DE102004017933A1 - New alkyne compounds having MCH antagonist activity and medicaments containing these compounds - Google Patents

Abstract

in der die Gruppen und Reste A, B, W, X, Y, Z, R¹ und R² die in Anspruch 1 angegebenen Bedeutungen aufweisen. Ferner betrifft die Erfindung Arzneimittel, enthaltend mindestens ein erfindungsgemäßes Alkin. Auf Grund der MCH-Rezeptor antagonistischen Aktivität eignen sich die erfindungsgemäßen Arzneimittel zur Behandlung von metabolischen Störungen und/oder Essstörungen, insbesondere von Adipositas, Bulimie, Anorexie, Hyperphagia und Diabetes.The present invention relates to alkyne compounds of general formula I,

in which the groups and radicals A, B, W, X, Y, Z, R ¹ and R ^{2 have} the meanings given in claim 1. Furthermore, the invention relates to medicaments containing at least one alkyne 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 alkyne 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. Other items This invention relates to processes for the preparation of the compounds of the 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 in recent decades the development of pathological overweight ("Obesity", obesity or also called obesity) favors. Obesity leads directly to a restriction of mobility and a Reduction of the quality of life. To make matters worse, that obesity is often more diseases diabetes, dyslipidaemia, hypertension, Atherosclerosis and coronary heart disease. Furthermore leads alone the high body weight to a reinforced Load on the support and musculoskeletal system, causing chronic discomfort and disease, like arthritis or osteoarthritis. Thus, obesity presents a serious health problem for society.

Of the Term obesity refers to an excess of adipose tissue in the body Body. In this context, obesity is basically considered to be any elevated degree at body fat content seeing that leads to a health risk. There are no sharp ones Separation between normal weight and those suffering from obesity Individuals, however, increases the obesity associated with health Risk is likely to be continuous with increasing obesity at. For reasons 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 divided by the body weight measured in kilograms Height (in meters) is defined in the square, above the value 25, in particular above 30, considered as 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 its development serious and even life-threatening diseases, It is all the more important to use pharmaceutical agents for prophylaxis and / or treatment of obesity. One in newest Time suggested approach is the therapeutic use of MCH antagonists (inter alia 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).

Studies of the function of MCH in animal models provide good evidence for a role of the peptide in the regulation of the energy balance, ie alteration of metabolic activity and feed intake [1, 2]. For example, after intraventricular administration of MCH in rats, feed intake is increased compared to control animals. In addition, transgenic rats that produce more MCH than control animals respond after administration of a high-fat diet with greater weight gain than animals with non-experimentally-altered MCH levels. It has also been found that there is a positive correlation between periods of increased craving for food and the amount of MCH mRNA in rat hypothalamus. However, experiments with MCH "knock out" mice are of particular relevance for the function of MCH. Loss of the neuropeptide leads to leaner animals with reduced fat mass consume significantly less food than control animals.

The anorectic effects of MCH are presumably in rodents through the G _αS -coupled MCH-1R mediated [3-6], daim contrast to primates, ferrets and dogs, in rodents previously no second MCH receptor could be detected. Loss of MCH-1R results in lower fat mass, higher energy expenditure in knock-out mice and no weight increase in high-fat diets compared to control animals.Another indication of the importance of the MCH system in the regulation of energy balance comes from experiments with a receptor antagonist (SNAP-7941). [3] In long-term trials, animals treated with this 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 melanin-concentrating 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 USA, 2002. 99 (5): p. 3240-5.
• 6. Takekawa, S., et al., T-226296: a novel, orally active and selective melanin-concentrating 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. Adipositas 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 Nhaltigen 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 a N-containing hetero ring, described as MCH antagonists for the treatment of, inter alia, obesity.

In the not yet disclosed international application PCT / EP0311887, which describes alkyne compounds as MCH antagonists, the following substances are mentioned, inter alia:
6- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydroquinoline,
6- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -1-methyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline,
5- (4-chloro-phenyl) -2- [2- (4-methyl-piperidin-1-ylmethyl) chroman-6-ylethynyl] -pyridine.

Of the present invention is based on the object new alkyne compounds show, in particular those which have a particularly high activity as MCH antagonists. It is also an object of this invention to provide new alkyne 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 disturbances, 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 alkyne 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 bedeuten unabhängig voneinander H, C_1-8-Alkyl, C_3-7-Cycloalkyl oder einen gegebenenfalls mit gleichen oder verschiedenen Resten R²⁰ ein- oder mehrfach und/oder mit Nitro einfach substituierten Phenyl- oder Pyridinylrest, wobei die Alkyl- oder Cycloalkyl-Gruppe mit gleichen oder verschiedenen Resten R¹¹ ein- oder mehrfach substituiert sein kann, und wobei eine -CH₂-Gruppe in Position 3 oder 4 einer 5, 6 oder 7-gliedrigen Cycloalkylgruppe durch -O-, -S- oder -NR¹³- ersetzt sein kann, oder
R¹ und R² bilden eine C_3-8-Alkylen-Brücke, in der eine nicht mit dem N-Atom der R¹R²N-Gruppe benachbarte -CH₂-Gruppe durch -CH=N-, -CH=CH-, -O-, -S-, -SO, -(SO₂)-, -CO-, -C(=CH₂)- oder -NR¹³- ersetzt sein kann,
wobei in der zuvor definierten Alkylen-Brücke ein oder mehrere H-Atome durch gleiche oder verschiedene Reste 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;

X eine C_1-4-Alkylen-Brücke, wobei in der Bedeutung C_2-4-Alkylen ein oder zwei C-Atome einfach mit R¹⁰ substituiert sein können, oder
eine C_3-4-Alkylen-Brücke, in der eine nicht mit dem N-Atom der R¹R²N-Gruppe unmittelbar benachbarte -CH₂-CH₂-Gruppe durch -CH=CH- oder -C≡C- ersetzt ist,
wobei die vorstehend für X angegebenen Bedeutungen einen Substituenten ausgewählt aus C_2-6-Alkenyl-, C_2-6-Alkinyl-, C_3-7-Cycloalkyl und C_3-7-Cycloalkyl-C_1-3-alkyl sowie unabhängig ein, zwei oder drei gleiche oder verschiedene C_1-4-Alkyl-Substituenten aufweisen können, wobei zwei Alkyl-Gruppen unter Ausbildung einer 3 bis 7-gliedrigen oder eine Alkyl- und eine Alkenyl-Gruppe unter Ausbildung einer 5 bis 7-gliedrigen cyclischen Gruppe miteinander verbunden sein können, und
W, Z unabhängig voneinander eine Einfachbindung oder eine C_1-2-Alkylen-Brücke,
wobei zwei benachbarte C-Atome mit einer zusätzlichen C_1-4-Alkylen-Brücke miteinander verbunden sein können, und
wobei ein oder zwei C-Atome unabhängig voneinander mit einem oder zwei gleichen oder verschiedenen C_1-3-Alkyl-Resten substituiert sein können, wobei zwei Alkylreste unter Ausbildung eines carbocyclischen Rings miteinander verbunden sein können, und
Y ist ausgewählt aus den Bedeutungen der Teilformeln Y1 und Y2

worin die Gruppe M O, S oder NR^M bedeutet, wobei R^M ausgewählt ist aus den Bedeutungen H, C_1-6-Alkyl, C_3-6-Alkenyl, C_3-6-Alkinyl, C_3-7-Cycloalkyl und C_3-7-Cycloalkyl-C_1-3-alkyl, und
wobei in den Teilformeln Y1 und Y2 eine oder mehrere C-Atome unabhängig voneinander mit R²⁰ substituiert sein können, und
A ausgewählt ist aus der Gruppe der bivalenten cyclischen Gruppen Phenyl, Pyridinyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, Naphthyl, Tetrahydronaphthyl, Indolyl, Dihydroindolyl, Chinolinyl, Dihydrochinolinyl, Tetrahydrochinolinyl, Isochinolinyl, Dihydroisochinolinyl, Tetrahydroisochinolinyl, Benzimidazolyl-, Benzoxazolyl, Thienyl, Furanyl, Benzothienyl oder Benzofuranyl, wobei die genannten cyclischen Gruppen ein- oder mehrfach an ein oder mehreren C-Atomen mit gleichen oder verschiedenen Resten R²⁰, im Falle eines Phenylrings auch zusätzlich einfach mit Nitro, und/oder eine oder mehrere NH-Gruppen mit R²¹ substituiert sein können,
B eine der für A angegebenen Bedeutungen oder
C_1-6-Alkyl, C_1-6-Alkenyl, C_1-6-Alkinyl, C_3-7-Cycloalkyl, C_5-7-Cycloalkenyl, C_3-7-Cycloalkyl-C_1-3-alkyl-, C_3-7-Cycloalkenyl-C_1-3-alkyl-, C_3-7-Cycloalkyl-C_1-3-alkenyl- oder C_3-7-Cycloalkyl-C_1-3-alkinyl-, worin ein oder mehrere C-Atome unabhängig voneinander ein- oder mehrfach mit Halogen und/oder einfach mit Hydroxy oder Cyano und/oder cyclische Gruppen ein- oder mehrfach mit gleichen oder verschiedenen Resten R²⁰ substituiert sein können,
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 gesättigten 6- oder 7-gliedrigen Gruppen auch als verbrückte Ringsysteme mit einer Imino-, (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 gleichen oder verschiedenen Resten R²⁰, im Falle einer Phenylgruppe auch zusätzlich einfach mit Nitro, und/oder ein oder mehrere NH-Gruppen mit R²¹ substituiert sein können,
R¹⁰ Hydroxy, ω-Hydroxy-C_1-3-alkyl, C_1-4-Alkoxy oder C_1-4-Alkoxy-C_1-3-alkyl-,
R¹¹ Halogen, C_1-6-Alkyl, C_2-6-Alkenyl, C_2-6-Alkinyl, R¹⁵-O-, R¹⁵-O-CO-, R¹⁵-CO-O-, Cyano, R¹⁶R¹⁷N-, R¹⁸R¹⁹N-CO- oder Cy-, wobei in den zuvor angegebenen Gruppen ein oder mehrere C-Atome unabhängig voneinander durch Substituenten ausgewählt aus Halogen, OH, CN, CF₃, C_1-3-Alkyl, Hydroxy-C_1-3-alkyl substituiert sein können;
R¹³ eine der für R¹⁷ angegebenen Bedeutungen,
R¹⁴ Halogen, Cyano, 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-SO₂-NH-, R¹⁵-O-CO-NN-C_1-3-alkyl-, R¹⁵-SO₂-NN-C_1-3-alkyl-, 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, C_1-4-Alkylcarbonyl, 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_1-3-alkyl, R²²-C_1-3-alkyl oder eine der für R²² angegebenen Bedeutungen,
R²¹ C_1-4-Alkyl, ω-Hydroxy-C_2-6-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, Phenyl-C_1-3-alkyl, C_1-4-Alkyl-carbonyl, C_1-4-Alkoxy-carbonyl, C_1-4-Alkylsulfonyl, Aminosulfonyl, C_1-4-Alkylaminosulfonyl, Di-C_1-4-alkylaminosulfonyl oder Cyclo-C_3-6-alkylenimino-sulfonyl,
R²² Pyridinyl, Phenyl, 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-alkylamino-carbonyl-, Cyclo-C_3-6-alkylenimino-carbonyl, Phenylaminocarbonyl, Cyclo-C_3-6-alkylenimino-C_2-4-alkyl-aminocarbonyl, C_1-4-Alkyl-sulfonyl, C_1-4-Alkyl-sulfinyl, 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, Phenylcarbonyl, Phenylcarbonylamino, Phenylcarbonylmethylamino, Hydroxy-C_2-3-alkylaminocarbonyl, (4-Morpholinyl)carbonyl, (1-Pyrrolidinyl)carbonyl, (1-Piperidinyl)carbonyl, (Hexahydro-1-azepinyl)carbonyl, (4-Methyl-1-piperazinyl)carbonyl, Methylendioxy, Aminocarbonylamino oder C_1-4-Alkylaminocarbonylamino bedeuten,
wobei in den zuvor genannten Gruppen und Resten, insbesondere in W, X, Z, R¹³ 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, Cyano, C_1-4-Alkyl, C_1-4-Alkoxy-, Difluormethyl-, Trifluormethyl-, Hydroxy-, Amino-, C_1-3-Alkylamino-, Di-(C_1-3-alkyl)-amino-, Acetylamino-, Aminocarbonyl-, 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-alkyl- aufweisen können 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, deren Tautomere, deren Diastereomere, deren Enantiomere, deren Gemische und deren Salze,
wobei folgende Verbindungen erfindungsgemäß nicht mit umfasst sind:
6-[5-(4-Chlor-phenyl)-pyridin-2-ylethinyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydrochinolin,
6-[5-(4-Chlor-phenyl)-pyridin-2-ylethinyl]-1-methyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-chinolin und
5-(4-Chloro-phenyl)-2-[2-(4-methyl-piperidin-1-ylmethyl)-chroman-6-ylethinyl]-pyridin.A first subject of the present invention are alkyne compounds of general formula I.

in the
R ¹ , R ² independently of one another are H, C _1-8 -alkyl, C _3-7 -cycloalkyl or a phenyl or pyridinyl radical which is mono- or polysubstituted and / or monosubstituted and / or monosubstituted by nitro, optionally with identical or different radicals R ²⁰ the alkyl or cycloalkyl group may be monosubstituted or polysubstituted with identical or different radicals R ¹¹ , and wherein a -CH ₂ - group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group is substituted by -O-, - S or NR ¹³ - may be replaced, or
R ¹ and R ² form a C _3-8 alkylene bridge in which a -CH ₂ group not adjacent to the N atom of the R ¹ R ² N group is replaced by -CH = N-, -CH = CH -, -O-, -S-, -SO, - (SO ₂ ) -, -CO-, -C (= CH ₂ ) - or -NR ¹³ - may be replaced,
wherein in the above-defined alkylene bridge one or more H atoms may be replaced by the same or different R ¹⁴ radicals, 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
• - About three or more C and / or N atoms takes place to form a bridged ring system;

