Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • 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 refers to an excess of adipose tissue in the body.
• obesity is basically to be seen as any increased level of body fat that leads to a health risk.
• BMI body mass index
• MCH antagonists including WO 01/21577, WO 01/82925.
• MCH Melanin-concentrating hormone
• Hypothalamus synthesizes and reaches further brain regions from there via the projections of hypothalamic neurons. Its biological activity is mediated in humans via two different G protein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, the MCH receptors 1 and 2 (MCH-1 R, MCH-2R).
• GPCRs G protein-coupled receptors
• the MCH-1 R antagonist SNAP-7941 In addition to its anorectic effect, the MCH-1 R antagonist SNAP-7941 also produces other anxiolytic and ant ⁇ depressive 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 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.
• 6- [5- (4-chlorophenyl) pyridin-2-ylethynyl] -2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydroquinoline, 6- [5- (4-chloro- phenyl) -pyhdin-2-ylethinyl] -1-methyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydroquinoline,
• 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 1, R 2 are independently H, -alkyl, C 3-7 cycloalkyl or an optionally mono- or with identical or different radicals R 20 repeatedly and / or monosubstituted by nitro phenyl or pyridinyl group, wherein 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 can be substituted 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- M alkylene bridge, and wherein one or two carbon atoms can be substituted independently of one another with one or two identical or different C 1-4 alkyl radicals, where two Alkyl radicals can be linked to form a carbocyclic ring, and
• Y is selected from the meanings of the sub-formulas Y1 and Y2
• the group is MO, S or NR M , wherein R M is selected from the meanings H, C ⁇ -Alky !, C 3 . 6 alkenyl, C 3 . 6 alkynyl, C 3-7 cycloalkyl, and C. 3 7 - Cycloalkyl-C ⁇ - 3 alkyl, and wherein in the partial formulas Y1 and Y2 one or more carbon atoms can be substituted independently of one another with R 20 , and
• A is selected from among the bivalent cyclic groups phenyl, pyridinyl pyrimidinyl, pyrazinyl, Pyridazinyi, 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,
• Cy a carbo- or heterocyclic group selected from one of the following meanings - a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, - a saturated 4- to 7 -linked or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as hetero atom, - a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and one O or S atom as heteroatoms, an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and / or S, the above-mentioned saturated 6 or 7-membered groups also as bridged ring systems with an imino, (C 1 - 4 alkyl) imino, methylene, (C 1 - 4 alkyl) methylene or di (C 4 al
• R 10 hydroxy, ⁇ -hydroxy-C ⁇ - 3 alkyl, C ⁇ . 4 -alkoxy or C- -alkoxy-cis-alkyl-,
• R 11 halogen, de-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 , d- 3- alkyl, hydroxy-d- 3 -alkyl;
• R 13 has one of the meanings given for R 17 ,
• R 14 is halogen, cyano, d-6 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 -Od- 3 -alkyl, R 15 -O-CO-d-3-alkyl, R 15 - SO 2 -NH-, R ⁇ -O-CO-NH-ds-alkyl-, R 15 -SO 2 -NH -d- 3 -alkyl-, R ⁇ -CO-ds-alkyl-, R ⁇ -CO-Ods-al kyl-, R 16 R 17 Nd- 3 -alkyl-, R 18 R 19 N-CO-d- 3- alkyl- or Cy-ds- alkyl-,
• R 15 H, C 1-4 alkyl, C 3 . 7- cycloalkyl, C 3 . 7- cycloalkyl-d- 3 -alkyl, phenyl, phenyl-d- 3 -alkyl, pyridinyl or P ridinyl-d- 3 -alkyl,
• R 16 H de-alkyl, C 3 _ v cycloalkyl, C 3 . 7- cycloalkyl-d- 3 -alkyl, C 4 . 7- cycloalkenyl, C 4 . 7 - cycloalkenyl-d- 3- alkyl, ⁇ -hydroxy-C 2 . 3 alkyl, ⁇ - (C 1-4 alkoxy) C 2 - 3 alkyl, amino-C. 2 e-alkyl, d-4 alkyl-amino-C 2 - 6 alkyl, di (C 1-4 -alkyl) -amino-C. 2 6 -alkyl or cyclo-C 3 .
• R 17 has one of the meanings given for R 16 or phenyl, phenyl-d- 3 -alkyl, pyridinyl, C ⁇ -alkylcarbonyl, hydroxycarbonyl-Ci-3-alkyl, d ⁇ -AJkoxycarbonyl-, C- -alkoxycarbonyl-C ⁇ - 3 - alkyl, d- -AIkylcarbonylamino 4-C 2 - 3 -alkyI, N- (C 1-4 alkylcarbonyl) -N- (C 1 ⁇ alkyl) amino-C.
• R 18 , R 19 independently of one another are H or C -, - 6 -alkyl, R 20 halogen, hydroxy, cyano, C ⁇ -AI kyl, C 2 . 6 -alkenyl, C 2 - 6 alkynyl, C. 3 7- cycloalkyl, C 3 - 7 -cycloalkyl-d- 3 -alkyl, hydroxy-d- 3 -alkyl, R 22 -d- 3 -alkyl or one of the meanings given for R 22 ,
• R 21 d-4-alkyl ⁇ -hydroxy-C 2 . 6 alkyl, co-C ⁇ - 4 -alkoxy-C 2 - 6 alkyl, ⁇ -C-alkyl-amino-C 2 - ⁇ - alkyl, ⁇ -di- (C 1-4 -alkyI) amino-C 2nd 6- alkyl, ⁇ -cyclo-C 3 - 6 -alkyleneimino-C 2 - 6 -alkyl, phenyl, phenyl-C ⁇ -3-alkyl, C ⁇ alkylcarbonyl, d ⁇ alkoxycarbonyl, C ⁇ - alkylsulfonyl , Aminosulfonyl, C ⁇ -alkylaminosulfonyl, di-d- 4 -alkylaminosulfonyl or cyclo-C 3 .
