Patent Application
20080312301
The present invention relates to substituted N-benzo[d]isoxazol-3-ylamine derivatives, process for their preparation, medicaments comprising these compounds, and the use of these compounds for producing medicaments.
Pain is one of the basic symptoms in clinical practice. There is a world-wide need for effective pain therapies. The pressing need for action for a treatment of chronic and non-chronic states of pain which is appropriate for patients and target-oriented, meaning by this the successful and satisfactory treatment of the patient's pain, is also demonstrated by the large number of scientific studies which have recently appeared in the field of applied analgesics and of basic research into nociception.
Classical opioids such as, for example, morphine are effective for the therapy of severe to very severe pain but often lead to unwanted side effects such as, for example, respiratory depression, vomiting, sedation, constipation or development of tolerance. They are moreover frequently insufficiently effective for neuropathic pain, from which tumor patients in particular suffer.
One object of the present invention was therefore to provide novel compounds which are suitable in particular as active pharmaceutical ingredients in medicaments, preferably in medicaments for the treatment of pain.
A further object of the present invention was to provide novel compounds which are suitable as pharmacological active ingredients in medicaments for the treatment of impairments or diseases which are mediated at least in part by mGluR5 receptors (mGluR5=metabotropic glutamate receptor 5) and/or serotonin (5-HT) receptors and/or noradrenaline receptors.
It has now been found, surprisingly, that substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formulae I and Ia indicated below have an excellent affinity for the mGluR5 receptor, for the serotonin (5-HT) receptor and for the noradrenaline receptor, and are therefore suitable in particular for the prophylaxis and/or treatment of disorders or diseases which are mediated at least partly by mGluR5 receptors (mGluR5=metabotropic glutamate receptor 5) and/or serotonin (5-HT) receptors and/or noradrenaline receptors.
The present invention therefore relates firstly to a medicament comprising at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the general formula I
in which
The aforementioned optionally substituted C1-10 alkyl radicals may preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —OH, —SH and —NO2.
The aforementioned optionally substituted C2-10 alkenyl radicals can likewise preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —OH, —SH and —NO2.
Where one or more of the substituents R1 to R4, R10 to R13 and R16 to R20 are a linear or branched C1-10-alkyl radical, this radical can preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl.
If one or more of the substituents R5, R6, R8, R14 and R15 are a linear or branched, optionally substituted C1-10-alkyl radical, this radical can preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl and optionally be substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN and —NO2.
Particularly preferred optionally substituted C1-10-alkyl radicals can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 3-heptyl, 3-octyl, 3,5,5-trimethylhexyl, —CF3, —CFH2, —CF2H, —CBr3, —CCl3, —CF2—CF3, —CH2—CF3, —CH2—CN, —CH2—NO2, —CF2—CF2—CF3, —CH2—CH2—CF3, —CH2—CH2—CN, —CH2—CH2—NO2, —CF2—CF2—CF2—CF3 and —CH2—CH2—CH2—CN.
If one or more of the substituents R5, R6, R8, R14 and R15 are a linear or branched optionally substituted C2-10-alkenyl radical, this radical can preferably be selected from the group consisting of 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and 2-methyl-1-propenyl and optionally be substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN and —NO2.
The aforementioned optionally substituted cycloaliphatic radicals can preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—O—C1-5-alkyl, —(CH2)—C(═O)—O—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —(CH2)-benzo[b]furanyl, —O-phenyl, —O-benzyl, phenyl, benzyl, naphthyl and —(CH2)-naphthyl, where in each case the cyclic part of the radicals —O-phenyl, —O-benzyl, phenyl, —(CH2)-benzo[b]furanyl, benzyl, naphthyl and —(CH2)-naphthyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—C1-5-alkyl, —C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
Where the substituent R5 and/or R21 is a cycloaliphatic radical which may optionally be bridged by 1 or 2 linear or branched C1-5-alkylene groups, this can preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, [6,6]-dimethyl-[3.1.1]-bicycloheptyl and adamantyl.
The cycloaliphatic radicals can particularly preferably each be optionally substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—O—CH3, —C(═O)—C2H5, —C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —N(CH(CH3)2)2, —(CH2)-benzo[b]furanyl, —O-phenyl, —O-benzyl, phenyl, benzyl, naphthyl and —(CH2)-naphthyl, where in each case the cyclic part of the radicals —O-phenyl, —O-benzyl, phenyl, —(CH2)-benzo[b]furanyl, benzyl, naphthyl and —(CH2)-naphthyl can be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—CH3, —O—C2H5, —O—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
The aforementioned optionally substituted aryl or heteroaryl radicals may likewise preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —O—C2-5-alkenyl, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, —C(═O)—N—(C1-5-alkyl)2, —S(═O)2—NH2, —S(═O)2—NH—C1-5-alkyl, —S(═O)2—N(C1-5-alkyl)2, —S(═O)2-phenyl, —S(═O)2—C1-5-alkyl, —(CH2)-benzo[b]furanyl, dihydrobenzo[b]furanyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, pyridinyl and benzyl, where in each case the cyclic part of the radicals —S(═O)2-phenyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, —(CH2)-benzo[b]furanyl, dihydro[b]benzofuranyl, pyridinyl and benzyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—C1-5-alkyl, —C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
The aforementioned heteroaryl radicals may preferably optionally each have 1, 2, 3, 4 or 5 heteroatom(s) independently of one another selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s).
Where one or more of the substituents R5 to R9, R14, R15, R17, R18 and R20 to R22 are an aryl radical, this can preferably be selected from the group consisting of phenyl and naphthyl (1-naphthyl and 2-naphthyl).
Where one or more of the substituents R5 to R9, R14, R15 and R21 are a heteroaryl radical, this can preferably be selected from the group consisting of thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzo[2,1,3]thiadiazolyl, [1,2,3]-benzothiadiazolyl, [2,1,3]-benzoxadiazolyl and [1,2,3]-benzoxadiazolyl.
The aryl or heteroaryl radicals can particularly preferably optionally each be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —O—CH2—CH═CH2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—C(CH3)3, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—C2H5, —C(═O)—N—(CH3)2, —C(═O)—N—(C2H5)2, —S(═O)2—NH2, —S(═O)2—NH—CH3, —S(═O)2—N(CH3)2, —S(═O)2—N(C2H5)2, —S(═O)2—N(n-C3H7)2, —S(═O)2—N(CH(CH3)2)2, —S(═O)2-phenyl, —S(═O)2—CH3, —S(═O)2—C2H5, —S(═O)2—CH(CH3)2, —(CH2)-benzo[b]furanyl, dihydrobenzo[b]furanyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, pyridinyl and benzyl, where in each case the cyclic part of the radicals —S(═O)2-phenyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, —(CH2)-benzo[b]furanyl, dihydro[b]benzofuranyl, pyridinyl and benzyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—CH3, —O—C2H5, —O—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
The rings of the aforementioned optionally substituted mono- or polycyclic ring systems may likewise preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —O—C2-5-alkenyl, —NH2, —NO2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, —C(═O)—N—(C1-5-alkyl)2, —S(═O)2—NH2, —S(═O)2—NH—C1-5-alkyl, —S(═O)2—N(C1-5-alkyl)2, —S(═O)2-phenyl and —S(═O)2—C1-5-alkyl.
