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WO2005063239A1 - Derives d'acide 3-(4-piperidine-1ylmethyl-phenyl) propionique-phenylamide et composes apparentes, utilises comme antagonistes mch (hormone de concentration en melanine) pour le traitement de troubles dus a l'alimentation - Google Patents

Derives d'acide 3-(4-piperidine-1ylmethyl-phenyl) propionique-phenylamide et composes apparentes, utilises comme antagonistes mch (hormone de concentration en melanine) pour le traitement de troubles dus a l'alimentation Download PDF

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Publication number
WO2005063239A1
WO2005063239A1 PCT/EP2004/014378 EP2004014378W WO2005063239A1 WO 2005063239 A1 WO2005063239 A1 WO 2005063239A1 EP 2004014378 W EP2004014378 W EP 2004014378W WO 2005063239 A1 WO2005063239 A1 WO 2005063239A1
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Prior art keywords
alkyl
phenyl
group
amino
substituted
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PCT/EP2004/014378
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German (de)
English (en)
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WO2005063239A9 (fr
Inventor
Thorsten Lehmann-Lintz
Philipp Lustenberger
Gerald Jürgen Roth
Marcus Schindler
Leo Thomas
Stephan Georg Mueller
Dirk Stenkamp
Ralf R. H. Lotz
Klaus Rudolf
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34706476&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005063239(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to CA002550649A priority Critical patent/CA2550649A1/fr
Priority to EP04803987A priority patent/EP1708698A1/fr
Priority to JP2006546009A priority patent/JP2007520466A/ja
Publication of WO2005063239A1 publication Critical patent/WO2005063239A1/fr
Publication of WO2005063239A9 publication Critical patent/WO2005063239A9/fr

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    • C07D211/40—Oxygen atoms
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Definitions

  • the present invention relates to novel amide compounds, their physiologically acceptable salts and their use as MCH antagonists and their use for the preparation of a medicament which is used for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or with MCH are in a different causal relationship, is appropriate.
  • Another object of this invention relates to the use of a compound according to the invention for influencing the eating behavior as well as for reducing the body weight and / or for preventing an increase in the body weight of a mammal.
  • compositions and pharmaceutical compositions, each containing a compound of the invention ⁇ and processes for their preparation are the subject of this invention. Further objects of this invention relate to processes for the preparation of the compounds according to the invention.
  • the term obesity refers to an excess of adipose tissue in the body.
  • obesity is basically considered to be any elevated level of body fat, leading to a health risk.
  • the individuals having a body mass index (BMI) are above the value of 25, especially above 30, as being obese considered suffering.
  • BMI body mass index
  • MCH antagonists inter alia WO 01/21577, WO 01/82925.
  • MCH Melanin-concentrating hormone
  • MCH-1R G-galpha I coupled MCH-1 R in rodents [3-6], as opposed to primates, ferrets and dogs, no other MCH receptor subtype has been detected in rodents.
  • Loss of MCH-1R results in "knock out" mice to lower fat mass, an increased Energy conversion and high-fat diet to no weight increase compared to control animals.
  • Another indication of the importance of the MCH system in the regulation of the energy balance comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term experiments, the animals treated with this antagonist lose significant weight.
  • the MCH-1 R antagonist SNAP-7941 provides further anxiolytic and antidepressant effects in behavioral experiments with rats [3].
  • the MCH-MCH-1R system is involved not only in the regulation of the energy balance but also the affectivity.
  • WO 01/82925 also compounds of the formula in which Ar 1 is a cyclic group, X and Y spacer groups, Ar is an optionally substituted condensed polycyclic aromatic ring, R 1 and R 2 are independently H or a hydrocarbon group, wherein R 1 and R 2 together with the adjacent N Atom can form an N-containing heterocyclic ring and R 2 together with the adjacent N-atom and Y can form an N-containing hetero ring, described as MCH antagonists for the treatment of, inter alia, obesity.
  • EP 0 237 678 A1 describes indole derivatives for the treatment of migraine.
  • the compound is called N- [4 - [[(methylamino) sulphonyl] methyl] phenyl] -3- [2- (dimethylamino) ethyl] -1H-indole-5-propanamide oxalate.
  • JP 2000086603 describes propenamide derivatives which have a 2-hydroxypropoxy group in use as 5-HT 1A receptor antagonists.
  • N-imidazolyl and N-triazolylalkyl-phenyl-acetamide derivatives are described as inhibitors of retinoid metabolism.
  • the substance N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] -3-phenyl-2-propynamide is named as compound number 198.
  • aminobenzoic acid derivatives are described as VEGF receptor antagonists and include the compound 2- (methylthio) -5 - [[3- [4- (octadecylamino) phenyl] -1-oxopropyl] amino] benzoic acid.
  • JP 04054118 4- (acylamino) phenols are proposed as 5-lipoxygenase inhibitors and include the compounds 4-amino-N- (4-hydroxy-3, 5- dimethylphenyI) -benzenepropanamide and 4- (dimethylamino) -N- (4-hydroxy-3, 5-dimethylphenyl) benzimidopropanamide.
  • benzoxazole derivatives are described as inhibitors of the interaction between VCAM-1 and / or fibronectin and the integrin receptor VLA-4. It is u.a. the compound 4- [3 - [[1-oxo-3- [2- (phenylamino) -6-benzoxazolyl] propyl] amino] phenoxy] butanoic acid.
  • the present invention has for its object to show new amide compounds, especially those that have high activity as MCH antagonists.
  • Further objects of the present invention relate to the demonstration of advantageous uses of the compounds of the invention.
  • a first subject of the present invention are amide compounds of general formula I.
  • R 1, R 2 are independently H, an optionally monosubstituted with the group R 1 or polysubstituted C ⁇ -8 -AlkyI- or c. 3 7 -Cycloalkyl group, wherein a -CH 2 group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S-, -NR 13 -, or optionally with the remainder R 12 mono- or polysubstituted and / or nitro-substituted phenyl or pyridinyl, or
  • R 1 and R 2 form a C 2-8 alkylene bridge in which
  • alkylene bridge may be substituted with one or two identical or different carbo- or heterocyclic groups Cy such that the bond between the alkylene bridge and the group Cy
  • R 3 is H, C -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl or phenyl C 1-3 alkyl,
  • X is a single bond or a C -8 alkylene bridge in which
  • -CH CH- or -C ⁇ C- and / or - one or two non-adjacent -CH 2 Groups that are not with the group
  • R 1 R 2 N are directly connected, independently of one another by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 - may be replaced such that in each case two O, S or N atoms or an O with an S atom are not directly connected to each other,
  • bridge X may be connected to R 1 , including the N atom connected to R 1 and X to form a heterocyclic group, wherein the bridge X additionally with R 2 , including the R 2 and X connected to N atom under Formation of a heterocyclic group may be linked, and
  • W means a single bond
  • Y is one of the meanings given for Cy
  • X may be linked to Y to form a carbamoyl or heterocyclic group fused to Y, and / or
  • R 1 may be linked to Y including the group X and the N atom joined to R 1 and X to form a heterocyclic group fused to Y, and
  • A is one of the meanings given for Cy, in which case the index b has the value 0, the group Cy has no amino group as substituent in the ortho position to the bridge W;
  • b 0 or 1
  • Cy is a carbo or heterocyclic group selected from one of the following meanings
  • a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having an N, O or S atom as heteroatom a saturated or unsaturated 5- to 7-membered heterocyclic group having two or more N atoms or having one or two N atoms and one O or S atom as heteroatoms,
  • 6 or 7-membered groups one or two nonadjacent -CH 2 groups are independently of one another denoted by a --CO--, - C (CHCH 2 ) -, - (SO) - or - ( SO 2 ) group can be replaced, and
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R 20 , in the case of a phenyl group also additionally simply with nitro, and / or one or more NH groups with R 21 ,
  • R 4 is one of the meanings given for R 17 , C 2-6 -alkenyl or C 3-6 -alkynyl,
  • R 10 is hydroxy, hydroxyC 1-3 -alkyl, C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-3 -alkyl, carboxy, C 1-4
  • Alkoxycarbonyl amino, C 1-4 -alkylamino, di- (C 1-4 -alkyl) -amino, cyclo-C 3-6 -alkylenimino, amino-C 1-3 -alkyl, C 1 - 4 alkyl-amino-C 1-3 -alkyl, di- (C 1 -alkyl) - amino-C 1-3 -alkyl, cyclo-C 3-6 -alkylenimino-C 1-3 -alkyl- , Amino C 1-3 alkoxy, C -4 -
  • R 11 C 2-6 -AlkenyI, C ⁇ alkynyl, R 15 -O-, R 5 -O-C ⁇ . 3- alkyl, R 15 -O-CO-, R 15 -CO-O-,
  • R 12 is one of the meanings given for R 20 .
