DE10360745A1 - New amide compounds having MCH antagonist activity and medicaments containing these compounds - Google Patents

Abstract

The present invention relates to amide compounds of general formula I, DOLLAR F1 in which the groups and radicals A, B, b, W, X, Y, Z, R · 1 ·, R · 2 · and R · 3 · in Claim 1 have specified meanings. Furthermore, the invention relates to medicaments containing at least one amide according to the invention. Due to the MCH receptor antagonistic activity, the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and / or eating disorders, in particular of obesity, bulimia, anorexia, hyperphagia and diabetes.

Description

object The present invention relates to novel amide compounds whose physiological acceptable Salts and their use as MCH antagonists and their use for the preparation of a medicament which is used for prophylaxis and / or Treatment of phenomena and / or diseases caused by MCH caused or with MCH in another causal relationship stand, is suitable. Another object of this invention relates the use of a compound according to the invention for influencing the eating behavior and to reduce body weight and / or to prevent an increase in body weight of a mammal. Further, compositions and drugs are each containing a compound of the invention, and process for their preparation subject of this invention.

Background of the invention

The Ingestion of food and its implementation in the body plays for all living beings an existential role in life. Therefore, deviations in the recording result and implementation of food usually causes disorders and even diseases. The change human and food habits, especially in industrialized countries, has favored obesity in recent decades. Obesity leads to the Affected directly to a restriction of mobility and a Reduction of the quality of life. aggravating In addition, obesity often results in other diseases, such as diabetes, dyslipidaemia, hypertension, arteriosclerosis and coronary heart disease. In addition, that alone leads high body weight to a reinforced Load on the support and musculoskeletal system, causing chronic discomfort and disease, like arthritis or osteoarthritis. Thus, Obesitas a serious health problem for society.

Of the Obesity means a surplus on obese Tissue. In this context, obesity is basically as any heightened To see degrees of obesity, leading to a health risk leads. A distinction between normal and obesity individuals is ultimately not exactly possible however, the health risk associated with obesity increases probably continuously with increasing adiposity. Out establish The simplification will be in the context of the present invention preferably the individuals with a body weight index (BMI = Body mass index), which is the body weight measured in kilograms divided by height (in meters) is defined in the square, above the value 25, in particular above 30, considered suffering from obesity.

apart of physical activity and diet change There is currently no convincing treatment option to effectively reduce body weight. However, obesity is a high risk factor in the development of seriousness even life-threatening illnesses, it is even more important Pharmaceutical agents for the prophylaxis and / or treatment of To provide obesity. A recently proposed Approach is the therapeutic use of MCH antagonists (i.a. WO 01/21577, WO 01/82925).

Melanin-concentrating Hormone (melanin-concentrating hormone, MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is in mammals synthesized mainly in the hypothalamus and reaches from there more Brain regions over the projections of hypothalamic neurons. Its biological activity is in the People over two different G protein-coupled receptors (GPCRs) out the family of rhodopsin-related GPCRs mediates the MCH receptors 1 and 2 (MCH-1R, MCH-2R).

investigations The role of MCH in animal models provides good clues for one Role of the peptide in the regulation of the energy balance, i. change metabolic activity and feed intake [1, 2]. For example, after intraventricular administration of MCH in rats feed intake compared to control animals increased. In addition, transgenic rats that produce more MCHs react as control animals, after giving a high fat diet with one greater weight gain than animals with non-experimental modified MCH levels. Also could be found that a positive Correlation between periods of increased craving for food and the amount of MCH mRNA in the hypothalamus of rats. From particular significance regarding However, the function of MCH are experiments with MCH knock out mice. One Loss of the neuropeptide leads to lean animals with reduced fat, which is significantly less Take food as control animals.

The anorectic effects of MCH are mediated by the G _αs -coupled MCH-1R in rodents [3-6]. In contrast to primates, ferrets and dogs, no other receptor has been detected in rodents so far. After losing the MCH-1R, knock-out mice have less fat mass, increased energy expenditure and, on a high fat diet, no weight gain compared to control animals. Another indication of the importance of the MCH-MCH-1R system in the regulation of the energy balance comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term experiments, the animals treated with the antagonist lose significant weight.

Next its anorectic effect will be with the MCH-1R antagonist SNAP-7941 even more anxiolytic and antidepressant effects in behavioral experiments achieved with rats [3]. There are clear indications that the MCH-MCH-1R system involved not only in the regulation of the energy balance but also in the affectivity is.

Literature:

• 1. Qu, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature, 1996. 380 (6571): p. 243-7.
• 2. Shimada, M., et al., Mice Lacking melanin-concentrating hormones are hypophagic and lean. Nature, 1998. 396 (6712): p. 670-4.
• 3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a melaninconcentrating hormone-1 receptor antagonist. Nat Med, 2002. 8 (8): p. 825-30.
• 4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002. 143 (7): p. 2469-77.
• 5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99 (5): p. 3240-5.
• 6. Takekawa, S., et al., T-226296: a novel, orally active and selective melaninconcentrating hormone receptor antagonist. EUR J Pharmacol, 2002. 438 (3): p. 129-35.

in der Ar¹ eine cyclische Gruppe, X einen Spacer, Y eine Bindung oder einen Spacer, Ar einen aromatischen Ring, der mit einem nicht-aromatischen Ring kondensiert sein kann, R¹ und R² unabhängig voneinander H oder eine Kohlenwasserstoff-Gruppe bedeuten, wobei R¹ und R² zusammen mit dem angrenzenden N-Atom einen N-haltigen Heteroring bilden können und R² mit Ar auch einen spirocyclischen Ring bilden kann, R zusammen mit dem angrenzenden N-Atom und Y einen N-haltigen Heteroring bilden kann, als MCH-Antagonisten zur Behandlung von u.a. Obesitas beschrieben.In the patent literature, certain amine compounds are suggested as MCH antagonists. Thus, in WO 01/21577 (Takeda) compounds of the formula

in Ar ¹ a cyclic group, X a spacer, Y a bond or a spacer, Ar an aromatic ring which may be condensed with a non-aromatic ring, R ¹ and R ² independently of one another denote H or a hydrocarbon group, wherein R ¹ and R ² together with the adjacent N atom can form an N-containing hetero ring and R ² with Ar can also form a spirocyclic ring, R 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.

in der Ar¹ eine cyclische Gruppe, X und Y Spacer-Gruppen, Ar einen gegebenenfalls substituierten kondensierten polycyclischen aromatischen Ring, R¹ und R² unabhängig voneinander H oder eine Kohlenwasserstoff-Gruppe bedeuten, wobei R¹ und R² zusammen mit dem angrenzenden N-Atom einen N-haltigen heterocyclischen Ring bilden können und R² zusammen mit dem angrenzenden N-Atom und Y einen N-haltigen Heteroring bilden kann, als MCH-Antagonisten zur Behandlung von u.a. Obesitas beschrieben.Furthermore, in WO 01/82925 (Takeda) also compounds of the formula

in which Ar ^{1 is} a cyclic group, X and Y spacer groups, Ar is an optionally substituted condensed polycyclic aromatic ring, R ¹ and R ^{2 are} independently H or a hydrocarbon group, wherein R ¹ and R ² together with the adjacent N Atom can form an N-containing heterocyclic ring and R ² together with the adjacent N-atom and Y can form an N-containing hetero ring, described as MCH antagonists for the treatment of, inter alia, obesity.

In the EP 0 237 678 A1 Indole derivatives for the treatment of migraine are described. In Example 4, the compound is called N- [4 - [[(methylamino) sulphonyl] methyl] phenyl] -3- [2- (dimethylamino) ethyl] -1H-indole-5-propanamide oxalate.

In the JP 2000086603 For example, propenamide derivatives having a 2-hydroxypropoxy group are described as being used as 5-HT 1A receptor antagonists.

In WO 99/29674 discloses N-imidazolyl and N-triazolylalkyl-phenyl-acetamide derivatives as inhibitors of retinoid metabolism. The substance N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] -3-phenyl-2-propynamide is referred to as compound number 198.

J. Krapcho et al. in J. Med. Chem. (1969), 12 (1), 164-6 the title "Immunosuppressive activity of 2 '- (3-dimethylaminopropylthio) cinnamanilide (cinanserin) and realted compounds "inter alia the compound 2 '- [[3- (dimethylamino) propyl] thio] -3-phenylpropiolanilide.

In WO 2001002344 discloses aminobenzoic acid derivatives as VEGF receptor Described among other antagonists and the compound 2- (methylthio) -5 - [[3- [4- (octadecylamino) phenyl] -1-oxopropyl] amino] benzoic acid.

In the JP 04054118 4- (acylamino) phenols are proposed as 5-lipoxygenase inhibitors and include the compounds 4-amino-N- (4-hydroxy-3,5-dimethylphenyl) -benzolpropanamid and 4- (dimethylamino) -N- (4-hydroxy Called -3,5-dimethylphenyl) -benzolpropanamid.

The Preparation of [[(Benzoxyzolylalkanoyl) amino] phenyl] alkanoates and their suitability as integrin receptor ligands are described in WO 2000049005 described. It is u.a. the compound β-methyl-4 - [[3- [2 - [(2-methylphenyl) amino] -6-benzoxazolyl] -1-oxopropylamino] -benzenepropanoic acid.

In WO 2000005223 are benzoxazole derivatives as inhibitors of Interaction between VCAM-1 and / or fibronectin and the integrin Receptor VLA-4 described. It is u.a. the compound 4- [3 - [[1-oxo-3- [2- (phenylamino) -6-benzoxazolyl] propyl] amino] phenoxy] butanoic acid.

The Preparation of carboxylic acid derivatives as EDG-1 receptor agonists are described in WO 2002092068. There are u.a. 2-chloro-5 - [[1-oxo-3- [4 - [(5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid and called the corresponding methyl ester.

Of the present invention is based on the object, new amide compounds especially those that have activity as MCH antagonists have.

Also It is an object of this invention to provide novel amide compounds to make that allow eating behavior of mammals to influence and in particular in mammals a reduction of body weight to achieve and / or prevent an increase in body weight.

Further It is an object of the present invention to provide new medicines to provide, which for the prophylaxis and / or treatment of Appearances and / or diseases caused by MCH or are in a different causal relationship with MCH are. In particular, this invention is based on the object Medicines for the treatment of metabolic disorders, such as obesity and / or Diabetes as well as diseases associated with obesity and diabetes and / or disorders, to disposal to deliver. Other objects of the present invention relate to show advantageous uses of the compounds of the invention. It is also an object of this invention to provide a method for Preparation of the amide compounds of the invention ready to deliver. Further objects of the present invention result for the skilled person directly from the preceding and following Versions.

Subject of the invention

in der
R¹, R² unabhängig voneinander H, eine gegebenenfalls mit dem Rest R¹¹ substituierte C_1-8-Alkyl- oder C_3-7-Cycloalkyl-Gruppe, wobei eine -CH₂-Gruppe in Position 3 oder 4 einer 5, 6 oder 7-gliedrigen Cycloalkylgruppe durch -O-, -S-, -NH-, -N(C_1-4-Alkyl)- oder -N(CO-O-C_1-4-Alkyl)- ersetzt sein kann, oder ein gegebenenfalls mit dem Rest R¹² ein- oder mehrfach und/oder mit Nitro einfach substituierter Phenyl- oder Pyridinylrest, oder
R¹ und R² bilden eine C_2-8-Alkylen-Brücke, in der

• – ein oder zwei -CH₂-Gruppen unabhängig voneinander durch -CH=N- oder -CH=CH- ersetzt sein können und/oder
• – ein oder zwei -CH₂-Gruppen unabhängig voneinander durch -O-, -S-, -SO-, -(SO₂)-, -C=N-O-R¹⁸, -CO-, -C(=CH₂)- oder -NR¹³- derart ersetzt sein können, dass Heteroatome nicht unmittelbar miteinander verbunden sind, und dass eine Gruppe -C=N-O-R¹⁸ oder -CO- nicht unmittelbar mit der Gruppe R¹R²N- verbunden ist,

wobei in der zuvor definierten Alkylen-Brücke ein oder mehrere H-Atome durch R¹⁴ ersetzt sein können, und
wobei die zuvor definierte Alkylen-Brücke mit einer oder zwei gleichen oder verschiedenen carbo- oder heterocyclischen Gruppen Cy derart substituiert sein kann, dass die Bindung zwischen der Alkylenbrücke und der Gruppe Cy

• – über eine Einfach- oder Doppelbindung,
• – über ein gemeinsames C-Atom unter Ausbildung eines spirocyclischen Ringsystems,
• – über zwei gemeinsame, benachbarte C- und/oder N-Atome unter Ausbildung eines kondensierten bicyclischen Ringsystems oder
• – über drei oder mehrere C- und/oder N-Atome unter Ausbildung eines verbrückten Ringsystems erfolgt,

R³ H, C_1-6-Alkyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-4-Alkyl- oder Phenyl-C₁_₃-alkyl,
X eine Einfachbindung oder eine C_1-8-Alkylen-Brücke, in der

• – eine -CH₂-Gruppe, die nicht mit der Gruppe R¹R²N- unmittelbar verbunden ist, durch -CH=CH- oder -C≡C- ersetzt sein kann und/oder
• – ein oder zwei nicht benachbarte -CH₂-Gruppen, die nicht mit der Gruppe R¹R²N- unmittelbar verbunden sind, unabhängig voneinander durch -O-, -S-, -(SO)-, -(SO₂)-, -CO- oder -NR⁴- derart ersetzt sein können, dass jeweils zwei O-, S- oder N-Atome oder ein O- mit einem S-Atom nicht unmittelbar miteinander verbunden sind,

wobei die Brücke X mit R¹ unter Einschluss des mit R¹ und X verbundenen N-Atoms unter Ausbildung einer heterocyclischen Gruppe verbunden sein kann, wobei die Brücke X zusätzlich auch mit R² unter Einschluss des mit R² und X verbundenen N-Atoms unter Ausbildung einer heterocyclischen Gruppe verbunden sein kann, und
wobei zwei C-Atome oder ein C- und ein N-Atom der Alkylenbrücke durch eine zusätzliche C_1-4-Alkylen-Brücke miteinander verbunden sein können, und
wobei ein C-Atom mit R¹⁰ und/oder ein oder zwei C-Atome jeweils mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus C_1-6-Alkyl-, C_2-6-Alkenyl-, C_2-6-Alkinyl-, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl-, C_4-7-Cycloalkenyl und C_4-7-Cycloalkenyl-C_1-3-alkylsubstituiert sein können, wobei zwei Alkyl- und/oder Alkenyl-Substituenten unter Ausbildung eines carbocyclischen Ringsystems miteinander verbunden sein können, und
W bedeutet eine Einfachbindung, wobei
Z -C=C-C(=O)-, -CR^7a=CR^7c-C(=O)- oder -CR^7aR^7b-CR^7cR^7d-C(=O)- bedeutet, oder
W bedeutet -C(=O)-C=C-, wobei
Z eine Einfachbindung bedeutet; und
Y eine der für Cy angegebenen Bedeutungen,
wobei R¹ mit Y unter Einschluss der Gruppe X und des mit R¹ und X verbundenen N-Atoms unter Ausbildung einer an Y kondensierten heterocyclischen Gruppe verbunden sein kann, und/oder
wobei X mit Y unter Ausbildung einer an Y kondensierten carbo- oder heterocyclischen Gruppe verbunden sein kann, und
A eine der für Cy angegebenen Bedeutungen, wobei für den Fall, dass der Index b den Wert 0 besitzt, die Gruppe Cy keine Amino-Gruppe als Substituenten in ortho-Stellung zur Brücke W aufweist;
B eine der für Cy angegebenen Bedeutungen,
b den Wert 0 oder 1,
Cy eine carbo- oder heterocyclische Gruppe ausgewählt aus einer der folgenden Bedeutungen

• – eine gesättigte 3- bis 7-gliedrige carbocyclische Gruppe, eine ungesättigte 4- bis 7-gliedrige carbocyclische Gruppe,
• – eine Phenyl-Gruppe,
• – eine gesättigte 4- bis 7-gliedrige oder ungesättigte 5- bis 7-gliedrige heterocyclische Gruppe mit einem N-, O- oder S-Atom als Heteroatom, eine gesättigte oder ungesättigte 5- bis 7-gliedrige heterocyclische Gruppe mit zwei oder mehreren N-Atomen oder mit einem oder zwei N-Atomen und einem O- oder S-Atom als Heteroatome,
• – eine aromatische heterocyclische 5- oder 6-gliedrige Gruppe mit einem oder mehreren gleichen oder verschiedenen Heteroatomen ausgewählt aus N, O und/oder S,

wobei die zuvor angeführten 4-, 5-, 6- oder 7-gliedrigen Gruppen über zwei gemeinsame, benachbarte C-Atome mit einem Phenyl- oder Pyridin-Ring kondensiert sein können, und
wobei in den zuvor genannten 5-, 6- oder 7-gliedrigen Gruppen eine oder zwei nicht benachbarte -CH₂-Gruppen unabhängig voneinander durch eine -CO-, -C(=CH₂)-, -(SO)- oder -(SO₂)-Gruppe ersetzt sein können, und
wobei die zuvor angeführten gesättigten 6- oder 7-gliedrigen Gruppen auch als verbrückte Ringsysteme mit einer Imino-, N-(C_1-4-alkyl)-imino-, Methylen-, C_1-4-Alkyl-methylen- oder Di-(C_1-4-alkyl)-methylen-Brücke vorliegen können, und
wobei die zuvor genannten cyclischen Gruppen ein- oder mehrfach an ein oder mehreren C-Atomen mit R²⁰, im Falle einer Phenylgruppe auch zusätzlich einfach mit Nitro, und/oder ein oder mehrere NH-Gruppen mit
R²¹ substituiert sein können,
R⁴ eine der für R¹⁷ angegebenen Bedeutungen, C_2-6-Alkenyl oder C_3-6-Alkinyl,
R^7a, R^7c H, F, Cl, C_1-4-Alkyi oder CF₃,
R^7b, R^7d H, F, C_1-4-Alkyl, wobei R^7b und R^7d in der Bedeutung Alkyl unter Ausbildung einer Cyclopropylgruppe miteinander verbunden sein können;
R¹⁰ Hydroxy, ω-Hydroxy-C_1-3-alkyl, C_1-4-Alkoxy, ω-(C_1-4-Alkoxy)-C_1-3-alkyl-, Carboxy, C_1-4-Alkoxycarbonyl-, Amino, C_1-4-Alkyl-amino-, Di-(C_1-4-alkyl)-amino, Cyclo-C_3-6-alkylenimino-, Amino-C_1-3-alkyl-, C_1-4-Alkyl-amino-C_1-3-alkyl-, Di-(C_1-4-alkyl)-amino-C_1-3-alkyl-, Cyclo-C_3-6-alkylenimino-C_1-3-alkyl-, Amino-C_1-3-alkoxy-, C_1-4-Alkyl-amino-C_1-3-alkoxy-, Di-(C_1-4-alkyl)-amino-C_1-3-alkoxy- oder Cyclo-C_3-6-alkylenimino-C_1-3-alkoxy-, Aminocarbonyl-, C_1-4-Alkyl-aminocarbonyl-, Di-(C_1-4-alkyl)-aminocarbonyl- oder Cyclo-C_3-6-alkylenimino-carbonyl-,
R¹¹ C_2-6-Alkenyl, C_2-6-Alkinyl, R¹⁵-O-, R¹⁵-O-CO-, R¹⁵-CO-O-, R¹⁶R¹⁷N-, Cyano, R¹⁸R¹⁹N-CO- oder Cy-,
R¹² eine der für R²⁰ angegebenen Bedeutungen,
R¹³ eine der für R¹⁷ angegebenen Bedeutungen, ausgenommen Carboxy,
R¹⁴ Halogen, C_1-6-Alkyl, C_2-6-Alkenyl, C_2-6-Alkinyl, R¹⁵-O-, R¹⁵-O-CO-, R¹⁵-CO-, R¹⁵-CO-O-, R¹⁶R¹⁷N-, R¹⁸R¹⁹N-CO-, R¹⁵-O-C_1-3-alkyl- , R¹⁵-O-CO-C_1-3-alkyl-, R¹⁵-O-CO-NH-, R¹⁵-SO₂-NH-, R¹⁵-CO-C_1-3-alkyl-, R¹⁵-CO-O-C_1-3-alkyl-, R¹⁶R¹⁷N-C_1-3-alkyl-, R¹⁸R¹⁹N-CO-C_1-3-alkyl- oder Cy-C_1-3-alkyl-,
R¹⁵ H, C_1-4-Alkyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl-, Phenyl, Phenyl-C_1-3-alkyl-, Pyridinyl oder Pyridinyl-C_1-3-alkyl-,
R¹⁶ H, C_1-6-Alkyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl-, C_4-7-Cycloalkenyl, C_4-7-Cycloalkenyl-C_1-3-alkyl-, ω-Hydroxy-C_2-3-alkyl, ω-(C_1-4 -Alkoxy)-C_2-3-alkyl, Amino-C_2-6-alkyl-, C_1-4-Alkyl-Amino-C_2-6-alkyl-, Di-(C_1-4 -alkyl)-Amino-C_2-6-alkyl- oder Cyclo-C_3-6-alkylenimino-C_2-6-alkyl-,
R¹⁷ eine der für R¹⁶ angegebenen Bedeutungen oder Phenyl, Phenyl-C_1-3-alkyl, Pyridinyl, Dioxolan-2-yl, -CHO, C_1-4 -Alkylcarbonyl, Carboxy, Hydroxycarbonyl-C_1-3-alkyl-, C_1-4-Alkoxycarbonyl-, C_1-4-Alkoxycarbonyl-C_1-3-alkyl-, C_{1- 4}-Alkylcarbonylamino-C_2-3-alkyl-, N-(C_1-4-Alkylcarbonyl)-N-(C_1-4-Alkyl)-amino-C_2-3-alkyl-, C_1-4-Alkylsulfonyl, C_1-4-Alkylsulfonylamino-C_2-3-alkyl- oder N-(C_1-4-Alkylsulfonyl)-N(C_1-4-Alkyl)-amino-C_2-3-alkyl-
R¹⁸, R¹⁹ unabhängig voneinander H oder C_1-6-Alkyl,
R²⁰ Halogen, Hydroxy, Cyano, C_1-6-Alkyl, C_2-6-Alkenyl, C_2-6-Alkinyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl-, Hydroxy-C_1-4-alkyl, R²²-C_1-3-alkyloder eine der für R²² angegebenen Bedeutungen,
R²¹ C_1-4-Alkyl, ω-Hydroxy-C_2-3-alkyl, ω-C_1-4-Alkoxy-C_2-6-alkyl, ω-C_1-4-Alkylamino-C_2-6-alkyl-, ω-Di-(C_1-4-alkyl)-amino-C_2-6-alkyl-, ω-Cyclo-C_3-6-alkylenimino-C_2-6-alkyl-, Phenyl-C_1-3-alkyl-, C_1-4-Alkyl-carbonyl, C_1-4-Alkoxy-carbonyl oder C_1-4-Alkylsulfonyl,
R²² Phenyl-C_1-3-alkoxy, Cyclo-C_3-6-alkylenimino-C_2-4-alkoxy-, OHC-, HO-N=HC-, C_1-4-Alkoxy-N=HC-, C_1-4-Alkoxy, C_1-4-Alkylthio, Carboxy, C_1-4-Alkylcarbonyl, C_1-4-Alkoxycarbonyl, Aminocarbonyl, C_1-4-Alkylaminocarbonyl, Di-(C_1-4-alkyl)-aminocarbonyl, Cyclo-C_3-6-alkyl-amino-carbonyl-, Cyclo-C_3-6-alkylenimino-carbonyl, Cyclo-C_3-6-alkylenimino-C_2-4-alkyl-aminocarbonyl, Phenyl-amino-carbonyl, C_1-4-Alkyl-sulfonyl, C_1-4-Alkylsulfinyl, C_1-4-Alkyl-sulfonylamino-, Amino-, C_1-4-alkylamino-, Di-(C_1-4-alkyl)-amino-, C_1-4-Alkyl-carbonyl-amino-, Cyclo-C_3-6-alkylenimino-, Phenyl-C_1-3-alkylamino-, N-(C_1-4-Alkyl)-phenyl-C_1-3-alkylamino-, Acetylamino-, Propionylamino-, Phenylcarbonylamino, Phenylcarbonylmethylamino, Hydroxyalkylaminocarbonyl, (4-Morpholinyl)carbonyl, (1-Pyrrolidinyl)-carbonyl, (1-Piperidinyl)carbonyl, (Hexahydro-1-azepinyl)carbonyl, (4-Methyl-1-piperazinyl)carbonyl, Methylendioxy, Aminocarbonylamino- oder Alkylaminocarbonylamino-,
wobei in den zuvor genannten Gruppen und Resten, insbesondere in insbesondere A, B, W, X, Y, Z, R¹ bis R⁴, R^7a, R^7b, R^7c, R^7d, R¹⁰ bis R²², jeweils ein oder mehrere C-Atome zusätzlich ein- oder mehrfach mit F und/oder jeweils ein oder zwei C-Atome unabhängig voneinander zusätzlich einfach mit Cl oder Br und/oder jeweils ein oder mehrere Phenyl-Ringe unabhängig voneinander zusätzlich ein, zwei oder drei Substituenten ausgewählt aus der Gruppe F, Cl, Br, I, C_1-4-Alkyl, C_1-4-Alkoxy-, Difluormethyl-, Trifluormethyl-, Hydroxy-, Amino-, C_1-3-alkylamino-, Di-(C_1-3-alkyl)-amino-, Acetylamino-, Aminocarbonyl-, Cyano, Difluormethoxy-, Trifluormethoxy-, Amino-C_1-3-alkyl-, C_1-3-Alkylamino-C_1-3-alkyl- und Di-(C_1-3-Alkyl)-amino-C_1-3-alkylaufweisen und/oder einfach mit Nitro substituiert sein können, und
das H-Atom einer vorhandenen Carboxygruppe oder ein an ein N-Atom gebundenes H-Atom jeweils durch einen in-vivo abspaltbaren Rest ersetzt sein kann, bedeuten,
deren Tautomere, deren Diastereomere, deren Enantiomere, deren Gemische und deren Salze,
wobei folgende Verbindungen gemäß der Maßgaben (M1) bis (M14) nicht umfasst sind:

• (M1) N-[4-[[(Methylamino)sulphonyl]methyl]phenyl]-3-[2-(dimethylamino)-ethyl]-1-H-indole-5-propanamid oxalat,
• (M2) 3-[2-[3-[3,6-dihydro-4-(2-naphthyl)-1(2H)-pyridinyl]-2-hydroxypropoxy]phenyl)-N-methyl-N-phenyl-2-propenamid,
• (M3) 3-[2-[2-hydroxy-3-[4-(1-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-N-phenyl-2-propenamid,
• (M4) 3-[2-[2-hydroxy-3-[4-(2-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-N-phenyl-2-propenamid,
• (M5) 3-[2-[2-hydroxy-3-[4-(2-naphthalyl)-1-piperidinyl]propoxy]phenyl]-N-phenyl-2-propenamid,
• (M6) N-(4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-3-phenyl-2-propinamid,
• (M7) 2'-[[3-(dimethylamino)propyl]thio]-3-phenyl-propiolanilid,
• (M8) 2-(Methylthio)-5-[[3-[4-(octadecylamino)phenyl]-1-oxopropyl]amino]-benzoesäure, einschließlich dem Trifluoracetatsalz,
• (M9) 4-Amino-N-(4-hydroxy-3,5-dimethylphenyl)-benzolpropanamid,
• (M10) 4-(dimethylamino)-N-(4-hydroxy-3,5-dimethylphenyl)-benzolpropanamid,
• (M11) β-methyl-4-[[3-[2-[(2-methylphenyl)amino]-6-benzoxazolyl]-1-oxopropylamino]-benzolpropansäure,
• (M12) 4-[3-[[1-Oxo-3-[2-(phenylamino)-6-benzoxazolyl]-propyl]amino]phenoxy]-butansäure,
• (M13) 2-Chlor-5-[[1-oxo-3-[4-[(5-phenylpentyl)amino]phenyl]propyl]amino]-benzoesäure,
• (M14) 2-Chlor-5-[[1-oxo-3-[4-[(5-phenylpentyl)amino]phenyl]propyl]amino]-benzoesäuremethylester.

A first subject of the present invention are amide compounds of the general formula I amide compounds of the general formula I.

in the
R ¹ , R ² independently of one another H, an optionally substituted by the radical R ¹¹ C _1-8 alkyl or C _3-7 -Cy cloalkyl group, wherein a -CH ₂ group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group by -O-, -S-, -NH-, -N (C _1-4 alkyl) - or -N (CO-OC _1-4 alkyl) - may be replaced, or one optionally substituted by the radical R ¹² mono- or polysubstituted and polysubstituted and / or nitro single substituted phenyl or pyridinyl radical, or
R ¹ and R ² form a C _2-8 alkylene bridge in which

• - One or two -CH ₂ groups can be independently replaced by -CH = N- or -CH = CH- and / or
• - one or two -CH ₂ groups independently of one another by -O-, -S-, -SO-, - (SO ₂ ) -, -C = NOR ¹⁸ , -CO-, -C (= CH ₂ ) - or -NR ¹³ - may be replaced such that heteroatoms are not directly connected to each other, and that a group -C = NOR ¹⁸ or -CO- is not directly connected to the group R ¹ R ² N-,

wherein in the above-defined alkylene bridge, one or more H atoms may be replaced by R ¹⁴ , and
wherein the previously defined alkylene bridge may be substituted with one or two identical or different carbo- or heterocyclic groups Cy such that the bond between the alkylene bridge and the group Cy

• - via a single or double bond,
• Via a common C atom with formation of a spirocyclic ring system,
• Via two common, adjacent C and / or N atoms to form a fused bicyclic ring system or
• - takes place via three or more C and / or N atoms to form a bridged ring system,

R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-4 alkyl or phenyl-C ₁ _ ₃ alkyl,
X is a single bond or a C _1-8 alkylene bridge in which

• - a -CH ₂ group which is not directly connected to the group R ¹ R ² N-, may be replaced by -CH = CH- or -C≡C- and / or
• One or two non-adjacent -CH ₂ - groups which are not directly connected to the group R ¹ R ² N-, independently of one another by -O-, -S-, - (SO) -, - (SO ₂ ) - , -CO- or -NR ⁴ - can be replaced such that in each case two O, S or N atoms or an O with an S atom are not directly connected to one another,

wherein the bridge X may be connected to R ¹ , including the N atom connected to R ¹ and X to form a heterocyclic group, wherein the bridge X additionally with R ² , including the R ² and X connected to N atom under Formation of a heterocyclic group may be linked, and
wherein two C atoms or one C and one N atom of the alkylene bridge may be linked together by an additional C _1-4 alkylene bridge, and
wherein one C atom with R ¹⁰ and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl -, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _4-7 -cycloalkenyl and C _4-7 -cycloalkenyl-C _1-3 -alkyl may be substituted, wherein two alkyl - and / or alkenyl substituents may be joined together to form a carbocyclic ring system, and
W means a single bond, where
Z is -C = CC (= O) -, -CR ^7a = CR ^7c -C (= O) - or -CR ^7a R ^7b -CR ^7c R ^7d -C (= O) -, or
W is -C (= O) -C = C-, where
Z means a single bond; and
Y is one of the meanings given for Cy,
wherein R ^{1 may be} joined to Y including the group X and the N atom joined to R ¹ and X to form a heterocyclic group fused to Y, and / or
wherein X may be linked to Y to form a carbamoyl or heterocyclic group fused to Y, and
A is one of the meanings given for Cy, in which case the index b has the value 0, the group Cy has no amino group as substituent in the ortho position to the bridge W;
B is one of the meanings given for Cy,
b is 0 or 1,
Cy is 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-membered or unsaturated 5- to 7-membered heterocyclic group having an N, O or S atom as a heteroatom, a saturated or unsaturated 5- to 7-membered heterocyclic A 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,

wherein the above-mentioned 4-, 5-, 6- or 7-membered groups may be fused via two common, adjacent carbon atoms with a phenyl or pyridine ring, and
where in the abovementioned 5, 6 or 7-membered groups one or two nonadjacent -CH ₂ groups are independently of one another denoted by -CO-, -C (CHCH ₂ ) -, - (SO) - or - ( SO ₂ ) group can be replaced, and
the above-mentioned saturated 6- or 7-membered groups also being bridged ring systems with an imino, N- (C _1-4 -alkyl) -imino-, methylene-, C _1-4 -alkylmethylene- or di-, (C _1-4 alkyl) methylene bridge, and
wherein the aforementioned cyclic groups one or more times to one or more C atoms with R ²⁰ , in the case of a phenyl group also additionally simply with nitro, and / or one or more NH groups with
R ²¹ can be substituted,
R ^{4 is} one of the meanings given for R ¹⁷ , C _2-6 -alkenyl or C _3-6 -alkynyl,
R ^7a , R ^7c, H, F, Cl, C _1-4 alkyl or CF ₃ ,
R ^7b , R ^7d H, F, C _1-4 alkyl, wherein R ^7b and R ^7d may be linked together in the meaning of alkyl to form a cyclopropyl group;
R ^{10 is} hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, ω- (C _1-4 -alkoxy) C _1-3 -alkyl, carboxy, C _1-4 -alkoxycarbonyl- , Amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cycloC _3-6 alkyleneimino, amino C _1-3 alkyl, C _1-4 -Alkyl-amino-C _1-3 -alkyl, di- (C _1-4 -alkyl) -amino-C _1-3 -alkyl, cyclo-C _3-6 -alkyleneimino-C _1-3 -alkyl- , Amino C _1-3 alkoxy, C _1-4 alkylamino C _1-3 alkoxy, di (C _1-4 alkyl) amino C _1-3 alkoxy or cyclo C _3-6 alkyleneiminoC _1-3 alkoxy, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-4 alkyl) aminocarbonyl or cycloC _3-6 alkyleneimino-carbonyl,
R ^{11 is} C _2-6 alkenyl, C _2-6 alkynyl, R ^{15 is} -O-, R ^{15 is} -O-CO-, R ^{15 is} -CO-O-, R ^{16 is} R ¹⁷ N-, cyano, R ¹⁸ R ¹⁹ N-CO or cy,
R ^{12 is} one of the meanings given for R ²⁰ ,
R ^{13 is} one of the meanings given for R ¹⁷ , with the exception of carboxy,
R ^{14 is} halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁵ -CO-, R ¹⁵ -CO- O-, R ¹⁶ R ¹⁷ N-, R ¹⁸ R ¹⁹ N-CO-, R ¹⁵ -O-C _1-3 alkyl, R ¹⁵ -O-CO-C _1-3 alkyl, R ¹⁵ -O- CO-NH-, R ¹⁵ -SO ₂ -NH-, R ¹⁵ -CO-C _1-3 -alkyl, R ¹⁵ -CO-OC _1-3 -alkyl, R ¹⁶ R ¹⁷ NC _1-3 -alkyl R ¹⁸ R ^{19 is} N-CO-C _1-3 -alkyl or Cy-C _1-3 -alkyl-,
R ^{15 is} H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, phenyl, phenyl-C _1-3 -alkyl, pyridinyl or pyridinyl-C _1-3 alkyl,
R ^{16 is} H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _4-7 -cycloalkenyl, C _4-7 -cycloalkenyl-C _{1- 3} -alkyl, ω-hydroxy-C _2-3 -alkyl, ω- (C _1-4 -alkoxy) C _2-3 -alkyl, amino-C _2-6 -alkyl, C _1-4 -alkyl Amino C _2-6 alkyl, di (C _1-4 alkyl) amino C _2-6 alkyl or cyclo C _3-6 alkyleneimino C _2-6 alkyl,
R ^{17 is} one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl, pyridinyl, dioxolan-2-yl, -CHO, C _1-4 -alkylcarbonyl, carboxy, hydroxycarbonyl-C _1-3 -alkyl- , C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonyl-C _1-3 alkyl, C _{1- 4} alkylcarbonylamino-C _2-3 -alkyl, N- (C _1-4 alkylcarbonyl) - N- (C _1-4 alkyl) amino C _2-3 alkyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfonylamino C _2-3 alkyl or N- (C _1-4 Alkylsulfonyl) -N (C _1-4 alkyl) amino C _2-3 alkyl
R ¹⁸ , R ¹⁹ independently of one another are H or C _1-6 -alkyl,
R ^{20 is} halogen, hydroxy, cyano, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl- , HydroxyC _1-4 alkyl, R ²² -C _1-3 alkyl or one of the meanings given for R ²² ,
R ^{21 is} C _1-4 -alkyl, ω-hydroxy-C _2-3 -alkyl, ω-C _1-4 -alkoxy-C _2-6 -alkyl, ω-C _1-4 -alkylamino-C _2-6 - alkyl, ω-di (C _1-4 alkyl) amino C _2-6 alkyl, ω-cyclo C _3-6 alkyleneimino-C _2-6 alkyl, phenyl C _{1- 3-} alkyl, C _1-4 -alkylcarbonyl, C _1-4 -alkoxycarbonyl or C _1-4 -alkylsulfonyl,
R ^{22 is} phenyl-C _1-3 -alkoxy, cyclo-C _3-6 -alkyleneimino-C _2-4 -alkoxy, OHC-, HO-N = HC-, C _1-4 -alkoxy-N = HC-, C _1-4 -alkoxy, C _1-4 -alkylthio, carboxy, C _1-4 -alkylcarbonyl, C _1-4 -alkoxycarbonyl, aminocarbonyl, C _1-4 -alkylaminocarbonyl, di (C _1-4 -alkyl) - aminocarbonyl, cyclo-C _3-6 -alkyl-amino-carbonyl, cyclo-C _3-6 -alkylenimino-carbonyl, cyclo-C _3-6 -alkyleneimino-C _2-4 -alkyl-aminocarbonyl, phenyl-amino-carbonyl , C _1-4 alkylsulfonyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonylamino, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino , C _1-4 -alkyl-carbonyl-amino, cyclo-C _3-6 -alkyleneimino, phenyl-C _1-3 -alkylamino, N- (C _1-4 -alkyl) -phenyl-C _{1- 3} -alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4 Methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino,
wherein in the aforementioned groups and radicals, in particular in particular A, B, W, X, Y, Z, R ¹ to R ⁴ , R ^7a , R ^7b , R ^7c , R ^7d , R ¹⁰ to R ²² , each one or more C atoms additionally one or more times with F and / or in each case one or two C atoms independently additionally additionally simply with Cl or Br and / or in each case one or more phenyl rings independently additionally one, two or three substituents selected from the group F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino no-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl and di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl and / or simply with nitro may be substituted, and
the H atom of an existing carboxy group or an H atom bound to an N atom can each be replaced by an in-vivo leaving group,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts,
the following compounds according to provisos (M1) to (M14) are not included:

