WO2007107373A1 - Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments - Google Patents
Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments Download PDFInfo
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- WO2007107373A1 WO2007107373A1 PCT/EP2007/002569 EP2007002569W WO2007107373A1 WO 2007107373 A1 WO2007107373 A1 WO 2007107373A1 EP 2007002569 W EP2007002569 W EP 2007002569W WO 2007107373 A1 WO2007107373 A1 WO 2007107373A1
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- butyl
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- 0 *C1=C(CCN(C2)C(O*)=O)C2=C(*)**1 Chemical compound *C1=C(CCN(C2)C(O*)=O)C2=C(*)**1 0.000 description 13
- YRLORWPBJZEGBX-UHFFFAOYSA-N C1Nc2ccccc2OC1 Chemical compound C1Nc2ccccc2OC1 YRLORWPBJZEGBX-UHFFFAOYSA-N 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N C1c2ccccc2CNC1 Chemical compound C1c2ccccc2CNC1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N c1cc2n[o]nc2cc1 Chemical compound c1cc2n[o]nc2cc1 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- PDQRQJVPEFGVRK-UHFFFAOYSA-N c1cc2n[s]nc2cc1 Chemical compound c1cc2n[s]nc2cc1 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 description 1
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/10—Quaternary compounds
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to substituted tetrahydroisoquinoline compounds of general formula I,
- medicaments comprising said substituted tetrahydroisoquinoline compounds as well as the use of said substituted tetrahydroisoquinoline compounds for the preparation of medicaments, which are particularly suitable for the prophylaxis and/or treatment of disorders or diseases that are at least partially mediated via 5-HT 6 receptors.
- the superfamily of serotonin receptors includes 7 classes (5-HTi-5-HT 7 ) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419].
- the 5-HT 6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [FJ. Monsma et al., MoI. 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-HT 6 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-HT 6 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.
- Compounds with 5-HT 6 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. Gerard et al., Brain Research , 1997, 746, 207; M. R. Pranzatelli, Drugs of Today , 1997, 33, 379].
- ADHD attention deficit / hyperactivity disorder
- Food ingestion disorders 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 as well.
- an object of the present invention was to provide compounds that are particularly suitable as active ingredients in medicaments, especially in medicaments for the prophylaxis and/or treatment of disorders or diseases related to 5-HT 6 receptors such as food intake related disorders.
- the substituted tetrahydroisoquinoline compounds of general formula I given below show good to excellent affinity for 5-HT 6 -receptors. These compounds are therefore particularly suitable as pharmacologically active agents in a medicament for the prophylaxis and/or treatment of disorders or diseases related to 5- HT 6 -receptors such as food intake related disorders like obesity.
- the present invention relates to a medicament comprising a substituted tetrahydroisoquinoline compounds of general formula I 1
- Ci-i 0 aliphatic radical which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl 1 Br 1 1 1 -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, - NH 2 , -O-Ci- 5 -alkyl, -S-Ci -5 -alkyl, -NH(C 1-5 -alkyl) and -N(Ci -5 -alkyl) 2 ; or a saturated or unsaturated 3- to 9-membered cycloaliphatic radical, which may contain 1, 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s) and which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl 1 Br 1 1 1 -
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 independently of one another, each represent a linear or branched, saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 12 represents a phenyl radical of general formula (A),
- an unsubstituted or at least mono-substituted monocyclic heteroaryl radical which is condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- an unsubstituted or at least mono-substituted bi- or tricyclic heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 23 , R 27 , R 28 , R 29 and R 30 independently of one another, each represent a linear or branched, saturated or unsaturated C MO aliphatic radical which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -0-Ci -5 - alkyl, -S-C 1-5 -alkyl, -NH(C 1-5 -alkyl) and -N(Ci -5 -alkyl) 2 ;
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 24 , R 26 , R 31 , R 32 and R 33 each represent a linear or branched, saturated or unsaturated Ci--I 0 aliphatic radical which may be unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, - CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O-Ci -5 -alkyl, -S-d -5 -alkyl, -NH(C 1-5 -alkyl) and -N(C 1-5 -alkyl) 2 ;
- R 1 R 1 R and R represents a linear or branched, saturated or unsaturated Ci--I 0 aliphatic radical which may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl 1 Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O-Ci -5 -alkyl, -S-d -5 -alkyl, -NH(C 1-5 - alkyl) and -N(Ci -5 -alkyl) 2 ;
- R 37 represents a linear or branched, saturated or unsaturated Ci-i 0 aliphatic radical
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof;
- Preferred is a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I in form of its salt as defined in general formula II,
- A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n- pentyl;
- D represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2- oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate whereby said benzoate or naphthoate may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl 1 Br, -OH 1 -O-CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
- R 38 and R 39 independently of one another, in each case represent a radical selected from the group consisting Of -CF 3 , -C 2 F 5 , methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2- (6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl )-octy
- cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a -(CH 2 )-, -(CH 2 )-(CH 2 )- or -(CH 2 )- (CH 2 )-(CH 2 )-group.