  • R 13 is one of the meanings given for R 17 , with the exception of carboxy,
  • R 14 is halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 -O-, R 15 -O-CO-, R 16 -CO-, R 15 -
  • R 15 is H, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-3 -alkyl, pyridinyl or pyridinyl-C 1-3 -alkyl-,
  • R 16 is H, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 4-7 -cycloalkenyl, C 4-7 -
  • Cycloalkenyl C 1-3 alkyl, hydroxy C 2-3 alkyl, C 1-6 alkoxy C 1-8 alkyl, amino C 2-6 alkyl, C 1-4 alkyl amino C 2-6 alkyl, di (C 1-4 alkyl) amino C 2 . 6 -alkyl or cycloC 3-6 -alkyleneimino-C 2 . 6- alkyl,
  • R 17 is one of the meanings given for R 16 or
  • R 18 , R 19 independently of one another are H or C 1-6 -alkyl
  • R 20 is halogen, hydroxy, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl,
  • R 21 is C 1-4 alkyl, hydroxy C 2-3 alkyl, C ⁇ alkoxy-C ⁇ e-alkyl, C 1 _ 4 -alkyl-amino-C 2-6 alkyl,
  • Alkoxy-N HC, C 1-4 alkoxy, C 1-4 alkylthio, carboxy, C 1-4 alkylcarbonyl, d.
  • each one or more C atoms can additionally be mono- or polysubstituted with F and / or in each case one or two C atoms independently additionally simply substituted with CI or Br and / or one or more phenyl rings independently of one another additionally one, two or more three substituents selected from the group F, CI, Br, I, C ⁇ alkyl, C 1-4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, -C.
  • the H atom of an existing carboxy group or an H atom bound to an N atom can each be replaced by an in-vivo leaving group
  • the compounds of the present invention have particular activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show very good affinities in MCH receptor binding studies.
  • the compounds of the invention have a high to very high selectivity with respect to the MCH receptor.
  • the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.
  • the invention also relates to the respective compounds in the form of the individual optical isomers, mixtures of the individual diastereomers, enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms are replaced by deuterium.
  • physiologically acceptable salts of the above and below described amide compounds according to the invention are also an object of this invention.
  • compositions comprising at least one amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • medicaments containing at least one amide compound according to the invention and / or an inventive salt in addition to optionally one or more inert carriers and / or diluents are the subject of the present invention.
  • an object of this invention is the use of at least one amide compound of the invention and / or a salt of the invention, including those excluded by provisos (M1) to (M14), for influencing the eating behavior of a mammal.
  • amide compound according to the invention and / or a salt according to the invention, including the compounds excluded by provisos (M1) to (M14), for the preparation of a medicament having MCH receptor antagonistic activity, in particular MCH-1 receptor antagonistic activity.
  • an object of this invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the excluded by the provisos (M1) to (M14) compounds for the preparation of a medicament, which for the prophylaxis and / or treatment of Phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • Another object of this invention is the use of at least one amide compound of the invention and / or a salt according to the invention, including the excluded by the provisos (M1) to (M14) compounds for the preparation of a medicament, which for the prophylaxis and / or treatment of metabolic Disorders and / or eating disorders, particularly of obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa or hyperphagia.
  • an object of this invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the compounds excluded by provisos (M1) to (M14), for the preparation of a medicament which is used for the prophylaxis and / or treatment of obesity-associated diseases and / or disorders, in particular diabetes, especially type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular disorders, in particular arteriosclerosis and hypertension, arthritis and gonitis is suitable.
  • the present invention has the use of at least one amide compound according to the invention and / or a salt according to the invention, including the excluded by the provisos (M1) to (M14) compounds for the preparation of a medicament, which for the prophylaxis and / or treatment of
  • the subject of the study is hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.
  • a further subject matter of this invention is the use of at least one amide compound according to the invention and / or of a salt according to the invention, including the compounds excluded by provisos (M1) to (M14), for the preparation of a medicament which is used for the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia and enuresis.
  • an object of this invention relates to processes for the preparation of a medicament according to the invention, characterized in that at least one amide compound according to the invention and / or a salt according to the invention is incorporated into one or more inert carriers and / or diluents by non-chemical means.
  • Another object of this invention is a pharmaceutical composition containing a first active ingredient selected from the amide compounds of the invention and / or the corresponding salts, including compounds excluded by provisos (M1) to (M14), and a second active ingredient who is from the A group consisting of drugs for the treatment of diabetes, drugs for the treatment of diabetic complications, drugs for the treatment of obesity, preferably other than MCH antagonists, drugs for the treatment of hypertension, drugs for the treatment of hyperlipidemia, including arteriosclerosis, drugs for the treatment of arthritis , Agents for the treatment of anxiety and drugs for the treatment of depression, besides optionally one or more inert carriers and / or diluents.
  • a first active ingredient selected from the amide compounds of the invention and / or the corresponding salts, including compounds excluded by provisos (M1) to (M14), and a second active ingredient who is from the A group consisting of drugs for the treatment of diabetes, drugs for the treatment of diabetic complications, drugs for the treatment of obesity, preferably other than MCH antagonist
  • radicals and / or substituents in a compound may each have the same or different meanings given.
  • Preferred embodiments of this invention include compounds which can each be described by the following formulas Ia, Ib, Ic and Id:
  • R 1 , R 2 , R 3 , R 7a , R 7b , R 7c , R 7d , X, Y, A, B and b have the meanings given above and below, in particular those given as preferred meanings.
  • radicals R 7a , R 7 , R 7c , R 7d are H or methyl, in particular H.
  • R 3 are H, C 1 alkyl, C 3 . 6 -cycloalkyl or C 3-6 -cycloalkyl-C 1-3 -alkyl-; in particular H or C 1-3 -alkyl.
  • R 3 particularly preferably denotes H or methyl, in particular H.
  • the substituents R 1 and R 2 may have a meaning as defined above and below as separate radicals or as a bridge connected to one another.
  • the preferred meanings of R 1 and R 2 are described below as separate radicals and then the preferred meanings of interconnected, bridging radicals R 1 and R 2 .
  • Preferred compounds according to the invention therefore have one of the preferred meanings of R 1 and R 2 described below as separate radicals combined with one of the preferred meanings of R 1 and R 2 described below as interconnected radicals forming a bridge.
  • R 1 and R 2 are not linked to one another via an alkylene bridge, then R 1 and R 2, independently of one another, preferably represent a C 1-8 -alkyl or C 3-7 -cycloalkyl radical which is optionally monosubstituted or polysubstituted by the radical R 11 A group in which one -CH 2 group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR 13 -, or may optionally be substituted by the radical R 12. or several times and / or with nitro single substituted phenyl or pyridinyl, and wherein one of the radicals R 1 and R 2 may also be H.
  • the radicals R 1, R 2 mutually independently represent C 1-6 alkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl C 1-3 alkyl, hydroxy-C 2-4 alkyl, NC-C 2-4 alkyl, C 1-4 -alkoxycarbonyl-d-alkyl, carboxyl-C 1-4 -alkyl, amino-C 1-6 -alkyl, C 1-4 -alkyl-amino-C 2-4 -alkyl, di- (d. 4-alkyl) -amino-C 2-4 -alkyl, cyclo-C3.
  • the aforementioned cycloalkyl rings may be substituted one or more times with substituents selected from hydroxy, hydroxyC 1-3 alkyl, C 1-3 alkyl or C 1-3 alkyloxy, in particular hydroxy, hydroxymethyl, methyl and methoxy his.
  • the C 2-4 alkyl bridges in the meanings hydroxy-C 2- alkyl- and d. 4 alkoxy-C 2-4 alkyl additionally be substituted by hydroxy, hydroxy-C 1-3 alkyl, C 1-3 alkyl or C 1-3 alkyloxy, especially hydroxy, hydroxymethyl, methyl or methoxy.
  • Preferred substituents R 12 of the abovementioned phenyl or pyridyl radicals are selected from the group F, Cl, Br, I, cyano, C 1-4 -alkyl, C 1- alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino -, C 1-3 alkylamino, di- (C 1-3 -alkyl) -amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C 1-3 alkyl, C ⁇ -3 - alkylamino-C 1-3 -alkyl- and di- (C 1-3 -alkyl) -amino-C 1 . 3 -alkyl-, wherein a phenyl radical may also be easily substituted with nitro.
  • radicals R 1 and / or R 2 are selected from the group consisting of C 1-6 -alkyl, C 3- cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, tetrahydropyran-3 - or -4-yl, tetrahydropyranyl C ⁇ -3 alkyl, piperidin-3- or -4-yl, wherein the NH group may be substituted with R 13, piperidinyl-C 1-3 alkyl, wherein the NH- group may be substituted with R 13, phenyl, pyridyl, phenyl-C 1-3 -alkyl, pyridyl-C 1-3 alkyl, hydroxy-C 2-4 alkyl, C 1-4 alkoxy C 2-4 -alkyl, amino-C 2-4 -alkyl, C 1-8 -alkyl-amino-C 2- -alkyl and di- (C 1-4 -
  • alkyl- additionally be monosubstituted by hydroxy, hydroxy-C ⁇ -3 alkyl, C 1-3 alkyl or C 1-3 alkyloxy, in particular hydroxy, hydroxymethyl, methyl or methoxy may be substituted, and wherein alkyl groups may be mono- or polysubstituted with F and / or simply substituted with CI, and wherein one of the radicals R and R 2 may also be H.