• (M1) N- [4 - [[(methylamino) sulphonyl] methyl] phenyl] -3- [2- (dimethylamino) ethyl] -1H-indole-5-propanamide oxalate,
• (M2) 3- [2- [3- [3,6-dihydro-4- (2-naphthyl) -1 (2H) -pyridinyl] -2-hydroxypropoxy] phenyl) -N-methyl-N-phenyl-2 -propenamid,
• (M3) 3- [2- [2-hydroxy-3- [4- (1-naphthyl) -1-piperidinyl] propoxy] phenyl] -N-methyl-N-phenyl-2-propenamide,
• (M4) 3- [2- [2-hydroxy-3- [4- (2-naphthyl) -1-piperidinyl] propoxy] phenyl] -N-methyl-N-phenyl-2-propenamide,
• (M5) 3- [2- [2-hydroxy-3- [4- (2-naphthyl) -1-piperidinyl] propoxy] phenyl] -N-phenyl-2-propenamide,
• (M6) N- (4- [1- (1H -imidazol-1-yl) -2-methylpropyl] phenyl] -3-phenyl-2-propynamide,
• (M7) 2 '- [[3- (dimethylamino) propyl] thio] -3-phenylpropiolanilide,
• (M8) 2- (methylthio) -5 - [[3- [4- (octadecylamino) phenyl] -1-oxopropyl] amino] benzoic acid, including the trifluoroacetate salt,
• (M9) 4-amino-N- (4-hydroxy-3,5-dimethylphenyl) -benzenepropanamide,
• (M10) 4- (dimethylamino) -N- (4-hydroxy-3,5-dimethylphenyl) -benzenepropanamide,
• (M11) β-methyl-4 - [[3- [2 - [(2-methylphenyl) amino] -6-benzoxazolyl] -1-oxopropylamino] -benzenepropanoic acid,
• (M12) 4- [3 - [[1-Oxo-3- [2- (phenylamino) -6-benzoxazolyl] -propyl] amino] phenoxy] -butanoic acid,
• (M13) 2-chloro-5 - [[1-oxo-3- [4 - [(5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid,
• (M14) 2-Chloro-5 - [[1-oxo-3- [4 - [(5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid methyl ester.

object The invention also relates to the respective compounds in the form of single optical isomers, mixtures of the individual diastereomers, Enantiomers or racemates, in the form of tautomers and in the form the free bases or the corresponding acid addition salts with pharmacological harmless 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 are represented by deuterium are exchanged.

Further are the physiologically tolerable Salts of the above-described and below described inventive amide compounds also an object of this invention.

Also an object of this invention are compositions containing at least one amide compound of the invention and / or a salt according to the invention optionally in addition to one or more physiologically acceptable Excipients.

Farther are medicaments containing at least one amide compound according to the invention and / or an inventive salt optionally together with one or more inert carriers and / or diluents Subject of the present invention.

Also An object of this invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the by the stipulations (M1) to (M14) excluded compounds, for influencing the eating behavior of a mammal.

Farther is the use of at least one amide compound of the invention and / or a salt according to the invention, including the by the stipulations (M1) to (M14) excluded compounds, to reduce the body weight and / or for preventing an increase in body weight of a mammal an object of this invention.

Also An object of the present invention is the use of at least an amide compound according to the invention and / or a salt according to the invention, including the by the stipulations (M1) to (M14) excluded compounds, for the preparation of a Drug with MCH receptor antagonistic activity, in particular with MCH-1 receptor antagonist activity.

In addition, an object of this invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the excluded by the provisos (M1) to (M14) compounds for the preparation of a medicament, which for the prophylaxis and / or treatment of Appearances and / or diseases caused by MCH or with MCH are in a different causal relationship, is appropriate.

One Another object of this invention is the use of at least an amide compound according to the invention and / or a salt according to the invention, including the by the stipulations (M1) to (M14) excluded compounds, for the preparation of a Medicament, which is used for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, especially of obesity, bulimia, bulimia nervosa, cachexia, anorexia, Anorexia nervosa and hyperphagia, is appropriate.

Also An object of this invention is the use of at least an amide compound according to the invention and / or a salt according to the invention, including by the stipulations (M1) bis (M14) excluded compounds, for the manufacture of a medicament, which is used for the prophylaxis and / or treatment of obesity Diseases and / or disorders, especially diabetes, especially type II diabetes, diabetic Complications, including diabetic retinopathy, diabetic neuropathy, diabetic Nephropathy, insulin resistance, pathological glucose tolerance, Encephalorrhagia, heart failure, cardiovascular disease, in particular Atherosclerosis and hypertension, arthritis and gonitis is.

Furthermore For example, the present invention has the use of at least one amide compound of the invention and / or a salt according to the invention, including the by the stipulations (M1) to (M14) excluded compounds, for the preparation of a Medicinal product used for the prophylaxis and / or treatment of hyperlipidemia, cellulitis, Fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, Depression, anxiety, Sleep disorders, Reproductive disorders, sexual disorders, Memory disorders, Epilepsy, forms of dementia and hormonal disorders is appropriate to the subject.

Farther An object of this invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the by the stipulations (M1) to (M14) excluded compounds, for the preparation of a Medicament which is used for the prophylaxis and / or treatment of voiding disorders, such as urinary incontinence, overactive bladder, urinary urgency, nocturia and enuresis, is appropriate.

Furthermore An article of this invention relates to methods of preparation a medicament according to the invention, characterized in that non-chemical way at least an amide compound of the invention and / or a salt according to the invention in one or more inert carriers and / or diluents is incorporated.

One Another object of this invention is a medicament containing a first active ingredient consisting of the amide compounds of the invention and / or the corresponding salts, including those specified by (M1) to (M14) excluded compounds, and a second active ingredient, who is selected from the group is composed of active ingredients for the treatment of diabetes, drugs for the treatment of diabetic complications, agents for treatment of obesity, preferably other than MCH antagonists, drugs for the treatment of hypertension, agents for the treatment of Hyperlipidemia, including Atherosclerosis, agents for the treatment of arthritis, drugs for the treatment of anxiety and agents for the treatment of depression, optionally with one or more inert carriers and / or diluents.

Detailed description the invention

Unless stated otherwise, the groups, radicals and substituents, in particular A, B, W, X, Y, Z, R ¹ to R ⁴ , R ^7a , R ^7b , R ^7c , R ^7d , R ¹⁰ to R ²² , as well as the index b has the meanings given above.

Come Groups, radicals and / or substituents in a compound several times before, so can each of these has the same or different meanings exhibit.

worin R¹, R², R³, R^7a, R^7b, R^7c, R^7d, X, Y, A, B und b die zuvor und nachfolgend angegebenen Bedeutungen, insbesondere die als bevorzugt angegebenen Bedeutungen besitzen.Preferred embodiments of this invention therefore comprise compounds which can each be described by the following formulas Ia, Ib, Ic and Id:

wherein R ¹ , R ² , R ³ , R ^7a , R ^7b , R ^7c , R ^7d , X, Y, A, B and b have the meanings given above and below, in particular those given as preferred meanings.

Particularly preferred meanings of the radicals R ^7a , R ^7b , R ^7c , R ^7d are H or methyl, in particular H.

Preferred meanings of the substituent R ³ are H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl-; in particular H or C _1-3 -alkyl. R ³ particularly preferably denotes H or methyl, in particular H.

If R ¹ and R ^{2 are} not linked to one another via an alkylene bridge, then R ¹ and R ² independently of one another preferably denote a C _1-8 -alkyl or C _3-7 -cycloalkyl group optionally substituted by the radical R ¹¹ , where -CH ₂ group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group by -O-, -S- or -NH-, -N (C _1-4 alkyl) - or -N (CO-OC _1-4 alkyl) - may be replaced, or one optionally substituted by the radical R ¹² mono- or polysubstituted and polysubstituted and / or nitro single substituted phenyl or pyridinyl, and wherein one of the radicals R ¹ and R ^{2 may} also be H.

Preferably, the radicals R ¹ , R ² independently of one another are H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, ω-hydroxy-C _2-3 alkyl, ω-NC-C _2-3 alkyl, ω- (C _1-4 alkoxy) C _2-3 alkyl, C _1-4 alkoxycarbonylC _1-4 alkyl , C _1-4 -alkyl, amino C _2-4 -alkyl, C _1-4 -alkyl-amino-C _2-4 -alkyl-, di- (C _1-4 -alkyl) -, aminoC _2-4 alkyl, cycloC _3-6 alkyleneiminoC _2-4 alkyl, pyrrolidin-3-yl, N- (C _1-4 alkyl) pyrrolidinyl, pyrrolidinyl C _{1 3-} alkyl-N- (C _1-4 -alkyl) -pyrrolidinyl-C _1-3 -alkyl, piperidinyl, N- (C _1-4 -alkyl) -piperidinyl, piperidinyl-C _1-3 -alkyl, N- (C _1-4 alkyl) piperidinyl C _1-3 alkyl, phenyl, phenyl C _1-3 alkyl, pyridyl or pyridyl C _1-3 alkyl, wherein in the groups indicated above and radicals one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another with Cl, Br or CN, and wherein the phenyl or pyridyl radical is mono- or polysubstituted with the previously defined R ¹² and / or may be substituted by nitro. Preferred substituents of the abovementioned phenyl or pyridyl radicals are selected from the group consisting of F, Cl, Br, I, cyano, C _1-4 -alkyl, C _1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxyl, amino , C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, aminoC _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl and di (C _1-3 alkyl) amino C _1-3 alkyl, wherein a phenyl radical may also be easily substituted with nitro.

Particularly preferred meanings of the radicals R ¹ and / or R ² are selected from the group consisting of C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, ω- Hydroxy C _2-3 alkyl, ω- (C _1-4 alkoxy) C _2-3 al kyl, C _1-4 alkoxy-carbonyl-C _1-4 -alkyl, carboxyl-C _1-4 -alkyl, where one of the radicals R ¹ and R ^{2 may} also be H.

Particularly preferably, at least one of the radicals R ¹ , R ² , very particularly preferably both radicals, has a meaning other than H.

• – eine nicht mit dem N-Atom der R¹R²N-Gruppe benachbarte -CH₂-Gruppe durch -CH=CH- ersetzt sein kann und/oder
• – eine -CH₂-Gruppe, die vorzugsweise nicht mit dem N-Atom der R¹R²N-Gruppe benachbart ist, durch -O-, -S-, -C(=N-O-R¹⁸)-, -CO-, -C(=CH₂)- oder -NR¹³-, besonders bevorzugt durch durch -O-, -S- oder -NR¹³-, derart ersetzt sein kann, dass Heteroatome nicht unmittelbar miteinander verbunden sind, und dass eine Gruppe -C=N-O-R¹⁸ oder -CO- nicht unmittelbar mit der Gruppe R¹R²N- verbunden ist,

wobei in der zuvor definierten Alkylen-Brücke ein oder mehrere H-Atome durch R¹⁴ ersetzt sein können, und
wobei die zuvor definierte Alkylen-Brücke mit einer carbo- oder heterocyclischen Gruppe Cy derart substituiert sein kann, dass die Bindung zwischen der Alkylenbrücke und der Gruppe Cy

• – über eine Einfach- oder Doppelbindung,
• – über ein gemeinsames C-Atom unter Ausbildung eines spirocyclischen Ringsystems,
• – über zwei gemeinsame, benachbarte C- und/oder N-Atome unter Ausbildung eines kondensierten bicyclischen Ringsystems oder
• – über drei oder mehrere C- und/oder N-Atome unter Ausbildung eines verbrückten Ringsystems erfolgt.

R¹³ bedeutet vorzugsweise H oder C_1-6-Alkyl.If R ¹ and R ^{2 form} an alkylene bridge, this is preferably a C _3-7 -alkylene bridge in which

• A -CH ₂ group adjacent to the N atom of the R ¹ R ² N group can be replaced by -CH = CH- and / or
• A --CH ₂ - group, which is preferably not adjacent to the N atom of the R ¹ R ² N group, by -O-, -S-, -C (= NOR ¹⁸ ) -, -CO-, - C (= CH ₂ ) - or -NR ¹³ -, particularly preferably by -O-, -S- or -NR ¹³ -, may be replaced such that heteroatoms are not directly connected to each other, and that a group -C = NOR ¹⁸ or -CO- is not directly connected to the group R ¹ R ² N-,

wherein in the above-defined alkylene bridge, one or more H atoms may be replaced by R ¹⁴ , and
wherein the previously defined alkylene bridge having a carbo- or heterocyclic group Cy may be substituted such that the bond between the alkylene bridge and the group Cy

• - via a single or double bond,
• Via a common C atom with formation of a spirocyclic ring system,
• Via two common, adjacent C and / or N atoms to form a fused bicyclic ring system or
• - About three or more C and / or N atoms takes place to form a bridged ring system.

R ¹³ is preferably H or C _1-6 alkyl.

Further preferably, R ¹ and R ^{2 form} an alkylene bridge such that R ¹ R ² N- is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1,2,3,6 Tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, wherein the free imine function is substituted with R ¹³ , piperidine-4 -on, piperidin-4-one oxime, piperidin-4-one-OC _1-4 alkyl oxime, morpholine and thiomorpholine, wherein according to the general definition of R ¹ and R ² one or more H atoms by R ¹⁴ may be replaced, and / or the abovementioned groups in a manner given in accordance with the general definition of R ¹ and R ² may be substituted with one or two identical or different carbo- or heterocyclic groups Cy. Particularly preferred groups Cy here are C _3-7 -cycloalkyl, aza-C _4-7 -cycloalkyl-, in particular cyclo-C _3-6 -alkyleneimino-, and also 1-C _1-4 -alkyl-aza-C _4-7 -cycloalkyl.

The C _2-8 alkylene bridge formed by R ¹ and R ² , in which -CH ₂ groups as indicated may be replaced, may be substituted as described with one or two identical or different carbo- or heterocyclic groups Cy ,

In the event that the alkylene bridge is linked to a group Cy via a single bond, Cy is preferably selected from the group consisting of C _3-7 cycloalkyl, cycloC _3-6 alkyleneimino, 1H-imidazole, thienyl and phenyl ,

In the event that the alkylene bridge is connected to a group Cy via a common carbon atom with the formation of a spirocyclic ring system, Cy is preferably selected from the group consisting of C _3-7 -cycloalkyl, aza-C _4-8 -cycloalky- , oxa-C _4-8 cycloalkyl, 2,3-dihydro-1H-quinazolin-4-one.

In the event that the alkylene bridge is connected to a group Cy via two common adjacent C and / or N atoms to form a fused bicyclic ring system, Cy is preferably selected from the group consisting of C _4-7 cycloalkyl, phenyl , Thienyl.

In the event that the alkylene bridge is connected to a group Cy via three or more C and / or N atoms to form a bridged ring system, Cy is preferably C _4-8 -cycloalkyl or aza-C _4-8 -cycloalkyl.

eine Bedeutung gemäß einer der folgenden Teilformeln

worin ein- oder mehrere H-Atome des durch die Gruppe R¹R²N- gebildeten Heterocyclus durch R¹⁴ ersetzt sein können und der mit dem durch die Gruppe R¹R²N-gebildeten Heterocyclus verbundene Ring ein- oder mehrfach an einem oder mehreren C-Atomen mit R²⁰, im Falle eines Phenyl-Rings auch zusätzlich einfach mit Nitro substituiert sein kann und
X', X'' unabhängig voneinander eine Einfachbindung oder C_1-3-Alkylen und
für den Fall, dass die Gruppe Y über ein C-Atom mit X' bzw. X'' verbunden ist, auch -C_1-3-Alkylen-O-, -C_1-3-Alkylen-NH- oder -C_1-3-Alkylen-N(C_1-3-alkyl)-, und
X'' zusätzlich auch -O-C_1-3-Alkylen, -NH-C_1-3-Alkylen oder -N(C_1-3-alkyl)-C_1-3-Alkylen und
für den Fall, dass die Gruppe Y über ein C-Atom mit X'' verbunden ist, auch -NH-, -N(C_1-3-alkyl)- oder -O- bedeutet,
wobei in den zuvor für X', X'' genannten Bedeutungen jeweils ein C-Atom mit R¹⁰, vorzugsweise mit einem Hydroxy-, ω-Hydroxy-C_1-3-alkyl-, ω-(C_1-4-Alkoxy)-C_1-3-alkyl- und/oder C_1-4-Alkoxy-Rest, und/oder ein oder zwei C-Atome jeweils mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus C_1-6-Alkyl-, C_2-6-Alkenyl-, C_2-6-Alkinyl-, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl, C_4-7-Cycloalkenyl und C_4-7-Cycloalkenyl-C_1-3-alkyl substituiert sein können, wobei zwei Alkyl- und/oder Alkenyl-Substituenten unter Ausbildung eines carbocyclischen Ringsystems miteinander verbunden sein können, und
wobei in X', X'' unabhängig voneinander jeweils ein oder mehrere C-Atome ein- oder mehrfach mit F und/oder jeweils ein oder zwei C-Atome unabhängig voneinander einfach mit Cl oder Br substituiert sein können und worin R², R¹⁰, R¹³, R¹⁴, R¹⁸, R²⁰, R²¹ und X die zuvor und nachstehend angegebenen Bedeutungen besitzen.Most preferably, the group has

a meaning according to one of the following sub-formulas

in which one or more H atoms of the heterocycle formed by the group R ¹ R ² N- may be replaced by R ¹⁴ and the ring connected to the heterocycle formed by the group R ¹ R ² N-one or more times on one or more more C atoms with R ²⁰ may be, in the case of a phenyl ring may also additionally be monosubstituted by nitro, and
X ', X''independently of one another a single bond or C _1-3 alkylene and
for the case that the group Y via a carbon atom to X 'or X''is connected, also C _1-3 alkylene-O-, -C _1-3 -alkylene-NH- or -C _{1 3-} alkylene-N (C _1-3 alkyl) -, and
X "additionally also -OC _1-3 -alkylene, -NH-C _1-3 -alkylene or -N (C _1-3 -alkyl) -C _1-3 -alkylene and
in the case that the group Y is connected to X '' via a C atom, also -NH-, -N (C _1-3 -alkyl) - or -O-,
wherein in the meanings given above for X ', X ", in each case one C atom with R ¹⁰ , preferably with one hydroxy, ω-hydroxy-C _1-3 -alkyl-, ω- (C _1-4 -alkoxy) C _1-3 alkyl and / or C _1-4 alkoxy, and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _4-7 cycloalkenyl and C _4-7 cycloalkenyl-C _1-3 alkyl may be substituted, wherein two alkyl and / or alkenyl substituents may be joined together to form a carbocyclic ring system, and
where in X ', X "independently of one another in each case one or more C atoms may be mono- or polysubstituted with F and / or in each case one or two C atoms independently of one another can be substituted simply by Cl or Br and in which R ² , R ¹⁰ , R ¹³ , R ¹⁴ , R ¹⁸ , R ²⁰ , R ²¹ and X have the meanings given above and below.

In the above-mentioned preferred and particularly preferred meanings of R ¹ R ² N, the following definitions of the substituent R ^{14 are} preferred: C _1-4 -alkyl, C _2-4 -alkenyl, C _2-4 -alkynyl, C _3-7 - Cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, hydroxy, hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, ω- (C _1-4 -alkoxy) -C _{1- 3-} alkyl, C _1-4 alkylcarbonyl, carboxy, C _1-4 alkoxycarbonyl, hydroxy-carbonylC _1-3 alkyl, C _1-4 alkoxycarbonylC _1-3 alkyl , C _1-4 -alkoxycarbonylamino, C _1-4 -alkoxycarbonylamino-C _1-3 -alkyl, amino, C _1-4 -alkylamino, C _3-7 -cycloalkylamino , N- (C _3-7 cycloalkyl) -N- (C _1-4 alkyl) amino, di (C _1-4 alkyl) amino, amino C _1-3 alkyl, C _1-4 alkyl-amino-C _1-3 -alkyl, C _3-7 -cycloalkylamino-C _1-3 -alkyl, N- (C _3-7 -cycloalkyl) -N- (C _1-4 -) alkyl) -amino-C _1-3 -alkyl-, di- (C _1-4 -alkyl) -amino-C _1-3 -alkyl-, cyclo-C _3-6 -alkyleneimino-C _1-3 -alkyl- , Aminocarbonyl, C _1-4 -alkylamino-carbonyl, C _3-7 -cycloalkyl-amino-carbonyl, N- (C _3-7 -cycloalkyl) -N- (C _1-4 alkyl) amino carbonyl, di (C _1-4 alkyl) amino carbonyl, pyridinyl oxy, pyridinyl amino, pyridinyl C _1-3 alkyl amino.

Very particularly preferred meanings of the substituent R ¹⁴ are C _1-4 -alkyl, hydroxy, hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, ω- (C _1-4 -alkoxy) C _1-3 alkyl, aminoC _1-3 alkyl, C _1-4 alkylaminoC _1-3 alkyl, C _3-7 cycloal kylamino-C _1-3 -alkyl-, N- (C _3-7 -cycloalkyl) -N- (C _1-4 -alkyl) -amino-C _1-3 -alkyl-, di- (C _{1- 4-} alkyl) aminoC _1-3 alkyl, cycloC _3-6 alkyleneiminoC _1-3 alkyl and aminocarbonyl.

In the above-mentioned preferred meanings of R ¹⁴ , one or more C atoms may additionally be monosubstituted or polysubstituted with F and / or in each case one or two C atoms independently of one another may additionally be substituted simply by Cl or Br.

• – eine nicht mit dem N-Atom der R¹R²N-Gruppe benachbarte -CH₂-Gruppe durch -CH=CH- oder -C≡C- ersetzt sein kann und/oder
• – eine nicht mit dem N-Atom der R¹R²N-Gruppe benachbarte -CH₂-Gruppe durch -O-, -S-, -CO- oder -NR⁴-, besonders bevorzugt durch -O-, -S- oder -NR⁴-, derart ersetzt sein kann, dass jeweils zwei O-, S- oder N-Atome oder ein O- mit einem S-Atom nicht unmittelbar miteinander verbunden sind,

wobei R⁴ mit Y unter Ausbildung eines heterocyclischen Ringsystems miteinander verbunden sein kann,
wobei die Brücke X mit R¹ unter Einschluss des mit R¹ und X verbundenen N-Atoms unter Ausbildung einer heterocyclischen Gruppe verbunden sein kann, wobei die Brücke X zusätzlich auch mit R² unter Einschluss des mit R² und X verbundenen N-Atoms unter Ausbildung einer heterocyclischen Gruppe verbunden sein kann, und
wobei zwei C-Atome oder ein C- und ein N-Atom der Alkylenbrücke durch eine zusätzliche C_1-4-Alkylen-Brücke miteinander verbunden sein können, und
wobei ein C-Atom mit R₁₀ und/oder ein oder zwei C-Atome jeweils mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus C_1-6-Alkyl-, C_2-6-Alkenyl-, C_2-6-Alkinyl-, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl-, C_4-7-Cycloalkenyl und C_4-7-Cycloalkenyl-C_1-3-alkyl- substituiert sein können, wobei zwei Alkyl- und/oder Alkenyl-Substituenten unter Ausbildung eines carbocyclischen Ringsystems, insbesondere einer Cyclopropyl-, Cyclobutyl- oder Cyclopentylgruppe, miteinander verbunden sein können.Preferably, X is a C _1-6 alkylene bridge in which

• A -CH ₂ group adjacent to the N atom of the R ¹ R ² N group can be replaced by -CH = CH- or -C≡C- and / or
• A -CH ₂ group not adjacent to the N atom of the R ¹ R ² N group by -O-, -S-, -CO- or -NR ⁴ -, particularly preferably -O-, -S- or -NR ⁴ -, may be replaced such that in each case two O, S or N atoms or an O with an S atom are not directly connected to one another,

wherein R ⁴ may be linked together with Y to form a heterocyclic ring system,
wherein the bridge X may be connected to R ¹ , including the N atom connected to R ¹ and X to form a heterocyclic group, wherein the bridge X additionally with R ² , including the R ² and X connected to N atom under Formation of a heterocyclic group may be linked, and
wherein two C atoms or one C and one N atom of the alkylene bridge may be linked together by an additional C _1-4 alkylene bridge, and
wherein one C atom with R ₁₀ and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl -, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _4-7 -cycloalkenyl and C _4-7 -cycloalkenyl-C _1-3 -alkyl- may be substituted, wherein two alkyl and / or alkenyl substituents to form a carbocyclic ring system, in particular a cyclopropyl, cyclobutyl or cyclopentyl group, may be joined together.

Preferably, in group X, an -NH adjacent to the group R ¹ R ² -NH ₂ group is not substituted by -O-, -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ -sets.

If, in group X, one or two -CH ₂ groups are independently replaced by -O- -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ -, these groups are preferably N-spaced by an alkylene bridge having at least 2 C atoms of the group R ¹ R ² .

If, in the group X, two -CH ₂ groups are independently replaced by -O-, -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ -, these groups are preferred separated by an alkylene bridge with at least 2 C atoms.

If, in the group X, a -CH ₂ group of the alkylene bridge is replaced according to the invention, this -CH ₂ group is preferably not directly linked to a heteroatom, a double bond or a triple bond.

Preferably, the alkylene bridge X, X 'or X "has no or at most one imino group. The position of the imino group within the alkylene bridge X, X 'or X "is preferably selected such that no aminal function is formed together with the amino group NR ¹ R ² or another adjacent amino group or two N atoms are not adjacent to one another.

Preferably, X is an unbranched C _1-4 alkylene bridge and
for the case that the group Y is connected to X via a C atom, also -CH ₂ -CH = CH-, -CH ₂ -C≡C-, C _2-4 -alkyleneoxy or C _2-4 -alkylene -NR ⁴ -,
wherein R ⁴ may be linked together with Y to form a heterocyclic ring system,
wherein the bridge X may be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and
wherein in X is a C atom with R ¹⁰ and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _4-7 cycloalkenyl and C _4-7 cycloalkenyl C _1-3 alkyl wherein two alkyl and / or alkenyl substituents may be linked together to form a carbocyclic ring system, and
wherein in the above-mentioned groups and radicals, one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another and may be substituted simply by Cl or Br, and
wherein R ¹ , R ⁴ and R ^{10 are} as defined above and below.

Particularly preferably X is -CH ₂ -, -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ - and
for the case that the group Y is connected to X via a C atom (the group Y), also -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -O -, CH ₂ -CH ₂ -CH ₂ -O- or -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -,
wherein R ⁴ may be linked together with Y to form a heterocyclic ring system,
wherein the bridge X may be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and
wherein in X is a C atom with R ¹⁰ , preferably a hydroxy, ω-hydroxy-C _1-3 alkyl, ω- (C _1-4 alkoxy) C _1-3 alkyl and / or C _1-4 alkoxy radical, and / or one or two C atoms independently of one another in each case with one or two identical or different C _1-4 alkyl radicals may be substituted, wherein two alkyl radicals to form a carbocyclic ring system with each other can be connected, and
wherein in each case one or more C atoms can be mono- or polysubstituted by F and / or in each case one or two C atoms independently of one another can be substituted simply by Cl or Br.

In the case where the group Y is connected to X via a C atom (the group Y), -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, very particularly preferably X , -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, which may be substituted as indicated.

In the event that R ^{4 is} linked to Y to form a heterocyclic ring system, preferably Y is phenyl and R ^{4 is} preferably C _2-6 -alkyl or C _2-6 -alkenyl. Preferred heterocyclic ring systems herein are indole, dihydroindole, quinoline, dihydroquinoline, tetrahydroquinoline and benzoxazole.

The radical R ⁴ preferably has the meaning vinyl only if R ⁴ is bonded to Y to form a heterocyclic ring system.

The Group X preferably has no carbonyl group.

Advantageously, the group X in the meaning C _2-4 alkyleneoxy, in particular -CH ₂ -CH ₂ -CH ₂ -O-, no hydroxy substituent.

When a C atom is substituted in X, X 'or X ", preferred substituents are selected from the group consisting of C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-4 -alkoxy) -C _1-3 alkyl and C _1-4 alkoxy radicals. Furthermore, in X, X 'or X "a C atom may be monosubstituted or disubstituted by one or two or one or two C atoms, preferred substituents being selected from the group consisting of C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 cycloalkyl and C _3-7 cycloalkyl-C _1-3 alkyl, and two C _1-4 alkyl and / or C _{2 4-} alkenyl substituents may also be linked together to form a saturated or monounsaturated carbocyclic ring.

All particularly preferred substituents of one or two C atoms in X, X 'or X "are selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl, wherein two alkyl substituents on a carbon atom, also forming a carbocyclic ring can be connected to each other.

In the previously and subsequently listed Meanings of the substituents of the bridges X, X 'and / or X' 'and the meanings of the bridges X, X 'and / or X "itself may each have one or more carbon atoms additionally one or more times with F and / or in each case one or two C atoms independently in addition to each other simply substituted with Cl or Br.

If Y denotes a fused bicyclic ring system, a preferred meaning of the group X is -CH ₂ -, -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -, in particular -CH ₂ - or -CH ₂ -CH ₂ -, which may be substituted as indicated.

In the event that the index b has the value 1, X is particularly preferably -CH ₂ -, where X may be linked to Y to form a bicyclic ring system as indicated and to this end the -CH ₂ -bridge with C _2-3 Alkyl is substituted. The -CH ₂ bridge may have one or two substituents independently selected from the group consisting of C _1-3 alkyl and C _3-5 cycloalkyl.

In the event that the index b has the value 0, X is particularly preferably -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, wherein said groups include or two substituents independently selected from the group consisting of C _1-3 alkyl and C _3-5 cycloalkyl may have.

If one or more C atoms in the group X, X 'or X "are substituted by a hydroxyl and / or C _1-4 alkoxy radical, the substituted C atom is preferably not immediately adjacent to another heteroatom ,

The bridge X can also mean a single bond. Preferably, the bridge X only represent a single bond when the compound of the invention according to a of the sub-formulas Ia, Ib or Id, in particular according to one of the sub-formulas Ia or Ib, most preferably the partial formula Ib described can be.

The group Y preferably has a meaning which is selected from the group of the bivalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl or benzoxazolyl, the abovementioned cyclic groups may be mono- or polysubstituted to one or more C atoms with R ²⁰ , in the case of a phenyl group also additionally simply with nitro, and / or to one or more N atoms with R ²¹ . Here, R ¹ may be connected to Y and / or X to Y as indicated above.

If the group Y which has the meaning phenyl or pyridinyl are the bridges X and Z are preferably connected in para-position to the group Y.

insbesondere weist Y eine der folgenden Bedeutungen auf

wobei die vorstehend aufgeführten cyclischen Gruppen ein- oder mehrfach an ein oder mehreren C-Atomen mit R²⁰ substituiert sein können, im Falle einer Phenylgruppe auch zusätzlich einfach mit Nitro, und/oder eine oder mehrere NH-Gruppen mit R²¹ substituiert sein.Particularly preferred is a meaning of the group Y selected from the group of bivalent cyclic groups

In particular, Y has one of the following meanings

where the abovementioned cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R ²⁰ , and in the case of a phenyl group may additionally also be monosubstituted by nitro, and / or one or more NH groups may be substituted by R ²¹ .

wobei die vorstehend aufgeführten cyclischen Gruppen ein- oder mehrfach an ein oder mehreren C-Atomen mit R²⁰ substituiert sein können, im Falle einer Phenylgruppe auch zusätzlich einfach mit Nitro, und/oder eine oder mehrere NH-Gruppen mit R²¹ substituiert sein.The group Y may be linked to the group X to form a carbamoyl or heterocyclic group fused to Y. Here preferred meanings of the interconnected groups -XY- are selected from the list consisting of

where the abovementioned cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R ²⁰ , and in the case of a phenyl group may additionally also be monosubstituted by nitro, and / or one or more NH groups may be substituted by R ²¹ .

