceptable adjuvants, which is not yet formulated into a medicament.
Preferably the medicament is suitable for 5-HT6-receptor regulation, for cognitive enhancement, for the prophylaxis and/or treatment of food ingestion (food intake) disorders, particularly for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (Non-insulin Dependent Diabetes Mellitus), preferably type II diabetes, which is caused by obesity, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrom, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus Huntington, schizophrenia, psychosis, infantile hyperkinesia, ADHC (attention deficit, hyperactivity disorders) and other 5-HT6 mediated disorders particularly in mammals, including humans.
A further aspect of the present invention is the use of at least one benzoxazinone-derived compound of general formula (I) for the manufacture of a medicament for 5-HT6-receptor regulation, for cognitive enhancement, for the prophylaxis and/or treatment of food ingestion (food intake) disorders, particularly for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (Non-insulin Dependent Diabetes Mellitus), preferably type II diabetes, which is caused by obesity, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrom, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus Huntington, schizophrenia, psychosis, infantile hyperkinesia, ADHC (attention deficit, hyperactivity disorders) and other 5-HT6 mediated disorders particularly in mammals, including humans.
In yet a further aspect, the present invention also provides for the use of at least one benzoxazinone-derived sulphonamide compound of general formula (Ia)
wherein
R1a, R2a, R3a, R4a are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR10a, —OC(═O)R11a, —C(═O)—OR11a, —SR12a, —SOR12a, —SO2R12a, —NH—SO2R12a, —SO2NH2 and a —NR13aR14a moiety,
R5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical- or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6a, R7a, R8a, R9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a —COOR15a moiety,
Wa represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, a NR16aR17a-moiety or a —COR18a-moiety,
R10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R11a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R12a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R13a and R14a each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R13a and R14a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
R15a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R16a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R17a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R18a represents an optionally at least mono-substituted aryl radical,
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, for the manufacture of a medicament for 5-HT6-receptor regulation, for cognitive enhancement, for the prophylaxis and/or treatment of food ingestion (food intake) disorders, particularly for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (Non-insulin Dependent Diabetes Mellitus), preferably type II diabetes, which is caused by obesity, disorders of the gastrointestinal tract, such as irritable intestine syndrom, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus Huntington, schizophrenia, psychosis, infantile hyperkinesia, ADHC (attention deficit, hyperactivity disorders) and other 5-HT6 mediated disorders particularly in mammals, preferably humans.
If one or more of the residues R1a—R17a and Wa represents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein the C1-4-alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a—R15a represents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, keto, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, keto, benzoyl, phenoxy, cyclohexyl, —CF3, —CO—CH3, —CO—OCH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a—R4a and R10a—R15a and Wa comprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C, 4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, methoxy, ethoxy, CF3 and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a—R4a and R10a—R15a comprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluorocarbonyl, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF3, —(C═O)—CF3, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a—R4a, R10a—R15a and R18a represents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC14-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, OCF3,—CO—CH3, —CO—OCH3, SO2—CH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF3, methyl and methoxy.
If one or more of the residues R1a—R4a and R10a—R15a represents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, OCF3, —CO—CH3, —CO—OCH3, SO2—CH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF3, methyl and methoxy.
If R13a and R14a form a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R13a and R14a form a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.
If one or more of the residues R1a—R15a and Wa represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If one or more of the residues R1a—R4a, R10a—R15a and Wa represents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If Wa represents or comprises a cycloaliphatic radical, a heteroaryl radical, an aryl radical and/or a mono- or polycyclic ring system, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, C1-20-alkyl, partially fluorinated C1-4 alkyl, partially chlorinated C1-4 alkyl, partially brominated C1-4 alkyl, C1-5-alkoxy, partially fluorinated C1-4 alkoxy, partially chlorinated C1-4 alkoxy, partially brominated C1-4 alkoxy, C2-6-alkenyl, SO2—C1-4-alkyl, —(C═O)—C1-5-alkyl, —(C═O)—O—C1-5-alkyl, —(C═O)—Cl, —S—C1-4-alkyl-, —(C═O)—H, —NH—(C═O)—NH—C1-5-alkyl, —(C═O)—C1-4-perfluoroalkyl, —NRARB, wherein RA and RB are independently selected from the group consisting of H, C1-4-alkyl and phenyl, NH—(C═O)C1-5-alkyl, —C1-5-alkylen-(C═O)—C1-5-alkyl, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO2-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH2-thiazolyl-, NH-phenyl, and —C1-4-Alkylen-NH—(C═O)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C1-12-alkyl, CH2F, CHF2, CF3, CH2Cl, CH2Cl2, CCl3, CH2Br, CHBr2, CBr3, OCF3, OCHF2, OCH2F, O—CH2—CF3, vinyl, SO2—CH3, —(C═O)—CH3, —(C═O)—C2H5, —(C═O)—O—CH3, —(C═O)—O—C2CH5, —(C═O)—Cl, —S—CH3—, —(C═O)—H, —NH—(C═O)—NH—CH3, —(C═O)—CF3, dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butyamino, NH—(C═O)—CH3, —CH2—(C═O)—CH3, —CH2—(C═O)—C2H5, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO2-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH2-thiazolyl-, NH-phenyl, and —CH2—NH—(C═O)-phenyl.
If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, —(C═O)—C1-4-alkyl, C1-4-alkyl, at least partially fluorinated C1-4-alkyl, at least partially chlorinated C1-4-alkyl, at least partially brominated C1-4-alkyl, —S—C1-4-alkyl, —C(═O)—O—C1-5-alkyl, —(C═O)—CH2—F, —(C═O)—CH2—Cl, —(C═O)—CH2—Br, preferably from the group consisting of F, Cl, Br, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3, nitro, cyano, hydroxy, —(C═O)—CH3, CH3, C2H5, —S—CH3, —C(═O)—O—CH3, —C(═O)—O—C2H5, —(C═O)—CH2—F, —(C═O)—CH2—Cl and —(C═O)—CH2—Br.
Preferred is the use of compounds of general formula (Ia), wherein R1a, R2a, R3a, R4a are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR10a, —OC(═O)R11a, —SR12a, —SOR12a, —SO2R2a, —NH—SO2R12a, —SO2NH2 and a —NR13aR14a moiety,
preferably selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C1-3-aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C5- or C6-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1- or C2-alkylene group, a nitro, cyano, —OR10a, —OC(═O)R11a, SR12a and —NR13aR14a moiety,