  • R 13 is preferably H, C 1-6 alkyl, C 1-4 alkylcarbonyl or C 1-4 alkyloxycarbonyl. More preferably R 13 is H or d 1 alkyl, especially H, methyl, ethyl or propyl.
  • radicals R 1 and / or R 2 are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, Cyclohexylmethyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, tetrahydropyran-4-yl-methyl, piperidin-4-yl, which may be substituted at the N-atom by R 13 , or piperidin-4-yl-methyl which may be substituted at the N atom with R 13 , said ethyl, propyl and butyl radicals may be monosubstituted by amino, methylamino or dimethylamino or mono- or di-hydroxy, me
  • radicals R 1 and / or R 2 are methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl , 2-methoxyethyl, 3-aminopropyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, (1-hydroxycyclopropyl) methyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methylpiperidin-4-yl, N- (methylcarbonyl) -piperidin-4-yl and N- (tert-butyloxycarbonyl) -piperidin-4-yl, wherein hydroxyalkyl groups may additionally be substituted by hydroxy, and wherein one of the radicals R 1 , R 2
  • the substituent R 1 has one of the meanings given above as preferred, but not H
  • the substituent R 2 very particularly preferably denotes H, methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl or 2-methoxyethyl.
  • R 1 , R 2 are one or more groups selected from 2-hydroxyethyl, 2-hydroxy-2-methyl- propyl, 2-methoxyethyl, 3-aminopropyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, (1-hydroxycyclopropyl) methyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methyl-piperidin-4-yl , N- (methylcarbonyl) -piperidin-4-yl and N- (tert-butyloxycarbonyl) -piperidin-4-yl, in particular selected from 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl, 2-methoxyethyl, tetrahydropyran
  • At least one of the radicals R 1 , R 2 has a meaning other than H.
  • R 1 and R 2 form an alkylene bridge
  • one or more H atoms may be replaced by R 14 , and
  • R 13 is preferably H, C 1-6 -alkyl, With particular preference R 13 is H or C 1-6 -alkyl, in particular H, methyl, ethyl or propyl.
  • R 1 and R 2 form such an alkylene bridge that R 1 R 2 N- is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1, 2,3,6 Tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free imine function is substituted with R 13 , piperidine-4 -on, piperidin-4-one oxime, piperidin-4-one-OC 1-4 alkyl oxime, morpholine and thiomorpholine,
  • R 1 and R 2 wherein according to the general definition of R 1 and R 2, one or more H atoms may be replaced by R 14 , and / or the abovementioned groups in a manner indicated by the general definition of R 1 and R 2 with one or two identical or different carbo- or heterocyclic groups Cy may be substituted.
  • Particularly preferred groups Cy are phenyl, C 3 .
  • the alkylene bridge formed by R 1 and R 2 in which, as indicated, -CH 2 - groups may be replaced, may be substituted as described with one or two identical or different carbo- or heterocyclic groups Cy.
  • Cy is preferably selected from the group consisting of C 3-7 -cycloalkyl, cyclo-C 3-6 -alkyleneimino, piperazinyl, 1H-imidazole, thienyl and phenyl, in particular C 3-6 -cycloalkyl, pyrrolidinyl, piperidinyl and piperazinyl, which may be substituted as indicated, in particular wherein the N-atoms may each be substituted by C 1-4 -alkyl.
  • Cy is preferably selected from the group consisting of C 3-7 -cycloalkyl, aza-C 1 -a-cycloalky-, Oxa-C "- cycloalkyl, 2,3-dihydro-1 H-quinazolin-4-one, in particular cyclopentyl and cyclohexyl, which may be substituted as indicated, in particular wherein the N-atoms in each case substituted by C 1-4 alkyl could be.
  • Cy is preferably selected from the group consisting of C 4-7 cycloalkyl, aza -C ⁇ -cycloalky-, phenyl, thienyl, in particular phenyl and pyrrolidinyl, which may be substituted as indicated, in particular wherein the N atoms may each be substituted by C 1-4 alkyl.
  • a bridged ring system is connected with the formation means Cy preferably C -8 cycloalkane or aza-C -8 -cycIoalkan, in particular cyclopentane , Cyclohexane, pyrrolidine or piperidine, where the N atoms may each be substituted by C 4 alkyl.
  • the group has a meaning according to one of the following sub-formulas
  • the one or more times with R 20 in particular with F, hydroxy, C 1-3 -alkyl, CF 3 , C 1-3 -alkyloxy, OCF 3 or hydroxy-C 1-3 -alkyl may be substituted, and wherein the group represented by R 1 R 2 N- formed heterocycle connected ring one or more times at one or more carbon atoms with R 20 , in the case of a phenyl ring may also be additionally substituted with nitro and additionally easy X ', X "independently of one another a single bond or C 1-3 alkylene and
  • X meanings each denote a C atom with R 0 , preferably with a hydroxy, ⁇ -hydroxy-C 1-3 alkyl, co- (C 1-4 alkoxy) -C 1-3 alkyl and / or C 1-4 alkoxy radical, and / or one or two C atoms each having one or two identical or different substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 -CycIoalkyl, C 3 _ 7 cycloalkyl C 1-3 alkyl, C 4-7 - cycloalkenyl, and C 4-7 cycloalkenyl-C ⁇ -3 -alkyl may be substituted, wherein two alkyl and / or alkenyl substituents may be linked together to form a carbocyclic ring system, and
  • R 2 , R 10 , R 13 , R 14 , R 18 , R 20 , R 21 and X are those given above and below
  • X, X "independently of one another are a single bond or C 1-3 -alkylene and, in the case where the group Y is connected to X or X" via a C atom, also -C 1-3 -alkylene-O -, C 1-3 -alkylene-NH- or -C 1-3 -alkylene-N (C 1-3 -alkyl) -, and X "additionally also -OC 1-3 -alkylene, -NH-C 1 3- alkylene or -N (C 1-3 -alkyl) C 1-3 -alkylene, and in the event that the group Y is linked to X "via a C atom, X" also denotes -NH-, -N (C 1-3 -alkyl) - or -O-, more preferably X, X "independently of one another are a single bond or methylene and in the event that the group Y is connected to X
  • R 14 the following definitions of the substituent R 14 are preferred: F, Cl, Br, C 1-4 -alkyl, C 2- alkenyl, C 2-4 -alkynyl, C 5-7 -cycloalkyl-C 1-3 -alkyl, hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 -alkoxy, ⁇ - (C 1-4 -alkoxy) -C-1. 3- alkyl, ⁇ -alkyl-carbonyl, carboxy, d.
  • one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another simply substituted with CI or Br, in particular alkyl radicals one or more times with fluorine be substituted.
  • substituent R 14 are F, Cl, C 1-4 alkyl, C 3-6 - cycloalkyl-C ⁇ -3 alkyl, hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 - Alkoxy, C 1-4 alkoxy-C 1-3 -alkyl, amino-C- ⁇ .
  • Cy is preferably C 3 -6 cycloalkyl and R 20 is preferably F, hydroxy, C 1-3 alkyl, CF 3, C 1-3 alkyloxy, OCF 3, or hydroxy-C 1-3 -alkyl, in particular F, hydroxy, methyl, methoxy, CF 3 , OCF 3 or hydroxymethyl.
  • Particularly preferred meanings of Cy are C 3 . 6 - cycloalkyl and 1-hydroxy-C 3-5 cycloalkyl.
  • the group has a meaning according to one of the following sub-formulas
  • ring connected to the heterocycle formed by the group R 1 R 2 N- may be monosubstituted or polysubstituted, preferably simply substituted on one or more carbon atoms by R 20 , and in the case of a phenyl ring may additionally also be substituted simply by nitro and in which
  • R 14 are each independently of one another F, Cl, C 1-4 alkyl, C 3-6 cycloalkylC 1-3 alkyl, hydroxy, hydroxyC 1-3 alkyl, C 1-4 alkyloxy, C 1-4 alkoxy-C 1-3 -alkyl, pyridylamino or aminocarbonyl, where in each case one or more C atoms, in particular alkyl radicals may additionally be mono- or polysubstituted by F; most preferably methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methyl-ethyl, 1-hydroxycyclopropyl, methoxy, ethoxy, methoxymethyl, pyridylamino or aminocarbonyl; and
  • R 13 is as defined above, in particular H or C 1-3 -AlkyI means.
