EP1737839A1 - Neue alkin-verbindungen mit mch-antagonistischer wirkung und diese verbindungen enthaltende arzneimittel - Google Patents

Neue alkin-verbindungen mit mch-antagonistischer wirkung und diese verbindungen enthaltende arzneimittel

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Publication number
EP1737839A1
EP1737839A1 EP05739806A EP05739806A EP1737839A1 EP 1737839 A1 EP1737839 A1 EP 1737839A1 EP 05739806 A EP05739806 A EP 05739806A EP 05739806 A EP05739806 A EP 05739806A EP 1737839 A1 EP1737839 A1 EP 1737839A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
phenyl
substituted
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05739806A
Other languages
German (de)
English (en)
French (fr)
Inventor
Dirk Stenkamp
Stephan Georg Mueller
Thorsten Lehmann-Lintz
Philipp Lustenberger
Leo Thomas
Marcus Schindler
Gerald Jürgen ROTH
Klaus Rudolf
Ralf R. H. Lotz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP1737839A1 publication Critical patent/EP1737839A1/de
Withdrawn legal-status Critical Current

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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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/14—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 three or more hetero rings

Definitions

  • New alkyne compounds with MCH-antagonistic activity and drugs containing these compounds are described in detail below.
  • the present invention relates to new alkyne compounds, their physiologically tolerable salts and their use as MCH antagonists and their use in the manufacture of a medicament which is used for the prophylaxis and / or treatment of symptoms and / or diseases which are caused by MCH or with MCH have a different causal connection, is suitable.
  • Another object of this invention relates to the use of a compound according to the invention for influencing the eating behavior and for reducing the body weight and / or for preventing an increase in the body weight of a mammal.
  • compositions and medicaments, each containing a compound according to 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.
  • Obesity leads directly to a reduction in mobility and a decrease in quality of life for those affected.
  • obesity often results in other diseases, such as diabetes, dyslipidaemia, high blood pressure, arteriosclerosis and coronary artery disease
  • obesity refers to an excess of adipose tissue in the body.
  • body weight index body mass index
  • MCH antagonists including WO 01/21577, WO 01/82925.
  • MCH Melanin-concentrating hormone
  • Rhodopsin-related GPCRs mediate the MCH receptors 1 and 2 (MCH-1 R, MCH-2R).
  • the MCH-1R antagonist SNAP-7941 In addition to its anorectic effect, the MCH-1R antagonist SNAP-7941 also achieves other anxiolytic and antidepressant effects in behavioral experiments with rats [3]. There are clear indications that the MCH-MCH-1R system is not only involved in regulating the energy balance but also in affectivity.
  • WO 01/82925 also contains 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 independently of one another are H or a hydrocarbon group, 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.
  • WO 2004/024702 describes carboxamide compounds of the formula I.
  • Y, A and B cyclic groups and X, Z and W can mean bridges or bonds, proposed as MCH antagonists.
  • WO 04/039780 A1 describes alkyne compounds of the formula I.
  • Y, A and B can be cyclic groups and X, Z and W can represent bridges or bonds, described as MCH antagonists.
  • the present invention has for its object to show new alkyne compounds, especially those which have a particularly high activity as MCH antagonists. It is also an object of this invention to provide new alkyne compounds which make it possible to influence the eating behavior of mammals and, in particular in mammals, to achieve a reduction in body weight and / or to prevent an increase in body weight.
  • an object of the present invention to provide new medicaments which are suitable for the prophylaxis and / or treatment of symptoms and / or diseases which are caused by MCH or have another causal connection with MCH.
  • this invention is based on the object of providing medicaments for the treatment of metabolic disorders, such as obesity and / or diabetes, and of diseases and / or disorders associated with obesity and diabetes.
  • Further objects of the present invention relate to demonstrating advantageous uses of the compounds according to the invention.
  • Another object of this invention is to provide a process for the preparation of the alkyne compounds according to the invention.
  • a first subject of the present invention are alkyne compounds of the general formula I. R ⁇ .N- Y— Z -WA— B 2 / R in the
  • R 1 , R 2 independently of one another denote H, ds-alkyl, C 3 - 7 cycloalkyl or a phenyl or pyridinyl radical which is monosubstituted or polysubstituted by the same or different radicals R 20 and / or monosubstituted by nitro, where the alkyl or cycloalkyl group with identical or different radicals R 11 can be substituted one or more times, and wherein a -CH 2 - group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group by -O-, -S- or -NR 13 - can be replaced, or
  • W, Z independently of one another a single bond or a where two adjacent carbon atoms can be connected to one another with an additional C 1-4 alkylene bridge, and where one or two carbon atoms can be substituted independently of one another with one or two identical or different C 3 alkyl radicals, where two alkyl radicals can be linked to form a carbocyclic ring, and
  • the groups M, K and L represent a CH group, where one of the groups M, K, L can also mean an N atom, and wherein in the sub-formulas Y1 to Y9 one or more C atoms independently of one another with R 20 may be substituted, and in the sub-formulas Y5 and Y6 an NH group may be substituted by C 1-4 alkyl,
  • A is selected from among the bivalent cyclic groups, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, thienyl, furanyl , Benzothienyl or benzofuranyl, where the cyclic groups mentioned one or more times on one or more carbon atoms with the same or different radicals R 20 , in the case of a phenyl ring also simply with nitro, and / or one or more NH groups with R 21 can be substituted,
  • R 11 is halogen, C 1-4 alkyl, C 2 . 6 alkenyl, C 2 . 6 -alkynyl, R 15 -O-, R 15 -O-CO-, R 15 -CO-O-, cyano, R 16 R 17 N-, R 18 R 19 N-CO- or Cy-, wherein in the previously specified groups one or more C atoms can be substituted independently of one another by substituents selected from halogen, OH, CN, CF 3 , C 1-4 alkyl, hydroxy-C.] - 3 - alkyl;
  • R 13 has one of the meanings given for R 17 ,
  • R 14 halogen, cyano, C ⁇ alkyl, C 2 . 6 -alkenyl, C 2 - 6 -alkynyl, R 15 -O-, R 15 -O-CO-, R 15 - CO-, R 15 -CO-O-, R 16 R 17 N-, R 18 R 19 N-CO-, R 15 -OC, - 3 -alkyl, R 16 -O-CO-C ⁇ - alkyl, R 15 -SO 2 -NH-, R ⁇ -O-CO-NH-C ⁇ -alkyl- , R ⁇ -SOz-NH-C ⁇ -alkyl-, R 15 -CO- d- 3 -alkyl-, R 15 -CO-OC, - 3 -alkyl-, R ⁇ R ⁇ NC ⁇ -alkyl-, R ⁇ R ⁇ N-CO-C ⁇ -alky! - or Cy-d- 3 -
  • R 15 is H, C- ⁇ - 4 alkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-d-C3 alkyl, phenyl, phenyl-d- 3 - alkyl, pyridinyl or pyridinyl-d 3 - alkyl,
  • R 17 has one of the meanings given for R 16 or phenyl, phenyl-d- 3 -alkyl, pyridinyl, d- 4 -alkylcarbonyl, hydroxycarbonyl-C ⁇ -j-alkyl, d- -alkoxycarbonyl-, C ⁇ - 4 -alkoxycarbonyl-C ⁇ - 3- Alkyl, d - rAlkylcarbonylamino-C 2 - 3 -alkyl, N- (C 1 - 4 -Alkylcarbonyl) -N- (C ⁇ - 4 -alkyl) -amino-C 2 .
  • R 18 , R 19 independently of one another are H or d- 6 -alkyl
  • R 20 halogen, hydroxy, cyano, de-alkyl, C 2 . 6 -alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-d- C3 alkyl, hydroxy-C ⁇ - 3 alkyl, R 22 -C ⁇ - 3 alkyl, or one of the meanings given for R 22 , R 21 d- 4 -alkyl, ⁇ -hydroxy-C 2 . 6 alkyl, ⁇ -C ⁇ alkoxy-C ⁇ e-alkyl, ⁇ -d- 4 -alkyl-amino-C 2 - (.
  • the H atom of an existing carboxy group or an H atom bound to an N atom can in each case be replaced by a residue which can be split off in vivo,
  • the invention also relates to the respective compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the 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 according to the invention, including their salts, in which one or more hydrogen atoms have been replaced by deuterium.