more preferably selected from the group consisting of H, F, Cl, CH3, CH2CH3, CF3, CF2CF3, cyclopentyl, cyclohexyl, a nitro group, a cyano group and —OR10a, and R5a—R18a and Wa have the meaning as defined above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (Ia), wherein R5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical,
preferably represents H or a branched or unbranched C1-3-alkyl radical,
more preferably H, —CH3 or —CH2CH3,
and R1a—R4a, R6a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Preference is also given to the use of compounds of general formula (Ia), wherein R6a, R7a, R8a, R9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, a cyano group and a —COOR15a moiety,
preferably selected from the group consisting of H, a branched or unbranched C1-3-alkyl radical, a cyano group and a —COOR15a group,
more preferably from the group consisting of H, —CH3, —CH2CH3 and a cyano moiety, and R1a—R5a, R10a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (Ia), wherein Wa represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-20 aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8 cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, a NR16aR17a-moiety or a COR18a-moiety,
preferably is selected from the group consisting of 1-Naphthyl-, 5-Dimethylamino-napth-1-yl, 2-Naphthyl-, 2-Acetamido-4-methyl-5-thiazolyl-, 2-Thienyl, 8-Quinolinyl-, Phenyl-, Pentafluorophenyl-, 2,4,5-Trichloro-phenyl-, 2,5-Dichloro-phenyl-, 2-Nitrophenyl-, 2,4-Dinitro-phenyl-, 3,5-Dichloro-2-hydroxy-phenyl-, 2,4,6-Trisisopropyl-phenyl-, 2-Mesityl-, 3-Nitro-phenyl-, 4-Bromo-phenyl-, 4-Fluoro-phenyl-, 4-Chlorophenyl-, 4-Chloro-3-nitro-phenyl-, 4-Iodo-phenyl-, N-Acetyl-sulfanilyl-, 4-Nitro-phenyl-, 4-Methoxy-phenyl-, Benzoic-acid-4-yl-, 4-tert-Butyl-phenyl-, p-Tolyl-, Trifluoromethyl-, Trichloromethyl-, Isopropyl-, Methyl-, Benzyl-, trans-styryl-, 2,2,2-Trifluoroethyl-, Ethyl-, Hexadecyl-, 2-Chloroethyl-, n-Propyl-, 3-Chloro-propyl-, n-Butyl-, Methyl-benzoate-2-yl-, 2-Nitro-4-(trifluoromethyl)-phenyl-, Pentamethyl-phenyl-, 2,3,5,6-Tetramethyl-phenyl-, 3-(Trifluoromethyl)-phenyl-, 3,5-Bis-(Trifluoromethyl)-phenyl-, Dichloromethyl-, Chloromethyl-, Dodecyl-, 1-Octyl-, 2,3,4-Trichloro-phenyl-, 2,5-Dimethoxy-phenyl-, o-Tolyl-, p-xylyl-2-yl-, Benzoic-acid-3-yl-, 4-Chloro-3-(trifluoromethyl)-phenyl-, 4-Chloro-5-nitro-benzoic acid-3-yl-, 6-(p-toluidino)-naphth-2-yl-, 4-Methoxy-2,3,6-trimethylphenyl-, 3,4-Dichlorophenyl-, 4,5-Dibromo-thiophene-2-yl-, 3-Chloro-4-fluoro-phenyl-, 4-Ethyl-phenyl-, 4-n-Propyl-phenyl-, 4-(1,1-Dimethylpropyl)-phenyl-, 4-Isopropyl-phenyl-, 4-Bromo-2,5-difluoro-phenyl-, 2-Fluoro-phenyl-, 3-Fluoro-phenyl-, 4-(Trifluoromethoxy)-phenyl-, 4-(Trifluoromethyl)-phenyl-, 2,4-Difluoro-phenyl-, 2,4-Dichloro-5-methyl-phenyl-, 4-Chloro-2,5-dimethyl-phenyl-, 5-Diethylamino-napth-2-yl-, Benzoyl chloride-3-yl-, 2-Chloro-phenyl-, 1-Octadecyl-, 4-Bromo-2,5-dichloro-thiophene-3-yl-, 2,5-Dichloro-thiophene-3-yl-, 5-Chloro-thiophene-2-yl-, 2-Methyl-5-nitro-phenyl-, 2-(Trifluoromethyl)-phenyl-, 3-Chloro-phenyl-, 3,5-Dichloro-phenyl-, 1-Decyl-, 3-Methyl-phenyl-, 2-Chloro-6-methyl-, 5-Bromo-2-methoxy-phenyl-, 3,4-Dimethoxy-phenyl-, 2-3-Dichloro-phenyl-, 2-Bromo-phenyl-, 3,5-Dichloro-4-(2-chloro-4-nitrophenoxy)-phenyl-, 2,3-Dichloro-thiophene-5-yl-, 3-Bromo-2-chloro-thiophene-5-yl-, 3-Bromo-5-chloro-thiophene-2-yl-, 2-(Benzoylaminomethyl)-thiophene-5-yl-, 4-(Phenyl-sulphonyl)-thiophene-2-yl-, 2-Phenyl-sulphonyl-thiophene-5-yl-, 3-Chloro-2-methyl-phenyl-, 2-[1-Methyl-5-(trifluoromethyl)pyrazol-3-yl]-thiophene-5-yl-, 5-Pyrid-2-yl-thiophene-2-yl-, 2-Chloro-5-(trifluoromethyl)-phenyl-, 2,6-Dichloro-phenyl-, 3-Bromo-phenyl-, 2-(Trifluoromethoxy)-phenyl-, 4-Cyano-phenyl-, 2-Cyano-phenyl-, 4-n-Butoxy-phenyl-, 4-Acetamido-3-chloro-phenyl, 2,5-Dibromo-3,6-difluoro-phenyl-, 5-Chloro-1,3-dimethylpyrazole-4-yl-, 3,5-Dimethylisoxazole-4-yl-, 2-(2,4-Dichlorophenoxy)-phenyl-, 4-(2-Chloro-6-nitro-phenoxy)-phenyl-, 4-(3-Chloro-2-cyano-phenoxy)-phenyl-, 2,4-Dichloro-phenyl-, 2,4-Dimethyl-1,3-thiazole-5-yl-, Methyl-methane-sulfonyl-, 2,5-Bis-(2,2,2-Trifluoroethoxy)-phenyl-, 2-Chloro-4-(trifluoromethyl)-phenyl-, 2-Chloro-4-fluoro-phenyl-, 5-Fluoro-2-methyl-phenyl-, 5-Chloro-2-methoxy-phenyl-, 2,4,6-Trichloro-phenyl-, 2-Hydroxy-benzoic acid-5-yl-, 5-(Di-n-propylamino)-naphth-1-yl-, 6-Methoxy-m-tolyl-, 2,5-Difluoro-phenyl-, 2,4-Dimethoxy-phenyl-, 2,5-Dibromo-phenyl-, 3,4-Dibromo-phenyl-, 2,2,5,7,8-Pentamethyl-chroman-6-yl-, 2-Methoxy-benzoic-acid-5-yl-, 5-Chloro-4-nitro-thiophene-2-yl-, 2,1,3-Benzothiadiazole-4-yl-, 1-Methyl-imidazole-4-yl-, Benzofurazan-4-yl-, 2-(Methoxycarbonyl)-thiophene-3-yl-, 5-(Isoxazol-3-yl)-thiophene-2-yl-, 2,4,5-Trifluoro-phenyl-, Biphenyl-4-yl-, Vinyl-phenyl-4-yl-, 2-Nitro-benzyl-, 5-Dichloro-methyl-furan-2-yl-, 5-Bromo-thiophene-2-yl-, 5-(4-Chlorobenzamidomethyl)-thiophene-2-yl-, 2,6-Difluoro-phenyl-, 2,5-Dimethoxy-4-nitro-phenyl-, Dibenzo[b,d]-furan-2-yl-, 2,3,4-Trifluoro-phenyl-, 3-Nitro-p-tolyl-, 4-Methoxy-2-nitro-phenyl-, 3,4-Difluoro-phenyl-, 4-(Bromoethyl)-phenyl-, 3,5-Dichloro-4-hydroxy-phenyl-, 4-n-Amyl-phenyl-, 5-Chloro-3-methylbenzo[b]-thiophene-2-yl-, 3-Methoxy-4-(methoxycarbonyl)-thiophene-2-yl-, 4-n-Butyl-phenyl-, 2-Chloro-4-cyano-phenyl-, 5-[2-(Methylthio)-pyrimidin-4-yl-]-thiophene-2-yl-, 3,5-Dinitro-4-methoxy-phenyl-, 4-Bromo-2-(trifluoromethoxy)-phenyl-, 4-Chloro-2,1,3-Benzoxadiazole-7-yl-, 2-(1-Naphthyl)-ethyl-, 3-Cyano-phenyl-, 5-Chloro-2,1,3-Benzoxadiazole-4-yl-, 3-Chloro-4-methyl-phenyl-, 4-Bromo-2-ethyl-phenyl-, 2,4-Dichloro-6-methyl-phenyl-, 6-Chloro-imidazo(2,1-B)-thiazole-5-yl-, 3-Methyl-benzo[b]-thiophene-2-yl-, 4-Methyl-sulphonyl-phenyl-, 2-Methyl-sulphonyl-phenyl-, 4-Bromo-2-methyl-phenyl-, 2,6-Dichloro-4-(trifluoromethyl)-phenyl-, 4-[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]-phenyl-, 5-Chloro-naphth-1-yl-, 5-Chloro-naphth-2-yl-, 9,10-Dibromoanthracene-2-yl-, Isoquinoline-5-yl-, 4-Methoxy-2,3,6-trimethyl-phenyl-, 4′-Nitro-biphenyl-4-yl-, [(4-Phenoxy)-phenyl-, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl-)-4-phenyl-, 4-Acetyl-phenyl-, 5-(2-Methyl-1,3-thiazole-4-yl)-thiophene-2-yl-, 5-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl-]-thiophene-2-yl-, 5-[5-Trifluoromethyl)-isoxazol-3-yl]-thiophene-2-yl-, 2-Iodo-phenyl-, p-Dodecyl-phenyl-, 4-[(3-Cyano-4-methoxy-2-pyridinyl)oxy]-phenyl-, 4-(N-phthalimidinyl)-phenyl-, 1,2,3,4-Tetrahydro-2-(trifluoroacetyl)-isoquinoline-7-yl-, 4-Bromo-2-fluoro-phenyl-, 2-Fluoro-5-(trifluoromethyl)-phenyl-, 4-Fluoro-2-(trifluoromethyl)-phenyl-, 4-Fluoro-3-(trifluoromethyl)-phenyl-, 2,4,6-Trifluoro-phenyl-, 3-(Trifluoromethoxy)-phenyl-, 1,2-Dimethylimidazole-4-yl-, Ethyl-4-Carboxylate-3-yl-, 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-yl-, 3-Bromo-2-chloropyridine-5-yl-, 3-Methoxy-phenyl-, 2-Methoxy-4-methyl-phenyl-, 2-Chloro-4-fluorobenzoic-acid-5-yl-, 4-Chloro-naphth-1-yl-, 2,5-Dichloro-4-nitro-thiophene-3-yl-, 4-(4-Methoxy-phenoxy)-phenyl-, 4-(4-Chloro-phenoxy)-phenyl-, 4-(3,5-Dichloro-phenoxy)-phenyl-, 4-(3,4-Dichloro-phenoxy)-phenyl-, 4-(4-Fluoro-phenoxy)-phenyl-, 4-(4-Methyl-phenoxy)-phenyl-, 4-[4-(Trifluormethyl)-phenoxy-phenyl-, 4-[3,5-Bis-(trifluoromethyl)-phenoxy]-phenyl-, 3-(2-Methoxy-phenoxy)-phenyl-, [3-(2-Chloro-phenoxy)-phenyl-, 3-(2-Methyl-phenoxy)-phenyl-, 4-[2-(Trifluoromethyl)-phenoxy]-phenyl-, 3-Phenyl-phenyl-, 3-(4-Methoxy-phenyl)-phenyl-, 3-(4-Chloro-phenyl)-phenyl-, 3-(3,5-Dichloro-phenyl)-phenyl-, 3-(3,4-Dichloro-phenyl)-phenyl-, 3-(4-Fluorophenyl)-phenyl-, 3-(4-Methylphenyl)-phenyl-, 3-[4-(Trifluoromethyl)-phenyl]-phenyl-, 3-[3,5-Bis-(Trifluoromethyl)-phenyl]-phenyl-, 4-(4-Pyridyloxy)-phenyl)-, 4-(2-Methoxy-phenoxy)-phenyl-, 4-(2-Chloro-phenoxy)-phenyl-, 4-(2-Methyl-phenoxy)-phenyl-, 4-(4-Methoxy-phenoxy)-phenyl-, 4-(4-Chlorophenyl)-phenyl-, 4-(3,5-Dichlorophenyl)-phenyl-, 4-(3,4-Dichlorophenyl)-phenyl-, 4-(4-Fluorophenyl)-phenyl-, 4-(4-Methylphenyl)-phenyl-, 4-[4-(Trifluormethyl)-phenyl]-phenyl-, 