- Preferred is a medicament comprising at least one substituted tetrahydroisoquinoline compound in form of its salt as defined in general formula II, wherein
- A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl and n-pentyl;
- D represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5-sulfo- napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2-oxo- bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 1 represents a hydrogen atom
- Ci -10 alkyl radical C 2- io alkenyl radical or C 2-10 alkinyl radical
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 independently of one another, each represent a linear or branched C-i-ioalkyl radical, C 2- i 0 alkenyl radical or C 2- i 0 alkinyl radical;
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 12 represents a phenyl radical of general formula (A),
- R 23 , R 27 , R 28 , R 29 and R 30 independently of one another, each represent a linear or branched C 1-10 alkyl radical, C 2-1O alkenyl radical or C 2-1O alkinyl radical;
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 24 , R 26 , R 31 , R 32 and R 33 each represent a linear or branched C 1-10 alkyl radical, C 2-10 alkenyl radical or C 2- - I0 alkinyl radical;
- a C 3- 9cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched d- ⁇ alkylene, C 2-6 alkenylene or C 2- 6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 25 , R 34 , R 35 and R 36 represents a linear or branched C MO alkyl radical, C 2 -io alkenyl radical or C 2- I 0 alkinyl radical;
- R 37 represents a linear or branched Ci -10 alkyl radical, C 2- io alkenyl radical or C 2- io alkinyl radical;
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- C 3- g cycloalkyl radicals and C 4-9 cycloalkenyl radicals in each case may optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
- Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene groups may in each case be unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O- Ci- 5 -alkyl, -S-Ci -5 -alkyl, -NH(Ci -5 -alkyl) and -N(C 1-5 -alkyl) 2 ;
- the rings of the aforementioned ring system are in each case independently of one another 5-, 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
- heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 1 represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , - CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2l -CH 2 -N(C 2
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or Il is preferred as well, wherein
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or Il is preferred as well, wherein
- R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, - CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN 1 -CH 2 -O-CF 3 , -CH 2 -S- CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or Il is preferred, wherein
- R 12 represents a phenyl radical of general formula (A),
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein R 23 , R 27 , R 28 , R 29 and R 30 , independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, ally), ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 - CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 24 , R 26 , R 31 , R 32 and R 33 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 - CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -CH 2
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 25 , R 34 , R 35 and R 36 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , - CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, - CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -NH-CH 3 ,
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 37 represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, - CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S- CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH-CH 3 , -CH 2 - N(CHa) 2 , -CH
- substituents have any of the above defined meanings, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 1 represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , - CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CHa) 2 , -CH 2 -N(C 2
- R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, - CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S- CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2
- R 12 represents a phenyl radical of general formula (A),
- R 23 , R 27 , R 28 , R 29 and R 30 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, - CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S- CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH 1 -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -CH
- R 24 , R 26 , R 31 , R 32 and R 33 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 - CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -CH 2
- R 25 , R 34 , R 35 and R 36 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , - CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, - CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH 2 , -CH 2 -NH-CH 3 ,
- R 37 represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 , -CF 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH 2 -O-CF 3 , -CH 2 -S-CF 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -SH, -CH 2 -CH 2 -SH, -CH 2 -NH-CH 3 , -CH 2 -N(CHa) 2 , -CH 2
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 1 represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -NH-C 2 H 5 , -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH 2 -NH-C 2 H 5 , -CH 2 -CH 2 -NH 2 , -
- R 8 and R 9 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thioph)
- ⁇ 12 represents a phenyl radical of general formula (A)
- R 23 and R 27 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be bonded via a -(CH 2 )i i 2 o r3- group and which may be unsubstituted or optionally substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethy
- R 24 and R 26 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be unsubstituted or optionally substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl
- R 25 represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -CF 3 , -CFH 2 , -CF 2 H, -
- R 37 represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and fluorenyl, which may be bonded via a -(CH 2 )i, 2 or 3 - group and which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 1 represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 J 2 , -CH 2 -N(C 2 H 5 J 2 , -CH 2 -NH-C 2 H 5 , -CH 2 - CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 J 2 , -CH 2 -CH 2 -N(C 2 H 5 J 2 , -CH 2 -CH 2 -NH- C 2 H 5 , -CH 2 -CH 2 -NH-CH 3 ,
- R 12 represents a phenyl radical of general formula (A),
- pyridinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -NO 2 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 -CF 3 and -CF 2 -CF 3 ;
- R 37 represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I and/or II, wherein
- R 12 represents a phenyl radical of general formula (A),
- R 19 , R 20 , R 21 and R 22 independently of one another, . each represent a hydrogen atom; F, Cl, Br, I, -0-CH 3 ; -0-C 2 H 5 ; -0-CF 3 ; -0-CFH 2 ; -0-CF 2 H; -0-CH 2 -CF 3 ; -0-CF 2 -CF 3 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
- R 37 represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula Ia,
- R 12a represents a phenyl radical of general formula (Aa),
- pyridinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -NO 2 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 -CF 3 and -CF 2 -CF 3 ;
- R 37a represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula Ib,
- R ,12b represents a phenyl radical of general formula (Ab)
- pyridinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -NO 2 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 -CF 3 and -CF 2 -CF 3 ;
- R 37b represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula Ic,
- R 12c represents a phenyl radical of general formula (Ac),
- pyridinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -NO 2 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 -CF 3 and -CF 2 -CF 3 ;
- R 37c represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula Id,
- R 12d represents a phenyl radical of general formula (Ad),
- pyridinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -NO 2 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 -CF 3 and -CF 2 -CF 3 ;
- R 37d represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula Ih as described hereinafter.
- a medicament comprising at least one substituted tetrahydroisoquinoline compound as defined above selected from the group consisting of
- 6-yl)-amide Hydrochloride [157] 6-Chloro-imidazo[2,1-b] thiazole-5-sulfonic acid (2-cyclopropanecarbonyl- 1 ,2,3,4- tetrahydro-isoquino lin-6-yl)-amide and [158] 6-Chloro-imidazo[2,1-b] thiazole-5-sulfonic acid (2-cyclopropylmethyl-1 ,2,3,4- tetrahydro-isoquinolin-6-yl)-amide hydrochloride
- a further aspect of the present invention relates to a medicament comprising at least one substituted tetrahydroisoquinoline compound of general formula I, II, III, Ia, Ib, Ic, Id, Ie, If, or Ig given above or Ih given below, in the following only referred to as tetrahydroisoquinoline compound of general formula I, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, and optionally at least one physiologically acceptable auxiliary agent.
- Said medicament is particularly suitable for 5-HT 6 -receptor regulation and therefore for the prophylaxis and/or treatment of a disorder or a disease that is at least partially mediated via 5-HT 6 -receptors.