  • physiologically tolerated salts of the alkyne compounds according to the invention described above and below are also a subject of this invention.
  • This invention also relates to compositions containing at least one alkyne compound according to the invention and / or a salt according to the invention in addition to, if appropriate, one or more physiologically tolerable auxiliaries.
  • the present invention furthermore relates to medicaments comprising at least one alkyne compound according to the invention and / or a salt according to the invention in addition to, if appropriate, one or more inert carriers and / or diluents.
  • the present 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.
  • the present 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 the production of a medicament with MCH receptor antagonistic activity, in particular with MCH-1 receptor antagonistic activity.
  • an object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the production of a medicament which is used for the prophylaxis and / or treatment of
  • Appearances and / or diseases that are caused by MCH or have another causal connection with MCH are suitable.
  • Another object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the manufacture of a medicament which is used for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, in particular obesity, bulimia, bulimia nervosa, cachexia , Anorexia, anorexia nervosa and hyperphagia.
  • Another subject of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention Production of a medicament which is used for the prophylaxis and / or treatment of diseases and / or disorders associated with obesity, in particular of diabetes, particularly type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, Encephalorrhagia, heart failure,
  • Cardiovascular diseases especially arteriosclerosis and high blood pressure, arthritis and gonitis is suitable.
  • the present invention has the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the production of a medicament which is used for the prophylaxis and / or treatment of hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affectivity disorders , Depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders is appropriate to the subject.
  • Another object of this invention is the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the manufacture of a medicament which is suitable for the prophylaxis and / or treatment of urinary disorders such as urinary incontinence, overactive bladder, urge to urinate, nocturia and enuresis ,
  • the present invention relates to the use of at least one alkyne compound according to the invention and / or a salt according to the invention for the production of a medicament which is suitable for the prophylaxis and / or treatment of addictions and / or withdrawal symptoms.
  • an object of this invention relates to methods for producing a medicament according to the invention, characterized in that at least one alkyne compound according to the invention and / or a salt according to the invention is incorporated into one or more inert carriers and / or diluents in a non-chemical way.
  • Another object of this invention is a medicament containing a first active ingredient which is selected from the alkyne compounds according to the invention and / or the corresponding salts, and a second active ingredient which is selected from the group selected is existing.
  • active substances for the treatment of diabetes active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of dyslipidemia or hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety and active substances for the treatment of depression, in addition, if appropriate, one or more inert carriers and / or diluents.
  • an object of this invention relates to a process for the preparation of alkyne compounds of the formula A.5
  • shark is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula A.2
  • Another object of this invention is a process for the preparation of alkyne compounds of the formula B.5
  • shark is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula B.2
  • halide derivative B.4 in which Hai 'Cl, Br or I,
  • an object of this invention relates to a process for the preparation of alkyne compounds of the formula C.3
  • R 1 , R 2 , Y, W, A and B have one of the meanings given above and below,
  • shark is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula C.2
  • Another object of this invention is a process for the preparation of alkyne compounds of the formula D.3
  • R 1 , R 2 , Y, Z, A and B have one of the meanings given above and below,
  • shark is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula D.1 R 1 R 2 NYZC ⁇ CH (D.1)
  • the starting materials and intermediates used in the synthesis according to the invention are also a subject of this invention.
  • radicals and / or substituents occur more than once in a compound, they can each have the same or different meanings.
  • R 1 and R 2 are not connected to one another via an alkylene bridge, R 1 and R 2 independently of one another are preferably an unsubstituted or a d- 8 -alkyl- or C 3 which is mono- or polysubstituted by identical or different R 11 radicals.
  • R 11 Preferred meanings of the radical R 11 here are F, Cl, Br, d- 6- alkyl, C 2 . 6 alkenyl, C 2 . 6 - alkynyl, R 15 -O-, cyano, R 16 R 17 N-, C 3 .
  • Phenyl group also simply with nitro, and / or with one or more NH groups R 21 can be substituted. If one of the meanings R 11 R 15 -O-, cyano, R 16 R 17 N-, or cyclo C 3 - 6 has -alkylenimino- is preferably substituted with R 11 not C-atom of the alkyl or cycloalkyl group directly connected to a heteroatom, such as the group -NX-.
  • the radicals R 1 , R 2 are preferably, independently of one another, H, d- 6- alkyl, C 3 . 5 alkenyl, C 3 . 5 alkynyl, C 3 . 7- cycloalkyl, hydroxy-C 3 . 7 -cycloalkyl, C 3 - 7 -cycloalkyl-C ⁇ - 3 -alkyl-, (hydroxy-C 3. 7 - cycloalkyl) -d- 3 -alkyl-, hydroxy-C 2 - -alkyl-, ⁇ -NC-C 2 -3 alkyl, C 1-4 alkoxy-C. 2 4 alkyl, hydroxy C- ⁇ - 4 -alkoxy-C.
  • Preferred substituents of the aforementioned phenyl or pyridyl radicals are selected from the group F, Cl, Br, I, cyano, d- 4 -alkyl, d- 4 ⁇ alkoxy, difluoromethyl, trifluoromethyl, hydroxyl, amino, d - 3 -Alkylamino-, di- (C 1, 3 -alkyl) -amino-, acetylamino-, aminocarbonyl-, difluoromethoxy-, trifluoromethoxy-, amino-C ⁇ - 3 -alkyl-, C ⁇ - 3 -alkylamino-d- 3rd -alkyl- and
  • radicals R 1 and / or R 2 are selected from the group consisting of H, C ⁇ alkyl, hydroxy-C 1-4 -alkyl, C. 3 5 alkenyl, C 3 . 5 alkynyl, C 3 - 7 - cycloalkyl, hydroxy-C. 3 7- cycloalkyl, dihydroxy-C 3 .
  • R 1 and / or R 2 are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, but-2-enyl, prop-2-ynyl, But- 2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-C 3 - 7 -cycloalkyl, (hydroxy-C ⁇ .
  • R 1 and / or R 2 are therefore H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, Cyclopropylmethyl, cyclopentylmethyl, hydroxy-cyclopentyl, hydroxy-cyclohexyl, (hydroxymethyl) -hydroxy-cyclopentyl, (hydroxymethyl) -hydroxy-cyclohexyl, 2,3-dihydroxypropyl, (l-hydroxy-cyclopropyl) -methyl, tetrahydropyran-3-yl, Tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, dimethylaminoethyl, benzyl
  • At least one of the radicals R 1 , R 2 has a meaning different from H.
  • R 1 and R 2 form an alkylene bridge
  • the previously defined alkylene bridge can be substituted with a carbo- or heterocyclic group Cy such that the bond between the alkylene bridge and the group Cy via a single or double bond, via a common C atom to form a spirocyclic ring system, via two common, adjacent C and / or N atoms to form a condensed bicyclic ring system or - via three or more C and / or N -Atoms are formed with the formation of a bridged ring system.
  • R 1 and R 2 preferably form an alkylene bridge such that RR 2 N - is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1 H-pyrrole, 1, 2, 3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1 H-azepine, 2,3,6,7-tetrahydro-1 H-azepine, piperazine, in which the free imine function is substituted by R 13 is, piperidin-4-one, morpholine and thiomorpholine,
  • pyrrolidine is particularly preferably selected from pyrrolidine, piperidine, piperazine, in which the free imine function is substituted by R 13 , and morpholine,
  • one or more H atoms can be replaced by identical or different radicals R 14 , and / or the aforementioned groups in a manner specified according to the general definition of R 1 and R 2 can be substituted with one or two identical or different carbo- or heterocyclic groups Cy, where the group Cy can be substituted one or more times with R 20 .
  • Groups Cy which are particularly preferred here are C 3 . 7- cycloalkyl, aza-C 4 . 7 -cycloalkyl-, especially cyclo-C 3 . 6 -alkylenimino-, and 1-d- -alkyl-aza-C - 7 -cycloalkyl-, where the group Cy can be substituted one or more times with R 20 .
  • R 1 and R 2 3 - 8 alkylene bridge, 2 groups can be replaced in as -CH specified, may be substituted with one or two identical or different carbo- or heterocyclic groups Cy as described which can be substituted as previously indicated.