The Group Y is preferably unsubstituted or one or two times substituted.

Particularly preferred substituents R ^{20 of} the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C _1-4 -alkyl, C _2-6 -alkenyl, hydroxy, ω-hydroxy-C _1-3 alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _2-4 alkynyl, C _1-4 alkoxycarbonyl, ω- (C _1-4 alkoxy) C _1-3 alkyl, C _{1 4-} alkoxycarbonylamino, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, aminocarbonyl, C _1-4 alkyl aminocarbonyl, di ( C _1-4 alkyl) amino carbonyl, -CH = N-OH and -CH = NOC _1-4 alkyl.

Very particularly preferred substituents R ^{20 of} the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, C _1-3 -alkyl, C _1-3 -alkoxy, trifluoromethyl, trifluoromethoxy, in the case of a phenyl ring also nitro.

worin L¹ eine der zuvor für R²⁰ angegebenen Bedeutungen, vorzugsweise F, Cl, Br, I, CH₃, CF₃, OCH₃, OCF₃, CN oder NO₂, besitzt oder H bedeutet.Most preferably, the group Y represents substituted phenylene of the partial formula

wherein L ^{1 has} one of the meanings given above for R ²⁰ , preferably F, Cl, Br, I, CH ₃ , CF ₃ , OCH ₃ , OCF ₃ , CN or NO ₂ , or H means.

A preferred meaning of group A is aryl or heteroaryl.

Preferably, the group A is selected from the group of cyclic groups phenyl, pyridinyl or naphthyl, which may be mono- or polysubstituted to one or more carbon atoms with R ²⁰ , in the case of a phenyl ring also additionally simply with nitro, wherein for In the case that the index b has the value 0, the group Cy has no amino group as a substituent in the ortho position to the bridge W.

Preferably, the group A does not have a substituent selected from the group consisting of C _1-4 alkylsulfonylamino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylaminoC _1-3 alkyl , C _1-4 -alkyl-carbonyl-amino-C _1-3 -alkyl and phenylcarbonylamino-. Further non-preferred substituents are aminocarbonyl, C _1-4 -alkylaminocarbonyl, di- (C _1-4 -alkyl) aminocarbonyl, cyclo-C _3-6 -alkyl-aminocarbonyl, cyclo-C _3-6 -alkyleneimino-carbonyl, Cyclo-C _3-6 -alkyleneimino-C _2-4 -alkylaminocarbonyl, phenyl-amino-carbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-4 -alkylaminocarbonyl-C _1-3 -alkyl, di (C _{1 4-} alkyl) aminocarbonylC _1-3 alkyl, cycloC _3-6 alkylaminocarbonylC _1-3 alkyl, cycloC _3-6 alkylene-carbonyl-C _1-3 alkyl , Cyclo-C _3-6 -alkyleneimino-C _2-4 -alkyl-aminocarbonyl-C _1-3 -alkyl and phenyl-amino-carbonyl-C _1-3 -alkyl.

Furthermore the group A preferably has no substituent selected the group consisting of nitro and tert-butyloxycarbonylamino respectively in ortho position to the bridge W on.

has b is 0, the group A is preferably one, two or trisubstituted.

has b is 1, the group A is preferably unsubstituted or substituted once or twice. Does b have the value 1 and is the Group A is simply substituted, so is the substituent preferably in the ortho position based on the group W.

wobei die aufgeführten Gruppen wie angegeben mit R²⁰ ein- oder mehrfach substituiert sein können, wobei für den Fall, dass der Index b den Wert 0 besitzt, die Gruppe Cy keine Amino-Gruppe als Substituenten in ortho-Stellung zur Brücke W aufweist. Die angegebenen Bedeutungen der Gruppe A Phenyl und Pyridyl sind in dem Fall bevorzugt, dass b den Wert 1 besitzt.Most preferably, A is one of the groups listed below

where the groups listed can be monosubstituted or polysubstituted with R ²⁰ as indicated, in which case the group b has the value 0, the group Cy has no amino group as substituent in the ortho position to the bridge W. The meanings given for the group A phenyl and pyridyl are preferred in the case where b has the value 1.

Particularly preferred substituents R ²⁰ of group A are selected from the group consisting of fluorine, chlorine, bromine, cyano, C _1-4 -alkyl, C _2-6 -alkenyl, -CHO, hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _2-4 alkynyl, carboxy, C _1-4 alkoxycarbonyl, ω- (C _1-4 alkoxy) C _1-3 alkyl, C _1-4 alkoxycarbonylamino, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cycloC _3-6 alkyleneimino, aminocarbonyl, C _{1 4-} alkyl-amino-carbonyl, di- (C _1-4 -alkyl) -aminocarbonyl, -CH = N-OH and -CH = NOC _1-4 -alkyl.

Very particularly preferred substituents R ²⁰ of group A are selected from among fluorine, chlorine, bromine, cyano, C _1-4 -alkyl, C _1-4 -alkoxy, trifluoromethyl, trifluoromethoxy, carboxy, C _1-4 -alkoxycarbonyl , C _1-4 alkylamino and di (C _1-4 alkyl) amino.

worin
L² eine der für R²⁰ angegebenen Bedeutungen besitzt oder H, vorzugsweise F, Cl, Br, I, CH₃, CF₃, OCH₃, OCF₃, CN oder NO₂ bedeutet,
L³ eine der für R²⁰ angegebenen Bedeutungen besitzt oder H, vorzugsweise F, Cl, Br, I, CF₃, OCF₃, CN, NO₂, C_1-4-Alkyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3 -alkyl, C_1-4-Alkoxy, C_3-7-Cycloalkyl-O-, C_3-7-Cycloalkyl-C_1-3-alkoxy, -COO-C_1-4-alkyl oder -COOH bedeutet,
q den Wert 0, 1 oder 2 besitzt.
mit der Maßgabe, dass die Phenyl- und Naphthyl-Gruppe lediglich maximal einfach mit Nitro substituiert sein kann.In the event that b has the value 0, a particularly preferred meaning of the group A is substituted phenyl of the partial formula

wherein
L ^{2 has} one of the meanings given for R ²⁰ or H, preferably F, Cl, Br, I, CH ₃ , CF ₃ , OCH ₃ , OCF ₃ , CN or NO ₂ ,
L ^{3 has} one of the meanings given for R ²⁰ or H, preferably F, Cl, Br, I, CF ₃ , OCF ₃ , CN, NO ₂ , C _1-4 -alkyl, C _3-7 -cycloalkyl, C _{3- 7} -cycloalkyl-C _1-3 -alkyl, C _1-4 -alkoxy, C _3-7 -cycloalkyl-O-, C _3-7 -cycloalkyl-C _1-3 -alkoxy, -COO-C _1-4 - alkyl or -COOH,
q has the value 0, 1 or 2.
with the proviso that the phenyl and naphthyl group can only be substituted with nitro at most.

A is particularly preferably substituted phenyl according to the above sub-formula in which q is 1 or 2 and / or at least one substituent L ^{2 is} in the meta position to the substituent L ³ .

wobei die Bindung zur Gruppe W über das C-Atom mit der Positionsnummer 2 oder 3 erfolgt.Furthermore, a preferred sub-formula for A, in particular for the case that b has the value 0, is

wherein the bond to the group W via the C-atom with the position number 2 or 3 takes place.

In the case, That b has the value 1 is a preferred meaning of the group B is aryl or heteroaryl which may be substituted as indicated.

Preferred meanings of group B are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl. Most preferably, the group B is phenyl. The group B in the meanings given may be monosubstituted or polysubstituted by R ²⁰ , a phenyl group may additionally also be monosubstituted by nitro.

Preferably is the group B one, two or three times, in particular one or doubly substituted. In the case of a single substitution, the Substituent preferably in para position to the group A.

Particularly preferred substituents R ²⁰ of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C _1-4 -alkyl, hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 Alkoxy, trifluoromethyl, trifluoromethoxy, C _2-4 alkynyl, carboxy, C _1-4 alkoxycarbonyl, ω- (C _1-4 alkoxy) C _1-3 alkyl, C _1-4 alkoxycarbonylamino , Amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cycloC _3-6 alkyleneimino, aminocarbonyl, C _1-4 alkylamino carbonyl and di (C _1-4 alkyl) amino carbonyl.

Very particularly preferred substituents R ²⁰ of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF ₃ , C _1-3 -alkyl, C _1-4 -alkoxy and trifluoromethoxy.

R ⁴ has one of the meanings given for R ¹⁷ , preferably one of R ¹⁶ .

Particularly preferred meanings of the substituent R ⁴ are H, C _1-6 -alkyl and C _3-6 -alkenyl. If R ^{4 is} linked to Y to form a heterocyclic ring system, particularly preferred meanings of R ^{4 are} C _2-6 -alkyl and C _2-6 -alkenyl.

When R ^{11 is} a C _2-6 alkenyl or C _2-6 alkynyl group, then the meanings are -CH = CH ₂ , -CH = CH (CH ₃ ), -CH = C (CH ₃ ) ₂ and also -C≡CH, -C≡C-CH ₃ preferred.

• a) -CO-Aryl oder -CO-Heteroaryl, insbesondere -CO-Phenyl, wobei Heteroaryl, Aryl und Phenyl substituiert sein können,
• b) -C(=NH)-NH-, wobei die N-Atome substituiert sein können und/oder
• c) -NH-CO-NH-, wobei die H-Atome substituiert sein können.

The substituent R ²⁰ preferably has none of the following structural elements:

• a) -CO-aryl or -CO-heteroaryl, in particular -CO-phenyl, it being possible for heteroaryl, aryl and phenyl to be substituted,
• b) -C (= NH) -NH-, where the N atoms may be substituted and / or
• c) -NH-CO-NH-, where the H atoms may be substituted.

Preferred meanings of the group R ²⁰ are halogen, hydroxy, cyano, C _1-4 -alkyl, C _3-7 -cycloalkyl and C _1-4 -alkoxy, where, as defined above, in each case one or more C atoms additionally or several times with F and / or in each case one or two C atoms independently of one another can additionally be substituted simply with Cl or Br. More preferably R ^{20 is} F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.

Preferred meanings of the group R ²¹ are C _1-4 -alkyl, C _1-4 -alkylcarbonyl, C _1-4 -alkylsulphonyl, -SO ₂ -NH ₂ , -SO ₂ -NH-C _1-3 -alkyl, SO ₂ -N (C _1-3 -alkyl) ₂ and cyclo-C _3-6 -alkyleneimino-sulfonyl-, where, as defined above, in each case one or more C atoms additionally one or more times with F and / or in each case one or two carbon atoms can additionally be substituted, independently of one another, additionally simply with Cl or Br.

Cy is preferably a C _3-7 -cycloalkyl, in particular a C _5-7 -cycloalkyl group, a C _5-7 -cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, wherein aryl or Heteroaryl is preferably a monocyclic or condensed bicyclic ring system, and where the abovementioned cyclic groups are mono- or polysubstituted to one or more C atoms with R ²⁰ , in the case of a phenyl group additionally also simply with nitro, and / or one or more NH- Groups with R ²¹ can be substituted.

Those Compounds of the invention are preferred in which one or more of the groups, radicals, substituents and / or indices one of the meanings given above as preferred exhibit.

In particular, those compounds according to the invention are preferred in which
Y is phenyl, 1H-indolyl, 2,3-dihydro-1H-indolyl or 1,2,3,4-tetrahydroquinoline according to the meaning described above as preferred, in particular L ¹ -substituted phenyl in accordance with the above-stated partial formula and / or
A is substituted by L ² and L ³ substituted phenyl according to the partial formula given above.

Very particular preference is given to those compounds according to the invention in which A, B, b, X, Y, Z, R ¹ , R ² , R ³ and W independently of one another have one or more of the abovementioned preferred meanings.

wobei die in den Formeln Ia.1 bis Ia.7, Ib.1, Ic.1 und Id.1 enthaltenen Brücken X in den Bedeutungen -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-NR⁴-, -CH₂-CH₂-CH₂-NR⁴-, -CH₂-CH₂-Ound -CH₂-CH₂-CH₂-O- ein oder zwei Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus C_1-3-Alkyl und C_3-5-Cycloalkyl aufweisen können,
wobei R¹, R², R³, R⁴ und R²⁰ die zuvor angegebenen Bedeutungen aufweisen und mehrfach vorkommende Substituenten die gleiche oder verschiedene Bedeutungen aufweisen können und
R³ vorzugsweise H oder Methyl bedeutet,
Q CH oder N bedeutet, wobei CH durch R²⁰ substituiert sein kann,
L¹ vorzugsweise Fluor, Chlor, Brom, Cyano, C_1-3-Alkyl, C_1-3-Alkoxy, Trifluormethyl, Trifluormethoxy oder Nitro bedeutet,
p den Wert 0 oder 1 besitzt,
R²⁰ jeweils unabhängig voneinander vorzugsweise Fluor, Chlor, Brom, Cyano, C_{1- 4}-Alkyl, C_2-6-Alkenyl, -CHO, Hydroxy, ω-Hydroxy-C_1-3-alkyl, C_1-4-Alkoxy, Trifluormethyl, Trifluormethoxy, C_2-4-Alkinyl, Carboxy, C_1-4-Alkoxycarbonyl-, ω-(C_1-4-Alkoxy)-C_1-3-alkyl, C_1-4-Alkoxy-carbonylamino-, Amino-, C_1-4-Alkylamino-, Di-(C_1-4-alkyl)-amino-, Cyclo-C_3-6-alkylenimino-, Aminocarbonyl-, C_1-4-Alkyl-amino-carbonyl-, Di-(C_1-4-alkyl)-amino-carbonyl-, -CH=N-OH und -CH=N-O-C_1-4-alkyl bedeutet, wobei für den Fall, dass der Index b den Wert 0 besitzt, die Gruppe Cy keine Amino-Gruppe als Substituenten in ortho-Stellung zur Brücke W aufweist;
besonders bevorzugt ist R²⁰ ausgewählt aus Fluor, Chlor, Brom, Cyano, Nitro, C_1-4-Alkyl, Hydroxy, ω-Hydroxy-C_1-3-alkyl, C_1-4-Alkoxy, Trifluormethyl, Trifluormethoxy, C_2-4-Alkinyl, Carboxy, C_1-4-Alkoxycarbonyl- und ω-(C_{1- 4}-Alkoxy)-C_1-3-alkyl-;
r, s jeweils unabhängig voneinander den Wert 0, 1, 2 oder 3 besitzen, vorzugsweise mindestens ein Index r oder s nicht den Wert 0 bedeutet, und
wobei die Verbindungen gemäß der Maßgaben (M1) bis (M14) nicht umfasst sind.Preferred groups of compounds according to this invention can be described by the following formulas

wherein the bridges X contained in the formulas Ia.1 to Ia.7, Ib.1, Ic.1 and Id.1 in the meanings -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ - NR ⁴ -, -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, -CH ₂ -CH ₂ -O and -CH ₂ -CH ₂ -CH ₂ -O- one or two substituents independently selected from the group consisting of C _1-3 -alkyl and C _3-5 -cycloalkyl,
wherein R ¹ , R ² , R ³ , R ⁴ and R ^{20 have} the meanings given above and multiply occurring substituents may have the same or different meanings, and
R ^{3 is} preferably H or methyl,
Q is CH or N, where CH may be substituted by R ²⁰ ,
L ^{1 is} preferably fluorine, chlorine, bromine, cyano, C _1-3 -alkyl, C _1-3 -alkoxy, trifluoromethyl, trifluoromethoxy or nitro,
p has the value 0 or 1,
R ²⁰ each independently represents preferably fluorine, chlorine, bromine, cyano, C _{1- 4} alkyl, C _2-6 alkenyl, -CHO, hydroxy, hydroxy-C _1-3 alkyl ω, C _1-4 alkoxy , Trifluoromethyl, trifluoromethoxy, C _2-4 -alkynyl, carboxy, C _1-4 -alkoxycarbonyl, ω- (C _1-4 -alkoxy) C _1-3 -alkyl, C _1-4 -alkoxycarbonylamino, Amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cyclo C _3-6 alkyleneimino, aminocarbonyl, C _1-4 alkylamino-carbonyl, Di- (C _1-4 alkyl) -amino-carbonyl, -CH = N-OH and -CH = NOC _1-4 alkyl, in which case the index b has the value 0, the Grup pe Cy has no amino group as a substituent ortho to the bridge W;
R ²⁰ is more preferably selected from fluorine, chlorine, bromine, cyano, nitro, C _1-4 -alkyl, hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, trifluoromethyl, trifluoromethoxy, C _{2 -4} alkynyl, carboxy, C _1-4 alkoxycarbonyl and ω- (C _{1- 4} alkoxy) -C _1-3 alkyl-;
r, s each independently of one another have the value 0, 1, 2 or 3, preferably at least one index r or s does not denote the value 0, and
wherein the compounds according to the provisos (M1) to (M14) are not included.

in the Following are terms used previously and below for description the compounds of the invention be used, closer Are defined.

The Designation Halogen denotes an atom selected from the group consisting from F, Cl, Br and I, especially F, Cl and Br.

The term C _1-n -alkyl, wherein n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group having 1 to n carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C _1-n -alkylene, where n can have a value of 1 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge having 1 to n C atoms. Examples of such 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.

The term C _2-n -alkenyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and a C = C double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.

The term C _2-n alkynyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and a C≡C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.

The term C _1-n -alkoxy refers to a C _1-n -alkyl-O-group in which C _1-n -alkyl is as defined above. Examples of such 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.

The term C _1-n -alkylthio refers to a C _1-n -alkyl-S-group in which C _1-n -alkyl is as defined above. Examples of such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, tert-pentylthio, n-butylthio Hexylthio, iso-hexylthio, etc.

The term C _1-n -alkylcarbonyl refers to a C _1-n -alkyl-C (= O) group, wherein C _1-n -alkyl is as defined above. Examples of such 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.

The term C _3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.

The term C _5-n -cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group having 5 to n C atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.

The term C _3-n -cycloalkylcarbonyl refers to a C _3-n -cycloalkyl-C (= O) group, wherein C _3-n -cycloalkyl is as defined above.

Of the Term aryl refers to a carbocyclic aromatic ring system, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, Fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc .. One particularly preferred meaning of "aryl" is Phenyl.

The term cyclo-C _3-7 -alkyleneimino- denotes a 4- to 7-membered ring which has 3 to 7 methylene units and an imino group, the bond to the rest of the molecule being via the imino group.

The term cyclo-C _3-7 -alkyleneimino-carbonyl designates a previously defined cyclo-C _3-7 -alkyleneimino ring, which is connected via the imino group with a carbonyl group.

Of the Term used in this application is heteroaryl heterocyclic, aromatic ring system, in addition to at least a C atom comprises one or more heteroatoms selected from N, O and / or S. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, Benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, Benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, Quinolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, Pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc .. The Term heteroaryl also includes the partially hydrogenated representatives heterocyclic, aromatic ring systems, in particular those above listed Ring systems. Examples of such partially hydrogenated heterocycles are 2,3-dihydrobenzofuranyl, Pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc .. Heteroaryl particularly preferably represents a heteroaromatic mono- or bicyclic ring system.

Terms such as arylC1 _-n- alkyl, heteroarylC1- _n- alkyl, etc. refer to C1 _-n- alkyl as defined above which is substituted with an aryl or heteroaryl group.

Some the previously mentioned Can terms be used multiple times in the definition of a formula or group and each have independent each one of the meanings given.

Of the Term "unsaturated", for example in "unsaturated carbocyclic Group "or" unsaturated heterocyclic Group ", like him is used in particular in the definition of the group Cy in addition to the monounsaturated or polyunsaturated groups, the corresponding Completely unsaturated Groups, but especially the mono- and diunsaturated Groups.

Of the As used in this application, the term "optionally substituted" means that the so designated group either unsubstituted or one or more times is substituted with the specified substituents. If the relevant Group is multiply substituted, so the substituents can be the same or be different.

The spelling used above and below, in which in one cyclic group is a bond of a substituent to the middle of this cyclic group is indicated, unless otherwise stated indicated that this substituent on any free, carrying a H atom Position of the cyclic group can be bound.

der Substituent R²⁰ im Falls = 1 an jede der freien Positionen des Phenylrings gebunden sein; im Falls = 2 können unterschiedlich voneinander ausgewählte Substituenten R²⁰ an unterschiedliche, freie Positionen des Phenylrings gebunden sein.So in the example

the substituent R ²⁰ in case = 1 is attached to each of the free positions of the phenyl ring; in case = 2, substituents R ²⁰ selected from one another can be bonded to different, free positions of the phenyl ring.

The H atom of an existing carboxy group or an H atom bound to an N atom (imino or amino group) can each be replaced by a residue which can be split off in vivo. A radical which can be split off from an N atom in vivo is understood as meaning, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C _1-16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert -butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, An undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenylC _1-6 alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C _1-3 -alkylsulfonyl-C _2-4 -alkoxycarbonyl, C _1-3 -alkoxy C _2-4 alkoxy-C _2-4 alkoxycarbonyl or R _e CO-O- (R _f CR _g ) -O-CO- group in which
R _{e is} a C _1-8 -alkyl, C _5-7 -cycloalkyl, phenyl or phenyl-C _1-3 -alkyl group,
R _{f is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{g is} a hydrogen atom, a C _1-3 alkyl or ReCO-O- (R _f CR _g ) -O- group in which
R _e to R _g are defined as mentioned above,
in addition, for an amino group, the phthalimido group is contemplated, wherein the above-mentioned ester groups can also be used as in vivo into a carboxy group convertible group.

The previously described radicals and substituents may be as described be mono- or polysubstituted with fluorine. Preferred fluorinated Alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl. preferred fluorinated alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are Trifluoromethylsulfinyl and trifluoromethylsulfonyl.

The Compounds of the invention of general formula I can acid groups own, mainly Carboxyl groups, and / or basic groups such as e.g. 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 pharmaceutically usable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. Diethylamine, triethylamine, triethanolamine et al available.

The Compounds of the invention are obtainable using in principle known synthesis methods. The compounds are preferably used in analogy to the following explained in more detail Obtained manufacturing process, which is also the subject of this Invention invention. The abbreviations used below are in the introduction to the experimental part or familiar to those skilled in the art.

If the starting materials or intermediates listed below contain radicals R ¹ , R ² , R ³ , X, Y, Z, A or B with amine functions, these are preferably used in protected form, for example with a Boc, Fmoc or Cbz protective group and released at the end of the reactions according to standard methods. Scheme 1:

In order to obtain a compound of general formula Ib, a compound of general formula A1 is reacted with a compound of general formula A2 in the sense of a Sonogashira coupling in the presence of a catalyst such as palladium with or without ligands and copper iodide in a solvent such as Dioxane, DMF, toluene, acetonitrile or THF or solvent mixture using an amine base such as triethylamine or inorganic base such as cesium carbonate at temperatures between -20 ° C and 200 ° C to. Scheme 2:

To obtain compounds of formula 6, an aniline derivative of formula 1 is reacted with a compound of formula 2. When Compound 2 is an arylboronic acid derivative, the reaction to Compound 3 is carried out in the presence of a catalyst such as palladium with or without ligands in a solvent or solvent mixture of, for example, dioxane, DMF, toluene, THF or water using a base such as triethylamine or potassium carbonate at temperatures between room temperature and 200 ° C. Instead of arylboronic acid derivatives, it is also possible to use organometallic aryl compounds, for example tin or zinc compounds. If compound 2 is an alkyne derivative, the reaction to compound 3 takes place in the sense of a Sonogashira coupling in the presence of a catalyst such as palladium with or without ligands and copper iodide in a solvent or solvent mixture of, for example, dioxane, DMF, toluene , Acetonitrile or THF using a base such as triethylamine at temperatures between -20 ° C and 200 ° C. A compound of formula 4 is obtained by reaction of a compound of formula 3 with propynoic acid in the presence of a base and activating reagents such as CDI, TBTU or DCC. Propionic acid chloride can also be used instead of the propionic acid. Compounds of the formula 4 can be converted into compounds of the formula 6 in the sense of a Sonogashira coupling as described above. Alternatively, a compound of formula 4 in the sense of a Sonogashira coupling as described with compound 7 are reacted. The resulting compound of formula 8 is converted to the sulfonic acid derivative 9 by reaction with methanesulfonyl chloride in the presence of a base such as triethylamine in an inert solvent such as dichloromethane at a temperature between 0 ° C and 50 ° C. For the conversion to a compound of formula 6, it is conceivable instead of Mesylates 9 to use an analog tosylate or a corresponding halogen compound. A compound of formula 9 is reacted with the corresponding amine in a solvent such as THF at a temperature between 0 ° C and 150 ° C to give a compound of formula 6. Scheme 3a:

In order to obtain a compound of the general formula A4, a compound of the general formula A3 is reacted with an ester of propynoic acid, preferably with propynoic acid ethyl ester, in the manner of a Sonogashira coupling in the presence of a catalyst such as, for example, palladium with or without ligands and copper iodide in one Solvent such as dioxane, DMF, toluene, acetonitrile or THF or solvent mixture using an amine base such as triethylamine or inorganic base such as cesium carbonate at temperatures between -20 ° C and 200 ° C to. The compound of general formula A4 is converted in the course of ester cleavage into a compound of general formula A5. The ester cleavage can be carried out in a solvent such as ethanol, dioxane or THF with or without the addition of water in the presence of an inorganic base such as sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate at temperatures of 0 ° C to 150 ° C. An ester cleavage is also possible in an organic solvent such as THF or dioxane in the presence of acid, for example aqueous hydrochloric acid or sulfuric acid. Scheme 3b:

A compound of general formula A5 may also be prepared by reacting a compound of general formula A7 in an organic solvent such as dioxane, ethanol or THF with or without addition of water with a base such as potassium tertiarybutylate, sodium hydroxide or sodium ethylate at temperatures of 0 ° C to 150 ° C converts. But it is also possible to bring for this reaction, a compound of general formula A7 with pyridine or quinoline at temperatures of 0 ° C to 150 ° C to the reaction. A compound of general formula A7 is obtained by bromination of a compound of general formula A6 in a solvent such as carbon tetrachloride at temperatures between -20 ° C to 100 ° C, preferably at temperatures between 0 ° C and room temperature. Scheme 3c:

A compound of general formula Ia is obtained by reaction of a compound of general formula A8 with a compound of general formula A5 in an organic solvent such as DMF, THF, dioxane, acetonitrile or toluene in the presence of a base such as triethylamine and activating reagents such Example CDI, TBTU or DCC. Instead of the compound A5, the carboxylic acid chloride or a mixed anhydride of the compound A5 may also be used Scheme 4:

A compound of general formula Ic is advantageously obtained by hydrogenating a compound of general formula A12 in an organic solvent such as methanol, ethanol, THF or dioxane in the presence of a catalyst such as Raney nickel, palladium or platinum at temperatures between 0 ° C and 150 ° C. However, the reaction of compound A12 to compound Ic can also be carried out in the presence of other hydrogen-transferring reagents. A compound of general formula A12 is obtained by reacting a compound of general formula A9 with a compound of general formula A11 in an organic solvent such as DMF, THF, dioxane, acetonitrile or toluene in the presence of a base such as triethylamine and activating reagents such as Example CDI, TBTU or DCC. Instead of the compound A9, the carboxylic acid chloride of the compound A9 can also be used. Compound Ic can also be obtained by reacting a compound of general formula A10 with a compound of general formula A11 under conditions as described above for the reaction of A9 and A11 to A12. The compound of general formula A10 can be obtained by reduction of a compound of general formula A9 analogously to the reaction of A12 to Ic. Scheme 5:

A compound of the general formula A21 can be obtained as follows. The cinnamic acid derivative A13 is converted into the protected cinnamic acid derivative A14 by reaction with formic acid orthomethyl ester with or without organic solvent such as methanol, THF or dioxane at temperatures between room temperature and 200 ° C. This is reacted in the course of an amide linkage with the amine of general formula A11 in the presence of TBTU and triethylamine in an organic solvent such as DMF or THF at a temperature between 0 ° C and room temperature to give a compound of general formula A15. By the action of acid such as trifluoroacetic acid on compound A15 in a solvent such as dichloromethane, chloroform and water or combinations thereof at temperatures between 0 ° C and 100 ° C to obtain a compound of general formula A16. Reduction of compound A16 by the action of a hydride transfer agent such as sodium triacetoxyborohydride or sodium borohydride in an organic solvent such as THF in the presence of an acid such as acetic acid at temperatures between 0 ° C and 100 ° C provides a Compound of general formula A17. Reaction of A17 with methanesulfonyl chloride in an organic solvent such as dichloromethane in the presence of a base such as triethylamine at temperatures between 0 ° C and 100 ° C gives a compound of general formula A18. For the conversion of A17 into A18, the reaction of A17 with thionyl chloride can also be used. Compound A20 is obtained by reacting A18 with a compound of general formula A19 in an organic solvent such as DMF, acetonitrile or THF at temperatures of 0 ° C and 100 ° C. A compound of general formula A21 is obtained by hydrogenating a compound of general formula A20 in an organic solvent such as methanol, ethanol, THF or dioxane in the presence of a catalyst such as Raney nickel, palladium or platinum at temperatures between 0 ° C and 150 ° C. However, the reaction of the compound A20 to the compound A21 can also be carried out in the presence of other hydrogen-transferring reagents.

The Compounds of the invention are also advantageous according to those described in the following examples Method accessible, this also with the expert, for example, from the literature known methods can be combined.

stereoisomers In principle, compounds of the formula (I) can be prepared by customary methods Separate methods. The separation of the respective diastereomers succeeds due to their different physicochemical properties, e.g. by fractional crystallisation from suitable solvents, by high-pressure liquid or column using chiral or preferably achiral stationary phases.

The Separation of racemates covered by the general formula (I) succeeds for example by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates, which is a basic or acidic function can also be visualized via the diastereomers 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) -Brucine, arise.

To a usual one Isomer separation process becomes the racemate of a compound of the general formula (I) with one of the abovementioned optically active acids or bases in equimolar amount in a solvent reacted and the resulting crystalline diastereomers, optically active salts taking advantage of their different solubility separated. This reaction can be carried out in any kind of solvents, as long as they have a sufficient difference in solubility having the salts. Preferably, methanol, ethanol or their mixtures, for example, in the volume ratio 50:50 used. thereupon each of the optically active salts is dissolved in water, with a base, such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or waterier methane, carefully neutralized and thus the corresponding free compound in the (+) - or (-)-Shape receive.

Each only the (R) - or (S) -enantiomer or a mixture of two optical active, under the general formula (I) falling diastereomeric Compounds are also obtained by using the ones described above Syntheses each with a suitable (R) or (S) -configured Reaction component performs.

As mentioned above the compounds of the formula (I) in their salts, in particular for the pharmaceutical Application, in their physiologically and pharmacologically acceptable Salts are transferred. These salts can on the one hand as physiologically and pharmacologically acceptable acid addition salts of Compounds of formula (I) with inorganic or organic acids. On the other hand, the compound of formula (I) in the case of acidic bound hydrogen by reaction with inorganic bases, too in physiologically and pharmacologically acceptable salts with alkali or Alkaline earth metal cations are converted as counterion. To the representation the acid addition salts for example, hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, Acetic acid, fumaric acid, Succinic acid, Lactic acid, Citric acid, tartaric acid or maleic acid into consideration. Furthermore, can Mixtures of the abovementioned acids be used. To illustrate the alkali and alkaline earth metal salts the compound of formula (I) with acidic hydrogen preferably the alkali and Alkaline earth hydroxides and hydrides into consideration, wherein the hydroxides and hydrides of alkali metals, especially of sodium and potassium preferred, sodium and potassium hydroxide are particularly preferred.

The compounds of the present invention, including the physiologically acceptable salts, have activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies. Pharmacological test systems for MCH antago nistic properties are described in the following experimental section.

When Antagonists of the MCH receptor are the compounds of the invention advantageous as pharmaceutical active ingredients for prophylaxis and / or Treatment of phenomena and / or diseases suitable, the caused by MCH or MCH in another causal Related. In general, the compounds of the invention low toxicity, a good oral absorbability and intracerebral transitivity, in particular brain penetration, on.

Therefore are MCH antagonists which are at least one compound of the invention have, especially in mammals, such as rats, mice, Guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, Cattle, monkeys and humans, for treatment and / or prophylaxis of apparitions and / or diseases caused by MCH be in another causal relationship with MCH, suitable.

Diseases, caused by MCH or MCH in another causal one Particular metabolic disturbances, such as obesity, and eating disorders, such as Bulimia, including Bulimia nervosa. The indication of obesity mainly includes exogenous obesity, hyperinsulinärer Obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic Obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary Obesity, hypogonadal obesity, central obesity. Furthermore are Cachexia, anorexia and hyperphagia are also included in this indication to call.

Compounds of the invention can especially suitable to reduce hunger, appetite too curb, to control the eating behavior and / or to create a feeling of satiety.

Furthermore can to diseases caused by MCH or MCH in another causal relationship, including hyperlipidemia, cellulitis, Fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, Depression, anxiety, Sleep disorders, Reproductive disorders, sexual disorders, Memory disorders, Epilepsy, forms of dementia and hormonal disorders is suitable.

Compounds of the invention are also as active ingredients for the prophylaxis and / or treatment of others Diseases and / or disorders, especially those associated with obesity, such as Diabetes, diabetes mellitus, especially 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, in particular arteriosclerosis and hypertension, Arthritis and Gonitis is suitable.

MCH antagonists according to the invention and formulations can advantageous in combination with an alimentary therapy, such as an alimentary Diabetes Therapy, and Exercise be used.

One further indication, for the compounds of the invention are advantageously suitable, the prophylaxis and / or treatment of micturition, such as urinary incontinence, overactive bladder, urinary urgency, Nocturia, enuresis, being overactive Bladder and urinary urgency with or not with benign prostatic hyperplasia need to be connected.

The To achieve a corresponding effect required dosage is expediently at intravenous or subcutaneous administration 0.001 to 30 mg / kg of body weight, preferably 0.01 up to 5 mg / kg body weight, and by oral, nasal or inhalation administration 0.01 to 50 mg / kg Body weight, preferably 0.1 to 30 mg / kg of body weight, once to three times a day.

For this purpose, the compounds of general formula I according to the invention, optionally in combination with other active substances, as described in more detail below, together with one or more inert conventional carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, Magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, dragees, Capsules, wafers, pul ver, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories.

Next Medicaments, the invention also includes compositions containing at least one amide compound of the invention and / or a salt according to the invention optionally in addition to one or more physiologically acceptable Excipients. Such compositions may include, for example, foods, the solid or liquid could be, in which the compound of the invention is incorporated.