X is a C _1-4 -alkylene bridge, wherein in the meaning C _2-4 -alkylene one or two C atoms may be monosubstituted by R ¹⁰ , or
a C _3-4 alkylene bridge in which a -CH ₂ -CH ₂ group immediately adjacent to the N atom of the R ¹ R ² N group is replaced by -CH = CH- or -C≡C- is
wherein the meanings given above for X have a substituent selected from C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl and C _3-7 cycloalkyl C _1-3 alkyl and independently , two or three identical or different C _1-4 alkyl substituents, wherein two alkyl groups to form a 3 to 7-membered or an alkyl and an alkenyl group to form a 5- to 7-membered cyclic group can be connected to each other, and
W, Z are independently a single bond or a C _1-2 alkylene bridge,
wherein two adjacent carbon atoms may be linked together with an additional C _1-4 alkylene bridge, and
wherein one or two C atoms may be independently substituted with one or two identical or different C _1-3 alkyl radicals, wherein two alkyl radicals to form a carbocyclic Rings can be connected to each other, and
Y is selected from the meanings of the subformulae Y1 and Y2

wherein the group MO, S or NR is ^M , wherein R ^{M is} selected from the meanings H, C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-7 cycloalkyl and C _3-7 -cycloalkyl-C _1-3 -alkyl, and
wherein in the sub-formulas Y1 and Y2, one or more carbon atoms may be independently substituted with R ²⁰ , and
A is selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoxazolyl, thienyl, furanyl, benzothienyl or benzofuranyl, where said cyclic groups are monosubstituted or polysubstituted by one or more C atoms having the same or different radicals R ²⁰ , and in the case of a phenyl ring also additionally simply by nitro, and / or one or more NH groups having R ²¹ could be,
B is one of the meanings given for A or
C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _3-7 cycloalkyl C _1-3 -alkyl, C _3-7 cycloalkenyl C _1-3 alkyl, C _3-7 cycloalkyl C _1-3 alkenyl or C _3-7 cycloalkyl C _1-3 alkynyl, wherein one or more C Atoms can be substituted one or more times independently of one another by halogen and / or simply by hydroxy or cyano and / or cyclic groups one or more times with identical or different radicals R ²⁰ ,
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 heteroatom,
• A saturated or unsaturated 5- to 7-membered heterocyclic group having two or more N atoms or having one or two N atoms and one O or S atom as heteroatoms,
• 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 saturated 6- or 7-membered groups are also available as bridged ring systems with an imino, (C _1-4 alkyl) imino, methylene, (C _1-4 alkyl) methylene or (C _1-4 alkyl) methylene bridge, and
where the abovementioned cyclic groups may be monosubstituted or polysubstituted by one or more C atoms having the same or different radicals R ²⁰ , and in the case of a phenyl group may also be additionally monosubstituted by nitro, and / or one or more NH groups having R ²¹ .
R ^{10 is} hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy or C _1-4 -alkoxy-C _1-3 -alkyl-,
R ^{11 is} halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁵ -CO-O-, cyano, R ¹⁶ R ¹⁷ N, R ¹⁸ R ¹⁹ N-CO- or Cy-, where in the abovementioned groups one or more C atoms independently of one another are selected from substituents selected from among halogen, OH, CN, CF ₃ , C _1-3 Alkyl, hydroxyC _1-3 alkyl may be substituted;
R ^{13 is} one of the meanings given for R ¹⁷ ,
R ^{14 is} halogen, cyano, 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 -SO ₂ -NH-, R ¹⁵ -O-CO-NN-C _1-3 -alkyl, R ¹⁵ -SO ₂ -NN-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-, alkyl or R ¹⁸ R ¹⁹ N-CO-C _1-3 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 alkyleneiminoC _2-6 alkyl,
R ^{17 is} one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl, pyridinyl, C _1-4 -alkylcarbonyl, hydroxycarbonyl-C _1-3 -alkyl, C _1-4 -alkoxycarbonyl, C _{1 4-} alkoxycarbonylC _1-3 alkyl, C _1-4 alkylcarbonylaminoC _2-3 alkyl, N- (C _1-4 alkylcarbonyl) -N- (C _1-4 alkyl) aminoC _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, Hydroxy-C _1-3 -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 _2-6 -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 alkyleniminoC _2-6 alkyl, phenyl, phenylC _1-3 alkyl, C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, C _1-4 alkylsulfonyl, aminosulfonyl, C _1-4 alkylaminosulfonyl, diC _1-4 -alkylaminosulfonyl or cycloC _{3 -6} -alkyleneimino-sulfonyl,
R ^{22 is} pyridinyl, phenyl, phenylC _1-3 -alkoxy, cycloC _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 -alkylamino-carbonyl, cyclo-C _3-6 -alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C _3-6 -alkyleneimino-C _2-4 -alkylaminocarbonyl, 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, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C _2-3 -alkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4- Methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or C _1-4 Alkylaminocarbonylamino,
wherein in the abovementioned groups and radicals, in particular in W, X, Z, R ¹³ to R ²² , in each case one or more C atoms are additionally mono- or polysubstituted with F and / or in each case one or two C atoms independently of one another 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 consisting of F, Cl, Br, I, cyano, C _1-4 -alkyl, C _1-4 Alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl and di (C _1-3 alkyl) amino C _1-3 alkyl and / or simply may be substituted with nitro, and
the H atom of an existing carboxy group or an H atom bound to an N atom can be replaced in each case by an in-vivo leaving residue, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts,
wherein the following compounds are not included according to the invention:
6- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydroquinoline,
6- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -1-methyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline and
5- (4-chloro-phenyl) -2- [2- (4-methyl-piperidin-1-ylmethyl) chroman-6-ylethynyl] -pyridine.

The Compounds according to the present invention Invention, including the physiologically acceptable salts, possess in comparison to known, structurally comparable compounds a particular effect as antagonists of the MCH receptor, in particular of the MCH-1 receptor, and show very good affinities in MCH receptor binding studies. About that In addition, the compounds according to the invention have a high to very high selectivity in terms of the MCH receptor. In general, the compounds of the invention low toxicity, a good oral absorbability and intracerebral transitivity, in particular brain penetration, on.

object The invention also relates to the respective compounds in the form of single optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Also with the object This invention includes the compounds of the invention, including their Salts in which one or more hydrogen atoms are deuterated are exchanged.

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

Also an object of this invention are compositions containing at least one alkyne 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 alkyne 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 Alkyne compound of the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.

Farther is the use of at least one alkyne compound of the invention and / or a salt according to the invention to reduce 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 alkyne compound of the invention and / or a salt according to the invention for the preparation of a drug with MCH receptor antagonistic Activity, in particular with MCH-1 receptor antagonist activity.

Furthermore an object of this invention is the use of at least one Alkyne compound of the invention and / or a salt according to the invention 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.

One Another object of this invention is the use of at least an alkyne compound of the invention and / or a salt according to the invention for the preparation of a medicament which is used for prophylaxis and / or Treatment of metabolic disorders and / or eating disorders, especially 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 alkyne compound of the invention and / or a salt according to the invention for the preparation of a medicament which is used for prophylaxis and / or Treatment of obesity-related 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 diseases, in particular arteriosclerosis and hypertension, Arthritis and Gonitis is suitable.

Furthermore For example, the present invention has the use of at least one alkyne compound of the invention and / or a salt according to the invention for the preparation of a medicament which is used for 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 Alkyne compound of the invention and / or a salt according to the invention for the preparation of a medicament which is used for prophylaxis and / or Treatment of micturition 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 alkyne 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 alkyne compounds of the invention and / or the corresponding salts, and a second one 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, if appropriate one or more inert carriers and / or diluents.

Furthermore, an object of this invention relates to a process for the preparation of alkyne compounds of the formula A.5 R 1 R 2 NXYC≡CWAB (A.5) where in the formulas A.1, A.2, A.3, A.4 and A.5 R ¹ , R ² , Y, X, W, A and B have one of the meanings given above and below,
in which a halogen compound of the formula A.1 HO-XY-Hal (A.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula A.2 HC≡CWAB (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide is reacted in a suitable solvent, and
the resulting compound of the formula A.3 HO-XYC≡CWAB (A.3) is reacted with methanesulfonyl chloride (MsCl) to methanesulfonate derivative A.4, MsO-XYC≡CWAB (A.4) which is further reacted with an amine of the formula H-NR ¹ R ² to the final product A.5.

Another object of this invention is a process for the preparation of alkyne compounds of formula B.5 R 1 R 2 NXYZC≡CAB (B.5) where in the formulas B.1, B.2, B.3, B.4 and B.5 R ¹ , R ² , X, Y, Z, A and B have one of the meanings given above and below,
in which a halogen compound of the formula B.1 Hal-AB (B.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula B.2 HO-XYZC≡CH (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide is reacted in a suitable solvent, and
the resulting compound of formula B.3 HO-XYZC≡CAB (B.3) with methanesulfonyl chloride (MsCl) is converted to the methanesulfonate derivative B.4, MsO-XYZC≡CAB (B.4) which is further reacted with an amine of formula H-NR ¹ R ² to give the final product B.5.

Furthermore, an object of this invention relates to a process for the preparation of alkyne compounds of the formula C.3 R 1 R 2 NXYC≡CWAB (C.3) where in the formulas C.1, C.2 and C.3 R ¹ , R ² , X, Y, W, A and B have one of the meanings given above and below,
in which a halogen compound of the formula C.1 R 1 R 2 NXY-Hal (C.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula C.2 HC≡CWAB (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent to the final product C.3 is further reacted.

Another object of this invention is a process for the preparation of alkyne compounds of the formula D.3 R 1 R 2 NXYZC≡CAB (D.3) where in the formulas D.1, D.2 and D.3 R ¹ , R ² , X, Y, Z, A and B have one of the meanings given above and below,
in which a halogen compound of the formula D.2 Hal-AB (D.2) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula D.1 R 1 R 2 NXYZC≡CH (D.1) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent to the final product D.3 is reacted.

Detailed description the invention

Unless otherwise specified, the occurring groups, radicals and substituents, in particular A, B, W, X, Y, Z, Cy, R ¹ , R ¹ , R ² , R ¹⁰ , R ¹¹ , R ¹³ to R ²² , R have ^M , the meanings given above and below.

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

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 C _1-8 -alkyl or C _{3- which is} unsubstituted or monosubstituted or polysubstituted by identical or different radicals R ¹¹ ₇ -Cycloalkyl group, wherein a -CH ₂ group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR ¹³ -, or optionally with the same or various radicals R ²⁰ mono- or polysubstituted and / or nitro single-substituted phenyl or pyridinyl, and wherein one or both of the radicals R ¹ and R ^{2 may} also be H.

Preferred meanings of the radical R ¹¹ here are F, Cl, Br, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, R ¹⁵ -O-, cyano, R ¹⁶ R ¹⁷ N-, C _3-7 cycloalkyl, cycloC _3-6 alkyleneimino, pyrrolidinyl, N- (C _1-4 alkyl) pyrrolidinyl, piperidinyl, N- (C _1-4 alkyl) piperidinyl, phenyl and Pyridyl, wherein in the groups and radicals specified above, one or more C atoms independently of one another or more times with F, C _1-3 alkyl or Nydroxy-C _1-3 alkyl, and / or one or two C atoms independently of one another can simply be substituted by Cl, Br, OH, CF ₃ or CN, and wherein the aforementioned cyclic groups one or more times to one or more carbon atoms having the same or different radicals R ²⁰ , in the case of a phenyl group also in addition may be substituted with nitro, and / or one or more NH groups with R ²¹ . If R ^{11 has} one of the meanings R ¹⁵ -O-, cyano, R ¹⁶ R ¹⁷ N- or cyclo-C _3-6 -alkyleneimino-, preferably the R ¹¹ -substituted carbon atom of the alkyl or cycloalkyl group is not directly linked to a heteroatom such as the -NX- group.

The radicals R ¹ , R ² independently of one another preferably denote H, C _1-6 -alkyl, C _3-5 -alkenyl, C _3-5 -alkynyl, C _3-7 -cycloalkyl, hydroxy-C _3-7 -cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, (hydroxy C _3-7 cycloalkyl) C _1-3 alkyl, hydroxy C _2-4 alkyl, ω-NC-C _{2 3-} alkyl, C _1-4 alkoxyC _2-4 alkyl, hydroxyC _1-4 alkoxyC _2-4 alkyl, C _1-4 alkoxycarbonylC _{1- 4-} alkyl, carboxyl-C _1-4 -alkyl, amino-C _2-4 -alkyl, C _1-4 -alkyl-amino-C _2-4 -alkyl-, di- (C _1-4 -alkyl) alkyl) amino C _2-4 alkyl, cyclo C _3-6 alkyleneimino-C _2-4 alkyl, pyrrolidin-3-yl, N- (C _1-4 alkyl) pyrrolidine-3 -yl, pyrrolidinyl-C _1-3 -alkyl, N- (C _1-4 -alkyl) -pyrrolidinyl-C _1-3 -alkyl, piperidin-3-yl, piperidin-4-yl, N- (C _{1 4-} alkyl) piperidin-3-yl, N- (C _1-4 alkyl) alkyl) piperidinyl C _1-3 alkyl, tetrahydropyran-3-yl, piperidin-4-yl, piperidinyl C _1-3 alkyl, N- (C _1-4 tetrahydropyran-4-yl, phenyl, phenylC _1-3 alkyl, pyridyl or pyridylC _1-3 alkyl, wherein in the above Groups and residues one or a plurality of C atoms independently of one another or more than once with F, C _1-3 -alkyl or hydroxy-C _1-3 -alkyl, and / or one or two C atoms independently of one another with Cl, Br, OH, CF ₃ or CN may be substituted, and where the abovementioned cyclic groups are mono- or polysubstituted by one or more C atoms having the same or different radicals R ²⁰ , in the case of a phenyl group also additionally simply by nitro, and / or one or more NH 3 Groups with R ²¹ can be substituted. Preferred substituents of the abovementioned phenyl or pyridyl radicals are selected from the group 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 H, C _1-4 -alkyl, hydroxy-C _1-4 -alkyl, C _3-5 -alkenyl, C _3-5 -alkynyl , C _3-7 cycloalkyl, hydroxyC _3-7 cycloalkyl, dihydroxyC _3-6 alkyl, C _3-7 cycloalkylC _1-3 alkyl, tetrahydropyran-3-yl, tetrahydropyran-4 -yl, (hydroxy-C _3-7 cycloalkyl) -C _1-3 alkyl, (C _1-4 alkoxy) C _2-3 ω- alkyl, pyridyl and benzyl, wherein an alkyl, cycloalkyl - or Cycloalkylalkylgruppe additionally one or two times with hydroxy and / or hydroxy-C _1-3 alkyl, and / or one or more times with F or C _1-3 alkyl and / or simply with CF ₃ , Br, Cl or CN can be substituted, and wherein one of the radicals R ¹ and R ^{2 can} also be H.

Very particularly preferred radicals R ¹ and / or R ² are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-C _3-7 cycloalkyl, (hydroxy-C _1-3 alkyl) _{-hydroxy-C3-7} cycloalkyl, dihydroxy C _3-5 alkyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1,1-di (hydroxymethyl) ethyl, (1-hydroxyC _3-6 cycloalkyl) methyl, tetrahydropyran-3 yl, tetrahydropyran-4-yl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl, where said groups may be mono- or polysubstituted by F and / or C _1-3 -alkyl, and wherein the phenyl and pyridyl Rings may be substituted as indicated.