  • Cy is preferably selected from the group consisting of C 3-7 -CycloalkyI, cyclo-C. 3 6- alkyleneimino, 1 H-imidazole, thienyl and phenyl.
  • Cy is preferably selected from the group consisting of C 3 . 7 cycloalkyl, aza-C 4 - 8 cycloalkyl, oxa-C 4 - 8 - cycloalkyl, 2,3-dihydro-1H-quinazolin-4-one.
  • Cy is preferably selected from the group consisting of C 4 . 7 - cycloalkyl, phenyl, thienyl.
  • Cy is preferably C 4 . 8 cycloalkyl or aza-C 4-8 cycloalkyl.
  • the group Cy is preferably connected to the group R 1 R 2 N- via a single bond, Cy preferably being selected from the group consisting of C 3 . 7 cycloalkyl, and cyclo C. 3 6 -alkylenimino-, where these groups can be substituted, as indicated, preferably by fluorine, C.- 3 - alkyl, hydroxy-C ⁇ - 3 -alkyl and hydroxy.
  • the group particularly preferably has meaning according to one of the following sub-formulas
  • heterocycle formed by the group R 1 R 2 N- by one or two, preferably a C 3 . 7 -Cycioalkyl group may be substituted, wherein the cycloalkyl group may be substituted one or more times with R 20 , and
  • ring connected to the heterocycle formed by the group R 1 R 2 N- may be substituted one or more times on one or more carbon atoms with R 20 , in the case of a phenyl ring also additionally simply with nitro and
  • R, R, R, R have the meanings given above and below.
  • the substituents R 20, the heterocycle formed by the group R 1 R 2 N- as given off by one or two R 20 or multiply substituted cycloalkyl groups are substituted, independently of one another are preferably C 1 - alkyl, d-4 alkoxy -C ⁇ - 3 -alkyl, hydroxy-d- 3 -alkyl, hydroxy, fluorine, chlorine, bromine or CF 3 , especially hydroxy.
  • the group R 1 - N IT very particularly preferably has a meaning according to one of the following sub-formulas
  • heterocycle formed by the group R 1 R 2 N- with C 3 . 6- cycloalkyl, hydroxy-C 3 . 6 - cycloalkyl or (hydroxy-C 3 6 cycloalkyl.) -D- 3 may be substituted alkyl, and wherein the heterocycle formed by the group R 1 R 2 N- can be substituted once, twice or three times with identical or different radicals R 14 .
  • R 14 means in this case preferably each independently F, Cl, Br, OH, C ⁇ - 4 alkyl, d ⁇ alkoxy d-, 4 -alkoxy-d- C3 alkyl, hydroxy-C 14 alkyl, or CF 3 , in particular hydroxy, d- 3 -alkyl, CF 3 or hydroxy-C ⁇ - 3 alkyl.
  • R 1 R 2 N are particularly preferred: hydroxypyrrolidinyl, hydroxypiperidinyl, 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl) pyrrolidinyl , (Hydroxymethyl) -piperidinyl, (hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl,
  • a hydroxymethyl group on the C atom can be mono- or disubstituted with methyl, where two methyl substituents can be linked to form a cyclopropyl group, and
  • methyl or ethyl groups can be mono-, di- or trisubstituted by fluorine, and in which one or more carbon atoms of the heterocycle of the heterocycle formed by the group RR 2 N- independently of one another by fluorine, chlorine, CN, CF 3 , D- 3 -alkyl, hydroxy-C ⁇ - 3 alkyl, in particular d- 3 alkyl or CF 3 , preferably methyl, ethyl, CF 3 may be substituted.
  • R 14 F, Cl, Br, cyano, d-4 alkyl, C 2 - 4 - alkenyl, C ⁇ alkynyl, C 3 - 7 -cycloalkyl, C 3 - 7 -cycloalkyl-d- 3 -alkyl-, hydroxy, hydroxy-d- 3 -alkyl-, C ⁇ - 4 -alkoxy, ⁇ - (C 1 - -alkoxy) -C 1 , 3 -alkyl-, d ⁇ -alkyl-carbonyl-, carboxy, C ⁇ - 4 -alkoxycarbonyl-, hydroxy-carbonyl-C ⁇ - 3 -alkyl-, C ⁇ .
  • Ci -_.- alkoxy-carbonylan.ino- Ci- -alkoxy-carbonylamino-d- 3 -alkyl, amino-, d- 4 -alkyl-amino-, C 3 , 7- cycloalkyl-amino-, N- (C 3.
  • substituent R 14 are F, Cl, Br, d- 4 -alkyl, hydroxy, hydroxy-d- 3 -alkyl, C ⁇ -altoxy, co- (C 1 - 4 -alkoxy) -C - 3 - alkyl, amino-C 3 -alkyl-, C 1 - 4 -alkyl-amino-C t - 3 -alkyl-, C 3 .
  • one or more C atoms can additionally be substituted one or more times with F and / or one or two C atoms in each case independently of one another additionally with Cl or Br.
  • preferred meanings of R 14 also include -CF 3 , -OCF 3 , CF 3 -CO- and CF 3 - CHOH-.
  • the bridge W preferably denotes a single bond or ethylene, particularly preferably a single bond.
  • the bridge Z is preferably a single bond or ethylene, which can have one or two methyl substituents which can be linked to form a cyclopropyl group.
  • Z particularly preferably denotes a single bond.
  • group Y the groups K, L-.
  • M preferably denote CH, where one or more CH groups can be substituted independently of one another by R 20 .
  • one of the groups K, L and M preferably denotes an N atom, the other two groups selected from K, L, M representing a CH group, which can be substituted independently of one another by R 20 .
  • group Y is selected from the sub-formulas
  • the groups M, K and L represent a CH group, where one of the groups M, K, L can also mean an N atom, and
  • one or more CH groups can be independently substituted by R 20 .
  • an NH group can be substituted with C 1-4 alkyl.
  • the group Y very particularly preferably denotes quinoline according to the partial formula Y1, where K, L and M represent a CH group, the quinoline radical preferably being unsubstituted or one or more CH groups of the quinoline radical being independently substituted by R 20 are.
  • the group Y is preferably unsubstituted or mono- or disubstituted.
  • a very particularly preferred meaning of the group Y is quinoline, which can be substituted, in particular which can be substituted in the 4-position. Therefore, Y preferably means
  • R 20 is as defined below, and in particular C 1-4 alkyl, and very particularly methyl.
  • substituents R 20 of group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C 4 alkyl, C 2 . 6 alkenyl, hydroxy, ⁇ -hydroxy-3 d- alkyl, C ⁇ - 4 alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ alkynyl, C 1 - 4 alkoxy carbonyl, ⁇ - (C ⁇ - alkoxy) - C 1 .
  • Very particularly preferred substituents R 20 of group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, C 1-4 alkyl, C 2 . 3- alkenyl, C 2 . 3 alkynyl, C. - 3 - Alkoxy, d ⁇ -alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, in the case of a phenyl ring also nitro.
  • Examples of very particularly preferred meanings of the substituent R 20 are F, Cl, Br, methyl, ethyl, acetyl or methoxy.
  • Group A is preferably selected from the group of the divalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which one or more times on one or more carbon atoms with identical or different radicals R 20 , in the case of a phenyl ring also additionally simple can be substituted with nitro.
  • A is very particularly preferably one of the groups listed below
  • substituents R 20 of group A are independently fluorine, chlorine, bromine, amino, CF 3 , methoxy and C 3 alkyl.
  • Group A is preferably unsubstituted or monosubstituted with R 20 , as indicated.
  • group B is selected from the group consisting of phenyl, pyridyl, thienyl and furanyl.
  • Group B is particularly preferably phenyl.
  • the group B in the meanings given can be substituted one or more times with the same or different radicals R 20 , and a phenyl group can also be substituted simply with nitro.
  • Group B is preferably unsubstituted or mono-, di- or trisubstituted, in particular unsubstituted or mono- or disubstituted. In the case of single substitution, the substituent is preferably para to group A.