• – Wirkstoffe zur Behandlung von Diabetes,
• – Wirkstoffe zur Behandlung diabetischer Komplikationen,
• – Wirkstoffe zur Behandlung von Obesitas, vorzugsweise andere als MCH-Antagonisten,
• – Wirkstoffe zur Behandlung von Bluthochdruck,
• – Wirkstoffe zur Behandlung von Hyperlipidemia, einschließlich Arteriosklerose,
• – Wirkstoffe zur Behandlung von Arthritis,
• – Wirkstoffe zur Behandlung von Angstzuständen,
• – Wirkstoffe zur Behandlung von Depressionen.

For the above-mentioned combinations, suitable further active substances are, in particular, those which, for example, enhance the therapeutic efficacy of an MCH antagonist according to the invention with regard to one of the indicated indications and / or which allow a reduction in the dosage of an MCH antagonist according to the invention. Preferably, one or more further active substances are selected from the group consisting of

• - drugs for the treatment of diabetes,
• - agents for the treatment of diabetic complications,
• - agents for the treatment of obesity, preferably other than MCH antagonists,
• - agents for the treatment of high blood pressure,
• - active substances for the treatment of hyperlipidemia, including arteriosclerosis,
• - agents for the treatment of arthritis,
• - agents for the treatment of anxiety,
• - agents for the treatment of depression.

following be the aforementioned classes of drugs by way of examples explained in more detail.

Examples of drugs for the treatment of diabetes are insulin sensitizers, Insulin secretion accelerators, biguanides, insulins, α-glucosidase Inhibitors, β3 Adreno receptor agonists.

insulin Sensitizers include pioglitazones and its salts (preferably Hydrochlorides), troglitazones, rosiglitazones and its salts (preferably Maleate), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929.

insulin Secretion enhancers include sulfonylureas, such as Tolbutamide, Chlorpropamide, Tolzamide, Acetohexamide, Glyclopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinides, Nateglinide, Mitiglinide (KAD-1229), JTT-608.

biguanides include metformin, buformin, phenformin.

insulins include those derived from animals, in particular cattle or pigs Insulins, semi-synthetic human insulins that are enzymatically derived from animal be synthesized insulin, human insulin, the genetic engineering, for example, from Escherichia coli or yeasts. Further is insulin as insulin zinc (containing 0.45 to 0.9 weight percent Zinc) and protamine-insulin-zinc obtainable from zinc chloride, protamine sulfate and insulin, understood. About that In addition, insulin may consist of insulin fragments or derivatives (e.g. INS-1, etc.).

insulin may also include different types, for example regarding the Entry time and duration of action ("ultra-immediate action type", "immediate action type "," two phase type "," intermediate type "," extended action type ", etc.), the dependent on be selected from the pathological condition of the patients.

α-glucosidase Inhibitors include acarbose, voglibose, miglitol, emiglitate.

β3 Adreno Receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.

Other as the aforementioned agents for the treatment of diabetes Ergoset, pramlintide, leptin, BAY-27-9955 and glycogen phosphorylase Inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine Phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipizide, Glyburide.

drugs For example, to treat diabetic complications Aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors.

aldose Reductase inhibitors are for example Tolrestat, Epalrestat, Imirestate, Zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.

One An example of a glycation inhibitor is pimagedine.

protein Kinase C inhibitors are, for example, NGF, LY-333531.

Other as the aforementioned active ingredients for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine Hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).

drugs for the treatment of obesity, preferably other than MCH antagonists, include lipase inhibitors and anorectics.

One preferred example of a lipase inhibitor is orlistat.

Examples preferred anorectic agents are phentermine, mazindol, dexfenfluramine, Fluoxetine, Sibutramine, Baiamine, (S) -sibutramine, SR-141716, NGD-95-1.

Other as the aforementioned agents for the treatment of obesity Lipstatin.

Furthermore, anorectics are also counted for the purposes of this application to the drug group of anti-obesity drugs, the β ₃ agonists, thyromimetic agents and NPY antagonists are highlighted. The scope of the substances which may be considered as preferred antiobesity or anorectic agents is exemplified by the following list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake Inhibitor (such as sibutramine), a sympathomimetic drug, a serotonergic drug (such as dexfenfluramine or fenfluramine), a dopamine antagonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, an analog of the melanocyte-stimulating hormone, a cannabinoid receptor antagonist, an MCH antagonist, the OB protein (hereinafter referred to as leptin), a leptin analog, a leptin receptor agonist, a galanin antagonist, a GI lipase inhibitor or reducer (such as orlistat). Other anorectives include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor, such as exendin and ciliary neurotrophic factors, such as axokines.

drugs for the treatment of hypertension include inhibitors of angiotensin converting enzyme, calcium antagonist, potassium channel opener, angiotensin II antagonists.

inhibitors 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 opener include Levcromakalim, L-27152, AL0671, NIP-121.

angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, Valsartan, Irbesartan, CS-866, E4177.

drugs for the treatment of hyperlipidemia, including arteriosclerosis HMG-CoA reductase inhibitors, fibrate compounds.

HMG-CoA Reductase inhibitors include pravastatin, simvastatin, lovastatin, Atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and its salts.

Fibrate compounds include bezafibrates, clinofibrates, clofibrates, simfibrates.

drugs for the treatment of arthritis include ibuprofen.

drugs for the treatment of anxiety include chlordiazepoxides, diazepam, oxazolam, medazepam, cloxazolam, Bromazepam, Lorazepam, Alprazolam, Fludiazepam.

drugs for the treatment of depression include fluoxetine, fluvoxamine, Imipramine, Paroxetine, Sertraline.

The Dose for these active substances is this expediently 1/5 of the usual recommended lowest dosage up to 1/1 of the normally recommended Dosage.

In a further embodiment The invention also relates to the use of at least one amide compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal. This use is based, in particular, on the fact that compounds according to the invention are suitable can, reduce hunger, curb appetite, control eating habits and / or to cause a feeling of satiety. The eating behavior is favorably influenced to the effect that the Food intake is reduced. Therefore, find the compounds of the invention advantageous application for reducing body weight. Another use according to the invention is preventing an increase in body weight, for example in people who took action before to reduce weight and then to are interested in maintaining the reduced body weight. According to this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic use may be a cosmetic application, for example, to change the external appearance, or an application to improve the general condition. The Compounds of the invention are preferably for mammals, especially people, non-therapeutically used, no diagnosed disorders eating habits, no diagnosed obesity, bulimia, diabetes and / or no diagnosed voiding disorders, especially urinary incontinence exhibit.

Prefers are the compounds of the invention suitable for non-therapeutic use for people whose Body Weight Index (BMI = body mass index), which is the body weight measured in kilograms divided by height (in meters) is defined in square, below the value 30, in particular below 25, lies.

The following examples should the invention in more detail explain:

Preliminary remarks:

For prepared compounds are usually present IR, ¹ H-NMR and / or mass spectra. Unless otherwise stated, R _f values are determined using GCF Finished Tops Kieselgel 60 F ₂₅₄ (E. Merck, Darmstadt, Article No. 1.05714) with no chamber saturation. The R _f values determined under the name Alox are determined using DC precast plates aluminum oxide 60 F ₂₅₄ (E.

Merck, Darmstadt, article no. 1.05713) without chamber saturation. The ratios indicated for the flow agents relate to volume units of the respective solvents. The indicated volume units at NH ₃ refer to a concentrated solution of NH ₃ in water. For chromatographic purifications, silica gel from Millipore (MATREX ^™ , 35-70 my) is used. For chromatographic purifications Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 microns, item no: 1.01097.9050) is used. The indicated HPLC data are measured under the parameters listed below: Analytical columns: Zorbax column (Agilent Technologies), SB (stable bond) - C18; 3.5 μm; 4.6 × 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 μL; Detection at 254 nm (Methods A and B)
Symmetry 300 (Waters), 3.5 μm; 4.6 × 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 μL; Detection at 254 nm (Method C) Method A: Water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 over 9 min Method B: Water: acetonitrile: formic acid 9: 1: 0.01 after 1: 9: 0.01 over 4 min, then 6 min 1: 9: 0.01 Method C: Water: acetonitrile: formic acid 9: 1: 0.01 after 1: 9: 0.01 over 4 min, then 6 min 1: 9: 0.01

preparative Pillar: Zorbax column (Agilent Technologies), SB (Stable Bond) - C18; 3.5 μm; 30 × 100 mm; Column temperature: room temperature; Flow: 30 mL / min; Detection at 254 nm.

at preparative HPLC purifications usually use the same gradients used in the collection of analytical HPLC data.

The Collection of products is mass-controlled, containing the product Fractions are combined and freeze-dried.

If details Information about the configuration is missing, remains open, whether it is pure Enantiomers or whether partial or even complete racemization occurred is.

The following abbreviations are used above and below: Section. made absolute Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl CDI N, N'-carbonyldiimidazole CDT 1,1'-carbonyldi (1,2,4-triazole) DMF N, N-dimethylformamide ether diethyl ether EtOAc ethyl acetate EtOH ethanol Fmoc 9-fluorenylmethoxycarbonyl ges. saturated half-concentrated. semi focused HCl hydrochloric acid HOAc acetic acid HOBt 1-hydroxybenzotriazole hydrate Hunig base N-ethyldiisopropylamine HV high vacuum i. vac. in vacuo (in vacuum) KOH potassium hydroxide conc. concentrated MeOH methanol MTBE Methyl tert-butyl ether NaCl sodium chloride NaOH sodium hydroxide org. organic Ph phenyl RT room temperature TBTU 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate TEBAC triethylbenzylammonium TFA trifluoroacetic THF tetrahydrofuran → * denotes the binding site of a residue

Example 1.1:

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4-prop-1-ynyl-plhenyl) -amide

1.1.a. 4-prop-1-ynyl-phenylamine

5.47 g (25 mmol) of 4-iodoaniline, 0.878 g (1.25 mmol) of bis-triphenylphosphine palladium dichloride, 0.47 g (2.5 mmol) of copper (I) iodide and 20 ml of piperidine are placed in a pressure apparatus. Subsequently, 6.1 bar of gaseous propyne are introduced into the pressure apparatus, with the temperature rising to 39.degree. Therefore, it is cooled with water. The mixture is stirred for two hours at room temperature and then the reaction mixture is extracted with ethyl acetate and water. The organic phase is dried over sodium sulfate, concentrated and the residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 4: 1).
Yield: 2.1 g (64% of theory)
C ₉ H ₉ N (M = 131.17)
Calc .: Molpeak (M + H) ⁺ : 132 Found: Molepeak (M + H) ⁺ : 132

1.1.b. Propinsäure- (4-prop-1-ynyl-phenyl) -amide

1.2 g (5.86 mmol) of DCC are added at 0 ° C. to a solution of 375 mg (5.35 mmol) of propynoic acid in 10 ml of dichloromethane and the mixture is stirred for 30 minutes. Then 0.7 g (5.35 mmol) of 4-prop-1-ynyl-phenylamine dissolved in dichloromethane are slowly added dropwise and the mixture is stirred at 0 ° C. for a further 2 hours. The reaction mixture is then filtered through Celite and the filtrate is concentrated. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol = 40: 1).
Yield: 0.7 g (71.4% of theory)
C ₁₂ H ₉ NO (M = 183.21)
Calc .: Molpeak (M + H) ⁺ : 184 Found: Molepeak (M + H) ⁺ : 184
R _f value: 0.65 (silica gel, dichloromethane / ethanol / acetic acid 20: 1)

1.1.c. 1- (4-iodo-benzyl) -pyrrolidine

A solution of 5 g (16.83 mmol) of 4-iodobenzylbromide, 1.41 ml (17 mmol) of pyrrolidine and 4.8 ml (34.43 mmol) of triethylamine in 50 ml of dichloromethane are stirred for 14 hours at room temperature. The reaction mixture is mixed with water, the organic phase separated and dried over sodium sulfate.
Yield: 4 g (82.7% of theory)
C ₁₁ H ₁₄ IN (M = 287.14)
Calc .: Molpeak (M + H) ⁺ : 288 Found: Molepeak (M + H) ⁺ : 288

1.1.d. 3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4-prop-1-ynyl-phenyl) -amide

10 ml of acetonitrile are degassed and treated with 0.35 ml (2 mmol) of ethyldiisopropylamine and 0.2 g (0.69 mmol) of 1- (4-iodobenzyl) -pyrrolidine. Then it is degassed again and there are successively added 13 mg of copper (I) iodide, 34 mg Tetrakistriphenylphosphinpalladium and 137 mg (0.75 mmol) of propynoic acid (4-prop-1-ynyl-phenyl) -amide. The reaction mixture is stirred for 24 hours at room temperature and then admixed with 60 mg of propynoic acid (4-prop-1-ynylphenyl) -amide. After 24 hours, the batch is concentrated. The purification is carried out by column chromatography on silica gel (dichloromethane / methanol / ammonia = 30: 1: 0.1 to 20: 1: 0.1).
Yield: 24 mg (10% of theory)
C ₂₃ H ₂₂ N ₂ O (M = 342.44)
Calc .: Molpeak (M + H) ⁺ : 343 Found: Molepeak (M + H) ⁺ : 343
R _f value: 0.2 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.2:

3- (4-piperidin-1-ylmethyl-phenyl) -propinsäure- (4-prop-1-ynyl-phenyl) -amide

1.2.a. 3- (4-hydroxymethyl-phenyl) -propinsäure- (4-prop-1-ynyl-phenyl) -amide

40 ml of THF are degassed, treated with 2.62 g (8.03 mmol) of cesium carbonate and 4-iodobenzyl alcohol and degassed again. 138 mg (0.12 mmol) of tetrakistriphenylphosphine palladium, 53 mg (0.28 mmol) of copper (I) iodide and 0.7 g (3.2 mmol) of propynoic acid (4-prop-1-ynyl) are successively added to this reaction mixture. phenyl) -amide. It is stirred for 24 hours at room temperature and the reaction mixture is subsequently concentrated. The residue is purified by column chromatography on silica gel (eluant: dichloromethane / ethanol = 60: 1).
Yield: 0.5 g (57.8% of theory)
C ₁₉ H ₁₅ NO ₂ (M = 289.33)
Calc.: Molpeak (M + H) ⁺ : 290 Found: Molepeak (M + H) ⁺ : 290
R _f value: 0.21 (silica gel, dichloromethane / ethanol = 50: 1)

1.2.b. Methanesulfonic acid 4 - [(4-prop-1-ynyl-phenylcarbamoyl) ethynyl] benzyl ester

To a solution of 0.5 g (1.72 mmol) of 3- (4-hydroxymethyl-phenyl) -propynoic acid (4-prop-1-ynyl-phenyl) -amide and 0.49 ml (3.6 mmol) 0.14 ml (1.8 mmol) of methanesulfonyl chloride are slowly added dropwise at room temperature to triethylamine in 20 ml of dichloromethane and the reaction mixture is stirred at room temperature for two hours. It is extracted three times with water and the organic phase dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether.
Yield: 0.48 g (75.6% of theory)
C ₂₀ H ₁₇ NO ₄ S (M = 367.42)
Calc .: Mol peak (M + H) ⁺ : 368 Found: Mol peak (M + H) ⁺ : 368
R _f value: 0.48 (silica gel, dichloromethane / ethanol = 20: 1)

1.2.c. 3- (4-piperidin-1-ylmethyl-phenyl) -propinsäure- (4-prop-1-ynyl-phenyl) -amide

A reaction mixture of 0.5 mg (0.13 mmol) of methanesulfonic acid 4 - [(4-prop-1-ynyl-phenylcarbamoyl) -ethynyl] benzyl ester, 0.028 ml (0.28 mmol) of piperidine in 5 ml of THF becomes 14 Stirred hours at room temperature. The reaction mixture is concentrated. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol = 25: 1 to 15: 1).
Yield: 13 mg (26.8% of theory)
Melting point: 180-181 ° C
C ₂₄ H ₂₄ N ₂ O (M = 356.47)
Calc .: Mol peak (M + H) ⁺ : 357 Found: Mol peak (M + H) ⁺ : 357
R _f value: 0.21 (silica gel, dichloromethane / ethanol = 20: 1)

The following compounds were prepared analogously to Example 1.2.c:

Example 1.8:

3- (4-piperidin-1-ylmethyl-phenyl) -propinsäure- (4'-methoxy-biphenyl-4-yl) -amide

1.8.a. Propinsäure- (4'-methoxy-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.b from propynoic acid and 4'-methoxy-biphenyl-4-ylamine.
Yield: 1.3 g (17.2% of theory)
C ₁₆ H ₁₃ NO ₂ (M = 251.28)
Calc .: Mol peak (M + H) ⁺ : 252 Found: Mol peak (M + H) ⁺ : 252
R _f value: 0.6 (silica gel, dichloromethane / ethanol = 20: 1)

1.8.b. 3- (4-hydroxymethyl-phenyl) -propinsäure- (4'-methoxy-biphenyl-4-yl) -amide

Prepared analogously to Example 1.2.a from iodobenzyl alcohol and propynoic acid (4'-methoxybiphenyl-4-yl) amide.
Yield: 0.21 g (22.9% of theory)
C ₂₃ H ₁₉ NO ₃ (M = 357.41)
Calc .: Molpeak (M + H) ⁺ : 358 Found: Molepeak (M + H) ⁺ : 358
R _f value: 0.35 (silica gel, dichloromethane / ethanol = 20: 1)

1.8.c. Methanesulfonic acid 4 - [(4'-methoxy-biphenyl-4-ylcarbamoyl) ethynyl] benzyl ester

Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propinsäure- (4'-methoxy-biphenyl-4-yl) -amide and methanesulfonyl chloride.
Yield: 0.18 g (70.3% of theory)
C ₂₄ H ₂₁ NO ₅ S (M = 435.50)
R _f value: 0.58 (silica gel, dichloromethane / ethanol = 20: 1)

1.8.d. 3- (4-piperidin-1-ylmethyl-phenyl) -propinsäure- (4'-methoxy-phenyl) -amide

Prepared analogously to Example 1.2.c from methanesulfonic acid 4 - [(4'-methoxy-biphenyl-4-ylcarbamoyl) -ethynyl] benzyl ester and piperidine.
Yield: 5 mg (18.8% of theory)
Melting point: 170 ° C
C ₂₈ H ₂₈ N ₂ O ₂ (M = 424.54)
Calc .: Molpeak (M + H) ⁺ : 425 Found: Molepeak (M + H) ⁺ : 425
R _f value: 0.28 (silica gel, dichloromethane / ethanol = 20: 1)

The following compounds were prepared analogously to Example 1.8.d:

Example 1.17:

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-3-fluoro-biphenyl-4-yl) -amide

1.17.a. 4'-chloro-3-fluoro-biphenyl-4-ylamine

To a reaction mixture of 2.28 g (12 mmol) of 4-bromo-2-fluoroaniline and 0.6 g (0.51 mmol) of tetrakistriphenylphosphine palladium in 90 ml of dioxane are added successively 1.95 g (12.47 mmol) of 4-chlorophenylboronic acid , dissolved in 10 ml of methanol and 3.9 g (36.79 mmol) of sodium carbonate, dissolved in 10 ml of water, added and stirred at 80 ° C for 14 hours. Subsequently, ethyl acetate is added and the reaction mixture is filtered. The filtrate is concentrated and extracted with ethyl acetate and water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 3: 1).
Yield: 2 g (75.2% of theory)
C ₁₂ H ₉ FN (M = 221.66)
Calc .: Mol peak (M + H) ⁺ : 222 Found: Mol peak (M + H) ⁺ : 222
R _f value: 0.41 (silica gel, cyclohexane / ethyl acetate 3: 1)

1.17.b. Propinsäure- (4'-chloro-3-fluoro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.b from 4'-chloro-3-fluoro-biphenyl-4-ylamine and propynic acid.
Yield: 0.16 g (43.7% of theory)
C ₁₅ H ₉ ClFNO (M = 273.69)
Calc .: Molpeak (M + H) ⁺ : 274/276 Found: Molpeak (M + H) ⁺ : 274/276
R _f value: 0.3 (silica gel, cyclohexane / ethyl acetate 3: 1)

1.17.c. 3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-3-fluoro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -pyrrolidine and propynoic acid (4'-chloro-3-fluoro-biphenyl-4-yl) -amide.
Yield: 20 mg (13% of theory)
Melting point: 136 ° C
C ₂₆ H ₂₂ ClFN ₂ O (M = 432.92)
Calc.: Molpeak (M + H) ⁺ : 433/435/437 Found: Molpeak (M + H) ⁺ : 433/435/437
R _f value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.18:

3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-2'-fluoro-biphenyl-4-yl) -amide

1.18.a. 3- (4-hydroxymethyl-phenyl) -propinsäure- (4'-chloro-2'-fluoro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.2.a from propynoic acid (4'-chloro-3-fluoro-biphenyl-4-yl) -amide and 4-iodobenzyl alcohol.
Yield: 0.4 g (41% of theory)
C ₂₂ H ₁₅ ClFNO ₂ (M = 379.82)
Calc .: Molpeak (M + H) ⁺ : 380/382 Found: Molpeak (M + H) ⁺ : 380/382
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 20: 1: 0.1)

1.18.b. Methanesulfonic acid 4 - [(4'-chloro-2'-fluoro-biphenyl-4-ylcarbamoyl) ethynyl] benzyl ester

Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propinsäure- (4'-chloro-2'-fluoro-biphenyl-4-yl) -amide and methanesulfonyl chloride.
Yield: 0.23 g (50% of theory)
C ₂₃ N ₁₇ ClFN ₂ O ₂ S (M = 457.91)
Calc.: Molpeak (M + H) ⁺ : 456/458 Found: Molepeak (M + H) ⁺ : 456/458
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 20: 1: 0.1)

1.18.c. 3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-2'-fluoro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.2.c from methanesulfonic acid 4 - [(4'-chloro-2'-fluorobiphenyl-4-ylcarbamoyl) ethynyl] benzyl ester and 4-methylpiperidine.
Yield: 13 mg (21% of theory)
Melting point: 149-150 ° C
C ₂₈ H ₂₆ ClFN ₂ O (M = 460.98)
Calc .: Molpeak (M + H) ⁺ : 461/463 Found: Molepeak (M + H) ⁺ : 461/463
R _f value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 20: 1: 0.1)

The following compounds were prepared analogously to Example 1.2.c:

Example 1.23:

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide

1.23.a. Propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.b from 4'-chloro-biphenyl-4-ylamine and propynic acid.
Yield: 0.4 g (29.2% of theory)
C ₁₅ H ₁₀ ClNO (M = 255.70)
Calc .: Mol peak (M + H) ⁺ : 256/258 Found: Mol peak (M + H) ⁺ : 256/258
R _f value: 0.35 (silica gel, dichloromethane / ethanol 20: 1)

1.23.b. Propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide

To a solution of 0.4 g (1.56 mmol) of propynoic acid (4'-chloro-biphenyl-4-yl) -amide in 10 ml of THF at 0 ° C 75 mg (1.72 mmol) of sodium hydride (55 %) and stirred for one hour at this temperature. Subsequently, 0.098 ml (1.56 mmol) of methyl iodide are added dropwise and stirred for 14 hours, while allowing the reaction mixture to warm to room temperature. Subsequently, the reaction mixture is extracted with water and ethyl acetate and the organic phase dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 3: 1).
Yield: 0.15 g (35.6% of theory)
C ₁₆ H ₁₂ ClNO (M = 269.73)
Calcd .: Mol peak (M + H) ⁺ : 270/272 Found: Mol peak (M + H) ⁺ : 270/272
R _f value: 0.61 (silica gel, cyclohexane / ethyl acetate 1: 1

1.23.c. 3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) pyrrolidine and propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide.
Yield: 38 mg (25.4% of theory)
Melting point: 161-164 ° C
C ₂₇ H ₂₅ ClN ₂ O (M = 428.96)
Calc .: Molpeak (M + H) ⁺ : 429/431 Found: Molpeak (M + H) ⁺ : 429/431
R _f value: 0.41 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.24:

3- [4- (4-pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) methyl-amide ditrifluoroacetat

1.24.a. 1- (4-iodo-benzyl) -4-pyrrolidin-1-yl-piperidine

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-pyrrolidin-1-yl-piperidine.
Yield: 0.57 g (51% of theory)
C ₁₆ H ₂₃ IN ₂ (M = 370.28)
Calcd .: Mol peak (M + H) ⁺ : 371 Found: Mol peak (M + H) ⁺ : 371
R _f value: 0.3 (silica gel, dichloromethane / ethanol 20: 1)

1.24.b. 3- [4- (4-pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide ditrifluoroacetat

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -4-pyrrolidin-1-yl-piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide.
Yield: 5 mg (4% of theory)
Melting point: 161-164 ° C
C ₃₂ H ₃₄ ClN ₃ OX 2 CF ₃ CO ₂ H (M = 740.14)
Calc .: Molpeak (M + H) ⁺ : 512/514 Found: Molepeak (M + H) ⁺ : 512/514
R _f value: 0.41 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.25:

3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) methyl-amide

1.25.a. 3- (4-hydroxymethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide

Prepared analogously to Example 1.2.a from 4-iodo-benzyl alcohol and propynoic acid (4'-chlorobiphenyl-4-yl) -methyl-amide.
Yield: 0.52 g (90% of theory)
C ₂₃ H ₁₈ ClNO ₂ (M = 375.85)
Calc .: Molpeak (M + H) ⁺ : 376/378 Found: Molpeak (M + H) ⁺ : 376/378
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

1.25.b. Methanesulfonic acid 4 - {[(4'-chloro-biphenyl-4-yl) -methyl-carbamoyl] -ethynyl} benzyl ester

Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide.
Yield: 0.54 g (100% of theory)
C ₂₄ H ₂₀ ClNO ₄ S (M = 453.94
Calc.: Molpeak (M + H) ⁺ : 454/456 Found: Molepeak (M + H) ⁺ : 454/456

1.25.c. 3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide

Prepared analogously to Example 1.2.c from methanesulfonic acid 4 - {[(4'-chloro-biphenyl-4-yl) -methyl-carbamoyl] -ethynyl} -benzyl ester and 4-methylpiperidine.
Yield: 8 mg (16% of theory)
C ₂₉ H ₂₉ ClN ₂ O (M = 457.02)
Calc .: Molpeak (M + H) ⁺ : 457/459 Found: Molpeak (M + H) ⁺ : 457/459
R _f value: 0.41 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1) The following compounds were prepared analogously to Example 1.2.c:

Example 1.33:

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.33.a. 1- (4-Trimethylsilanylethynyl-benzyl) -pyrrolidine

A reaction mixture of 1 g (3.48 mmol) of 1- (4-iodobenzyl) -pyrrolidine, 5 ml of piperidine, 105 mg (0.091 mmol) of tetrakistriphenylphosphine palladium and 10 mg (0.053 mmol) of copper (I) iodide is brought to 0 ° C cooled. At this temperature, 0.59 ml (4.18 mmol) of trimethylsilylacetylene are added dropwise and then removed the cooling bath. It is stirred for three hours at room temperature, then treated with a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 1: 1).
Yield: 0.75 g (83.6% of theory)
C ₁₆ H ₂₃ NSi (M = 257.45)
Calc .: Mol peak (M + H) ⁺ : 258 Found: Mol peak (M + H) ⁺ : 258

1.33.b. 1- (4-ethynyl-benzyl) -pyrrolidine

A solution of 0.75 g (2.91 mmol) of 1- (4-trimethylsilanylethynyl-benzyl) -pyrrolidine in 10 ml of dichloromethane and 10 ml of methanol is added 2.4 ml of a 1 M sodium hydroxide solution and stirred for three hours at room temperature. The reaction mixture is concentrated and the residue extracted with water and ethyl acetate. The organic phase is stirred with activated charcoal, filtered and then dried over sodium sulfate.
Yield: 0.4 g (74.1% of theory)
C ₁₃ H ₁₅ N (M = 185.27)
Calc .: Molpeak (M + H) ⁺ : 186 Found: Molepeak (M + H) ⁺ : 186

1.33.c. (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure

To a solution of 2.3 g (12.41 mmol) of 1- (4-ethynylbenzyl) -pyrrolidine in 50 ml of THF at -78 ° C 5.98 ml (14.85 mmol) of a 1.6 M Butyllithiumlösung added dropwise in n-hexane and stirred for one hour at this temperature. Subsequently, dry ice is added to the reaction mixture. Thereafter, the reaction mixture is allowed to come to room temperature and stirred for 14 hours. The reaction mixture is treated with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is separated and dried over sodium sulfate. The sodium sulfate is separated and the solvent removed.
Yield: 0.3 g (10.5% of theory)
C ₁₄ H ₁₅ NO ₂ (M = 229.28)
Calcd .: Mol peak (M + H) ⁺ : 230 Found: Mol peak (M + H) ⁺ : 230
R _f value: 0.15 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

1.33.d. 3- (4-pyrrolidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

A solution of 0.3 g (1.30 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -propynoic acid, 0.27 g (1.32 mmol) of 4'-chloro-biphenyl-4-ylamine, O, 42 g (1.32 mmol) of TBTU and 0.18 ml (1.32 mmol) of triethylamine in 30 ml of DMF are stirred for 14 hours at room temperature. The reaction mixture is concentrated and the residue is extracted with water and dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol = 10: 1).
Yield: 0.095 g (17.5% of theory)
Melting point: from 180 ° C
C ₂₆ H ₂₃ ClN ₂ O (M = 414.93)
Calc.: Molpeak (M + H) ⁺ : 415/417 Found: Molepeak (M + H) ⁺ : 415/417
R _f value: 0.3 (silica gel, dichloromethane / ethanol = 5: 1)

Example 1.34:

3- {4- [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-ylmethyl] -phenyl} -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.34.a. 2- [1- (4-iodo-benzyl) -piperidin-4-yl] -propan-2-ol

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 2-piperidin-4-yl-propan-2-ol.
Yield: 1.01 g (67% of theory)
C ₁₅ H ₂₂ INO (M = 359.25)
Calc .: Mol peak (M + H) ⁺ : 360 F: Mol peak (M + H) ⁺ : 360
R _f value: 0.4 (silica gel, dichloromethane / ethanol 20: 1)

1.34.b. 3- {4- [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-ylmethyl] -phenyl} -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 2- [1- (4-iodo-benzyl) -piperidin-4-yl] -propan-2-ol and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.
Yield: 45 mg (30% of theory)
Melting point: 194-195 ° C
C ₃₀ H ₃₁ ClN ₂ O ₂ (M = 487.04)
Calc .: Molpeak (M + H) ⁺ : 487/489 Found: Molpeak (M + H) ⁺ : 487/489
R _f value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.35:

3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.35.a. 1- (4-iodo-benzyl) -4-methyl-piperidine

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-methyl-pipiridine.
Yield: 0.95 g (71.6% of theory)
C ₁₃ H ₁₈ IN (M = 315.20)
Calc .: Molpeak (M + H) ⁺ : 316 Found: Molepeak (M + H) ⁺ : 316
R _f value: 0.6 (silica gel, dichloromethane / ethanol 20: 1)

1.35.b. 3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -4-methyl-piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.
Yield: 50 mg (27% of theory)
C ₂₈ H ₂₇ ClN ₂ O (M = 442.99)
Calc .: Molpeak (M + H) ⁺ : 443/445 Found: Molepeak (M + H) ⁺ : 443/445
R _f value: 0.45 (silica gel, dichloromethane / methanol = 10: 1)

Example 1.36:

3- [4- (4-methoxy-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.36.a. 1- (4-iodo-benzyl) -4-methoxy-piperidine

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-methoxy-piperidine.
Yield: 0.93 g (66.7% of theory)
C ₁₃ H ₁₈ INO (M = 331.19)
Calcd .: Mol peak (M + H) ⁺ : 332 Found: Mol peak (M + H) ⁺ : 332
R _f value: 0.55 (silica gel, dichloromethane / ethanol 20: 1)

1.36.b. 3- [4- (4-methoxy-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -4-methoxy-piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.
Yield: 25 mg (13% of theory)
Melting point: 145-146 ° C
C ₂₈ H ₂₇ ClN ₂ O ₂ (M = 458.99)
Calc.: Molpeak (M + H) ⁺ : 459/461 Found: Molepeak (M + H) ⁺ : 459/461
R _f value: 0.4 (silica gel, dichloromethane / methanol = 10: 1)

Example 1.37:

3- [4- (4-hydroxy-4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.37.a. 1- (4-iodo-benzyl) -4-methyl-piperidin-4-ol

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-methyl-piperidin-4-ol.
Yield: 0.22 g (30% of theory)
C ₁₃ H ₁₈ INO (M = 331.19)
Calcd .: Mol peak (M + H) ⁺ : 332 Found: Mol peak (M + H) ⁺ : 332
R _f value: 0.45 (silica gel, dichloromethane / ethanol 20: 1)

1.37.b. 3- [4- (4-hydroxy-4-methyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -4-methyl-piperidin-4-ol and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.
Yield: 25 mg (13% of theory)
Melting point: 192-193 ° C
C ₂₈ H ₂₇ ClN ₂ O ₂ (M = 458.99)
Calc.: Molpeak (M + H) ⁺ : 459/461 Found: Molepeak (M + H) ⁺ : 459/461
R _f value: 0.2 (silica gel, dichloromethane / methanol = 10: 1)

Example 1.38:

3- [4- (4-pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.38.a. 3- [4- (4-pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -4-pyrrolidin-1-yl-piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.
Yield: 15 mg (7% of theory)
Melting point: 191-192 ° C
C ₃₁ H ₃₂ ClN ₃ O (M = 498.07)
Calc .: Molpeak (M + H) ⁺ : 498/500 Found: Molpeak (M + H) ⁺ : 498/500
R _f value: 0.45 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.39:

3- (4-piperidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

1.39.a. 1- (4-iodo-benzyl) -piperidin

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and pipiridine.
Yield: 0.85 g (67% of theory)
C ₁₂ H ₁₆ IN (M = 301.17)
calc .: Mol peak (M + H) ⁺ : 322 found: Mol peak (M + H) ⁺ : 302
R _f value: 0.55 (silica gel, dichloromethane / ethanol 20: 1)

1.39.b. 3- (4-piperidin-1-ylmethyl-phenyl) -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodo-benzyl) -piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.
Yield: 6 mg (4% of theory)
Melting point: 179.5 ° C
C ₂₇ H ₂₅ ClN ₂ O (M = 428.96)
Calc .: Molpeak (M + H) ⁺ : 429/431 Found: Molpeak (M + H) ⁺ : 429/431
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1) The following compounds are prepared analogously to Example 1.2.c:

Example 2.1 .:

3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure-biphenyl-4-ylamide

2.1.a. 2- (4-iodo-phenyl) -ethanol

0.474 g (2.48 mmol) of copper (I) iodide, 5 g (24.86 mmol of 2- (4-bromo-phenyl) -ethanol and 7.45 g (49.73 mmol) of sodium iodide are heated in an argon atmosphere successively in Thereafter, 0.438 g (4.97 mmol) of dimethylenediamine and 25 ml of dioxane are added and the reaction mixture is heated to reflux for 14 hours, then the reaction mixture is admixed at room temperature with 20 ml of concentrated ammonia solution, diluted with 100 ml of water and washed with water The organic phase is extracted three times with water and dried over sodium sulfate.
Yield: 5.4 g (87.5% of theory)
C ₈ H ₉ IO (M = 248.06)
Calc .: Molpeak (M) ⁺ : 248 Found: Molpeak (M) ⁺ : 248
R _f value: 0.6 (silica gel, dichloromethane / ethanol = 10: 1)