- said medicament is suitable for the prophylaxis and/or treatment of the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably 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, type Il diabetes (non insulin dependent diabetes mellitus), preferably type Il diabetes that is caused by obesity; for the prophylaxis and/or treatment of stroke; migraine; head trauma; epilepsy; irritable colon syndrome; irritable bowl syndrome; emesis; vertigo; disorders of the central nervous system; anxiety; panic attacks; depression; bipolar disorders; obsessive compulsory disorder; cognitive disorders; cognitive dysfunction associated with psychiatric diseases; memory disorders; s
- said medicament is suitable for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably 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 Il diabetes (non insulin dependent diabetes mellitus), preferably type Il diabetes that is caused by obesity.
- More preferably said medicament is suitable for improvement of cognition (cognitive enhancement) or cognitive memory (cognitive memory enhancement).
- said medicament is suitable for the prophylaxis and/or treatment of obesity and/or disorders or diseases related thereto.
- the present invention relates to the use of at least one substituted tetrahydroisoquinoline compound of general formula I given above, optionally in form of one of their stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the preparation of a medicament suitable for 5-HT 6 - receptor regulation, preferably for the prophylaxis and/or treatment of a disorder or a disease that is least partially mediated via 5-HT 6 -receptors.
- the present invention relates to the use of at least one substituted tetrahydroisoquinoline compound of general formula I given above, optionally in form of one of their stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite; for the maintenance, increase or reduction of body weight; or for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type Il diabetes (non insulin dependent diabetes mellitus), more preferably for the prophylaxis and/or treatment of obesity.
- the present invention also relates to the use of at least one substituted tetrahydroisoquinoline compound of general formula I given above, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the prophylaxis and/or treatment of stroke; migraine; head trauma; epilepsy; irritable colon syndrome; irritable bowl syndrome; emesis; vertigo; disorders of the central nervous system; anxiety; panic attacks; depression; bipolar disorders; obsessive compulsory disorder; cognitive disorders; cognitive dysfunction associated with psychiatric diseases; memory disorders; senile dementia; mood disorders; sleep disorders; psychosis; neurodegenerative disorders, preferably selected from the group consisting of Morbus Alzheimer, Morbus Parkinson, Morbus Huntington and Multiple Sclerosis; schizophrenia
- the present invention also relates to the use of at least one substituted tetrahydroisoquinoline compound of general formula I given above, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the manufacture of a medicament for the improvement of cognition (cognitive enhancement) and/or for the improvement of cognitive memory (cognitive memory enhancement).
- the present invention also relates to the use of at least one substituted tetrahydroisoquinoline compound of general formula I given above, optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the manufacture of a medicament for the prophylaxis and/or treatment of drug addiction and/or withdrawal, preferably for the prophylaxis and/or treatment of addiction and/or withdrawal related to one or more of drugs selected from the group consisting of benzodiazepines, natural, semisynthetic or synthetic opioids like cocaine, ethanol and/or nicotine.
- drugs selected from the group consisting of benzodiazepines, natural, semisynthetic or synthetic opioids like cocaine, ethanol and/or nicotine.
- At least one substituted tetrahydroisoquinoline compound of general formula I as defined above optionally in form of one of their stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the preparation of a medicament for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type Il diabetes (non insulin dependent diabetes mellitus), preferably type Il diabetes that is caused by obesity.
- At least one substituted tetrahydroisoquinoline compound of general formula I as defined above optionally in form of one of their stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the preparation of a medicament for the improvement of cognition (cognitive enhancement) and/or for the improvement of cognitive memory (cognitive memory enhancement).
- Any medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults.
- the medicament can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "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 CT. (Eds.) Marcel Dekker, Inc.
- composition of the medicament may vary depending on the route of administration.
- the medicament of the present invention may, for example, be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
- conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
- These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
- Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
- compositions may take any convenient form, such as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
- the multiparticulate forms, such as pellets or granules may e.g. be filled into a capsule, compressed into tablets or suspended in a suitable liquid.
- Suitable controlled release formulations, materials and methods for their preparation are known from the prior art, e.g. from the table of contents of "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", VoI, I, Basic Concepts, Bruck, S.D. (Ed.), CRD Press Inc., Boca Raton (1983) y de Takada, K.
- Medicaments according to the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value. Due to said coating the medicament can pass the stomach undissolved and the respective tetrahydroisoquinoline compound is liberated in the intestinal tract.
- the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are are known from the prior art.
- the medicaments according to the present invention may contain 1-60 % by weight of one or more substituted tetrahydroisoquinoline compounds as defined herein and 40-99 % by weight of one or more auxiliary substances (additives).
- liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
- Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
- compositions of the present invention may also be administered topically or via a suppository.
- 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 may preferably be in the range fromi to 2000 mg, preferably 1 to 1000 mg, more preferably 1 to 500 mg, even more preferably 1 to 200 mg, of active substance to be administered during one or several intakes per day.
- the present invention relates to a substituted tetrahydroisoquinoline compound of general formula Ie,
- Ci-io aliphatic radical which may be unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O-d -5 -alkyl, - S-Ci.s-alkyl, -NH(Ci -5 -alkyl) and -N(Ci -5 -alkyl) 2 ;
- a linear or branched, saturated or unsaturated, unsubstituted or at least mono- substituted aliphatic radical a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 6e , R 7e , R 86 , R 9e , R 1Oe , R 13e , R 14e , R 15e , R 16e , R 17e and R 18e independently of one another, each represent a linear or branched, saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- an unsubstituted or at least mono-substituted monocyclic heteroaryl radical which is condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- an unsubstituted or at least mono-substituted bi- or tricyclic heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- en tiy o f each represent a linear or branched, saturated or unsaturated C 1- I 0 aliphatic radical which may be unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O-d -5 -alkyl, - S-Ci- 5 -alkyl, -NH(C 1-5 -alkyl) and -N(C 1-5 -alkyl) 2 ; a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical,
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 25e , R 34e , R 35e and R 368 represents a linear or branched, saturated or unsaturated C MO aliphatic radical which may be unsubstituted or substituted with 1, 2 or
- j n ear or branched, saturated or unsaturated C MO aliphatic radical which may be unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, - CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O-Ci -5 -alkyl, -S-C 1-5 -alkyl, -NH(d -5 -alkyl) and - N(C 1-5 -alkyl) 2 ;
- R 37e represents a linear or branched, saturated or unsaturated Ci-i 0 aliphatic radical
- aryl or heteroaryl radical which may be bonded via a linear or branched alkylene, alkenylene or alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- Preferred is a substituted tetrahydroisoquinoline compound of general formula Ie in form of its salt
- A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl;
- D represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2- oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate whereby said benzoate or naphthoate may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -O-CH 3 and -O-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
- R 38e and R 39e independently of one another, in each case represent a radical selected from the group consisting Of -CF 3 , -C 2 F 5 , methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2- (6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl)-oct
- cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )- or -(CH 2 )- (CH 2 )-(CH 2 )-group.