The rings of the aforementioned optionally substituted mono- or polycyclic ring systems may particularly preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —NH2, —NO2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—C(CH3)3, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—C2H5, —C(═O)—N—(CH3)2, —C(═O)—N—(C2H5)2, —S(═O)2—NH2, —S(═O)2—NH—CH3, —S(═O)2—N(CH3)2, —S(═O)2—N(C2H5)2, —S(═O)2—N(n-C3H7)2, —S(═O)2—N(CH(CH3)2)2, —S(═O)2-phenyl, —S(═O)2—CH3, —S(═O)2—C2H5 and —S(═O)2—CH(CH3)2.
A mono- or polycyclic ring system means in the context of the present invention mono- or polycyclic hydrocarbon radicals which may be saturated or unsaturated and optionally have 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s) which are selected independently of one another from the group consisting of oxygen, nitrogen and sulfur.
Such a mono- or polycyclic ring system may for example be fused to an aryl radical or a heteroaryl radical.
If a polycyclic ring system such as, for example, a bicyclic ring system is present, the various rings may each independently of one another have a different degree of saturation, i.e. be saturated or unsaturated. A polycyclic ring system is preferably a bicyclic ring system.
The rings of the aforementioned mono- or polycyclic ring systems preferably each have 5, 6 or 7 members and may each have 1, 2 or 3 heteroatom(s) as ring member(s) which are selected independently of one another from the group consisting of oxygen, nitrogen and sulfur.
Examples which may be mentioned of aryl radicals which may be fused to a mono- or polycyclic ring system are [1,3]-benzodioxolyl, [1,4]-benzodioxanyl, [1,2,3,4]-tetrahydronaphthyl, [1,2,3,4]-tetrahydroquinolinyl, [1,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-1,4-benzoxazinyl.
Where the radical R5 has a linear or branched C1-5-alkylene group, this can preferably be selected from the group consisting of —(CH2)—, —(CH2)2—, —C(H)(CH3)—, —C(CH3)2—, —(CH2)3—, —(CH2)4—, —(CH2)5—, —C(H)(C(H)(CH3)2)— and —C(C2H5)(H)—.
Preferred medicaments comprise at least one compound of the general formula I indicated above, in which
R6, R8, R14 and R15 independently of one another each
are a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 3-heptyl, 3-octyl, 3,5,5-trimethylhexyl, —CF3, —CFH2, —CF2H, —CBr3, —CCl3, —CF2—CF3, —CH2—CF3, —CH2—CN, —CH2—NO2, —CF2—CF2—CF3, —CH2—CH2—CF3, —CH2—CH2—CN, —CH2—CH2—NO2, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CN, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and 2-methyl-1-propenyl;
or are a radical selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, where the radical may in each case optionally be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl;
and in each case R1 to R5, R7, R9 to R13 and R16 to R22 have the aforementioned meaning, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Further preferred medicaments comprise at least one compound of the general formula I indicated above, in which
R7 and R9 independently of one another each are
a radical selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, where the radical may in each case optionally be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl;
and in each case R1 to R6, R8 and R10 to R22 have the aforementioned meaning, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Likewise preferred medicaments comprise at least one compound of the general formula I indicated above, in which
R10 and R11 independently of one another each are a hydrogen radical
or are an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl;
and in each case R1 to R9 and R12 to R22 have the aforementioned meaning, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Further preferred medicaments comprise at least one compound of the general formula I indicated above, in which
R12, R13, R16 and R19 independently of one another each are an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl;
and in each case R1 to R11, R14, R15, R17, R18 and R20 to R22 have the aforementioned meaning, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Likewise preferred medicaments comprise at least one compound of the general formula I indicated above, in which
Likewise preferred medicaments comprise at least one compound of the general formula I indicated above, in which
Likewise preferred medicaments comprise at least one compound of the general formula I indicated above, in which
Further preferred medicaments comprise at least one compound of the general formula I indicated above, in which
Particularly preferred medicaments comprise at least one compound of the general formula I indicated above, characterized in that
Very particularly preferred medicaments comprise at least one compound of the general formula I indicated above, characterized in that
Yet further preferred medicaments comprise at least one compound of the general formula I selected from the group consisting of
The medicaments of the invention are particularly suitable for mGluR5 receptor regulation, preferably for inhibiting the mGluR5 receptor, and/or for noradrenaline receptor regulation, preferably for noradrenaline reuptake inhibition, and/or for serotonin (5-HT) receptor regulation, preferably for serotonin reuptake inhibition, and thus also for the prophylaxis and/or treatment of disorders and diseases which are mediated at least partly by mGluR5 receptors and/or noradrenaline receptors and/or serotonin receptors.
The medicament of the invention is preferably suitable for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia;
pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraines; chronic paroxysmal hemicrania; depression; urinary incontinence; cough, asthma; glaucoma; tinitus; inflammations; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; narcolepsy; diarrhea; gastritis, gastric ulcer; pruritus; anxiety states; panic attacks; schizophrenia; cerebral ischemia; muscle spasms; cramps; gastroesaphageal reflux syndrome; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency;
for the prophylaxis and/or reduction of a development of tolerance to medicaments and/or drugs, especially medicaments based on opioids; for regulating food intake; for modulating motor activity, for regulating the cardiovascular system; for local anesthesia; for increasing vigilance; for increasing libido; for diuresis and/or for antinatriuresis.
The medicament of the invention is particularly preferably suitable for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); anxiety states; panic attacks; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency.
The medicament of the invention is very particularly preferably suitable for the treatment and/or prophylaxis of pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
The present invention further relates to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula I indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for the manufacture of a medicament for mGluR5 receptor regulation, preferably for inhibiting the mGluR5 receptor, and/or for noradrenaline receptor regulation, preferably for noradrenaline reuptake inhibition, and/or for serotonin (5-HT) receptor regulation, preferably for serotonin reuptake inhibition.
Preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-yl-amine derivative of the invention, of the general formula I indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the prophylaxis and/or treatment of disorders and diseases which are mediated at least partly by mGluR5 receptors and/or noradrenaline receptors and/or serotonin receptors.
Particular preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula I indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraines; chronic paroxysmal hemicrania; depression; urinary incontinence; cough, asthma; glaucoma; tinitus; inflammations; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; narcolepsy; diarrhea; gastritis, gastric ulcer; pruritus; anxiety states; panic attacks; schizophrenia; cerebral ischemia; muscle spasms; cramps; gastroesaphageal reflux syndrome; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency; for the prophylaxis and/or reduction of a development of tolerance to medicaments and/or drugs, especially medicaments based on opioids; for regulating food intake; for modulating motor activity, for regulating the cardiovascular system; for local anesthesia; for increasing vigilance; for increasing libido; for diuresis and/or for antinatriuresis.
Very particular preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula I indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); anxiety states; panic attacks; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency.
Yet more preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula I indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
The medicament of the invention is suitable for administration to adults and children, including infants and babies.