4-[3,5-Bis-(Trifluoromethyl)-phenyl]-phenyl-, [3-(Trifluoromethyl)-phenyl]-methyl-, (4-Chlorophenyl)-methyl-, (3,5-Dichlorophenyl)-methyl-, (3,5-Dichlorophenyl)-methyl-, (4-Fluorophenyl)-methyl-, 4-Methylphenylmethyl-, [4-(Trifluoromethyl)-phenyl]-methyl-, Cyclopropyl-, 2-(2-Chlorophenyl)-2-Phenylethyl-, 2-(2-Trifluoromethylphenyl)-2-phenylethyl-, 5-[4-Cyano-1-methyl-5-(methylthio)-1H-pyrazol-3-yl-thiophene-2-yl-, 3-Cyano-2,4-bis-(2,2,2-Trifluorothoxy)-phenyl-, 4-[(2-Chloro-1,3-Thiazol-5-yl)-methoxy]-phenyl-, 3-Nitro-phenylmethyl-, 4-Formylphenyl-, 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl-, [3,5-Bis-(Trifluoromethyl)-phenyl]-methyl-, (4-(2-Pyridyloxy)-phenyl)-, (4-(3-Pyridyloxy)-phenyl)-, 5-Iodo-naphth-1-yl-, Ethyl-2,5-dimethyl-1-phenylpyrrole-4-carboxylate-3-yl-, Ethyl-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate-4yl-, Ethyl-5-(4-chlorophenyl)-2-methyl-3-furoate-4-yl, Ethyl-5-(4-chlorophenyl)-2-methyl-1-phenyl-3-carboxylate-4-yl-, Ethyl-2,5-dimethyl-3-furoate-4-yl-, 3-Chloro-4-(1,3-dioxo-2-Azaspiro[4,4]non-2-yl)-phenyl-, 5-Bromo-2,4-difluoro-phenyl-, 5-Chloro-2,4-difluorophenyl-, Coumarin-6-yl, 2-Methoxy-phenyl, (3-Phenoxy)-phenyl-, 3-(4-Methoxy-phenoxy)-phenyl-, 3-(4-Chlorophenoxy)-phenyl-, 3-(3,5-Dichlorophenoxy)-phenyl-, 3-(3,4-Dichlorophenoxy)-phenyl-, 3-(4-Fluorophenoxy)-phenyl-, 3-(4-Methylphenoxy)-phenyl-, 3-[4-(Trifluoromethyl)-phenoxy]-phenyl-, 3-[3,5-(Trifluoromethyl)-phenoxy]-phenyl-, 3-[2-(Trifluoromethyl)-phenoxy]-phenyl-, 2,2-Diphenylethyl-, 4-Phenyl-5-(trifluoromethyl)-thiophene-3-yl-, Methyl-4-Phenyl-5-(Trifluoromethyl)-thiophene-2-carboxylate-3-yl-, Methyl-1,2,5-trimethylpyrrole-3-Carboxylate-4-yl-, 4-Fluoro-naphth-1-yl-, 3,5-Difluorophenyl-, 3-Fluoro-4-methoxy-phenyl-, 4-Chloro-2,5-difluorophenyl-, 2-Chloro-4,5-difluoro-phenyl-, 5-Fluoro-3-methylbenzo[b]-thiophene-2-yl-, Methyl-3-phenylpropionate-4-yl, Dihydrocinnamic Acid-4-yl-, Methyl-2,5-dimethyl-3-furoate-4-yl-, Methyl-2-furoate-5-yl-, Methyl-2-methyl-3-furoate-5-yl-, Methyl-1-methyl-1H-pyrrole-2-Carboxylate-5-yl-, 2-(5-Chloro-1,2,4-Thiadiazol-3-yl)-thiophene-5-yl-, 1,3,5-Trimethyl-1H-pyrazole-4-yl-, 3-Chloro-5-fluoro-2-methylphenyl-, Pentafluoroethoxytetrafluoroethyl-, 5-(5-Isoxazyl)-thiophene-2-yl-, 5-(5-Isoxazol-yl)-2-furyl-, 5-Methyl-2,1,3-benzothiadiazole-4-yl-, Biphenyl-2-yl-, 2,3-Dihydro-1,4-benzodioxine-6-yl-, 4-Methyl-Naphth-1-yl-, 5-Methyl-2-(Trifluormethyl)-3-Furyl-, 2,3-Dihydrobenzo[b]furan-5-yl-, 1-Benzothiophene-3-yl-, 4-Methyl-3,4-dihydro-2H-1,4-Benzoxazine-7-yl-, 5-Methyl-1-phenyl-1H-pyrazole-4-yl-, 6-Morpholino-3-Pyridinyl-, 4-(1H-Pyrazol-1-yl)-phenyl-, 6-Phenoxy-3-Pyridyl-, 3,4-Dihydro-2H-1,5-benzodioxepine-7-yl-, 5-(1,3-Oxazol-5-yl)-2-thienyl-, 4-(1,3-Oxazol-5-yl)-phenyl-, 5-Methyl-4-isoxazolyl, 2,1,3-Benzothiadiazole-5-yl-, 3-Thienyl-, 2-Methyl-benzyl-, 3-Chloro-benzyl-, 5-Acetamido-naphth-1-yl-, 3-Methyl-8-Quinolinyl-, 4-Chloro-2-nitrophenyl-, 6-Quinolinyl-, 1,3-Benzothiazole-6-yl-, 2-Morpholino-3-Pyridyl-, 2,5-Dimethyl-3-thienyl-, 5-[5-(Chloromethyl)-1,2,4-oxadiazol-3-yl]-2-thienyl-, Ethyl-3-[5-yl-2-thienyl-]1,2,4-oxadiazole-5-carboxylate-, 3-(5-Methyl-1,3,4-oxadiazol-2-yl)-phenyl-, 4-Isopropoxyphenyl-, 2,4-Dibromophenyl-, 3-Cyano-4-fluorophenyl-, 2,5-Bis-(Trifluoromethyl)-phenyl, 2-Bromo-4-fluorophenyl-, 4-Bromo-3-fluorophenyl-, 4-(Difluoromethoxy)-phenyl-, 3-(Difluoromethoxy)-phenyl-, 5-Chloro-2-fluoro-phenyl-, 3-Chloro-2-fluorophenyl-, 2-Fluoro-4-methylphenyl-, 4 Nitro-3-(trifluoromethyl)-phenyl-, 3-Fluoro-4-methylphenyl-, 4-Fluoro-2-methylphenyl-, 4-Bromo-3-(tifluoromethyl)-phenyl-, 4-Bromo-2-(trifluoromethyl)-phenyl-, 3-Bromo-5-(trifluoromethyl)-phenyl-, 2-Bromo-4-(trifluoromethyl)-phenyl-, 2-Bromo-5-(trifluoromethyl)-phenyl-, 2,4-Dichloro-5-fluorophenyl-, 4,5-Dichloro-2-fluorophenyl-, 3,4,5-Trifluorophenyl-, 4-Chloro-2-fluorophenyl-, 2-Bromo-4,6-Difluorophenyl-, 2-Ethylphenyl-, 4-Bromo-2-chlorophenyl-, 4-Bromo-2,6-dichlorophenyl-, 2-Bromo-4,6-dichloro-phenyl-, 4-Bromo-2,6-dimethylphenyl-, 3,5-Dimethylphenyl-, 4-Bromo-3-methylphenyl-, 2-Methoxy-4-nitrophenyl-, 2,2-Dimethyl-6-Chromanyl-, Ethyl-3,5-dimethyl-1H-pyrrole-2-carboxylate-4-yl-, Imidazo[1,2-A]pyridine-3-yl-, 3-(1,3-Oxazol-5-yl)-phenyl-, Ethyl-5-[4-yl)-phenyl]-2-methyl-3-furoate, Methyl-3-(yl)-4-methoxybenzoate, 1-Pyrrolidinylphenylsulfonyl-, Methyl-5-yl-4-methyl-2-thiophene-carboxylate, Methyl-3-yl-4-(isopropylsulfonyl)-2-thiophene, 2-Pyridyl-, 3-Fluoro-4-nitrophenyl-, 7-Chlorochromone-3-yl-, 4′-Bromobiphenyl-4-yl-, 4′-Acetyl-biphenyl-4-yl-, 4′-Bromo-2′-fluoro-biphenyl-4-yl-, 2-Chloro-4-(3-propyl-Ureido)-phenyl-, 3-(-Bromoacetyl)-phenyl-, 2-Bromo-3-(trfluoromethyl)-phenyl-, 1-Methyl-5-isatinyl-, 4-Isopropyl-benzoic-acid-3-yl-, 2-Chloro-3-thiophenecarboxylic-acid-5-yl-, 3-Pyridyl-, Cyclohexylmethyl-, 2-Methoxy-5-(N-phthalimidinyl)-phenyl-, 1-Benzothiophene-2-yl-, Morpholinophenylsulfonyl-, 3-(2-Methyl-4-pyrimidinyl)-phenyl-, and 2-Cyano-5-methylphenyl-, and R1a—R18a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Furthermore, the use of compounds of general formula (Ia) is preferred, wherein R10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical,
more preferably H, —CH3, —C2H5 or phenyl,
and R1a—R9a, R12a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Moreover, the use of compounds of general formula (Ia) is preferred, wherein R11a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, more preferably H, —CH3, —C2H5 or phenyl,
and R1a—R10a, R12a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Preference is also given to the use of compounds of general formula (Ia), wherein R12a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably represents H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical,
more preferably H, —CH3, —C2H5 or phenyl,
and R1a—R11a, R13a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (Ia), wherein R13a and R14a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably are each independently selected from the group consisting of H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical and a phenyl radical,
more preferably are each independently selected from the group consisting of H, —CH3, —C2H5 and phenyl,
and R1a—R12a, R15a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Furthermore, the use of compounds of general formula (Ia) is preferred, wherein R13a and R14a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
preferably form an unsubstituted piperidin or morpholine group,
and R1a—R12a, R15a—R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ia), wherein R15a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably represents H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical,
more preferably represents H, —CH3, —C2H5 or phenyl,
and R1a—R14a, R16a—R13a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (Ia), wherein R16a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical,
preferably an unbranched or branched,.saturated, unsubstituted C1-3 alkyl radical,
more preferably a methyl radical,
and R1a—R15a, R17a, R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (Ia), wherein R17a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical,
preferably an unbranched or branched, saturated, unsubstituted C1-3 alkyl radical,
more preferably a methyl radical,
and R1a—R16a, R18a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ia), wherein R18a represents a phenyl radical, which is optionally at least mono-substituted by a C1-6 aliphatic radical, more preferably a phenyl radical, which is optionally at least mono-substituted by a methyl group and R1a—R17a and Wa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Particularly preferred is the use of one or more benzoxazinone-derived sulfonamide compound of general formula (Ia) selected from the list A given above.