- A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl;
- D represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5-sulfo- napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2-oxo- bicyclo[2.2.1]-hept-1-yl-methanesulfonate.
- R 1e represents a hydrogen atom
- Ci-io alkyl radical C 2- -I 0 alkenyl radical or C 2- io alkinyl radical
- Ci-I 0 alkyl radical C 2- -I 0 alkenyl radical or C 2- ioalkinyl radical
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 6e , R 7e , R 8e , R 9e , R 1Oe , R 13e , R 14e , R 15e , R 16e , R 17e and R 18e independently of one another, each represent a linear or branched CI-IQ alkyl radical, C 2- i 0 alkenyl radical or C 2- I 0 alkinyl radical;
- a C 3 - 9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- an unsubstituted or at least mono-substituted monocyclic 5- or 6-membered heteroaryl radical which is condensed with an unsubstituted or at least mono-substituted saturated or unsaturated, but not aromatic, mono- or bicyclic ring system;
- R 23e ⁇ R 27 ⁇ R 28 ⁇ j R 29e and R 3 o ⁇ ] independently of one another, each represent a linear or branched Ci-- I0 alkyl radical, C 2- ioalkenyl radical or C 2- io alkinyl radical;
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2- 6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 25e , R 34e , R 35e and R 36e represents a linear or branched C LIO alkyl radical, C 2 - 10 alkenyl radical or C 2- i 0 alkinyl radical;
- R 26e , R 31e , R 32e and R 33e each represent a linear or branched C1-1 0 alkyl radical, C 2- i 0 alkenyl radical or C 2- io alkinyl radical;
- a C 3- C) cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- R 37e represents a linear or branched Ci_i 0 alkyl radical, 02-10 alkenyl radical or C2-10 alkinyl radical;
- a C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical which may be bonded via a linear or branched Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene group and which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
- Ci-i 0 alkyl radical, C 2- Io alkenyl radical or C 2- i 0 alkinyl radicals may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , - SCF 3 , -OH, -SH, -NH 2 , -O-Ci -5 -alkyl, -S-Ci -5 -alkyl, -NH(Ci -5 -alkyl) and -N(C 1-5 -alkyl) 2 ;
- Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkinylene groups may in each case be unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -O- d-s-alkyl, -S-C 1-5 -alkyl, -NH(C 1-5 -alkyl) and -N(C 1-5 -alkyl) 2 ;
- the rings of the aforementioned ring system are in each case independently of one another 5-, 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- a substituted tetrahydroisoquinoline compound of general formula Ie and/or III is particularly preferred, wherein
- R 1e represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -NH-C 2 H 5 , -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CHa) 2 , -CH 2 -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH 2 -NH-C 2 H 5 , -CH 2 - CH 2 -CH 2 -NH-
- R 8e and R 9e independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be bonded via a - (CH 2 )i, 2 Or 3 -group and which may be unsubstitute
- R 12e represents a radical selected from the group consisting of [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, [1 ,2,3,4]-tetrahydronaphthyl, (2,3)-dihydro-1 H- cyclopenta[b]indolyl, [1 ,2,3,4]-tetrahydroquinolinyl, [1 ,2,3,4]-tetrahydroisoquinolinyl, [1 ,2,3,4]-tetrahydroquinazolinyl, [3,4]-dihydro-2H-benzo[1 ,4]oxazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]
- R 37e represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- R 1e represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -NH-C 2 H 5 , -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CHs) 2 , -CH 2 -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH 2 -NH-C 2 H 5 , -CH 2 -CH 2 -NH 2 , -
- R 12e represents a radical selected from the group consisting of [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1,2,3]- benzoxadiazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobut
- pyridinyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl 1 -NO 2 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 -CF 3 and -CF 2 -CF 3 ;
- R 37e represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- R 1e represents a hydrogen atom; or a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl or in general formula
- R 12e represents a radical selected from the group consisting of benzo[b]thiophenyl and imidazo[2,1-b]thiazolyl, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, F, Cl and Br;
- a pyridinyl radical which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
- R 37e represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, or a corresponding solvate thereof.
- the present invention relates to a salt of a substituted tetrahydroisoquinoline compound of general formula If,
- A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl;
- D represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5-sulfo- napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2-oxo- bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
- R 1f represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -NH-C 2 H 5 , -CH 2 - CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 ) 2 , -CH 2 -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH 2 -NH- C 2 H 5 , -CH 2 -CH 2 -CH 2 -
- R 8f and R 9f independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be bonded via a - (CH 2 )i, 2 ⁇ r 3 -group and which may be unsub
- R 12f represents a phenyl radical of general formula (Af),
- a naphthyl radical which may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -0-CH 3 , -0-C 2 H 5 , -O- CH 2 -CH 2 -CH 3 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -S-CH 3 , -S-C 2 H 5 , -S-CH 2 -CH 2 -CH 3 , -S- CH(CH 3 ) 2) -S-C(CH 3 J 3 , F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH
- R 23f and R 27f independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be bonded via a -(CH 2 )i, 2 or 3 -group and which may be unsubstituted or optionally substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl
- R 24f and R 26f independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be unsubstituted or optionally substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, iso
- R 25f represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 .