Examples of very particularly preferred radicals R ¹ and / or R ² are therefore H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, Cyclopropylmethyl, cyclopentylmethyl, hydroxycyclopentyl, hydroxycyclohexyl, (hydroxymethyl) hydroxycyclopentyl, (hydroxymethyl) hydroxycyclohexyl, 2,3-dihydroxypropyl, (1-hydroxycyclopropyl) methyl, tetrahydropyran-3-yl, Tetrahydropyran-4-yl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl.

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

• – 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.

If R ¹ and R ^{2 form} an alkylene bridge, this is preferably a C _3-7 -alkylene bridge or a C _3-7 -alkylene bridge, in particular C _4-7 -alkylene bridge, in which a -CH ₂ groups not adjacent to the N atom of the R ¹ R ² N group by -CH = N-, -CH = CH-, -O-, -S-, -CO- or -NR ¹³ - is replaced,
wherein in the above-defined alkylene bridge one or more H atoms may be replaced by the same or different R ¹⁴ radicals, 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.

Further preferably, R ¹ and R ^{2 form} an alkylene bridge such that R ¹ R ² N- represents 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 with R ^{13 is} substituted, piperidin-4-one, morpholine and thiomorpholine,
is particularly preferably selected from pyrrolidine, piperidine, piperazine, in which the free imine function is substituted by R ¹³ , and morpholine,
wherein, according to the general definition of R ¹ and R ^2, one or more H atoms may be replaced by identical or different R ¹⁴ radicals and / or the abovementioned groups in a manner specified in the general definition of R ¹ and R ² with one or two identical or different carbo- or heterocyclic Cy groups may be substituted, wherein the Cy group may be mono- or polysubstituted with R ²⁰ .

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-, where the group Cy may be mono- or polysubstituted with R ²⁰ .

The C _3-8 alkylene bridge formed by R ¹ and R ² , in which, as indicated, -CH ₂ - groups may be replaced, may be substituted as described with one or two identical or different carbo- or heterocyclic groups Cy which may be substituted as indicated above.

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

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.

In the event that the heterocyclic group R ¹ R ² N- is substituted with a group Cy, the group Cy is preferably linked via a single bond to the group R ¹ R ² N-, wherein Cy is preferably selected from the group consisting of C _3-7 cycloalkyl and cyclo C _3-6 alkyleneimino, these groups being as indicated, preferably substituted by fluorine, CF ₃ , C _1-3 alkyl, hydroxyC _1-3 alkyl and hydroxy can.

eine Bedeutung gemäß einer der folgenden Teilformeln

worin ein- oder mehrere H-Atome des durch die Gruppe R¹R²N- gebildeten Heterocyclus durch gleiche oder verschiedene Reste R¹⁴ ersetzt sein können, und
wobei der durch die Gruppe R¹R²N- gebildete Heterocyclus durch ein oder zwei, vorzugsweise eine C_3-7-Cycloalkylgruppe substituiert sein kann, wobei die Cycloalkyl-Gruppe ein oder mehrfach mit R²⁰ substituiert sein kann, und
wobei 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
worin R¹³, R¹⁴, R²⁰, R²¹ die zuvor und nachstehend angegebenen Bedeutungen besitzen.Most preferably, 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 identical or different radicals R ¹⁴ , and
wherein the heterocycle formed by the group R ¹ R ² N- may be substituted by one or two, preferably a C _3-7 cycloalkyl group, wherein the cycloalkyl group may be mono- or polysubstituted by R ²⁰ , and
wherein the ring connected to the heterocycle formed by the group R ¹ R ² N- may be monosubstituted or polysubstituted on one or more C atoms with R ²⁰ , and in the case of a phenyl ring may additionally also be substituted simply by nitro, and
wherein R ¹³ , R ¹⁴ , R ²⁰ , R ^{21 have} the meanings given above and below.

If the heterocycle formed by the group R ¹ R ² N-N is substituted by one or two cycloalkyl groups mono- or polysubstituted with R ²⁰ as indicated, then the substituents R ²⁰ independently of one another are preferably C _1-4 -alkyl, C _1-4 AlkoxyC _1-3 alkyl, hydroxyC _1-3 alkyl, hydroxy, fluoro, chloro, bromo or CF ₃ , especially hydroxy.

eine Bedeutung gemäß einer der folgenden Teilformeln

insbesondere

wobei R¹³ die zuvor und nachstehend angegebenen Bedeutungen besitzt, und
wobei der durch die Gruppe R¹R²N- gebildete Heterocyclus mit C_3-6-Cycloalkyl, Hydroxy-C_3-6-cycloalkyl oder (Hydroxy-C_3-6-cycloalkyl)-C_1-3-alkyl substituiert sein kann, und
wobei der durch die Gruppe R¹R²N- gebildete Heterocyclus ein-, zwei- oder dreifach mit gleichen oder verschiedenen Resten R¹⁴ substituiert sein kann. Die Substituenten R¹⁴ bedeutet hierbei vorzugsweise unabhängig voneinander F, Cl, Br, OH, C_1-4-Alkyl, C_1-4-Alkoxy, C_1-4-Alkoxy-C_1-3-alkyl, Hydroxy-C_1-4-alkyl oder CF₃, insbesondere Hydroxy, C_1-3-Alkyl, CF₃ oder Hydroxy-C_1-3-alkyl.Most preferably, the group has

a meaning according to one of the following sub-formulas

especially

wherein R ^{13 has} the meanings given above and below, and
wherein the heterocycle formed by the group R ¹ R ² N- may be substituted by C _3-6 cycloalkyl, hydroxyC _3-6 cycloalkyl or (hydroxyC _3-6 cycloalkyl) C _1-3 alkyl , and
wherein the heterocycle formed by the group R ¹ R ² N- may be mono-, di- or trisubstituted by identical or different radicals R ¹⁴ . The substituents R ¹⁴ here preferably independently of one another are F, Cl, Br, OH, C _1-4 -alkyl, C _1-4 -alkoxy, C _1-4 -alkoxy-C _1-3 -alkyl, hydroxy-C _{1- 4-} alkyl or CF ₃ , in particular hydroxy, C _1-3 -alkyl, CF ₃ or hydroxy-C _1-3 -alkyl.

If the abovementioned partial formulas are substituted as indicated, the following meanings of the group R ¹ R ² N are particularly preferred: hydroxypyrrolidinyl, hydroxypiperidinyl, 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl) -pyrrolidinyl , (Hydroxymethyl) piperidinyl, (hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl,
wherein in the specified groups a hydroxymethyl group on the carbon atom may be mono- or disubstituted by methyl, wherein two methyl substituents may be joined together to form a cyclopropyl group, and
wherein in one or two hydroxy groups, the H atom may be replaced by a methyl group, and
wherein the groups indicated have no further substituents or one or two substituents independently of one another selected from fluorine, hydroxy, C _1-3 -alkyl, hydroxy-C _1-3 -alkyl, CF ₃ .

dar:

worin die angegebenen Gruppen nicht weiter substituiert sind, oder
worin Methyl- oder Ethylgruppen durch Fluor ein-, zwei- oder dreifach substituiert sein können, und worin ein oder mehrere an Kohlenstoff gebundene H-Atome des durch die Gruppe R¹R²N- gebildeten Heterocyclus unabhängig voneinander durch Fluor, Chlor, CN, CF₃, C_1-3-Alkyl, Hydroxy-C_1-3-alkyl, insbesondere C_1-3-Alkyl oder CF₃, vorzugsweise Methyl, Ethyl, CF₃ substituiert sein können.The following sub-formulas represent very particularly preferred meanings of the heterocyclic group given above

represents:

wherein the specified groups are not further substituted, or
in which methyl or ethyl groups may be mono-, di- or trisubstituted by fluorine, and in which one or more carbon-bonded hydrogen atoms of the heterocycle formed by the group R ¹ R ² N- independently of one another by fluorine, chlorine, CN, CF ₃ , C _1-3 alkyl, hydroxyC _1-3 alkyl, especially C _1-3 alkyl or CF ₃ , preferably methyl, ethyl, CF ₃ may be substituted.

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: F, Cl, Br, cyano, 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-carbonyl-C _1-3 -alkyl-, C _1-4 - AlkoxycarbonylC _1-3 alkyl, C _1-4 alkoxycarbonylamino, C _1-4 alkoxycarbonylaminoC _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, cyclo- C _3-6 alkyleneimino, amino C _1-3 alkyl, C _1-4 alkylamino 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 -alkyl-amino-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-, pyridinyloxy -, pyridinyl-amino, pyridinyl-C _1-3 -alkyl-amino-.

Particularly preferred meanings of the substituent R ¹⁴ are F, Cl, Br, C _1-4 -alkyl, hydroxy, hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, ω- (C _1-4 -alkoxy) - C _1-3 -alkyl, amino-C _1-3 -alkyl, C _1-4 -alkyl-amino-C _1-3 -alkyl, C _3-7 -cycloalkyl-amino-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, cycloC _3-6 alkyleneiminoC _1-3 alkyl, aminocarbonyl and pyridylamino.

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. Thus, preferred meanings of R ¹⁴ include, for example, -CF ₃ , -OCF ₃ , CF ₃ -CO-, and CF ₃ -CHOH-.

Very particularly preferred meanings of the substituent R ¹⁴ are C _1-3 -alkyl, hydroxy-C _1-3 -alkyl, methoxymethyl, hydroxy, CF ₃ , CF ₃ -CHOH-, in particular hydroxy, methyl, ethyl, CF ₃ and hydroxymethyl.

According to a preferred first embodiment, the group X is a methylene, ethylene or propylene bridge, particularly preferably a methylene or ethylene bridge, which is unsubstituted or with one or two identical or different C _1-3 -alkyl substituents and / or or a substituent selected from C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl C _1-3 alkyl, wherein two alkyl substituents are substituted under Formation of a 3- to 6-membered cycloalkyl group or an alkyl and an alkenyl substituent to form a 5- or 6-membered cycloalkenyl group may be interconnected. In this embodiment, X is methyl or ethyl preferably unsubstituted or mono- or di-substituted by methyl, ethyl or i-propyl, where two alkyl substituents may be joined together to form a C _3-6 cycloalkyl group.

Particularly preferred according to this embodiment, X is a -CH ₂ -bridge, which is unsubstituted or monosubstituted or disubstituted with methyl, where two methyl groups can be linked together to form a cyclopropyl group. Most preferably, X is an unsubstituted -CH ₂ - bridge.

Examples of particularly preferred meanings of X are therefore

In another embodiment, the group X is preferably a straight chain propylene or butylene bridge wherein one or two C atoms are simply substituted with hydroxy, hydroxyC _1-3 alkyl or C _1-3 alkoxy, especially hydroxy and wherein one or two C atoms each having one or two identical or different C _1-3 alkyl substituents and / or a substituent selected from C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl may be substituted, wherein two alkyl substituents to form a 3- to 6-membered cycloalkyl group or an alkyl and an alkenyl substituent Formation of a 5- or 6-membered cycloalkenyl group may be linked together. In group X, one or more C atoms may be monosubstituted or polysubstituted by F and / or Cl, preferably F.

According to yet another embodiment, the group X is preferably a straight-chain propylene or butylene bridge in which a -CH ₂ -CH ₂ group not directly adjacent to the N atom of the R ¹ R ² N group is replaced by -CH = CH- or -C≡C- is replaced, in particular a -CH ₂ -CH = CH- or -CH ₂ -C≡C- bridge, wherein the meanings given for X are unsubstituted or one or two identical or different substituents independently selected from fluorine and C _1-3 alkyl and / or have a cyclopropyl substituent, wherein two alkyl groups may be connected together to form a C _3-6 cycloalkyl group.

Another preferred meaning of X is also C _3-4 -alkylene, in particular propylene, which has one or two identical or different substituents independently of one another selected from fluorine, chlorine, hydroxyl and C _1-3 -alkyl and / or a cyclopropyl substituent where two alkyl substituents may be linked together to form a C _3-6 cycloalkyl group.

In the meaning substituted propylene preferred meanings are, for example

Moreover, preferred meanings of X are -CH ₂ -CH = CH- or -CH ₂ -C≡C-, where the meanings given for X are unsubstituted or one or two identical or different substituents independently selected from fluorine and C ₁ Have _3- alkyl and / or a cyclopropyl substituent, wherein two alkyl groups may be connected together to form a C _3-6 cycloalkyl group. The meanings mentioned above for X are particularly preferably monosubstituted or disubstituted by identical or different radicals selected from among methyl, ethyl and isopropyl, it being possible for two alkyl groups to be linked together as indicated to form a cyclic group.

Further preferred meanings of X is -CH ₂ -CH = CH- and substituted -CH ₂ -CH = CH- selected from the group consisting of

For X in the Meaning substituted alkenylene is above only one the two possible E / Z configurations specified. Of course is also the other of the two E / Z configurations according to the invention respectively includes.

Preferred meanings of the radical R ¹⁰ are -OH, methoxy and hydroxymethyl, in particular -OH.

The bridge W is preferably a single bond or ethylene, especially preferably a single bond.

The bridge Z is preferably a single bond or ethylene containing a or may have two methyl substituents which are under formation a cyclopropyl group may be linked together. Especially Z is preferably a single bond.

Preferred meanings of the radical R ^M in the group Y, in the case where M denotes NR ^M , are selected from H, C _1-3 -alkyl, prop-2-enyl, prop-2-ynyl, C _3-6 - Cycloalkyl, C _3-6 -cycloalkylmethyl. Most preferably, R ^{M here is} H or C _1-3 -alkyl, in particular H or methyl.

Those Alkyne compounds are preferred in which M is preferably O or S means.

wobei beide Teilformeln unsubstituiert sind oder in beiden Teilformeln ein oder mehrere, vorzugsweise ein oder zwei C-Atome unabhängig voneinander mit R²⁰ substituiert sind.Preferred meanings of the group Y are selected from the part formulas

wherein both partial formulas are unsubstituted or in both partial formulas one or more, preferably one or two C atoms are independently substituted with R ²⁰ .

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 _1-3 alkyl) amino, aminocarbonyl, C _1-4 alkylamino-carbonyl and di - (C _1-4 alkyl) amino carbonyl-.

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 _2-3 -alkenyl, C _2-3 -alkynyl, C _1-3 Alkoxy, C _1-4 alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, in the case of a phenyl ring also nitro. Examples are especially preferred Meanings of the substituent R ²⁰ are F, Cl, Br, methyl, ethyl, acetyl or methoxy.