  • Preferred substituents R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C 1-4 alkyl, hydroxy, CHF 2 , CHF 2 -O-, hydroxy-C ⁇ - 3 alkyl, d- 4 -alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ -alkynyl, carboxy, d- 4 -alkoxycarbonyl-, ⁇ - (d- 4 -alkoxy) -C- ⁇ - 3 -alkyl-, d ⁇ -alkoxy-carbonylamino-, amino - d ⁇ alkyl-amino, di- (C 1 - alkyl) - amino, cyclo-C 3 - 6 -alkylenimino-, aminocarbonyl, d ⁇ alkyl-amino-carbonyl-D and D * - alkyl) amino carbonyl.
  • substituents R 2 ° of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF 3 , C 3 alkyl, d 4 alkoxy and trifluoromethoxy.
  • Very particularly preferred substituents R 20 of group B are selected from the group consisting of chlorine, bromine and methoxy.
  • the meaning of group B is preferably selected from C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 7- cycloalkyl, C 5 . 7 -cycloalkenyl, C 3 - 7 - cycloalkyl-C, - alkyl 3, C. 3 7 -cycloalkenyl-C ⁇ - 3 -alkyl-, C 3 - 7 -cycloalkyl-d- 3 -alkenyl-, C 3 .
  • groups C 3 are particularly preferred. 6 alkyl, C 3 - 6 - alkenyl, C 3 - 6 alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclopentyl-D-3 alkyl, cyclopentenyl-C ⁇ alkyl, cyclohexyl-Cis -alkyl-, cyclohexenyl-d-3-alkyl-, cycloheptyl-d- 3 -alkyl-, cycloheptenyl-d- 3 -alkyl-, where one or more carbon atoms in the groups mentioned for B one or more times with Fluorine can be substituted, and in cyclic groups one or more carbon atoms can be substituted with the same or different R 20 .
  • B very particularly preferably denotes cyclohexenyl which is unsubstituted or has 1, 2 or 3 identical or different substituents R 20 , in particular methyl.
  • substituents R 20 in particular methyl.
  • R 13 preferably has one of the meanings given for R 16 .
  • R 13 is H, C ⁇ alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-d- 3 alkyl, ⁇ -hydroxy-C 2 - 3 -alkyl, ⁇ - (C ⁇ - -Alkoxy) -C 2 . 3 -alkyl-.
  • R 13 very particularly preferably denotes H or C 1-4 alkyl.
  • the alkyl groups mentioned above can be substituted simply with Cl or one or more times with F.
  • R 15 are H, d- 4 alkyl, C 3 . 7- cycloalkyl, C 3 . 7 - Cycloalkyl-C ⁇ . 3 -alkyl-, where, as defined in the introduction, one or more C atoms can additionally be substituted one or more times with F and / or in each case one or two C atoms, independently of one another, additionally simply with Cl or Br.
  • R 15 particularly preferably denotes H, CF 3 , methyl, ethyl, propyl or butyl.
  • the substituent R 16 preferably denotes H, d ⁇ -alkyl, C 3 . 7 -Cycloalkyi, C 3 - 7 cycloalkyl-d- 3 - alkyl, co-hydroxy-C. 2 3 -alkyl- or ⁇ - (C 1, 4 -alkoxy) -C 2 - 3 -alkyl-, where, as defined in the introduction, one or more C atoms in each case one or more times with F and / or in each case one or two C atoms independently of one another can additionally be simply substituted with Cl or Br.
  • R 16 particularly preferably denotes H, CF 3> d- 3 alkyl, C 3 . 6- CycloalkyI or C 3 . 6 - Cycloalkyl-C ⁇ - 3 alkyl
  • R 17 preferably has one of the meanings given as preferred for R 16 or is phenyl, phenyl- 3- alkyl, pyridinyl or -CC alkylcarbonyl. R 17 particularly preferably has one of the meanings given for R 16 as preferred.
  • substituents R 18 and R 19 independently of one another denote hydrogen or d ⁇ -alkyl, in particular hydrogen.
  • the substituent R 20 preferably denotes halogen, hydroxy, cyano, d- 4 -alkyl, C 1-4 alkenyl, C 2 . -Alkynyl, C 3 . 7- cycloalkyl, C 3 . 7 -Cycloalkyl- C ⁇ - 3 -alkyl-, hydroxy-C ⁇ alkyl, R 22 -d- 3 -alkyl or one of the meanings given as preferred for R 22 , wherein, as defined in the introduction, in each case one or more C atoms can additionally be substituted one or more times with F and / or one or two carbon atoms, independently of one another, additionally simply with Cl or Br.
  • Particularly preferred meanings of the group R 20 are halogen, hydroxy, cyano, d- 4 -alkyl, C 3 . 7- cycloalkyl and d- 4 -alkoxy, where, as defined at the outset, one or more C atoms in each case are additionally substituted one or more times with F and / or in each case one or two C atoms, independently of one another, additionally simply with Cl or Br can.
  • R 20 very particularly preferably denotes F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, acetyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso- propoxy.
  • the substituent R 22 is preferably d- 4 -alkoxy, d- 4 -alkylthio, carboxy, C ⁇ - 4 -alkylcarbonyl, d- 4 -alkoxycarbonyl, aminocarbonyl, d- 4 -alkylaminocarbonyl, di- (d- -alkyl) -aminocarbony ], C ⁇ -alkyl-sulfonyl, C ⁇ - 4 -alkyl-sulfinyl, C ⁇ -alkyl-sulfonylamino-, amino-, d- 4 -alkylamino-, di- (d- 4 -alkyl) -amino-, d ⁇ -Alkyl-carbonyl-amino-, hydroxy-d- 3 - alkylaminocarbonyl, aminocarbonylamino or C ⁇ - -Alkylaminocarbonyl-amino-, where, as defined
  • R 22 are C- ⁇ - 4 - alkoxy, d ⁇ alkylcarbonyl, amino, C 1 - 4 alkylamino, di- (C 1 - 4 -alkyI) -amino, wherein one or more H atoms can be replaced by fluorine.
  • R 21 Preferred meanings of the group R 21 are d ⁇ -alkyl, d ⁇ -alkylcarbonyl, d- 4 -
  • R 21 very particularly preferably denotes d- 4 -alkyl or CF 3 .
  • Cy preferably denotes a C 3-7 -cycloalkyl, in particular a C 3 - 6 cycloalkyl group, a C. 5 7- cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, and wherein the aforementioned cyclic groups are attached one or more times to one or more carbon atoms with identical or different radicals R 20 , in the case of a phenyl group can also be substituted simply with nitro and / or one or more NH groups with R 21 .
  • Most particularly preferred definitions of the group Cy are C 3 - 6 cycloalkyl, pyrrolidinyl and piperidinyl which may be substituted as indicated.
  • aryl preferably means phenyl or naphthyl, especially phenyl.
  • heteroaryl preferably includes pyridyl, indolyl, quinolinyl and benzoxazolyl.
  • Particularly preferred compounds according to the invention can be of a general formula IIIa, IIb, IIc and 'ild, in particular Ha and Mb,
  • quinoline and benzimidazole groups are unsubstituted or mono- or disubstituted with L 1 , a quinoline group preferably being unsubstituted or simply substituted with R 20 , in particular d- 3- alkyl, very particularly methyl, in position 4, and
  • R 1 , R 2 and Z have one of the meanings mentioned above and
  • L 3 independently of one another, have one of the meanings given for R 20 , • i and
  • n, p independently of one another denote the values 0, 1 or 2, p also the value 3.
  • L 3 is independently selected from the meanings fluorine, chlorine, bromine, cyano, nitro, d ⁇ alkyl, hydroxy, ⁇ -hydroxy-d -3 alkyl, d ⁇ alkoxy, trifluoromethyl, trifluoromethoxy, C 2 . 4 -alkynyl, carboxy, C ⁇ -alkoxycarbonyl-, ⁇ - (C 1. -Alkoxy) -C 1 .
  • p 0, 1, 2 or 3, especially 1 or 2.
  • R 1 , R 2 independently of one another d ⁇ -alkyl, hydroxy-C ⁇ -alkyl, C 3 . 5- alkenyl, C 3 - 5 alkynyl, C 3 - 7 cycloalkyl, hydroxy-C 3 .