- Preferred is a salt of a substituted tetrahydroisoquinoline compound of general formula If, wherein A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl;
- D represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5-sulfo- napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2-oxo- bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
- R 1f represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CHa) 2 , -CH 2 -N(C 2 Hg) 2 , -CH 2 -NH-C 2 H 5 , -CH 2 - CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CHa) 2 , -CH 2 -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH 2 -NH- C 2 H 5 , -CH 2 -CH 2 -CH 2 -NH-
- 2 o r3- group and which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and isobutyl;
- R 12f represents a phenyl radical of general formula (Af),
- a naphthyl radical which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -0-CH 3 , -0-C 2 H 5 , F, CI, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -CF 2 H and -CFH 2 .
- R 1f represents a hydrogen atom; or a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl;
- R 12f represents a phenyl radical of general formula (Af),
- R 19f , R 20f , R 21f and R 22f independently of one another, each represent a hydrogen atom; F, Cl, Br, I, -0-CH 3 ; -0-C 2 H 5 ; -O-CF 3 ; -0-CFH 2 ; -0-CF 2 H; -0-CH 2 -CF 3 ; -0-CF 2 -CF 3 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
- substituents R 19f , R 20f , R 21f and R 22f is unlike hydrogen; or a naphthyl radical, which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, F, Cl and Br.
- the present invention relates to a substituted tetrahydroisoquinoline compound of general formula Ig,
- R 1g represents a hydrogen atom; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -NH-C 2 H 5 , -CH 2 - CH 2 -NH 2 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 );?, -CH 2 -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH 2 -NH- C 2 H 5 , -CH 2 -CH 2 -CH 2 -NH
- R 8g and R 9g independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be bonded via a - (CH 2 )i, 2 ⁇ r 3 -group and which may be unsubsti
- R 12g represents a phenyl radical of general formula (Ag),
- a naphthyl radical which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -O-CH 3 , -0-C 2 H 5 , -O- CH 2 -CH 2 -CH 3 , -O-CH(CH 3 ) 2 , -0-C(CH 3 J 3 , -S-CH 3 , -S-C 2 H 5 , -S-CH 2 -CH 2 -CH 3 , -S- CH(CHs) 2 , -S-C(CHa) 3 , F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -
- R 23g and R 27g independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be bonded via a -(CH 2 )i, 2or 3 -group and which may be unsubstituted or optionally substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl
- R 24g and R 26g independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, ethinyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3 ; or an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, and pyridinyl, which may be unsubstituted or optionally substituted with 1, 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl
- R 25g represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -CF 3 , -CFH 2 , -CF 2 H, -CH 2 -CF 3 and -CF 2 -CF 3
- R 37g represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenyl methyl, phenyl, benzyl and naphthyl.
- Preferred is a substituted tetrahydroisoquinoline compound of general formula Ig, wherein
- R 1g represents a hydrogen atom; or a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl;
- R 12g represents a phenyl radical of general formula (Ag),
- R 19g , R 20g , R 21g and R 22g independently of one another, each represent a hydrogen atom; F, Cl, Br, I, -0-CH 3 ; -0-C 2 H 5 ; -O-CF 3 ; -0-CFH 2 ; -O-CF 2 H; -0-CH 2 -CF 3 ; -O-CF 2 - CF 3 ; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
- a naphthyl radical which may be unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, F, Cl and Br;
- R 37g represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, fluorenyl, fluorenylmethyl, phenyl, benzyl and naphthyl.
- any of the substituents in any of the above defined formulae represents or comprises a 3- to 9-membered (hetero)cycloaliphatic radical, C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical
- said (hetero)cycloaliphatic radical, C 3-9 cycloalkyl radical or C 4-9 cycloalkenyl radical may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
- any of the substituents in any of the above defined formulae represents or comprises a cycloaliphatic radical, C 3-9 cycloalkyl radical or C 4-9 CyClOaI kenyl radical which contains one or more, preferably 1 , 2 or 3 heteroatom(s) as ring member(s), unless defined otherwise, each of these heteroatom(s) may preferably be selected independently from the group consisting of N, O and S.
- Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals, C 3-9 cycloalkyl radicals or C 4- g cycloal kenyl radicals may preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl
- Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals, C 3- g cycloalkyl radicals or C ⁇ g cycloal kenyl radicals which are condensed with an unsubstituted or at least mono-substituted mono- or bicyclic ring system may preferably be selected from the group consisting of indolinyl, isoindolinyl, decahydronaphthyl, (1 ,2,3,4)-tetrahydroquinolinyl, (1,2,3,4)- tetrahydroisoquinolinyl, (1 ,2,3,4)-tetrahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)-hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a )-hexahydro-indolizinyl, decahydr
- any of the substituents in any of the above defined formulae represents an alkylene group, preferably an C 1-6 alkylene group, an alkenylene group, preferably an C 2-6 alkenylene group or an alkinylene group, preferably an C 2-6 alkinylene group, which may be substituted, said alkylene group, C 2- 6 alkylene group, alkenylene group, C 2-6 alkenylene group, alkinylene group or C 2-6 alkinylene group may be unsubstituted or substituted by one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2 or 3 substituent(s).
- Said substituent(s) may preferably be selected independently from the group consisting of -O-Ci -5 -alkyl, -S-Ci -5 -alkyl, -F, Cl, Br, I, -CN, - CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -NH(Ci. 5 -alkyl) and -N(C 1-5 -alkyl) 2 , whereby in each occurrence Ci- 5 -alkyl may be linear or branched.
- An alkenylene group comprises at least one carbon-carbon double bond
- an alkinylene group comprises at least one carbon- carbon triple bond.
- any of the substituents in any of the above defined formulae represents or comprises an aryl radical, including a 6-membered aryl radical such as phenyl or a 10-membered aryl radical such as naphthyl or a 14-membered aryl radical such as anthracenyl, said aryl radical may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s).
- Preferred aryl radicals which may optionally be at least mono-substituted, are phenyl and naphthyl.
- any of the substituents in any of the above defined formulae represents or comprises a heteroaryl radical, including a monocyclic 5- or 6-membered heteroaryl radical or a bi- or tricyclic 8-, 9-, 10-, 11-, 12-, 13- or 14 membered heteroaryl radical
- said heteroaryl radical may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s).
- heteroatom(s), which are present as ring member(s) in the heteroaryl radical may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulphur.