• 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 compounds according to the present invention include the physiologically tolerable salts, have a particular activity as antagonists of the MCH receptor, in particular the MCH-1 receptor, compared to known, structurally comparable compounds, and show very good affinities in MCH receptor binding studies.
• the compounds according to the invention have a high to very high selectivity with regard to the MCH receptor.
• the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular brain mobility.
• 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. The 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 symptoms and / or diseases caused by MCH or with MCH in have another causal relationship.
• 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 production 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 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 diseases and / or disorders associated with obesity, in particular diabetes, particularly of 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.
• diabetes particularly of 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 manufacture 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 are suitable for 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 consists of the alkyne compounds according to the invention and / or the corresponding salts is selected, and a second active ingredient selected from the group consisting of active ingredients for the treatment of diabetes, active ingredients for the treatment of diabetic complications, active ingredients for the treatment of obesity, preferably other than MCH antagonists, active ingredients for the treatment of high blood pressure, active ingredients for the treatment of dyslipidemia or hyperiipidemia, including arteriosclerosis, agents for treating arthritis, agents for treating anxiety, and agents for treating depression, along with optionally 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
• R 1 , R 2 , Y, X, 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 A.2
• Another object of this invention is a process for the preparation of alkyne compounds of the formula B.5
• R 1 , R 2 , X, 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 B.2
• an object of this invention relates to a process for the preparation of alkyne compounds of the formula C.3 R 1 R 2 NXYC ⁇ CWAB (C.3)
• R 1 , R 2 , X, 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 aikine 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 , X, 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 aikine compound of the formula D.1
• R 1 R 2 NXYZC ⁇ CH (D.1) is reacted in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent to give the end product D.3.
• 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 and R 2 independently of one another are preferably an unsubstituted or a d- 8 -alkyl or C 3 mono- or polysubstituted with the same or different R 11 radicals.
• radical R 11 are F, CI, Br, d. 6 alkyl, C 2 - 6 alkenyl, C. 2 6 -
• R 11 has one of the meanings R 15 -O-, cyano, R 16 R 17 N- or cyclo-C 3 . 6 -alkylenimino-
• the R 11 substituted C atom of the alkyl or cycloalkyl group is preferably not directly connected to a hetero atom, such as the group -NX-.
• the radicals R 1 , R 2 are preferably independently of one another H, Ci-e-alkyl, C 3 . 5 alkenyl, C 3 . 5 - alkynyl, C 3 - 7 cycloalkyl, hydroxy-C.
• Preferred substituents of the aforementioned phenyl or pyridyl radicals are selected from the group F, CI, Br, I, cyano, d ⁇ alkyl, C ⁇ alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, d- 3 -Alkyiamino-, di- (d- 3 -alkyl) -amino-, acetylamino-, aminocarbonyl-, difluoromethoxy-, trifluoromethoxy-, amino-C ⁇ - 3 -alkyl-, C ⁇ - 3 -alkylamino-C ⁇ - 3 -alkyl- and di- (C 1-3 -alkyl) -amino-C. 1 3 -alkyl-, where a phenyl radical can also be simply substituted with nitro.
• radicals R 1 and / or R 2 are selected from the group consisting of H, C 1-4 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 . 6 -alkyl, C 3 .
• alkyl, pyridyl and benzyl wherein an alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and / or hydroxy-3 C ⁇ - alkyl, and / or mono- or polysubstituted by F or d-3-alkyl and / or can simply be substituted with CF 3 , Br, CI or CN, and wherein one of the radicals R 1 and R 2 can also denote H.
• 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 .
• 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, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl.
• 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 in such a way that the bond between the alkylene bridge and the group Cy - via a single or double bond, via a common carbon 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 to form a bridged ring system.
• R 1 and R 2 furthermore preferably form an alkylene bridge such that R 1 R 2 N - denotes a group which is 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 with R 13 is substituted, piperidin-4-one, morphoün and thiornorpholine, is particularly preferably selected from pyrrolidine, piperidine, piperazine, in which the free imine function is substituted by R 13 , and morphoin,
• 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-d-rcycloalkyl-, especially cyclo-C 3 . 6 -alkylenimino- and 1 -C ⁇ -alkyl-aza-d-rcycloalkyl-, where the group Cy can be substituted one or more times with R 20 .
• the C 3 formed by R 1 and R 2 . 8- alkylene bridge, in which -CH 2 groups can be replaced as indicated, can, as described, be substituted with one or two identical or different carbo- or heterocyclic groups Cy, which can be substituted as indicated above.
• Cy is preferably selected from the group consisting of C 3 . 7 -cycloalkyl, cyclo-C 3 - 6 - alkylenimino-, 1H-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-1 H-quinazolin-4-one.