  • R 1 , R 2 are connected to one another and together with the N atom to which they are attached form a heterocyclic group which is selected from pyrrolidine, piperidine, piperazine, in which the free imine function is substituted by R 13 , and Morpholine, in which one or more H atoms can be replaced by identical or different radicals R 14 , and wherein the previously defined heterocyclic group can be substituted by a single bond with a carbo- or heterocyclic group Cy, where Cy is selected from the group consisting of from C 3-7 -CycIoalkyl and cyclo-C 3 - 6 - alkylenimino-, wherein Cy may be mono- or polysubstituted by identical or different radicals R 20, wherein R 20 is as previously defined and is preferably selected from fluoro, CF 3 , C ⁇ . 3- alkyl, hydroxy-d- 3- alkyl and hydroxy, and
  • R 14 is selected from F, Cl, Br, d ⁇ -alkyl, hydroxy, hydroxy-d- 3- alkyl, d- 4 -alkoxy, ⁇ - (C 1 - 4 -alkoxy) -C 1 . 3 -alkyl, amino-d- 3 -alkyl-, C- M -alkylamino-C ⁇ - 3 -alkyl-, C 3 . 7 - cycloalkylamino-d- 3- alkyl-, N- (C 3. 7 -cycloalkyl) -N- (C 1 - -alkyl) -amino-C 1 - 3 -alkyl-, di- (C 1 .
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.
  • d- n -alkyl where n has a value from 3 to 8, means a saturated, branched or unbranched hydrocarbon group with 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.
  • - n -alkylene where n can have a value from 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge with 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.
  • groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 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 2nd n -alkynyl where n has a value from 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C ⁇ C-
  • Triple bond examples include ethynyl, 1-propynyl, 2-propynyl, iso- Propynyl, 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.
  • Ci n alkoxy refers to a d-n-alkyl-O group wherein n d- 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.
  • d- n- alkylthio denotes a C- n- alkyl-S group, wherein C- n- alkyl is as defined above. Examples of such groups include methylthio, ethylthio, n-propylthio, iso-
  • 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- Hexylcarbonyl, iso-hexylcarbonyl, etc.
  • C 3rd n- Cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 3 to n carbon atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
  • C 5 - n cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 5 to n C atoms.
  • examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
  • aryl denotes a carbocyclic, aromatic ring system, such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, Pentalenyl, azulenyl, biphenylenyl, etc.
  • a particularly preferred meaning of "aryl” is phenyl.
  • cyclo-C. 3 6 -alkylenimino- denotes a 4- to 7-membered ring which has 3 to 6 methylene units and an imino group, the bond to the rest of the molecule taking place via the imino group.
  • cyclo-C 3 - 6 -alkylenimino-.carbonyl refers to a previously defined cyclo-C. 3 6 - alkylenimino-RingV which is connected to a carbonyl group via the imino group. - ..
  • heteroaryl used in this application denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, O and / or S.
  • 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-thi
  • heteroaryl means a heteroaromatic mono- or bicyclic ring system.
  • the H atom of an existing carboxy group or an H atom (imino or amino group) bound to an N atom can in each case be replaced by a residue which can be split off in vivo.
  • a residue which can be split off from an N atom in vivo is understood to mean, for example, a hydroxyl group, an acyl group such as the benzoyl or pyridinoyl group or a d- 16 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or Hexanoyl group, an allyloxycarbonyl group, ad- 16 alkoxycarbonyl group like that
  • R e CO-O- (R f CR g ) -O-CO group in the R e ad 8 alkyl, C 5 . 7- cycloalkyl, phenyl or phenyl-d- 3 -alkyl group,
  • R f is a hydrogen atom, ad- 3 -alkyl-, C 5 . 7- cycloalkyl or phenyl group and
  • R g represents a hydrogen atom, a C- ⁇ - 3 alkyl or R e CO-O- (R f CR g ) -O group, in which R e to R q are as defined above,
  • the phthalimido group also being suitable for an amino group
  • the ester radicals mentioned above also being able to be used as a group which can be converted into a carboxy group in vivo.
  • radicals and substituents described above can be substituted one or more times with 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 general formula I according to the invention can have acid groups, mainly carboxyl groups, and / or basic groups such as e.g.
  • Compounds of the general formula I can therefore be used as internal salts, as salts with pharmaceutically usable 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 usable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine and others available.
  • pharmaceutically usable 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 usable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, trie
  • the compounds according to the invention can be obtained using synthesis processes which are known in principle.
  • the compounds are preferably obtained by the production processes according to the invention which are explained in more detail below.
  • reaction schemes A and B below show the synthesis of the compounds A.5 and B.5 according to the invention, where R 1 , R 2 , X, Y, Z, W, A and B have one of the meanings described above.
  • Shark means chlorine, bromine or iodine, especially bromine or iodine, particularly preferably iodine.
  • reaction scheme A the halogen compound A.1 with the alkyne compound A.2 in a molar ratio of about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide reacted in a suitable solvent.
  • a preferred amount of copper (I) iodide is in the range from 1 to 15 mol%, in particular from 5 to 10 mol%, based on the starting material A.1.
  • Suitable palladium catalysts are, for example, Pd (PPh 3 ) 4 , Pd 2 (dba) 3 , Pd (OAc) 2 , Pd (PPh 3 ) 2 CI 2 , Pd (CH 3 CN) 2 CI 2 , Pd (dppf) CI 2nd
  • the palladium catalyst is preferably used in an amount of 1 to 15 mol%, in particular 5 to 10 mol%, based on the starting material A.1.
  • Suitable bases are, in particular, amines, such as, for example, triethylamine or ethyldiisopropylamine, and Cs 2 CO 3 .
  • the base is preferably used at least in an equimolar amount, based on the starting material A.1, in excess or as a solvent.
  • Suitable solvents are also dimethylformamide or ether, such as tetrahydrofuran, including mixtures thereof.
  • the reaction takes place over a period of about 2 to 24 hours in a temperature range of about 20 to 90 ° C.
  • the alkyne compound A.3 obtained is reacted directly or after prior purification with a suitable halogenating agent to give the halide derivative A.4, where shark is chlorine, bromine or iodine.
  • Suitable halogenating agents are, for example, POCI 3 or N (butyl) 4 Br with P 2 O 5 .
  • the reaction conditions to be observed are known as such to the person skilled in the art. Suitable reaction temperatures are usually in a range from 15 to 150 ° C.
  • reaction solution containing the halide derivative A.4 or the purified halide derivative A.4, dissolved in a suitable solvent is reacted with an amine H-NR 1 R 2 to give the end product A.5 and then optionally purified. If the amine H-NR 1 R 2 has a further primary or secondary amine function, this is advantageously provided beforehand with a protective group, which, after the reaction has ended, has a
  • the product thus obtained can be converted into the salt form, for example, by reaction with an appropriate acid.
  • a preferred molar ratio of the derivative A.4 to the amine compound is in the range from 1.5: 1 to 1: 1.5.
  • Suitable solvents are dimethylformamide or ethers, such as tetrahydrofuran, including their mixtures.
  • the conversion to product A.5 is advantageously carried out in a temperature range from about 20 to 90 ° C.
  • the halogen compound B.2 is mixed with the alkyne compound B.1 in a molar ratio of about 1.5: 1 to 1: 1.5 in a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and
  • the alkyne compound B.3 obtained is reacted directly or after prior purification with a suitable halogenating agent to give the halide derivative B.4, where shark 'chlorine, Bromine or iodine.
  • the reaction conditions to be complied with here can again be found in what has been said about Scheme A.
  • reaction solution containing the halide derivative B.4 or the purified halide derivative B.4, dissolved in a suitable solvent, is reacted with an amine H-NR 1 R 2 to give the end product B.5 and then optionally purified.
  • the explanations for Scheme A also apply here.
  • a suitable palladium catalyst e.g., palladium
  • a suitable base e.g., palladium
  • copper ( l) iodide e.g., copper ( l) iodide
  • the reactions according to schemes A, B, C and D can be carried out particularly advantageously with the corresponding iodine compounds A.1, B.2, C.1 and D.2.