2.1.b. Methanesulfonic acid 2- (4-iodo-phenyl) -ethyl ester

Prepared analogously to Example 1.2.b from 2- (4-iodo-phenyl) -ethanol and methanesulfonyl chloride.
Yield: 5.7 g (77.4% of theory)
C ₉ H ₁₁ IO ₃ S (M = 326.15)
Calc .: Molpeak (M) ⁺ : 326 Found: Molpeak (M) ⁺ : 326

2.1.c. 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine

To a solution of 2 g (6.13 mmol) of methanesulfonic acid 2- (4-iodo-phenyl) -ethyl ester in 30 ml of DMF, 1 ml (12.26 mmol) of pyrrolidine are added and the reaction solution is stirred at 70 ° C for six hours , The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The sodium sulfate is separated and the solvent removed.
Yield: 1.28 g (69.3% of theory)
C ₁₂ H ₁₆ IN (M = 301.17)
Calc .: Molpeak (M + H) ⁺ : 302 Found: Molpeak (M + H) ⁺ : 302
R _f value: 0.4 (silica gel, dichloromethane / methanol = 10: 1)

2.1.d. Propionic-biphenyl-4-yl-amide

To a solution of 2.89 g (41.36 mmol) of propionic acid in 100 ml of dichloromethane 9.38 g (45.5 mmol) of DCC are added in portions at -15 ° C and stirred for one hour. Then a -15 ° C cold solution of 7 g (41.36mmol) of biphenyl-4-ylamine in 30 ml of dichloromethane is added dropwise and stirred for two hours. After this time, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. To the reaction mixture, 20 g of Celite are added and then filtered. The filtrate is concentrated in vacuo. The residue is treated with acetonitrile and stirred. The suspension is filtered, the filtrate is concentrated and the residue is stirred with petroleum ether and pentane. The solid is isolated by filtration.
Yield: 5.5 g (60.1% of theory)
C ₁₅ N ₁₁ NO (M = 221.26)
Calc .: Mol peak (M + H) ⁺ : 222 Found: Mol peak (M + H) ⁺ : 222
R _f value: 0.7 (silica gel, dichloromethane / methanol = 10: 1)

2.1.e. 3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure-biphenyl-4-ylamide

25 ml of THF are degassed and treated with 0.25 g (0.83 mmol) of 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine, 0.81 g (2.49 mmol) of cesium carbonate, 16 mg of 0.083 mmol) of copper (I) iodide and 38 mg (0.033 mmol) tetrakistriphenylphosphine palladium. It is then degassed again, and there are added 184 mg (0.83 mmol) of propynoic acid biphenyl-4-ylamide. The reaction mixture is stirred at room temperature for 3 hours, poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. Purification by column chromatography on silica gel (dichloromethane / methanol / ammonia = 10: 1: 0.1)
Yield: 90 mg (27.5% of theory)
Melting point: 180-189 ° C
C ₂₇ H ₂₆ N ₂ O (M = 394.52)
Calc .: Mol peak (M + H) ⁺ : 395 Found: Mol peak (M + H) ⁺ : 395

Example 2.2 .:

3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure-4-chloro-phenylamide

2.2.a. Propinsäure- (4-chloro-phenyl) -amide

Prepared analogously to Example 1.1.b from propionic acid and 4-chloroaniline.
Yield: 0.56 g (31.2% of theory)
C ₉ N ₆ CINO (M = 179.60)
Calc .: Molpeak (MH) ^- : 178/180 Found: Molpeak (MH) ^- : 178/180
R _f value: 0.53 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

2.2.b. 3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure-4-chloro-phenylamide

Prepared analogously to Example 2.1.e from propynoic acid (4-chlorophenyl) amide and 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine.
Yield: 80 mg (34.1% of theory)
Melting point: 153-154 ° C
C ₂₁ H ₂₁ ClN ₂ O (M = 352.86)
Calc .: Molpeak (M + H) ⁺ : 353/355 Found: Molepeak (M + H) ⁺ : 353/355

Example 2.3 .:

3- (1-pyrrolidin-1-yl-indan-5-yl) -propin- (4'-chloro-biphenyl-4-yl) -amide

2.2.a. 5-bromo-indan-1-ol

To a solution of 5 g (22.98 mmol) of 5-bromo-1-indanone in 100 ml of isopropanol, 0.9'87 g (23 mmol) of sodium borohydride are added at room temperature and the reaction mixture is stirred for five hours. Subsequently, an acidic pH is adjusted by careful addition of potassium bisulfate solution and the reaction mixture is extracted with tert-butyl methyl ether. The organic phase is extracted with saturated sodium chloride solution and then dried with magnesium sulfate. The filtrate is concentrated after separation of the magnesium sulfate in vacuo. The residue is dissolved in tert.butyl methyl ether and extracted successively with dilute sodium bicarbonate solution and water. It is then dried over magnesium sulfate and filtered through activated charcoal. The filtrate is concentrated in vacuo.
Yield: 3.6 g (73.5% of theory)
C ₉ H ₉ BrO (M = 213.07)
R _f value: 0.6 (silica gel, petroleum ether / ethyl acetate = 6: 4)

2.3.b. 5-bromo-1-chloro-indan

To a solution of 3.8 g (17.83 mmol) of 5-bromo-indan-1-ol in 200 ml of dichloromethane at -10 ° C 3.09 ml (37.45 mmol) of thionyl chloride, dissolved in cooled dichloromethane, is added dropwise, the reaction mixture is allowed to slowly warm to room temperature and stirred for 14 hours at room temperature. Subsequently, successively ice and 100 ml of dilute sodium bicarbonate solution are added. The organic phase is extracted twice with 50 ml of water each time. The combined organic phases are dried over magnesium sulfate, filtered and the solvent is distilled off.
Yield: 3.7 g (90% of theory)
C ₉ H ₈ BrCl (M = 231.52)
R _f value: 0.91 (silica gel, petroleum ether / ethyl acetate = 6: 4)

2.3.c. 1- (5-bromo-indan-1-yl) -pyrrolidine

To a solution of 3.71 g (16.92 mmol) of 5-bromo-1-chloro-indane in 250 ml of dichloromethane at 0 ° C is added 7 ml (85.23 mmol) of pyrrolidine. The reaction mixture is allowed to warm to room temperature and stirred for 24 hours. It is then extracted once with water and the organic phase extracted with potassium bisulfate solution. The aqueous phase is extracted once with dichloromethane. Subsequently, the aqueous phase is basified with sodium carbonate solution to liberate the product. This solution is extracted with dichloromethane, the organic phase extracted with water and dried over magnesium sulfate.
Yield: 1.81 g (42.4% of theory)
C ₁₃ H ₁₆ BrN (M = 266.18)
Calc .: Molpeak (M + H) ⁺ : 266/268 Found: Molepeak (M + H) ⁺ : 266/268

2.3.c. 1- (5-iodo-indan-1-yl) -pyrrolidine

Prepared analogously to Example 2.1.a from 1- (5-bromo-indan-1-yl) -pyrrolidine.
Yield: 1.42 g (83.5% of theory)
C ₁₃ H ₁₆ IN (M = 313.18)
Calc .: Mol peak (M + H) ⁺ : 314 Found: Mol peak (M + H) ⁺ : 314

2.3.d. (1-pyrrolidin-1-yl-indan-5-yl) -propinsäure

Under an argon atmosphere, 0.5 g (1.59 mmol) of 1- (5-iodo-indan-1-yl) -pyrrolidine and 123 mmol (2 mmol) of propynoic acid are dissolved in 25 ml of acetonitrile at 0 ° C. To this solution, 0.66 ml (4.79 mmol) of triethylamine, 30 mg (0.16 mmol) of copper (I) iodide and 80 mg (0.11 mmol) of Ditriphenylphophinpalladiumdichlorid be added and stirred for two hours, with the solution Room temperature can be heated. Purification by preparative HPLC (eluent: dichloromethane / methanol / ammonia = 8: 2: 0.2)
Yield 0.1 g (24.5% of theory)
C ₁₆ H ₁₇ NO ₂ (M = 255.31)
Calc .: Molpeak (M + H) ⁺ : 256 Found: Molepeak (M + H) ⁺ : 256

2.3.f. 3- (1-pyrrolidin-1-yl-indan-5-yl) -propin- (4'-chloro-biphenyl-4-yl) -amide

A solution of 0.1 g (0.39 mmol) of (1-pyrrolidin-1-yl-indan-5-yl) -propynoic acid and 47 mmol (0.43 mmol) of N-methylmorpholine in 5 ml of absolute THF is added at - 15 ° C with 56 microliters (0.43 mmol) of isobutyl chloroformate and stirred for ten minutes. Thereafter, 87 mg (0.43 mmol) of 4'-chlorobiphenyl-4-ylamine are added at room temperature and the reaction mixture is stirred for 14 hours. Subsequently, 3 ml of dichloromethane are added to the reaction mixture and stirred for 48 hours. Thereafter, the reaction mixture is filtered, the filtrate is concentrated, treated with water and extracted with dichloromethane. The organic phase is concentrated. Purification by preparative HPLC (eluent: dichloromethane / methanol / ammonia = 8: 2: 0.2)
Yield: 9 mg (5.7% of theory)
C ₂₈ H ₂₅ ClN ₂ O (M = 440.97)
Calc .: Molpeak (M + H) ⁺ : 441/443 Found: Molepeak (M + H) ⁺ : 441/443

Example 2.4 .:

3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

2.3.a. 3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure- (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 2.1.e from propynoic acid (4'-chloro-biphenyl-4-yl) -amide and 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine.
Yield: 70 mg (32.8% of theory)
Melting point: 217-218 ° C
C ₂₇ H ₂₅ ClN ₂ O (M = 428.96)
Re: Moipeak (M + H) ⁺ : 429/431 Found: Molpeak (M + H) ⁺ : 429/431
R _f value: 0.3 (silica gel, dichloromethane / methanol = 10: 1)

Example 2.5 .:

3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure- (4-prop-1-ynyl-phenyl) -amide

2.4.a. 3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propinsäure- (4-prop-1-ynyl-phenyl) -amide

Prepared analogously to Example 2.1.e from propynoic acid (4-prop-1-ynyl-phenyl) -amide and 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine.
Yield: 20 mg (11% of theory)
Melting point: 198-199 ° C
C ₂₄ H ₂₄ N ₂ O (M = 356.47)
R _f value: 0.1 (silica gel, dichloromethane / methanol = 10: 1)

Example 3.1 .:

3-phenyl-propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

3.1.a. Diethyl [2- (4-nitro-phenoxy) -ethyl] -amine

To a suspension of 71.7 g (515.41 mmol) of p-nitrophenol and 284.94 g (2.061 mol) of potassium carbonate in 600 ml of DMF at room temperature 88.7 g (515.41 mmol) (2-chloro-ethyl ) -diethylamine hydrochloride and the reaction mixture heated at 80 ° C for eight hours. The reaction mixture is concentrated and the residue is poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the filtrate is concentrated.
Yield: 110.52 g (90% of theory)
C ₁₂ H ₁₈ N ₂ O ₃ (M = 238.28)
R _f value: 0.52 (silica gel, dichloromethane / methanol = 10: 1)

3.1.B. 4- (2-diethylamino-ethoxy) -phenylamine

A reaction mixture of 110.52 g (0.464 mol) of diethyl [2- (4-nitro-phenoxy) ethyl] amine and 17 g of Raney nickel in 700 ml of methanol is hydrogenated for 30 hours at 20 ° C and 3 bar of hydrogen , The catalyst is filtered off and the filtrate is concentrated.
Yield: 93 g (96.2% of theory)
C ₁₂ H ₂₀ N ₂ O (M = 208.30)
Calc .: Molpeak (M) ⁺ : 209 Found: Molpeak (M) ⁺ : 209

3.1.c. [4- (2-diethylamino-ethoxy) -phenyl] -carbamic acid methyl ester

76.38 g (366.66 mmol) of 4- (2-diethylamino-ethoxy) -phenylamine and 101.65 ml (733.33 mmol) of triethylamine are dissolved in 400 ml of THF. To this solution, a solution of 49.16 g (366.66 mmol) of dimethyl pyrocarbonate in 200 ml of THF is added dropwise within 45 minutes at 25 ° C and stirred for two hours at room temperature. The reaction mixture is concentrated, the residue is added to water and extracted with ethyl acetate. The combined organic phases are extracted twice with water. The organic phase is concentrated to give a precipitate which is filtered off. The filtrate is further concentrated. The purification is carried out by column chromatography on aluminum oxide (eluant: ethyl acetate / petroleum ether = 3: 1).
Yield: 63.3 g (64.8% of theory)
C ₁₄ H ₂₂ N ₂ O ₃ (M = 266.34)
calc .: Mol peak (M + H) ⁺ : 267 found: Mol peak (M + H) ⁺ : 267
R _f value: 0.62 (alumina, ethyl acetate / petroleum ether = 3: 1)

3.1.d. [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine

To a suspension of 10.68 g (281.59 mmol) of lithium aluminum hydride in 600 ml of absolute THF are added 30 g (112.63 mmol) of methyl [4- (2-diethylamino-ethoxy) -phenyl] -carbamate, dissolved in 300 ml of absolute THF, slowly added dropwise with ice cooling and nitrogen atmosphere. The mixture is subsequently stirred for 14 hours, during which the reaction mixture is allowed to warm to room temperature. Then, after reaction control, 7 g of lithium aluminum hydride are added and stirred for 14 hours. By adding 60 ml of 20% sodium hydroxide solution, the reaction is stopped. The precipitate is filtered off and rinsed with diisopropyl ether. The filtrate is dried over sodium sulfate and the solvent is distilled off.
Yield: 24.7 g (98.6% of theory)
C ₁₃ H ₂₂ N ₂ O (M = 222.33)
Calc .: Molpeak (M + H) ⁺ : 223 Found: Molepeak (M + H) ⁺ : 223
R _f value: 0.44 (silica gel, dichloromethane / methanol / ammonia = 10: 1)

3.1.e. 3-phenyl-propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

A solution of 0.29 g (2 mmol) of phenyl-propynoic acid, 0.44 g (2 mmol) of [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine, 0.7 g (2.2 mmol ) TBTU 0.29 g (2.2 mmol) HOBT and 0.51 ml (3 mmol) Hünig base in 30 ml THF and 2 ml DMF is stirred for 14 hours at room temperature. The reaction mixture is concentrated. Purification by column chromatography on silica gel (dichloromethane / methanol = 80:20)
Yield: 130 mg (18.5% of theory)
C ₂₂ H ₂₆ N ₂ O ₂ (M = 350.46)
Calc .: Molpeak (M + H) ⁺ : 351 Found: Molepeak (M + H) ⁺ : 351
R _f value: 0.39 (silica gel, dichloromethane / methanol = 80:20)

Example 3.2 .:

3- (4-methoxy-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

3.2.a. 3- (4-methoxy-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

Prepared analogously to Example 3.1.e from [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine and (4-methoxyphenyl) -propynoic acid in dichloromethane as solvent.
Yield: 300 mg (46.3% of theory)
C ₂₃ H ₂₈ N ₂ O ₃ (M = 380.49)
Calc .: Mol peak (M + H) ⁺ : 381 Found: Mol peak (M + H) ⁺ : 381
R _f value: 0.42 (silica gel, dichloromethane / methanol = 80:20)

Example 3.3:

3- (4-chloro-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

3.3.a. 3- (4-chloro-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

Prepared analogously to Example 3.1.e from [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine and (4-chloro-phenyl) -propynoic acid in dichloromethane as solvent.
Yield: 36 mg (5% of theory)
C ₂₂ H ₂₅ ClN ₂ O ₂ (M = 384.91)
Calc .: Molpeak (M + H) ⁺ : 385/387 Found: Molpeak (M + H) ⁺ : 385/387
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 3.4:

3- (2,4-dichloro-phenyl-propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -amide

3.4.a. 2,3-dibromo-3- (2,4-dichloro-phenyl) -propancarbonsäure

9.45 g (59.14 mmol) of bromine, dissolved in 20 ml of carbon tetrachloride, are added dropwise at 0 ° C. to a suspension of 11.67 g (53.76 mmol) of 2,6-dichlorocinnamic acid in 500 ml of carbon tetrachloride and the mixture is stirred for three hours stirred at room temperature. Subsequently, the solvent is distilled off and the residue is treated with petroleum ether. The solid is filtered off and dried in a convection oven at 50 ° C.
Yield: 19.22 g (94.9% of theory)
Melting point: 184-185 ° C
C ₉ H ₆ Br ₂ Cl ₂ O ₂ (M = 376.86)

3.4.b. (2,4-dichloro-phenyl) -propinsäure

A solution of 19.2 g (50.94 mmol) of 2,3-dibromo-3- (2,4-dichloro-phenyl) -propanecarboxylic acid in 130 ml of tert-butanol is added in portions with a total of 22.86 (203.78 mmol ) Potassium tertiary butylate is added so that the temperature does not exceed 40 ° C. The mixture is then stirred for a further 90 minutes at this temperature. The reaction mixture is poured into 2N hydrochloric acid and the precipitate taken up in ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the solvent distilled off. The residue is dried in a circulating air drying oven at 80.degree.
Yield: 9.73 g (88.8% of theory)
Melting point: 168-171 ° C
C ₉ H ₄ Cl ₂ O ₂ (M = 215.03)
R _f value: 0.5 (silica gel, dichloromethane / ethanol / glacial acetic acid = 10: 1: 0.1)

3.4.c. 3- (2,4-dichloro-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 4- (2-diethylamino-ethoxy) -phenylamine and (2,4-dichloro-phenyl) -propynoic acid.
Yield: 0.62 g (85% of theory)
Melting point: 107-109 ° C
C ₂₁ H ₂₂ Cl ₂ N ₂ O ₂ (M = 405.32)
Calc .: Molpeak (M + H) ⁺ : 405/407/409 Found: Molpeak (M + H) ⁺ : 405/407/409
R _f value: 0.6 (silica gel, dichloromethane / methanol / ammonia = 5: 1: 0.1)

Example 3.5:

3- (2,4-dichloro-phenyl) -propinsäure- [4- (2-diethylamino-propoxy) -phenyl] -amide

3.5.a. 3- (2,4-dichloro-phenyl) -propinsäure- [4- (2-diethylamino-propoxy) -phenyl] -amide

Prepared analogously to Example 3.4.c from 4- (2-diethylamino-propoxy) -phenylamine and (2,4-dichloro-phenyl) -propynoic acid.
Yield: 0.41 g (65.2% of theory)
Melting point: 70-72 ° C
C ₂₂ H ₂₄ Cl ₂ N ₂ O ₂ (M = 419.35)
Calc.: Molpeak (M + H) ⁺ : 419/421/423 Found: Molepeak (M + H) ⁺ : 419/421/423
R _f value: 0.4 (silica gel, dichloromethane / ethanol / ammonia = 5: 1: 0.01)

Example 3.6:

3- (4'-chloro-biphenyl-4-yl) -propinsäure- (4-piperidin-1-ylmethyl-phenyl) -amide

3.6.a. (E) -3- (4'-chloro-biphenyl-4-yl) -acrylic acid ethyl ester

To a solution of 1.124 g (4.04 mmol) of ethyl (E) -3- (4-bromo-phenyl) -acrylate in 50 ml of dioxane are added 173 mg (0.15 mmol) of tetrakistriphenylphosphine palladium and 4.4 ml (8 , 8 mmol) of a 2M sodium carbonate solution. To this reaction mixture are added 0.689 g (4.404 mmol) of 4-chlorophenylboronic acid dissolved in 10 ml of methanol and heated to reflux for five hours. The reaction mixture is concentrated, the residue taken up in dichloromethane and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 9: 1).
Yield: 0.94 g (74.4% of theory)
C ₁₇ H ₁₅ ClO ₂ (M = 286.76)
Calc .: Molpeak (M + H) ⁺ : 287/289 Found: Mol peak (M + H) ⁺ : 287/289
R _f value: 0.44 (silica gel, petroleum ether / ethyl acetate = 40:10)

3.6.b. [(E) -3- (4'-chloro-biphenyl-4-yl) -acrylic acid

To a solution of 0.9 g (3.13 mmol) of ethyl (E) -3- (4'-chlorobiphenyl-4-yl) acrylate in 30 ml of ethanol is added 6.27 ml of a 1M sodium hydroxide solution and stirred for three hours stirred at room temperature. The reaction is stopped by adding 6.27 ml of 1N hydrochloric acid and the reaction mixture is stirred for two hours. The mixture is then concentrated, the residue is mixed with water and the precipitate is filtered off. The precipitate is repeatedly rinsed with water and dried in a vacuum oven at 80 ° C.
Yield: 0.68 g (67% of theory)
C ₁₅ H ₁₁ ClO ₂ (M = 258.70)
Calc .: Molpeak (MH) ^- : 257/259 Found: Molpeak (MH) ^- : 257/259
R _f value: 0.5 (silica gel, dichloromethane / methanol = 90:10)

3.6.c. (E) -3- (4'-chloro-biphenyl-4-yl) -N- (4-piperidin-1-ylmethyl-phenyl) -acrylamide

Prepared analogously to Example 3.1.e from [(E) -3- (4'-chlorobiphenyl-4-yl) -acrylic acid and 4-piperidin-1-ylmethyl-phenylamine.
Yield: 0.57 g (62.9% of theory)
Melting point: 265-270 ° C
C ₂₇ N ₂₇ ClN ₂ O (M = 430.98)
Calc .: Molpeak (M + H) ⁺ : 431/433 Found: Molpeak (M + H) ⁺ : 431/433
R _f value: 0.31 (silica gel, dichloromethane / methanol = 90:10)

3.6.d. 2,3-dibromo-3- (4'-chloro-biphenyl-4-yl) -N- (4-piperidin-1-ylmethyl-phenyl) -propionamide

A suspension of 150 mg (0.348 mmol) of (E) -3- (4'-chlorobiphenyl-4-yl) -N- (4-piperidin-1-ylmethyl-phenyl) -acrylamide in 15 ml of dichloromethane is added 0 , 02 ml (0.383 mmol) of bromine and stirred for three hours at room temperature. The reaction mixture is then concentrated, the residue recrystallized from petroleum ether and dried in a vacuum oven at 70 ° C.
Yield: 0.19 g (92.4% of theory)
Melting point: 145-150 ° C
C ₂₇ H ₂₇ Br ₂ ClN ₂ OI (M = 590.79)
calc .: Molpeak (M + H) ⁺ : 589/591/593/595
Found: Molpeak (M + H) ⁺ : 589/591/593/595
R _f value: 0.47 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

3.6.e. 3- (4'-chloro-biphenyl-4-yl) -propinsäure- (4-piperidin-1-ylmethyl-phenyl) -amide

Prepared analogously to Example 3.4.b from 2,3-dibromo-3- (4'-chloro-biphenyl-4-yl) -N- (4-piperidin-1-ylmethyl-phenyl) -propionamide.
Yield: 26 mg (23.9% of theory)
C ₂₇ H ₂₅ ClN ₂ OI (M = 428.96)
Calc .: Molpeak (M + H) ⁺ : 429/431 Found: Molpeak (M + H) ⁺ : 429/431
R _f value: 0.42 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 3.7:

3- [5- (4-chloro-phenyl) -pyridin-2-yl] -propinsäure- (4-piperidin-1-ylmethyl-phenyl) -amide

3.7.a. 5-bromo-2-trimethylsilanylethynyl-pyridine

To a solution of 20 g (81.89 mmol) of 2,5-dibromopyridine in 250 ml of absolute THF in an atmosphere of argon is added 1.15 g (1.63 mmol) of tetrakistriphenylphosphine palladium, 0.311 g (1.63 mmol) of copper (I). iodide and 50 ml of triethylamine. At 17 ° C., a solution of 13 ml (90.14 mmol) of trimethylsilylacetylene in 20 ml of THF is added dropwise rapidly to this reaction mixture. After ten minutes, the cooling is removed. After 20 minutes the temperature is 30 ° C. It is then cooled to 20 ° C and stirred for a short time. The reaction mixture is concentrated, the residue taken up in ethyl acetate and extracted twice with Natriumhydrogencarbonatlösunge. The combined organic phases are dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether).
Yield: 20.4 g (98% of theory)
C ₁₀ H ₁₂ BrNSi (M = 254.20)
Calc .: Molpeak (M + H) ⁺ : 254/256 Found: Molepeak (M + H) ⁺ : 254/256
R _f value: 0.72 (silica gel, petroleum ether)

3.7.b. 5- (4-chloro-phenyl) -2-trimethylsilanylethynyl-pyridine

In an argon atmosphere, to a solution of 20.4 g (80.25 mmol) of 5-bromo-2-trimethylsilanylethinyl-pyridine and 26.33 g (160 mmol) of 4-chlorophenylboronic acid in 350 ml of dioxane 6.93 g (6 mmol ) Tetrakistriphenylphosphine palladium and 17 ml of a 2M sodium carbonate solution, and the reaction mixture was stirred at 90 ° C for five hours, with 7 ml of 2M sodium carbonate solution added every 30 minutes. Subsequently, 1000 ml of ethyl acetate are added at room temperature, and it is extracted twice with 400 ml of sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether to petroleum ether / ethyl acetate = 9: 1).
Yield: 7.9 g (34.4% of theory)
C ₁₆ H ₁₆ ClNSi (M = 285.85)
Calc .: Molpeak (MH) ^- : 286/288 Found: Molpeak (MH) ^- : 286/288
R _f value: 0.6 (silica gel, petroleum ether / ethyl acetate = 8: 2)

3.7.c. 5- (4-chloro-phenyl) -2-ethynyl-pyridine

A reaction mixture of 7.4 g (25.88 mmol) of 5- (4-chlorophenyl) -2-trimethylsilanylethynylpyridine and 7.18 g (52 mmol) of potassium carbonate in 80 ml of methanol is stirred for 30 minutes at room temperature. 500 ml of dichloromethane are added and the reaction mixture is extracted with water and sodium bicarbonate solution. The combined organic phases are dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether to petroleum ether / ethyl acetate = 8: 2).
Yield: 2 g (36.2% of theory)
C ₁₃ H ₈ ClN (M = 213.66)
Calcd .: Mol peak (M + H) ⁺ : 214/216 Found: Mol peak (M + H) ⁺ : 214/216

3.7.d. [5- (4-chloro-phenyl) -pyridin-2-yl] -propinsäure

To a solution of 0.5 g (2.34 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-pyridine in 30 ml of absolute THF are added at -10 ° C 1.6 ml (2.46 mmol) Butyllithiumlösung (1.6M in hexane) was added dropwise and stirred at -8 ° C for five minutes. The reaction mixture is added in portions at -70 ° C with dry ice, stirred for one hour at room temperature and concentrated. The residue is suspended in 5 ml of water and treated with 1.6 ml of 1N hydrochloric acid, whereupon a precipitate is formed. Subsequently, ethyl acetate is added and the suspension is filtered. The solid is dried in a vacuum oven at 70 ° C.
Yield: 0.25 g (41.5% of theory)
Melting point: 210 ° C
C ₁₄ H ₈ ClNO ₂ I (M = 257.67)
Calc .: Molpeak (M + H) ⁺ : 258/260
Found: Molepeak (M + H) ⁺ : 258/260

3.7.e. 3- [5- (4-chloro-phenyl) -pyridin-2-yl] -propinsäure- (4-piperidin-1-ylmethyl-phenyl) -amide

Prepared analogously to Example 2.3.f from [5- (4-chloro-phenyl) -pyridin-2-yl] -propynoic acid and 4-piperidin-1-ylmethyl-phenylamine.
Yield: 0.2 g (48% of theory)
C ₂₆ H ₂₄ ClN ₃ OI (M = 429.95)
Calc .: Molpeak (M + H) ⁺ : 430/432 Found: Molepeak (M + H) ⁺ : 430/432
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

Example 3.8:

3- (2,4-dichloro-phenyl) -propinsäure- [4- (2-diethylamino-ethyl) -phenyl] -amide hydrochloride

3.8.a. 3- (2,4-dichloro-phenyl) -propinsäure- [4- (2-diethylamino-ethyl) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f from 4- (2-diethylamino-ethyl) -phenylamine and (2,4-dichloro-phenyl) -propynoic acid.
Yield: 0.3 g (47% of theory)
Melting point: 204-208 ° C
C ₂₁ H ₂₂ Cl ₂ N ₂ O (M = 425.78)
Calc .: Molpeak (M + H) ⁺ : 389/391/393 Found: Molpeak (M + H) ⁺ : 389/391/393
R _f value: 0.6 (silica gel, dichloromethane / ethanol / ammonia = 5: 1: 0.01)

Example 3.9.

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (2-diethylamino-ethyl) -phenyl] -amide

Prepared analogously to Example 2.3.f from 90 mg (0.44 mmol) of 4- (2-diethylamino-ethyl) -phenylamine and 99 mg (0.40 mmol) of 2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 71 mg (42% of theory)
Melting point: 145-150 ° C
C ₂₂ H ₂₂ ClF ₃ N ₂ O (M = 422.88)
Calc .: Molpeak (M + H) ⁺ : 423/425 Found: Molepeak (M + H) ⁺ : 423/425
R _f value: 0.30 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.10

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {4- [N- (2-dimethylamino-ethyl) -methyl-amino] -phenyl} -amide formate

Prepared analogously to Example 2.3.f. from 90 mg (0.44 mmol) of 4- [N- (2-dimethylamino-ethyl) -methylamino] -phenylamine (preparation see international patent application WO 01/27081) and 99 mg (0.40 mmol) of 2-chloro-4 -trifluoromethyl-phenyl) -propinsäure.
Yield: 64 mg (38% of theory)
C ₂₁ H ₂₁ ClF ₃ N ₃ O x CH ₂ O 2 (M = 469.89)
Calc .: Molpeak (M + H) ⁺ : 424/426 Found: Molepeak (M + H) ⁺ : 424/426
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.11

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (2-diethylamino-propoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 67 mg (0.3 mmol) of 4- (2-diethylamino-propoxy) -phenylamine and 75 mg (0.3 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 71 mg (52% of theory)
Melting point: 172-176 ° C
C ₂₃ H ₂₄ ClF ₃ N ₂ O ₂ (M = 452.90)
Calc.: Molpeak (M + H) ⁺ : 453/455 Found: Molepeak (M + H) ⁺ : 453/455
R _f value: 0.30 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.12

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 69 mg (0.33 mmol) of 4- (2-diethylamino-ethoxy) -phenylamine and 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 70 mg (53% of theory)
Melting point: 194-197 ° C
C ₂₂ H ₂₂ ClF ₃ N ₂ O ₂ (M = 438.88)
Calc.: Molpeak (M + H) ⁺ : 439/441 Found: Molepeak (M + H) ⁺ : 439/441
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.13

3- (2-chloro-4-methyl-phenyl) -propinsäure- [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

Prepared analogously to Example 2.3.f from [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 60 mg (22% of theory)
Melting point: 135-138 ° C
C ₂₃ H ₂₄ ClF ₃ N ₂ O ₂ (M = 452.90)
Calc.: Molpeak (M + H) ⁺ : 453/455 Found: Molepeak (M + H) ⁺ : 453/455
R _f value: 0.4 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.14

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- (4-diethylaminomethyl-phenyl) -amide

Prepared analogously to Example 2.3.f from 4-diethylaminomethyl-phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 72 mg (59% of theory)
C ₂₁ H ₂₀ ClF ₃ N ₂ O (M = 408.85)
Calc.: Molpeak (M + H) ⁺ : 409/411 Found: Molepeak (M + H) ⁺ : 4091411
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.15

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (2-imidazol-1-yl-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 4- (2-imidazol-1-yl-ethoxy) -phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 78 mg (60% of theory)
Melting point: 182-186 ° C
C ₂₁ H ₁₅ ClF ₃ N ₃ O ₂ (M = 433,82)
Calc .: Molpeak (M + H) ⁺ : 434/436 Found: Molepeak (M + H) ⁺ : 434/436
R _f value: 0.33 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.16

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (2-pyrazol-1-yl-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 4- (2-pyrazol-1-yl-ethoxy) -phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 56 mg (43% of theory)
Melting point: 120-125 ° C
C ₂₁ H ₁₅ ClF ₃ N ₃ O ₂ (M = 433,82)
Calc .: Molpeak (M + H) ⁺ : 434/436 Found: Molepeak (M + H) ⁺ : 434/436
R _f value: 0.6 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.17

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (2- [1,2,4] triazol-4-yl-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 4- (2- [1,2,4] triazol-4-yl-ethoxy) -phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.
Yield: 51 mg (39.4% of theory)
Melting point: 223-227 ° C
C ₂₀ H ₁₄ ClF ₃ N ₄ O ₂ (M = 434.80)
Calc .: Molpeak (M + H) ⁺ : 435/437 Found: Molpeak (M + H) ⁺ : 435/437
R _f value: 0.31 (silica gel, dichloromethane / methanol = 9: 1)

In analogy to the examples mentioned above, the following compounds can be prepared:

Example 4.1:

3- (2,4-dichloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.1.a. [2- (2-chloro-4-nitro-phenoxy) -ethyl] -diethyl-amine

To a solution of 35 g (0.202 mol) of 2-chloro-4-nitro-phenol in 350 ml of DMF is added 112 g (0.81 mol) of potassium carbonate. Subsequently, the reaction mixture is mixed with 35 g (0.203 mol) of (2-chloroethyl) -diethyl-amine hydrochloride and stirred for three hours at 80 ° C and 14 hours at room temperature. The reaction mixture is concentrated and the residue is poured into 1000 ml of water and this mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated.
Yield: 49.6 g (90% of theory)
C ₁₂ H ₁₇ ClN ₂ O ₃ (M = 272.73)
Calc .: Molpeak (M + H) ⁺ : 273 Found: Molepeak (M + H) ⁺ : 273
R _f value: 0.36 (silica gel, dichloromethane / methanol = 90:10)

4.1.b. [2- (2-chloro-4-amino-phenoxy) -ethyl] -diethyl-amine

Prepared analogously to Example 3.1.b from [2- (2-chloro-4-nitro-phenoxy) ethyl] -diethyl-amine in methanol in a reaction time of 4.5 hours.
Yield: 36.12 g (81.8% of theory)
C ₁₂ H ₁₉ ClN ₂ O (M = 242.75)
Calc .: Molpeak (M + H) ⁺ : 243/245 Found: Molepeak (M + H) ⁺ : 243/245
R _f value: 0.36 (silica gel, dichloromethane / methanol = 90:10)

4.1.C. (2,4-dichloro-phenyl) -propinsäurechlorid

A Reaction mixture of 0.34 g (1.58 mmol) of (2,4-dichloro-phenyl) -propynoic acid and 0.14 ml (1.9 mmol) of thionyl chloride in 15 ml of absolute toluene three hours at 70 ° C touched and subsequently concentrated. The residue is taken up in absolute toluene and the solution is concentrated to dryness. This process will follow repeated again and the residue continued raw.