• Cy is preferably selected from the group consisting of C 4 . -Cycloalkyl, phenyl, thienyl.
• Cy preferably denotes C - 8 -cycloalkyl or aza-C. 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-, these groups being as specified, preferably by fluorine, CF 3, d 3 - alkyl, hydroxy-d- 3 -alkyl and hydroxy, may be substituted.
• the group particularly preferably has 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 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 13 , R 14 , R 20 , R 21 have the meanings given above and below.
• R 20 preferably denote d ⁇ alkyl, C ⁇ _ 4 alkoxy-C 1 - 3 -alkyl, hydroxy-C ⁇ - 3 -alkyl, hydroxy, fluorine, chlorine, bromine or CF 3 , especially hydroxy.
• the group very particularly preferably has meaning according to one of the following sub-formulas
• R 13 has the meanings given above and below, and
• heterocycle formed by the group R 1 R 2 N- with C 3 . May be substituted, or cycloalkyl (hydroxy-Cs-e-cycloalkyO-ds-alkyl, and - 6 cycloalkyl, hydroxy-C 3 - 6
• 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 .
• the substituents R 14 here preferably mean independently of one another F, CI, Br, OH, C 1-4 -alkyl, d- -alkoxy, d- 4 - alkoxy-C ⁇ - 3 -alkyl, hydroxy-C-, - 4 -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: hydroxypyrroudinyl, hydroxypiperidinyl, 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl) pyrrolidinyl , (Hydroxymethyl) -piperidinyl, (hydroxymethyl) -hydroxy-pyrroüdinyl, (hydroxymethyl) -hydroxy-piperidinyl,
• methyl or ethyl groups may be mono-, di- or trisubstituted by fluorine, and in which one or more carbon atoms of the H-atoms of the heterocycle formed by the group R 1 R 2 N- independently of one another by fluorine, chlorine, CN, CF 3 , -C 3 alkyl, hydroxy-d 3 alkyl, in particular C 3 alkyl or CF 3 , preferably methyl, ethyl, CF 3 may be substituted.
• R 14 F, CI, Br, cyano, C 1-4 alkyl, C 2 -j-alkenyl, d-kinyl, C 3 - 7- cycloalkyl, C 3 . 7 -cycloalkyl-C ⁇ - 3 -alkyl-, hydroxy, hydroxy-C. ⁇ - 3 -alkyl-, d- 4 alkoxy, ⁇ - (C 1 - 4 alkoxy) -C 1 - alkyl 3, C ⁇ alkyl-carbonyl, carboxy, d- 4 alkoxycarbonyl, hydroxy-carbonyl-C ⁇ .
• Cycioalkyl -N- (C 1 - 4 alkyl) amino -carbonyl, di- (C 1-4 -alkyl) -amino-carbonyl, pyridinyl-oxy, pyridinyl-amino-, pyridinyl-d- 3 -alkyl-amino.
• substituent R 14 are F, CI, Br, d ⁇ -alkyl, hydroxy, hydroxy-C ⁇ - 3 alkyl, d- alkoxy, ⁇ - (C - alkoxy) -C 1 - 3 alkyl, Amino -CC 3 -alkyl-, d- 4 -alkyl-amino-Ci-3-alkyl-, C ⁇ -cycloalkyl-amino-C ⁇ a-alkyl-, N- (C 3 - 7 cycloalkyl) -N - (C ⁇ - 4 -alkyl) -amino-C 1 - 3 alkyl, di (C 1 - 4 alkyl) amino-3 C ⁇ - alkyl, cyclo-C. 3 6 -alkylenimino-d-. 3- alkyl-, aminocarbonyl and pyridylamino.
• 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 CI or Br.
• preferred meanings of R 14 also include -CF 3 , -OCF 3 , CF 3 -CO- and CF 3 -CHOH-.
• substituent R 14 are d-3-alkyl, hydroxy-d-3-alkyl, methoxymethyl, hydroxy, CF 3 , CF 3 -CHOH-, in particular hydroxy, methyl, ethyl, CF 3 and hydroxymethyl.
• the group X is a methylene, ethylene or propylene bridge, particularly preferably a methylene or ethylene bridge, which is unsubstituted or with one or two identical or different C
• X is preferably unsubstituted in the meaning methylene or ethylene or mono- or disubstituted by methyl, ethyl or i-propyl, while two alkyl substituents with each other to form a C. 3 6 cycloalkyl group can be connected.
• X is particularly preferably a —CH 2 bridge which is unsubstituted or mono- or disubstituted by methyl, it being possible for two methyl groups to be linked to form a cyclopropyl group.
• X is very particularly preferably an unsubstituted -CH 2 bridge.
• the group X is preferably an unbranched propylene or butylene bridge, where one or two carbon atoms are simply linked with hydroxy, hydroxy-C ! - 3-alkyl or d- 3 -A! Koxy, in particular hydroxy, can be substituted, and wherein one or two carbon atoms each with one or two identical or different d- 3 -alkyl substituents and / or a substituent selected from C 2 . 6 alkenyl, C 2 - 6 alkynyl, C. 3 6 - cycloalkyl or C 3 .
• 6- Cycloalkyl-C ⁇ - 3 alkyl can be substituted, wherein two alkyl substituents to form a 3- to 6-membered cycloalkyl group or an alkyl and an alkenyl substituent to form a 5- or 6-membered cycloalkenyl group with each other can be connected.