More particularly preferred is the use of one or more benzoxazinone-derived sulfonamide compound of general formula (Ia) selected from the group consisting of
1-[1-(Naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
1-(1-Phenylsulfonyl-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]-oxazin-2-one,
1-[1-(5-Chloro-3-methyl-benzo[b]thiophenyl-2-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
8-Methyl-1-[1-naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
1-[1-(Quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
8-Methyl-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
1-[1-(5-Dimethylamino-naphthyl-1-sulfonyl)-piperidine-4-yl]-8-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one,
1-[1-(5-Dimethylamino-naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
1-[1-(2,3-Dichloro-phenylsulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
1-[1-(2,3-Dichloro-phenylsulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, and
corresponding salts thereof, or corresponding solvates thereof.
The compounds of general formula (Ia), their stereoisomers, corresponding salts and corresponding solvates may be obtained analogously by the methods described above for compounds of general formula (I).
In another aspect the present invention relates to benzoxazinone-derived sulfonamide compounds of general formula (Ib),
wherein
R1b, R2b, R3b, R4b are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR10b, —OC(═O)R11b, —(C═O)—OR11b, —SR12b, —SOR12b, —SO2R12b, —NH—SO2R12b, SO2NH2 and a —NR13bR14b moiety,
R5b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6b, R7b, R8b, R9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a —COOR15b moiety,
Wb represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, a NR16bR17b-moiety or a COR18b-moiety,
R10b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R13b and R14b each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R13b and R14b together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
R15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R18b represents an optionally at least mono-subsituted aryl radical,
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively.
If one or more of the residues R1b—R17b and Wb represents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein the C1-4-alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b—R15b represents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, keto, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2-C1-4-alkyl, wherein C1-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, keto, benzoyl, phenoxy, cyclohexyl, —CF3, —CO—CH3, —CO—OCH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b—R4b and R10b—R15b and Wb comprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido,-cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, methoxy, ethoxy, CF3 and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b—R4b and R10b—R15b comprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluorocarbonyl, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF3, —(C═O)—CF3, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b—R4b, R10b—R15b and R18b represents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2'C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, OCF3,—CO—CH3, —CO—OCH3, SO2—CH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF3, methyl and methoxy.
If one or more of the residues R1b—R4b and R10b—R15b represents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, OCF3,—CO—CH3, —CO—OCH3, SO2—CH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF3, methyl and methoxy.
If R13b and R14b form a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R13b and R14b form a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.
If one or more of the residues R1b—R5b and Wb represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If one or more of the residues R1b—R4b, R10b—R15b and Wb represents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If Wb represents or comprises a cycloaliphatic radical, a heteroaryl radical, an aryl radical and/or a mono- or polycyclic ring system, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, C1-20-alkyl, partially fluorinated C1-4 alkyl, partially chlorinated C1-4 alkyl, partially brominated C1-4 alkyl, C1-5-alkoxy, partially fluorinated C1-4 alkoxy, partially chlorinated C1-4 alkoxy, partially brominated C1-4 alkoxy, C2-6-alkenyl, SO2—C1-4-alkyl, —(C═O)—C1-5-alkyl, —(C═O)—O—C1-5-alkyl, —(C═O)—Cl, —S—C1-4-alkyl-, —(C═O)—H, —NH—(C═O)—NH—C1-5-alkyl, —(C═O)—C1-4-perfluoroalkyl, —NRARB, wherein RA and RB are independently selected from the group consisting of H, C1-4-alkyl and phenyl, NH—(C═O)—C1-5-alkyl, —C1-5-alkylen-(C═O)—C1-5-alkyl, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO2-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH2-thiazolyl-, NH-phenyl, and —C1-4-Alkylen-NH—(C═O)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C1-12-alkyl, CH2F, CHF2, CF3, CH2Cl, CH2Cl2, CCl3, CH2Br, CHBr2, CBr3, OCF3, OCHF2, OCH2F, O—CH2—CF3, vinyl, SO2—CH3, —(C═O)—CH3, —(C═O)—C2H5, —(C═O)—O—CH3, —(C═O)—O—C2CH5, —(C═O)—Cl, —S—CH3—, —(C═O)—H, —NH—(C═O)—NH—CH3, —(C═O)—CF3, dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butyamino, NH—(C═O)—CH3, —CH2—(C═O)—CH3, —CH2—(C═O)—C2H5, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO2-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH2-thiazolyl-, NH-phenyl, and —CH2—NH—(C═O)-phenyl.
If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, —(C═O)—C1-4-alkyl, C1-4-alkyl, at least partially fluorinated C1-4-alkyl, at least partially chlorinated C1-4-alkyl1 at least partially brominated C1-4-alkyl, —S—C1-4-alkyl, —C(═O)—O—C1-5-alkyl, —(C═O)—CH2—F, —(C═O)—CH2—Cl, —(C═O)—CH2—Br, preferably from the group consisting of F, Cl, Br, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3, nitro, cyano, hydroxy, —(C═O)—CH3, CH3, C2H5, —S—CH3, —C(═O)—O—CH3, —C(═O)—O—C2H5, —(C═O)—CH2—F, —(C═O)—CH2—Cl and —(C═O)—CH2—Br.
