DE102004017935A1 - New alkyne compounds having MCH antagonist activity and medicaments containing these compounds - Google Patents

Abstract

The present invention relates to alkyne compounds of general formula I, DOLLAR F1 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 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 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 not only in the regulation of the energy balance but also of affectivity is involved.

Literature:

• 1. Qu, D., et al., A role for melanin-concentrating hormones 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., al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci US A, 2002. 99 (5): p. 3240-5.
• 6. Takekawa, S., et al., T-226296: a novel, orally active and selective melaninconcentrating hormone receptor antagonist. EUR J Pharmacol, 2002. 438 (3): p. 129-35.

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

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

In the not yet disclosed international application PCT / EP0311887, which describes alkyne compounds as MCH antagonists, the following substances are mentioned, inter alia:
(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -methyl-prop-2-ynyl-amine,
(2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl-prop-2-ynyl-amine,
{4- [6- (4-chloro-phenyl) -quinoline-2-ylethynyl] -benzyl} -methyl- (tetrahydro-pyran-4-yl) -amine,
Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl-amine,
Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amine,
Allyl (2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl-amine.

Object of the invention

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.

Also It is 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 according to the invention to provide. 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 C_3-6-Alkenyl, C_3-6-Alkinyl, (Hydroxy-C_3-7-cycloalkyl)-C_1-3-alkyl, Oxa-C_4-7-cycloalkyl, Dihydroxy-C_3-7-alkyl,
wobei die angegenben Gruppen ein- oder mehrfach substituiert sein können mit Substituenten, die unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Halogen, Hydroxy, Cyano, C_1-4-Alkyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl, C_1-4-Alkoxy-C_1-4-Alkyl, C_1-4-Alkoxy, C_1-4-Alkenyl, C_1-4-Alkinyl, Amino, C_1-4-Alkyl-amino und Di-(C_1-4-Alkyl)-amino, wobei die Alkyl, Alkoxy, Cylcoalkyl-Gruppen einen oder mehrere gleiche oder verschiedene Substituenten ausgewählt aus Halogen und Hydroxy aufweisen können; und
R² weist unabhängig von R¹ eine der zuvor für R¹ angegebenen Bedeutungen auf oder R² besitzt eine Bedeutung aus der Gruppe bestehend aus H, C_1-8-Alkyl, C_3-7-Cycloalkyl oder ein gegebenenfalls mit gleichen oder verschiedenen Resten R²⁰ ein- oder mehrfach und/oder mit Nitro einfach substituierter 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-, -Soder -NR¹³- ersetzt sein kann, oder
die Reste R¹, R² bilden zusammen mit dem N-Atom, an das diese gebunden sind, eine heterocyclische Gruppe, die ausgewählt ist aus den Bedeutungen
– Dihydroxy-cyclo-C_4-7-alkylen-imino,
– (Hydroxy-C_1-4-alkyl)-hydroxy-cyclo-C_3-7-alkylen-imino,
– (Hydroxy-C_1-3-alkyl)-cyclo-C_3-7-alkylen-imino, wobei in der letzten Bedeutung die C_1-3-alkyl-Gruppe durch eine oder mehrere gleiche oder verschiedene C_1-3-Alkyl-Gruppen substituiert ist, die miteinander unter Ausbildung einer C_3-7-Cyloalkyl-Gruppe verbunden sein können;
wobei die genannten heterocyclischen Gruppen ein- oder mehrfach substituiert sein können mit Substituenten, die unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Halogen, Hydroxy, Cyano, C_1-4-Alkyl, C_3-7-Cycloalkyl, C_3-7-Cycloalkyl-C_1-3-alkyl, C_1-4-Alkoxy-C_1-4-Alkyl, C_1-4-Alkoxy, C_1-4-Alkenyl, C_1-4-Alkinyl, Amino, C_1-4-Alkyl-amino und Di-(C_1-4-Alkyl)-amino, wobei Alkyl, Alkoxy, Cyccoalkyl-Gruppen einen oder mehrere gleiche oder verschiedene Substituenten ausgewählt aus Halogen und Hydroxy aufweisen können;
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-, -C≡C-, -CH₂-O-, -CH₂-S- oder -CH₂-NR⁴- 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, A unabhängig voneinander ausgewählt sind aus der Gruppe der bivalenten cyclischen Gruppen Phenyl, Pyridinyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, Naphthyl, Tetrahydronaphthyl, Indolyl, Dihydroindolyl, Chinolinyl, Dihydrochinolinyl, Tetrahydrochinolinyl, Isochinolinyl, Dihydroisochinolinyl, Tetrahydro-isochinolinyl, Benzimidazolyl-, Benzoxazolyl, Chromanyl, Chromen-4-onyl, 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 Y, A angegebenen Bedeutungen oder
C_1-6-Alkyl, C1-6-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,
R⁴ H, C_1-4-Alkyl, C_3-7-Cycloalkyl oder C_3-7-Cycloalkyl-C_1-3-alkyl,
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-, R¹⁰-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 ein- oder mehrfach substituiert sein können;
R¹³ eine der für R¹⁷ angegebenen Bedeutungen,
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)-C₂_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-C₂_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-Alkyl-amino-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-Alkylcarbonyl, C_1-4-Alkoxy-carbonyl, C_1-4-Alkylsulfonyl, Aminosulfonyl, C_1-4-Alkylaminosulfonyl, Di-C_1-4-alkylaminosulfonyl oder Cyclo-C_3-6-alkylen-imino-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-alkyl-amino-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, R⁴, R¹⁰, R13 und R¹⁵ 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-Aalkylamino-, 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 N-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:
(2-{4-[5-(4-Chlor-phenyl)-pyridin-2-ylethinyl)-2-methyl-phenoxy}-ethyl)-methyl-prop-2-inyl-amin,
(2-{5-[5-(4-Chlor-phenyl)-pyridin-2-ylethinyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-prop-2-inyl-amin,
{4-[6-(4-Chlor-phenyl)-chinolin-2-ylethinyl]-benzyl}-methyl-(tetrahydro-pyran-4-yl)-amin,
Allyl-(2-{4-[5-(4-chlor-phenyl)-pyridin-2-ylethinyl]-phenoxy}-ethyl)-cyclopropylmethyl-amin,
Allyl-(2-{4-[5-(4-chlor-phenyl)-pyridin-2-ylethinyl]-2-methyl-phenoxy}-ethyl)-cyclopropylmethyl-amin,
Allyl-(2-{5-[5-(4-chlor-phenyl)-pyridin-2-ylethinyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amin.A first subject of the present invention are alkyne compounds of general formula I.