• group X one or more carbon atoms can be substituted one or more times with F and / or CI, preferably F.
• X is also C 3 --alkylene, in particular propylene, which has one or two identical or different substituents selected independently of one another from fluorine, chlorine, hydroxy and C 3 alkyl and / or a cyclopropyl substituent, where two alkyl substituents to form a C 3 - 6 may be cycloalkyl group connected to each other.
• the meanings given above for X are particularly preferably substituted once or twice with the same or different radicals selected from methyl, ethyl and i-propyl, it being possible for two alkyl groups, as indicated, to be linked to form a cyclic group.
• 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.
• R M in the group Y in the event that M represents NR M are selected from H, d-3 alkyl, prop-2-enyl, prop-2-ynyl, C 3 - 6 cycloalkyl , C 3 . 6 - cycloalkylmethyl.
• R M very particularly preferably denotes H or d- 3- alkyl, in particular H or methyl.
• M is preferably O or S.
• group Y is selected from the sub-formulas
• both sub-formulas are unsubstituted or one or more, preferably one or two, carbon atoms are substituted independently of one another by R 20 in both sub-formulas.
• substituents R 20 of group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C 1 -C 4 -alkyl, C 2 . 6 -alkenyl, hydroxy, ⁇ -hydroxy-C ⁇ - 3 -alkyl, d- -alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ -alkynyl, C ⁇ -alkoxy-carbonyl-, ⁇ - (C ⁇ - 4 -alkoxy) -C 1 , 3- alkyl-, d- 4 -alkoxy-carbonylarnino-, amino-, C ⁇ -alkyl-amino-, di- (C- M -alkyl-amino-, aminocarbonyl-, d- 4 -alkyl-amino-carbonyl- and di- (d- 4 -alkyl) -amino-carbonyl-.
• Very particularly preferred substituents R 20 of group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, d- 3- alkyl I, C 2 . 3- alkenyl, C 2 - 3 alkynyl, d-3-alkoxy, C 1 - 4 - 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, CI, 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 d- 3 alkyl.
• Group A is preferably unsubstituted or monosubstituted with R 20 , as indicated.
• Preferred meanings of group B according to a first preferred embodiment are 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 di-substituted, in the case of a single substitution the substituent is preferably para to the group A.
• Preferred substituents R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, d- 4 -alkyl, hydroxy, CHF 2 , CHF 2 -O-, hydroxy-Ci-s-alkyl, d , 4 -alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ -alkynyl, carboxy, C- M -alkoxycarbonyl-, ⁇ - (C- ⁇ - 4 -alkoxy) -C 1 .
• substituents R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF 3 , d- 3 alkyl, C 1-4 alkoxy and trifluoromethoxy.
• Very particularly preferred substituents R 20 of group B are selected from the group consisting of chlorine and methoxy.
• group B is preferably selected from de-alkyl, C 2 . 6 alkenyl, C 2 . 6- alkynyl, C 3 - 7 cycloalkyl, C 5 - 7 cycloalkenyl, C 3 - -
• groups C 3 are particularly preferred. 6 alkyl, C 3 . 6 alkenyl, C 3 - 6 alk nyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, Cyclopentyl-C ⁇ - 3 -alkyl-, cyclopentenyl-ds-alkyl-, cyclohexyl-d- 3 -alkyl-, cyclohexenyl-d. 3 -alkyl, cycloheptyl -CC.
• B very particularly preferably denotes cyclohexeny 1 which is unsubstituted or has 1, 2 or 3 identical or different substituents R 20 , in particular methyl.
• R 4 preferably denotes H, -CC alkyl, C 3 . 6- cycloalkyl and C 3 . 6- Cycloalkyl-methyl, in particular H, methyl, ethyl, propyl, i-propyl, n-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexymethyl.
• R 4 very particularly preferably denotes H or methyl.
• R 13 preferably has one of the meanings given for R 16 .
• R 13 is particularly preferably H, d- alkyl, C 3 . 7- cycloalkyl, C 3 - 7 -cycloalkyl-d- 3 -alkyl-, ⁇ -hydroxy-C 2 . 3 -alkyl-, ⁇ - (C ⁇ - -alkoxy) -C 2 - 3 -alkyl very particularly preferably R 13 is H or d- 4 -alkyl.
• the alkyl groups mentioned above can be substituted simply with CI or one or more times with F.
• R 15 are H, d- alkyl, C 3 - 7 cycloalkyl, C 3 . 7 - Cycloalkyl-d- 3 -alkyl-, where, as defined in the introduction, one or more C atoms in each case are substituted one or more times with F and / or in each case one or two C atoms, independently of one another, additionally simply with CI or Br could be.
• R 15 particularly preferably denotes H, CF 3 , methyl, ethyl, propyl or butyl.
• the substituent R 16 is preferably H, C 1-4 alkyl, C 3 _ -cycloalkyl, C 3 . 7- Cycloalkyl-C ⁇ - 3 - alkyl, ⁇ -hydroxy-C 2 - 3 alkyl or ⁇ - (C 1, 4 alkoxy) -C 2 . 3 -alkyl-, where, as defined at the outset, one or more C atoms in each case can be 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 CI or Br.
• R 16 particularly preferably denotes H, CF 3 , i.e. 3 alkyl, C 3 - 6 cycloalkyl, or C.