Preferred are compounds of general formula (Ib) given above, wherein R1b, R2b, R3b, R4b are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, OR10b, —OC(═O)R11b, —SR12b, —SOR12b,—SO2R12b, —NH—SO2R12b, —SO2NH2 and a —NR13bR14b moiety, preferably selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C1-3-aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C5- or C6-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1- or C2-alkylene group, a nitro group, a cyano group, —OR10b, —OC(═O)R11b, —SR12b and —NR13bR14b moiety, more preferably selected from the group consisting of H, F, Cl, Br, —CH3, —CH2CH3, —CF3, —CF2CF3, cyclopentyl, cyclohexyl, nitro, cyano and —OR10b, and R5b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R5b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, preferably represents H or a branched or unbranched C1-3-alkyl radical, more preferably H, —CH3 or —CH2CH3, most preferably a hydrogen atom, and R1b—R4b, R6b—R8b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R6b, R7b, R8b, R9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, a cyano group and a —COOR15b moiety, preferably selected from the group consisting of H, a branched or unbranched C1-3-alkyl radical, a cyano group and a COOR15b group, more preferably from the group consisting of H, —CH3, —CH2CH3 and a cyano moiety, most preferably each of R6b, R7b, R8b and R9b represent a hydrogen atom, and R1b—R5b, R10b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein Wb represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-20 aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8 cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, a NR16bR17b-moiety or a COR18b-moiety,
preferably Wb represents
a linear or branched C1-20-alkyl radical, preferably an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and 1,1-dimethyl-propyl; a linear or branched C2-20-alkenyl radical; preferably a vinyl radical; —CF3; —CHF2; —CH2F; —CCl3; —CHCl2; —CH2Cl; —CH2—CF3; —CH2—CH2—Cl; —CH2—CH2—CH2—Cl; —CH2—S(═O)2—CH3; a cyclopropyl radical; a cyclobutyl radical; a cyclopentyl radical; a cyclohexyl radical; —CH2-cyclopropyl; —CH2-cyclobutyl; —CH2-cyclopentyl; —CH2-cyclohexyl; —N(CH3)2; —N(C2H5)2; —N(n-CH2—CH2—CH3)2; phenyl; benzyl; naphthyl; —CH═CH-phenyl; —(CF2)—(CF2)—O-phenyl; —(CH2)-naphtyl; —(CH2)—(CH2)-naphthyl; anthracenyl; —(C═O)-phenyl; thiophenyl; benzo[b]thiophenyl; furanyl; 2-oxo-2H-chromanyl; dibenzofuranyl; 2,3-dihydrobenzofuranyl; chromanyl; 2,3-dihydro-benzo[1,4]dioxinyl; 3,4-dihydro-2H-1,5-benzo-dioxepinyl; chromonyl; 1H-imidazolyl; pyridinyl; pyrrolidine-2,5-dionyl; pyrrolyl; 1H-pyrazolyl; 1H-pyrimidine-2,4-dionyl; quinolinyl; isoquinolinyl; 1H-Benzoimidazolyl; 1,4-dihydro-quinoxaline-2,3-dionyl; 1,2,3,4-tetrahydro-isoquinolinyl; 1,4-dihydro-benzo[b][1,4]diazepine-2,4-dionyl; 1,3-dihydro-1-oxo-2H-isoindolyl; phthalimidinyl; 2-(1,3dioxo-1,3-dihydro-isoindol-2-yl)-ethyl; imidazo[1,2-a]pyridine; isatinyl; thiazolyl; 1,3-thiazolyl; 1,2,4-thiadiazolyl; imidazo[2,1-b]thiazolyl; 1,3-benzothiazolyl; benzo[1,2,5]thiadiazolyl; 2-oxo-2,3-dihydro-benzothiazolyl; 2,1,3-benzothiadiazolyl; imidazo[2,1-b]thiazolyl; isoxazolyl; benzo[1,2,5]oxadiazolyl; benzo[d]isoxazolyl; benzofurazanyl; 2-oxo-2,3-dihydro-benzooxazolyl; 3,4-dihydro-2H-benzo[1,4]oxazinyl; or 2,1,3-benzoxadiazolyl;
whereby each of these afore mentioned cyclic moieties may optionally be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; 1,1-dimethyl-propyl; n-pentyl; vinyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; morpholino; methoxy; ethoxy; n-propoxy; iso-propoxy; n-propoxy; F; Cl; Br; I; —CN; —OH; —CF3; —CF2H; —CH2F; —CCl3; —CClH2; —CHCl2; —CH2—F; —CH2—Cl;—CH2—Br; —(C═O)—CH2—Br; —OCF3; —O—CH2—CF3; —O—CHF2; —NO2; —NH2; —N(CH3)2; —N(C2H5)2; —N(n-CH2—CH2—CH3)2; —N(n-CH2—CH2—CH2—CH3)2;—NH—(C═O)—CH3; —NH-phenyl; —(C═O)—CF3; —(C═O)—OH; ═O(oxo); —(C═O)—H; —S(═O)2—CH3; —S(═O)2-isopropyl; —S(═O)2-phenyl; —S(═O)2-pyrrolidinyl; —S(═O)2-morpholino; —(CH2)—(CH2)—(C═O)—O—CH3; —NH—(C═O)—NH—CH2—CH2—CH3; —(C═O)—CH3; —(C═O)—O—CH3; —(C═O)—O—C2H5; —(CH2)NH—(C═O)-phenyl; —CH2—C(H)(phenyl)(phenyl); —O—CH2-thiazolyl; 1,3-dioxo-2-azaspiro[4.4]non-2-yl; phenyl; phenoxy; isoxazolyl; 1,3-oxazolyl; 1,2,4-oxadiazolyl; 1,3,4-oxadiazolyl; pyridinyl; pyridinyloxy; pyrazolyl; pyrimidinyl and phthalimidinyl; and
whereby each of the cyclic moieties of these afore mentioned substituents may optionally be substituted with 1, 2, 3, 4 or 5 substituents that are independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; F; Cl; Br; I; CN; —CH2—F; —CH2—Cl; —CH2—Br; —CF3 and —S—CH3,
more preferably Wb represents
an alkyl radical selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.butyl; iso-butyl and tert-butyl; vinyl (CH2═CH—); —N(CH3)2; 1-naphthyl; benzyl; 2-naphtyl; phenyl; 2-methyl-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; 2-ethyl-phenyl; 3-ethyl-phenyl; 4-ethyl-phenyl; 2-n-propyl-phenyl; 3-n-propyl-phenyl; 4-n-propyl-phenyl; 2-isopropyl-phenyl; 3-isopropyl-phenyl; 4-isopropyl-phenyl; 2-n-butyl-phenyl; 3-n-butyl-phenyl; 4-n-butyl-phenyl; 2-iso-butyl-phenyl; 3-iso-butyl-phenyl; 4-iso-butyl-phenyl; 2-tert-butyl-phenyl; 3-tert-butyl-phenyl; 4-tert-butyl-phenyl; 1,1-dimethylpropyl-phenyl; 2-cyclopentyl-phenyl; 3-cyclopentyl-phenyl; 4-cyclopentyl-phenyl 2-cyclohexyl-phenyl; 3-cyclohexyl-phenyl; 4-cyclohexyl-phenyl; 2-methoxy-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2-ethoxy-phenyl; 3-ethoxy-phenyl; 4-ethoxy-phenyl; 2-n-propoxy-phenyl; 3-n-propoxy-phenyl; 4-n-propoxy-phenyl; 2-iso-propoxy-phenyl; 3-iso-propoxy-phenyl; 4-isopropoxy-phenyl;2-fluoro-phenyl; 3-fluoro-phenyl; 4-fluoro-phenyl; 2-chloro-phenyl; 3-chloro-phenyl; 4-chloro-phenyl; 2-bromo-phenyl; 3-bromo-phenyl; 4-bromo-phenyl; 2-trifluoromethyl-phenyl; 3-trifluoromethyl-phenyl; 4-trifluoromethyl-phenyl; 2-trifluoromethoxy-phenyl; 3-trifluoromethoxy-phenyl; 4-trifluoromethoxy-phenyl; 2-carboxy-phenyl; 3-carboxy-phenyl; 4-carboxy-phenyl; 2-acetyl-phenyl; 3-acetyl-phenyl; 4-acetyl-phenyl; 2—(C═O)—O—CH3-phenyl; 3-(C═O)—O—CH3-phenyl; 4-(C═O)—O—CH3-phenyl; 2-(CH2)—(CH2)—(C═O)—O—CH3; 3-(CH2)—(CH2)—(C═O)—O—CH3; 4-(CH2)—(CH2)—(C═O)—O—CH3; 2-cyano-phenyl; 3-cyano-phenyl; 4-cyano-phenyl; 2-nitro-phenyl; 3-nitro-phenyl; 4-nitro-phenyl; 4-(4-bromophenoxy)-phenyl; 2-methylsulfonyl-phenyl; 3-methylsulfonyl-phenyl; 4-methylsulfonyl-phenyl; 2-phenyl-phenyl(biphenyl-2-yl); 3-phenyl-phenyl(biphenyl-3-yl); 4-phenyl-phenyl(biphenyl-4-yl); 2-phenoxy-phenyl; 3-phenoxy-phenyl; 4-phenoxy-phenyl; 2,4-dimethyl-phenyl; 3,4-dimethyl-phenyl; 2,4,6-trimethyl-phenyl; 2,3,5,6-tetramethyl-phenyl; pentamethyl-phenyl; 2,5-dimethoxy-phenyl; 3,4-dimethoxy-phenyl; 2,3-dichloro-phenyl; 2,4-dichloro-phenyl; 2,5-dichloro-phenyl; 3,4-dichloro-phenyl; 3,5-dichloro-phenyl; 2,6-dichloro-phenyl; 2,4-difluoro-phenyl; 3,4-difluoro-phenyl; 2,5-difluoro-phenyl; 2,6-difluoro-phenyl; 3-chloro-2-fluoro-phenyl; 3-chloro-4-fluoro-phenyl; 5-chloro-2-fluoro-phenyl; 2,3,4-trichloro-phenyl; 2,4,5-trichloro-phenyl; 2,4,6-trichloro-phenyl; 2,4,5-trifluoro-phenyl; 2,3,4-trifluoro-phenyl-; 2-chloro-4,5-difluoro-phenyl; 2-bromo-4-fluoro-phenyl; 2-bromo-4,6-difluoro-phenyl; 4-chloro-2,5-difluoro-phenyl; 5-chloro-2,4-difluoro-phenyl; 4-bromo-2,5-difluoro-phenyl; 5-bromo-2,4-difluoro-phenyl; pentafluoro-phenyl; 2,4-dinitro-phenyl; 4-chloro-3-nitro-phenyl; 2-methyl-5-nitro-phenyl; 5-bromo-2-methoxy-phenyl; 3-chloro-2-methyl-phenyl; 4-bromo-3-methyl-phenyl; 4-chloro-2,5-dimethyl-phenyl; 4-fluoro-3-methyl-phenyl; 5-fluoro-2-methyl-phenyl; 2-nitro-4-trifluoromethyl-phenyl; 2-methoxy-4-methyl-phenyl; 3,5-dichloro-2-hydroxy-phenyl; 3,5-dichloro-4-hydroxy-phenyl; 5-chloro-2,4-difluoro-phenyl; 3-chloro-4-(NH)—(C═O)—CH3-phenyl; 2-chloro-6-methyl-phenyl; 2-chloro-5-trifluoromethyl-phenyl; 2-chloro-5-trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethyl-phenyl; 4-bromo-3-trifluoromethyl-phenyl; 3-carboxy-4-fluoro-phenyl; 3-carboxy-4-chloro-6-fluoro-phenyl; 4-methoxy-2,3,6-trimethyl-phenyl-; or one of the following groups:
whereby in each case X denotes the position by which the respective substituent Wb is bonded to the —SO2 group of formula (Ib),
and R1b—R18b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R10b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, more preferably H, —CH3, —C2H5 or phenyl, and R1b—R9b, R11b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, more preferably H, —CH3, —C2H5 or phenyl, and R1b—R10b, R12b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably represents H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, more preferably H, —CH3, —C2H5 or phenyl, and R1b—R11b, R13b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R13b and R14b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably are each independently selected from the group consisting of H, a linear or branched C1-4-alkyl radical, cyclohexyl and a phenyl radical, more preferably are each independently selected from the group consisting of H, —CH3, —C2H5 and phenyl, and R1b—R12b, R15b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R13b and R14b together with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member, preferably form an unsubstituted piperidin or morpholine group, and R1b—R12b, R15b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, preferably represents H, a linear or branched C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, more preferably represents H, —CH3, —C2H5 or phenyl, and R1b—R14b, R16b—R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical, preferably an unbranched or branched, saturated, unsubstituted C1-3 alkyl radical, more preferably a methyl radical, and R1b—R15b, R17b and R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical, preferably an unbranched or branched, saturated, unsubstituted C1-3 alkyl radical, more preferably a methyl radical, and R1b—R16b, R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (Ib) given above, wherein R18b represents a phenyl radical, which is optionally at least mono-substituted by a C1-6 aliphatic radical, more preferably a phenyl radical, which is optionally at least mono-substituted by a methyl group, and R1b—R17b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
More preferred are compounds of general formula (Ib) given above, wherein
R1b, R2b, R3b, R4b are each independently selected from the group consisting of a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group and a methoxy group;
R5b represents a hydrogen atom;
R6b, R7b, R8b, R9b each represent a hydrogen atom;
Wb represents
an alkyl radical selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec butyl; iso-butyl and tert-butyl; vinyl (CH2═CH—); —N(CH3)2; 1-naphthyl; benzyl; 2-naphtyl; phenyl; 2-methyl-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; 2-ethyl-phenyl; 3-ethyl-phenyl; 4-ethyl-phenyl; 2-n-propyl-phenyl; 3-n-propyl-phenyl; 4-n-propyl-phenyl; 2-isopropyl-phenyl; 3-isopropyl-phenyl; 4-isopropyl-phenyl; 2-n-butyl-phenyl; 3-n-butyl-phenyl; 4-n-butyl-phenyl; 2-iso-butyl-phenyl; 3-iso-butyl-phenyl; 4-iso-butyl-phenyl; 2-tert-butyl-phenyl; 3-tert-butyl-phenyl; 4-tert-butyl-phenyl; 1,1-dimethylpropyl-phenyl; 2-cyclopentyl-phenyl; 3-cyclopentyl-phenyl; 4-cyclopentyl-phenyl 2-cyclohexyl-phenyl; 3-cyclohexyl-phenyl; 4-cyclohexyl-phenyl; 2-methoxy-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2-ethoxy-phenyl; 3-ethoxy-phenyl; 4-ethoxy-phenyl; 2-n-propoxy-phenyl; 3-n-propoxy-phenyl; 4-n-propoxy-phenyl; 2-iso-propoxy-phenyl; 3-iso-propoxy-phenyl; 4-isopropoxy-phenyl;2-fluoro-phenyl; 3-fluoro-phenyl; 4-fluoro-phenyl; 2-chloro-phenyl; 3-chloro-phenyl; 4-chloro-phenyl; 2-bromo-phenyl; 3-bromo-phenyl; 4-bromo-phenyl; 2-trifluoromethyl-phenyl; 3-trifluoromethyl-phenyl; 4-trifluoromethyl-phenyl; 2-trifluoromethoxy-phenyl; 3-trifluoromethoxy-phenyl; 4-trifluoromethoxy-phenyl; 2-carboxy-phenyl; 3-carboxy-phenyl; 4-carboxy-phenyl; 2-acetyl-phenyl; 3-acetyl-phenyl; 4-acetyl-phenyl; 2-(C═O)—O—CH3-phenyl; 3-(C═O)—O—CH3-phenyl; 4-(C═O)—O—CH3-phenyl; 2-(CH2)—(CH2)—(C═O—O—CH3; 3-(CH2)—(CH2)—(C═O)—O—CH3; 4-(CH2)—(CH2)—(C═O)—O—CH3; 2-cyano-phenyl; 3-cyano-phenyl; 4-cyano-phenyl; 2-nitro-phenyl; 3-nitro-phenyl; 4-nitro-phenyl; 4-(4-bromophenoxy)-phenyl; 2-methylsulfonyl-phenyl; 3-methylsulfonyl-phenyl; 4-methylsulfonyl-phenyl; 2-phenyl-phenyl(biphenyl-2-yl); 3-phenyl-phenyl(biphenyl-3-yl); 4-phenyl-phenyl(biphenyl-4-yl); 2-phenoxy-phenyl; 3-phenoxy-phenyl; 4-phenoxy-phenyl; 2,4-dimethyl-phenyl; 3,4-dimethyl-phenyl; 2,4,6-trimethyl-phenyl; 2,3,5,6-tetramethyl-phenyl; pentamethyl-phenyl; 2,5-dimethoxy-phenyl; 3,4-dimethoxy-phenyl; 2,3-dichloro-phenyl; 2,4-dichloro-phenyl; 2,5-dichloro-phenyl; 3,4-dichloro-phenyl; 3,5-dichloro-phenyl; 2,6-dichloro-phenyl; 2,4-difluoro-phenyl; 3,4-difluoro-phenyl; 2,5-difluoro-phenyl; 2,6-difluoro-phenyl; 3-chloro-2-fluoro-phenyl; 3-chloro-4-fluoro-phenyl; 5-chloro-2-fluoro-phenyl; 2,3,4-trichloro-phenyl; 2,4,5-trichloro-phenyl; 2,4,6-trichloro-phenyl; 2,4,5-trifluoro-phenyl; 2,3,4-trifluoro-phenyl-; 2-chloro-4,5-difluoro-phenyl; 2-bromo-4-fluoro-phenyl; 2-bromo-4,6-difluoro-phenyl; 4-chloro-2,5-difluoro-phenyl; 5-chloro-2,4-difluoro-phenyl; 4-bromo-2,5-difluoro-phenyl; 5-bromo-2,4-difluoro-phenyl; pentafluoro-phenyl; 2,4-dinitro-phenyl; 4-chloro-3-nitro-phenyl; 2-methyl-5-nitro-phenyl; 5-bromo-2-methoxy-phenyl; 3-chloro-2-methyl-phenyl; 4-bromo-3-methyl-phenyl; 4-chloro-2,5-dimethyl-phenyl; 4-fluoro-3-methyl-phenyl; 5-fluoro-2-methyl-phenyl; 2-nitro-4-trifluoromethyl-phenyl; 2-methoxy-4-methyl-phenyl; 3,5-dichloro-2-hydroxy-phenyl; 3,5-dichloro-4-hydroxy-phenyl; 5-chloro-2,4-difluoro-phenyl; 3-chloro-4-(NH)—(C═O)—CH3-phenyl; 2-chloro-6-methyl-phenyl; 2-chloro-5-trifluoromethyl-phenyl; 2-chloro-5-trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethyl-phenyl; 4-bromo-3-trifluoromethyl-phenyl; 3-carboxy-4-fluoro-phenyl; 3-carboxy-4-chloro-6-fluoro-phenyl; 4-methoxy-2,3,6-trimethyl-phenyl-; or one of the following groups:
whereby in each case X denotes the position by which the respective substituent Wb is bonded to the —SO2 group of formula (Ib).
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively.
Most particularly preferred are compounds of general formula (Ib) selected from the following group given in list B:
Preferably, the compound 1-[[(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl]sulfonyl]-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl-piperidine may be excluded. More preferably, the compound 1-[[(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl]sulfonyl]-4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl-piperidine, salts thereof and solvates thereof may be excluded.
The compounds of general formula (Ib), their stereoisomers, corresponding salts and corresponding solvates may be obtained analogously by the methods described above for compounds of general formula (I). For details of the process reference is made to the description given above for compounds of general formula (I).
Thus, in another aspect the present invention relates to a process for the preparation of benzoxazinone-derived sulfonamide compounds of general formula (Ib) given above, which comprises reacting at least one piperidine compound of general formula (IIb), wherein R1b to R9b have the meaning given above and/or a salt, preferably a hydrochloride salt, thereof,
with at least one compound of general formula (IIIb),
wherein Wb has the meaning given above, in a suitable reaction medium, optionally in the presence of at least one base and/or at least one auxiliary agent.