in the
R ^{1 is} C _3-6 alkenyl, C _3-6 alkynyl, (hydroxyC _3-7 cycloalkyl) C _1-3 alkyl, oxaC _4-7 cycloalkyl, dihydroxyC _3-7 - alkyl,
wherein the angegenben groups may be mono- or polysubstituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkenyl, C _1-4 alkynyl, amino, C _1-4 Alkyl-amino and di- (C _1-4 -alkyl) -amino, wherein the alkyl, alkoxy, cycloalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy; and
R ² has, independently of R ^1, one of the meanings given above for R ¹ or R ² has one meaning from the group consisting of H, C _1-8 -alkyl, C _3-7 -cycloalkyl or an optionally with identical or different radicals R ²⁰ mono- or polysubstituted and / or nitro-substituted phenyl or pyridinyl, wherein the alkyl or cycloalkyl group may be mono- or polysubstituted by 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 may be replaced by -O-, -Soder -NR ¹³ -, or
the radicals R ¹ , R ² together with the N-atom to which they are attached form a heterocyclic group which is selected from the meanings
- dihydroxy-cyclo-C _4-7 -alkylene-imino,
(HydroxyC _1-4 alkyl) hydroxycycloC _3-7 alkylene imino,
- (hydroxy-C _1-3 -alkyl) -cyclo-C _3-7 -alkylene-imino, wherein in the last meaning the C _1-3 alkyl group by one or more identical or different C _1-3 alkyl Substituted groups which may be linked together to form a C _3-7 -cycloalkyl group;
wherein said heterocyclic groups may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 - CycloalkylC _1-3 alkyl, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkenyl, C _1-4 alkynyl, amino, C _1-4 -Alkyl-amino and di- (C _1-4 -alkyl) -amino, wherein alkyl, alkoxy, cycoalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy;
X is a C _1-4 -alkylene bridge, wherein in the meaning C _2-4 -alkylene one or two C-atoms simply with R ¹⁰ substitui 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 can not be replaced by -CH = CH-, - C≡C-, -CH ₂ -O-, -CH ₂ -S- or -CH ₂ -NR ⁴ - is replaced,
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 carbon atoms may be independently substituted with one or two identical or different C _1-3 alkyl radicals, wherein two alkyl radicals may be linked together to form a carbocyclic ring, and
Y, A are independently 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 , Chromanyl, chromen-4-onyl, thienyl, furanyl, benzothienyl or benzofuranyl, where the cyclic groups mentioned one or more times to one or more carbon atoms having the same or different radicals R ²⁰ , in the case of a phenyl ring also additionally simply with nitro , and / or one or more NH groups may be substituted by R ²¹ ,
B is one of 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, alkenyl C _3-7 cycloalkyl C _1-3 or C _3-7 cycloalkyl C _1-3 alkynyl group wherein one or more C-atoms independently of one another may be monosubstituted or polysubstituted with halogen and / or monosubstituted or polysubstituted by hydroxy or cyano and / or cyclic groups, or may be substituted several times 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 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 ^{4 is} H, C _1-4 -alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3 -alkyl,
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 ¹⁰ -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, hydroxy-C _1-3 alkyl may be mono- or polysubstituted;
R ^{13 is} one of the meanings given for R ¹⁷ ,
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 -alkyl-amino-C _{2- 6} -alkyl, ω-di- (C _1-4 -al kyl) -amino-C _2-6 -alkyl, ω-cyclo-C _3-6 -alkyleneimino-C _2-6 -alkyl, phenyl, phenyl-C _1-3 -alkyl, C _1-4 -alkylcarbonyl, 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 _1-4 -alkyl) -aminocarbonyl, cyclo-C _3-6 -alkyl-amino-carbonyl, cyclo-C _3-6 -alkylenimino-carbonyl, phenylaminocarbonyl, cyclo-C _3-6 -alkyleneimino-C _2-4 -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 alkylcarbonylamino, cycloC _3-6 alkyleneimino, phenylC _1-3 alkylamino, N- (C _1-4 alkyl) phenylC _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 aforementioned groups and radicals, in particular in W, X, Z, R ⁴ , R ¹⁰ , R 13 and R ¹⁵ 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 one another additionally additionally with Cl or Br and / or in each case one or more phenyl rings independently of one another additionally one, two or three substituents selected from the group F, Cl, Br, I, 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, aminoC _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl and di- (C _1-3 -alkyl) -amino-C _1-3 alkyl and / or may be substituted by nitro, and
the H atom of an existing carboxy group or an N atom bound to an N atom can each be replaced by a residue which can be split off in vivo,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts,
wherein the following compounds are not included according to the invention:
(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl) -2-methyl-phenoxy} -ethyl) -methyl-prop-2-ynyl-amine,
(2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl-prop-2-ynyl-amine,
{4- [6- (4-chloro-phenyl) -quinoline-2-ylethynyl] -benzyl} -methyl- (tetrahydro-pyran-4-yl) -amine,
Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl-amine,
Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amine,
Allyl (2- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl-amine.