  • shark in the compounds A.1, B.2, C.1 or D.2 is bromine
  • the method is the Aryl-Finkelstein reaction (Klapars, Artis; Buchwald, Stephen L. Copper-Catalyzed Halogen Exchange in Aryl Halides: An Aromatic Finkelstein Reaction. Journal of the American Chemical Society (2002), 124 (50), 14844- 14845).
  • the halogen compound A.1, B.2, C.1 or D.2 can be reacted with sodium iodide in the presence of ⁇ /, ⁇ / '- dimethylethylenediamine and copper (I) iodide in a suitable solvent to give the corresponding iodine compound become.
  • An advantageous molar ratio of the halogen compound to sodium iodide is 1: 1.8 to 1: 2.3.
  • ⁇ /, A / '- Dimethyl-ethylenediamine is advantageously used in a molar ratio of 10 to 30 mol% based on the halogen compound A.1, B.2, C.1 or D.2.
  • Preferred amounts of copper (I) iodide are in the range from 5 to 20 mol%, based on the halogen compound A.1, B.2, C.1 or D.2.
  • a suitable solvent is, for example, 1,4-dioxane.
  • Suitable reaction temperatures range from about 20 to 110 ° C. The reaction is essentially complete after 2 to 72 hours.
  • stereoisomeric compounds of the formula (I) can be separated by customary methods.
  • the respective diastereomers can be separated 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 falling under the general formula (I) can be separated, for example, by HPLC on suitable chiral stationary phases (for example Chiral AGP, Chiralpak AD). Racemates containing a basic or acidic function can also be separated using the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (- ) -Diacetyltartaric acid, (+) - or (-) - monomethyltartrate or (+) - camphorsulfonic acid, or an optically active base, for example with (R) - (+) - 1-phenylethylamine, (S) - (-) - 1-phenylethylamine or (S) -Brucin arise.
  • an optically active acid for example (+) - or (-) - tartaric acid, (+) - or (- ) -Diacetyltartaric acid, (+) - or (-
  • the racemate of a compound of general formula (I) is reacted with one of the optically active acids or bases given above in an equimolar amount in a solvent and the resulting ones crystalline, diastereomeric, optically active salts separated using their different solubility.
  • This reaction can be carried out in any type of solvent as long as they have a sufficient difference in the solubility of the salts.
  • Methanol, ethanol or mixtures thereof are preferably used, for example in a volume ratio of 50:50.
  • Each of the optically active salts is then 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, and the corresponding free compound in the (+) - or ( -) - Get shape.
  • 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 pharmaceutical use, into their physiologically and pharmacologically acceptable salts.
  • these salts can be in the form of physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids.
  • the compound of the formula (I) in the case of acidically bound hydrogen, can also be converted into physiologically and pharmacologically tolerable salts with alkali metal or alkaline earth metal cations as counterions by reaction with inorganic bases.
  • 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 can be used to prepare the acid addition salts.
  • Mixtures of the aforementioned acids can also be used.
  • alkali and alkaline earth metal salts of the compound of formula (I) with acidic hydrogen preference is given to the alkali and alkaline earth metal hydroxides and hydrides, the hydroxides and hydrides of the alkali metals, in particular sodium and potassium being preferred, sodium and potassium hydroxide are particularly preferred.
  • the compounds according to the present invention have an effect as antagonists of the MCH receptor, in particular the MCH-1 receptor, and show good affinities in MCH- Receptor binding studies.
  • Pharmacological test systems for MCH-antagonistic properties are described in the following experimental section.
  • the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prophylaxis and / or treatment of symptoms and / or diseases which are caused by MCH or which have another causal relationship with MCH.
  • the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular brain mobility.
  • MCH antagonists which have at least one compound according to the invention, especially in mammals, such as, for example, rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and / or prophylaxis of Appearances and / or illnesses that are caused by MCH or have another causal connection with MCH are suitable.
  • Diseases that are caused by MCH or have another causal connection with MCH are, in particular, metabolic disorders, such as, for example, obesity, and eating disorders, such as, for example, bulimia, including bulimia nervosa.
  • the indication of obesity mainly includes exogenous obesity, hyperinsulinic obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, central obesity, obesity.
  • cachexia, anorexia and hyperphagia should also be mentioned in this indication environment.
  • Compounds according to the invention can be particularly suitable for reducing hunger, curbing appetite, controlling eating behavior and / or causing a feeling of satiety.
  • Compounds according to the invention are also active ingredients for the prophylaxis and / or treatment of further diseases and / or disorders, in particular those associated with obesity, such as, for example, diabetes, diabetes mellitus, in particular type II diabetes, hyperglycemia, in particular chronic hyperglycemia, diabetic complications, including diabetic Retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance ⁇ , encephalorrhagia, heart failure, cardiovascular diseases, particularly arteriosclerosis ' and high blood pressure, arthritis and gonitis are suitable.
  • further diseases and / or disorders in particular those associated with obesity, such as, for example, diabetes, diabetes mellitus, in particular type II diabetes, hyperglycemia, in particular chronic hyperglycemia, diabetic complications, including diabetic Retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance ⁇ , encephalorrhagia, heart failure, cardiovascular diseases, particularly ar
  • 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 according to the invention are advantageously suitable is the prophylaxis and / or treatment of micturition disorders, such as, for example, urinary incontinence, overactive urinary bladder, urge to urinate, nocturia, enuresis, the overactive bladder and urge to urinate with or not with benign prostatic hyperplasia Need to be connected.
  • micturition disorders such as, for example, urinary incontinence, overactive urinary bladder, urge to urinate, nocturia, enuresis, the overactive bladder and urge to urinate with or not with benign prostatic hyperplasia Need to be connected.
  • the compounds according to the invention are potentially suitable for preventing and / or treating addictions, such as, for example, alcohol and / or nicotine dependency, and / or withdrawal symptoms, such as, for example, an increase in weight when smoking cessation from smoking.
  • “Dependency” here generally means an irresistible urge to take an addictive substance and / or to perform certain actions, in particular in order to either achieve a feeling of well-being or to eliminate sensations.
  • “addiction” is understood here as an addiction addiction.
  • “Withdrawal symptoms” are generally understood here to be symptoms that occur or may occur when addictive substances are withdrawn in patients who are dependent on one or more such addictive substances.
  • the compounds according to the invention are in particular potentially active as active ingredients for reducing or ending tobacco consumption, for treating or preventing nicotine dependence and / or for treating or preventing nicotine withdrawal symptoms, for reducing the craving for tobacco and / or nicotine and generally suitable as an anti-smoking agent. Furthermore, the compounds according to the invention can be useful in order to prevent or at least to reduce the weight gain typical in the smoking cessation of smokers. The substances can furthermore be suitable as active substances which prevent or at least reduce the craving for and / or relapse into addiction.
  • Addictive substances are understood to mean, in particular, but not exclusively, psycho-motorically active substances, such as narcotics or intoxicants, in particular alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates.
  • the dosage required to achieve a corresponding effect is expediently 0.001 to 30 mg / kg body weight with intravenous or subcutaneous administration, preferably 0.01 to 5 mg / kg body weight, and 0.01 to 50 mg / kg with oral, nasal or inhalation administration Body weight, preferably 0.1 to 30 mg / kg body weight, once to three times a day.
  • the compounds of general formula I prepared according to the invention optionally in combination with other active substances, as are described in more detail below, together with one or more inert customary carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water,
  • inert customary carriers and / or diluents e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water,
  • the invention also includes compositions containing at least one alkyne compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically tolerable substances . lfsstoffen.
  • Such compositions can, for example, also be foods, which can be solid or liquid, into which the compound according to the invention is incorporated.
  • further active substances are in particular those which, for example, increase the therapeutic effectiveness of an MCH antagonist according to the invention with regard to one of the indications mentioned and / or reduce the dosage of an MCH antagonist according to the invention. Allow antagonists.
  • One or more further active substances are preferably selected from the group consisting of active substances for the treatment of diabetes,
  • Active substances for the treatment of diabetic complications active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidemia, including arteriosclerosis,
  • dyslipidemia including arteriosclerosis
  • insulin sensitizers examples include insulin sensitizers, insulin secretion accelerators, biguanides, insulins, ⁇ -glucosidase inhibitors, ⁇ 3 adreno receptor agonists.