  • H atoms can be replaced as indicated above and the ring connected to the heterocycle formed by the group R 1 R 2 N- one or more times, preferably simply at one or more C atoms with R 20 , in the case of
  • phenyl rings may additionally be substituted by nitro, or
  • H atom of the heterocycle formed by the group R 1 R 2 N- by a substituent selected from hydroxy, hydroxy-C 3 alkyl, 1-hydroxy-C 3-5 cycloalkyl, C 1-4 -Alkyloxy and C ⁇ -4 -alkoxy-C ⁇ -3 -alkyI is substituted, and wherein additionally a or more, preferably one or two, H atoms of the heterocycle formed by the group R 1 R 2 N- through the previously defined substituent R 14 and / or an H atom of the heterocycle formed by the group R 1 R 2 N- by Cy in the meaning C 3-6 -cycloalkyl which is mono- or polysubstituted with R 20 , in particular with F, hydroxyl, C 1-3 -alkyl, CF 3 , C 1-3 -alkyloxy, OCF 3 or hydroxy-C 1 3- alkyl, particularly preferably with F, hydroxy, methyl, methoxy, CF 3 , OCF 3 or hydroxy-C 1
  • R 4 may be linked together with Y to form a heterocyclic ring system
  • bridge X may be connected to R 1 including the N atom connected to R 1 and X to form a heterocyclic group
  • a -CH 2 - group immediately adjacent to the group R 1 R 2 N- is not denoted by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 - replaced. If, in group X, one or two -CH 2 groups are independently replaced by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 -, these are Preferably, groups are spaced from the group R 1 R 2 N- by an alkylene bridge having at least 2 C atoms.
  • two -CH 2 groups are independently replaced by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 -, these groups are preferred separated by an alkylene bridge with at least 2 C atoms.
  • this -CH 2 group is preferably not directly linked to a heteroatom, a double bond or a triple bond.
  • the alkylene bridge X, X 'or X has no or at most one imino group
  • the position of the imino group within the alkylene bridge X, X or X" is preferably selected such that together with the amino group NR 1 R 2 or another adjacent amino group, no aminal function is formed or two N atoms are not adjacent to each other.
  • substituents are selected from the group of the C 1 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3-7 -Cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, hydroxy, ⁇ -hydroxy-d -3 -alkyl, ⁇ - (C M -alkoxy) C 1-3 -alkyl and C 1 -4 alkoxy radicals.
  • X, X or X " is a carbon atom doubly and / or one or two carbon atoms mono- or disubstituted, preferred substituents are selected from the group d.
  • 4- alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl and C 3-7 cycloalkyl-C 1-3 alkyl, and two C 1-6 alkyl and or C 2-4 alkenyl substituents may also be linked together to form a saturated or monounsaturated carbocyclic ring.
  • the group X in the meaning C 2 -Alkylenoxy, in particular -CH 2 - CH 2 -CH 2 -O-, no hydroxy substituent on.
  • Very particularly preferred substituents of one or two C atoms in X, X or X are selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl, where two alkyl substituents on a C atom also form a carbocyclic ring can be connected to each other.
  • one or more carbon atoms can additionally be mono- or polysubstituted with F and or in each case one or two C atoms, in each case independently of one another, may additionally be monosubstituted by Cl or Br.
  • Is in the group X, X or X ' is a more C-atoms or with a hydroxy and / or C ,. 4 alkoxy radical is substituted, the substituted C atom is preferably not directly adjacent to another heteroatom.
  • X is an unbranched C 1-4 alkylene bridge and
  • R may be linked to Y to form a heterocyclic ring system
  • bridge X may be connected to R 1 including the N atom connected to R 1 and X to form a heterocyclic group
  • X is a C atom with R 10 and / or one or two C atoms each having one or two identical or different substituents selected from d. 6 -alkyl, C 2-6 -alkenyl, C 2 . 1-3 alkyl, C ⁇ cycloalkenyl, and C 4-7 cycloalkenyl C ⁇ -3 alkyl alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C, in particular selected from C - B 1-3 alkyl may be substituted, wherein two alkyl and / or alkenyl substituents may be linked together to form a carbocyclic ring system, and
  • R 1 , R 4 and R 10 are as defined above and below.
  • the substituent R 10 is preferably a hydroxy, hydroxy-d. 3- alkyl, C 1-4 alkoxy C 1-3 alkyl and / or C M alkoxy radical, especially hydroxy, hydroxymethyl or methoxy.
  • Preferred meanings of the substituent R 4 are H, d. 6- alkyl and C 3-6 -AIkenyI. More preferably, R 4 is H or C 1-4 alkyl. If R 4 is linked to Y to form a heterocyclic ring system, particularly preferred meanings of R 4 are C 2-6 -alkyl and C 2-6 -alkenyl.
  • R 4 is linked to Y to form a heterocyclic ring system
  • Y is phenyl and R 4 is preferably C 2-6 -alkyl or C 2-6 -alkenyl.
  • Preferred heterocyclic ring systems herein are indole, dihydroindole, quinoline, dihydroquinoline, tetrahydroquinoline and benzoxazole.
  • X is -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - and
  • -CH 2 -CH CH-, -CH 2 OC-, -CH 2 -CH 2 -O-, - CH 2 -CH 2 -CH 2 -O- or
  • R may be linked to Y to form a heterocyclic ring system
  • bridge X may be connected to R 1 including the N atom connected to R 1 and X to form a heterocyclic group
  • a C atom with R 10 and / or one or two C atoms can each independently be substituted by one or two identical or different d ⁇ -alkyl radicals, two alkyl radicals with formation of a carbocyclic ring system with one another can be connected; preferably wherein in X one or two carbon atoms may each independently be substituted with one or two identical or different C 1-3 -alkyl radicals, two alkyl radicals with formation of a carbocyclic ring system, in particular a cyclopropyl group, with one another can be connected, and
  • one or more C atoms may be mono- or polysubstituted with F and / or in each case one or two C atoms independently of one another may be substituted by CI or Br, preferably in each case one or more C atoms are mono- or polysubstituted by F may be substituted.
  • the group Y is connected to X via a C atom (the group Y), -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, 1,1-Cyclopropylene, -CH 2 - CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, -CH 2 -CH 2 -NR 4 - or -CH 2 -CH 2 -CH 2 -NR 4 -, where these groups are unsubstituted or in which the alkylene bridge is as indicated, preferably mono- or disubstituted by methyl and / or fluorine.
  • the radical R 4 preferably has the meaning vinyl only if R 4 is bonded to Y to form a heterocyclic ring system.
  • the group X preferably has no carbonyl group.
  • Y denotes a fused bicyclic ring system
  • a preferred meaning of the group X is a single bond, -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -, in particular a single bond, -CH 2 - or -CH 2 -CH 2 -, most preferably -CH 2 - or -CH 2 -CH 2 -, which may be substituted as indicated.
  • X is more preferably -CH 2 - or 1,1-cyclopropylene.
  • X in the meaning -CH 2 - may be linked together with Y to form a bicyclic ring system as indicated, for which purpose the -CH 2 -bridge is substituted by C 2-3 -alkyl.
  • the -CH 2 bridge can be one or two
  • Substituents independently selected from the group consisting of C 1-3 alkyl, wherein two alkyl radicals may be connected together to form a carbocyclic ring system.
  • X is particularly preferably -CH 2 - CH 2 -, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, -CH 2 -CH 2 -NR 4 - or -CH 2 -CH 2 -CH 2 -NR 4 -, wherein said groups may have one or two substituents independently selected from the group consisting of C 1-3 -alkyl, wherein two Alkyl radicals may be connected together to form a ring system.
  • the bridge X can also mean a single bond.
  • the bridge X forms a single bond only when Y represents a bicyclic ring system.
  • the bridge X may preferably only be a single bond if the compound according to the invention can be described according to one of the partial formulas Ia, Ib or Id, in particular according to one of the partial formulas Ia or Ib, very particularly preferably of the partial formula Ib.
  • the group Y preferably has a meaning which is selected from the group of the bivalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl or benzoxazolyl, the abovementioned cyclic groups may be mono- or polysubstituted to one or more carbon atoms with R 20 , in the case of a phenyl group also additionally simply with nitro, and / or to one or more N atoms with R 21 .
  • R 1 may be connected to Y and / or X to Y as indicated above.
  • the bridges X and Z are preferably connected in para-position with the group Y.
  • Y has one of the following meanings
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R 20 , and in the case of a phenyl group may additionally also be monosubstituted by nitro, and / or one or more NH groups may be substituted by R 21 .
  • the group Y may be linked to the group X to form a carbamoyl or heterocyclic group fused to Y.
  • preferred meanings of the interconnected groups -X-Y- are selected from the list consisting of
  • the phenyl ring may be monosubstituted or polysubstituted with R 20 or additionally simply with nitro, and the saturated carbocyclic ring may be monosubstituted or disubstituted with d 1-4 -alkyl.
  • the group Y is preferably unsubstituted or monosubstituted or disubstituted.
  • substituents R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, hydroxy, hydroxy-C 1-3 -alkyI, C- M alkoxy, trifluoromethyl, trifluoromethoxy, C 2 alkynyl, C 1-4 alkoxy carbonyl, C ⁇ _ alkoxy!
  • R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, C 1-3 -alkyl, C 1-3 -alkoxy, C 1-4 -alkoxycarbonyl, trifluoromethyl, Trifluoromethoxy, amino, in the case of a phenyl ring also nitro.
  • the group Y represents substituted phenylene
  • a preferred meaning of group A is aryl or heteroaryl.