• R 17 preferably has one of the meanings given as preferred for R "16 or denotes phenyl, phenyl- 3- alkyl, pyridinyl or 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 C 1-4 -alkyl, in particular hydrogen.
• the substituent R 20 preferably denotes halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkenyl, C 2 . 4 alkynyl, C 3 . Cycloalkyl, C 3 . 7- Cycloalkyl-d-3-a'kyl- » hydroxy-d- 4- alkyl, R 22 -d-3-alkyl or one of the meanings given for R 22 as preferred, where, 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 in each case one or two C atoms, independently of one another, additionally simply with CI or Br.
• Particularly preferred meanings of the group R 20 are halogen, hydroxy, cyano, d ⁇ -alkyl, d ⁇ -alkylcarbonyl, 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 CI or Br can.
• R 20 very particularly preferably denotes F, CI, 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 preferably denotes C 4 alkoxy, C 4 alkylthio, carboxy, d 4 alkyl carbonyl, 4 alkoxycarbonyl, aminocarbonyl, C 1 alkylaminocarbonyl, di (C 1 alkyl) - aminocarbonyl, C ⁇ -alkyl-sulfonyl, C ⁇ -alkyl-sulfinyl, C ⁇ - 4 -alkyl-sulfonylamino-, amino-, C ⁇ - 4 -alkylamino-, di- (C 1 - -alkyl) -amino-, Hydroxy-C ⁇ - 3 - alkylaminocarbonyl, aminocarbonylamino or d ⁇ -Akylaminocarbonyl-amino-, where, as defined in the introduction, one or more C atoms each additionally one or more times with F and / or one or two C atoms independently can be easily substituted with one another by
• R 22 are d- 4 -alkoxy, d- 4 -alkylcarbonyl, amino-, C ⁇ -alkylamino-, di- (C ⁇ - -alkyl) -amino-, in which one or more H atoms by fluorine can be replaced.
• R 21 are d- 4 -alkyl, d- 4 -alkylcarbonyl, C ⁇ - 4 -alkylsulfonyl-, - SO 2 -NH 2 , -SO 2 -NH-d- 3 -alkyl, -SO 2 -N (C ⁇ . 3 -alkyl) 2 and cyclo-C 3 - 6 -alkylenimino-sulfonyl-, where, as defined in the introduction, one or more C atoms in each case one or more times with F and / or one or two carbon atoms, independently of one another, can additionally be simply substituted with CI or Br.
• R 21 very particularly preferably denotes d- 4 -alkyl or CF 3 .
• Cy is preferably a C 3 . 7 cycloalkyl, in particular a C 3 - 6 cycloalkyl group, a C. 5 -Cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, and the aforementioned cyclic groups one or more times on one or more carbon atoms with identical or different radicals R 20 , in the case of a phenyl group also can also be substituted simply with nitro, and / or one or more NH groups with R 21 .
• Very particularly preferred meanings of the group Cy are C 3 . 6- cycloalkyl, pyrrolidinyl and piperidinyl, which can 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 have a general formula III to III, in particular III and IIB
• the chroman and chromenon group is unsubstituted or mono- or disubstituted with L 1 ,
• R, R, X and Z have one of the meanings mentioned above and
• L 3 independently of one another, have one of the meanings given for R, and
• n, p independently of one another denote the values 0, 1 or 2, p also the value 3.
• Ila to Ild preferably mean, in particular Ila and IIb
• X is an unsubstituted -CH 2 bridge or a -CH 2 bridge which is mono- or disubstituted with d- 3 alkyl, in particular methyl, where two alkyl substituents form a C 3 . 6 - cycloalkyl group, in particular cyclopropyl, can be bonded to one another, a single bond, L 1 fluorine, chlorine, bromine, cyano, C 3 alkyl, C 3 alkoxy, 4 alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, in particular C 3 alkyl,
• L 3 is independently selected from the meanings fluorine, chlorine, bromine, cyano, nitro, C ⁇ alkyl, hydroxy, ⁇ -hydroxy-C ⁇ - 3 alkyl, ⁇ alkoxy, trifluoromethyl, trifluoromethoxy, C 2 . 4 -alkynyl, carboxy, ⁇ - (C 1 - 4 alkoxy) - d-3 alkyl, d-4 alkoxy-carbonylamino, amino, C ⁇ - alkyl-4 arnino-, di- (C ⁇ - 4 alkyl) - amino -, Cyclo-C 3 .
• p 0, 1, 2 or 3, especially 1 or 2.
• R 1 , R 2 independently of one another d- -A ⁇ kyl, hydroxy-d- -alkyl, C 3 - 5 -alkenyl, C 3 . 5 alkynyl, C 3 . 7- cycloalkyl, hydroxy-C 3 . 7 -cycloalkyl, dihydroxy-C 3 . 6 -alkyI, C 3 - 7 -C-ycloalkyl-d- 3 -alkyl-, tetrahydropyran-3-yl, tetrahydropyran-4-yI, (hydroxy-C ⁇ -cycloalky -Ci-s-alkyl-, ⁇ - ( C 1 -.
• alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted with Hyd roxy and / or hydroxy-d- 3 alkyl, and / or can be substituted one or more times with F or d- 3 alkyl and / or simply with CF 3 , Br, CI or CN, and one of the radicals R 1 and R 2 can also be H, and where phenyl- and pyridyl rings can be substituted one or more times with the same or different radicals R 20 , phenyl or simply with nitro, or
• R 1 , R 2 are linked to one another and, together with the IM 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 Morphoün, wherein 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 C 3rd 7- Cycloalkyl and Cyclo-C 3 - 6 - alkylenimino-, where Cy can be substituted one or more times with the same or different radicals R 20 , where R 20 is as previously defined and is preferably selected from fluorine, CF 3 , C ⁇ -Alkyl, hydroxy-C ⁇ - 3 -alky! and hydroxy, and
• R 14 is selected from F, Cl, Br, d-4 alkyl, hydroxy, hydroxy-d- C3 alkyl, -alkoxy, ⁇ - (C 1. 4, alkoxy) -d-3 d-alkyl, amino d- 3 -alkyl-, d ⁇ -alkylamino-ds-alkyl-, C 3 . Cycloalkyl amino-Ci- 3 alkyl, N- (C 3 - 7 cycloalkyl) -N- (C 1 - alkyl) amino-C. 1 3 alkyl, di (C 1 - 4 alkyl) - amino-3 C ⁇ - alkyl, cyclo C 3 - 6 -aIkylenimino-C-
• halogen denotes an atom selected from the group consisting of F, CI, Br and I, in particular F, CI 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.
• d- n -alkylene where n can have a value from 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge with 1 to n carbon atoms.
• groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methylethylene (- CH (CH 3 ) -CH 2 -), 1,1-dimethylethylene (-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.
• groups include ethynyl, 1-propynyl, 2-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.
• n -alkoxy denotes a C ⁇ - n- alkyl-O group, wherein Ci- 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.
• d- alkylthio n denotes a C n alkyl-S-group wherein n C ⁇ - alkyl is as defined above.
• groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert-pentylthio, n- Hexylthio, iso-hexylthio, etc.
• groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentyicarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n- Hexylcarbonyl, iso-hexylcarbonyl, etc.
• C 3rd n -CycIoalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 3 to n carbon atoms.
• examples of such 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- alkyleneimino-carbonyl denotes a previously defined cyclo-C 3 . 6 - alkylenimino ring 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-thazolyl, 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-thio
• heteroaryl particularly preferably denotes a heteroaromatic mono- or bicyclic ring system.
• unsaturated for example in “unsaturated carbocyclic group” or “unsaturated heterocyclic group”, as it is used in particular in the definition of the group Cy, in addition to the mono- or polyunsaturated groups, also includes the corresponding fully unsaturated groups, but especially the mono- and di-unsaturated groups.
• 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 C 1 -C 6 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a -CC 6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, decyloxycarbonyl Undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl
• R f is a hydrogen atom, ad 3 alkyl, C 5 . 7- cycloalkyl or phenyl group and
• R g represents a hydrogen atom, a d- 3 -alkyl or R e CO-0- (R f CR g ) -O group, in which R e to R g are defined as mentioned above,
• the phthaemido 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 amino functions.
• 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 pharmaceutical usable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as diethylamine, triethylamine, triethanolamine, etc. are present.
• 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)
• pharmaceutical usable bases such as alkali or
• reaction scheme A the halogen compound A.1 with the aikine compound A.2 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 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 aikine compound A.3 obtained is reacted directly or after previous purification with methanesulfonic acid chloride to give the methanesulfonate derivative A.4.
• the reaction conditions to be observed are known as such to the person skilled in the art. Halogenated hydrocarbons, such as dichloromethane, are advantageous solvents. Suitable reaction temperatures are usually in a range from 0 to 30 ° C.
• the reaction solution containing the methanesulfonate derivative A.4 or the purified methanesulfonate 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.
• 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 can be split off again after the reaction has ended using methods known from the literature.
• 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.
• reaction scheme B the halogen compound B.2 with the aikine compound B.1 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.
• the aikine compound B.3 obtained is reacted directly or after previous purification with methanesulfonic acid chloride to give the methanesulfonate derivative B.4.
• the reaction conditions to be complied with here can again be found in what has been said about Scheme A.
• reaction solution containing the methanesulfonate derivative B.4 or the purified methanesulfonate 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.
• reaction scheme C the halogen compound C.1 with the aikine compound C.2 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 copper ( l) iodide in a suitable solvent immediately converted to the product C.3.
• 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, it is advantageous to convert them beforehand into the corresponding iodine compound.
• a particularly advantageous method here 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 with sodium iodide in the presence of rs, ⁇ / '- dimethyl-ethylenediamine and Copper (I) iodide can be reacted in a suitable solvent to give the corresponding iodine compound.
• 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 (-) - monomethyl tartrate 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 the 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 crystalline, diastereomerically, optically active salts obtained using their different solubilities Cut.
• 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 in water dissolved, 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 is thereby obtained in the (+) or (-) form.
• 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 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 of the present invention act as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies.
• Pharmacological test systems for IvlCH 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 invention Compounds have a low toxicity, a good oral absorbability and intracerebral transitivity, in particular ease of passage.
• 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 adiposity, 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 melutus, in particular type II diabetes, hyperglycaemia, in particular chronic hyperglycaemia, diabetic comications, 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.
• 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.