Preferably, the group A is selected from the group of bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, the one or more times to one or more C atoms having the same or different radicals R ²⁰ , in the case of a phenyl ring also additionally simple with nitro, may be substituted.

insbesondere

ganz besonders bevorzugt

wobei die aufgeführten Gruppen, wie zuvor angegeben substituiert sein können.Most preferably, A is one of the groups listed below

especially

very particularly preferred

where the groups listed may be substituted as indicated above.

Particularly preferred substituents R ²⁰ of group A are independently of one another fluorine, chlorine, bromine, amino, CF ₃ , methoxy and C _1-3 -alkyl.

Preferably, the groups A are unsubstituted or monosubstituted with R ²⁰ as indicated.

Preferred meanings of group B according to a first preferred embodiment are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl. Most preferably, the group B is phenyl. The group B in the meanings indicated may be monosubstituted or polysubstituted by identical or different radicals R ²⁰ , and additionally a phenyl group may also be monosubstituted by nitro. Preferably, the group B is unsubstituted or monosubstituted, disubstituted or trisubstituted, in particular unsubstituted or monosubstituted or disubstituted. In the case of a single substitution, the substituent is preferably in the para position to the group A.

Preferred substituents R ²⁰ of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C _1-4 -alkyl, hydroxy, CHF ₂ , CHF ₂ -O-, hydroxy-C _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- and di- (C _1-4 -alkyl) -aminocarbonyl-.

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

Very particularly preferred substituents R ²⁰ of group B are selected from the group consisting of chlorine and methoxy.

In a second embodiment, the meaning of group B is preferably selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _{3 -7-} cycloalkyl-C _1-3 -alkyl, C _3-7 -cycloalkenyl-C _1-3 -alkyl, C _3-7 -cycloalkyl-C _1-3 -alkenyl, C _3-7 -cycloalkyl- C _1-3 alkynyl, where one or more C atoms in the groups previously mentioned for B may be monosubstituted or polysubstituted by fluorine. In the cyclic groups according to the above-mentioned embodiment, one or more C atoms may be substituted with R ²⁰ .

Particularly preferred according to this embodiment are the groups C _3-6 -alkyl, C _3-6 -alkenyl, C _3-6 -alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclopentyl-C _1-3 -alkyl- , Cyclopentenyl C _1-3 alkyl, cyclohexyl C _1-3 alkyl, cyclohexenyl C _1-3 alkyl, cycloheptyl C _1-3 alkyl, cycloheptenyl C _1-3 alkyl in which one or more C atoms in the groups mentioned above for B may be monosubstituted or polysubstituted by fluorine, and where in cyclic groups one or more C atoms may be substituted by identical or different R ²⁰ .

Most preferably, B according to this second embodiment is cyclohexenyl which is unsubstituted or has 1, 2 or 3 identical or different substituents R ²⁰ , in particular methyl.

The following are preferred definitions of further substituents according to the invention:
R ⁴ is preferably H, C _1-4 -alkyl, C _3-6 -cycloalkyl and C _3-6 -cycloalkyl-methyl, in particular H, methyl, ethyl, propyl, i-propyl, n-propyl, cyclopropyl, cyclopentyl, Cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexymethyl. Most preferably, R ^{4 is} H or methyl.

The substituent R ¹³ preferably has one of the meanings given for R ¹⁶ . Particularly preferably, R ^{13 is} H, C _1-4 -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. Most preferably, R ^{13 is} H or C _1-4 alkyl. The abovementioned alkyl groups can be monosubstituted by Cl or monosubstituted or polysubstituted by F.

Preferred meanings of the substituent R ¹⁵ are H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, where, as defined above, in each case one or more carbonyls Atoms additionally one or more times with F and / or in each case one or two C-atoms independently of each other additionally simply with Cl or Br can be substituted. More preferably R ^{15 is} H, CF ₃ , methyl, ethyl, propyl or butyl.

The substituent R ¹⁶ is preferably H, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, ω-hydroxy C _2-3 alkyl or ω - (C _1-4 alkoxy) C _2-3 alkyl, wherein, as defined above, in each case one or more carbon atoms additionally one or more times with F and / or in each case one or two C atoms independently additionally can be substituted simply with Cl or Br. More preferably R ^{16 is} H, CF ₃ , C _1-3 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl-C _1-3 alkyl.

The substituent R ¹⁷ preferably has one of the meanings given for R ¹⁶ as being preferred or denotes phenyl, phenyl-C _1-3 -alkyl, pyridinyl or C _1-4 -alkylcarbonyl. R ¹⁷ particularly preferably has one of the meanings given for R ¹⁶ as being preferred.

Preferably, one or both of the substituents R ¹⁸ and R ¹⁹ independently of one another are hydrogen or C _1-4 -alkyl, in particular hydrogen.

The substituent R ²⁰ is preferably halogen, hydroxy, cyano, 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-C _1-4 -alkyl, R ²² -C _1-3 -alkyl or one of the meanings given for R ²² as being preferred, 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 simply substituted by Cl or Br.

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

The substituent R ²² is preferably 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, 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-carbonylamino, hydroxy-C _1-3 -alkylaminocarbonyl, aminocarbonylamino or C _1-4 -alkylaminocarbonyl-amino-, where, as defined above, in each case one or several C atoms additionally one or more times with F and / or in each case one or two C-atoms independently of each other additionally simply with Cl or Br can be substituted. Most particularly preferred meanings of R ²² are C _1-4 alkoxy, C _1-4 alkylcarbonyl, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, wherein one or Several H atoms can be replaced by fluorine.

Preferred meanings of the group R ²¹ are C _1-4 -alkyl, C _1-4 -alkylcarbonyl, C _1-3 -alkylsulfonyl, -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. Most preferably, R ^{21 is} C _1-4 alkyl or CF ₃ .

Cy preferably denotes a C _3-7 -cycloalkyl, in particular a C _3-6 -cycloalkyl group, a C _5-7 -cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, and wherein the previously mentioned cyclic groups may be monosubstituted or polysubstituted to one or more carbon atoms having the same or different radicals R ²⁰ , and in the case of a phenyl group may additionally be substituted simply by nitro, and / or one or more NH groups may be substituted by R ²¹ .

Very particularly preferred meanings of the group Cy are C _3-6 -cycloalkyl, pyrrolidinyl and piperidinyl, which may be substituted as indicated.

Of the The term aryl is preferably phenyl or naphthyl, in particular Phenyl.

Of the The term heteroaryl preferably includes pyridyl, indolyl, quinolinyl and benzoxazolyl.

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.

beschrieben werden, in der
die Chroman- und Chromenon-Gruppe unsubstituiert oder ein- oder zweifach mit L¹ substituiert ist,
R¹, R², X und Z eine der zuvor genannten Bedeutungen besitzen und
L¹, L², L³, unabhängig voneinander eine der für R²⁰ angegebenen Bedeutungen besitzen, und
n, p unabhängig voneinander die Werte 0, 1 oder 2, p auch den Wert 3, bedeuten.Particularly preferred compounds according to the invention may have a general formula IIa to IId, in particular IIa and IIb

be described in the
the chroman and chromenone group is unsubstituted or monosubstituted or disubstituted by L ¹ ,
R ¹ , R ² , X and Z have one of the meanings mentioned above, and
L ¹ , L ² , L ³ , independently of one another have one of the meanings given for R ²⁰ , and
n, p are independently of one another the values 0, 1 or 2, p also the value 3.

Preferred in the formulas IIa to IId, in particular IIa and IIb
X is an unsubstituted -CH ₂ -bridge or
a -CH ₂ -bridge which is monosubstituted or disubstituted by C _1-3 -alkyl, in particular methyl, where two alkyl substituents may be linked together to form a C _3-6 -cycloalkyl group, in particular cyclopropyl,
Z is a single bond,
L ^{1 is} fluorine, chlorine, bromine, cyano, C _1-3 -alkyl, C _1-3 -alkoxy, C _1-4 -alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, in particular C _1-3 -alkyl,
L ^{2 is} fluorine, chlorine, bromine, CN, amino, CF ₃ , methoxy and C _1-3 -alkyl,
n 0 or 1,
L ^{3 are} independently selected from the meanings 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, cyclo C _3-6 alkyleneimino, aminocarbonyl, C _1-4 alkylamino-carbonyl or di (C _{1 4-} alkyl) -amino-carbonyl, most preferably fluoro, chloro, bromo, cyano, CF ₃ , C _1-3 alkyl, C _1-4 alkoxy and trifluoromethoxy, with the proviso that a phenyl ring is only may be substituted by nitro, and
p is 0, 1, 2 or 3, in particular 1 or 2.

Very particularly preferably, in the formulas IIa, IIb, IIc, IId
R ¹ , R ^{2 are} independently C _1-4 alkyl, hydroxyC _1-4 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, C _3-7 cycloalkyl, hydroxyC _3-7 cycloalkyl, dihydroxyC _3-6 alkyl, C _3-7 cycloalkylC _1-3 alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (hydroxyC _3-7 cycloalkyl) C _1-3 -alkyl, ω- (C _1-4 -alkoxy) C _2-3 -alkyl, pyridyl or benzyl, where an alkyl, cycloalkyl or cycloalkyl-alkyl group additionally contains one or two times hydroxy and / or or hydroxy-C _1-3 -alkyl, and / or may be mono- or polysubstituted by F or C _1-3 -alkyl and / or simply by CF ₃ , Br, Cl or CN, and where one of the radicals R ¹ and R ^{2 can} also be H, and where phenyl and pyridyl rings may be mono- or polysubstituted by identical or different radicals R ²⁰ , phenyl may also be monosubstituted by nitro, or
R ¹ , R ² are joined together and, together with the N atom to which they are attached, form a heterocyclic group selected from pyrrolidine, piperidine, piperazine in which the free imine function is substituted with R ¹³ , and morpholine,
wherein one or more H atoms may be replaced by the same or different R ¹⁴ radicals, and
wherein the previously defined heterocyclic group may be substituted via a single bond with a carbo- or heterocyclic group Cy, wherein Cy is selected from the group consisting of C _3-7 -cycloalkyl and cyclo-C _3-6 -alkyleneimino-, wherein Cy is a - or may be substituted several times with identical or different radicals R ²⁰ , wherein R ^{20 is} as defined above and is preferably selected from fluorine, CF ₃ , C _1-3 -alkyl, hydroxy-C _1-3 -alkyl and hydroxy, and
R ^{14 is} selected from F, Cl, Br, C _1-4 alkyl, hydroxy, hydroxyC _1-3 alkyl, C _1-4 alkoxy, ω- (C _1-4 alkoxy) -C _1-3 -alkyl, amino-C _1-3 -alkyl, C _1-4 -alkyl-amino-C _1-3 -alkyl, C _3-7 -cycloalkyl-amino-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 and pyridylamino, where in the meanings mentioned in each case one or more C atoms additionally one or more times with F and / or in each case one or two C atoms independently of one another may additionally be substituted simply with Cl or Br.

The compounds listed in the experimental section, including theirs Tautomers, their diastereomers, their enantiomers and mixtures thereof and their salts are preferred according to the invention.

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, preferably monocarbocyclic 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 _3-6 -alkyleneimino- refers to a 4- to 7-membered ring having from 3 to 6 methylene units and an imino group, the bond to the rest of the molecule being via the imino group.

The term cyclo-C _3-6 -alkylenimino-carbonyl designates a previously defined cyclo-C _3-6 -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 heterocyclic, aromatic Ring systems, in particular the ring systems listed above. Examples 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 C _3-7 cycloalkyl-C 1- _n -alkyl, aryl-C 1- _n -alkyl, heteroaryl-C 1- _n -alkyl, etc. denote C 1- _n -alkyl as defined above is substituted with a C _3-7 cycloalkyl, aryl or heteroaryl group.

Some of the previously mentioned terms can be used multiple times in the definition of a formula or group and each independently have one of the meanings given. Thus, for example, in the group di-C _1-4 -alkylamino, the two alkyl groups may have the same or different meanings.

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

the substituent R ²⁰ in the case of s = 1 may be bonded to any of the free positions of the phenyl ring; in the case of s = 2 independently selected substituents R ²⁰ may 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 represents} a hydrogen atom, a C _1-3 alkyl or R _e CO-O- (R _f CR _g ) -O- group, in which R _e to R _g are 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. Preferably, the compounds are explained in more detail below inventive production process receive.

In the two following Reaction Schemes A and B, the synthesis of the compounds A.5 and B.5 according to the invention is shown, wherein R ¹ , R ² , X, Y, Z, W, A and B have one of the meanings described above. Hal is chlorine, bromine or iodine, in particular bromine or iodine, particularly preferably iodine.

According to reaction scheme A is the halogen compound A.1 with the alkyne A.2 in a molar ratio from about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence a suitable palladium catalyst, a suitable base and Copper (I) iodide reacted in a suitable solvent.

A in this case preferred amount of copper (I) iodide is in the range of 1 to 15 mol%, in particular from 5 to 10 mol%, based on the educt A.1.

Suitable palladium catalysts are, for example, Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd (CH ₃ CN) ₂ Cl ₂ , Pd (dppf) Cl ₂ . The palladium catalyst is preferably used in an amount of 1 to 15 mol%, in particular 5 to 10 mol%, based on the educt A.1.

Suitable bases are in particular amines, such as triethylamine or ethyldiisopropylamine, and Cs ₂ CO ₃ . The base is preferably used in at least equimolar amount based on the educt A.1, in excess or as a solvent. Further, suitable solvents are dimethylformamide or ethers such as tetrahydrofuran, including mixtures thereof. The reaction is carried out in a period of about 2 to 24 hours in a temperature range of about 20 to 90 ° C.

The obtained alkyne compound A.3 is directly or after prior purification with methanesulfonyl chloride reacted to methanesulfonate derivative A.4. The here to be observed Reaction conditions are known to those skilled in the art. advantageous solvent are halogenated hydrocarbons, such as dichloromethane. Suitable reaction temperatures are usually in the range from 0 to 30 ° C.

The reaction solution containing the methanesulfonate derivative A.4 or the purified methanesulfonate derivative A.4 dissolved in a suitable solvent is reacted with an amine H-NR ¹ R ² to give the final product A.5 and then optionally purified. If the amine H-NR ¹ R ^{2 has} a further primary or secondary amine function, then this is advantageously provided beforehand with a protective group which can be cleaved off again after the reaction has ended using methods known from the literature. The product thus obtained can be converted into the salt form, for example, by reaction with a corresponding acid. A preferred molar ratio of the derivative A.4 to the amine compound is in the range from 1.5: 1 to 1: 1.5. Suitable solvents are dimethylformamide or ethers such as tetrahydrofuran, including mixtures thereof.

The Reaction to the product A.5 is advantageously carried out in a temperature range from about 20 to 90 ° C.

Reaction Scheme A:

According to reaction scheme B is the halogen compound B.2 with the alkyne B.1 in a molar ratio from about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent implemented. Information on appropriate reaction conditions, including catalysts, Bases and solvents, can the explanations to Reaction Scheme A.