The medicament of the invention can be in the form of a liquid, semisolid or solid pharmaceutical form, for example in the form of solutions for injection, drops, elixirs, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, where appropriate compressed to tablets, packed into capsules or suspended in a liquid, and be administered as such. Besides at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the general formula I indicated above, where appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemate or in the form of mixtures of stereoisomers, in particular of enantiomers or diastereomers or rotamers, in any mixing ratio, or where appropriate in the form of a corresponding salt or in each case in the form of a corresponding solvate, the medicament of the invention normally comprises further physiologically tolerated pharmaceutical excipients which can preferably be selected from the group consisting of carrier materials, fillers, solvates, diluents, surface-active substances, colorants, preservatives, disintegrants, glidants, lubricants, flavorings and binders.
The selection of the physiologically tolerated excipients and the amounts thereof to be employed depends on whether the medicament is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, the mucous membranes and of the eyes. Suitable and preferred for oral administration are preparations in the form of tablets, coated tablets, capsules, granules, pellets, drops, elixiers and syrups, and for parenteral, topical and inhalational administration are solutions, suspensions, easily reconstitutable dry preparations, and sprays.
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula I indicated above, which are employed in the medicament of the invention may be in the form of a depot, in dissolved form or in a plaster, where appropriate with the addition of agents promoting skin penetration, as suitable percutaneous administration preparations.
Formulations which can be used orally or percutaneously may also release the particular substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula I indicated above, in a delayed manner. It is possible in principle to add to the medicament of the invention other further active ingredients known to the skilled worker.
The medicaments of the invention are manufactured with the aid of conventional means, apparatuses, methods and processes known from the prior art, as described for example in “Remington's Pharmaceutical Sciences”, edited by A. R. Gennaro, 17th edition, Mack Publishing Company, Easton, Pa., 1985, especially in part 8, chapter 76 to 93. The corresponding description is introduced hereby as reference and forms part of the disclosure.
The amount of the particular substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula I indicated above, to be administered to the patient may vary and depends for example on the weight or age of the patient and on the mode of administration, the indication and the severity of the disorder. Normally, 0.005 to 100 mg/kg, preferably 0.05 to 75 mg/kg, of the patient's body weight of at least one such compound of the invention are administered.
The present application further relates to substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia,
in which
The aforementioned optionally substituted cycloaliphatic radicals may preferably each be unsubstituted or optionally substituted in each case by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—O—C1-5-alkyl, —(CH2)—C(═O)—O—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —(CH2)-benzo[b]furanyl, —O-phenyl, —O-benzyl, phenyl, benzyl, naphthyl and —(CH2)-naphthyl, where in each case the cyclic part of the radicals —O-phenyl, —O-benzyl, phenyl, —(CH2)-benzo[b]furanyl, benzyl, naphthyl and —(CH2)-naphthyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—C1-5-alkyl, —C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
Where the substituent R5a and/or R19a is a cycloaliphatic radical which may optionally be bridged by 1 or 2 linear or branched C1-5-alkylene groups, this can preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, [6,6]-dimethyl-[3.1.1]-bicycloheptyl and adamantyl.
The cycloaliphatic radicals may particularly preferably each optionally be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—O—CH3, —C(═O)—C2H5, —C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —N(CH(CH3)2)2, —(CH2)-benzo[b]furanyl, —O-phenyl, —O-benzyl, phenyl, benzyl, naphthyl and —(CH2)-naphthyl, where in each case the cyclic part of the radicals —O-phenyl, —O-benzyl, phenyl, —(CH2)-benzo[b]furanyl, benzyl, naphthyl and —(CH2)-naphthyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—CH3, —O—C2H5, —O—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
Unless indicated otherwise, the aforementioned optionally substituted aryl, heteroaryl, naphthyl, furanyl or thiophenyl radicals can likewise preferably each be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —O—C2-5-alkenyl, —NO2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, —C(═O)—N—(C1-5-alkyl)2, —S(═O)2—NH2, —S(═O)2—NH—C1-5-alkyl, —S(═O)2—N(C1-5-alkyl)2, —S(═O)2-phenyl, —S(═O)2—C1-5-alkyl, —(CH2)-benzo[b]furanyl, dihydrobenzo[b]furanyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, pyridinyl and benzyl, where in each case the cyclic part of the radicals —S(═O)2-phenyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, —(CH2)-benzo[b]furanyl, dihydro[b]benzofuranyl, pyridinyl and benzyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—C1-5-alkyl, —C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
The aforementioned heteroaryl radicals may preferably optionally each have 1, 2, 3, 4 or 5 heteroatom(s) independently of one another selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s).
Where one or more of the substituents R5a to R9a, R15a, R16a and R18a to R20a are an aryl radical, this can preferably be selected from the group consisting of phenyl and naphthyl (1-naphthyl and 2-naphthyl).
The aryl radicals can particularly preferably optionally each be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —O—CH2—CH═CH2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—C(CH3)3, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—C2H5, —C(═O)—N—(CH3)2, —C(═O)—N—(C2H5)2, —S(═O)2—NH2, —S(═O)2—NH—CH3, —S(═O)2—N(CH3)2, —S(═O)2—N(C2H5)2, —S(═O)2—N(n-C3H7)2, —S(═O)2—N(CH(CH3)2)2, —S(═O)2-phenyl, —S(═O)2—CH3, —S(═O)2—C2H5, —(CH2)-benzo[b]furanyl, dihydrobenzo[b]furanyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, pyridinyl and benzyl, where in each case the cyclic part of the radicals —S(═O)2-phenyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, —(CH2)-benzo[b]furanyl, dihydro[b]benzofuranyl, pyridinyl and benzyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—CH3, —O—C2H5, —O—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
Where one or more of the substituents R5a to R9a and R19a are a heteroaryl radical or include one such, this can preferably be selected from the group consisting of thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzo[2,1,3]thiadiazolyl, [1,2,3]-benzothiadiazolyl, [2,1,3]-benzoxadiazolyl and [1,2,3]-benzoxadiazolyl.
The heteroaryl radicals may particularly preferably optionally each be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —O—CH2—CH═CH2, —NO2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—C(CH3)3, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—C2H5, —C(═O)—N—(CH3)2, —C(═O)—N—(C2H5)2, —S(═O)2—NH2, —S(═O)2—NH—CH3, —S(═O)2—N(CH3)2, —S(═O)2—N(C2H5)2, —S(═O)2—N(n-C3H7)2, —S(═O)2—N(CH(CH3)2)2, —S(═O)2-phenyl, —S(═O)2—CH3, —S(═O)2—C2H5, —S(═O)2—CH(CH3)2, —(CH2)-benzo[b]furanyl, dihydrobenzo[b]furanyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, pyridinyl and benzyl, where in each case the cyclic part of the radicals —S(═O)2-phenyl, —O-phenyl, —O-benzyl, —S-phenyl, —S-benzyl, phenyl, —(CH2)-benzo[b]furanyl, dihydro[b]benzofuranyl, pyridinyl and benzyl may be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —O—CH3, —O—C2H5, —O—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
The aforementioned optionally substituted C1-10 alkyl radicals may likewise preferably each be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —OH, —SH, —CN and —NO2.