  • the group A is selected from the group of cyclic groups phenyl, pyridinyl or naphthyl, which may be mono- or polysubstituted to one or more C atoms with R 20 , in the case of a phenyl ring also additionally simply with nitro, wherein the Group A has no amino group as a substituent in the ortho position to the bridge W.
  • the group A does not have a substituent selected from the group consisting of C 1-4 -alkyl-sulfonylamino, C 1-4 -alkyl-carbonyl-amino, C 1- alkyl -sulfonylamino-C 1-3 -alkyl, C 1- alkyl-carbonyl-amino-C 1-3 alkyl, and phenylcarbonylamino on.
  • non-preferred substituents are aminocarbonyl, C 1 -alkylaminocarbonyl, di- (C 1- -alkyl) -aminocarbonyl, cyclo-C 3-6 -alkyl-amino-carbonyl, cyclo-C 3-6 -alkylenimino-carbonyl, cyclo-C 3-6 -alkyleneimino-C 2-4 -acyl-aminocarbonyl, phenyl -amino-carbonyl, aminocarbonyl-d.
  • the group A preferably has no substituent selected from the group consisting of nitro and tert-butyloxycarbonylamino in each case in the ortho position to the bridge W.
  • the group A is preferably monosubstituted, disubstituted or trisubstituted.
  • the group A is preferably unsubstituted or monosubstituted or disubstituted. If b has the value 1 and the group A is monosubstituted, then the substituent is preferably in the ortho position with respect to the group W.
  • A is one of the groups listed below
  • R 20 of group A are selected from among fluorine, chlorine, bromine, cyano, C 1-4 -alkoxy, trifluoromethyl, trifluoromethoxy, carboxy, C 1-4 -alkoxycarbonyl, C 1 -alkyl amino and di (C M alkyl) amino
  • R 20 or H has one of the meanings given for R 20 or H, preferably F, CI, Br, I, CH 3 , CF 3 , OCH 3 , OCF 3> CN or NO 2 ; particularly preferably F, Cl or Br;
  • R 20 or H has one of the meanings given for R 20 or H, preferably F, Cl, Br, I, CF 3 , OCF 3 , CN, NO 2 , C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl- C ⁇ -3 alkyl, C 1- alkoxy, C 3-7 cycloalkyl-O-, C 3-7 cycloalkyl-C 1-3 -alkoxy, -COO-C M alkyl or -COOH; particularly preferably F, Cl, Br, C 1-4 alkyl, CF 3 , methoxy, OCF 3 , CN or NO 2 ; most preferably CI, Br, CF 3 or NO 2 ;
  • q has the value 0, 1 or 2.
  • A is particularly preferably substituted phenyl according to the above sub-formula in which q is 1 or 2 and / or at least one substituent L 2 is in the meta position to the substituent L 3 . Furthermore, a preferred sub-formula for A, in particular for the case where b is the value 0
  • b has the value 1
  • a preferred meaning of the group B is aryl or heteroaryl, which may be substituted as indicated.
  • group B are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl. Most preferably, the group B is phenyl.
  • the group B in the meanings given may be mono- or polysubstituted with R 20 , a
  • Phenyl group additionally also be easily substituted with nitro.
  • the group B is mono-, di- or trisubstituted, in particular monosubstituted or disubstituted.
  • the substituent is preferably in ortho or para position, in particular para position to group A.
  • substituents R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C 1 -alkyl, hydroxy, hydroxy-C 3 -3 -alkyl, d. 4 -alkoxy, trifluoromethyl, trifluoromethoxy, C 2-4 alkynyl, carboxy, C 1-4 alkoxycarbonyl, d.
  • R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF 3 , C 1-3 -alkyl, C 1 -alkoxy and trifluoromethoxy or nitro; in particular fluorine, chlorine, bromine, methoxy, CF 3 and trifluoromethoxy.
  • R 4 has one of the meanings given for R 17 , preferably one of R 16 .
  • R 4 Particularly preferred meanings of the substituent R 4 are H, C 1-6 -alkyl and C 3-6 -alkenyl. If R 4 is linked to Y to form a heterocyclic ring system, particularly preferred meanings of R 4 are C 2-6 -alkyl and C 2-6 -alkenyl.
  • R 20 are halogen, hydroxy, cyano, C 1-4 - alkyl, C 3-7 cycloalkyl, C ⁇ -4 alkoxy, C 1-4 alkoxycarbonyl or amino, wherein, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted with F and / or in each case one or two C atoms, in each case independently of one another, may additionally be substituted simply by Cl or Br.
  • R 20 is particularly preferably F, CI, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, methoxycarbonyl , Ethoxycarbonyl or amino.
  • R 21 are C 1- alkyl, C 1-4 -AlkyIcarbonyl, C 1- -
  • R 21 are H, C 1-4 -alkyl, C 1-4 -alkylcarbonyl, C 1-4 -alkoxycarbonyl, in particular H and C 1-3 -alkyl.
  • Cy preferably denotes a C 3-7 -cycloalkyl, in particular a C 5-7 -cycloalkyl group, a C 5-7 -cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, where aryl or Heteroaryl is preferably a monocyclic or condensed bicyclic ring system, and where the abovementioned cyclic groups are mono- or polysubstituted to one or more C atoms with R 20 , in the case of a phenyl group additionally also simply with nitro, and / or one or more NH- Groups with R 21 can be substituted.
  • Those compounds according to the invention are preferred in which one or more of the groups, radicals, substituents and / or indices has one of the meanings given above as being preferred.
  • the bridge X is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or 1,1-cyclopropylene, and
  • -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, -CH 2 -CH 2 -NR 4 - or -CH 2 -CH 2 -CH 2 -NR 4 - may mean
  • groups indicated for X are unsubstituted or in which the alkylene bridge is as indicated, preferably one or two times substituted with methyl and / or fluorine, where two methyl groups may be linked together to form a cyclopropyl ring;
  • phenyl rings or bicyclic groups having heteroatoms are monosubstituted or polysubstituted by R 20 and phenyl rings are also additionally monosubstituted by nitro, and the saturated carbocyclic ring in the indane skeleton is monosubstituted or disubstituted by C 1-3 -alkyl can be, and
  • Group A is one of the subformulae listed below
  • b has the value 0 or 1.
  • Preferred groups of compounds according to this invention can be obtained by the following formulas, more preferably by the formulas la.1, la.2a, la.2b, la.3, la.5, la.6, la.7, la.8, lb.1, lb.2, lc.1 and ld.1 describe
  • R 1 are alkyl from the group consisting of C ⁇ -6 alkyl, C 3 _ 7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 2 independently selected, tetrahydropyran-3- or -4- yl, tetrahydropyranylC 1-3 alkyl, piperidin-3 or -4-yl, where the NH group may be substituted with R 13 , piperidinyl-C 1-3 alkyl, wherein the NH group with R 13 may be substituted, phenyl, pyridyl, phenyl C 1-3 alkyl, pyridyl-C 1-3 alkyl, hydroxy-C 2-4 alkyl, d.
  • R 1 , R 2 are linked together in such a way that the group a meaning according to one of the following sub-formulas
  • the one or more times with R 20 in particular with F, hydroxy, -C. 3- alkyl, CF 3 , C 1-3 alkyloxy, OCF 3 or hydroxy-C 1-3 alkyl, particularly preferably with F, hydroxy, methyl, methoxy, CF 3 , OCF 3 or hydroxymethyl may be substituted can, and
  • ring connected to the heterocycle formed by the group R 1 R 2 N- may be monosubstituted or polysubstituted, preferably simply substituted on one or more carbon atoms by R 20 , and in the case of a phenyl ring may additionally also be substituted simply by nitro and
  • R 3 is preferably H or methyl
  • R 14 are each independently of one another F, Cl, C 1-4 alkyl, C 3-6 cycloalky [-d -3 alkyl, hydroxy, hydroxyC 1-3 alkyl, C 1-4 alkoxy, C 1- alkoxy-C 1-3 -alkyl, pyridylamino or aminocarbonyl, where in each case one or more C atoms may additionally be monosubstituted or polysubstituted by F or in each case one C atom may simply be substituted by Cl; very particularly preferably methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxy,
  • R 13 is H, C 1- alkyl, C 1-4 -Alkylcarbonyi or C 1- alkyloxycarbonyl group; particularly preferably H or C 1-3 alkyl;
  • Q is CH or N, where CH can be substituted by R 1 ⁇ ,
  • L 1 is preferably fluorine, chlorine, bromine, cyano, C 1-3 -alkyl, d 1-4 -alkyl, trifluoromethyl,
  • Ethoxycarbonyl, cyano, amino or nitro has the value 0 or 1
  • R 20 each independently preferably fluoro, chloro, bromo, cyano, nitro, d. 4-alkyl, C 2-6 alkenyl, hydroxy, hydroxyC 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, C 2-4 alkynyl, carboxy, C 1-4 alkoxycarbonyl, C 1 -4- alkoxy-C 1-3 -alkyl, Amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, aminocarbonyl, C- M alkylamino-carbonyl, di (C 1-4 alkyl) ) -amino-carbonyl-, wherein in the event that the index b has the value 0, the group Cy has no amino group as substituent in the ortho position to the bridge W;
  • R 20 is selected from fluorine, chlorine, bromine, cyano, nitro, C 1 - alkyl, hydroxy, hydroxy-C 1-3 -alkyI, C ⁇ -4 alkoxy, trifluoromethyl, trifluoromethoxy, C 2 - alkynyl, Carboxy, C 1-4 alkoxycarbonyl and C, M alkoxy-ds-alkyl;
  • r, s each independently of one another have the value 0, 1, 2 or 3, preferably at least one index r or s does not denote the value 0, and
  • R 20 has one of the meanings given above, including H, and wherein multiple occurring substituents R 20 may have the same or different meanings, and preferably wherein at least one substituent R 20 has a different meaning from H.