• addiction here is generally understood to be an irresistible urge to take an addictive substance and / or to perform certain actions, in particular 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 substances for reducing or stopping 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 in general suitable as an anti-smoking agent. Furthermore, the compounds according to the invention can be useful in order to prevent or at least reduce the weight gain which is 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 when administered intravenously or subcutaneously, preferably 0.01 to 5 mg / kg body weight, and in the case of oral, nasal or inhalation administration 0.01 to 50 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, in each case 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, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or suitable fat-containing substances or mixtures of these with suitable fat such as hard fat , into common galenical preparations such as tablets, dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories.
• inert customary carriers and / or diluents e
• 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 auxiliaries.
• 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 which allow a reduction in the dosage of an MCH antagonist according to the invention.
• One or more further active substances are preferably selected from the group consisting of
• Active substances for the treatment of diabetic complications active substances for the treatment of obesity, preferably other than MCH antagonists,
• dyslipidemia including arteriosclerosis
• active substances for the treatment of diabetes are 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, rosigueta zone and its salts (preferably maleates), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13- 1258, KRP-297, R-119702, GW-1929.
• glitazones especially pioglitazone and its salts (preferably hydrochloride), troglitazone, rosigueta zone 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 Repagünide, Nateglinide, Mitiglinide (KAD-1229), JTT-608.
• Biguanides include metformin, buformin, phenformin.
• Insulins include insulins obtained from animals, in particular cattle or pigs, semi-synthetic 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. Furthermore, insulin-zinc (containing 0.45 to 0.9% by weight zinc) and protamine-insulin zinc obtainable from zinc chloride, protamine sulfate and insulin are understood. In addition, 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, Emigütate.
• ⁇ 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.
• Protein kinase C inhibitors are, for example, NGF, LY-333531.
• DPPIV blockers examples include LAF237 (Novartis), MK431 (Merck) and 815541, 823093 and 825964 (all GlaxoSmithküne).
• GLP-1 analogs are, for example, liraglutide (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.
• 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
• anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, 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, CJ10-1, or GR313, DPPIV inhibitors and ciliary neurotrophic factors such as 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, trandoiapril, 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, E4 77.
• 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.
• Agents for the treatment of dyslipidemia include e.g. Medicines that increase HDL spittle, such as Nicotinic acid and its derivatives or preparations, such as Niaspan, as well as agonists of the nicotinic acid receptor.
• Medicines that increase HDL spittle such as Nicotinic acid and its derivatives or preparations, such as Niaspan, as well as agonists of the nicotinic acid receptor.
• NSAIDs non-steroidal anti-inflammatory drugs
• 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 of the invention are therefore found beneficial application for reducing 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 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.
• the R r values determined under the designation Alox are determined using ready-made TLC plates Alurniniumoxid 60 F254 (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation.
• 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.
• AD-Mix Alpha article number: 39.275-8
• AD-Mix-Beta article number: 39.276-6 sold by Aldrich are used for the asymmetrical dihydroxy reactions.
• Silica gel from Millipore MATREX TM, 35-70 my
• Alox E. Merck, Darmstadt, alumina 90 standardized, 63-200 ⁇ m, article no .: 1.01097.9050
• chromatographic purifications is used for chromatographic purifications.
• HPLC data are measured using the parameters listed below: Analytical columns: Zorbax column (Agilent Technologies), SB (Stable 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, B and C)
• Preparative column Zorbax column (Agilent Technologies), SB (Stable 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).
• A1 c (3S, 4R) -1-benzyl-4-trifluoromethyl-piperidine-3,4-diol 43.80 g of AD mix beta are placed in 3 L of tert-butanol / water (1: 1) and 20 min at RT touched. The mixture is cooled to 0 ° C., 2.97 g (31.25 mmol) methanesulfonamide and 7.54 g (31.25 mmol) 1-benzyl-4-trifluoromethyl-1, 2,3,6-tetrahydro-pyridine are added, the cooling bath is removed and 8 d stirred at RT.
• a further 22 g of AD mix beta and 1.5 g of methanesulfonamide are added and the mixture is stirred again at RT for 7 d.
• 11.2 g of sodium sulfite are added and the mixture is stirred for 1 h.
• 200 mL semi-saturated NaHCO 3 solution are added and the aqueous phase is exhaustively extracted with DCM.
• the combined organic phases are dried over Na 2 SO 4 and i. vac. concentrated.
• the crude product is purified by means of MPLC-MS (Grom-Sil 120 ODS 4, 10 ⁇ m, gradient 0.15% formic acid in water / acetonitrile 90:10 ⁇ 10:90 in 10 minutes).
• the eluates are united, i. vac.
• the catalyst is filtered off and the filtrate i. vac. concentrated.
• the product is obtained analogously to A1d starting from (3R, 4S) -1-benzyl-4-trifluoromethyl-piperidine-3,4-diol.
• A3c (3R, 4S) -4-methyl-piperidine-3,4-diol The product is prepared analogously to A1d starting from 1.23 g (5.57 mmol) of (3R, 4S) -1-benzyl-4-methyl-piperidine-3,4 -diol received.
• A4b (3S, 4R) -4-methyl-piperidine-3,4-diol
• the product is prepared analogously to A1d starting from 4.68 g (21.14 mmol) (3S, 4R) -1-benzyl-4-methylpiperidin-3, Obtain 4-diol.
• the product is obtained analogously to A1a starting from 100 mL (933 mmol) of 4-ethylpyridine.
• A5d (3S, 4R) -4-ethyl-piperidine-3,4-diol The product can be obtained analogously to A1d starting from (3S, 4R) -1-benzyl-4-ethyl-piperidine-3,4-diol.