Where one or more of the substituents R1a to R4a, R10a to R18a are a linear or branched C1-10-alkyl radical, this can preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl.
If R5a is a linear or branched C2-10-alkyl radical, this can preferably be selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl.
If the substituent R6a and/or R8a is a linear or branched, optionally substituted C1-10-alkyl radical, this can preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, n-octyl, 2-octyl, 3-octyl, n-nonyl, 2-nonyl, 3-nonyl and 3,5,5-trimethylhexyl and optionally each be substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, —CN and —NO2.
Particularly preferred optionally substituted C1-10-alkyl radicals can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 3-heptyl, 3-octyl, 3,5,5-trimethylhexyl, —CF3, —CFH2, —CF2H, —CBr3, —CCl3, —CF2—CF3, —CH2—CF3, —CH2—CN, —CH2—NO2, —CF2—CF2—CF3, —CH2—CH2—CF3, —CH2—CH2—CN, —CH2—CH2—NO2, —CF2—CF2—CF2—CF3 and —CH2—CH2—CH2—CN.
If R5a is a C2-10-alkenyl radical, this radical can preferably be selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl and 3-pentenyl.
A mono- or polycyclic ring system means in the context of the present invention mono- or polycyclic hydrocarbon radicals which may be saturated or unsaturated and optionally have 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s) which are selected independently of one another from the group consisting of oxygen, nitrogen and sulfur.
Such a mono- or polycyclic ring system can for example be fused to an aryl radical or a heteroaryl radical.
Where a polycyclic ring system such as, for example, a bicyclic ring system is present, the various rings may each independently of one another have a different degree of saturation, i.e. be saturated or unsaturated. A polycyclic ring system is preferably a bicyclic ring system.
The rings of the aforementioned mono- or polycyclic ring systems preferably each have 5, 6 or 7 members and may each have 1, 2 or 3 heteroatom(s) as ring member(s) which are selected independently of one another from the group consisting of oxygen, nitrogen and sulfur.
The rings of the aforementioned optionally substituted mono- or polycyclic ring systems may preferably be unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —O—C2-5-alkenyl, —NH2, —NO2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, —C(═O)—N—(C1-5-alkyl)2, —S(═O)2—NH2, —S(═O)2—NH—C1-5-alkyl, —S(═O)2—N(C1-5-alkyl)2, —S(═O)2-phenyl and —S(═O)2—C1-5-alkyl.
The rings of the aforementioned optionally substituted mono- or polycyclic ring systems may particularly preferably be unsubstituted or optionally each substituted by 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C3H7, —NH2, —NO2, —O—CF3, —O—CHF2, —O—CH2F, —S—CF3, —S—CHF2, —S—CH2F, —SH, —S—CH3, —S—C2H5, —S—C3H7, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—C(CH3)3, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—C(CH3)3, —NH—CH3, —NH—C2H5, —N(CH3)2, —N(C2H5)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—C2H5, —C(═O)—N—(CH3)2, —C(═O)—N—(C2H5)2, —S(═O)2—NH2, —S(═O)2—NH—CH3, —S(═O)2—N(CH3)2, —S(═O)2—N(C2H5)2, —S(═O)2—N(n-C3H7)2, —S(═O)2—N(CH(CH3)2)2, —S(═O)2-phenyl, —S(═O)2—CH3, —S(═O)2—C2H5 and —S(═O)2—CH(CH3)2.
Examples which may be mentioned of aryl radicals which are fused to a mono- or polycyclic ring system are [1,3]-benzodioxolyl, [1,4]-benzodioxanyl, [1,2,3,4]-tetrahydronaphthyl, [1,2,3,4]-tetrahydroquinolinyl, [1,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-1,4-benzoxazinyl.
Where the radical R5a includes a linear or branched C1-5-alkylene group, this can preferably be selected from the group consisting of —(CH2)—, —(CH2)2—, —C(H)(CH3)—, —C(CH3)2—, —(CH2)3—, —(CH2)4—, —(CH2)5—, —C(H)(C(H)(CH3)2)— and —C(C2H5)(H)—.
Preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Further preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Likewise preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Further preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Likewise preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Likewise preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Further preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Likewise preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Particularly preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Very particularly preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are those in which
Even more preferred substituted N-benzo[d]isoxazol-3-ylamine derivatives of the general formula Ia indicated above are selected from the group consisting of
The present invention further relates to a process for preparing compounds of the general formula Ia indicated above, in which at least one compound of general formula IIa
in which R1a to R4a have the aforementioned meaning, is reacted
in a reaction medium, where appropriate in the presence of at least one base, with at least one compound of the general formula R5a—C(═O)—X in which R5a has the aforementioned meaning, and X is a leaving group, preferably a halogen radical, particularly preferably a chlorine atom,
or in a reaction medium in the presence of at least one coupling reagent, where appropriate in the presence of at least one base, with at least one compound of the general formula R5a—C(═O)—OH in which R5a has the aforementioned meaning, to give a compound of the general formula Ia,
in which R1a to R5a have the aforementioned meaning, and the latter is isolated and/or purified where appropriate.
The process of the invention for preparing substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula Ia indicated above, is also indicated in scheme 1 below. The method of the invention is likewise suitable for preparing substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula I indicated above.
In stage 1, substituted 2-fluorobenzonitriles of the general formula IIIa in which R1a to R4a have the aforementioned meaning are reacted in a reaction medium, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide and dichloromethane, in the presence of at least one base, preferably in the presence of at least one alkali metal alcoholate salt, particularly preferably in the presence of an alkali metal alcoholate salt selected from the group consisting of potassium methanolate, sodium methanolate, potassium tert-butoxide and sodium tert-butoxide, with acetohydroxamic acid (A), preferably at temperatures of from 20° C. to 100° C., to give compounds of the general formula IIa. In stage 2, compounds of the general formula IIa indicated above are reacted with carboxylic acids of the general formula R5a—C(═O)—OH in which R5a has the aforementioned meaning, in a reaction medium, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide and dichloromethane, where appropriate in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniom hexafluorophosphate (HBTU) and 1-hydroxy-7-azabenzotriazole (HOAt), where appropriate in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and cesium carbonate, or of an organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine and diisopropylethylamine, preferably at temperatures of from −70° C. to 100° C., to give compounds of the general formula Ia.
Alternatively, compounds of the general formula IIa are reacted with carboxylic acid derivatives or carbonic acid derivatives of the general formula R5a—C(═O)—X where X is a halogen radical, preferably chlorine or bromine, in a reaction medium, preferably selected from the group consisting of diethyl ether, pyridine, tetrahydrofuran, acetonitrile, dimethylformamide and dichloromethane, preferably in the presence of at least one organic or inorganic base, for example triethylamine, dimethylamino-pyridine, pyridine, diisopropylamine, alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides and alkaline earth metal carbonates, particularly preferably in the presence of an organic base selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine, at temperatures of preferably from −70° C. to 100° C., to give compounds of the general formula Ia.