In a further aspect the present invention relates to a process for the preparation of a physiologically acceptable salt of the benzoxazinone-derived sulphonamide compounds of general formula (Ib) given above or a corresponding stereoisomer thereof, characterized in that at least one compound of general formula (Ib) having at least one basic group is reacted with at least one acid, preferably an inorganic or organic acid, preferably in the presence of a suitable reaction medium.
In a further aspect the present invention relates to a process for the preparation of a physiologically acceptable salt of the benzoxazinone-derived sulphonamide compounds of general formula (Ib) given above or a corresponding stereoisomer thereof, characterized in that at least one compound of general formula (Ib) having at least one acidic group is reacted with at least one base, preferably in the presence of a suitable reaction medium.
In yet another aspect the present invention relates to a pharmaceutical composition comprising at least one benzoxazinone-derived sulphonamide compound of general formula (Ib) given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or more pharmaceutically acceptable adjuvants.
In yet another aspect the present invention provides for a medicament comprising at least one benzoxazinone-derived sulphonamide compound of general formula (Ib) given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or more pharmaceutically acceptable adjuvants.
The medicament of the present invention is suitable for the prophylaxis and/or treatment of disorders that are at least partially mediated via 5-HT6-receptors.
In particular, the medicament of the present invention is suitable for the prophylaxis and/or treatment of food intake disorders, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, for the prophylaxis and/or treatment of bulimia, for the prophylaxis and/or treatment of anorexia, for the prophylaxis and/or treatment of cachexia, for the prophylaxis and/or treatment type II diabetes (non-insulin dependent diabetes mellitus).
Also in particular, the medicament of the present invention is suitable for the prophylaxis and/or treatment of gastrointestinal disorders, preferably irritable colon syndrome; for the prophylaxis and/or treatment of disorders of the central nervous system; for the prophylaxis and/or treatment of anxiety; for the prophylaxis and/or treatment panic attacks; for the prophylaxis and/or treatment of depression; for the prophylaxis and/or treatment of bipolar disorders; for the prophylaxis and/or treatment cognitive disorders, preferably memory disorders; for improvement of cognition (for cognitive enhancement); for the prophylaxis and/or treatment of senile dementia; for the prophylaxis and/or treatment of psychosis; for the prophylaxis and/or treatment neurodegenerative disorders; preferably selected from the group consisting of Morbus Alzheimer, Morbus Parkinson, Morbus Huntington and Multiple Sclerosis; for the prophylaxis and/or treatment of schizophrenia or for the prophylaxis and/or treatment hyperactivity disorder (ADHD, attention deficit, hyperactivity disorder).
Another aspect of the present invention is the use of at least one benzoxazinone-derived sulphonamide compound of general formula (Ib) given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, for the manufacture of a medicament for 5-HT6 receptor-regulation, in particular for the manufacture of a medicament for the prophylaxis and/or treatment of disorders that are at least partially mediated via 5-HT6 receptors.
Preferred is the use of at least one benzoxazinone-derived sulphonamide compound of general formula (Ib) given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, for the manufacture of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably for the regulation of appetite, for the reduction, increase or maintenance of body weight; for the prophylaxis and/or treatment of obesity, for the prophylaxis and/or treatment of bulimia, for the prophylaxis and/or treatment of anorexia; for the prophylaxis and/or treatment of cachexia; or for the prophylaxis and/or treatment of type II diabetes.
Also preferred is the use of at least one benzoxazinone-derived sulphonamide compound of general formula (Ib) given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, for the manufacture of a medicament for the prophylaxis and/or treatment of of gastrointestinal disorders, preferably irritable colon syndrome; for the prophylaxis and/or treatment of disorders of the central nervous system; for the prophylaxis and/or treatment of anxiety; for the prophylaxis and/or treatment panic attacks; for the prophylaxis and/or treatment of depression; for the prophylaxis and/or treatment of bipolar disorders; for the prophylaxis and/or treatment cognitive disorders, preferably memory disorders; for improvement of cognition (for cognitive enhancement); for the prophylaxis and/or treatment of senile dementia; for the prophylaxis and/or treatment of psychosis; for the prophylaxis and/or treatment neurodegenerative disorders; preferably selected from the group consisting of Morbus Alzheimer, Morbus Parkinson, Morbus Huntington and Multiple Sclerosis; for the prophylaxis and/or treatment of schizophrenia; or for the prophylaxis and/or treatment hyperactivity disorder (ADHD, attention deficit, hyperactivity disorder).
The medicament according to the present invention may be in any form suitable for the application to humans and/or animals, particularly mammals, including humans, and can be produced by standard procedures known to those skilled in the art. The composition of the medicament may vary depending on the route of administration.
The preparation of corresponding pharmaceutical compositions as well as of the formulated medicaments may be carried out by conventional methods known to those skilled in the art, e.g. from the tables of contents from “Pharmaceutics: the Science of Dosage Forms”, Second Edition, Aulton, M. E. (Ed.) Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology”, Second Edition, Swarbrick, J. and Boylan J. C. (Eds.), Marcel Dekker, Inc. New York (2002); “Modern Pharmaceutics”, Fourth Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc. New York 2002 and “The Theory and Practice of Industrial Pharmacy”, Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective literature descriptions are incorporated by reference and are part of the disclosure.
The pharmaceutical compositions as well as the formulated medicaments prepared according to the present invention may in addition to at least one compound of general formula (I), (Ia) or (Ib), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt or a corresponding solvate, comprise further conventional auxiliary substances known to those skilled in the art, such as carriers, fillers, solvents, diluents, colouring agents, coating agents, matrix agents and/or binders. As is also known to those skilled in the art, the choice of the auxiliary substances and the amounts thereof to be used are dependent on the intended route of administration, e.g. oral, rectal, intravenous, intraperitoneal, intramuscular, intranasal, buccal or topical route.
Medicaments suitable for oral administration are for example, tablets, sugar-coated pills, capsules or multiparticulates, such as granules or pellets, optionally compressed into tablets, filled into capsules or suspended in a suitable liquid, solutions or suspensions.
Medicaments suitable for parenteral, topical or inhalatory administration may preferably be selected from the group consisting of solutions, suspensions, readily reconstitutable dry preparations and also sprays.
Suitable medicaments, e.g. medicaments for oral or percutaneous use may release the compounds of general formula (I), (Ia) or (Ib) and/or in each case stereoisomers thereof in a delayed manner, whereby the preparation of these delayed release medicaments is generally known to those skilled in the art.
Suitable delayed-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from “Modified-Release Drug Delivery Technology”, Rathbone, M. J. Hadgraft, J. and Roberts, M. S. (Eds.), Marcel Dekker, Inc., New York (2002); “Handbook of Pharmaceutical Controlled Release Technology”, Wise, D. L. (Ed.), Marcel Dekker, Inc. New York, (2000); “Controlled Drug Delivery”, Vol. 1, Basic Concepts, Bruck, S. D. (Ed.), CRC Press Inc., Boca Raton (1983) and from Takada, K. and Yoshikawa, H., “Oral Drug delivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., “Oral drug delivery, small intestine and colon”, Encylopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are incorporated by reference and are part of the disclosure.
The medicament of the present invention may also have at least one enteric coating which dissolves as a function of pH. Because of this coating, the medicament can pass through the stomach undissolved and the compounds of general formula (I), (Ia) or (Ib) are only released in the intestinal tract. The enteric coating preferably dissolves at a pH of between 5 and 7.5. Suitable materials and methods for the preparation of enteric coatings are also known to those skilled in the art
The compositions of the present invention may also be administered topically or via a suppository.
The above mentioned compositions include preferably 1 to 60% by weight of one or more of the benzoxazinone-derived sulphonamide compounds of general formulas (I), (Ia) or (Ib), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and 40 to 99% by weight of the appropriate pharmaceutical vehicle(s).
The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans usally ranges from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of substace to be administered during one or several intakes.
Pharmacological Methods:
Binding to Serotonin Receptor 5HT6
Cell membranes of HEK-293 cells expressing the 5HT6human recombinant receptor were supplied by Receptor Biology. In said membranes the receptor concentration is 2.18 pmol/mg protein and the protein concentration is 9.17 mg/mi. The experimental protocol follows the method of B. L. Roth et al. [B. L. Roth, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding of Typical and Atypical Antipsychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytriptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403] with the following slight changes. The respective part of the literature description is hereby incorporated by reference and forms part of the disclosure.
The commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris-HCl, 10 mM MgCl2, 0.5 mM EDTA (pH 7.4). The radioligand used is [3H]-LSD at a concentration of 2.7 nM with a final volume of 200 μl. incubation is initiated by adding 100 μl of membrane suspension, ≈22.9 μg membrane protein), and is prolonged for 60 minutes at a temperature of 37° C. The incubation is ended by fast filtration in a Brandel Cell Harvester through fiber glass filters made by Schleicher & Schuell GF 3362 pretreated with a solution of polyethylenimine at 0.5%. The filters are washed three times with three milliliters of buffer Tris-HCl 50 mM pH 7.4. The filters are transferred to flasks and 5 ml of Ecoscint H liquid scintillation cocktail are added to each flask. The flasks are allowed to reach equilibrium for several hours before counting with a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 100 μM of serotonin. Tests were made in triplicate. The inhibition constants (Kl, nM) were calculated by non-linear regression analysis using the program EBDA/LIGAND described in Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220, which is hereby incorporated by reference and forms part of the disclosure.