The obtained alkyne compound B.3 is directly or after previous purification with methanesulfonyl chloride converted to methanesulfonate derivative B.4. The here to be observed Reaction conditions are in turn to refer to Scheme A said.

The reaction solution containing the methanesulfonate derivative B.4 or the purified methanesulfonate derivative B.4 dissolved in a suitable solvent is reacted with an amine H-NR ¹ R ² to give the final product B.5 and then optionally purified. Again, the comments on Scheme A apply.

Reaction scheme B:

According to the other Scheme C is the halogen compound C.1 with the alkyne C.2 in a molar ratio from about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence a suitable palladium catalyst, a suitable base and Copper (I) iodide in a suitable solvent immediately to implemented the product C.3. Information on suitable reaction conditions, including Catalysts, bases and solvents, can the explanations to Reaction Scheme A.

Reaction Scheme C:

An alternative synthesis is shown in Reaction Scheme D. Thereafter, the halogen compound D.2 with the alkyne compound D.1 in a molar ratio of about 1.5: 1 to 1: 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in reacted directly to the product D.3 a suitable solvent. Again, here are For information on appropriate reaction conditions, including catalysts, bases and solvents, see the Explanatory Notes to Scheme A.

Reaction scheme D:

The Reactions according to the schemes A, B, C and D are particularly advantageous with the corresponding iodine compounds A.1, B.2, C.1 or D.2. For the In the case where Hal in the compounds A.1, B.2, C.1 or D.2 is bromine, it is advantageous this previously in the corresponding iodine compound to convict. One in this case, a particularly advantageous process is the aryl-Finkelstein reaction (Klapars, Artis; Buchwald, Stephen L. Copper-Catalyzed Halogen Exchange in Aryl Halides: An Aromatic Finkelstein Reaction. journal of the American Chemical Society (2002), 124 (50), 14844-14845). Thus, for example, the halogen compound A.1, B.2, C.1 or D.2 with sodium iodide in the presence of N, N-dimethyl-ethylenediamine and copper (I) iodide in a suitable solvent for the corresponding Iodine compound can be implemented. An advantageous molar relationship the halogen compound to sodium iodide is 1: 1.8 to 1: 2.3. N, N'-dimethyl-ethylenediamine is advantageously based in a molar ratio of 10 to 30 mol% used on the halogen compound A.1, B.2, C.1 and D.2. preferred Amounts of copper (I) iodide are in the range of 5 to 20 mol% to the halogen compound A.1, B.2, C.1 or D.2. A hiebei suitable Solvent is for example, 1,4-dioxane. Suitable reaction temperatures are in the range of about 20 to 110 ° C. The reaction is essentially complete after 2 to 72 hours.

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 (-) form 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 the alkali metals, especially of sodium and potassium preferred, sodium and potassium hydroxide are particularly preferred.

The Compounds according to the present invention Invention, including the physiologically acceptable salts, have an effect as antagonists of the MCH receptor, in particular of the MCH-1 receptor, and show good affinities in MCH receptor binding studies. pharmacological Test systems for MCH antagonistic properties are described in the following experimental Part described.

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 obesity includes above all exogenous Obesity, hyperinsulinarian Obesity, hyperplastic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic Obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary Obesity, hypogonadal obesity, central obesity. Of others in this indication environment are Cachexia, anorexia and to call hyperphagia.

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 of 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 can be prepared according to the invention Compounds of the general formula I, if appropriate in combination with other active substances, as described in more detail below be, along with one or more inert usual excipients and / or diluents, e.g. with cornstarch, Lactose, cane sugar, microcrystalline cellulose, magnesium stearate, Polyvinylpyrrolidone, citric acid, Tartaric acid, Water, water / ethanol, Water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, Cetylstearyl alcohol, carboxymethylcellulose or fatty substances like hard fat or their suitable mixtures, in usual galenic Preparations such as tablets, dragees, capsules, wafers, powders, Granules, solutions, Emulsions, syrups, inhalation aerosols, ointments, suppositories.

Next Medicaments, the invention also includes compositions containing at least one alkyne 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 Adipositas, 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,
• - drugs 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-1929th

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 insulins derived from animals, particularly cattle or swine, semi-synthetic human insulins synthesized enzymatically from animal-derived insulin, human in sulin, which is obtained by genetic engineering, for example from Escherichia coli or yeasts. Further, insulin is understood as meaning insulin zinc (containing 0.45 to 0.9% by weight of zinc) and protamine insulin zinc available from zinc chloride, protamine sulfate and insulin. In addition, insulin can be obtained from 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, DPPIV blockers, GLP-1 or GLP-1 analogs, SGLT-2 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.

DPPIV Blockers are for example LAF237 (Novartis), MK431 (Merck) as well 815541, 823093 and 825964 (all GlaxoSmithkline).

GLP-1 Analogs are, for example, liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), exenatide (amlyin).

SGLT-2 Inhibitors are, for example, AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson).

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 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 include 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 anti-adiposity 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 ( reuptake) inhibitor (such as Si9butramine), a sympathomimetic drug, a serotonergic agent (such as dexfenfluramine, fenfluramine, or a 5-HT2C agonist such as BAT.933), a dopamine agonist (such as bromocriptine or pramipexole), a melanocyte stimulating hormone receptor agonist or mimetic, an analog of melanocyte stimulia hormone, a cannabinoid receptor antagonist (rimonabant, ACOMPLIA ™), 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 for example 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. In addition, therapies should be mentioned in this context, which lead to weight loss by increasing the fatty acid oxidation in peripheral tissue, such as inhibitors of acetyl-CoA carboxylase.

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 NSAIDs (non-steroidal antiinflammatory drugs), in particular COX2 inhibitors, such as meloxicam or 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 alkyne compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal. This use is based in particular on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing satiety. The eating behavior is favorably influenced so that the food intake is reduced. Therefore, the compounds of the invention find advantageous application for reducing body weight. Another use of the invention is to prevent an increase in body weight, for example, in people who have previously taken weight-loss measures and are subsequently interested in maintaining the reduced body weight. In accordance with this embodiment, it is preferably a non-therapeutic use. Such a non-therapeutic use may be a cosmetic application, for example, for altering the appearance or an application for improving the general condition. The compounds of the invention are preferably used non-therapeutically for mammals, particularly humans, who have no diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and / or no diagnosed voiding disorders, especially urinary incontinence. Preferably, the compounds of the invention are for non-therapeutic use for people whose body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, is below the value of 30, in particular below 25.

The The following examples are intended to explain the invention in more detail:

Preliminary remarks:

For prepared compounds are usually present IR, ¹ H-NMR and / or mass spectra. Unless otherwise indicated, R _f values are determined using GCF Finished Tops Kieselgel 60 F254 (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 volume units indicated for NH ₃ solutions refer to a concentrated solution of NH ₃ in water.

So far Unless otherwise stated, the acid, base and acid used in the workup of the reaction solutions and salt solutions aqueous Systems of specified concentrations.

at the asymmetric dihydroxylations are those of the company Aldrich distributed "AD-Mix Alpha" (article number: 39,275-8) and "AD-Mix-Beta" (article number: 39,276-6).

Methode B:

Methode C:

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 following parameters:
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, B and C) Method A:

Method B:

Method C:

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.

temperatures be in degrees Celsius (° C) specified; periods are usually in minutes (min), hours (h) or days (d) specified.

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

abs.

absolut

CDI

Carbonyldiimidazol

Cyc

Cyclohexan

DCM

Dichlormethan

DIPE

Diisopropylether

DMF

Dimethylformamid

DMSO

Dimethylsulfoxid

dppf

1,1'-Bis(diphenylphosphino)ferrocen

EtOAc

Essigsäureethylester

EtOH

Ethanol

i. vac.

im Vakuum

MeOH

Methanol

MTBE

Methyl-tert-butylether

PE

Petrolether

RT

Raumtemperatur (ca. 20°C)

TBAF

Tetrabutylammoniumfluorid-hydrat

THF

Tetrahydrofuran

verd.

verdünnt

→*

kennzeichnet die Bindungsstelle eines Rests

The following abbreviations are used above and below:

Section.

absolutely

CDI

carbonyldiimidazole

Cyc

cyclohexane

DCM

dichloromethane

DIPE

diisopropylether

DMF

dimethylformamide

DMSO

dimethyl sulfoxide

dppf

1,1'-bis (diphenylphosphino) ferrocene

EtOAc

ethyl acetate

EtOH

ethanol

i. vac.

in a vacuum

MeOH

methanol

MTBE

Methyl tert-butyl ether

PE

petroleum ether

RT

Room temperature (about 20 ° C)

TBAF

Tetrabutylammonium fluoride hydrate

THF

tetrahydrofuran

dil.

dilute

→ *

denotes the binding site of a residue

Amine A1

(3S, 4R) -4-trifluoromethyl-piperidine-3,4-diol

A1a 1-Benzyl-4-trifluoromethyl-pyridinium chloride

To a solution of 10.0 g (65.94 mmol) of 4-trifluoromethylpyridine in 40 ml of acetonitrile is added a solution of 7.59 ml (65.94 mmol) of benzyl chloride in 10 ml of acetonitrile and the mixture is stirred at 80 ° C. for 2 h. Another 1.5 mL of benzyl chloride are added and the mixture is stirred at 80 ° C for 22 h. The reaction mixture is cooled to RT and admixed with MTBE. The precipitate is filtered off, washed with MTBE, i. vac. dried and stored in a desiccator.
Yield: 14.48 g (80% of theory)
C ₁₃ H ₁₁ F ₃ N · Cl (M = 273,681)
Calc .: Mol peak (M + H) ⁺ : 238 Found: Mol peak (M + H) ⁺ : 238

A1b 1-Benzyl-4-trifluoromethyl-1,2,3,6-tetrahydro-pyridine

3.0 g (79.36 mmol) of NaBH _{4 are} added in portions to a solution of 14.48 g (52.91 mmol) of 1-benzyl-4-trifluoromethylpyridinium chloride in 100 ml of EtOH with vigorous cooling at 0 ° C., then the cooling is removed and the reaction mixture 1.5 Stirred at 14 ° C h. While cooling, 50 mL of water and then 50 mL of EtOH are added over 30 minutes. The reaction mixture is stirred for a further 30 min, the resulting suspension is filtered and the filtrate i. vac. concentrated.
Yield: 11.72 g (92% of theory)
C ₁₃ H ₁₄ F ₃ N (M = 241,252)
Calc .: Molpeak (M + H) ⁺ : 242 Found: Molepeak (M + H) ⁺ : 242
HPLC-MS: 3.60 min (Method B)

A1c (3S, 4R) -1-Benzyl-4-trifluoromethyl-piperidine-3,4-diol

43.80 g of AD-Mix-Beta are initially charged in 3 l of tert-butanol / water (1: 1) and stirred at RT for 20 min. The mixture is cooled to 0 ° C, 2.97 g (31.25 mmol) of methanesulfonamide and 7.54 g (31.25 mmol) of 1-benzyl-4-trifluoromethyl-1,2,3,6-tetrahydropyridine are added, the cooling bath removed and 8 d stirred at RT. Another 22 g of AD-Mix Beta and 1.5 g of methanesulfonamide are added and stirred again at RT for 7 d. 11.2 g of sodium sulfate are added and stirred for 1 h. 200 mL of semi-saturated NaHCO ₃ solution are added and the aqueous phase is exhaustively extracted with DCM. The combined organic phases are dried over Na ₂ SO ₄ and i. vac. concentrated. The crude product is purified by MPLC-MS (Grom-Sil 120 ODS 4, 10 μm, gradient 0.15% formic acid in water / acetonitrile 90:10 → 10:90 in 10 min). The eluates are combined, i. vac. concentrated and neutralized with 100 mL semisaturated NaHCO ₃ solution. The aqueous phase is extracted with EtOAc, the combined organic phases are dried over Na ₂ SO ₄ and concentrated i. vac. concentrated.
Yield: 1.51 g (17% of theory)
C ₁₃ H ₁₆ F ₃ NO ₂ (M = 275,267)
Calc .: Mol peak (M + H) ⁺ : 276 Found: Mol peak (M + H) ⁺ : 276
R _f value: 0.40 (silica gel, Cyc / EtOAc 2: 1)

A1d (3S, 4R) -4-trifluoromethyl-piperidine-3,4-diol

A mixture of 1.50 g (5.45 mmol) of (3S, 4R) -1-benzyl-4-trifluoromethyl-piperidine-3,4-diol and 170 mg of Pd / C (10%) in 17 mL MeOH at RT and 3 bar Hydrogen pressure hydrogenated for 5 h. The catalyst is filtered off and the filtrate i. vac. concentrated.
Yield: 910 mg (90% of theory)
C ₆ H ₁₀ F ₃ NO ₂ (M = 185.144)
Calc .: Molpeak (M + H) ⁺ : 186 Found: Molepeak (M + H) ⁺ : 186
R _f value: 0.35 (silica gel, EtOAc / MeOH / NH ₃ 7: 3: 0.3)

Amine A2

(3R, 4S) -4-trifluoromethyl-piperidine-3,4-diol

A2a (3R, 4S) -1-Benzyl-4-trifluoromethyl-piperidine-3,4-diol

The product is obtained analogously to A1c starting from intermediate product A1b and AD-mix alpha. The crude product is purified by HPLC-MS.
Yield: 1.09 g (16% of theory)
C ₁₃ H ₁₆ F ₃ NO ₂ (M = 275,267)
Calc .: Mol peak (M + H) ⁺ : 276 Found: Mol peak (M + H) ⁺ : 276
HPLC-MS: 3.70 min (Method A)

A2b (3R, 4S) -4-trifluoromethyl-piperidine-3,4-diol

The product is obtained analogously to A1d starting from (3R, 4S) -1-benzyl-4-trifluoromethylpiperidine-3,4-diol.
Yield: 665 mg (91% of theory)
C ₆ H ₁₀ F ₃ NO ₂ (M = 185.144)
Calc .: Molpeak (M + H) ⁺ : 186 Found: Molepeak (M + H) ⁺ : 186
R _f value: 0.35 (silica gel, EtOAc / MeOH / NH ₃ 7: 3: 0.3)

Amine A3

(3R, 4S) -4-methyl-piperidine-3,4-diol

A3a 1-Benzyl-4-methyl-1,2,3,6-tetrahydro-pyridine

The product is obtained analogously to Alb starting from 10.0 g (45.5 mmol) of 1-benzyl-4-methylpyridinium chloride.
Yield: 7.15 g (84% of theory)
C ₁₃ H ₁₇ N (M = 187,281)
Calc.: Molpeak (M + H) ⁺ : 188 Found: Molepeak (M + H) ⁺ : 188
R _f value: 0.95 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A3b (3R, 4S) -1-Benzyl-4-methylpiperidine-3,4-diol