The reactions described above can in each case be carried out under usual conditions familiar to the skilled worker, for example in relation to pressure or sequence or addition of the components. It is possible where appropriate for the skilled worker to ascertain the optimal management of the process under the respective conditions by simple preliminary tests.
The compounds of the formulae IIIa indicated above and of the general formulae R5a—C(═O)—OH and R5a—C(═O)—X can in each case be purchased commercially and/or can be prepared by usual processes known to the skilled worker.
The intermediates and final products obtained after the reactions described above can in each case, if desired and/or necessary, be purified and/or isolated by usual methods known to the skilled worker. Suitable purification methods are for example extraction methods and chromatographic methods such as column chromatography or preparative chromatography.
All of the process steps described above, and in each case also the purification and/or isolation of intermediates and final products, can be carried out partly or completely under an inert gas atmosphere, preferably under nitrogen atmosphere or argon atmosphere.
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the aforementioned general formulae I and Ia, and corresponding stereoisomers can be isolated both in the form of their free bases, their free acids and in the form of corresponding salts, especially physiologically tolerated salts.
The free bases of the respective substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the aforementioned general formulae I and Ia, and corresponding stereoisomers can be converted for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid, into the corresponding salts, preferably physiologically tolerated salts.
The free bases of the respective substituted N-benzo[d]isoxazol-3-ylamine derivatives of the aforementioned general formulae I and Ia and corresponding stereoisomers can likewise be converted with the free acid or a salt of a sugar substitute, such as, for example, saccharin, cyclamate or acesulfame, into the corresponding physiologically tolerated salts.
Correspondingly, the free acids of the substituted N-benzo[d]isoxazol-3-ylamine derivatives of the aforementioned general formulae I and Ia and corresponding stereoisomers can be converted by reaction with a suitable base into the corresponding physiologically tolerated salts. Examples which may be mentioned are the alkali metal salts, alkaline earth metal salts or ammonium salts [NHxR4-x]+, in which x is 0, 1, 2, 3 or 4 and R is a linear or branched C1-4-alkyl radical.
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the aforementioned general formulae I and Ia, and corresponding stereoisomers can also where appropriate, just like the corresponding acids, the corresponding bases or salts of these compounds, be obtained in the form of their solvates, preferably in the form of their hydrates, by usual methods known to the skilled worker.
Where the substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the aforementioned general formulae I and Ia, are obtained after their preparation in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and/or diastereomers, these can be separated and, where appropriate, isolated by usual methods known to the skilled worker. Examples which may be mentioned are chromatographic separation methods, in particular liquid chromatographic methods under atmospheric pressure or under elevated pressure, preferably MPLC and HPLC methods, and methods of fractional crystallization. It is possible in this connection in particular for individual enantiomers to be separated from one another for example by means of HPLC on a chiral stationary phase or by means of crystallization of diastereomeric salts formed with chiral acids, for instance (+)-tartaric acid, (−)-tartaric acid or (+)-10-camphor sulfonic acid.
The present invention further relates to a medicament comprising at least one compound of the invention of the general formula Ia, where appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemate or in the form of mixtures of stereoisomers, in particular of enantiomers or diastereomers, in any mixing ratio, or where appropriate in the form of a corresponding salt or in each case in the form of a corresponding solvate, and where appropriate one or more physiologically tolerated excipients.
The medicaments of the invention are particularly suitable for mGluR5 receptor regulation, preferably for inhibiting the mGluR5 receptor, and/or for noradrenaline receptor regulation, preferably for noradrenaline reuptake inhibition, and/or for serotonin (5-HT) receptor regulation, preferably for serotonin reuptake inhibition, and thus also for the prophylaxis and/or treatment of disorders and diseases which are mediated at least partly by mGluR5 receptors and/or noradrenaline receptors and/or serotonin receptors.
The medicament of the invention is preferably suitable for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia;
pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraines; chronic paroxysmal hemicrania; depression; urinary incontinence; cough, asthma; glaucoma; tinitus; inflammations; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; narcolepsy; diarrhea; gastritis, gastric ulcer; pruritus; anxiety states; panic attacks; schizophrenia; cerebral ischemia; muscle spasms; cramps; gastroesaphageal reflux syndrome; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency;
for the prophylaxis and/or reduction of a development of tolerance to medicaments and/or drugs, especially medicaments based on opioids; for regulating food intake; for modulating motor activity, for regulating the cardiovascular system; for local anesthesia; for increasing vigilance; for increasing libido; for diuresis and/or for antinatriuresis.
The medicament of the invention is particularly preferably suitable for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); anxiety states; panic attacks; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency.
The medicament of the invention is very particularly preferably suitable for the treatment and/or prophylaxis of pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
The present invention further relates to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula Ia indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for the manufacture of a medicament for mGluR5 receptor regulation, preferably for inhibiting the mGluR5 receptor, and/or for noradrenaline receptor regulation, preferably for noradrenaline reuptake inhibition, and/or for serotonin (5-HT) receptor regulation, preferably for serotonin reuptake inhibition.
Preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-yl-amine derivative of the invention, of the general formula Ia indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the prophylaxis and/or treatment of disorders and diseases which are mediated at least partly by mGluR5 receptors and/or noradrenaline receptors and/or serotonin receptors.
Particular preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula Ia indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraines; chronic paroxysmal hemicrania; depression; urinary incontinence; cough; asthma; glaucoma; tinitus; inflammations; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; narcolepsy; diarrhea; gastritis, gastric ulcer; pruritus; anxiety states; panic attacks; schizophrenia; cerebral ischemia; muscle spasms; cramps; gastroesaphageal reflux syndrome; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency; for the prophylaxis and/or reduction of a development of tolerance to medicaments and/or drugs, especially medicaments based on opioids; for regulating food intake; for modulating motor activity, for regulating the cardiovascular system; for local anesthesia; for increasing vigilance; for increasing libido; for diuresis and/or for antinatriuresis.
Very particular preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula Ia indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of disorders of food intake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; pain, preferably pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); anxiety states; panic attacks; alcohol and/or drug abuse, preferably nicotine or cocaine, and/or medicament abuse; alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency, preferably for the prophylaxis and/or reduction of withdrawal manifestations associated with alcohol and/or drug dependency, preferably nicotine or cocaine, and/or medicament dependency.
Yet more preference is given to the use of at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the invention, of the general formula Ia indicated above, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemates or in the form of a mixture of stereoisomers, in particular of enantiomers and/or diastereomers and/or rotamers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and where appropriate one or more pharmaceutically acceptable excipients for manufacturing a medicament for the treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
The medicament of the invention is suitable for administration to adults and children, including infants and babies.
The medicament of the invention can be in the form of a liquid, semisolid or solid pharmaceutical form, for example in the form of solutions for injection, drops, elixiers, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, where appropriate compressed to tablets, packed into capsules or suspended in a liquid, and be administered as such. Besides at least one substituted N-benzo[d]isoxazol-3-ylamine derivative of the general formula Ia indicated above, where appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers or rotamers, its racemate or in the form of mixtures of stereoisomers, in particular of enantiomers or diastereomers or rotamers, in any mixing ratio, or where appropriate in the form of a corresponding salt or in each case in the form of a corresponding solvate, the medicament of the invention normally comprises further physiologically tolerated pharmaceutical excipients which can preferably be selected from the group consisting of carrier materials, fillers, solvates, diluents, surface-active substances, colorants, preservatives, disintegrants, glidants, lubricants, flavorings and binders.