4.1.d. 3- (2,4-dichloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

0.37 g (1.58 mmol) of (2,4-dichloro-phenyl) -propionic acid chloride are dissolved in 15 ml of absolute toluene and, with ice cooling, 0.77 g (3.16 mmol) of [2- (2-chloro) 4-amino-phenoxy) ethyl] -diethyl-amine dissolved in 10 ml of absolute toluene, and stirred for four hours at room temperature. Subsequently, the reaction mixture is extracted with ethyl acetate and dilute aqueous ammonia solution. The organic phase is extracted with water and dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol = 9: 1). The product obtained is recrystallized from petroleum ether and dried in a vacuum oven at 50 ° C.
Yield: 0.21 g (30.2% of theory)
Melting point: 98-100 ° C
C ₂₁ H ₂₁ Cl ₃ N ₂ O ₂ (M = 439.77)
Calc .: Molpeak (M + H) ⁺ : 439/441/443 Found: Molpeak (M + H) ⁺ : 439/441/443
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.2:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.2.a. (2-chloro-4-trifluoromethyl-phenyl) -propinsäurechlorid

Produced analogously to Example 4.1.c from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid. The Connection is continued raw.

4.2.b. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 4.1.d from (2-chloro-4-trifluoromethyl-phenyl) propenoic acid chloride and [2- (2-chloro-4-amino-phenoxy) ethyl] -diethyl-amine.
Yield: 0.26 g (27.5% of theory)
C ₂₂ H ₂₁ Cl ₂ F ₃ N ₂ O ₂ (M = 473.32)
Calc .: Molpeak (M + H) ⁺ : 473/475 Found: Molepeak (M + H) ⁺ : 473/475
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.3:

3-Pyridin-2-yl-propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

4.3.a. Pyridin-2-yl-propynoic

6.3 ml of n-butyllithium solution (1.6 M in hexane) are added dropwise at -10 ° C. to a solution of 1 g (9.7 mmol) of 2-ethynylpyridine in 30 ml of absolute THF and the mixture is stirred for 30 minutes. Dry ice is added in portions at -78 ° C. and the reaction mixture is allowed to warm to room temperature. After about one hour, the reaction mixture is concentrated and the residue taken up under ice-cooling in 10 ml of 1N hydrochloric acid. The precipitate is filtered off, rinsed with isopropanol and diethyl ether and dried in a vacuum drying oven at 70.degree.
Yield: 0.6 g (42% of theory)
Melting point: 130 ° C
C ₈ H ₅ NO ₂ (M = 147.13)
Calc .: Molpeak (M + H) ⁺ : 148 Found: Molepeak (M + H) ⁺ : 148

4.3.b. 3-Pyridin-2-yl-propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f from pyridin-2-yl-propric acid and [2- (2-chloro-4-amino-phenoxy) ethyl] -diethyl-amine.
Yield: 0.37 g (53.3% of theory)
C ₂₀ H ₂₂ ClN ₃ O ₂ X HCl (M = 408.33)
Calc .: Molpeak (M + H) ⁺ : 372/374 Found: Molepeak (M + H) ⁺ : 372/374
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.4:

3-biphenyl-4-yl-propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.4.a. 3-biphenyl-4-y1-2,3-dibromo-propane carboxylic acid

Prepared analogously to Example 3.4.a from 3-biphenyl-4-yl-acrylic acid.
Yield: 5 g (91.2% of theory)
Melting point: 200-203 ° C
C ₁₅ H ₁₂ Br ₂ O ₂ (M = 384.07)
R _f value: 0.4 (silica gel, dichloromethane / methanol / acetic acid = 90: 10: 1)

4.4.b. Biphenyl-4-yl-propynoic

Prepared analogously to Example 3.4.b from 3-biphenyl-4-yl-2,3-dibromo-propane carboxylic acid.
Yield: 2.8 g (96.8% of theory)
C ₁₅ H ₁₀ O ₂ (M = 222.24)
Melting point: 170 ° C
Calc .: Molpeak (M + H) ⁺ : 223 Found: Molepeak (M + H) ⁺ : 223
R _f value: 0.4 (silica gel, dichloromethane / methanol / acetic acid = 90: 10: 1)

4.4.c. Biphenyl-4-yl-propinsäurechlorid

Produced analogously to Example 4.1.c of biphenyl-4-yl-propric acid. The connection becomes raw implemented further.

4.4.d. 3-biphenyl-4-yl-propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 4.1.d from biphenyl-4-yl-propric acid chloride and [2- (2-chloro-4-amino-phenoxy) ethyl] -diethyl-amine.
Yield: 0.28 g (31.3% of theory)
Melting point: 105-108 ° C
C ₂₇ H ₂₇ ClN ₂ O ₂ (M = 446.98)
Calc .: Molpeak (M + H) ⁺ : 447/449 Found: Molpeak (M + H) ⁺ : 447/449
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.5:

3- (2,4,6-trichloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

4.5.a. Triphenyl- (2,4,6-trichloro-phenylethynyl) silane

In an argon atmosphere, 9 g (34.6 mmol) of 1-bromo-2,4,6-trichlorobenzene, 9.8 g (34.45 mmol) of triphenylsilylacetylene and 15 ml of triethylamine are dissolved in 100 ml of absolute dioxane and at 90 ° C. with 0.2 g (1.04 mmol) of copper (I) iodide and 1.2 g (1.04 mmol) Tetrakistriphenylphosphinpalladium and stirred for 20 hours. The reaction mixture is filtered through Celite and the filtrate is concentrated. The residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether / toluene = 5: 1). The product is recrystallized from petroleum ether and dried in a vacuum oven at 70 ° C.
Yield: 6.9 g (43% of theory)
Melting point: 115-120 ° C
C ₂₆ H ₁₇ Cl ₃ Si (M = 463.87)
calc .: Molpeak (M + H) ⁺ : 463/465/467/469
Found: Molpeak (M + H) ⁺ : 463/465/467/469
R _f value: 0.6 (silica gel, petroleum ether / toluene = 4: 1)

4.5.b. 1,3,5-trichloro-2-ethynyl-benzene

A reaction mixture of 5 g (10.8 mmol) of triphenyl- (2,4,6-trichloro-phenylethynyl) -silane and 4.2 g (16.2 mmol) of tetrabutylammonium fluoride in 50 ml of absolute THF is stirred for half an hour at room temperature and then concentrated, the residue is taken up in diethyl ether and water and extracted. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether / toluene = 9: 1).
Yield: 0.46 g (20.7% of theory)
R _f value: 0.6 (silica gel, petroleum ether / toluene = 9: 1)

4.5.c. (2,4,6-trichloro-phenyl) -propinsäure

Prepared analogously to Example 4.3.a from triphenyl (2,4,6-trichloro-phenylethynyl) silane and dry ice.
Yield: 3.3 g (77.7% of theory)
Melting point: 170-175 ° C
C ₉ H ₃ Cl ₃ O ₂ (M = 249.48)
Calc.: Molpeak (M + H) ⁺ : 249/251/253 Found: Molepeak (M + H) ⁺ : 249/251/253
R _f value: 0.4 (silica gel, dichloromethane / methanol / acetic acid = 50: 10: 1)

4.5.d. 3- (2,4,6-trichloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f from (2,4,6-trichloro-phenyl) -propynoic acid and [2- (2-chloro-4-amino-phenoxy) -ethyl] -diethyl-amine.
Yield: 0.72 g (82.9% of theory)
Melting point: 188-191 ° C
C ₂₁ H ₂₀ Cl ₄ N ₂ O ₂ X HCl (M = 510.67)
Calc .: Molpeak (M + H) ⁺ : 473/475/477/479/481
Found: Molpeak (M + H) ⁺ : 473/475/477/479/481
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

Example 4.6:

3- (2,4-dichloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-propoxy) -phenyl] -amide hydrochloride

4.6.a. [2- (2-chloro-4-nitro-phenoxy) -propyl] -diethyl-amine

To a solution of 5.3 g (30 mmol) of 3-chloro-4-fluoro-nitrobenzene and 4.3 g (33 mmol) of 3-diethylaminopropan-1-ol in 50 ml of DMF at 0 ° C 1.6 g (33 mmol) sodium hydride (50% in oil) was added and stirred for two hours. The mixture is then warmed to room temperature and stirred for one hour. The reaction mixture is concentrated, treated with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia = 9: 1: 0.1).
Yield: 8 g (93% of theory)
C ₁₃ H ₁₉ ClN ₂ O ₃ (M = 286.76)
R _f value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

4.6.b. [2- (2-chloro-4-amino-phenoxy) -propyl] -diethyl-amine

Prepared analogously to Example 3.1.b from [2- (2-chloro-4-nitro-phenoxy) -propyl] -diethyl-amine in methanol in a reaction time of 8 hours.
Yield: 6.7 g (93.5% of theory)
C ₁₃ H ₂₁ ClN ₂ O (M = 256.77)
Calc.: Molpeak (M + H) ⁺ : 257/259 Found: Molpeak (M + H) ⁺ : 257/259
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

4.6.c. 3- (2,4-dichloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-propoxy) -phenyl] -amide hydrochloride

Prepared analogously to Example 3.4.c from [2- (2-chloro-4-amino-phenoxy) -propyl] -diethyl-amine and (2,4-di chloro-phenyl) -propinsäure
Yield: 0.62 g (84.3% of theory)
Melting point: 180-185 ° C
C ₂₂ H ₂₃ Cl ₃ N ₂ O ₂ X HCl (M = 490.26)
Calc .: Molpeak (M + H) ⁺ : 453/455/457/459
Found: Molpeak (M + H) ⁺ : 453/455/457/459
R _f value: 0.7 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

Example 4.7:

3- (2,4-dichloro-phenyl) -propinsäure- [3-methoxy-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

4.7.a. 3- (2,4-dichloro-phenyl) -propinsäure- [3-methoxy-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f from (2,4-dichloro-phenyl) -propinyl chloride and [2- (2-methoxy-4-amino-phenoxy) -ethyl] -diethyl-amine.
Yield: 0.25 g (31.2% of theory)
Melting point: 205-207 ° C
C ₂₂ H ₂₄ Cl ₂ N ₂ O ₃ X HCl (M = 471.81)
Calc.: Molpeak (M + H) ⁺ : 435/437/439 Found: Molpeak (M + H) ⁺ : 435/437/439
R _f value: 0.6 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

Example 4.8:

3- (2,4-dichloro-phenyl) -propinsäure- [2-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.8.a. (2- (3-chloro-4-nitro-phenoxy) -ethyl] -diethyl-amine

Prepared analogously to Example 4.1.a from 3-chloro-4-nitro-phenol and (2-chloroethyl) -diethyl-amine hydrochloride.
Yield: 1.25 g (79.5% of theory)
C ₁₂ H ₁₇ ClN ₂ O ₃ (M = 272.73)
Calc .: Molpeak (M + H) ⁺ : 273/275 Found: Molepeak (M + H) ⁺ : 273/275
R _f value: 0.44 (silica gel, dichloromethane / methanol = 90:10)

4.8.b. [2- (3-chloro-4-amino-phenoxy) -ethyl] -diethyl-amine

Prepared analogously to Example 3.1.b from [2- (3-chloro-4-nitro-phenoxy) ethyl] -diethyl-amine in ethyl acetate.
Yield: 1.05 g (95.4% of theory)
C ₁₂ H ₁₉ ClN ₂ O (M = 242.75)
Calc .: Molpeak (M + H) ⁺ : 243/245 Found: Molepeak (M + H) ⁺ : 243/245
R _f value: 0.41 (silica gel, dichloromethane / methanol = 90:10)

4.8.c. 3- (2,4-dichloro-phenyl) -propinsäure- [2-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f from (2,4-dichloro-phenyl) -propinsäurechlorid and [2- (3-chloro-4-amino-phenoxy) -ethyl] -diethyl-amine.
Yield: 0.53 g (65.5% of theory)
Melting point: 128-130 ° C
C ₂₁ H ₂₁ Cl ₃ N ₂ O ₂ X HCl (M = 476.23)
Calc .: Molpeak (M + H) ⁺ : 439/441/443 Found: Molpeak (M + H) ⁺ : 439/441/443
R _f value: 0.7 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

Example 4.9:

3- (4-chloro-phenyl) -propincarbonsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide

4.9.a. 5-nitro-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole

A reaction mixture of 16.22 g (0.1 mol) of 5-nitroindole, 35 g (0.205 mol) of 1- (2-chloroethyl) pyrrolidine hydrochloride and 51 g (0.369 mol) of potassium carbonate in 500 ml of DMF becomes 48 Stirred at room temperature for hours and then filtered. The filtrate is concentrated, the residue dissolved in dichloromethane and dried over sodium sulfate. The desiccant is filtered off and the filtrate is concentrated.
Yield: 25 g (96.3% of theory)
C ₁₄ H ₁₇ N ₃ O ₂ (M = 259.31)
Calc .: Mol peak (M + H) ⁺ : 260 Found: Mol peak (M + H) ⁺ : 260
R _f value: 0.65 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

4.9.b. 5-Amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole

Prepared analogously to Example 3.1.b from 5-nitro-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole in THF as a solvent.
Yield: 0.83 g (93.9% of theory)
C ₁₄ H ₁₉ N ₃ (M = 229.32)
Calcd .: Mol peak (M + H) ⁺ : 230 Found: Mol peak (M + H) ⁺ : 230
R _f value: 0.37 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

4.9.c. 3- (4-chloro-phenyl) -propincarbonsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide

Prepared analogously to Example 3.1.e from 5-amino-1- (2-pyrrolidin-1-yl-ethyl) -11H-indole and (4-chloro-phenyl) -propynoic acid in THF as solvent.
Yield: 186 mg (47.5% of theory)
C ₂₃ H ₂₂ ClN ₃ O (M = 391.90)
Melting point: 135-144 ° C
Calc .: Molpeak (M + H) ⁺ : 393/394 Found: Molpeak (M + H) ⁺ : 393/394
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 4.10:

3- (4-chloro-phenyl) -propincarbonsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide

Prepared analogously to Example 3.1.e from 5-amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole and (2,4-dichloro-phenyl) -propynoic acid in THF as solvent.
Yield: 133 mg (31.2% of theory)
C ₂₃ H ₂₁ Cl ₂ N ₃ O (M = 426.34)
Melting point: 127-129 ° C
Calc.: Molpeak (M + H) ⁺ : 426/428/430 Found: Molepeak (M + H) ⁺ : 426/428/430
R _f value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 4.11:

3- (2-chloro-4-trifluoromethyl-phenyl) -propincarbonsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide

4.11.a. (2-chloro-4-trifluoromethyl-phenyl) -propinsäureethylester

A reaction mixture of 0.556 ml (5.42 mmol) of propionic acid ethyl ester, 875 mg (2.8 mmol) of 3-chloro-4-iodo-benzotrifluoride, 214 mg (0.3 mmol) of bis-triphenylphosphine palladium dichloride, 57.1 mg (0.3 mmol ) Copper (I) iodide and 1.17 g (3.6 mmol) of cesium carbonate in 50 ml of THF are degassed and stirred in an argon atmosphere for 24 hours at room temperature. The reaction mixture is treated with a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases are extracted with saturated sodium chloride solution and dried over sodium sulfate.
Yield: 0.65 g (43.3% of theory)
C ₁₂ H ₈ ClF ₃ O ₂ (M = 276.64)
Calcd .: Mol peak: (M + H) ⁺ : 277/279 Found: Mol peak (M + H) ⁺ : 277/279

4.11.b. (2-Chlior-4-trifluoromethyl-phenyl) -propinsäure

0.65 g (1.175 mmol) of ethyl (2-chloro-4-trifluoromethylphenyl) propionate are dissolved in 20 ml of ethanol, treated with 2 ml of 2M sodium hydroxide solution and stirred for three hours at room temperature. The reaction mixture is concentrated, the residue taken up in water and extracted with ethyl acetate. The aqueous phase is mixed with 2 ml of 1M hydrochloric acid and stirred for one hour at room temperature. It is then extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate.
Yield: 0.14 g (48% of theory)
C ₁₀ H ₄ ClF ₃ C ₂ (M = 248.59)
calc .: Molpeak (MH) ^- : 247/249 found: Molpeak (MH) ^- : 247/249
R _f value: 0.09 (silica gel, petroleum ether / ethyl acetate = 4: 1)

4.11.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propincarbonsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide

Prepared analogously to Example 2.3.f from 5-amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole and (2-chloro-4-trifluorophenyl) propynoic acid.
Yield: 160 mg (66.5% of theory)
C ₂₄ H ₂₁ ClF ₃ N ₃ O (M = 459,90)
Melting point: 200-205 ° C
Calc .: Molpeak (M + H) ⁺ : 460/462 Found: Molepeak (M + H) ⁺ : 460/462
R _f value: 0.45 (silica gel, dichloromethane / methanol = 90:10 :)

Example 4.12:

3- (2,4-dichloro-phenyl) -propinsäure- [2- (2-pyrrolidin-1-yl-ethyl) -benzooxazol-5-yl] -amide

4.12.a. 5-nitro-2-vinyl-benzoxazol

A reaction mixture of 1.54 g (10 mmol) of 2-amino-4-nitrophenol, 1.36 g (10 mmol) of ethyl 3-chloropropionate and 20 g of polyphosphoric acid is stirred at 170 ° C. for two hours. The mixture is then neutralized by the addition of saturated sodium bicarbonate solution at room temperature. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol = 20: 1).
Yield: 0.3 g (15.8% of theory)
C ₉ H ₆ N ₂ O ₃ (M = 190.16)
Calc.: Molpeak (M + H) ⁺ : 191 Found: Molepeak (M + H) ⁺ : 191
R _f value: 0.8 (silica gel, dichloromethane / ethanol = 20: 1)

4.12.b. 5-nitro-2- (2-pyrrolidin-1-yl-ethyl) benzoxazol

A solution of 1 g (5.25 mmol) of 5-nitro-2-vinylbenzoxazole and 0.66 ml (8 mmol) of pyrrolidine in 8 ml of ethanol is stirred for two hours at room temperature. Subsequently, the reaction solution is concentrated. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia = 20: 1: 0.1).
Yield: 0.74 g (53.9% of theory)
C ₁₃ H ₁₅ N ₃ O ₃ (M = 261.28)
Calc .: Molpeak (M + H) ⁺ : 262 Found: Molepeak (M + H) ⁺ : 262
R _f value: 0.2 (silica gel, dichloromethane / ethanol / ammonia = 20: 1: 0.1)

4.12.c. 5-amino-2- (2-pyrrolidin-1-yl-ethyl) benzoxazol

A reaction mixture of 0.74 g (2.83 mmol) of 5-nitro-2- (2-pyrrolidin-1-yl-ethyl) -benzoxazole and 0.1 g of palladium (on charcoal 10%) in 20 ml of ethanol hydrogenated at 3 bar and 20 ° C for three hours. The catalyst is filtered off and the filtrate is concentrated.
Yield: 0.6 g (91.6% of theory)
C ₁₃ H ₁₇ N ₃ O (M = 231.30)
Calc .: Mol peak (M + H) ⁺ : 232 Found: Mol peak (M + H) ⁺ : 232
R _f value: 0.3 (silica gel, dichloromethane / ethanol / ammonia = 20: 1: 0.1)

4.12.d. 3- (2,4-dichloro-phenyl) -propinsäure- [2- (2-pyrrolidin-1-yl-ethyl) -benzooxazol-5-yl] -amide

Prepared analogously to Example 3.1.e from 5-amino-2- (2-pyrrolidin-1-yl-ethyl) -benzoxazole and (2,4-dl-chlorophenyl) -propynoic acid.
Yield: 43 mg (33.1% of theory)
C ₂₂ H ₁₉ Cl ₂ N ₃ O ₂ (M = 428.32)
Melting point: 130 ° C
Calc .: Molpeak (M + H) ⁺ : 428/430/432 Found: Molepeak (M + H) ⁺ : 428/430/432
C ₁₃ H ₁₇ N ₃ O (M = 231.30)
Calc .: Mol peak (M + H) ⁺ : 232 Found: Mol peak (M + H) ⁺ : 232
R _f value: 0.21 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 4.13

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-ethoxycarbonyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.13.a. 2- (2-diethylamino-ethoxy) -5-nitro-benzoic acid ethyl ester

1.06 g (5.00 mmol) of ethyl 2-fluoro-5-nitrobenzoate and 0.58 ml (5.00 mmol) of 2-diethylaminoethanol are dissolved in 20 ml of dimethylformamide and 0.36 g (7 , 45 mmol) sodium hydride (50 percent). The mixture is stirred for 45 minutes at 0 ° C, poured onto ice-water and finally extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is stripped off and the residue is purified on a silica gel column with petroleum ether / ethyl acetate 4.1 as eluent.
Yield: 0.30 g (19% of theory)
C ₁₅ H ₂₂ N ₂ O ₅ (M = 310.35)
Calc .: Mol peak (M + H) ⁺ : 311 Found: Mol peak (M + H) ⁺ : 311
R _f value: 0.1 (silica gel, petroleum ether / ethyl acetate 4: 1)

4.13.b. 5-amino-2- (2-diefhylamino-ethoxy) -benzoic acid ethyl ester

Prepared analogously to Example 3.1.b. from 0.30 g of 2- (2-diethylamino-ethoxy) -5-nitro-benzoic acid ethyl ester in ethyl acetate.
Yield: 0.27 g (100% of theory)
C ₁₅ H ₂₄ N ₂ O ₃ (M = 280.37)
Calc .: Mol peak (M + H) ⁺ : 281 Found: Mol peak (M + H) ⁺ : 281
R _f value: 0.40 (silica gel, dichloromethane / methanol / ammonia = 39: 1: 0.1)

4.13.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-ethoxycarbonyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 120 mg (0.44 mmol) of ethyl 5-amino-2- (2-diethylamino-ethoxy) -benzoate.
Yield: 44 mg (22% of theory)
C ₂₅ H ₂₆ ClF ₃ N ₂ O ₄ (M = 510.94)
Calc .: Molpeak (M + H) ⁺ : 511/513 Found: Molepeak (M + H) ⁺ : 511/513
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.14

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-bromo-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.14.a. [2- (2-bromo-4-nitro-phenoxy) -ethyl] -diethyl-amine

Prepared analogously to regulation 4.13.a. starting from 0.66 g (2.00 mmol) of 2-bromo-1-fluoro-4-nitro-benzene and 0.40 ml (3.00 mmol) of 2-diethylamino-ethanol.
Yield: 0.95 g (100% of theory)
C ₁₂ H ₁₇ BrN ₂ O ₃ (M = 317.185)
Calc.: Molpeak (M + H) ⁺ : 317/319 Found: Molpeak (M + H) ⁺ : 317/319
R _f value: 0.50 (silica gel, dichloromethane (methanol 9: 1).

4.14.b. 3-bromo-4- (2-diethylamino-ethoxy) -phenylamine

Prepared analogously to Example 3.1.b. from 1.10 g (3.47 mmol) of [2- (2-bromo-4-nitro-phenoxy) -ethyl] -diethyl-amine in ethyl acetate.
Yield: 0.58 g (58% of theory)
C ₁₂ H ₁₉ BrN ₂ O (M = 287.202)
Calc .: Molpeak (M + H) ⁺ : 287/289 Found: Mol peak (M + H) ⁺ : 287/289
R _f value: 0.30 (silica gel, dichloromethane / methanol 9: 1).

4.14.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-bromo-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 450 mg (1.80 mmol) of (2-chloro-4-trifluoromethylphenyl) -propynoic acid and 550 mg (1.92 mmol) of 3-bromo-4- (2-diethylamino-ethoxy) -phenylamine.
Yield: 370 mg (40% of theory)
C ₂₂ H ₂₁ BrClF ₃ N ₂ O ₂ (M = 517.77)
Calc.: Molpeak (M + H) ⁺ : 517/519/521 Found: Molpeak (M + H) ⁺ : 517/519/521
R _f value: 0.45 (silica gel, dichloromethane / methanol = 19: 1)

Example 4.15

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-nitro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.15.a. N- [4- (2-diethylamino-ethoxy) -3-nitro-phenyl] -acetamide

To a solution of 1.52 g (6.07 mmol) of N- [4- (2-diethylamino-ethoxy) -phenyl] -acetamide in 25 mL conc. Sulfuric acid are added at -10 ° C in portions 0.74 g (7.29 mmol) of potassium nitrate and the mixture stirred at -10 ° C for 1 hour. The reaction mixture is poured onto a mixture of ice and concentrated aqueous ammonia, and the aqueous phase is exhaustively extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated.
Yield: 1.8 g (100% of theory)
C ₁₄ H ₂₁ N ₃ O ₄ (M = 295.34)
Calc .: Molpeak (M + H) ⁺ : 296 Found: Molepeak (M + H) ⁺ : 296
R _f value: 0.50 (Alox, dichloromethane / methanol 39: 1).

4.15.b. 4- (2-diethylamino-ethoxy) -3-nitro-phenylamine

A solution of 1.85 g (6.26 mmol) N- [4- (2-diethylamino-ethoxy) -3-nitro-phenyl] -acetamide in half-concentrated aqueous hydrochloric acid is stirred for 2 hours at 100 ° C, cooled to room temperature, with Made basic ice and concentrated aqueous ammonia and exhaustively extracted the aqueous phase with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate.
Yield: 1.38 g (87% of theory)
C ₁₂ H ₁₉ N ₃ O ₃ (M = 253.30)
Calc .: Mol peak (M + H) ⁺ : 254 Found: Mol peak (M + H) ⁺ : 254
R _f value: 0.68 (Alox, dichloromethane / methanol 39: 1).

4.15.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-nitro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 450 mg (1.80 mmol) of (2-chloro-4-trifluoromethylphenyl) -propynoic acid and 500 mg (1.98 mmol) of 4- (2-diethylamino-ethoxy) -3-nitro-phenylamine.
Yield: 590 mg (68% of theory)
C ₂₂ H ₂₁ CIF ₃ N ₃ O ₄ (M = 483.87)
Calc .: Molpeak (M + H) ⁺ : 484/486 Found: Molepeak (M + H) ⁺ : 484/486
R _f value: 0.40 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.16:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (3-diethylamino-propoxy) -phenyl] -amide formate

Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) of (2-chloro-4-trifluoromethylphenyl) -propynoic acid and 110 mg (0.44 mmol) of [2- (2-chloro-4-amino-phenoxy) -propyl] -diethyl-amine ,
Yield: 49 mg (25% of theory)
Melting point: 112-116 ° C
C ₂₃ H ₂₂ Cl ₂ F ₃ N ₂ O ₂ x CH ₂ O ₂ (M = 533.37)
Calc .: Molpeak (M + H) ⁺ : 487/489/491 Found: Molepeak (M + H) ⁺ : 487/489/491
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.17:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

4.17.a. [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -carbamic acid tert-butyl ester

Prepared analogously to regulation 3.1.c. starting from 3.00 g (12.4 mmol) of 3-chloro-4- (2-diethylamino-ethoxy) -phenylamine and 2.97 g (13.6 mmol) of di-tert-butyl-pyrocarbonate in dichloromethane.
Yield: 2.85 g (67% of theory)
C ₁₇ H ₂₇ ClN ₂ O ₃ (M = 342.86)
Calc .: Molpeak (M + H) ⁺ : 343/345 Found: Molpeak (M + H) ⁺ : 343/345

4.17.b. [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine

Prepared analogously to Example 3.1.d. of 2.85 g (8.31 mmol) of [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -carbamic acid tert -butyl ester with 10.63 ml (24.9 mmol) of 10 percent strength Lithium aluminum hydride solution in tetrahydrofuran.
Yield: 0.72 g (34% of theory)
C ₁₃ H ₂₁ ClN ₂ O (M = 256.77)
Calc.: Molpeak (M + H) ⁺ : 257/259 Found: Molpeak (M + H) ⁺ : 257/259
R _f value: 0.80 (silica gel, ethyl acetate / methanol / ammonia 9: 1: 0.1).

4.17.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) of (2-chloro-4-trifluoromethylphenyl) -propynoic acid and 110 mg (0.44 mmol) of [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methylamine.
Yield: 54 mg (28% of theory)
Melting point: 97-100 ° C
C ₂₃ H ₂₃ Cl ₂ F 3 N ₂ O ₂ (M = 487.35)
Calc .: Molpeak (M + H) ⁺ : 487/489/491 Found: Molepeak (M + H) ⁺ : 487/489/491
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.18:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-methoxy-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl) -propynoic acid and 79 mg (0.33 mmol) of [2- (2-methoxy-4-amino-phenoxy) -ethyl] -diethyl-amine.
Yield: 14 mg (10% of theory)
C ₂₃ H ₂₄ ClF ₃ N ₂ O ₃ (M = 468.90)
Calc.: Molpeak (M + H) ⁺ : 469/471 Found: Molepeak (M + H) ⁺ : 469/471
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.19:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-methyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.19.a. Diethyl [2- (2-methyl-4-nitro-phenoxy) -ethyl] -amine

To a solution of 2.70 g (17.4 mmol) of 2-fluoro-5-nitro-toluene and 2.54 ml (19.2 mmol) of 2-diethylaminoethanol in 50 mL of DMF under argon atmosphere at 0 ° C 0, Added 92 g (19.2 mmol) of sodium hydride (50 percent in oil) and the mixture for 2 hours at 0 ° C and stirred for 1 hour at room temperature. The solvent is stripped off, the residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate and i. vac. concentrated. The mixture is then purified by silica gel column chromatography with dichloromethane / methanol 9: 1 as eluent.
Yield: 3.1 g (71% of theory)
C ₁₃ H ₂₀ N ₂ O ₃ (M = 252.31)
Calc .: Mol peak (M + H) ⁺ : 253 Found: Mol peak (M + H) ⁺ : 253
R _f value: 0.60 (silica gel, dichloromethane / methanol 9: 1)

4.19.b. 4- (2-diethylamino-ethoxy) -3-methyl-phenylamine

3.10 g (12.3 mmol) of diethyl [2- (2-methyl-4-nitro-phenoxy) ethyl] -amine are dissolved in 250 ml of ethyl acetate, 0.55 g of Raney nickel are added and the mixture 36 Hydrogenated at 50 psi and room temperature for hours. The catalyst is filtered off and the filtrate i. vac. concentrated.
Yield: 2.70 g (99% of theory)
C ₁₃ H ₂₂ N ₂ O (M = 222.33)
Calc .: Molpeak (M + H) ⁺ : 223 Found: Molepeak (M + H) ⁺ : 223
R _f value: 0.35 (silica gel, dichloromethane / methanol 9: 1)

4.19.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-methyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl) -propynoic acid and 73 mg (0.33 mmol) of 4- (2-diethylamino-ethoxy) -3-methyl-phenylamine.
Yield: 134 mg (99% of theory)
C ₂₃ H ₂₄ ClF ₃ N ₂ O ₂ (M = 452.90)
Calc.: Molpeak (M + H) ⁺ : 453/455 Found: Molepeak (M + H) ⁺ : 453/455
R _f value: 0.40 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.20

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-amino-4- (2-diethylamino-ethoxy) -phenyl] -amide

To a solution of 250 mg (0.52 mmol) of 3- (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-nitro-4- (2-diethylamino-ethoxy) -phenyl] -amide in 50 ml Ethyl acetate at room temperature is added 870 mg (10.3 mmol) of sodium bicarbonate and 1.17 g (5.17 mmol) of tin (II) chloride dihydrate. The mixture is heated to reflux for twelve hours. After cooling, water is added and the organic phase is separated off. The aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent removed. The residue is purified by column chromatography on Alox (eluent: dichloromethane / methanol = 39: 1).
Yield: 100 mg (43% of theory)
Melting point: 127-130 ° C
C ₂₂ H ₂₃ ClF ₃ N ₃ O ₂ (M = 453.89)
Calc.: Molpeak (M + H) ⁺ : 454/456 Found: Molepeak (M + H) ⁺ : 454/456
R _f value: 0.60 (Alox, dichloromethane / methanol = 39: 1)

Example 4.21:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (3-diethylamino-ethoxy) -3-methanesulfonylamino-phenyl] -amide

To a solution of 0.1 g (0.22 mmol) of 3- (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-amino-4- (2-diethylamino-ethoxy) -phenyl] -amide in 5 ml of pyridine are added dropwise at 0 ° C 0.019 ml (0.242 mmol) of methanesulfonyl chloride. The reaction mixture is slowly warmed to room temperature and stirred for three hours. Subsequently, the reaction mixture is poured into ice-water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent distilled off. The residue is freeze-dried.
Yield: 101 mg (86.3% of theory)
Melting point: 57-60 ° C
C ₂₃ H ₂₅ ClF ₃ N ₃ O ₄ S (M = 531.98)
Calc .: Molpeak (M + H) ⁺ : 532/534 Found: Molepeak (M + H) ⁺ : 532/534
R _f value: 0.32 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.22:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (3-diethylamino-ethoxy) -3-methoxy-phenyl] -methyl-amide

4.22.a. [4- (3-diethylamino-ethoxy) -3-methoxy-phenyl] -carbaminsäuretertiärbutylester

Prepared analogously to 3.1.c from 4- (3-diethylamino-ethoxy) -3-methoxyphenylamine.
Yield: 0.26 g (91.6% of theory)
C ₁₈ H ₃₀ N ₂ O ₄ (M = 338.45)
Calc .: Molpeak (M + H) ⁺ : 339 Found: Molepeak (M + H) ⁺ : 339
R _f value: 0.45 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

4.22.b. [4- (3-diethylamino-ethoxy) -3-methoxy-phenyl] -methyl-amine

Prepared analogously to 3.1.d from [4- (3-diethylamino-propoxy) -3-methoxyphenyl] -carbamic acid tert-butyl ester.
Yield: 0.08 g (44.7% of theory)
C ₁₄ H ₂₄ N ₂ O ₂ (M = 252.36)
Calc .: Mol peak (M + H) ⁺ : 253 Found: Mol peak (M + H) ⁺ : 253

4.22.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (3-diethylamino-ethoxy) -3-methoxy-phenyl] -methyl-amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and [4- (3-diethylamino-propoxy) -3-methoxy-phenyl] -methyl-amine.
Yield: 33 mg (30% of theory)
C ₂₄ N ₂₆ ClF ₃ N ₂ O ₃ (M = 482.93)
Calc.: Molpeak (M + H) ⁺ : 483/485 Found: Molepeak (M + H) ⁺ : 483/485
R _f value: 0.43 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.23:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (3-diethylamino-ethoxy) -3-fluoro-phenyl] -amide

4.23.a. [Diethyl- [3- (2-fluoro-4-nitro-phenoxy) -ethyl] -amine

Prepared analogously to 4.6.a from 3,4-difluoro-nitrobenzene and 2-diethylaminoethanol.
Yield: 6.94 g (87.4% of theory)
C ₁₂ H ₁₇ FN ₂ O ₃ (M = 256.27)
Calc .: Mol peak (M + H) ⁺ : 257 Found: Mol peak (M + H) ⁺ : 257
R _f value: 0.46 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