Under nitrogen atmosphere, 14 g of AD mix alpha in 50 ml of water and 50 ml of tert-butanol are initially taken and the mixture is stirred at RT for 20 min. It is then cooled to 0 ° C, 0.95 g (10.0 mmol) of methanesulfonamide and 1.87 g (10.0 mmol) of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine was added, the cooling bath was removed and the reaction mixture 24 Stirred at RT. 3.5 g of sodium sulfite are added to the reaction mixture and stirring is continued for 1 h. It is mixed with 200 mL DCM and 200 mL saturated NaHCO ₃ solution, the organic phase is separated off and extracted with 100 mL KHSO ₄ solution. The aqueous phase is made alkaline with saturated K ₂ CO ₃ solution, extracted with 200 mL EtOAc and the organic phase dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the crude product is purified by chromatography (silica gel, EtOAc / MeOH / NH ₃ 19: 1: 0.1).
Yield: 1.23 g (56% of theory)
C ₁₃ H ₁₉ NO ₂ (M = 221,296)
Calc .: Mol peak (M + H) ⁺ : 222 Found: Mol peak (M + H) ⁺ : 222
R _f value: 0.56 (silica gel, EtOAc / MeOH / NH ₃ 19: 1: 0.1)

A3c (3R, 4S) -4-methylpiperidine-3,4-diol

The product is obtained analogously to Ald starting from 1.23 g (5.57 mmol) of (3R, 4S) -1-benzyl-4-methylpiperidine-3,4-diol.
Yield: 730 mg (quant.
C ₆ H ₁₃ NO ₂ (M = 131.173)
Calc .: Molpeak (M + H) ⁺ : 132 Found: Molepeak (M + H) ⁺ : 132
HPLC-MS: 0.93 min (Method C)

Amin A4

(3S, 4R) -4-methyl-piperidine-3,4-diol

A4a (3S, 4R) -1-Benzyl-4-methylpiperidine-3,4-diol

The product is obtained analogously to A3b starting from 5.0 g (26.7 mmol) of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine and AD-Mix-Beta.
Yield: 4.68 g (79% of theory)
C ₁₃ H ₁₉ NO ₂ (M = 221,296)
Calc .: Mol peak (M + H) ⁺ : 222 Found: Mol peak (M + H) ⁺ : 222
R _f value: 0.54 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A4b (3S, 4R) -4-methylpiperidine-3,4-diol

The product is obtained analogously to Ald starting from 4.68 g (21.14 mmol) of (3S, 4R) -1-benzyl-4-methylpiperidine-3,4-diol.
Yield: 2.33 g (84% of theory)
C ₆ H ₁₃ NO ₂ (M = 131.173)
Calc .: Molpeak (M + H) ⁺ : 132 Found: Molepeak (M + H) ⁺ : 132
R _f value: 0.05 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

Amine A5

(3S, 4R) -4-ethyl-piperidine-3,4-diol

A5a 1-Benzyl-4-ethylpyridinium chloride

The product is obtained analogously to Ala starting from 100 ml (933 mmol) of 4-ethylpyridine.
Yield: 143 g (66% of theory)
C ₁₄ H ₁₆ N · Cl (M = 233,736)
Calc .: Mol peak (M + H) ⁺ : 198 Found: Mol peak (M + H) ⁺ : 198
R _f value: 0.12 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A5b 1-Benzyl-4-ethyl-1,2,3,6-tetrahydropyridine

The product is obtained analogously to Alb starting from 143 g (614 mmol) of 1-benzyl-4-ethylpyridinium chloride.
Yield: 99 g (80% of theory)
C ₁₄ H ₁₉ N (M = 201,307)
Calc .: Molpeak (M + H) ⁺ : 202 Found: Molepeak (M + H) ⁺ : 202
R _f value: 0.91 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A5c (3S, 4R) -1-Benzyl-4-ethyl-piperidine-3,4-diol

The product is obtained analogously to A3b starting from 14.37 g (71.4 mmol) of 1-benzyl-4-ethyl-1,2,3,6-tetrahydropyridine and AD-Mix-Beta.
Yield: 11.46 g (68% of theory)
C ₁₄ H ₂₁ NO ₂ (M = 235,322)
Calc .: Molpeak (M + H) ⁺ : 236 Found: Molepeak (M + H) ⁺ : 236
R _f value: 0.58 (silica gel, EtOAc / MeOH / NH ₃ 95: 5: 0.5)

A5d (3S, 4R) -4-ethyl-piperidine-3,4-diol

The Product can be obtained analogously to A1d starting from (3S, 4R) -1-benzyl-4-ethyl-piperidine-3,4-diol.

Analogous to the described sequence, the enantiomer (3R, 4S) -4-ethyl-piperidine-3,4-diol can be obtained.

Amine A6

cis-pyrrolidine-3,4-diol

A6a 1-Benzyl-2,5-dihydro-1H-pyrrole

To a solution of 10 mL (127 mmol) of 2,5-dihydro-1H-pyrrole in 100 mL acetonitrile 14.6 mL (127 mmol) of benzyl chloride are added dropwise, with the reaction mixture warmed to 45 ° C. After 1.5 h, 300 ml of MTBE are added to the suspension, the precipitate is filtered off and the filtrate is concentrated. The residue is purified by chromatography (silica gel, EtOAc / MeOH / NH ₃ 19: 1: 0.1).
Yield: 4.0 g (20% of theory)
C ₁₁ H ₁₃ N (M = 159.228)
Calc .: Mol peak (M + H) ⁺ : 160 F: Mol peak (M + H) ⁺ : 160
R _f value: 0.60 (silica gel, EtOAc / MeOH / NH ₃ 19: 1: 0.1)

A6b cis-1-benzylpyrrolidine-3,4-diol

The product is obtained analogously to A3b starting from 4.0 g (25.1 mmol) of 1-benzyl-2,5-dihydro-1H-pyrrole and AD-Mix-Beta.
Yield: 0.97 g (20% of theory)
C ₁₁ H ₁₅ NO ₂ (M = 193,242)
Calc .: Molpeak (M + H) ⁺ : 194 Found: Molpeak (M + H) ⁺ : 194
R _f value: 0.15 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A6c cis-pyrrolidine-3,4-diol

The product is obtained analogously to Ald starting from 0.97 g (5.04 mmol) of cis-1-benzylpyrrolidine-3,4-diol.
Yield: 0.52 g (quant.
C ₄ H ₉ NO ₂ (M = 103.120)
Calc .: Mol peak (M + H) ⁺ : 104 Found: Mol peak (M + H) ⁺ : 104
R _f value: 0.05 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A7

4-hydroxymethyl-piperidin-4-ol

A7a 1-Benzyl-4-hydroxymethyl-piperidin-4-ol

The product is analogously to A3b starting from 3.15 g (16.83 mmol) of 1-benzyl-4-methylene-piperidine and Obtained AD mix alpha.
Yield: 2.92 g (79% of theory)
C ₁₃ H ₁₉ NO ₂ (M = 221,296)
Calc .: Mol peak (M + H) ⁺ : 222 Found: Mol peak (M + H) ⁺ : 222
R _f value: 0.12 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A7b 4-hydroxymethyl-piperidin-4-ol

The product is obtained analogously to Ald starting from 2.92 g (13.21 mmol) of 1-benzyl-4-hydroxymethyl-piperidin-4-ol.
Yield: 1.88 g (quant.
C ₆ H ₁₃ NO ₂ (M = 131.173)
Calc .: Molpeak (M + H) ⁺ : 132 Found: Molepeak (M + H) ⁺ : 132
R _f value: 0.06 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A8

(S) -1-pyrrolidin-2-yl-cyclopropanol

A8a 1 - ((S) -1-Benzylpyrrolidin-2-yl) -cyclopropanol

To a cooled to -15 ° C solution of 5.0 g (21.43 mmol) of N-benzyl-L-proline in 80 mL of dry diethyl ether are first slowly 6.91 mL (23.57 mmol) of titanium (IV) isopropoxide and then 14.3 mL (42.9 mmol , 3 M in diethyl ether) was added dropwise Ethylmagnesiumbromid and the reaction mixture stirred for 30 min at this temperature. Subsequently, at about 10.degree. C., 5.4 ml (42.9 mmol) of boron trifluoride-diethyl ether complex are added and the mixture is stirred at RT for a further 75 h. While cooling, 50 ml of 1 M NaOH are added, stirring is continued for 1 hour at RT, 100 ml of diethyl ether are added, and the organic phase is separated off and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, EtOAc).
Yield: 0.745 g (16% of theory)
C ₁₄ H ₁₉ NO (M = 217,307)
Calc .: Mol peak (M + H) ⁺ : 218 Found: Mol peak (M + H) ⁺ : 218
R _f value: 0.17 (silica gel, EtOAc)

A8b (S) -1-pyrrolidin-2-yl-cyclopropanol

The product is obtained analogously to Ald starting from 745 mg (3.43 mmol) of 1- ((S) -1-benzylpyrrolidin-2-yl) -cyclopropanol.
Yield: 350 mg (80% of theory)
C ₇ H ₁₃ NO (M = 127.184)
Calc .: Mol peak (M + H) ⁺ : 128 Found: Mol peak (M + H) ⁺ : 128
R _f value: 0.10 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Intermediate A9

5- (4-chloro-phenyl) -2-ethynyl-3-fluoro-pyridine

A9a 2,5-Dibromo-3-fluoro-pyridine

To a solution of 6.50 g (25.80 mmol) of 2,5-dibromo-pyridin-3-ylamine and 15 mL of conc. HCl (180.62 mmol) in 15 mL of water at -5 ° C, a solution of 1.78 g (25.80 mmol) of sodium nitrite in 3.5 mL of water was added dropwise and the mixture was stirred for 30 min. At 0 ° C. 11.41 mL (77.41 mmol) of hexafluorophosphoric acid (60% in water) are added and the mixture is stirred at 0 ° C. for 1 h. The diazonium salt formed is filtered off, washed with cold water, isopropanol and diethyl ether and concentrated in a desiccator i. vac. dried. Petroleum ether (100-140 ° C) is heated to 90 ° C, the diazonium salt is added in portions and the mixture stirred until no gas evolution can be observed. The reaction mixture is cooled to RT, made alkaline with saturated Na ₂ CO ₃ solution and the aqueous phase is exhaustively extracted with MTBE. The combined organic phases are washed with saturated Na ₂ CO ₃ solution and water, dried over MgSO ₄ and concentrated i. vac. concentrated. The residue is dissolved in DCM, filtered through silica gel and the filtrate i. vac. concentrated.
Yield: 3.30 (51% of theory)
C ₅ H ₂ Br ₂ FN (M = 254,883)
Calc .: Mol peak (M + H) ⁺ : 253/255/257 (Br ₂ ) Found: Mol peak (M + H) ⁺ : 253/255/257 (Br ₂ )
R _f value: 0.63 (silica gel, PE / EtOAc 9: 1)

A9b 5-Bromo-2 - [(tert -butyl-dimethyl-silanyl) -ethynyl] -3-fluoro-pyridine

Under an argon atmosphere, to a solution of 3.20 g (12.56 mmol) of 2,5-dibromo-3-fluoropyridine, 5.22 mL of triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) of CuI and 220.3 mg (0.31 mmol) of bis- triphenylphosphine palladium (II) chloride in 30 mL abs. THF at 15 ° C 2.62 mL (13.811 mmol) of tert-butyl-ethynyl-dimethyl-silane was added and the mixture stirred for 2 h at RT. Then 1 mL tert-butyl-ethynyl-dimethylsilane are added again and stirred at RT for 1 h. The reaction mixture is i. vac. concentrated and the residue taken up in EtOAc. The organic phase is washed with half-saturated NaHCO ₃ solution, 5% NH ₃ solution and water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, PE / DCM 9: 1).
Yield: 1.62 g (41% of theory)
C ₁₃ H ₁₇ BrFNSi (M = 314,269)
Calc .: Molpeak (M + H) ⁺ : 314/316 (Br) Found: Molepeak (M + H) ⁺ : 314/316 (Br)
HPLC-MS: 7.85 min (Method B)

A9c 2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -5- (4-chloro-phenyl) -3-fluoro-pyridine

To a solution of 1.61 g (5.14 mmol) of 5-bromo-2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -3-fluoropyridine and 0.90 g (5.65 mmol) of 4-chlorophenylboronic acid in 30 ml of 1, To 4-dioxane, 10 mL MeOH, 10 mL 2N Na ₂ CO ₃ solution and 94 mg (0.13 mmol) PdCl ₂ (dppf) are added and the mixture is refluxed for 15 min. The reaction mixture is i. vac. concentrated and diluted with EtOAc. The organic phase is washed with water and half-saturated NaHCO ₃ solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, PE / DCM 1: 1).
Yield: 1.25 g (70% of theory)
C ₁₉ H ₂₁ ClFNSi (M = 345,913)
Calc .: Mol peak (M + H) ⁺ : 346/348 (Cl) Found: Mol peak (M + H) ⁺ : 346/348 (Cl)
HPLC-MS: 8.83 min (Method B)

A9d 5- (4-Chloro-phenyl) -2-ethynyl-3-fluoro-pyridine

To a solution of 1.25 g (3.61 mmol) of 2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -5- (4-chlorophenyl) -3-fluoropyridine in 30 mL DCM at RT 1.14 g (3.61 mmol) TBAF was added and the mixture stirred for 2 h. The organic phase is washed with water and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is stirred with PE, the precipitate is filtered off, washed with PE and dried in air.
Yield: 0.72 g (86% of theory)
C ₁₃ H ₇ ClFN (M = 231,653)
Calcd .: Mol peak (M + H) ⁺ : 232/234 (Cl) Found: Mol peak (M + H) ⁺ : 232/234 (Cl)
HPLC-MS: 5.81 min (Method B)

Example 1.1

((S) -1- {6- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -1-benzopyran-2-ylmethyl} -pyrrolidin-2-yl) -methanol

1.1a (6-iodo-1-benzopyran-2-yl) -methanol

To a solution of 1.64 g (10.00 mmol) of 1-benzopyran-2-yl-methanol and 1.40 g (5.50 mmol) of iodine in 15 mL DCM is a finely ground mixture of 4 g of silica gel (0.2-0.5 mm) and 2.02 g ( 5.0 mmol) of iron (III) nitrate nonahydrate was added and stirred at RT for 12 h. Furthermore, 5 g of silica gel are added and the reaction mixture i. vac. concentrated. Column chromatography (silica gel, PE / EtOAc 7: 3) gave the product.
Yield: 1.80 g (62% of theory)
C ₁₀ H ₁₁ O ₂ (M = 290,098)
Calc.: Molpeak (M + H) ⁺ : 290 Found: Molepeak (M + H) ⁺ : 290
R _f value: 0.45 (silica gel, PE / EtOAc 4: 1)