The selection of the physiologically tolerated excipients and the amounts thereof to be employed depends on whether the medicament is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, the mucous membranes and of the eyes. Suitable and preferred for oral administration are preparations in the form of tablets, coated tablets, capsules, granules, pellets, drops, elixirs and syrups, and for parenteral, topical and inhalational administration are solutions, suspensions, easily reconstitutable dry preparations, and sprays.
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula Ia indicated above, which are employed in the medicament of the invention may be in the form of a depot, in dissolved form or in a plaster, where appropriate with the addition of agents promoting skin penetration, as suitable percutaneous administration preparations. Formulations which can be used orally or percutaneously may also release the particular substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula Ia indicated above, in a delayed manner. It is possible in principle to add to the medicament of the invention other further active ingredients known to the skilled worker.
The medicaments of the invention are manufactured with the aid of conventional means, apparatuses, methods and processes known from the prior art, as described for example in “Remington's Pharmaceutical Sciences”, edited by A. R. Gennaro, 17th edition, Mack Publishing Company, Easton, Pa., 1985, especially in part 8, chapter 76 to 93. The corresponding description is introduced hereby as reference and forms part of the disclosure.
The amount of the particular substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula Ia indicated above, to be administered to the patient may vary and depends for example on the weight or age of the patient and on the mode of administration, the indication and the severity of the disorder. Normally, 0.005 to 100 mg/kg, preferably 0.05 to 75 mg/kg, of the patient's body weight of at least one such compound of the invention are administered.
For in vitro studies, synaptosomes were freshly isolated from rat brain areas as described in the publication “The isolation of nerve endings from brain” by E. G. Gray and V. P. Whittaker, J. Anatomy 96, pages 79-88, 1962. The corresponding literature description is introduced hereby as reference and forms part of the disclosure.
The tissue (hypothalamus for determining the noradrenaline uptake inhibition and medulla and pons for determining the 5HT uptake inhibition) was homogenized in ice-cold 0.32 M sucrose (100 mg of tissue/1 ml) in a glass homogenizer with Teflon pestle using five full up and down strokes at 840 revolutions/minute. The homogenate was centrifuged at 1000 g and at 4° C. for 10 minutes. After subsequent centrifugation at 17 000 g for 55 minutes, the synaptosomes (P2 fraction) are obtained and were resuspended in 0.32 M glucose (0.5 ml/100 mg of the original weight).
The respective uptake was measured in a 96-well microtiter plate. The volume was 250 μl and incubation took place at room temperature (approx. 20-25° C.) under an O2 atmosphere.
The incubation time was 7.5 minutes for [3H]-NA and 5 minutes for [3H]-5-HT. The 96 samples were then filtered through a Unifilter GF/B® microtiter plate (Packard) and washed with 200 ml of incubated buffer using a “Brabdel MPXRI-96T Cell Harvester”. The Unifilter GF/B plate was dried at 55° C. for 1 h. The plate was then sealed with a Back Seal® (Packard) and 35 μl of scintillation fluid were added per well (Ultima Gold®, Packard). After sealing with a top Seal® (Packard), the radioactivity was determined, after equilibrium had been reached (about 5 h), in a “Trilux 1450 Microbeta” (Wallac).
The following characteristic data were found for the NA transporter:
NA uptake: Km=0.32±0.11 μM
The amount of protein employed in the above determination corresponded to the value disclosed in the literature, as described for example in “Protein measurement with the folin phenol reagent”, Lowry et al., J. Biol. Chem., 193, 265-275, 1951. A detailed description of the method can also be found in the literature, for example from M. Ch. Frink, H.-H. Hennies, W. Engelberger, M. Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036. The corresponding literature descriptions are hereby introduced as reference and form part of the disclosure.
II. Method for Determining the Affinity for the mGluR5 Receptor
Pig brain homogenate is prepared by homogenizing (Polytron PT 3000, Kinematica AG, 10 000 revolutions per minute for 90 seconds) pig brain hemispheres without medulla, cerebellum and pons in buffer of pH 8.0 (30 mM hepes, Sigma, order No. H3375+1 tablet of complete for 100 ml, Roche Diagnostics, order No. 1836145) in the ratio 1:20 (brain weight/volume) and differential centrifugation at 900×g and 40 000×g. In each case 450 μg of protein from brain homogenate are incubated with 5 nM3[H]-MPEP (Tocris, order No. R1212) (MPEP=2-methyl-6-(3-methoxyphenyl)-ethynylpyridine) and the compounds to be investigated (10 μM in the assay) in buffer (as above) in 250 μl incubation mixtures in 96-well microtiter plates at room temperature for 60 min.
The mixtures are then filtered with the aid of a Brandel Cell Harvester (Brandel, TYP Robotic 9600) on unifilter plates with glass fiber filter mats (Perkin Elmer, order No. 6005177) and subsequently washed with buffer (as above) 3 times with 250 μl per sample each time. The filter plates were then dried at 55° C. for 60 min. 30 μl of Ultima Gold™ scintillator (Packard BioScience, order No. 6013159) are then added to each well and, after 3 hours, the samples are measured in a β counter (Mikrobeta, Perkin Elmer). The nonspecific binding is determined by adding 10 μM MPEP (Tocris, order No. 1212).
The invention is explained by means of examples below. These explanations are merely by way of example and do not restrict the general concept of the invention.
The yields of the prepared compounds are not optimized.
All temperatures are uncorrected.
aq. aqueous
APCI atmospheric pressure chemical ionisation
DCM dichloromethane
DMF dimethylformamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
h hours
min minutes
NMR nuclear magnetic resonance spectroscopy
RT room temperature
sat. saturated
The chemicals and solvents employed were purchased commercially from conventional suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized by methods known to the skilled worker.
The stationary phase employed for the column chromathography was silica gel 60 (0.040-0.063 mm) supplied by E. Merck, Darmstadt.
The thin-layer chromatographic investigations were carried out with HPTLC precoated plates, silica gel 60 F 254, supplied by E. Merck, Darmstadt.
The mixing ratios of solvents, mobile phases or for chromatographic investigations are always stated in volume/volume.
Analyses took place by mass spectroscopy and NMR.
General Methods for Preparing Exemplary Substituted N-benzo[d]isoxazol-3-ylamine Derivatives
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula Ia, can be obtained from substituted 2-fluorobenzonitriles of the general formula IIIa in two stages as depicted in scheme 2.