  • the compounds listed in the examples and tables, including their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, are preferred according to the invention. Particularly preferred compounds are listed below, with the example number in question in brackets:
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.
  • C 1-n -alkyl wherein n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group having 1 to n carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, iso -propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • Substituted alkyl radicals such as the C 2-4 alkyl group in hydroxyC 2-4 alkyl or C 1-4 alkoxyC 2-4 alkyl may also be branched or unbranched.
  • C 1-n -alkylene where n can have a value of 1 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge having 1 to n C atoms.
  • groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methyl-ethylene (-CH (CH 3 ) -CH 2 -), 1,1-dimethyl-ethylene (- C (CH 3 ) 2 -CH 2 -), n -prop-1, 3-ylene (-CH 2 -CH 2 -CH 2 -), 1-methylprop-1, 3-ylene (-CH (CH 3 ) -CH 2 -CH 2 -), 2-methylprop-1, 3-ylene (-CH 2 -CH (CH 3 ) -CH 2 -), etc., as well as the corresponding mirror-image forms.
  • Double bond Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3 Pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.
  • C 2-n -alkynyl where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and an O ⁇ C-
  • Triple bond examples include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
  • C 1-n -alkoxy refers to a C 1-n -alkyl-O-group in which C 1-n -alkyl is as defined above.
  • groups include methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- Hexoxy, iso-hexoxy etc.
  • C 1-n- alkylthio denotes a C 1 . n -Alkyl-S group, wherein C ⁇ - n- alkyl is as defined above.
  • groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, tert-pentylthio, n-butylthio Hexylthio, iso-hexylthio, etc.
  • groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso -propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-butyl Hexylcarbonyl, iso-hexylcarbonyl, etc.
  • C 3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group having 3 to n C atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl. Etc..
  • C 5 . n -Cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group having 5 to n carbon atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
  • aryl refers to a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc.
  • a particularly preferred meaning of "aryl” is phenyl.
  • cyclo-C 3-7 -alkyleneimino- refers to a 4- to 7-membered ring containing 3 to 7
  • Molecule takes place via the imino group.
  • cyclo-C 3-7 -alkylenimino-carbonyl designates a previously defined cyclo-C 3-7 -alkyleneimino ring which is connected via the imino group with a carbonyl group.
  • heteroaryl used in this application denotes a heterocyclic aromatic ring system which, in addition to at least one C atom, has one or more
  • Heteroatoms selected from N, O and / or S includes.
  • Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- Oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
  • heteroaryl also includes the partially hydrogenated heterocyclic aromatic ring systems, in particular the ring systems listed above.
  • partially hydrogenated heterocycles are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
  • Particularly preferred heteroaryl means a heteroaromatic mono- or bicyclic ring system.
  • arylC1 -n- alkyl refers to C1 -n- alkyl as defined above which is substituted with an aryl or heteroaryl group.
  • the H atom of an existing carboxy group or an H atom bound to an N atom (imino or amino group) can each be replaced by a residue which can be split off in vivo.
  • a cleavable by a N-atom in vivo radical is understood to mean, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C ⁇ -16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or Hexanoyl, an allyloxycarbonyl, a -C ⁇ 6 alkoxycarbonyl such as
  • R f is a hydrogen atom, a d ⁇ -Alky! -, C 5-7 -cycloalkyl or phenyl group and
  • R g is a hydrogen atom, a C 1-3 alkyl or R e CO-O- (R f CR g ) -O- group in which R e to
  • R g are as defined above,
  • the phthalimido group is contemplated, wherein the above-mentioned ester groups can also be used as in vivo into a carboxy group convertible group.
  • radicals and substituents described above may be mono- or polysubstituted by fluorine in the manner described.
  • Preferred fluorinated alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.
  • the compounds of the general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups, e.g. Amino functions.
  • Compounds of general formula I can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.
  • pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid)
  • pharmaceutically acceptable bases such
  • the compounds according to the invention can be obtained using synthesis methods known in principle.
  • the compounds are preferably obtained in analogous application to the production process explained in more detail below, which likewise
  • a compound of general formula A1 is reacted with a compound of general formula A2 in the sense of a Sonogashira coupling in the presence of a catalyst such as palladium with or without ligands and copper iodide in a solvent such as Dioxane, DMF, toluene, acetonitrile or THF or solvent mixture using an amine base such as triethylamine or inorganic base such as cesium carbonate at temperatures between -20 ° C and 200 ° C to.
  • a catalyst such as palladium with or without ligands and copper iodide
  • a solvent such as Dioxane, DMF, toluene, acetonitrile or THF or solvent mixture
  • an amine base such as triethylamine or inorganic base such as cesium carbonate at temperatures between -20 ° C and 200 ° C to.
  • an aniline derivative of formula 1 is reacted with a compound of formula 2.
  • Compound 2 is an arylboronic acid derivative
  • the reaction to Compound 3 is carried out in the presence of a catalyst such as palladium with or without ligands in a solvent or solvent mixture of, for example, dioxane, DMF, toluene, THF or water using a base such as triethylamine or potassium carbonate at temperatures between room temperature and 200 ° C.
  • a catalyst such as palladium with or without ligands
  • a solvent or solvent mixture of, for example, dioxane, DMF, toluene, THF or water
  • a base such as triethylamine or potassium carbonate at temperatures between room temperature and 200 ° C.
  • organometallic aryl compounds for example tin or zinc compounds.
  • reaction to compound 3 takes place in the sense of a Sonogashira coupling in the presence of a catalyst such as, for example, palladium with or without ligands and copper iodide in a solvent or solvent mixture of, for example, dioxane, DMF, toluene , Acetonitrile or THF using a base such as For example, triethylamine at temperatures between -20 ° C and 200 ° C.
  • a compound of formula 4 is obtained by reaction of a compound of formula 3 with propynoic acid in the presence of a base and activating reagents such as CDI, TBTU or DCC.
  • Propionic acid chloride can also be used instead of the propionic acid.
  • a compound of the general formula A3 is reacted with an ester of propynoic acid, preferably with propynoic acid ethyl ester, in the manner of a Sonogashira coupling in the presence of a catalyst, for example palladium with or without ligands and copper iodide a solvent such as dioxane, DMF, toluene, acetonitrile or THF or solvent mixture using an amine base such as triethylamine or inorganic base such as cesium carbonate at temperatures between -20 ° C and 200 ° C to.
  • a catalyst for example palladium with or without ligands and copper iodide a solvent such as dioxane, DMF, toluene, acetonitrile or THF or solvent mixture using an amine base such as triethylamine or inorganic base such as cesium carbonate at temperatures between -20 ° C and 200 ° C to.
  • the compound of general formula A4 is converted in the course of ester cleavage into a compound of general formula A5.
  • the ester cleavage may be carried out in a solvent such as ethanol, dioxane or THF with or without addition of water in the presence an inorganic base such as sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate at temperatures from 0 ° C to 150 ° C.
  • An ester cleavage is also possible in an organic solvent such as THF or dioxane in the presence of acid, for example aqueous hydrochloric acid or sulfuric acid.
  • a compound of general formula A5 may also be prepared by reacting a compound of general formula A7 in an organic solvent such as dioxane, ethanol or THF with or without addition of water with a base such as potassium tertiarybutylate, sodium hydroxide or sodium ethylate at temperatures of 0 ° C to 150 ° C converts. But it is also possible to bring for this reaction, a compound of general formula A7 with pyridine or quinoline at temperatures of 0 ° C to 150 ° C to the reaction.
  • a compound of general formula A7 is obtained by bromination of a compound of general formula A6 in a solvent such as carbon tetrachloride at temperatures between -20 ° C to 100 ° C, preferably at temperatures between 0 ° C and room temperature.
  • a compound of general formula Ia is obtained by reacting a compound of general formula A8 with a compound of general formula A5 in an organic solvent such as DMF, THF, dioxane, acetonitrile or toluene in the presence of a base such as triethylamine and activating reagents such as Example CDI, TBTU or DCC.
  • an organic solvent such as DMF, THF, dioxane, acetonitrile or toluene
  • a base such as triethylamine
  • activating reagents such as Example CDI, TBTU or DCC.