  • Insulin sensitizers include glitazones, especially pioglitazone and its salts (preferably hydrochloride), troglitazone, rosiglitazone and its salts (preferably maleates), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13- 1258, KRP-297, R-119702, GW-1929.
  • Insulin secretion accelerators include sulfonylureas, such as, for example, tolbutamide, chlorpropamide, tolzamide, acetohexamide, glyclopyramide and its ammonium salts, glibenclamides, gliclazides, glimepirides. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608.
  • Biguanides include metformin, buformin, phenformin.
  • Insulins include insulins obtained from animals, in particular cattle or pigs, semisynthetic human insulins which are enzymatically synthesized from animal-derived insulin, human insulin which is obtained by genetic engineering, for example from Escherichia coli or yeasts.
  • insulin zinc is called insulin (containing 0.45 to 0.9 weight percent zinc) and 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 can also include different types, for example with regard to the onset time and duration of the action ("ultra immediate action type”, “immediate action type”, “two phase type”, “intermediate type”, “prolonged action type”, etc.), which are selected depending on the pathological condition of the patient.
  • ⁇ -Glucosidase inhibitors include acarbose, Voglibose, Miglitol, Emiglitate.
  • ⁇ 3 adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
  • Active ingredients other than the aforementioned for the treatment of diabetes include Ergoset, Pramlintide, Leptin, BAY-27-9955 and glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1 B inhibitors, dipeptidyl protease inhibitors, glipizide, glyburide.
  • Active substances 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 analogues, SGLT-2 inhibitors.
  • Aldose reductase inhibitors are, 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 are, for example, liragiutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), exenatide (Amlyin).
  • SGLT-2 inhibitors include AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson).
  • Active ingredients other than the aforementioned for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).
  • Active ingredients for the treatment of obesity include lipase inhibitors and anorectics.
  • a preferred example of a lipase inhibitor is orlistat.
  • Examples of preferred anorectics are phentermine, mazindole, dexfenfluramine, fluoxetine, sibutramine, baiamine, (S) -sibutramine, SR-141716, NGD-95-1.
  • Active ingredients for the treatment of obesity other than the aforementioned include lipstatin.
  • the anorectics are also included in the active ingredient group of the anti-obesity active ingredients, the ⁇ 3 agonists, thyromimetic active ingredients and NPY antagonists being emphasized.
  • the scope of the substances which are considered to be preferred anti-obesity or anorectic active substances is exemplified by the following further list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake ( reuptake) inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine, fenfluramine, or a 5-HT2C agonist such as BVT.933 or APD356, or Duloxetine), a dopamine agonist (such as bromocriptine or Pr
  • anorectics include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor Agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucogon-like peptide-1 receptor, such as, for example, Exendin, AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors, such as, for example, axokines.
  • forms of therapy are to be mentioned in this connection which lead to weight loss by increasing the fatty acid oxidation in peripheral tissue, such as inhibitors of acetyl-CoA carboxylase.
  • Active ingredients for the treatment of high blood pressure include inhibitors of the angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists.
  • Inhibitors of the angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).
  • Examples of calcium antagonists are 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.
  • Active ingredients for the treatment of hyperiipidemia include HMG-CoA reductase inhibitors, fibrate compounds.
  • HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and their salts.
  • Fibrate compounds include bezafibrate, clinofibrate, clofibrate, simfibrate.
  • Active ingredients for the treatment of dyslipidemia include, for example, drugs that increase the HDL level, such as nicotinic acid and its derivatives or preparations such as Niaspan, and agonists of the nicotinic acid receptor.
  • Active substances for the treatment of arthritis include NSAIDs (non-steroidal anti-inflammatory drugs), in particular COX2 inhibitors, such as, for example, meloxicam or ibuprofen.
  • Active substances for the treatment of anxiety include chlordiazepoxides, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
  • Active substances 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 dose up to 1/1 of the normally recommended dose.
  • 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 the compounds according to the invention can be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or producing a feeling of satiety.
  • the eating behavior is advantageously influenced in that the food intake is reduced.
  • the compounds according to the invention are therefore advantageously used to reduce body weight.
  • Another use according to the invention is the prevention of an increase in body weight, for example in people who have previously taken measures to reduce weight and are subsequently interested in maintaining the reduced body weight. According to this embodiment, it is preferably a non-therapeutic use.
  • Such a non-therapeutic use can be a cosmetic application, for example to change the external appearance, or an application to improve the general condition.
  • the compounds according to the invention are preferably used non-therapeutically for mammals, in particular humans, which have no diagnosed disorders in eating behavior, no diagnosed obesity, bulimia, diabetes and / or no diagnosed micturition disorders, in particular urinary incontinence.
  • IR, ⁇ H-NMR and / or mass spectra are generally available for the compounds produced.
  • R r values are determined using ready-made silica gel 60 F 2 54 TLC plates (E. Merck, Darmstadt, Article No. 1.05714) without chamber saturation.
  • the R r values determined under the name Alox are determined using ready-made aluminum oxide 60 F254 DC plates (E. Merck, Darmstadt, item no. 1.05713) without chamber saturation.
  • silica gel from Millipore MATREX TM, 35-70 my
  • Alox E.
  • the ratios given for the flow agents relate to volume units of the respective solvents.
  • the volume units given for NH 3 solutions relate to a concentrated solution of NH 3 in water. Unless otherwise noted, the acid, base and salt solutions used in the processing of the reaction solutions are aqueous systems of the stated concentrations.
  • HPLC data are measured using the parameters listed below: Analytical columns: Zorbax column (Agilent Technologies), SB (Stahle Bond) - C18; 3.5 ⁇ m; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 ⁇ L; Detection at 254 nm (methods A and B)
  • Preparative column Zorbax column (Agilent Technologies), SB (Stabie Bond) - C18; 3.5 ⁇ m; 30 x 100 mm; Column temperature: room temperature; Flow: 30 mL / min; Detection at 254 nm.
  • preparative HPLC cleaning the same gradients are generally used that were used to collect the analytical HPLC data.
  • the products are collected in a mass-controlled manner, the product-containing fractions are combined and freeze-dried. Temperatures are given in degrees Celsius (° C); Periods are usually given in minutes (min), hours (h) or days (d). If more detailed information on the configuration is missing, it remains open whether the enantiomers are pure or whether partial or even complete racemization has occurred.
  • reaction mixture kept at this temperature for 5 h.
  • the reaction solution is cooled in an ice bath, the precipitate which has separated out is filtered and washed with toluene until the
  • Example 1 k Analogously to Example 1 k, the following examples can be started from 2-chloro-6- [5- (4-chlorophenyl) pyridin-2-ylethynyl] -4-methyl-quinoline (Example 1 h) or 2-bromo-6- [5- (4-chloro-phenyl) -pyridin-
  • Example 1.13 was prepared by microwave heating in DMF (150W, 170 ° C; 10 min).
  • Example 1.51 was produced as a by-product.
  • the precipitate is filtered off, washed with water and dried in a forced-air drying cabinet at 30 ° C.
  • Example 1k The following examples are prepared analogously to Example 1k, starting from 90 mg of 2-chloro-6- [5- (4-chlorophenyl) pyridin-2-ylethynyl] -4-methyl-quinoline (Example 1 h) and the corresponding amines:
  • test methods for determining an MCH receptor antagonistic activity are described below.
  • other test methods known to the person skilled in the art for example inhibition of cAMP production mediated by the inhibition of the MCH receptor, as described by Hoogduijn M et al. in "Melanin-concentrating hormones and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and on the biosensory measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by plasmon resonance, as described by Karlsson OP and Lofas S.
  • Test cell hMCH-1 R stably transfected in CHO / Galpha16 cells
  • Results IC50 values
  • Membranes from CHO / Galpha16 cells stably transfected with human hMCH-1 R are resuspended with a syringe (needle 0.6 x 25 mm) and in test buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, pH 7.00; 0.1% Bovine serum albumin (protease-free), 0.021% bacitracin, 1 ⁇ g / mL aprotinin, 1 ⁇ g / mL leupeptin and 1 ⁇ M phosphoramidone) diluted to a concentration of 5 to 15 ⁇ g / mL.