- the heteroaryl radical comprises 1 , 2, 3 or 4 heteroatom(s).
- Suitable bi- or tricyclic heteroaryl radicals may preferably be selected from the group consisting of indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, imidazo[2,1-b]thiazolyl, 2H-chromenyl, indazolyl and quinazolinyl.
- Suitable mono-, bi- or tricyclic heteroaryl radicals which are condensed with an unsubstituted or at least mono-substituted saturated or unsaturated mono- or bicyclic ring system, may preferably be selected from the group consisting of [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, [1 ,2,3,4]-tetrahydronaphthyl, (2,3)-dihydro-1 H-cyclopenta[b]indolyl, [1 ,2,3,4]-tetrahydroquinolinyl, [1 ,2,3,4]-tetrahydroisoquinolinyl, [1 ,2,3,4]- tetrahydroquinazolinyl and [3,4]-dihydro-2H-benzo[1 ,4]oxazinyl.
- Suitable monocyclic heteroaryl radicals may preferably be selected from the group consisting of pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and pyranyl.
- a mono- or bicyclic ring system according to the present invention - if not defined otherwise - means a mono- or bicyclic hydrocarbon ring system that may be saturated, unsaturated or aromatic. Each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic.
- each of the rings of the mono- or bicyclic ring system may contain one or more, preferably 1 , 2 or 3, heteroatom(s) as ring member(s), which may be identical or different and which can preferably be selected from the group consisting of N, O and S.
- the rings of the mono- or bicyclic ring system are preferably 5-, 6- or 7-membered.
- a mono-or bicyclic ring system according to the present invention is a phenyl or naphthyl ring system.
- condensed means that a ring or ring system is attached to another ring or ring system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
- Such a mono- or bicyclic ring system may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s).
- any of the substituents in any of the above defined formulae represents a saturated or unsaturated aliphatic radical, i.e. an alkyl radical, preferably an Ci-i O alkyl radical; an alkenyl radical, preferably an C 2- - I0 alkenyl radical or an alkinyl radical, preferably an C 2- i 0 alkinyl radical; said aliphatic radical may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s).
- an alkyl radical preferably an Ci-i O alkyl radical
- an alkenyl radical preferably an C 2- - I0 alkenyl radical or an alkinyl radical, preferably an C 2- i 0 alkinyl radical
- said aliphatic radical may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably
- Said substituent(s) may preferably be selected independently from the group consisting of -O-Ci -5 -alkyl, -S-d -5 -alkyl, F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , - SCF 3 , -OH, -SH, -NH 2 , -NH(Ci -5 -alkyl) and -N(C 1-5 -alkyl) 2 , whereby in each occurrence Ci -5 -alkyl may be linear or branched.
- said substituent(s) may preferably be selected independently from the group consisting of -O-CH 3 , -O-C 2 H 5> -0-CH 2 -CH 2 - CH 3 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -S-CH 3 , -S-C 2 H 5 , -S-CH 2 -CH 2 -CH 3 , -S-CH(CH 3 ) 2 , -S- C(CH 3 ) 3 , F 1 Cl, Br 1 I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , NH-CH 3 , -NH-C 2 H 5 , - NH-CH 2 -CH 2 -CH 3 , -NH-CH(CH 3 J 2 , -NH-C(CH 3 ) 3 , -N(CH 3 J 2 ,
- An alkenyl radical comprises at least one carbon-carbon double bond
- an alkinyl radical comprises at least one carbon-carbon triple bond
- Suitable alkyl radicals which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n- decyl.
- Suitable alkenyl radicals which may be substituted by one or more substituents, may preferably be selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl and 3-butenyl.
- Suitable alkinyl radicals which may be substituted by one or more substituents, may preferably be selected from the group consisting of ethinyl, 1-propinyl, 2-propinyl, 1- butinyl, 2-butinyl and 3-butinyl.
- the present invention relates to a substituted tetrahydroisoquinoline compound of general formula Ih
- B represents a radical selected from the group consisting of
- a h represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl and tert-butyl;
- D h represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate and benzenesulfonate;
- R 11h represents a radical selected from the group consisting of H, methyl and ethyl
- R 12h represents a radical selected from the group consisting of
- R 1h , R 2h , R 3h , R 4h , R 5h and R 11h have the meaning as defined above;
- R >12h represents a radical selected from the group consisting of
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, or a corresponding base thereof.
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, or a corresponding base thereof.
- a h , D h , R 1h , R 2h , R 4h , R 5h , R 11h and R 12h have the meaning as defined above;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, or a corresponding base thereof.
- a h , D h , R 1h , R 2h , R 3h , R 5h , R 11h and R 12h have the meaning as defined above;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, or a corresponding base thereof.
- a h , D h , R 1h , R 2h , R 3h , R 4h , R 11h and R 12h have the meaning as defined above;
- stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, or a corresponding base thereof.
- a substituted tetrahydroisoquinoline compound selected from the group consisting of [I] N-(1 ,2, 3,4-tetrahydroisoquinolin-6-yl)naphthalene-1 -sulfonamide hydrochloride, [2] 2 > 2-dimethyl-6-(N-methylnaphthalene-1-sulfonamido)-1 ,2,3,4- tetrahydroisoquinolinium iodide, [3] N-(2-methyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)naphthalene-1 -sulfonamide hydrochloride, [4] 5-chloro-3-methyl-N-(1 ,2,3,4-tetrahydroisoquinolin-6-yl)benzo[b]thiophene-2- sulfonamide hydrochloride, [5] 5-chloro-3-methyl-N-(2-methyl-1 ,2,3,4-tte
- 6-yl)-amide Hydrochloride [157] 6-Chloro-imidazo[2,1-b] thiazole-5-sulfonic acid (2-cyclopropanecarbonyl- 1 ,2,3,4- tetrahydro-isoquino lin-6-yl)-amide and [158] 6-Chloro-imidazo[2,1-b] thiazole-5-sulfonic acid (2-cyclopropylmethyl-i ,2,3,4- tetrahydro-isoquinolin-6-yl)-amide hydrochloride;
- the present invention relates to a process for the preparation of a substituted tetrahydroisoquinoline compound of general formula Ie, wherein at least one compound of general formula IV,
- R 12e has the meaning given above and X represents a leaving group, preferably a halogen atom, particularly preferably a chlorine atom, is reacted with at least one compound of general formula V,
- R 1e to R 5e have the meaning given above, with the proviso that at least one substituent of the group consisting of R 2e , R 3e , R 4e and R 5e represents a -N(H)(R 11e ) moiety, wherein R 11e has the meaning given above, or a protected derivative thereof, in a reaction medium, preferably in a reaction medium selected from the group consisting of pyridine, chloroform, dichloromethane, tetrahydrofurane and mixtures thereof, preferably in the presence of at least one base, more preferably in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine and diethylisopropylamine, preferably at a temperature between 0 0 C and 30 0 C.