  • the carboxylic acid chloride or a mixed anhydride of the compound A5 may also be used
  • a compound of general formula Ic is advantageously obtained by hydrogenating a compound of general formula A12 in an organic solvent such as methanol, ethanol, THF or dioxane in the presence of a catalyst such as Raney nickel, palladium or platinum at temperatures between 0 ° C and 150 ° C.
  • a catalyst such as Raney nickel, palladium or platinum at temperatures between 0 ° C and 150 ° C.
  • the reaction of compound A12 to compound Ic can also be carried out in the presence of other hydrogen-transferring reagents.
  • a compound of general formula A12 is obtained by reacting a compound of general formula A9 with a compound of general formula A11 in an organic solvent such as DMF, THF, dioxane, acetonitrile or toluene in the presence of a base such as For example, triethylamine and activating reagents such as CDI, TBTU or DCC.
  • a base such as triethylamine and activating reagents such as CDI, TBTU or DCC.
  • the carboxylic acid chloride of the compound A9 can also be used.
  • Compound Ic can also be obtained by reacting a compound of general formula A10 with a compound of general formula A11 under conditions as described above for the reaction of A9 and A11 to A12.
  • the compound of general formula A10 can be obtained by reduction of a compound of general formula A9 analogously to the reaction of A12 to Ic.
  • a compound of the general formula A21 can be obtained as follows.
  • the cinnamic acid derivative A13 is converted into the protected cinnamic acid derivative A14 by reaction with formic acid orthomethyl ester with or without organic solvent such as methanol, THF or dioxane at temperatures between room temperature and 200 ° C.
  • organic solvent such as methanol, THF or dioxane
  • DMF or THF are reacted at a temperature between 0 ° C and room temperature to give a compound of general formula A15.
  • Reaction of A17 with methanesulfonyl chloride in an organic solvent such as dichloromethane in the presence of a base such as triethylamine at temperatures between 0 ° C and 100 ° C gives a compound of general formula A18.
  • a base such as triethylamine
  • the reaction of A17 with thionyl chloride can also be used.
  • Compound A20 is obtained by reacting A18 with a compound of general formula A19 in an organic solvent such as DMF, acetonitrile or THF at temperatures of 0 ° C and 100 ° C.
  • a compound of general formula A21 is obtained by hydrogenating a compound of general formula A20 in an organic solvent such as methanol, ethanol, THF or dioxane in the presence of a catalyst such as Raney nickel, palladium or platinum at temperatures between 0 ° C and 150 ° C.
  • a catalyst such as Raney nickel, palladium or platinum at temperatures between 0 ° C and 150 ° C.
  • the reaction of the compound A20 to the compound A21 can also be carried out in the presence of other hydrogen-transferring reagents.
  • stereoisomeric compounds of the formula (I) can be separated by customary methods.
  • the separation of the respective diastereomers is possible due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • racemates covered by the general formula (I) succeeds, for example, by HPLC on suitable chiral stationary phases (eg chiral AGP,
  • Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which, when reacted with an optical active acid, for example (+) - or (-) - tartaric acid, (+) - or (-) - diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid, or an optically active base, for example, with (R) - (+) - 1-phenylethylamine, (S) - (-) - 1-phenylethylamine or (S) -brucine arise.
  • an optical active acid for example (+) - or (-) - tartaric acid, (+) - or (-) - diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid, or an optically active base, for example, with (R) - (+) - 1-pheny
  • the racemate of a compound of the general formula (I) is reacted with one of the above-mentioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, optically active salts taking advantage of their different solubility separated.
  • This reaction can be carried out in any kind of solvents as long as they have a sufficient difference in the solubility of the salts.
  • methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used.
  • each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.
  • a base such as sodium carbonate or potassium carbonate
  • a suitable acid for example, with dilute hydrochloric acid or aqueous methanesulfonic acid
  • the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen by reaction with inorganic bases, the compound of formula (I) can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion.
  • Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid come into consideration for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used.
  • alkali metal and alkaline earth metal salts of the compound of the formula (I) with acidically bonded hydrogen are preferably the Alkali and alkaline earth hydroxides and hydrides into consideration, wherein the hydroxides and hydrides of the alkali metals, especially of sodium and potassium are preferred, sodium and potassium hydroxide are particularly preferred.
  • the compounds of the present invention have activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies.
  • Pharmacological test systems for MCH antagonistic properties are described in the experimental section below.
  • the compounds of the invention are advantageously useful as pharmaceutical agents for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.
  • MCH antagonists having at least one compound of the invention are particularly useful in mammals, such as rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys, and especially in humans, for treatment and / or Prophylaxis of symptoms and / or diseases caused by MCH or in another causal relationship with MCH.
  • Diseases caused by MCH or in another causal relationship with MCH are, in particular, metabolic disorders such as obesity and eating disorders such as bulimia including bulimia nervosa.
  • the indications of obesity include especially exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity.
  • cachexia, anorexia and hyperphagia are to be mentioned in this indication environment.
  • compounds of the invention may be useful in reducing hunger, curbing appetite, controlling eating behavior, and / or inducing satiety.
  • diseases caused by MCH or otherwise causally related to MCH may also include hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders,
  • Reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders is suitable.
  • Compounds of the invention are also useful as agents for the prophylaxis and / or treatment of other diseases and / or disorders, in particular those with
  • Obesity such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, heart failure, cardiovascular disease , especially arteriosclerosis and hypertension, arthritis and gonitis is suitable.
  • MCH antagonists and formulations according to the invention can advantageously be used in combination with an alimentary therapy, such as, for example, an alimentary diabetes therapy, and exercise.
  • Another area of indication for which the compounds of the invention are advantageously useful is the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.
  • voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.
  • the dosage required to achieve a corresponding effect is expediently from 0.001 to 30 mg / kg body weight, preferably from 0.01 to 5 mg / kg body weight, by intravenous or subcutaneous administration, and from 0.01 to 50 mg / kg by oral, nasal or inhalative administration Body weight, preferably 0.1 to 30 mg / kg body weight, once to three times daily.
  • the compounds of general formula I according to the invention optionally in combination with other active substances, as described in more detail below, together with one or more inert conventional carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, Dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories.
  • inert conventional carriers and / or diluents for example with corn starch, lactose, cane sugar,
  • compositions comprising at least one amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • Such compositions may, for example, also be foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.
  • suitable further active substances are, in particular, those which, for example, enhance the therapeutic effectiveness of an MCH antagonist according to the invention with regard to one of the indicated indications and / or which allow a reduction in the dosage of an MCH antagonist according to the invention.
  • one or more further active substances are selected from the group consisting of - active ingredients for the treatment of diabetes,
  • Active ingredients for the treatment of obesity preferably other than MCH antagonists, agents for the treatment of hypertension,
  • Active ingredients for the treatment of hyperlipidemia including arteriosclerosis, - agents for the treatment of arthritis,
  • Examples of drugs for the treatment of diabetes are insulin sensitizers, insulin secretagogues, biguanides, insulins, ⁇ -glucosidase inhibitors, ⁇ 3 adreno receptor agonists.
  • Insulin sensitizers include glitazones, especially pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably Maleate), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929.
  • glitazones especially pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably Maleate), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929.
  • Insulin secretion enhancers include sulfonylureas such as tolbutamide, chlorpropamide, tolzamide, acetohexamide, glyclopyramide and its
  • Ammonium salts glibenclamide, gliclazides, glimepirids.
  • Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608.
  • Biguanides include metformin, buformin, phenformin.
  • Insulins include insulins derived from animals, particularly cattle or swine, semi-synthetic human insulins enzymatically synthesized from animal-derived insulin, human insulin obtained by genetic engineering, for example from Escherichia coli or yeasts. Further, as insulin insulin zinc
  • protamine insulin zinc available from zinc chloride, protamine sulfate and insulin.
  • insulin can be obtained from insulin fragments or derivatives (e.g., INS-1, etc.).
  • Insulin may also include different types, for example with respect to
  • ⁇ -glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
  • ⁇ 3 adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
  • Agents for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-1 analogs, SGLT-2 inhibitors.
  • Aldose reductase inhibitors include, for example, Tolrestat, Epalrestat, Imirestat, Zenarestat, SNK-860, Zopolrestat, ARI-50i, AS-3201.
  • An example of a glycation inhibitor is pimagedine.
  • Protein kinase C inhibitors are, for example, NGF, LY-333531.
  • DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541, 823093 and 825964 (all GlaxoSmithkline).
  • GLP-1 analogs include Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin).
  • SGLT-2 inhibitors are, for example, AVE-2268 (Aventis) and T-1095 (Tanabe,
  • Agents for the treatment of obesity include lipase inhibitors and anorectics.
  • a preferred example of a lipase inhibitor is orlistat.
  • Examples of preferred anorectic agents are phentermine, mazindol, fluoxetine, sibutramine, baiamine, (S) -sibutramine, SR-141716, NGD-95-1.
  • anorectics are also counted for the purposes of this application to the drug group of anti-obesity drugs, the ß 3 agonists, thyromimetic agents and NPY antagonists are highlighted.