  • test buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, pH 7.00; 0.1% Bovine serum albumin (protease-free), 0.021% bacitracin, 1 ⁇ g / mL aprotinin, 1 ⁇ g / m
  • Unlabeled MCH competes with labeled 125 I-MCH for receptor binding with a
  • the KD value of the radioligand is 0.156 nM.
  • Test cells CHO / Galpha 16 cells stably transfected with hMCH-R1
  • HBSS (10x) (GIBCO) HEPES Buffer (1M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) Specimen Oath (Sigma) MCH (Bachern) Bovine Serum Albumin (Serva) (Protease Free) DMSO (Serva) Harm's F12 (BioWhittaker) FCS (BioWhittaker) L-Glutamine (GIBCO) Hygromycin B (GIBCO) PENStrep (BioWhittaker) Zeocin (Invitrogen)
  • Clonal CHO / Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat.Nr .: BE12-615F). This contains 10 mL FCS, 1% PENStrep, 5 mL L-glutamine (200 mM stock solution), 3 mL hygromycin B (50 mg / mL in PBS) and 1.25 mL Zeocin (100 ⁇ g / mL stock solution) per 500 mL.
  • the cells are plated on a 384-well microtiter plate (black-walled with transparent bottom, manufacturer: Costar) at a density of 2500 cells per cavity and in the Medium described above cultured overnight at 37 ° C, 5% CO 2 and 95% relative humidity.
  • the cells are incubated with cell culture medium to which 2 mM Fluo- 4 and 4.6 mM probenicide have been added at 37 ° C. for 45 minutes.
  • the cells are washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which is mixed with 0.07% probenicide.
  • the test substances are diluted in Hanks buffer solution, mixed with 2.5% DMSO.
  • the background fluorescence of non-stimulated cells is measured in the presence of substance in the 384-well microtitre plate five minutes after the last washing step in the FLIPR 384 IPMENT (Molecular Devices; 'excitation wavelength: 488 nm; emission wavelength: bandpass 510 to 570 nm).
  • MCH is diluted in Hanks buffer with 0.1% BSA, pipetted to the 384-well cell culture plate 35 minutes after the last washing step and the MCH-stimulated fluorescence is then measured in the FLIPR 384 device.
  • 1st measurement The cellular Ca 2+ mobilization is measured as a peak of the relative fluorescence minus the background and expressed as a percentage of the maximum signal of the reference (MCH 10 "6 M). This measurement serves to identify a possible agonistic effect of a test substance.
  • Measurement The cellular Ca 2+ mobilization is measured as the peak of the relative fluorescence minus the background and expressed as a percentage of the maximum signal of the reference (MCH 10 "6 M, signal is normalized to 100%).
  • the EC50 values of the MCH dose-response curve with and without test substance (defined concentration) are determined graphically by the GraphPad Prism 2.01 curve program. MCH antagonists cause a shift of the MCH stimulation curve to the right in the created graphic.
  • pKB l ⁇ g (EC50 (test substance + MCH) / ECsofMCH) "1)" l ⁇ g C (test substance)
  • the compounds according to the invention show an MCH receptor antagonistic effect in the tests mentioned.
  • IC 50 values were determined using the MCH-1 receptor binding test described above: Compound IC50 value according to example - substance name No. 1.44 ⁇ 6- [5- (4-chlorophenyl) pyridin-2-ylethynyl] -4- 6.8 nM methyl-quinolin-2-yl ⁇ -isopropyl-amine 1.43 6 - [5- (4-Chlorophenyl) pyridin-2-ylethynyl] -4- 246 nM methyl-2- (4-methyl-piperidin-1-yl) quinoline
  • active ingredient means one or more compounds according to the invention, including their salts.
  • active substance also includes the further active substances.
  • 1 capsule for powder inhalation contains:
  • the active ingredient is ground to the grain size required for inhalants.
  • the ground active ingredient is mixed homogeneously with the milk sugar. The mixture is filled into hard gelatin capsules.
  • 1 hub includes:
  • Example C Inhalation solution for nebulizers with 1 mg of active ingredient Composition: 1 vial contains:
  • Active ingredient sodium chloride and benzalkonium chloride are dissolved in water.
  • 1 stroke contains: Active ingredient 1.0 mg
  • the micronized active ingredient is homogeneously suspended in the mixture of lecithin and propellant.
  • the suspension is filled into a pressure vessel with a metering valve.
  • the active ingredient and excipients are dissolved in water and in a corresponding
  • Preparation Dissolve glycofurol and glucose in water for injections (Wfl); Add human serum albumin; Dissolve the active ingredient while heating; fill up to batch volume with Wfl; Fill into ampoules under nitrogen gas.
  • Disodium hydrogen phosphate Na2HP ⁇ 4'2H2 ⁇ 2 mg sodium chloride 180 mg
  • Dissolve mannitol in water for injections Wfl
  • Add human serum albumin Dissolve the active ingredient while heating; fill up to batch volume with Wfl; fill in vials; freeze-dry.
  • Polysorbate 80 Tween 80 20 mg
  • Preparation Dissolve mannitol in water for injections (Wfl); Add human serum albumin; Dissolve the active ingredient while heating; fill up to batch volume with Wfl; Fill into ampoules under nitrogen gas.

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EP05739806A 2004-04-14 2005-04-08 Neue alkin-verbindungen mit mch-antagonistischer wirkung und diese verbindungen enthaltende arzneimittel Withdrawn EP1737839A1 (de)

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DE102004017932A DE102004017932A1 (de) 2004-04-14 2004-04-14 Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
PCT/EP2005/003684 WO2005103029A1 (de) 2004-04-14 2005-04-08 Neue alkin-verbindungen mit mch-antagonistischer wirkung und diese verbindungen enthaltende arzneimittel

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US7452911B2 (en) 2002-10-31 2008-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
DE10323345A1 (de) 2003-05-23 2004-12-16 Zentaris Gmbh Neue Pyridopyrazine und deren Verwendung als Kinase-Inhibitoren
US8217042B2 (en) 2005-11-11 2012-07-10 Zentaris Gmbh Pyridopyrazines and their use as modulators of kinases
EP1790342A1 (de) 2005-11-11 2007-05-30 Zentaris GmbH Pyridopyrazin-Derivate und deren Verwendung als Modulatoren der Signaltransduktionswege
NZ575520A (en) 2006-08-25 2012-03-30 Boehringer Ingelheim Int New pyridone derivatives with mch antagonistic activity and medicaments comprising these compounds
TW200831485A (en) * 2006-12-11 2008-08-01 Boehringer Ingelheim Int New pyridazine derivatives with MCH antagonistic activity and medicaments comprising these compounds
US8198307B2 (en) * 2007-05-11 2012-06-12 Korea Research Institute Of Chemical Technology Imidazole derivatives having aryl piperidine substituent, method for preparation thereof and pharmaceutical compositions containing same
JP5535931B2 (ja) 2008-10-27 2014-07-02 武田薬品工業株式会社 二環性化合物
HRP20181746T1 (hr) * 2011-12-16 2018-12-28 Poseida Therapeutics, Inc. Trpc4 modulatori za uporabu u liječenju ili prevenciji bola
AU2018351059B2 (en) 2017-10-19 2022-05-12 Teijin Pharma Limited Benzimidazole derivatives and their uses

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AU7315700A (en) * 1999-09-20 2001-04-24 Takeda Chemical Industries Ltd. Melanin concentrating hormone antagonist
JP2002003370A (ja) * 1999-09-20 2002-01-09 Takeda Chem Ind Ltd メラニン凝集ホルモン拮抗剤
JP2002241274A (ja) * 2000-04-28 2002-08-28 Takeda Chem Ind Ltd メラニン凝集ホルモン拮抗剤
DE10139416A1 (de) * 2001-08-17 2003-03-06 Aventis Pharma Gmbh Aminoalkyl substituierte aromatische Bicyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
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JP4487774B2 (ja) * 2002-09-30 2010-06-23 萬有製薬株式会社 ２−アミノベンズイミダゾール誘導体
DE10250708A1 (de) * 2002-10-31 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
JP4630555B2 (ja) * 2003-02-12 2011-02-09 武田薬品工業株式会社 アミン誘導体

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CA2559237A1 (en) 2005-11-03

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