1. General Method for Preparing Substituted benzo[d]isoxazol-3-ylamines of the General Formula IIa
Acetohydroxamic acid (A) (1.1 equivalents) was suspended under an inert gas atmosphere in DMF (1.45 ml per mmol of the compound of the general formula IIIa). Potassium tert-butoxide (1.1 equivalents) were added and the reaction mixture was stirred at RT for 30 min, the compound of the general formula IIIa (1 equivalent) was added, and the mixture was stirred at 50° C. for 1 h. After cooling, the reaction mixture was added to a mixture of sat. aq. NaCl solution (0.9 ml per mmol of A) and EtOAc (0.9 ml per mmol of A) and stirred for 30 min. The phases were separated and the aqueous phase was extracted several times with EtOAc (in each case 0.8 ml per mmol of A). The combined organic phases were washed several times with sat. aq. NaCl solution (in each case 0.8 ml per mmol of A), dried over MgSO4 and the solvent was removed in vacuo.
If it was necessary to form the corresponding hydrochloride for purification, the residue was taken up in each case in methyl ethyl ketone (8.7 ml per g of residue). After addition of water (0.1 ml per g of residue), trimethylchlorosilane (0.7 ml per g of residue) was added dropwise while stirring slowly and cooling in ice. The reaction mixture was cooled to 4° C. for crystallization. The precipitate which separated out was filtered off and dried in a desiccator with the aid of phosphorus pentoxide as desiccant.
In this way, the following compounds of the general formula IIa were obtained where appropriate in the form of the corresponding hydrochloride or dihydrochloride.
δ (DMSO, 300 MHz)=2.32 (s, 3H); 5.24 (s, 2H); 6.74 (d, 1H, J=7.9 Hz); 6.94 (d, 1H, J=8.3 Hz); 7.20 (d, 2H, J=8.3 Hz); 7.38 (dd, 3H, J=10.9 Hz, J=9.0 Hz).
δ (DMSO, 300 MHz)=6.09 (br.s, 4H); 7.25 (dd, 1H, J=0.8 Hz, J=7.5 Hz); 7.41-7.55 (m, 2H).
δ (DMSO, 300 MHz)=6.39 (t, 1H, J=8.7 Hz); 6.62 (d, 1H, J=8.7 Hz); 7.27 (dd, 1H, J=6.8 Hz, J=8.3 Hz); 8.10 (br.s, 3H).
δ (DMSO, 300 MHz)=3.04 (s, 3H), 3.07 (s, 3H); 6.70 (t, 1H, J=8.7 Hz); 6.77 (d, 1H, J=8.7 Hz); 7.15 (d, 1H, J=7.9 Hz); 7.33 (d, 1H, J=8.3 Hz); 7.41-7.58 (m, 1H).
δ (DMSO, 300 MHz)=4.91-5.11 (m, 2H); 5.80 (br.s, 2H), 7.08-7.31 (m, 2H); 7.73-7.85 (m, 1H).
δ (DMSO, 300 MHz)=7.39 (dt, 1H, J=2.2 Hz, J=9.0 Hz); 7.49 (dd, 1H, J=4.2 Hz, J=9.0 Hz); 7.78 (dd, 1H, J=2.2 Hz, J=7.5 Hz).
δ (DMSO, 300 MHz)=7.29 (dd, 1H, J=1.5 Hz, J=7.5 Hz); 7.59 (d, 1H, J=1.9 Hz); 7.93 (d, 1H, J=8.3 Hz); 8.73 (br.s, 1H).
δ (DMSO, 300 MHz)=6.53 (s, 2H); 7.22 (dt, J=4.2 Hz, J=7.5 Hz); 7.37 (dd, 1H, J=10.9 Hz, J=12.0 Hz); 7.66 (d, 1H, J=7.9 Hz).
MS (APCI)=204 [M++1]; 184 [M++1−HF]
2. General Method for Reacting Substituted benzo[d]isoxazol-3-ylamines to Give Substituted N-benzo[d]isoxazol-3-ylamine Derivatives of the General Formula Ia
a. Manual Synthesis
The substituted benzo[d]isoxazol-3-ylamines of the general formula IIa (2 equivalents) were dissolved in pyridine (0.5 ml per mmol of benzo[d]isoxazol-3-ylamine of the general formula IIa). The reaction mixture was cooled to −15° C., the appropriate carbonyl chloride R5a—C(═O)—Cl (1 equivalent) was slowly added, and the mixture was stirred overnight. For workup, the reaction mixture was poured into water (8.5 ml per mmol of benzo[d]isoxazol-3-ylamine of the general formula IIa). The resulting precipitate was filtered off with suction, washed with water, dried in vacuo and recrystallized from toluene.
The following substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention were prepared as described under 2a.
δ (DMSO, 600 MHz)=7.26 (t, 1H, J=4.5 Hz); 7.37 (t, 1H, J=7.6 Hz); 7.63-7.71 (m, 2H); 7.93 (d, 1H, J=4.5 Hz); 8.10 (d, 1H, J=7.6 Hz); 8.21 (d, 1H, J=3.0 Hz), 11.53 (s, 1H).
δ (DMSO, 600 MHz)=2.65-2.70 (m, 2H); 2.74-2.89 (m, 2H); 3.63 (s, 3H), 7.31-7.36 (m, 1H); 7.58-7.67 (m, 2H); 7.99-8.06 (m, 1H); 11.09 (s, 1H).
δ (DMSO, 600 MHz)=7.39 (t, 1H, J=7.3 Hz); 7.61-7.73 (m, 4H); 8.00-8.13 (m, 5H); 8.76 (s, 1H); 11.61 (s, 1H).
δ (DMSO, 600 MHz)=1.71-1.75 (m, 6H); 1.97-2.02 (m, 6H); 2.04-2.07 (m, 3H); 7.32 (dd, 1H, J=6.8 Hz, J=7.5 Hz); 7.58-7.67 (m, 2H); 7.84 (dd, 1H, J=6.8 Hz, J=7.5 Hz); 10.38 (s, 1H).
δ (DMSO, 600 MHz)=1.22-1.51 (m, 3H); 1.52-1.80 (m, 3H); 1.81-1.95 (m, 2H); 1.98-2.13 (m, 2H); 2.45-2.64 (m, 1H); 7.23-7, (m, 1H); 7.46-7.65 (m, 2H); 8.29 (d, 1H, J=8.3 Hz); 9.12 (s, 1H).
δ (DMSO, 600 MHz)=1.31 (s, 9H); 7.33 (t, 1H, 7.5 Hz); 7.59-7.65 (m, 2H); 7.83-7.86 (m, 1H); 10.47 (s, 1H).
b. Automated Synthesis
Firstly, the following stock solutions were produced:
Solution I (1 ml) was introduced into a dry screw-cap tube with septum cap at RT, and solution II (1 ml) and solution III (1 ml) were added. The reaction mixture was stirred in a hit reactor (supplied by Zymark, Rüsselsheim, Germany) at RT for 24 h and, in the quench station (supplied by Zymark, Rüsselsheim, Germany), 1 M hydrochloric acid solution (2 ml) was added at RT so that a pH of 3 was reached. After 30 min, DCM (2 ml) was added by pipette in the transfer block, and the reaction mixture was mixed in the spin reactor for 30 min. The stirrer bar was removed by filtration and the vessel was rinsed with DCM (2 ml).