Food Intake Measurement (Behavioral Model):
Male W rats (200-270 g) obtained from Harlan, S. A. are used. The animals are acclimatized to the animal facility for at least 5 days before they are subjected to any treatment. During this period the animals are housed (in groups of five) in translucid cages and provided with food and water ad libitum. At least 24 hours before the treatment starts, the animals are adapted to single-housing conditions.
The acute effect of the inventively used sulphonamide derivatives of general formula (I) on food intake in fasted rats is then determined as follows:
The rats were fasted for 23 hours in their single homecages. After this period, the rats are orally or intraperitoneally dosed with a composition comprising a sulphonamide derivative of general formula (I) or a corresponding composition (vehicle) without said sulphonamide derivative. Immediately afterwards, the rat is left with preweighed food and cumulative food intake is measured after 1, 2, 4 and 6 hours.
Said method of measuring food intake is also described in the literature publications of Kask et al., European Journal of Pharmacology 414 (2001), 215-224 and of Turnbull et al., Diabetes, Vol. 51, August 2002. The respective parts of the descriptions are hereby incorporated by reference and form part of the disclosure.
The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.
The intermediates of general formulas (II) and (III) were prepared by means of conventional organic chemistry methods known to those skilled in the art. The following example A shows the preparation of an intermediate of general formula (II):
Synthesis of an intermediate compound of general formula (II)
A solution of 1-(tert-butyloxycarbonyl)-4-piperidinone (20 g, 0.10 mol), 2-amino-5-chlorobenzylic alcohol (17.34 g, 0.11 mol) and acetic acid (14 mL, 0.22 mol) in dry toluene (500 mL) was heated at reflux temperature, with water elimination by means of azeotrope distillation with Dean-Stark, for 6 hours. The mixture was then cooled and vacuum concentrated up to half volume. NaBH3CN (20 g, 0.32 mol) and dry THF (300 mL) were added to the resulting solution. Acetic acid (10 mL, 0.17 mol) was then dripped for one hour. The reaction was stirred at room temperature for 24 hours. The mixture was vacuum concentrated and the residue was dissolved in ethyl acetate (750 mL), washed with a NaHCO3-saturated solution (4×250 mL) and a NaCl-saturated solution (250 mL), dried and evaporated to dryness. The residue was purified by means of flash chromatography eluting with a mixture of ethyl acetate: petroleum ether (1:3). The desired product was thus obtained as an oil (32.7 g, 96%).
1H NMR (CDCl3): 1.32 (d, J=11.2 Hz, 2H), 1.41 (s, 9H), 1.92 (d, J=11.2 Hz, 2H), 2.92 (t, J=12.0 Hz, 1H), 3.10 (s, 1H), 3.37 (m, 1H), 3.88 (d, J=13.7 Hz, 2H), 4.49 (s, 2H), 4.75 (s, 1H), 6.52 (d, J=8.6 Hz, 1H), 6.96 (s, 1H), 7.07 (d, J=8.6 Hz, 1).
N,N-diisopropylethylamine (DIEA) (43 mL, 0.25 mol) and triphosgene (8.65 g, 29.2 mmol) were added to a solution of 1-(tert-Butyloxycarbonyl)-4-[(4-chloro-(2-hydroxymethyl)phenyl-amino)]piperidine (27.0 g, 79 mmol) in dry THF (250 mL) cooled at 0° C. The reaction was stirred at 0° C. for 1 h and at room temperature for 72 h. Ethyl ether was added and the mixture was cooled at 0° C. for 3 h and the DIEA hydrochloride was then filtered. The filtered solution was evaporated to dryness and the residue was dissolved in ethyl acetate (750 mL), washed with 5% solution of critic acid (2×500 mL), water (250 mL) and NaHCO3-saturated solution (2×500 mL). The ethyl acetate solution was dried (MgSO4), filtered and evaporated under reduced pressure. The residue was brought to the boil with ethyl ether until the whole solid was dissolved and then cooled overnight to yield the desired compound in crystalline form (28.9 g, 67%). Melting point: 177-179° C.
1H NMR (CDCl3): 1.46 (s, 9H), 1.79 (d, J=10.1 Hz, 1H), 2.54 (m, 2H), 2.78 (m, 2H), 3.96 (m, 1H), 4.28 (m, 2H), 5.02 (s, 2H), 6.98 (d, J=8.7 Hz, 1H) 7.13 (d, J=2.4 Hz, 1H), 7.28 (dd, J=8.7 Hz, J=2.4 Hz, 1H).
A solution of 1-[(1-tert-Butyloxycarbonyl)-4-piperidinyl]-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2one (24 g, 65 mmol) in ethyl acetate (500 mL) was cooled at 0° C. A 5 M solution of hydrogen chloride in ethyl ether (500 mL) was then added and the resulting mixture was stirred at 0° C. for 4 h. The precipitate formed was collected by filtration, washed with ether and vacuum dried to yield the desired product as a solid (16.95 g, 97%).
Melting point: 254-257° C.
1H NMR (CD3OD): 2.13 (d, J=12.2 Hz, 2H), 2.88 (m, 2H), 3.20 (m, 2H), 3.53 (d, J=12.8 Hz, 2H), 4.24 (m, 1H), 5.16 (s, 2H), 7.31 (m, 2H), 7.41 (dd, J=8.8 Hz, J=2.6 Hz, 1H).
Several substituted 3,1-benzoxazin-2-one compounds were prepared via the respectively substituted benzyl alcohols by reducing the respectively substituted anthranilic acids with lithium aluminium hydride and other known reducing agents by methods well known to those skilled in the art (see scheme 1), e.g. por ejemplo 6-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methoxy-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methoxy-1-(piperidinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and others. The reaction of the respective 5-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and 6-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one compounds according to conventional methods, e.g. BBr3 in an inert organic solvent yields the respective 5-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and 6-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one compounds. The unsubstituted benzoxazin-2-one 1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one is prepared according the method described in J. Med. Chem. 1995, 38, 4634 and J. Med. Chem. 1998, 41, 2146, which are hereby incorporated by reference and form part of the disclosure.
The substituted anthranilic acids were reduced by conventional methods known to those skilled in the art, e.g. by the use of LiAlH4 as reducing agent in anhydrous THF under an inert-gas atmosphere, e.g. argon or nitrogen. This process is very efficient and in most cases the respective 2-aminobenzylalcohols are obtained in very good yields.
General instruction for the reduction of substituted anthranilic acids:
To a three neck flask, equipped with a mechanical stirrer and an inlet for gaseous nitrogen, 100 mL anhydrous THF and 116.6 mmoles of LiAlH4 were given and the resulting suspension cooled to 0° C. After the addition of 58.3 mmoles of the respective substituted anthranilic acid in 150 mL anhydrous THF, the resulting reaction mixture is warmed to room temperature and stirred or about an hour. Under cooling to 0° C. 4.7 mL water, 4.7 mL NaOH 15 wt.-%, and finally 14 mL water are carefully added to the mixture. The resulting suspension is filtered and washed with ethylacetate.
The organic phase is washed with water, dried and the solvent evaporated. In most cases the resulting product may be used without further purification.
150 mg (0.66 mmol) quinoline-8-sulfonyl chloride are added to a mixture of 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazinone hydrochloride (161 mg, 0.60 mmol) and diisopropylethylamin (230 mg, 1.80 mmol) in dichloromethane (10 ml) and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with water (3×15 mL) and the organic phase was separated, dryed and evaporated to dryness. A solid was obtained, which was recrystallized from ethanol. 182 mg of 1-[1-quinoline-8-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one were obtained as a white solid (yield 69%).
IR (cm−1) KBr: 1712, 1337, 1291, 1205, 1162, 1144, 1034, 717, 583
1H-NMR(δ in ppm): 1.8 (d, J=9.5 Hz, 2 H) 2.6 (qd, J=12.6, 4.4 Hz, 2 H) 3.0 (td, J=12.8, 2.5 Hz, 2 H) 4.1 (tt, J=12.5, 3.8 Hz, 1 H) 4.3 (ddd, J=13.0, 2.3 Hz, 2 H) 5.0 (s, 2 H) 7.1 (m, 3 H) 7.3 (m, 1 H) 7.6 (dd, J=8.4, 4.2 Hz, 1 H) 7.6 (m, 1 H) 8.1 (dd, J=8.2, 1.3 Hz, 1 H) 8.3 (dd, J=8.3, 1.7 Hz, 1 H) 8.5 (dd, J=7.3, 1.5 Hz, 1 H) 9.1 (dd, J=4.2, 1.8 Hz, 1 H) (CDCl3-d).
Melting point: 170-172° C.
The compounds according to examples 1-4 and 6-10 given in the following table I as well as the compounds according to lists A and B given above were prepared analogously to the methods described above.
Pharmacological Data:
The binding of the benzoxazinone derived sulphonamide compounds of general formulas (I), (Ia), and (Ib) was determined as described above.
The binding results of some these compounds are given in the following table 2:
| Number | Date | Country | Kind |
|---|---|---|---|
| P 200301812 | Jul 2003 | ES | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP04/08507 | 7/29/2004 | WO | 9/7/2006 |