- the present invention relates to a process for the preparation of a substituted tetrahydroisoquinoline compound of general formula Ih, wherein at least one compound of general formula Ih
- R 12h has the meaning given above and X represents a leaving group, preferably a halogen atom, particularly preferably a chlorine atom, is reacted with at least one compound of general formula VhA,
- R 1h to R 5h have the meaning given above, with the proviso that at least one substituent of the group consisting of R 2h , R 3h , R 4h and R 5h represents a -N(H)(R 11h ) moiety, wherein R 11e has the meaning given above, or a protected derivative thereof, in a reaction medium, preferably in a reaction medium selected from the group consisting of pyridine, chloroform, dichloromethane, tetrahydrofurane and mixtures thereof, preferably in the presence of at least one base, more preferably in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine and diethylisopropylamine, preferably at a temperature between 0 0 C and 30 0 C.
- substituted tetrahydroisoquinoline 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.
- 1 ,2,3,4-tetrahydroisoquinoline compounds with a nitro group in position 6 or 8 may be prepared by established procedures described in M. Tercel, Journal of Medicinal Chemistry, 1996, 39, 1084 to 1094.
- N-methyl-8-amino-substituted 1 ,2,3,4-tetrahydroisoquinoline compounds were prepared by bromination and nitration of the corresponding 1 ,2,3,4- tetrahydroisoquinolines followed by two-step standard reduction conditions as described in M. Rey, Helvetica Chimica Acta, 1985, 66, 1828 to 1834 .
- protecting groups for the nitrogen atom may be used.
- Some examples include cyclic imide derivatives, such as maleimides or succinimides, a variety of carbamates, such as tert-butoxy-carbonyl (BOC) and fluorenylmethyloxycarbonyl (Fmoc)m a variety of amides, such as acetamides, and alkyl and aryl amine derivatives, such as ⁇ /-benzyl or ⁇ /-allyl amines.
- BOC tert-butoxy-carbonyl
- Fmoc fluorenylmethyloxycarbonyl
- Additional examples of nitrogen protecting groups can be found in reference books such as Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1999.
- the present invention relates to a process for the preparation of a salt of a substituted tetrahydroisoquinoline compound of general formula If, wherein at least one compound of general formula Vl,
- the present invention relates to a process for the preparation of a salt of a substituted tetrahydroisoquinoline compound of general formula Ih, wherein at least one compound of general formula VIhA,
- salt is to be understood as meaning any form of the substituted tetrahydroisoquinoline compounds of general formula I in which they assume an ionic form or are charged and are coupled with a counter-ion (a cation or anion) or are in solution.
- a counter-ion a cation or anion
- complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
- physiologically acceptable salt is understood in particular, in the context of this invention, as salt (as defined above) formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals - or with at least one, preferably inorganic, cation which are physiologically tolerated - especially if used on humans and/or mammals.
- physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, hydrobromide, monohydrobromide, monohydrochloride or hydrochloride, methiodide, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, hippuric acid picric acid and/or aspartic acid.
- physiologically tolerated salts of particular bases are salts of alkali metals and alkaline earth metals and with NH 4 .
- Solvates, preferably hydrates, of the substituted tetrahydroisoquinoline compounds of general formula I or in each case of corresponding stereoisomers may also be obtained by standard procedures known to those skilled in the art.
- solvate is to be understood as meaning any form of the substituted tetrahydroisoquinoline compounds of general formula I in which they have attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
- the commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris- HCI, 10 mM MgCI 2 , 0.5 mM EDTA (pH 7.4).
- the radioligand used is [ 3 H]-LSD at a concentration of 2.7 nM with a final volume of 200 ⁇ l.
- Incubation is initiated by adding 100 ⁇ l of membrane suspension, ( « 22.9 ⁇ g membrane protein), and is prolonged for 60 minutes at a temperature of 37 0 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-HCI 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 ⁇ M of serotonin. Tests were made in triplicate.
- mice 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 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 substituted tetrahydroisoquinoline compound or a corresponding composition (vehicle) without said substituted tetrahydroisoquinoline compound. Immediately afterwards, the rat is left with preweighed food and cumulative food intake is measured after 1 , 2, 4 and 6 hours.
- example compounds 1 , 4, 8, 10, 11 and 12 were prepared analogously to the process described for the preparation of example compound 6.
- example compound 2 2,2-Dimethyl-6-[methyl-(naphthalene-1-sulfonyl)-amino]-1,2,3,4-tetrahydro isoquinolinium iodide
- Naphthalene-1 -sulfonic acid (1,2,3,4-tetrahydrisoquinolin-6-yl)-amide hydrochloride 100 mg, 0.26 mmol
- potassium carbonate 111 mg, 0.80 mmol
- acetone 20 ml
- methyl iodide 150mg,1.04mmol
- the solution was heated under reflux for 6 hours.
- the solution was evaporated and the crude quaternary ammonium salt was crystallised by addition of ethanol ( 5 ml ) to afforded the title compound (120 mg, 91%).
- the binding of the substituted tetrahydroisoquinoline compounds to the 5-HT 6 receptor was determined as described above.