• the enantiomer (3R, 4S) -4-ethyl-piperidine-3,4-diol can be obtained analogously to the sequence described.
• the product is obtained analogously to A1d starting from 0. ⁇ 7 g (5.04 mmol) of cis-1-benzyl-pyrroüdin-3,4-diol.
• the product is obtained analogously to A3b starting from 3.15 g (16.83 mmol) of 1-benzyl-4-methylene-piperidine and AD-Mix-Alpha.
• A7b 4-hydroxymethyl-piperidin-4-ol The product is obtained analogously to A1d starting from 2.92 g (13.21 mmol) of 1-benzyl-4-hydroxymethyl-piperidin-4-ol.
• the diazonium salt formed is filtered off, washed with cold water, isopropanol and diethyl ether and i. In a desiccator. vac. dried. Petroleum ether (100-140 ° C) is heated to 90 ° C, the diazonium salt is added in portions and the mixture is stirred until no more gas evolution can be observed.
• the reaction mixture is cooled to RT, made alkaline with saturated Na 2 CO 3 solution and the aqueous phase extracted exhaustively with MTBE.
• the combined organic phases are washed with saturated Na 2 CO 3 solution and water, dried over gSO 4 and i. vac. concentrated. The residue is dissolved in DCM, filtered through silica gel and the filtrate i. vac. concentrated.
• the reaction mixture is stirred at RT for 3.5 h, then filtered and the filtrate i. vac. concentrated.
• the residue was dissolved in 1 L EtOAc, the organic phase washed with water and saturated NaCl solution, dried over Na 2 SO 4 and i. vac. concentrated.
• the crude product was used in the subsequent reaction step without further purification.
• Example 1.1d The product is prepared analogously to Example 1.1e starting from 6-iodo-2- (4-methyl-piperidin-1-ylmethyl) -1-benzopyran-4-one and 5- (4-chlorophenyl) -2-ethynyl- pyridine (Example 1.1d) obtained.
• 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
• test buffer 50 mM HEPES, 10 mM
• MgCl 2 2mM EGTA, pH 7.00; 0.1% bovine serum albumin (protease-free), 0.021% bacitracin,
• Nonspecific binding is defined as bound radioactivity in the presence of 1
• the KD value of the radioligand is 0.156 nM.
• Human test cells CHO / Galpha 16 cells stably transfected with hMCH-R1
• HBSS (10x) (GIBCO) HEPES Buffer (1M) (GIBCO) PIuronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) Specimen Oath (Sigma) MCH (Bachern) Bovine Serum Albumin (Serva) (Protease Free) DMSO (Serva) Ham'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 384-well microtiter plates (black-walled with transparent bottom, manufacturer: Costar) at a density of 2500 cells per cavity and in the medium described above at 37 ° C., 5% CO 2 and overnight 95% relative humidity cultivated.
• 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 with 0.07% probenicide is added, washed.
• 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 microtiter plate five minutes after the last washing step in the FLIPR 384 device (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.
• 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.
• 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 (EC 5 o (test substance + CH) / EC 50 (CH) -1) "l ⁇ g C estsubstanz)
• 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 the example - substance name No. 1.1 ((S) -1- ⁇ 6- [5- (4-chlorophenyl) pyridin-2-ylethinyll- 6 nM 1-benzopyran-2-ylmethyl ⁇ -pyrroüdin -2-yl) - methanol 2.1 6- [5- (4-chlorophenyl) pyridin-2-ylethynyl] -2- (4- 3 nM methylpiperidin-1-ylmethyl) -1-benzopyran-4- on
• active substance 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.
• Production method The active ingredient and excipients are dissolved in water and filled into a suitable container.
• Preparation Dissolve polysorbate 80, sodium chloride, monocaine dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Add human serum albumin; Dissolve the active ingredient while heating; fill up to batch volume with Wfl; fill in ampoules.
• Example H Lvophilisate with 10 mg of Active Substance Composition: Active substance 10 mg
• Dissolve mannitol in water for injections Wfl
• Add human serum albumin Dissolve the active ingredient while heating; fill up to volume with Wfl; fill in vials; freeze-dry.
• Polysorbate 80 Tween 80 20 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 into ampoules under nitrogen gas.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Neurology (AREA)
• Diabetes (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Hematology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Obesity (AREA)
• Urology & Nephrology (AREA)
• Endocrinology (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Pain & Pain Management (AREA)
• Vascular Medicine (AREA)
• Immunology (AREA)
• Ophthalmology & Optometry (AREA)
• Anesthesiology (AREA)
• Addiction (AREA)
• Emergency Medicine (AREA)
• Reproductive Health (AREA)
• Child & Adolescent Psychology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Rheumatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=34982288

Family Applications (1)

Country Status (5)

Families Citing this family (3)

Family Cites Families (2)

• 2004
  • 2004-04-14 DE DE102004017933A patent/DE102004017933A1/de not_active Withdrawn
• 2005
  • 2005-04-08 EP EP05729108A patent/EP1742939A2/de not_active Withdrawn
  • 2005-04-08 WO PCT/EP2005/003710 patent/WO2005100285A2/de not_active Application Discontinuation
  • 2005-04-08 JP JP2007507719A patent/JP2007532599A/ja active Pending
  • 2005-04-08 CA CA002559698A patent/CA2559698A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events