1.1b 5-Bromo-2 - [(tert -butyl-dimethyl-silanyl) -ethynyl] -pyridine

Under an argon atmosphere to a solution of 49.90 g (201.01 mmol) of 2,5-dibromopyridine and 43.00 mL (225.57 mmol) of tert-butyl-ethynyl-dimethyl-silane in 500 mL abs. THF and 120 mL of triethylamine at -7 ° C 0.80 g (4.20 mmol) of CuI and 2.90 g (4.13 mmol) of bis-triphenylphosphine-palladium (II) chloride was added and the mixture was stirred at 0 ° C for 30 min. The reaction mixture is stirred for 3.5 h at RT, then filtered and the filtrate i. vac. concentrated. The residue was dissolved in 1 L EtOAc, the organic phase washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i. vac. concentrated. The crude product was used without further purification in the subsequent reaction step.
Yield: 59.5 g (quant.
C ₁₃ H ₁₈ BrNSi (M = 296.278)
Calc .: Molpeak (M + H) ⁺ : 296/298 (Br) Found: Molpeak (M + H) ⁺ : 296/298 (Br)
R _f value: 0.75 (silica gel, Cyc / EtOAc 8: 1)

1.1c 2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -5- (4-chloro-phenyl) -pyridine

To a solution of 59.5 g (201.01 mmol) of 5-bromo-2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -pyridine and 36.5 g (233.40 mmol) of 4-chlorophenylboronic acid in 600 mL of 1,4-dioxane 250 mL MeOH, 220 mL 2N Na ₂ CO ₃ solution and 1.80 g (2.46 mmol) PdCl ₂ (dppf) were added and the mixture heated at reflux for 1 h. The reaction mixture is i. vac. concentrated and diluted with EtOAc. The organic phase is washed with water and semisaturated NaHCO ₄ solution, dried over Na ₂ SO ₄ and i. vac. concentrated. The residue is purified by column chromatography (silica gel, Cyc / EtOAc 9: 1).
Yield: 38.5 g (58% of theory)
C ₁₉ H ₂₂ ClNSi (M = 327,923)
Calcd .: Mol peak (M + H) ⁺ : 328/330 (Cl) Found: Mol peak (M + H) ⁺ : 328/330 (Cl)
R _f value: 0.60 (silica gel, Cyc / EtOAc 8: 1)

1.1d 5- (4-Chloro-phenyl) -2-ethynyl-pyridine

To a solution of 46.50 g (142.00 mmol) of 2 - [(tert-butyl-dimethyl-silanyi) -ethynyl] -5- (4-chlorophenyl) -pyridine in 1 L DCM at RT 43.66 g (156.00 mmol) TBAF was added and the mixture stirred for 2 h. The organic phase is washed with water, dried over Na ₂ SO ₄ and i. vac. concentrated. The residue is stirred with DIPE, the precipitate is filtered off and washed with PE.
Yield: 26.0 g (86% of theory)
C ₁₃ H ₈ ClN (M = 213.662)
Calcd .: Mol peak (M + H) ⁺ : 214/216 (Cl) Found: Mol peak (M + H) ⁺ : 214/216 (Cl)
R _f value: 0.30 (silica gel, Cyc / EtOAc 4: 1)

1.1e {6- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -1-benzopyran-2-yl} -methanol

Under an argon atmosphere, to a solution of 1.62 g (5.58 mmol) of (6-iodo-1-benzopyran-2-yl) -methanol, 1.20 g (5.60 mmol) of 5- (4-chloro-phenyl) -2-ethynyl pyridine, 204.1 mg (0.25 mmol) PdCl ₂ (dppf) and 2.36 mL (17.00 mmol) triethylamine in 50 mL acetonitrile 48.6 mg (0.25 mmol) CuI was added and the mixture stirred at RT for 6 h. The reaction mixture is poured into water, the precipitate is filtered off and dried in air. The residue is purified by column chromatography (silica gel, gradient DCM / EtOAc 100: 0 → 50:50 in 30 min).
Yield: 0.85 g (41% of theory)
C ₂₃ H ₁₈ ClNO ₂ (M = 375,847)
Calc .: Molpeak (M + H) ⁺ : 376/378 (Cl) Found: Molepeak (M + H) ⁺ : 376/378 (Cl)
R _f value: 0.20 (silica gel, DCM / EtOAc 9: 1)

1.1f Methanesulfonic acid 6- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -1-benzopyran-2-ylmethyl ester

To a solution of 0.85 g (2.26 mmol) of 6- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -1-benzopyran-2-yl} -methanol and 403 μL (5.00 mmol) of pyridine in 20 389 μL (5.00 mmol) of methanesulfonyl chloride are added dropwise at 0 ° C. to DCMC and the mixture is stirred at RT for 2 h. Another 806 μL (10.00 mmol) of methanesulfonyl chloride are added and the mixture is stirred for 16 h. The reaction mixture is washed with water and dil. Sodium bicarbonate solution, dried over Na ₂ SO ₄ , filtered through activated charcoal and i. vac. concentrated. The crude product is purified by column chromatography (silica gel, DCM / EtOAc 4: 1).
Yield: 0.70 g (68% of theory)
C ₂₄ H ₂₀ ClNO ₄ S (M = 453,939)
Calcd .: Mol peak (M + H) ⁺ : 454/456 (Cl) Found: Mol peak (M + H) ⁺ : 454/456 (Cl)
R _f value: 0.53 (silica gel, DCM / EtOAc 9: 1)

1.1 g of ((S) -1- {6- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -1-benzopyran-2-ylmethyl} -pyrrolidin-2-yl) -methanol

A solution of 113.5 mg (0.25 mmol) of methanesulfonic acid 6- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -1-benzopyran-2-ylmethyl ester and 120 μL (1.10 mmol) of (S) -1 -Pyrrolidin-2-yl-methanol in 2 mL of DMF is stirred for 24 h at 80 ° C and then poured onto water. The precipitate is washed with water, a little acetone and DIPE and dried in air.
Yield: 80 mg (70% of theory)
C ₂₈ H ₂₇ ClN ₂ O ₂ (M = 458.979)
Calc .: Mol peak (M + H) ⁺ : 459/461 (Cl) Found: Mol peak (M + H) ⁺ : 459/461 (Cl)
R _f value: 0.28 (silica gel, DCM / EtOAc 9: 1)

The following examples are prepared analogously starting from methanesulfonic acid 6- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -1-benzopyran-2-ylmethyl ester (Example 1.1f):

Example 2.1

6- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2- (4-methyl-piperidin-1-ylmethyl) -1-benzopyran-4-one

2.1a 6-bromo-2-hydroxymethyl-1-benzopyran-4-one

17.03 g (105.00 mmol) of CDI are added to a solution of 26.91 g (100.00 mmol) of 6-bromo-4-oxo-4H-1-benzopyran-2-carboxylic acid in 250 ml of THF and the mixture is stirred in a water bath until the evolution of gas has ended heated. This mixture is poured onto a suspension of 1.89 g (50.00 mmol) of sodium borohydride in 500 ml of water, keeping the temperature below 10 ° C., and stirred at RT for a further 2 h. The reaction mixture is poured onto 500 ml of saturated ammonium chloride solution, stirred at RT for 1 h, and the aqueous phase is exhaustively extracted with DIPE. The combined organic phases are washed with water, dried over Na ₂ SO ₄ and i. vac. concentrated.
Yield: 19.50 g (76% of theory)
C ₁₀ H ₇ BrOs (M = 255,065)
Calc .: Mol peak (M + H) ⁺ : 255/257 (Br) Found: Mol peak (M + H) ⁺ : 255/257 (Br)
R _f value: 0.40 (silica gel, DCM / MeOH 9: 1)

2.1b 6-Bromo-2-bromomethyl-1-benzopyran-4-one

To a solution of 2.55 g (10.00 mmol) 6-bromo-2-hydroxymethyl-1-benzopyran-4-one in 50 mL MTBE is added dropwise at 0 ° C, a solution of 0.47 mL (5.00 mmol) phosphorus tribromide in 2.5 mL MTBE and the mixture was stirred at RT for 16 h. Ice water is added and the organic phase separated. The organic phase is washed with ice water, dried over MgSO ₄ and i. vac. concentrated. The residue is purified by column chromatography (silica gel, gradient PE / EtOAc 80:20 → 50:50 in 20 minutes).
Yield: 1.69 g (53% of theory)
C ₁₀ H ₆ Br ₂ O ₂ (M = 317,961)
Calc.: Molpeak (M + H) ⁺ : 317/319/321 (2Br) Found: Molepeak (M + H) ⁺ : 317/319/321 (2Br)
R _f value: 0.63 (silica gel, PE / EtOAc 6: 4)

2.1c 6-Bromo-2- (4-methylpiperidin-1-ylmethyl) -1-benzopyran-4-one

A mixture of 0.60 g (1.89 mmol) of 6-bromo-2-bromomethyl-1-benzopyran-4-one, 223 μL (1.89 mmol) of 4-methylpiperidine and 525 mg (3.80 mmol) of potassium carbonate in 50 mL of acetonitrile is added during 3 h RT stirred and then i. vac. concentrated. The residue is taken up in MTBE, the organic phase is washed with water, dried over MgSO ₄ , filtered through activated charcoal and dried i. vac. concentrated.
Yield: 450 mg (71% of theory)
C ₁₆ H ₁₈ BrNO ₂ (M = 336,224)
Calc .: Molpeak (M + H) ⁺ : 336/338 (Br) Found: Molepeak (M + H) ⁺ : 336/338 (Br)
HPLC-MS: 3.90 min (Method B)

2.1d 6-iodo-2- (4-methylpiperidin-1-ylmethyl) -1-benzopyran-4-one

Under an argon atmosphere, a mixture of 450 mg (1.34 mmol) 6-bromo-2- (4-methylpiperidin-1-ylmethyl) -1-benzopyran-4-one, 26 mg (0.134 mmol) CuI, 400 mg ( 2.68 mmol) NaI and 28 μL (0.268 mmol) of N, N'-dimethyl-ethane-1,2-diamine in 1.4 mL of 1,4-dioxane for 20 h at 110 ° C heated. Diluted NaHCO ₃ solution is added to the reaction mixture, and the aqueous phase is exhaustively extracted with MTBE. The combined organic phases are dried over MgSO ₄ and i. vac. concentrated. The residue is purified by means of HPLC-MS (Zorbax Bonus C18 amide phase 5 μm, gradient 0.15% formic acid in water / acetonitrile 10/90 → 90/10 v / v). The eluates are i. vac. concentrated, mixed with 5% Na ₂ CO ₃ solution and the aqueous phase exhaustively extracted with MTBE. The combined organic phases are dried over MgSO ₄ and i. vac. dried.
Yield: 220 mg (43% of theory)
C ₁₆ H ₁₈ INO ₂ (M = 383,224)
Calcd .: Mol peak (M + H) ⁺ : 384 Found: Mol peak (M + H) ⁺ : 384
HPLC-MS: 4.0 min (Method B)

2.1e 6- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2- (4-methylpiperidin-1-ylmethyl) -1-benzopyran-4-one

The product is prepared analogously to Example 1.1e starting from 6-1od-2- (4-methylpiperidin-1-ylmethyl) -1-benzopyran-4-one and 5- (4-chlorophenyl) -2-ethynyl pyridine (Example 1.1d). The crude product is purified by HPLC-MS (Zorbax Bonus C18 amide phase 5 μm, gradient 0.15% formic acid in water / acetonitrile 10/90 → 90/10 v / v).
Yield: 20.5 mg (22% of theory)
C ₂₉ H ₂₅ ClN ₂ O ₂ (M = 468,974)
Calcd .: Mol peak (M + H) ⁺ : 469/471 (Cl) Found: Mol peak (M + H) ⁺ : 469/471 (Cl)
HPLC-MS: 5.1 min (Method B)

The following compounds are obtained analogously to 2.1c, 2.1d and 2.1e:

Analogously to 2.1c, 2.1d and 2.1e (with compound A9 as starting material), the following compounds are obtained:

The following are test methods for determining MCH receptor antagonist activity described. 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-1R 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 × 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.

The KD value of the radioligand is 0.156 nM. MCH-1 receptor-coupled Ca ²⁺ mobilization test Method: Calcium mobilization test with human MCH (FLIPR ³⁸⁴ ) Species: humanely Test cells: Stably-transfected CHO / Galpha 16 cells with hMCH-R1 results: 1st measurement:% stimulation of the reference (MCH 10 ^-6 M) 2nd measurement: pKB value reagents: HBSS (10x) (GIBCO) HEPES buffer (1 M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) probenecid (Sigma) MCH (Bachem) Bovine serum albumin (protease free) (Serva) DMSO (Serva) Ham's F12 (BioWhittaker) FCS (BioWhittaker) L-Glutamine (GIBCO) Hygromycin B (GIBCO) penstrep (BioWhittaker) Zeocin (Invitrogen)

Clonal CHO / Galpha16 hMCH-R1 cells are 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 35 minutes after the last wash step to the 384-well cell culture plate 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 relative fluorescence minus background background and expressed as a percentage of the reference maximum signal (MCH 10 ^-6 M, signal normalized to 100%). The EC50 values of the MCH dose-response curve with and without test substance (defined concentration) are determined graphically by the GraphPad Prism 2.01 curve program. MCH antagonists cause a 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 recipe described above Tor binding assays will have antagonist activity in a dose range of about 10 ^-10 to 10 ^-6 M, especially 10 ^-10 to 10 ^-7 M.