4.23.b. 4- (3-diethylamino-ethoxy) -3-fluoro-phenylamine

Prepared analogously to 3.1.b from [diethyl [3- (2-fluoro-4-nitro-phenoxy) -ethyl] -amine.
Yield: 5.93 g (97.1% of theory)
C ₁₂ H ₁₉ FN ₂ O (M = 226.29)
Calc .: Molpeak (M + H) ⁺ : 229 Found: Molepeak (M + H) ⁺ : 227
R _f value: 0.33 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

4.23.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [4- (3-diethylamino-ethoxy) -3-fluoro-phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl) propynoic acid and 4- (3-diethylamino-ethoxy) -3-fluoro-phenylamine.
Yield: 0.14 g (33.5% of theory)
Melting point: 85-88 ° C
C ₂₂ H ₂₁ ClF ₄ N ₂ O ₂ (M = 456.87)
Calc .: Mol peak (M + H) ⁺ : 455/457 Found: Mol peak (M + H) ⁺ : 455/457
R _f value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.24:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenyl} -amide

4.24.a. 1- [2- (2-chloro-4-nitro-phenoxy) -ethyl] -4-methyl-piperidine

A reaction mixture of 7.8 g (27.81 mmol) of 1- (2-bromoethoxy) -2-chloro-4-nitrobenzene and 10.14 mL (84 mmol) of 4-methylpiperidine in 100 mL of dichloromethane is added 18 hours stirred at room temperature. The solution is then purified by column chromatography on 400 g Alox Akt. II-III (eluent: dichloromethane / methanol = 49: 1).
Yield: 6.9 g (83% of theory)
C ₁₄ H ₁₉ ClN ₂ O ₃ (M = 298.77)
Calc .: Mol peak (M + H) ⁺ : 209/301 Found: Mol peak (M + H) ⁺ : 209/301
R _f value: 0.48 (Alox, petroleum ether / ethyl acetate = 3: 1)

4.24.b. 3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine

Prepared analogously to 3.1.b from 1- [2- (2-chloro-4-nitro-phenoxy) ethyl] -4-methyl-piperidine.
Yield: 3.66 g (59% of theory)
C ₁₄ H ₂₁ ClN ₂ O (M = 268.78)
Calc .: Mol peak (M + H) ⁺ : 269/271 Found: Mol peak (M + H) ⁺ : 269/271
R _f value: 0.52 (silica gel, dichloromethane / methanol = 9: 1)

4.24.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine.
Yield: 0.33 g (66% of theory)
C ₂₄ H ₂₃ Cl ₂ F ₃ N ₂ O ₂ (M = 499.36)
Calc .: Molpeak (M + H) ⁺ : 499/501/503 Found: Molepeak (M + H) ⁺ : 499/501/503
R _f value: 0.68 (Alox, dichloromethane / methanol = 49: 1)

Example 4.25:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethylamino] -phenyl} -amide

4.25.a. (2-Chloro-4-nitro-phenyl) - [2- (4-methyl-piperidin-1-yl) -ethyl] -amine

A solution of 12.02 g (32.45 mmol) of 2- (4-methyl-piperidin-1-yl) -ethylamine in 100 ml of DMF is mixed with 17.94 g (64.82 mmol) of potassium carbonate and 15 minutes at Room temperature stirred. Subsequently, 5.81 g (32.45 mmol) of 3-chloro-4-fluoro-nitrobenzene are added and the reaction mixture is stirred for 18 hours. Subsequently, the reaction mixture is poured into ice-water and the crystalline residue is filtered off.
Yield: 8.85 g (91.6% of theory)
C ₁₄ H ₂₀ ClN ₃ O ₂ (M = 297.78)
Calc .: Molpeak (M + H) ⁺ : 298/300 Found: Molepeak (M + H) ⁺ : 298/300

4.25.b. 2-Chloro-N ¹ - [2- (4-methylpiperidin-1-yl) ethyl] benzene-1,4-diamine

Prepared analogously to 3.1.b from (2-chloro-4-nitrophenyl) - [2- (4-methyl-piperidin-1-yl) -ethyl] -amine.
Yield: 7 g (89.3% of theory)
C ₁₄ H ₂₂ ClN ₃ (M = 267.80)
Calc.: Molpeak (M + H) ⁺ : 268/270 Found: Molpeak (M + H) ⁺ : 2681270
R _f value: 0.6 (Alox, dichloromethane / methanol = 49: 1)

4.25.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethylamino] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl) propynoic acid and 2-chloro-N ¹ - [2- (4-methylpiperidin-1-yl) ethyl] benzene-1,4-diamine.
Yield: 0.35 g (70.2% of theory)
C ₂₄ H ₂₄ Cl ₂ F ₃ N ₃ O (M = 498.38)
Calc .: Mol peak (M + H) ⁺ : 455/457 Found: Mol peak (M + H) ⁺ : 455/457

Example 4.26:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethylamino} phenyl] amide formate

4.26.a. N- (2-chloro-4-nitro-phenyl) -N, N-diethyl-ethane-1,2-diamine

Prepared analogously to 4.25.a from N ¹ , N ¹ -diethyl-ethane-l, 2-diamine and 3-chloro-4-fluoro-nitrobenzene.
Yield: 9.2 g (99.1% of theory)
C ₁₂ H ₁₈ ClN ₃ O ₂ (M = 271.74)
Calc .: Mol peak (M + H) ⁺ : 272/274 Found: Mol peak (M + H) ⁺ : 272/274
R _f value: 0.72 (Alox, dichloromethane / methanol = 49: 1)

4.26.b. 2-Chloro-N ¹ - (2-diethylamino-ethyl) -benzene-1,4-diamine

Prepared analogously to 3.1.b from N- (2-chloro-4-nitro-phenyl) -N, N-diethyl-ethane-1,2-diamine.
Yield: 6.15 g (78% of theory)
C ₁₂ H ₂₀ ClN ₃ (M = 241.76)
Calc.: Molpeak (M + H) ⁺ : 242/244 Found: Molepeak (M + H) ⁺ : 242/244
R _f value: 0.62 (Alox, dichloromethane / methanol = 49: 1)

4.26.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethylamino) -phenyl) -amide formate

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 2-chloro-N ¹ - (2-diethylamino-ethyl) -benzene-1,4-diamine.
Yield: 0.17 g (32.8% of theory)
C ₂₂ H ₂₂ Cl ₂ F ₃ N ₃ O x HCOOH (M = 518.36)
Calc.: Molpeak (M + H) ⁺ : 472/474/476 Found: Molpeak (M + H) ⁺ : 472/474/476

Example 4.27:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -amide

4.27.a. 1- (2-chloro-4-nitro-benzyl) -4-methyl-piperidine

1 g (4.85 mmol of 2-chloro-4-nitrobenzyl chloride are slowly added dropwise at room temperature to 2 ml (16.22 mmol) of 4-methylpiperidine and the mixture is stirred for 15 minutes, the reaction mixture is diluted with ethyl acetate and extracted twice with water Phase is dried over sodium sulfate and concentrated.
Yield: 1.3 g (99.7% of theory)
C ₁₃ H ₁₇ ClN ₂ O ₂ (M = 268.74)
Calc .: Mol peak (M + H) ⁺ : 269/271 Found: Mol peak (M + H) ⁺ : 269/271
R _f value: 0.4 (Alox, petroleum ether)

4.27.b. 3-chloro-4- (4-methyl-piperidin-1-ylmethyl) -phenylamine

Prepared analogously to 3.1.b from 1- (2-chloro-4-nitro-benzyl) -4-methyl-piperidine.
Yield: 0.93 g (80% of theory)
C ₁₂ H ₂₀ ClN ₃ (M = 241.76)
Calc.: Molpeak (M + H) ⁺ : 242/244 Found: Molepeak (M + H) ⁺ : 242/244
R _f value: 0.59 (Alox, petroleum ether / ethyl acetate = 3: 1)

4.27.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-chloro-4- (4-methyl-piperidin-1-ylmethyl) -phenylamine.
Yield: 25 mg (5.3% of theory)
C ₂₃ H ₂₁ Cl ₂ F ₃ N ₂ O (M = 469.33)
Calc.: Molpeak (M + H) ⁺ : 469/471/473 Found: Molpeak (M + H) ⁺ : 469/471/473
R _f value: 0.59 (Alox, petroleum ether / ethyl acetate = 3: 1)

Example 4.28:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethyl) -phenyl] -amide

4.28.a. (2-Chloro-4-nitro-phenyl) -acetic acid chloride

Prepared analogously to 4.1.c from (2-chloro-4-nitro-phenyl) -acetic acid. The product is reacted further without further purification.
Yield: 8.8 g (100% of theory)
C ₈ N ₅ Cl ₂ NO ₃ (M = 234.04)

4.28.b. 2- (2-chloro-4-nitro-phenyl) -N, N-diethyl-acetamide

Prepared analogously to 4.1.d from (2-chloro-4-nitro-phenyl) -acetic acid chloride and diethylamine in ethyl acetate.
Yield: 3.7 g (100% of theory)
C ₁₂ H ₁₅ ClN ₂ O ₃ (M = 270.71)
Calc .: Mol peak (M + H) ⁺ : 271/273 Found: Mol peak (M + H) ⁺ : 271/273
R _f value: 0.45 (silica gel, petroleum ether / ethyl acetate = 1: 1)

4.28.c. [2- (2-chloro-4-nitro-phenyl) -ethyl] -diethyl-amine

To a solution of 3.7 g (13.67 mmol) of 2- (2-chloro-4-nitro-phenyl) -N, N-diethyl-acetamide in 130 ml of THF at room temperature 65 ml (65 mmol) of a 1 M Borane THF solution was added dropwise and stirred for four hours. Then the reaction mixture is concentrated and the residue with 15 ml of methanol and 15 ml of dilute hydrochloric acid. Thereafter, the mixture is stirred for 15 minutes at 100 ° C, cooled and diluted with water. The mixture is then made alkaline with sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases are extracted twice with water and once with saturated brine and dried over sodium sulfate. The purification is carried out by column chromatography on Alox, neutral, Akt.II-III (eluent: petroleum ether / ethyl acetate = 4: 1).
Yield: 2.1 g (59.8% of theory)
C ₁₂ H ₁₇ ClN ₂ O ₂ (M = 256.73)
R _f value: 0.63 (Alox, petroleum ether / ethyl acetate = 3: 1)

4.28.d. 3-chloro-4- (2-diethylamino-ethyl) -phenylamine

Prepared analogously to 3.1.b from [2- (2-chloro-4-nitro-phenyl) -ethyl] -diethyl-amine.
Yield: 1.8 g (100% of theory)
C ₁₂ H ₁₉ ClN ₂ (M = 226.75)
Calc .: Molpeak (M + H) ⁺ : 227/229 Found: Molpeak (M + H) ⁺ : 227/229
R _f value: 0.63 (Alox, petroleum ether / ethyl acetate = 1: 1)

4.28.e. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethyl) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and chloro-4- (2-diethylamino-ethyl) -phenylamine.
Yield: 0.21 g (46.8% of theory)
C ₂₂ H ₂₁ Cl ₂ F ₃ N ₂ O (M = 457.32)
Calc.: Molpeak (M + H) ⁺ : 457/459/461 Found: Molepeak (M + H) ⁺ : 457/459/461
R _f value: 0.63 (Alox, petroleum ether / ethyl acetate = 1: 1)

Example 4.29:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -phenyl} -amide

4.29.a. 3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -phenylamine

Prepared analogously to 4.28.a to c from (2-chloro-4-nitro-phenyl) -acetic acid chloride.
Yield: 0.71 g (99.3% of theory)
C ₁₄ H ₂₁ ClN ₂ (M = 252.79)
Calc .: Mol peak (M + H) ⁺ : 253/255 Found: Mol peak (M + H) ⁺ : 253/255

4.29.b. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -phenylamine.
Yield: 0.21 g (45.3% of theory)
C ₂₄ H ₂₃ Cl ₂ F ₃ N ₂ O (M = 483.36)
Calcd .: Molpeak (M + H) ⁺ : 483/485/487 Found: Molepeak (M + H) ⁺ : 483/485/487
R _f value: 0.65 (Alox, petroleum ether / ethyl acetate = 1: 1)

Example 4.30:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenyl} -amide

4.30.a. [(E) -2- (2-chloro-4-nitro-phenyl) -vinyl] -dimethyl-amine

A reaction mixture of 8.49 g (48 mmol) of 2-chloro-4-nitrotoluene and 15.03 ml (72.8 mmol) of tert-butoxybut (dimethylamino) methane in 200 ml of THF is refluxed for eight hours. The reaction solution is concentrated and the residue is treated with petroleum ether. The precipitate is filtered off, rinsed with petroleum ether and dried under high vacuum at room temperature. The product is reacted further without further purification.
Yield: 11 g
C ₁₀ H ₁₁ ClN ₂ O ₂ (M = 226.66)
Calc .: Molpeak (M + H) ⁺ : 227/229 Found: Molpeak (M + H) ⁺ : 227/229
R _f value: 0.55 (silica gel, petroleum ether / ethyl acetate = 3: 1)

4.30.b. (2-Chloro-4-nitro-phenyl) -acetaldehyde

To a solution of 10 g (30.88 mmol) of [(E) -2- (2-chloro-4-nitro-phenyl) -vinyl] -dimethyl-amine in 200 ml of ethanol are added dropwise 50 ml of 1N hydrochloric acid and the reaction mixture then heated to reflux for one hour. Thereafter, the reaction mixture is concentrated, diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 3: 1).
Yield: 4.5 g (73% of theory)
C ₈ H ₆ ClNO ₃ (M = 199.59)
R _f value: 0.62 (silica gel, petroleum ether / ethyl acetate = 1: 1)

4.30.c. [2- (2-chloro-4-nitro-phenyl) -ethyl] -cyclopropyl-methyl-amine

To a solution of 1 g (5.01 mmol) of (2-chloro-4-nitro-phenyl) -acetaldehyde in 50 ml of THF is added 1.07 g (10 mmol) of N-methyl-cyclopropylamine, followed by 4.46 g (20 mmol) sodium triacetoxyborohydride (95%) was added. The reaction mixture is stirred for 120 hours at room temperature and then poured into a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The purification is carried out by column chromatography on Alox, neutral, Akt.II-III (eluent: petroleum ether / ethyl acetate = 5: 1).
Yield: 0.75 g (58.8% of theory)
C ₁₂ H ₁₅ ClN ₂ O ₂ (M = 254.71)
Calc .: Mol peak (M + H) ⁺ : 255/257 Found: Molepeak (M + H) ⁺ : 255/257
R _f value: 0.61 (Alox, petroleum ether / ethyl acetate = 5: 1)

4.30.d. 3-chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenylamine

Prepared analogously to 3.1.b from [2- (2-chloro-4-nitro-phenyl) -ethyl] -cyclopropyl-methyl-amine.
Yield: 0.6 g (100% of theory)
C ₁₂ H ₁₇ ClN ₂ (M = 224.73)
Calc.: Molpeak (M + H) ⁺ : 225/227 Found: Molepeak (M + H) ⁺ : 225/227
R _f value: 0.57 (Alox, petroleum ether / ethyl acetate = 1: 1)

4.30.e. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenylamine.
Yield: 15 mg (3.4% of theory)
C ₂₂ H ₁₉ Cl ₂ F ₃ N ₂ O (M = 455.31)
Calc .: Molpeak (M + H) ⁺ : 455/457/459 Found: Molepeak (M + H) ⁺ : 455/457/459
R _f value: 0.3 (Alox, petroleum ether / ethyl acetate = 3: 1)

Example 4.31:

3- (2-chloro-4-nitro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.31.a. (2-Chloro-4-nitro-phenyl) -propinsäureethylester

Prepared analogously to 4.11.a from 3-chloro-4-iodo-nitrobenzene and ethyl propoxide
Yield: 1.6 g (46.5% of theory)
C ₁₁ H ₈ ClNO ₄ (M = 253.64)
Calc .: Molpeak (M + H) ⁺ : 254/256 Found: Molepeak (M + H) ⁺ : 254/256
R _f value: 0.6 (silica gel, petroleum ether / ethyl acetate = 6: 1)

4.31.b. (2-Chloro-4-nitro-phenyl) -propinsäure

Prepared analogously to 4.11.b from (2-chloro-4-nitro-phenyl) -propionate.
Yield: 0.76 g (66.8% of theory)
C ₉ H ₄ ClNO ₄ (M = 225.59)
Calc.: Molpeak (M + H) ⁺ : 225/227 Found: Molepeak (M + H) ⁺ : 225/227

4.31.c. 3- (2-chloro-4-nitro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-nitro-phenyl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethoxy) -phenylamine.
Yield: 0.49 g (54.4% of theory)
C ₂₁ H ₂₁ Cl ₂ N ₃ O ₄ (M = 450.32)
Calc.: Molpeak (M + H) ⁺ : 448/450/452 Found: Molepeak (M + H) ⁺ : 448/450/452
R _f value: 0.36 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.32:

3- (4-bromo-2-chloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.32.a. (4-Bromo-2-chloro-phenyl) -propinsäureethylester

Prepared analogously to 4.11.a from 3-chloro-4-iodo-bromobenzene and ethyl propoxide
Yield: 0.97 g (48.2% of theory)
C ₁₁ H ₈ BrClO ₂ (M = 287.54)
Calc .: Molpeak (M + H) ⁺ : 287/289/291 Found: Mol peak (M + H) ⁺ : 287/289/291
R _f value: 0.62 (silica gel, petroleum ether / ethyl acetate = 6: 1)

4.32.b. (4-Bromo-2-chloro-phenyl) -propinsäure

Prepared analogously to 4.11.b from (4-bromo-2-chloro-phenyl) -propinsäureethylester.
Yield: 0.8 g (93.4% of theory)
C ₉ H ₄ BrClO ₂ (M = 259.48)
Calcd .: Mol peak (M + H) ⁺ : 258/260/262 Found: Mol peak (M + H) ⁺ : 258/260/262

4.32.c. 3- (4-bromo-2-chloro-phenyl) -propinsäure- [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (4-bromo-2-chloro-phenyl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethoxy) -phenylamine.
Yield: 0.25 g (64.5% of theory)
C ₂₁ H ₂₁ BrCl ₂ N ₂ O ₂ (M = 484.22)
Calc .: Molpeak (M + H) ⁺ : 483/485/487/489 Found: Molepeak (M + H) ⁺ : 483/485/487/489
R _f value: 0.86 (silica gel, dichloromethane / methanol = 49: 1)

In analogy to the examples mentioned above, the following compounds can be prepared:

Example 4.273: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-methoxy-4- [2- (4-methylpiperidin-1-yl) -ethoxy] -phenyl} -amide

4.273.a. 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -4-methyl-piperidine

Prepared analogously to Method 1.1.c from 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and 4-methylpiperidine.
Yield: 0.7 g (88.2% of theory)
C ₁₅ H ₂₂ N ₂ O ₄ (M = 294.35)
Calc .: Molpeak (M + H) ⁺ : 295 Found: Molepeak (M + H) ⁺ : 295
R _f value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

4.273.b. 3-methoxy-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine

Prepared analogously to Example 3.1.b. from 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -4-methyl-piperidine.
Yield: 0.51 g (81.1% of theory)
C ₁₅ H ₂₄ N ₂ O ₂ (M = 264.37)
Calc .: Molpeak (M + H) ⁺ : 265 Found: Molepeak (M + H) ⁺ : 265
R _f value: 0.3 (silica gel, dichloromethane / methanol 9: 1).

4.273.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {3-methoxy-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-methoxy-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine.
Yield: 70 mg (23.5% of theory)
Melting point: 207-209 ° C
C ₂₅ H ₂₆ ClF ₃ N ₂ O ₃ (M = 494.94)
Calc .: Molpeak (M + H) ⁺ : 495/497 Found: Molpeak (M + H) ⁺ : 495/497
R _f value: 0.45 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.274:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {4- [2- (3,5-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

4.274.a. 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -3,5-dimethyl-piperidine

Prepared analogously to procedure 1.1.c from 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and 3,5-dimethylpiperidine.
Yield: 0.4 g (48.1% of theory)
C ₁₆ H ₂₄ N ₂ O ₄ (M = 308.38)
Calc .: Molpeak (M + H) ⁺ : 309 Found: Molepeak (M + H) ⁺ : 309
R _f value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

4.274.b. 4- [2- (3,5-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenylamine

Prepared analogously to Example 3.1.b. from 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -3,5-dimethyl-piperidine.
Yield: 0.35 g (96.9% of theory)
C ₁₅ H ₂₄ N ₂ O ₂ (M = 264.37)
Calc .: Molpeak (M + H) ⁺ : 279 Found: Molepeak (M + H) ⁺ : 279
R _f value: 0.3 (silica gel, dichloromethane / methanol 9: 1).

4.274.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {4- [2- (3,5-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 4- [2- (3,5-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenyl-amine.
Yield: 160 mg (52.1% of theory)
Melting point: 196-201 ° C
C ₂₆ H ₂₈ ClF ₃ N ₂ O ₃ (M = 508.97)
Calc.: Molpeak (M + H) ⁺ : 509/511 Found: Molepeak (M + H) ⁺ : 509/511
R _f value: 0.5 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.275:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {4- [2 - ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

4.275.a. {(S) -1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -pyrrolidin-2-yl} methanol

Prepared analogously to procedure 1.1.c from 1- (2-bromo-ethoxy) -2-methoxy-4-nitro-benzene and (S) -1-pyrrolidin-2-yl-methanol.
Yield: 0.2 g (25% of theory)
C ₁₄ H ₂₀ N ₂ O ₅ (M = 296.32)
Calc .: Mol peak (M + H) ⁺ : 297 Found: Mol peak (M + H) ⁺ : 297
R _f value: 0.55 (silica gel, dichloromethane / methanol 9: 1).

4.275.b. {(S) -1- [2- (4-Amino-2-methoxy-phenoxy) -ethyl] -pyrrolidin-2-yl} methanol

Prepared analogously to Example 3.1.b. of {(S) -1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -pyrrolidin-2-yl} -methanol.
Yield: 0.15 g (83.4% of theory)
C ₁₄ H ₂₂ N ₂ O ₃ (M = 266.34)
calc .: Mol peak (M + H) ⁺ : 267 found: Mol peak (M + H) ⁺ : 267
R _f value: 0.15 (silica gel, dichloromethane / methanol 9: 1).

4.275.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- {4- [2 - ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and {(S) -1- [2- (4-amino-2-methoxy-phenoxy) -ethyl] -pyrrolidin-2-yl} -methanol.
Yield: 140 mg (58.9% of theory)
Melting point: decomposition at 300 ° C
C ₂₄ H ₂₄ ClF ₃ N ₂ O ₄ (M = 496.91)
Calc .: Molpeak (M + H) ⁺ : 497/499 Found: Molpeak (M + H) ⁺ : 497/499
R _f value: 0.2 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.276:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenyl] -amide

4.276.a. 4- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -morpholine

Prepared analogously to Method 1.1.c from 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and morpholine.
Yield: 0.3 g (39.4% of theory)
C ₁₃ H ₁₈ N ₂ O ₅ (M = 282.29)
Calc .: Molpeak (M + H) ⁺ : 283 Found: Molepeak (M + H) ⁺ : 283
R _f value: 0.6 (silica gel, dichloromethane / methanol 9: 1).

4.276.b. 3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamine

Prepared analogously to Example 3.1.b. from 4- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -morpholine.
Yield: 0.23 g (85.8% of theory)
C ₁₃ H ₂₀ N ₂ O ₃ (M = 252.31)
Calc .: Mol peak (M + H) ⁺ : 253 Found: Mol peak (M + H) ⁺ : 253
R _f value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

4.276.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl) propynoic acid and 3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamine.
Yield: 20 mg (6.9% of theory)
Melting point: 209-211 ° C
C ₂₃ H ₂₂ ClF ₃ N ₂ O ₄ (M = 482.89)
Calc.: Molpeak (M + H) ⁺ : 483/485 Found: Molepeak (M + H) ⁺ : 483/485
R _f value: 0.5 (silica gel, dichloromethane / methanol = 9: 1)

Example 5.1:

(E) -N- (4'-methoxy-biphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl} -acrylamide

5.1.A. (E) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylic acid ethyl ester

To a suspension of 0.69 ml (8.2 mmol) of pyrrolidine and 2.05 g (14.86 mmol) of potassium carbonate in 40 ml of DMF are added 2 g (7.43 mmol) of (E) -3- (4-bromomethyl- phenyl) -acrylic acid ethyl ester and stirred for 18 hours at room temperature. The reaction mixture is concentrated and the residue extracted with water and ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the residue is purified by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia = 90: 10: 1).
Yield: 0.3 g (15.6% of theory)
C ₁₆ H ₂₁ NO ₂ (M = 259.35)
Calc .: Mol peak (M + H) ⁺ : 260 Found: Mol peak (M + H) ⁺ : 260
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia 90: 10: 1)

5.1.b. (E) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylic acid

A reaction mixture of 0.3 g (1.15 mmol) of ethyl (E) -3- (4-pyrrolidin-1-ylmethylphenyl) acrylate and 0.4 g (9.53 mmol) of lithium hydroxide monohydrate in 20 ml of a 1: 1 mixture of methanol, THF and water is stirred for 48 hours at room temperature. The reaction mixture is then concentrated, the residue is diluted with water and acidified with hydrochloric acid. The mixture is concentrated, treated with methanol and dichloromethane, filtered and the filtrate evaporated to dryness.
Yield: 0.27 g
C ₁₄ H ₁₇ NO ₂ (M = 231.29)
Calc .: Mol peak (M + H) ⁺ : 232 Found: Mol peak (M + H) ⁺ : 232
R _f value: start spot (silica gel, dichloromethane / methanol / ammonia 90: 10: 1)

5.1.c. (E) -N- (4'-methoxy-biphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide

Prepared analogously to 3.1.e from (E) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylic acid and 4'-methoxy-biphenyl-4-yl-amine.
Yield: 74 mg (15.4% of theory)
Melting point: 199-200 ° C
C ₂₇ H ₂₈ N ₂ O ₂ (M = 412.53)
Calc .: Molpeak (M + H) ⁺ : 413 Found: Molepeak (M + H) ⁺ : 413
R _f value: 0.77 (silica gel, dichloromethane / methanol / ammonia = 80: 20: 1)

Example 5.2:

(E) -N- (4'-chloro-biphenyl-4-yl) -3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -acrylamide

5.2.a. (E) -3- (4-Dimethoxymethyl-phenyl) -acrylic acid

To a suspension of 25 g (0.141 mol) of (E) -3- (4-formyl-phenyl) -acrylic acid in 350 ml of methanol is added 38.81 ml (0.354 mmol) of trimethyl orthoformate and heated to reflux for 48 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in 500 ml of dichloromethane and filtered through Celite. The filtrate is concentrated to 150 ml and cooled to 0 ° C. The precipitate is filtered off, washed with dichloromethane / petroleum ether (1: 1) and dried at 60 ° C in a convection oven.
Yield: 12.05 g (31.5% of theory)
C ₁₂ H ₁₄ O ₄ (M = 222.24)
Calc .: Molpeak (M + H) ⁺ : 245 Found: Molepeak (M + H) ⁺ : 245
Rf value: 0.6 (silica gel, petroleum ether / ethyl acetate = 1: 1)

5.2.b. (E) -N- (4'-chloro-biphenyl-4-yl) -3- (4-dimethoxymethyl-phenyl) -acrylamide

Prepared analogously to 3.1.e from (E) -3- (4-dimethoxymethylphenyl) -acrylic acid and 4'-chlorobiphenyl-4-yl-amine.
Yield: 9.8 g
C ₂₄ H ₂₂ ClNO ₃ (M = 407.90)
Calc .: Molpeak (M + H) ⁺ : 408/410 Found: Molepeak (M + H) ⁺ : 408/410
R _f value: 0.3 (silica gel, dichloromethane / ethanol 20: 1)

5.2.c. (E) -N- (4'-chloro-biphenyl-4-yl) -3- (4-formyl-phenyl) -acrylamide

To a suspension of 9.8 g (24.02 mmol) of (E) -N- (4'-chlorobiphenyl-4-yl) -3- (4-dimethoxymethyl-phenyl) -acrylamide in 280 ml of chloroform become 70 ml of water and 21 ml of trifluoroacetic acid and the reaction mixture was stirred for eight hours at room temperature. It is diluted with chloroform and water, the organic phase separated and extracted with water. The organic phase is dried, filtered through silica gel and the solvent distilled off.
Yield: 5.5 g
C ₂₂ H ₁₆ ClNO ₂ (M = 361.83)
Calc .: Molpeak (M + H) ⁺ : 362/364 Found: Molepeak (M + H) ⁺ : 362/364
R _f value: 0.6 (silica gel, cyclohexane / ethyl acetate 1: 1)

5.2.d. (E) -N- (4'-chloro-biphenyl-4-yl) -3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -acrylamide

Prepared analogously to 4.30.c from (E) -N- (4'-chlorobiphenyl-4-yl) -3- (4-formyl-phenyl) -acrylamide and 4-methyl-piperidine.
Yield: 80 mg (21.7% of theory)
Melting point: 207-208 ° C
C ₂₈ H ₂₉ ClN ₂ O (M = 445.00)
Calc .: Molpeak (M + H) ⁺ : 445/447 Found: Molepeak (M + H) ⁺ : 445/447
R _f value: 0.76 (silica gel, dichloromethane / methanol = 10: 1)

Example 5.3:

(E) -N- (4'-chloro-biphenyl-4-yl) -3- [4- (cis-3,5-dimethyl-piperidin-1-ylmethyl) -phenyl] -acrylamide

5.3.a. (E) -N- (4'-chloro-biphenyl-4-yl) -3- (4-hydroxymethyl-phenyl) -acrylamide

A solution of 4.4 g (12.16 mmol) of (E) -N- (4'-chlorobiphenyl-4-yl) -3- (4-formyl-phenyl) -acrylamide in 200 ml of THF is added with glacial acetic acid adjusted to a pH of three, with 8.14 g (36.48 mmol) of sodium triacetoxyborohydride and stirred for 18 hours at room temperature. Subsequently, the reaction mixture is poured into water and the precipitate is filtered off. The filtrate is extracted with ethyl acetate, washed with water and dried over sodium sulfate. The solvent is removed and the residue combined with the filtered solid. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia = 30: 1: 0.1).
Yield: 3.2 g (72.4% of theory)
C ₂₂ H ₁₈ ClNO ₂ (M = 363.84)
Calc .: Molpeak (M + H) ⁺ : 364/366 Found: Molpeak (M + H) ⁺ : 364/366
R _f value: 0.2 (silica gel, dichloromethane / ethanol = 20: 1)

5.3.b. (E) -N- (4'-chloro-biphenyl-4-yl) -3- (4-chloromethyl-phenyl) -acrylamide

A suspension of 2.1 g (5.77 mmol) of (E) -N- (4'-chlorobiphenyl-4-yl) -3- (4-hydroxymethyl-phenyl) -acrylamide in 100 ml of dichloromethane is treated with 1 , 7 ml (12.19 mmol) of triethylamine and then with 0.46 ml (5.88 mmol) of methanesulfonyl chloride. The reaction mixture is stirred at room temperature for three hours, diluted with water and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered through silica gel and the filtrate is concentrated.
Yield: 0.4 g (18.1% of theory)
C ₂₂ H ₁₇ Cl ₂ NO (M = 382.29)
Calc .: Molpeak (M + H) ⁺ : 381/383/385 Found: Molepeak (M + H) ⁺ : 381/383/385

5.3.c. (E) -N- (4'-chloro-biphenyl-4-yl) -3- [4- (cis-3,5-dimethyl-piperidin-1-ylmethyl) -phenyl] -acrylamide

Prepared analogously to 1.2.c from (E) -N- (4'-chlorobiphenyl-4-yl) -3- (4-chloromethyl-phenyl) -acrylamide and cis-3,5-dimethylpiperidine.
Yield: 30 mg (30% of theory)
Melting point: 217-218 ° C
C ₂₉ H ₃₁ ClN ₂ O (M = 459.03)
Calc.: Molpeak (M + H) ⁺ : 459/461 Found: Molepeak (M + H) ⁺ : 459/461

R_f-Wert: A= (Kieselgel, Dichlormethan/Methanol (10:1)
A= (Kieselgel, Dichlormethan/Methanol/Ammoniak (10:1:0,1)The following compounds were prepared analogously to Example 5.3.c:

R _f value: A = (silica gel, dichloromethane / methanol (10: 1)
A = (silica gel, dichloromethane / methanol / ammonia (10: 1: 0.1)

The following compounds are prepared analogously to Example 5.3.c:

Example 6.1:

N- (4'-methoxy-biphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -propionamide

A reaction mixture of 60 mg (0.14 mmol) of (E) -N- (4'-methoxybiphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide and 10 mg of Raney® Nickel in 30 ml of methanol is hydrogenated for four hours. The catalyst is filtered off and the filtrate is evaporated to dryness.
Yield: 56 mg (93.2% of theory)
Melting point: 185-188 ° C
C ₂₇ H ₃₀ N ₂ O ₂ (M = 414.55)
Calc .: Molpeak (M + H) ⁺ : 415 Found: Molepeak (M + H) ⁺ : 415
R _f value: 0.29 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 6.2:

N- (4'-chloro-biphenyl-4-yl) -3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -propionamide

A reaction mixture of 80 mg (0.18 mmol) of (E) -N- (4'-chlorobiphenyl-4-yl) -3- [4- (4-methyl-piperidin-1-yl-methyl) -phenyl] - acrylamide and 20 mg of Raney nickel in 15 ml of ethyl acetate and 15 ml of methanol is hydrogenated for one hour at 50 psi and room temperature. The catalyst is filtered off, the filtrate is evaporated to dryness and stirred with diisopropyl ether.
Yield: 40 mg (49.7% of theory)
Melting point: 150-151 ° C
C ₂₈ H ₃₁ ClN ₂ O (M = 447.02)
Calc .: Molpeak (M + H) ⁺ : 447/449 Found: Molpeak (M + H) ⁺ : 447/449
R _f value: 0.5 (silica gel, dichloromethane / methanol = 10: 1)

Analogous to example 6.2. the following compounds were prepared:

Example 7.1:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- (2-piperidin-1-yl-quinolin-6-yl) -amide

7.1.a. 6-amino-2-piperidin-2-yl-quinoline

Prepared analogously to 3.1.b from 6-nitro-2-piperidin-2-yl-quinoline.
Yield: 0.79 g (59.6% of theory)
C ₁₄ H ₁₇ N ₃ (M = 227.31)
Calc .: Molpeak (M + H) ⁺ : 228 Found: Molepeak (M + H) ⁺ : 228
R _f value: 0.37 (silica gel, dichloromethane / methanol 19: 1)

7.1.b. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- (2-piperidin-1-yl-quinolin-6-yl) -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 6-amino-2-piperidin-2-yl-quinoline.
Yield: 170 mg (37.1% of theory)
Melting point: 176-179 ° C
C ₂₄ H ₁₉ ClF ₃ N ₃ O (M = 457.88)
Calc.: Molpeak (M + H) ⁺ : 456/458 Found: Molepeak (M + H) ⁺ : 456/458
R _f value: 0.62 (silica gel, dichloromethane / methanol = 19: 1)

Example 7.2:

3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- (2-isopropylamino-quinolin-6-yl) -amide

7.2.a. Isopropyl- (6-nitro-quinolin-2-yl) -amine

To a solution of 1.25 g (5.99 mmol) of 2-chloro-6-nitro-quinoline in 50 ml of ethanol are added 2.55 ml (29.96 mmol) of isopropylamine and stirred at room temperature for 18 hours. Subsequently, the reaction mixture is heated in the microwave for two hours at 65 ° C. Thereafter, the reaction mixture is concentrated, the residue taken up in 20 ml of DMF, with 2.55 ml (29.96 mmol) of isopropylamine and stirred for 18 hours at room temperature. The reaction mixture is concentrated and the residue is combined with ethyl acetate and water. The organic phase is extracted twice with water. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is then removed. Yield: 0.75 g (54.1% of theory)
C ₁₂ H ₁₃ N ₃ O ₂ (M = 221.25)
Calc .: Mol peak (M + H) ⁺ : 232 Found: Mol peak (M + H) ⁺ : 232
R _f value: 0.48 (silica gel, petroleum ether / ethyl acetate 2: 1)

7.2.b N ² -isopropyl-quinoline-2,6-diamine

Prepared analogously to 3.1.b from isopropyl (6-nitro-quinolin-2-yl) -amine.
Yield: 0.51 g (78.1% of theory)
C ₁₂ H ₁₅ N ₃ (M = 201.27)
Calc .: Molpeak (M + H) ⁺ : 202 Found: Molepeak (M + H) ⁺ : 202
R _f value: 0.25 (silica gel, dichloromethane / methanol 19: 1)

7.2.c. 3- (2-chloro-4-trifluoromethyl-phenyl) -propinsäure- (2-isopropylamino-quinolin-6-yl) -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and N ² -isopropyl-quinoline-2,6-diamine.
Yield: 140 mg (46.3% of theory)
Melting point: 57-60 ° C
C ₂₂ H ₁₇ ClF ₃ N ₃ O (M = 431.84)
Calc.: Molpeak (M + H) ⁺ : 432/434 Found: Molepeak (M + H) ⁺ : 432/434
R _f value: 0.49 (silica gel, petroleum ether / ethyl acetate 2: 1)

Analogously to Example 7.1, the following compounds are prepared:

The following describes test methods for determining MCH receptor antagonist activity. In addition, other test methods known to those skilled in the art, for example via the inhibition of MCH receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and the biosensing measurement of the binding of MCH to the MCH receptor in the presence of plasmon resonance antagonistic substances, as described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors ", Anal. Biochem. 300 (2002), 132-138. Further test methods for MCH receptor antagonist activity are contained in the cited references and patent documents whose description of the test methods is hereby incorporated in this application. MCH-1 receptor binding test Method: MCH binding to hMCH-1R transfected cells Species: humanely Test cell: hMCH-1 R stably transfected into CHO / Galpha16 cells results: IC50 values

Membranes from human hMCH-1R stably transfected CHO / Galpha16 cells are resuspended by syringe (0.6 x 25 mm needle) and assay 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 μg / mL aprotinin, 1 μg / mL leupeptin, and 1 μM phosphoramidone) to a concentration of 5 to 15 μg / mL.