  • the scope of the substances which are suitable here as preferred anti-obesity or anorectic active substances is given by way of example by the following list: Phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic drug, a serotonergic drug (such as dexfenfluramine, fenfluramine, or a 5-HT2C agonist such as BAT.933 or APD356), a dopamine
  • Agonist such as bromocriptine or pramipexole
  • melanocyte-stimulating hormone receptor agonist or mimetic an analog of melanocyte-stimulating hormone
  • a cannabinoid receptor antagonist rimonabant, ACOMPLIA TM
  • MCH antagonist an MCH antagonist
  • leptin OB protein
  • leptin analog a leptin receptor agonist
  • galanin antagonist a
  • Gl lipase inhibitor or reducer such as orlistat.
  • Other anorectives include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor, such as exendin and ciliary neurotrophic factors, such as axokines.
  • therapies should be mentioned in this context, which lead to weight loss by increasing the fatty acid oxidation in peripheral tissue, such as inhibitors of acetyl-CoA carboxylase.
  • Agents for the treatment of hypertension include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists.
  • Inhibitors of the angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochlorides), lisinopril, imidapril, benazepril, cilazapril,
  • Temocapril Temocapril, trandolapril, manidipine (hydrochloride).
  • calcium antagonists examples include nifedipine, amlodipine, efonidipine, nicardipine.
  • Potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121.
  • Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.
  • HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and their salts.
  • Fibrate compounds include bezafibrates, clinofibrates, clofibrates, simfibrates.
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX2 inhibitors such as meloxicam or ibuprofen.
  • Agents for the treatment of anxiety include chlordiazepoxides, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
  • Agents for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage.
  • the invention also relates to the use of at least one alkyne compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.
  • This use is based in particular on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing satiety.
  • the eating behavior is favorably influenced so that the food intake is reduced. Therefore, find the inventive
  • Another use of the invention is to prevent an increase in body weight, for example, in people who have previously taken weight-loss measures and are subsequently interested in maintaining the reduced body weight.
  • it is preferably a non-therapeutic use.
  • a non-therapeutic use may be a cosmetic application, for example, for altering the appearance or an application for improving the general condition.
  • the compounds according to the invention are preferably used non-therapeutically for mammals, in particular humans, who have no diagnosed disorders of eating behavior, no diagnosed obesity, bulimia, diabetes and / or no diagnosed micturition disorders, in particular urinary incontinence.
  • Preferred are the Compounds of the invention are suitable for non-therapeutic use in humans whose body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, is below the value of 30, especially below 25, lies.
  • BMI body mass index
  • R r values are determined using DC precast plates silica gel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714
  • the R r values determined under the name Alox are determined using TLC finished plates alumina 60 F254 (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation
  • the ratios stated for the flow agents are based on The volume units given for NH 3 are based on a concentrated solution of NH 3 in water
  • silica gel from Millipore MATREX TM, 35-70 my
  • Merck, Darmstadt, alumina 90 standardized, 63-200 ⁇ m, Article No.: 1.01097.9050
  • the indicated HPLC data are listed below measured parameters measured:
  • H atoms at O and N atoms such as, for example, in hydroxyl or amino groups, for the sake of clarity are generally not explicitly depicted.
  • a reaction mixture of 0.5 mg (0.13 mmol) of methanesulfonic acid 4 - [(4-prop-1-ynyl-phenylcarbamoyl) -ethynyl] -benzyl ester, 0.028 ml (0.28 mmol) of piperidine in 5 ml of THF becomes 14 Stirred hours at room temperature. The reaction mixture is concentrated. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol 25: 1 to 15: 1).
  • Methanesulfonic acid 4 - [(4'-chloro-2'-fluorobiphenyl-4-ylcarbamoyl) ethynyl] benzyl ester Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propynoic acid (4'-methyl) chloro-2'-fluoro-biphenyl-4-yl) -amide and methanesulfonyl chloride.
  • Methanesulfonic acid 4 - ⁇ [(4'-chloro-biphenyl-4-yl) -methyl-carbamoyl] -ethynyl ⁇ -benzyiester Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propynoic acid (4 '). -chloro-biphenyl-4-yl) -methyl-amide.
  • a reaction mixture of 1 g (3.48 mmol) of 1- (4-iodobenzyl) pyrrolidine, 5 ml of piperidine, 105 mg (0.091 mmol) of tetrakistriphenylphosphine palladium and 10 mg (0.053 mmol) of copper (I) iodide is brought to 0 ° C cooled. At this temperature, 0.59 ml (4.18 mmol) of trimethylsilylacetylene are added dropwise and then removed the cooling bath. It is stirred for three hours at room temperature, then treated with a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate.
  • Example 1.34 3- ⁇ 4- [4- (1-Hydroxy-1-methyl-ethyl) -piperidin-1-ylmethyl] -phenyl ⁇ -propynoic acid (4'-chloro-biphenyl-4-yl) -amide
  • Example 1 40: 3- ⁇ 4- [cyclopropylmethyl-methyl-amino) -methyl] -phenyl ⁇ -propinklare- (4 '-chloro-biphenyl-4-yl) - amide
  • 1,422.a 1- (4-Bromo-phenyl) -cyclopropyl] -carbamic acid-tert-butyl ester 10 g (29.04 mmol) 1- (4-bromobenzene) 1-cyclopropanecarboxylic acid and 6.07 ml (43.55 mmol) Triethylamine was dissolved in 63 ml of ferf-butanol. At RT 9.68 ml (43.55 mmol) of diphenylphosphoryl azide (DPPA) were added dropwise and refluxed for 15 h.
  • DPPA diphenylphosphoryl azide
  • Carbon tetrachloride added dropwise and stirred for three hours at room temperature. Subsequently, the solvent is distilled off and the residue is treated with petroleum ether. The solid is filtered off and dried in a convection oven at 50 ° C.

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Abstract

L'invention concerne des composés amides, de formule générale (I), dans laquelle les groupes et les restes A, B, b, W, X, Y, Z, R1, R2 et R3 ont les significations données dans la revendication 1. En outre, l'invention concerne des médicaments renfermant au moins un amide selon l'invention. En raison de l'activité antagoniste du récepteur de MCH, les médicaments selon l'invention conviennent pour le traitement de troubles métaboliques et/ou de troubles dus à l'alimentation, en particulier, adipositas, boulimie, anorexie, hyperphagie et diabètes.
PCT/EP2004/014378 2003-12-23 2004-12-17 Derives d'acide 3-(4-piperidine-1ylmethyl-phenyl) propionique-phenylamide et composes apparentes, utilises comme antagonistes mch (hormone de concentration en melanine) pour le traitement de troubles dus a l'alimentation WO2005063239A1 (fr)

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CA002550649A CA2550649A1 (fr) 2003-12-23 2004-12-17 Derives d'acide 3-(4-piperidine-1ylmethyl-phenyl) propionique-phenylamide et composes apparentes, utilises comme antagonistes mch (hormone de concentration en melanine) pour le traitement de troubles dus a l'alimentation
EP04803987A EP1708698A1 (fr) 2003-12-23 2004-12-17 Derives d'acide 3-(4-piperidine-1ylmethyl-phenyl) propionique-phenylamide et composes apparentes, utilises comme antagonistes mch (hormone de concentration en melanine) pour le traitement de troubles dus a l'alimentation
JP2006546009A JP2007520466A (ja) 2003-12-23 2004-12-17 摂食障害を治療するためのｍｃｈアンタゴニスト（メラニン含有ホルモン）の形態で使用される３−（４−ピペリジン−１−イルメチル−フェニル）−プロピオン酸−フェニルアミド誘導体及び関連化合物

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DE10360745A DE10360745A1 (de) 2003-12-23 2003-12-23 Neue Amid-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel

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WO2007048802A1 (fr) * 2005-10-26 2007-05-03 Boehringer Ingelheim International Gmbh Composés hétéroaryliques dotés d'une activité antagoniste de mch et médicaments comprenant ces composés
WO2008022979A1 (fr) 2006-08-25 2008-02-28 Boehringer Ingelheim International Gmbh NOUVEAUX DÉRIVÉS DE LA PYRIDONE PRÉSENTANT UNE ACTIVITÉ ANTAGONISTE de MCH ET MÉDICAMENTS COMPRENANT CES COMPOSÉS
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WO2008071646A1 (fr) 2006-12-11 2008-06-19 Boehringer Ingelheim International Gmbh Nouveaux dérivés pyridazines à activité antagoniste du récepteur mch et médicaments comprenant ces composés
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EP1708698A1 (fr) 2006-10-11
AR048019A1 (es) 2006-03-22
TW200530180A (en) 2005-09-16
UY28689A1 (es) 2005-08-31
CA2550649A1 (fr) 2005-07-14
DE10360745A1 (de) 2005-07-28
JP2007520466A (ja) 2007-07-26
WO2005063239A9 (fr) 2006-03-09
PE20050678A1 (es) 2005-10-27

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