The organic phase was removed and collected. The aqueous phase was mixed with DCM (1.5 ml), treated in a vortexer and vigorously mixed in the spin reactor for 15 min. After centrifugation, the organic phase was separated off and combined with the first organic phase. The aqueous phase is extracted analogously with DCM a second time. The combined organic phases were then dried over a magnesium sulfate cartridge, and the solvent was removed in a GeneVac HT series 1 evaporator system (GeneVac, Wiesbaden, Germany).
The following substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention were prepared as described under 2b.
MS (APCI)=359 [M++1]
MS (APCI)=281 [M (79Br)++1]; 283 [M (81Br)++1], 213.
MS (APCI)=325 [M(35Cl35Cl)++1]; 327 [M(35Cl37Cl)++1]; 329 [M(37Cl37Cl)++1]
MS (APCI)=299 [M++1], 150
MS (APCI)=304 [M++1], 155.
MS (APCI)=313 [M++1], 161.
MS (APCI)=307 [M++1]; 287.
MS (APCI)=307 [M(35Cl35Cl)++1]; 309 [M(35Cl37Cl)++1]; 311 [M(37Cl37Cl)++1]
MS (APCI)=275 [M++1]
MS (APCI)=300 [M++1]
MS (APCI)=263 [M++1], 153.
MS (APCI)=237 [M++1], 153.
MS (APCI)=359 [M (35Cl)++1]; 361[M (37Cl)++1].
MS (APCI)=303 [M (35Cl)++1]; 305 [M (37Cl)++1], 135.
MS (APCI)=373 [M (79Br)++1]; 375 [M (81Br)++1].
MS (APCI)=347 [M (79Br)++1]; 349 [M (81Br)++1].
MS (APCI)=385 [M (79Br)++1]; 387 [M (81Br)++1].
MS (APCI)=375 [M (79Br)++1]; 377 [M (81Br)++1]
MS (APCI)=297 [M (79Br)++1]; 299 [M (81Br)++1], 213.
MS (APCI)=325 [M++1]; 305.
MS (APCI)=325 [M(35Cl35Cl)++1]; 327 [M(35Cl37Cl)++1]; 329 [M(37Cl37Cl)++1]
MS (APCI)=271 [M++1]; 119.
MS (APCI)=403 [M (79Br)++1];405 [M (81Br)++1], 363, 191.
MS (APCI)=353 [M (79Br)++1]; 355 [M (81Br)++1], 312, 216, 141.
MS (APCI)=321 [M++1], 301, 173.
MS (APCI)=271 [M++1].
MS (APCI)=297 [M++1]
MS (APCI)=271 [M++1]
MS (APCI)=418 [M++1].
MS (APCI)=415 [M (79Br)++1]; 417 [M (81Br)++1]
MS (APCI)=371 [M (35Cl)++1]; 373 [M (37Cl)++1], 139.
MS (APCI)=393 [M++1], 161.
MS (APCI)=367 [M++1], 134.
MS (APCI)=399 [M (35Cl)++1]; 401 [M (37Cl)++1]
MS (APCI)=323 [M++1]
MS (APCI)=363 [M (35Cl)++1]; 365 [M (37Cl)++1]
MS (APCI)=403 [M (79Br)++1]; 405 [M (81Br)++1]
MS (APCI)=403 [M(35Cl35Cl79Br)++1]; 405 [M(35Cl37Cl79Br)++1], [M(35Cl35Cl81Br)++1], 407 [M(37Cl37Cl79Br)++1], [M(37Cl35Cl81Br)++1], 409 [M(37Cl37Cl81Br)++1]
MS (APCI)=403 [M (79Br)++1]; 405 [M (31Br)++1]
MS (APCI)=403 [M (79Br)++1]; 405 [M (81Br)++1]
MS (APCI)=371 [M (79Br)++1]; 373 [M (81Br)++1]
MS (APCI)=359 [M (79Br)++1]; 361 [M (81Br)++1]
MS (APCI)=353 [M (79Br)++1]; 355 [M (79Br)++1]
MS (APCI)=307 [M (79Br)++1]; 309 [M (79Br)++1]
MS (APCI)=343 [M++1]
MS (APCI)=343 [M(35Cl35Cl)++1]; 345 M(35Cl37Cl)++1]; 347 M(37Cl37Cl)++1]
MS (APCI)=343 [M++1]
MS (APCI)=311 [M++1]
MS (APCI)=383 [M++1]
MS (APCI)=292 [M (35Cl)++1]; 294 [M (37Cl)++1]; 256 [M+-HCl]
MS (APCI)=307 [M++1]
MS (APCI)=298 [M++1]
MS (APCI)=293 [M++1]
MS (APCI)=343 [M++1]
MS (APCI)=287 [M++1], 135 [M+-benzisoxazole]
MS (APCI)=343 [M++1], 167 [CHPh2+]
MS (APCI)=247 [M++1]
MS (APCI)=276 [M(35Cl35Cl)++1]; 278 M(35Cl37Cl)++1]; 280 M(37Cl37Cl)++1], 191 [M(35Cl35Cl)+-benzisoxazole]
MS (APCI)=247 [M++1], 159 [M+-benzisoxazole]
MS (APCI)=317 [M(35Cl35Cl)++1]; 319 [M(35Cl37Cl)++1], 321 [M(37Cl37Cl)++1], 281 [M(35Cl35Cl)+-HCl],
MS (APCI)=332 [M++1], 155 [M+-benzisoxazole]
MS (APCI)=324 [M++1], 147 [M+-benzisoxazole]
MS (APCI)=324 [M++1], 147 [M+-benzisoxazole]
MS (APCI)=368 [M++1], 191 [M+-benzisoxazole]
MS (APCI)=312 [M++1], 135 [M+-benzisoxazole]
MS (APCI)=262 [M++1]
MS (APCI)=288 [M++1], 178 [benzisoxazole+1]
MS (APCI)=372 [M++1], 178 [benzisoxazole+1]
MS (APCI)=372 [M++1]
MS (APCI)=372 [M++1]
MS (APCI)=423 [M++1], 191 [M+-benzisoxazole]
MS (APCI) 423 [M(35Cl35Cl)++1]; 425 [M(35Cl37Cl)++1], 427 [M(37Cl37Cl)++1]
MS (APCI)=423 [M++1], 191 [M+-benzisoxazole]
MS (APCI)=391 [M++1], 159 [M+-benzisoxazole]
MS (APCI)=387 [M++1], 155 [M+-benzisoxazole]
MS (APCI)=373 [M++1], 141 [M+-benzisoxazole]
MS (APCI)=373 [M++1], 141 [M+-benzisoxazole]
The noradrenaline reuptake inhibition (NA uptake inhibition) and the serotonin reuptake inhibition (5-HT uptake inhibition) of the substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention was determined as described above.
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention exhibit an excellent affinity for the noradrenaline receptor and for the 5-HT receptor.
The affinity of the substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention, of the general formula I, for the mGluR5 receptor was determined as described above.
The substituted N-benzo[d]isoxazol-3-ylamine derivatives of the invention show an excellent affinity for the mGluR5 receptor.
3[H]-MPEP
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2005 026 194.9 | Jun 2005 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP06/05356 | 6/6/2006 | WO | 00 | 7/2/2008 |