200 microliters of this membrane fraction (containing 1 to 3 μg of protein) are incubated for 60 minutes at room temperature with 100 pM ¹²⁵ I-tyrosyl melanin concentrating hormone ( ¹²⁵ I-MCH commercially available from NEN) and increasing concentrations of the test compound in a final volume of 250 microliters , After incubation, the reaction is filtered using 0.5% PEI treated glass fiber filters (GF / B, Unifilter Packard) using a cell harvester. The membrane-bound radioactivity retained on the filter is then determined after addition of scintillator substance (Packard Microscint 20) in a measuring device (TopCount from Packard).

The Non-specific binding is defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.

The Analysis of the concentration-binding curve is made under the assumption a receptor binding site.

Default:

Unlabeled MCH competes with labeled ¹²⁵ I-MCH for receptor binding with an IC50 value between 0.06 and 0.15 nM.

Of the KD value of the radioligand is 0.156 nM.

MCH-1 receptor-coupled Ca ²⁺ mobilization test

Clonal CHO / Galpha16 hMCH-R1 cells are cultured in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat. No .: BE12-615F). This contains per mL mL 10% 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 μg / mL stock solution). One day prior to the experiment, the cells are plated on 384-well microtiter plate (black-walled with transparent bottom, manufacturer: Costar) at a density of 2500 cells per well and in the above-described medium overnight at 37 ° C, 5% CO ₂ and 95% relative humidity cultured. On the day of the experiment, the cells are incubated with cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid are added at 37 ° C for 45 minutes. After loading with fluorescent dye, the cells are washed four times with Hanks buffer solution (1 × HBSS, 20 mM HEPES) supplemented with 0.07% Probenicid. The test substances are diluted in Hanks buffer solution, mixed with 2.5% DMSO. The background fluorescence of unstimulated cells is measured in the presence of substance in the 384-well microtiter plate five minutes after the last wash in the FLIPR ³⁸⁴ device (Molecular Devices, excitation wavelength: 488 nm, emission wavelength: bandpass 510 to 570 nm). For cell stimulation, MCH is diluted in Hanks buffer with 0.1% BSA, pipetted to the 384-well cell culture plate 35 minutes after the last wash step and the MCH-stimulated fluorescence subsequently measured in the FLIPR ³⁸⁴ device.

Data analysis:

• 1st measurement: The cellular Ca ²⁺ mobilization is measured as the relative fluorescence minus background background and expressed as a percentage of the reference maximum signal (MCH 10 ^-6 M). This measurement serves to identify a possible agonistic effect of a test substance.
• 2nd measurement: The cellular Ca ²⁺ mobilization is measured as the peak of relative fluorescence minus background and as a percentage of the maximum signal of the reference (MCH 10 ^-6 M, signal is set to 100% nor miert). 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 right shift of the MCH stimulation curve in the generated graph.

The inhibition is expressed pKB value: pKB = log (EC 50 (test substance + MCH) / EC 50 (MCH) -1) -log C (Test substance)

The compounds according to the invention, including their salts, exhibit an MCH receptor antagonistic action in the abovementioned tests. Using the MCH-1 receptor binding assay described above, antagonist activity is obtained in a dose range of about 10 ^-10 to 10 ^-5 M, especially 10 ^-9 to 10 ^-6 M.

The following IC50 values were determined using the previously described MCH-1 receptor binding assay:

following Examples of dosage forms are described in which the term "active ingredient" is one or more compounds of the invention, including their salts means. In the case of one of the combinations described with one or more further active substances, the term "active substance" also includes the other Active substances.

Example A

Capsules for powder inhalation with 1 mg active ingredient Composition: 1 capsule for powder inhalation contains: active substance 1.0 mg lactose 20.0 mg Hard gelatin capsules 50.0 mg 71.0 mg

Production method:

Of the Active ingredient will be on the for Inhalativa required grain size ground. The ground active substance is mixed homogeneously with the milk sugar. The mixture is filled into hard gelatin capsules.

Example B

Inhalation solution for Respimat ^® with 1 mg active ingredient Composition: 1 hub contains: active substance 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg Water cleaned ad 15.0 μl

Production method:

The active ingredient and benzalkonium chloride are dissolved in water and filled into Respimat ^® cartridges.

Example C

Inhalation solution for nebulizers with 1 mg active ingredient Composition: 1 vial contains: active substance 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g Water cleaned ad 20.0 ml

Production method:

agent Sodium chloride and benzalkonium chloride are dissolved in water.

Example D

Propellant gas metered dose inhaler with 1 mg active ingredient 1 hub contains: Active ingredient 1.0 mg Lecithin 0.1 Propellant ad 50.0 μl

Production method:

Of the Micronized drug is in the mixture of lecithin and propellant homogeneously suspended. The suspension is in a pressure vessel with Dispensed filling valve.

Example E

Nasal spray with 1 mg active ingredient Composition: active substance 1.0 mg

sodium chloride 0.9 mg benzalkonium chloride 0025 mg disodium edetate 00:05 mg water cleaned ad 0.1 ml

Production method:

Of the Active ingredient and the excipients are dissolved in water and in a corresponding container bottled.

Example F

Injection solution with 5 mg active substance per 5 ml composition: active substance 5 mg glucose 250 mg Human serum albumin 10 mg glycofurol 250 mg Water for injections ad 5 ml

production:

glycofurol and glucose in water for Dissolve injections (Wfl); Human serum albumin release; Active ingredient with heating dissolve; fill with Wfl to batch volume; Fill into ampoules under nitrogen fumigation.

Example G

Injection solution with 100 mg active substance per 20 ml Composition: active substance 100 mg Monopotassium dihydrogenphosphate = KH ₂ PO ₄ 12 mg Disodium hydrogen phosphate = Na ₂ HPO ₄ .2H ₂ O 2 mg sodium chloride 180 mg Human serum albumin 50 mg

polysorbate 80 20 mg water for injections ad 20 ml

production:

Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Add human serum albumin; Active ingredient with heating to solve; fill with Wfl to batch volume; fill in ampoules.

Example H

Lyophilisate with 10 mg active substance Composition: active substance 10 mg mannitol 300 mg Human serum albumin 20 mg

production:

mannitol in water for Injection (Wfl) dissolve; Add human serum albumin; Dissolve active ingredient with heating; with Wfl on batch volume fill up; to fill in vials; freeze-dry.

Solvent for lyophilisate: Polysorbate 80 = Tween 80 20 mg mannitol 200 mg Water for injections ad 10 ml

production:

polysorbate 80 and mannitol in water for Injection (Wfl) dissolve; fill in ampoules.

Example I

Tablets containing 20 mg of active substance Composition: active substance 20 mg lactose 120 mg corn starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg

production:

Active substance, Lactose and corn starch mix homogeneously; with a watery solution granulate of povidone; mix with magnesium stearate; on a Press off tablet press; Tablet weight 200 mg.

Example J

Capsules with 20 mg active substance Composition: active substance 20 mg corn starch 80 mg Silica. highly dispersed 5 mg magnesium stearate 2.5 mg

production:

Active substance, corn starch and silica mix homogeneously; mix with magnesium stearate; Mix on one capsule in hard gelatin capsules size 3 fill.

Example K

Suppository with 50 mg active substance Composition: active substance 50 mg Hard fat (Adeps solidus) qs ad 1700 mg

production:

hard fat at about 38 ° C melt; homogeneously disperse the ground active substance in the molten hard fat; after cooling to about 35 ° C in pre-cooled Pour out molds.

Example L

Injection solution with 10 mg of active substance per 1 ml of composition: Active substance 10 mg Mannitol 50 mg Human serum albumin 10 mg Water for injections ad 1 ml

production:

mannitol in water for Dissolve injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; With Fill Wfl to batch volume; Fill into ampoules under nitrogen fumigation.

Claims (29)

Amide compounds of general formula I.

in the R ¹ , R ² independently of one another H, a C _1-8 -alkyl or C _3-7 -cycloalkyl group optionally substituted by the radical R ¹¹ , where a -CH ₂ - group in position 3 or 4 of a 5 , 6 or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR ¹³ -, or one optionally substituted by the radical R ¹² mono- or polysubstituted and polysubstituted and / or nitro single substituted phenyl or pyridinyl radical, or R ¹ and R ² form a C _2-8 -alkylene bridge in which - one or two -CH ₂ groups can independently be replaced by -CH = N- or -CH = CH- and / or - one or two -CH ₂ groups independently of one another by -O-, -S-, -SO, - (SO ₂ ) -, -C = NOR ¹⁸ , -CO-, -C (= CH ₂ ) - or -NR ¹³ -derart may be substituted, that heteroatoms are not directly connected to each other, and that a group -C = NOR ¹⁸ or -CO- is not directly connected to the group R ¹ R ² N-, wherein in the alkylene bridge previously defined one or more H atoms replaced by R ¹⁴ and wherein the previously defined alkylene bridge with one or two identical or different carbo- or heterocyclic groups Cy may be substituted 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, - over two common, adjacent C and / or N atoms to form a fused bicyclic ring system, or - over three or more C and / or N atoms takes place to form a bridged ring system , R ^{3 is} H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl or phenyl C _1-3 alkyl, X is a single bond or a C _{1 -8-} alkylene bridge in which - a -CH ₂ group which is not directly connected to the group R ¹ R ² N-, is bonded by -CH = CH- or -C≡C- may be replaced and / or - one or two non-adjacent -CH ₂ groups which are not directly connected to the group R ¹ R ² N-, independently of one another by -O-, -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ -derart can be replaced such that in each case two O, S or N atoms or an O are not directly connected to an S atom, wherein the bridge X may be joined to R ¹ , including the N atom connected to R ¹ and X, to form a heterocyclic group, wherein the bridge X additionally with R ² , including the N atom connected to R ² and X to form a heterocyclic Group may be connected, and wherein two carbon atoms or a C and an N-atom of the alkylene bridge may be connected to each other by an additional C _1-4 alkylene bridge, and wherein a C atom with R ¹⁰ and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _4-7 cycloalkenyl and C _4-7 cycloalkenyl C _{1 3} alkyl may be substituted, wherein two alkyl and / or alkenyl substituents may be joined together to form a carbocyclic ring system, and W represents a single bond, wherein Z is -C = CC (= O) -, CR ^7a = CR ^7c- C (= O) - or -CR ^7a R ^7b -CR ^7c R ^7d -C (= O), or W means -C (= O) -C = C-, where Z is a single bond; and Y is one of the meanings given for Cy, wherein R ^{1 may be} joined to Y including the group X and the N atom joined to R ¹ and X to form a heterocyclic group fused to Y, and / or wherein X is Y to Formation of a carbo or heterocyclic group fused to Y, and A is one of the meanings given for Cy, wherein in the event that the index b has the value 0, the group Cy no amino group as a substituent in the ortho position to the bridge W; B is one of the meanings given for Cy, b is 0 or 1, Cy is 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 group, - a phenyl group, - a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having an N, O or S atom as heteroatom, - a saturated or unsaturated 5-7 a heterocyclic heterocyclic group having two or more N atoms or having one or two N atoms and an O or S atom as heteroatoms, an aromatic heterocyclic 5- or 6-membered group having one or more identical or different heteroatoms selected from N, O and / or S, wherein the above-mentioned 4-, 5-, 6- or 7-membered groups may be connected via two common, adjacent carbon atoms condensed with a phenyl or pyridine ring, and wherein in the aforementioned 5, 6 or 7-membered groups one or two non-adjacent -CH ₂ groups independently of one another by a -CO-, -C (= CH ₂ ) -, - (SO) - or - (SO ₂ ), And wherein the previously mentioned saturated 6- or 7-membered groups are also bridged ring systems with an imino, N- (C _1-4 -alkyl) -imino, methylene, C _1-4 -Alkyl-methylene or di- (C _1-4 alkyl) -methylene bridge may be present, and wherein the aforementioned cyclic groups one or more times to one or more C atoms with R ²⁰ , in the case of a phenyl group also may additionally be substituted by nitro, and / or one or more NH groups with R ²¹ , R ^{4 is} one of the meanings given for R ¹⁷ , C _2-6 alkenyl or C _3-6 alkynyl, R ^7a , R ^7c H, F, Cl, C _1-4 -alkyl _O, the CF ₃ , R ^7b , R ^7d H, F, C _1-4 alkyl, wherein R ^7b and R ^7d in the meaning of alkyl to form a cyclopropyl group together can; R ^{10 is} hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, ω- (C _1-4 -alkoxy) C _1-3 -alkyl, carboxy, C _1-4 -alkoxycarbonyl, Amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cyclo C _3-6 alkyleneimino, amino C _1-3 alkyl, C _1-4 -Alkyl-amino-C _1-3 -alkyl, di- (C _1-4 -alkyl) -amino-C _1-3 -alkyl, cyclo-C _3-6 -alkyleneimino-C _1-3 -alkyl, amino C _1-3 alkoxy, C _1-4 alkylamino C _1-3 alkoxy, di (C _1-4 alkyl) amino C _1-3 alkoxy or cyclo C; _3-6 -alkyleneimino-C _1-3 -alkoxy, aminocarbonyl, C _1-4 -alkylaminocarbonyl, di- (C _1-4 -alkyl) -aminocarbonyl or cyclo-C _3-6 -alkyleneimino-carbonyl- , R ¹¹ 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 is} N-CO- or Cy-, R ^{12 is} one of the meanings given for R ²⁰ , R ^{13 is} one of the meanings given for R ¹⁷ , with the exception of carboxy, R ^{14 is} halogen, C _1-6 -alkyl, C _2-6 -alkenyl , C _2-6 -alkynyl, R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁵ -CO-, R ¹⁵ -CO-O-, R ¹⁶ R ¹⁷ N-, R ¹⁸ R ¹⁹ N-CO-, R ¹⁵ -O-C _1-3 alkyl, R ¹⁵ -O-CO-C _1-3 alkyl, R ¹⁵ -O-CO-NH-, R ¹⁵ -SO ₂ -NH -, R ¹⁵ -O-CO-NH-C _1-3 -alkyl, R ¹⁵ -SO ₂ -NH-C _1-3 -alkyl, R ¹⁵ -CO-C _1-3 -alkyl, R ¹⁵ -CO-OC _1-3 -alkyl-, R ¹⁶ R ¹⁷ NC _1-3 -alkyl-, R ¹⁸ R ¹⁹ N-CO-C _1-3 -alkyl- or cy-C _1-3 -alkyl-, R ¹⁵ H, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, phenyl, phenyl C _1-3 alkyl, pyridinyl or pyridinyl C _{1 3-} alkyl, R ^{16 is} H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _4-7 cycloalkenyl, C _4-7 Cycloalkenyl C _1-3 alkyl, ω-hydroxy C _2-3 alkyl, ω- (C _1-4 alkoxy) C _2-3 alkyl, amino C _2-6 alkyl -, C _1-4 alkyl-amino-C _2-6 -alkyl, di- (C _1-4 -alkyl) -amino-C _2-6 -alkyl- or cyclo-C _3-6 -alkyleneimino-C _2-6 -alkyl-, R ^{17 is} one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl, pyridinyl, dioxolan-2-yl, -CHO, C _1-4 -alkylcarbonyl, carboxy, hydroxycarbonyl- C _1-3 alkyl, C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonyl C _1-3 alkyl, C _1-4 Alkylcarbonylamino-C _2-3 alkyl, N- (C _1-4 alkylcarbonyl) -N- (C _1-4 alkyl) amino C _2-3 alkyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfonylamino C _2-3 alkyl or N- (C _1-4 alkylsulfonyl) -N (C _1-4 alkyl) amino C _2-3 alkyl, R ¹⁸ , R ¹⁹ independently of one another are H or C _1-6 -alkyl, R ^{20 is} halogen, hydroxyl, cyano, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-7 -cycloalkyl, C _{3- 7} -cycloalkyl-C _1-3 -alkyl-, hydroxy-C _1-4 -alkyl, R ²² -C _1-3 -alkyl or one of the meanings given for R ²² , R ²¹ C _1-4 -alkyl, ω- Hydroxy C _2-3 alkyl, ω C _1-4 alkoxy C _2-6 alkyl, ω C _1-4 alkyl amino C _2-6 alkyl, ω-di- (C _1-4 alkyl) amino C _2-6 alkyl, ω-cyclo C _3-6 alkylene-C _2-6 alkyl, phenyl C _1-3 alkyl, C _1-4 Alkylcarbonyl, C _1-4 alkoxycarbonyl or C _1-4 alkylsulphonyl, R ²² phenylC _1-3 alkoxy, cycloC _3-6 alkyleneiminoC _2-4 alkoxy, OHC -, HO-N = HC-, C _1-4 -alkoxy-N = HC-, C _1-4 -alkoxy, C _1-4 -alkylthio, carboxy, C _1-4 -alkylcarbonyl, C _1-4 -alkoxycarbonyl , Aminocarbony l, C _1-4 -alkylaminocarbonyl, di- (C _1-4 alkyl) aminocarbonyl, cyclo-C _3-6 alkyl-amino-carbonyl, cyclo-C _3-6 -alkylenimino-carbonyl, cyclo-C _3-6 -alkyleneimino-C _2-4 -alkylaminocarbonyl, phenylamino-carbonyl, C _1-4 -alkylsulfonyl, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonylamino, amino , C _1-4 alkylamino, di (C _1-4 alkyl) amino, C _1-4 alkylcarbonylamino, cycloC _3-6 alkyleneimino, phenyl C _{1 3} -alkylamino, N- (C _1-4 alkyl) phenyl C _1-3 alkylamino, acetylamino, propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl ) -carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or Alkylaminocarbonylamino-, wherein in the aforementioned groups and radicals, in particular in in particular A, B, W, X, Y, Z, R ¹ to R ⁴ , R ^7a , R ^7b , R ^7c , R ^7d , R ¹⁰ to R ²² , in each case one or more C atoms additionally one or more fa with F and / or in each case one or two C atoms independently of one another additionally additionally with Cl or Br and / or in each case one or more phenyl rings independently of one another additionally one, two or three substituents selected from the group F, Cl, Br, I, C _1-4 -alkyl, C _1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C _1-3 -alkylamino, di (C _1-3 -alkyl) amino , Acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, aminoC _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl- and di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl- and / or may be substituted by nitro, and the H atom of an existing carboxy group or an atom attached to an H atom in each case be replaced by a cleavable in vivo residue may denote their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, the following compounds according to provisos (M1) to (M14) are not included: (M1) N- [4 - [[(methylamino) sulphonyl ] methyl l] phenyl] -3- [2- (dimethylamino) -ethyl] -1-H-indole-5-propanamide oxalate, (M2) 3- [2- [3- [3,6-dihydro-4- (2 -naphthyl) -1 (2H) -pyridinyl] -2-hydroxy-propoxy] -phenyl] -N-methyl-N-phenyl-2-propenamide, (M3) 3- [2- [2-hydroxy-3- [4- (2-hydroxypropyl) 1-naphthyl) -1-piperidinyl] propoxy] phenyl] - N -methyl-N-phenyl-2-propenamide, (M4) 3- [2- [2-hydroxy-3- [4- (2-naphthyl) -] 1-piperidinyl] propoxy] phenyl] -N-methyl-N-phenyl-2-propenamide, (M5) 3- [2- [2-hydroxy-3- [4- (2-naphthyl) -1-piperidinyl] propoxy ] phenyl] -N-phenyl-2-propenamide, (M6) N - [4- [1- (1H -imidazol-1-yl) -2-methylpropyl] phenyl] -3-phenyl-2-propynamide, (M7 ) 2 '- [[3- (Dimethylamino) propyl] thio] -3-phenylpropiolanilide (M8) 2- (methylthio) -5 - [[3- [4- (octadecylamino) phenyl] -1-oxopropyl] -amino ] benzoic acid, including the trifluoroacetate salt, (M9) 4-amino-N- (4-hydroxy-3,5-dimethylphenyl) -benzenepropanamide, (M10) 4- (dimethylamino) -N- (4-hydroxy-3,5 -dimethylphenyl) -benzenepropanamide, (M11) β-methyl-4 - [[3- [2 - [(2-methylphenyl) amino] -6-benzoxazolyl] -1-oxopropylamino] -benzenepropanoic acid, (M12) 4- [3 - [ [1-Oxo-3- [2- (phenylamino) -6-benzoxazolyl] -propyl] amino] phenoxy] -butanoic acid, (M13) 2-chloro-5 - [[1-oxo-3- [4 - [( 5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid (M14) 2-Chloro-5 - [[1-oxo-3- [4 - [(5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid methyl ester Amide compounds according to claim 1, characterized in that the group

is selected from the group consisting of

wherein R ¹ , R ² , R ³ , X, Y, A, B and b have the meaning according to claim 1. Amide compounds according to claim 1, characterized in that the group

is selected from the group consisting of

wherein R ¹ , R ² , R ³ , R ^7a , R ^7b , R ^7c , R ^7d , X, Y, A, B and b have the meaning according to claim 1. Amide compounds according to one or more of the preceding claims, characterized in that R ¹ , R ² independently of one another are H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 - alkyl, ω-hydroxy-C _2-3 -alkyl, ω- (C _1-4 -alkoxy) C _2-3 -alkyl, C _1-4 -alkoxycarbonyl-C _1-4 -alkyl- , carboxyl-C _1-4 alkyl-, C _2-4 alkyl amino, C _1-4 alkyl-amino-C _2-4 -alkyl, di- (C _1-4 alkyl) amino C _2-4 alkyl, cyclo C _3-6 alkyleneimino-C _2-4 alkyl, pyrrolidinyl, N- (C _1-4 alkyl) pyrrolidinyl, pyrrolidinyl C _1-3 alkyl , N- (C _1-4 alkyl) pyrrolidinyl C _1-3 alkyl, piperidinyl, N- (C _1-4 alkyl) piperidinyl, piperidinyl C _1-3 alkyl, N- (C _1-4 alkyl) -piperidinyl-C _1-3 -alkyl, phenyl, phenyl-C _1-3 -alkyl, pyridyl or pyridyl-C _1-3 -alkyl-, where in the abovementioned groups and radicals one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another with Cl or Br and where the phenyl or P yridyl radical may be mono- or polysubstituted by the radical R ¹² defined in claim 1 and / or may simply be substituted by nitro. Amide compounds according to one or more of claims 1 to 3, characterized in that R ¹ and R ^{2 form} such an alkylene bridge according to claim 1 that R ¹ R ² N- is a group selected from azetidine, pyrrolidine, piperidine, azepane , 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine in which the free imine function is substituted with R ¹³ , piperidin-4-one oxime, piperidin-4-one-OC _1-4 alkyl oxime, morpholine and thiomorpholine forms, wherein according to claim 1 one or more H Atoms can be replaced by R ¹⁴ , and / or in the manner indicated in claim 1 with one or two identical or different carbocyclic or heterocyclic groups Cy may be substituted, wherein R ¹³ , R ¹⁴ and Cy have the meaning given in claim 1. Amide compounds according to one or more of the preceding claims, characterized in that the group

has a meaning according to one of the following sub-formulas

wherein one or more H atoms of the heterocycle formed by the group R ¹ R ² N- may be replaced by R ¹⁴ and the ring connected to the heterocycle formed by the group R ¹ R ² N- one or more times on one or more can also be substituted by nitro and X ', X''independently of one another a single bond or C _1-3 alkylene and in the event that the group Y is replaced by a plurality of carbon atoms with R ²⁰ , in the case of a phenyl ring a C atom is connected to X 'or X'', also C _1-3 -alkylene-O-, -C _1-3 -alkylene-NH- or -C _1-3 -alkylene-N (C _{1 3-} alkyl) -, and X "additionally also -OC _1-3 -alkylene, -NH-C _1-3 -alkylene or -N (C _1-3 -alkyl) -C _1-3 -alkylene and the case that the group Y is connected via a C atom with X ", also -NH-, -N (C _1-3 alkyl) - or -O-, wherein in the above for X ', X '' each mean a C atom with R ¹⁰ , preferably with a hydroxy, ω-hydroxy-C _1-3 alkyl, ω- (C _1-4 alkoxy) C _1-3 alkyl and or C _1-4 -alkoxy radical, and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 -alkyl, C _2-6 -alkenyl, C _{2- 6} alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _4-7 cycloalkenyl and C _4-7 cycloalkenyl C _1-3 alkyl in which two alkyl and / or alkenyl substituents can be linked together to form a carbocyclic ring system, and in which X ', X "independently of one another in each case one or more C atoms one or more times with F and / or in each case one or two carbon atoms independently of one another may be substituted by Cl or Br and in which R ² , R ¹⁰ , R ¹³ , R ¹⁴ , R ²⁰ , R ²¹ and X have the meanings given in claim 1. Amide compounds according to one or more of the preceding claims, characterized in that X is a straight-chain C _1-4 -alkylene bridge and, in the case that the group Y is connected to X via a C atom, also -CH ₂ - CH = CH-, -CH ₂ -C≡C-, C _2-4 -alkyleneoxy or C _2-4 -alkylene-NR ⁴ -, wherein the bridge X with R ¹ , including the R ¹ and X connected N Atom may also be joined to form a heterocyclic group, and wherein the bridge X may be additionally joined to R ² including the N atom joined to R ² and X to form a heterocyclic group, and wherein X is a C atom with R ¹⁰ and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _{3- 7-} cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _4-7 -cycloalkenyl and C _4-7 -cycloalkenyl-C _1-3 -alkyl- may be substituted, wherein two alkyl and / or or alkene yl substituents may be linked together to form a carbocyclic ring system, and wherein in the above-mentioned groups and radicals one or more carbon atoms one or more times with F and / or one or two carbon atoms may be independently substituted with Cl or Br independently and wherein R ¹ , R ⁴ and R ^{10 are} as defined in claim 1. Amide compounds according to claim 6, characterized in that X is -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CH ₂ -CH = CH-CH ₂ - and for the If the group Y is connected to X via a C atom, also -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, wherein the bridge X is linked to R ¹ , including the one connected to R ¹ and X. In addition, N-atom may be connected to form a heterocyclic group, and wherein the bridge X may be additionally joined to R ² including the N atom connected to R ² and X to form a heterocyclic group, and wherein in X a C- Atom with R ¹⁰ , preferably a hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-4 -alkoxy) C _1-3 -alkyl and / or C _1-4 -alkoxy Radical, and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 -Cycl oalkyl, C _3-7 cycloalkylC _1-3 alkyl, C _4-7 cycloalkenyl and C _4-7 cycloalkenylC _1-3 alkyl, where two alkyl and / or alkenyl Substituents may be linked together to form a carbocyclic ring system, and wherein in each case one or more C atoms mono- or polysubstituted with F and / or each one or two C atoms independently may be substituted with Cl or Br and R ¹ , R ⁴ and R ^{10 has} one of the meanings given in claim 1. Amide compounds according to one or more of the preceding claims, characterized in that the group Y is selected from the group of bivalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl and benzoxazolinyl, where the abovementioned cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R ²⁰ , and in the case of a phenyl group may additionally be substituted simply by nitro, and / or by one or more N atoms by R ²¹ in which R ^{1 may be} linked to Y and / or X to Y as defined in claims 1 and 2, and X, R ¹ , R ²⁰ and R ²¹ are as defined in claim 1. Amide compounds according to one or more of the preceding claims, characterized in that the group Y is selected from the group of bivalent cyclic groups

where the abovementioned cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R ²⁰ , in the case of a phenyl group also additionally simply with nitro, and / or one or more NH groups with R ²¹ , where R ²⁰ and R ^{21 are} as defined in claim 1. Amide compounds according to one or more of the preceding claims, characterized in that the group A is phenyl, pyridyl or naphthyl, wherein the aforementioned cyclic groups one or more times to one or more C atoms with R ²⁰ , in the case of a phenyl ring may also be additionally substituted with nitro, and / or one or more NH groups with R ²¹ , wherein the group Cy has no amino group as a substituent in the ortho position to the bridge W, and R ²⁰ and R ^{21 are} those specified in claim 1 Have meanings. Amide compounds after one or more of the previous ones Claims, characterized in that b has the value 0. Amide compounds according to one or more of the preceding claims, characterized in that b has the value 1 and B has a meaning selected from the group consisting of phenyl, furanyl, thienyl and pyridyl, wherein the aforementioned cyclic groups one or more times one or more carbon atoms may be substituted by R ²⁰ , in the case of a phenyl ring also additionally simply by nitro, and R ^{20 has} the meaning given in claim 1. Amide compounds after one or more of the previous ones Claims, characterized in that Y is a meaning according to claim 10 A is a meaning according to claim 11 B is a meaning according to claim 13 and b has the value 0 or 1. Amide compounds according to claim 14, characterized in that R ¹ , R ^{2 are} as defined in claim 4 or 5, X is as defined in claim 8, W and Z are as defined in claims 2 or 3. Amide compounds according to one or more of the preceding claims, characterized in that R ^{20 is} F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy , Amino, C _1-3 -alkylamino, di-C _1-3 -alkylamino, carboxy or C _1-4 -alkoxycarbonyl, where multiple occurring substituents R ^{20 may have the} same or different meanings and in the case a phenyl ring may additionally be substituted by nitro. Physiologically acceptable salts of the amide compounds according to one or more of claims 1 to 16. Composition containing at least one amide compound according to one or more of claims 1 to 16 and / or a salt according to claim 17 next to optionally one or more physiologically acceptable Excipients. Medicament containing at least one amide compound according to one or more of claims 1 to 16 and / or a salt according to claim 17 next to optionally one or more inert carriers and / or diluents. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, to influence the eating behavior of a mammal. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, to reduce body weight and / or for preventing an increase in body weight of a mammal. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, for the manufacture of a medicament with MCH receptor antagonist activity. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, for the manufacture of a medicament, which for the prophylaxis and / or treatment of phenomena and / or Diseases caused by MCH or MCH in one other causal relationship is appropriate. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, for the manufacture of a medicament, which is used for the prophylaxis and / or treatment of metabolic disorders and / or Eating disorder, especially of obesity, bulimia, bulimia nervosa, cachexia, anorexia, Anorexia nervosa and hyperphagia, is appropriate. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, for the manufacture of a medicament, which is used for the prophylaxis and / or treatment of obesity Diseases and / or disorders, especially diabetes, especially type II diabetes, diabetic Complications, including diabetic retinopathy, diabetic neuropathy, diabetic Nephropathy, insulin resistance, pathological glucose tolerance, Encephalorrhagia, heart failure, cardiovascular disease, in particular Atherosclerosis and hypertension, arthritis and gonitis is. Use of at least one amide compound according to one or more of Claims 1 to 16 and / or a salt according to Claim 17, including the compounds excluded by the provisos (M1) to (M14) according to Claim 1, for the preparation of a medicament which is for prophylaxis and / or treatment of hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders conditions, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders. Use of at least one amide compound according to one or more of the claims 1 to 16 and / or a salt according to claim 17, including through the stipulations (M1) to (M14) according to claim 1 excluded compounds, for the manufacture of a medicament, which is used for the prophylaxis and / or treatment of micturition disorders, such as urinary incontinence, overactive bladder, urinary urgency, Nocturia, enuresis, is appropriate. Process for the preparation of a composition or a drug according to one or more of the claims 18 to 27, characterized in that non-chemical ways at least one amide compound according to one or more of claims 1 to 16 and / or a salt according to claim 17 in one or more inert carriers and / or diluents is incorporated. Medicaments containing a first active ingredient, from the amide compounds according to one or more of claims 1 to 16 and / or a salt according to claim 17, including the by the stipulations (M1) to (M14) according to claim 1 excluded compounds, is selected as well a second Active substance selected from the group consisting of active substances for the treatment of diabetes, agents for the treatment of diabetic Complications, agents for the treatment of obesity, preferably other than MCH antagonists, agents for the treatment of hypertension, Active ingredients for the treatment of hyperlipidemia, including arteriosclerosis, Agents for the treatment of arthritis, agents for treatment of anxiety and drugs for the treatment of depression, besides possibly one or more inert carriers and / or diluents.