The following IC ₅₀ 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 of active ingredient

• Composition: 1 capsule for powder inhalation contains: Active ingredient 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 substance

• 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 of 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

LPG metered with 1 mg of active ingredient

• Composition: 1 hub contains: active substance 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 of active ingredient

• Composition: active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 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 of 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 of 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:

polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for Injection (Wfl) dissolve; Add human serum albumin; Dissolve active ingredient with heating; with Wfl on batch volume fill up; 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:

Dissolve mannitol in water for injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; 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

• 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 (27)

Alkyne compounds of general formula I.

in the R ¹ , R ² independently of one another are H, C _1-8 -alkyl, C _3-7 -cycloalkyl or a phenyl or pyridinyl radical which is optionally monosubstituted or polysubstituted by identical or different radicals R ²⁰ and / or monosubstituted or nitro-substituted in which the alkyl or cycloalkyl group may be monosubstituted or polysubstituted by identical or different radicals R ¹¹ , and in which a -CH ₂ group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group is replaced by -O- , -S- or -NR ¹³ - may be replaced, or R ¹ and R ² form a C _3-8 alkylene bridge, in which one not adjacent to the N atom of the R ¹ R ² N group -CH ₂ group by -CH = N-, -CH = CH-, -O-, -S-, -SO, - (SO ₂ ) -, -CO-, -C (= CH ₂ ) - or -NR ¹³ - Can be replaced, wherein in the above-defined alkylene bridge, one or more H atoms may be replaced by identical or different radicals R ¹⁴ , and wherein the previously defined alkylene bridge with one or two identical or different carbo- or heterocy clischen 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 carbon atom to form a spirocyclic ring system, - via 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; X is a C _1-4 -alkylene bridge, wherein in the meaning C _2-4 -alkylene one or two C atoms may simply be substituted by R ¹⁰ , or a C _3-4 -alkylene bridge in which one is not with the N atom of the R ¹ R ² N group immediately adjacent -CH ₂ -CH ₂ group is replaced by -CH = CH- or -C≡C-, wherein the meanings given above for X is a substituent selected from C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl and C _3-7 cycloalkyl C _1-3 alkyl; and one, two or three identical or different C _1-4 alkyl Substituents, wherein two alkyl groups may be bonded together to form a 3 to 7-membered or an alkyl and an alkenyl group to form a 5 to 7-membered cyclic group, and W, Z independently represent a single bond or a C _1-2 alkylene bridge, wherein two adjacent C atoms may be connected to each other with an additional C _1-4 alkylene bridge, and wherein an o the two C atoms may be substituted independently of one another by one or two identical or different C _1-3 -alkyl radicals, it being possible for two alkyl radicals to be linked together to form a carbocyclic ring, and Y is selected from the meanings of the sub-formulas Y1 and Y2

wherein the group MO, S or NR is ^M , wherein R ^{M is} selected from the meanings H, C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-7 cycloalkyl and C _3-7 -cycloalkyl-C _1-3 -alkyl, and wherein in the sub-formulas Y1 and Y2, one or more C atoms may be independently substituted with R ²⁰ , and A are independently selected from the group of bivalent cyclic groups phenyl , Pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoxazolyl, thienyl, furanyl, benzothienyl or benzofuranyl, wherein said cyclic groups include - or more than one or more C atoms with the same or different radicals R ²⁰ , in the case of a phenyl ring may also be additionally substituted with nitro, and / or to one or more NH groups with R ²¹ , B is a the meanings given for Y, A or C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _3-7 -cycloalkyl- C _1-3 alkyl, C _3-7 cycloalkenyl C _1-3 alkyl, C _3-7 cycloalkyl C _1-3 alkenyl or CC _3-7 cycloalkyl C _1-3 alkynyl-, in which one or more C atoms independently of one another may be monosubstituted or polysubstituted by halogen and / or monosubstituted or polysubstituted by hydroxy or cyano and / or cyclic groups or may be substituted by identical or different radicals R ²⁰ , 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 heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group having two or a plurality of N atoms or having one or two N atoms and one 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 previously mentioned saturated 6- or 7-membered groups as bridged ring systems with an imino, (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 having the same or different radicals R ²⁰ , in the case of a phenyl group also additionally simple with nitro, and / or one or more NH groups may be substituted with R ²¹ , R ^{10 is} hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy or C _1-4 -alkoxy-C _{1 3-} alkyl, R ^{11 is} halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁵ -CO- O, cyano, R ¹⁶ R ¹⁷ N, R ¹⁸ R ¹⁹ N-CO- od it Cy-, wherein in the above-mentioned groups one or more C atoms independently of one another by substituents selected from halogen, OH, CN, CF ₃ , C _1-3 alkyl, hydroxy-C _1-3 alkyl substituted one or more times could be; R ^{13 is} one of the meanings given for R ¹⁷ , R ^{14 is} halogen, cyano, 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 -SO ₂ -NH-, R ¹⁵ -O-CO-NH-C _1-3 -alkyl, R ¹⁵ -SO ₂ -NN-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 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 -al kyl) -amino-C _2-6 -alkyl or cyclo-C _3-6 -alkylenimino-C _2-6 -alkyl-, R ^{17 is} one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl, Pyridinyl, C _1-4 -alkylcarbonyl, 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 _1-3 -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 _2-6 -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 alkylene-C _2-6 alkyl, phenyl, phenyl C _1-3 alkyl, C _1-4 Alkyl-carbonyl, C _1-4 -alkoxycarbonyl, C _1-4 -alkylsulfonyl, aminosulfonyl, C _1-4 -alkylaminosulfonyl, di-C _1-4 -alkylaminosulfonyl or cyclo-C _3-6 -alkylene-iminosulfonyl , R ^{22 is} pyridinyl, phenyl, phenylC _1-3 -alkoxy, cycloC _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- 3-} alkyl) -aminocarbonyl, cyclo-C _3-6 -alkyl-amino-carbonyl-, Cyclo-C _3-6 -alkyleneimino-carbonyl, phenylaminocarbonyl, cycloCC _3-6 -alkyleneimino-C _2-4 -alkylaminocarbonyl, C _1-4 -alkylsulfonyl, 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 -alkyleneimino, phenyl- C _1-3 -alkylamino, N- (C _1-4 -alkyl) -phenyl-C _1-3 -alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C _2-3 -alkylaminocarbonyl, (4- Morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or C _1-4 -alkylaminocarbonylamino, wherein in the abovementioned groups and radicals, in particular in W, X, Z, R ¹⁰ , R ¹³ to R ²² , in each case one or more C atoms additionally one or more times with F and / or in each case one or two C atoms independently of each other additionally simply with Cl or Br and / or in each case one o the plurality of phenyl rings independently of one another in addition, two or three substituents selected from the group F, Cl, Br, I, cyano, C _1-4 alkyl, C _1-4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy -, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino C _1-3 alkyl, C _1-3 alkylamino-C _1-3 alkyl- and di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl may comprise and / or may be monosubstituted by nitro, and the H Atom of an existing carboxy group or an H atom bound to an N atom can each be replaced by a residue cleavable in vivo, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, the following compounds not being included: 6- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline, 6- [5- (4-chloro phenyl) -pyridin-2-ylethynyl] -1-methyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline and 5- (4-chloro-phenyl) -2- [2- (4-methyl-piperidin-1-ylmethyl) chroman-6-ylethynyl] -pyridine. Alkyn compounds according to claim 1, characterized in that the radicals R ¹ , R ^{2 are} independently selected from the group consisting of H, C _1-6 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, C _3-7 -cycloalkyl, hydroxyC _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, (hydroxyC _3-7 -cycloalkyl) -C _1-3 -alkyl-, Hydroxy C _2-4 alkyl, ω-NC-C _2-3 alkyl, C _1-4 alkoxy C _2-4 alkyl, hydroxy C _1-4 alkoxy C _2-4 alkyl, C _1-4 alkoxy-carbonyl-C _1-4 -alkyl, carboxyl C _1-4 -alkyl, amino-C _2-4 -alkyl, 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, pyrrolidine-3- yl, N- (C _1-4 alkyl) pyrrolidin-3-yl, pyrrolidinyl C _1-3 alkyl, N- (C _1-4 alkyl) pyrrolidinyl C _1-3 alkyl, piperidine 3-yl, piperidin-4-yl, N- (C _1-4 -alkyl) -piperidin-3-yl, N- (C _1-4 -alkyl) -piperidin-4-yl, piperidinyl-C _{1 3-} alkyl, N- (C _1-4 alkyl) piperidinyl C _1-3 alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, phenyl, phenylC _1-3 alkyl, Pyridyl or pyridyl-C _1-3 alkyl, wherein in the above-mentioned groups and radicals one or more C atoms independently of one another or more times with F, C _1-3 alkyl or hydroxy-C _1-3 alkyl , and / or one or two C atoms independently of one another may be substituted by Cl, Br, OH, CF ₃ or CN, and where the phenyl or pyridyl radical is mono- or polysubstituted by identical or different radicals R ²⁰ , im Case of a phenyl group may also be additionally substituted with nitro, and the radical R ^{20 have} the meaning given in claim 1. Alkyne compounds according to claim 1, characterized in that R ¹ and R ² together with the N-atom to which they are attached form a heterocyclic group which is selected from the meanings pyrrolidine, piperidine, piperazine, wherein the free imine Function is substituted with R ¹³ , and morpholine, wherein one or more N atoms may be replaced by identical or different radicals R ¹⁴ , and / or wherein the specified heterocyclic groups having 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, via two common adjacent C and / or N atoms to form a fused bicyclic ring system, or via three or more C and / or N atoms to form a bridged ring system takes place; and the radicals R ¹³ , R ¹⁴ and the group Cy are as defined in claim 1. Alkyne compounds according to one or more of the preceding claims, characterized in that X represents a methylene or ethylene bridge which is unsubstituted or selected from one or two identical or different C _1-3 -alkyl substituents and / or a substituent C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl C _1-3 alkyl, wherein two alkyl substituents to form a 3- to 6-membered carbocyclic ring system may be connected to each other. Alkyne compounds according to one or more of the previous Claims, characterized in that Z is a single bond or ethylene and W means a single bond. Alkyne compounds according to one or more of the preceding claims, characterized in that the group Y is selected from the group of the sub-formulas

wherein in the sub-formulas Y1.1 and Y2.1 one or more carbon atoms may be independently substituted with R ²⁰ , and wherein R ^{20 is} as defined in claim 1. Alkyne compounds according to one or more of the preceding claims, characterized in that the group A is selected from the group of bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, the one or more times to one or more carbon atoms with identical or different radicals R ²⁰ , in the case of a phenyl ring may also be additionally substituted with nitro, and R ^{20 has} the meaning given in claim 1. Alkyne compounds according to one or more of the preceding claims, characterized in that the group B is selected from phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, and wherein the abovementioned cyclic groups are mono- or polysubstituted by one or more carbon atoms identical or different radicals R ²⁰ , in the case of a phenyl group may also be additionally substituted with nitro, and R ^{20 has} the meanings given in claim 1. Alkyne compounds according to one or more of the preceding claims, characterized in that

A means A selected from

and / or B is phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, preferably phenyl, where Y and A are unsubstituted or monosubstituted by R ²⁰ , and B is unsubstituted or monosubstituted, disubstituted or trisubstituted independently of one another by R ²⁰ is, in the case of a phenyl ring may additionally be additionally substituted with nitro, and wherein R ^{20 has} the meaning given in claim 1. Alkyne compounds according to one or more of the preceding claims, characterized in that R ^{20 is} F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, amino, acetyl, methoxy , Difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy, where multiple occurring substituents R ^{20 may have the} same or different meanings. Physiologically acceptable salts of the alkyne compounds according to one or more of claims 1 to 10. Composition containing at least one alkyne compound according to one or more of claims 1 to 10 and / or a salt according to claim 11 next to optionally one or more physiologically acceptable Excipients. Medicament containing at least one alkyne compound according to one or more of claims 1 to 10 and / or a Salt according to claim 11 next to optionally one or more inert carriers and / or diluents. Use of at least one alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for influencing the eating behavior of a mammal. Use of at least one alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for reduction of body weight and / or for preventing an increase in body weight of a mammal. Use of at least one alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for the preparation a drug with MCH receptor antagonistic activity. Use of at least one alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for the preparation of a Medicament, which is used for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or MCH are in a different causal relationship, is suitable. Use of at least one alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for the preparation a drug which is used for prophylaxis and / or treatment of metabolic disorders and / or eating disorders, especially obesity, bulimia, bulimia nervosa, cachexia, Anorexia, anorexia nervosa and hyperphagia, is appropriate. Use of at least one alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for the preparation a drug which is used for prophylaxis and / or treatment obesity-related 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 alkyne compound according to one or more of the claims 1 to 10 and / or a salt according to claim 11 for the preparation a drug which is used for prophylaxis and / or treatment of hyperlipidemia, Cellulite, 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. Use of at least one alkyne compound according to one or more of claims 1 to 10 and / or a salt according to claim 11 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, enuresis, is appropriate. Process for the preparation of a composition or a drug according to one or more of the claims 12, 13 and 16 to 21, characterized in that non-chemical Make at least one alkyne compound according to one or more of claims 1 to 10 and / or a salt according to claim 11 in one or more inert carriers and / or diluents is incorporated. Medicaments containing a first active ingredient, from the alkyne compounds according to one or more of claims 1 to 10 and / or the salts according to claim 11 selected is as well a second active ingredient selected from the group consisting 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 drugs for the treatment of depression, besides possibly one or more inert carriers and / or diluents. Process for the preparation of alkyne compounds of the formula A.5 R 1 R 2 NXYC≡CWAB (A.5) where in the formulas A.1, A.2, A.3, A.4 and A.5 R ¹ , R ² , X, Y, W, A and B have one of the meanings given in claims 1 to 10, in which a halogen compound of the formula A.1 HO-XY-Hal (A.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula A.2 HC≡CWAB (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent, and the resulting compound of formula A.3 HO-XYC≡CWAB (A.3) is reacted with methanesulfonyl chloride (MsCl) to methanesulfonate derivative A.4, MsO-XYC≡CWAB (A.4) which is further reacted with an amine of the formula H-NR ¹ R ² to the final product A.5. Process for the preparation of alkyne compounds of formula B.5 R 1 R 2 NXYZC≡CAB (B.5) where in the formulas B.1, B.2, B.3, B.4 and B.5 R ¹ , R ² , X, Y, Z, A and B have one of the meanings indicated in claims 1 to 10, in which a halogen compound of the formula B.1 Hal-AB (B.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula B.2 HO-XYZC≡CH (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a ge suitable solvent is reacted, and the resulting compound of formula B.3 HO-XYZC≡CAB (B.3) with methanesulfonyl chloride (MsCl) is converted to the methanesulfonate derivative B.4, MsO-XYZC≡CAB (B.4) which is further reacted with an amine of formula H-NR ¹ R ² to give the final product B.5. Process for the preparation of alkyne compounds of the formula C.3 R 1 R 2 NXYC≡CWAB (C.3) where in the formulas C.1, C.2 and C.3 R ¹ , R ² , X, Y, W, A and B have one of the meanings given in claims 1 to 10, in which a halogen compound of the formula C. 1 R 1 R 2 NXY-Hal (C.1) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula C.2 HC≡CWAB (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent to the final product C.3 is further reacted. Process for the preparation of alkyne compounds of the formula D.3 R 1 R 2 NXYZC≡CAB (D.3) where in the formulas D.1, D.2 and D.3 R ¹ , R ² , X, Y, Z, A and B have one of the meanings given in claims 1 to 10, in which a halogen compound of formula D. 2 Hal-AB (D.2) wherein Hal is chlorine, bromine or iodine, preferably bromine or iodine, with an alkyne compound of the formula D.1 R 1 R 2 NXYZC≡CH (D.1) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent to the final product D.3 is reacted.