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Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2008012166A MX2008012166A (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments. |
US12/293,925 US20090209528A1 (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compound, their preparation and use in medicaments |
CA002647024A CA2647024A1 (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments |
EP07723520A EP2007729B1 (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments |
JP2009500780A JP2009531318A (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicine |
CN2007800182351A CN101454289B (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments |
ES07723520T ES2389789T3 (en) | 2006-03-23 | 2007-03-23 | Tetrahydroisoquinoline substituted compounds, their preparation and their use in medicines |
HK09105782.2A HK1128154A1 (en) | 2006-03-23 | 2009-06-26 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06380059.3 | 2006-03-23 | ||
EP06380059A EP1837332A1 (en) | 2006-03-23 | 2006-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007107373A1 true WO2007107373A1 (en) | 2007-09-27 |
Family
ID=36763582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2007/002569 WO2007107373A1 (en) | 2006-03-23 | 2007-03-23 | Substituted tetrahydroisoquinoline compounds, their preparation and use in medicaments |
Country Status (11)
Country | Link |
---|---|
US (1) | US20090209528A1 (en) |
EP (2) | EP1837332A1 (en) |
JP (1) | JP2009531318A (en) |
CN (1) | CN101454289B (en) |
AR (1) | AR060064A1 (en) |
CA (1) | CA2647024A1 (en) |
ES (1) | ES2389789T3 (en) |
HK (1) | HK1128154A1 (en) |
MX (1) | MX2008012166A (en) |
TW (1) | TW200804289A (en) |
WO (1) | WO2007107373A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2116547A1 (en) * | 2008-05-09 | 2009-11-11 | Laboratorios Del. Dr. Esteve, S.A. | Substituted N-imidazo(2, 1-b) thiazole-5-sulfonamide derivatives as 5-TH6 ligands |
WO2012120056A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120052A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120054A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2256105B1 (en) | 2008-03-26 | 2013-12-04 | Daiichi Sankyo Company, Limited | Novel tetrahydroisoquinoline derivative |
US10647679B2 (en) | 2015-03-15 | 2020-05-12 | Emory University | N-methyl-D-aspartate receptor (NMDAR) potentiators, pharmaceutical compositions, and uses related thereto |
CN108794460B (en) * | 2018-05-11 | 2021-05-28 | 贵州医科大学 | 1,2, 4-oxadiazole-3, 4-dihydroquinoline compound and preparation method and application thereof |
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WO2001032646A2 (en) | 1999-11-05 | 2001-05-10 | Smithkline Beecham P.L.C. | Sulfonamide derivatives |
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ES2187300B1 (en) * | 2001-11-14 | 2004-06-16 | Laboratorios Del Dr. Esteve, S.A. | DERIVATIVES OF SULFONAMIDS, ITS PREPARATION AND ITS APPLICATION AS MEDICINES. |
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-
2006
- 2006-03-23 EP EP06380059A patent/EP1837332A1/en not_active Withdrawn
-
2007
- 2007-03-22 AR ARP070101182A patent/AR060064A1/en unknown
- 2007-03-23 CN CN2007800182351A patent/CN101454289B/en not_active Expired - Fee Related
- 2007-03-23 ES ES07723520T patent/ES2389789T3/en active Active
- 2007-03-23 JP JP2009500780A patent/JP2009531318A/en active Pending
- 2007-03-23 US US12/293,925 patent/US20090209528A1/en not_active Abandoned
- 2007-03-23 CA CA002647024A patent/CA2647024A1/en not_active Abandoned
- 2007-03-23 MX MX2008012166A patent/MX2008012166A/en active IP Right Grant
- 2007-03-23 WO PCT/EP2007/002569 patent/WO2007107373A1/en active Application Filing
- 2007-03-23 EP EP07723520A patent/EP2007729B1/en not_active Not-in-force
- 2007-03-23 TW TW096110038A patent/TW200804289A/en unknown
-
2009
- 2009-06-26 HK HK09105782.2A patent/HK1128154A1/en not_active IP Right Cessation
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WO2001032646A2 (en) | 1999-11-05 | 2001-05-10 | Smithkline Beecham P.L.C. | Sulfonamide derivatives |
DE10053799A1 (en) | 2000-10-30 | 2002-05-08 | Bayer Ag | Tetrahydroisoquinoline N-phenylsulfonamide derivatives, useful for treating central nervous system disorders e.g. Alzheimer's disease, dementia are 5-HT6 receptor antagonists |
WO2002100822A1 (en) | 2001-06-11 | 2002-12-19 | Biovitrum Ab | Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes |
WO2003068752A1 (en) | 2002-02-13 | 2003-08-21 | Glaxo Group Limited | Benzenesulfonamide derivatives as antipsychotic agents |
WO2003095428A1 (en) | 2002-05-10 | 2003-11-20 | Glaxo Group Limited | Dopamine receptor modulators as antipsychotic agents |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2116547A1 (en) * | 2008-05-09 | 2009-11-11 | Laboratorios Del. Dr. Esteve, S.A. | Substituted N-imidazo(2, 1-b) thiazole-5-sulfonamide derivatives as 5-TH6 ligands |
WO2009135925A1 (en) * | 2008-05-09 | 2009-11-12 | Laboratorios Del Dr. Esteve, S.A. | Substituted n-imidazo[2,1-b]thiazole-5-sulfonamide derivatives as 5-ht6 ligands |
WO2012120056A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120052A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120054A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
Also Published As
Publication number | Publication date |
---|---|
CN101454289A (en) | 2009-06-10 |
TW200804289A (en) | 2008-01-16 |
US20090209528A1 (en) | 2009-08-20 |
ES2389789T3 (en) | 2012-10-31 |
MX2008012166A (en) | 2008-12-18 |
HK1128154A1 (en) | 2009-10-16 |
EP2007729A1 (en) | 2008-12-31 |
AR060064A1 (en) | 2008-05-21 |
EP2007729B1 (en) | 2012-06-27 |
JP2009531318A (en) | 2009-09-03 |
CA2647024A1 (en) | 2007-09-27 |
CN101454289B (en) | 2012-07-04 |
EP1837332A1 (en) | 2007-09-26 |
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