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 disease, in particular Atherosclerosis and hypertension, arthritis and gonitis is.

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 , X, Y, 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 NC≡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.

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 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 ge suitable solvent to the final product C.3 is further implemented.

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 stated otherwise, the occurring groups, radicals and substituents, in particular A, B, W, X, Y, Z, Cy, R ¹ , R ² , R ⁴ , R ¹⁰ , R ¹¹ , R ¹³ and R ¹⁵ to R have ²² , 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.

According to a first embodiment, the radical R ^{1 is} selected from the group of the meanings C _3-6 -alkenyl, C _3-6 -alkynyl, (hydroxy-C _3-7 -cycloalkyl) C _1-3 -alkyl, oxa-C _5-7 -cycloalkyl, dihydroxy-C _3-7- alkyl, wherein the angegenben groups may be mono- or polysubstituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 Alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkenyl , C _1-4 alkynyl, amino, C _1-4 alkylamino and di (C _1-4 alkyl) amino, wherein alkyl, alkoxy, cycloalkyl groups present in said substituents independently of one another identical or different substituents selected from halogen, in particular fluorine or chlorine, and may have hydroxy.

According to this embodiment, preferred meanings of the radical R ¹ are C _3-5 -alk-2-enyl, C _3-5 -alk-2-ynyl, (1-hydroxy-C _3-6 -cycloalkyl) C _1-3 Alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, dihydroxy-C _3-5 alkyl, wherein the angegenben groups may be mono- or polysubstituted as previously indicated.

According to this first embodiment, preferred substituents are independently fluorine, chlorine, bromine, hydroxy, cyano, CF ₃ , C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkoxy, amino, C _1-4 alkylamino and di (C _1-4 alkyl) amino wherein the alkyl, cycloalkyl Groups may have one or more identical or different substituents selected from fluorine and hydroxy.

Particularly preferred substituents independently of one another are fluorine, chlorine, hydroxyl, cyano, CF ₃ , hydroxymethyl, hydroxyethyl, C _1-3 -alkyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-methyl, C _1-3 -alkoxy C _1-3 alkyl, C _1-3 alkoxy, amino, C _1-3 alkylamino and di (C _1-3 alkyl) amino.

Particularly preferred meanings of the radical R ¹ according to this embodiment are prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, (1-hydroxy-C _3-6 -cycloalkyl) -methyl, Tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2,3-dihydroxy-C _3-5 -alkyl. Very particularly preferred meanings here are prop-2-enyl, prop-2-ynyl, (1-hydroxycyclopropyl) methyl, tetrahydropyran-4-yl, 2,3-dihydroxypropyl, 2-hydroxy-1- (hydroxymethyl) -ethyl, 1 , 1-di (hydroxymethyl) ethyl.

According to this first embodiment, R ² independently of R ^{1 has} one of the meanings given above for R ¹ or R ² has one meaning from the group consisting of H, C _1-8 alkyl, C _3-7 cyclo alkyl or optionally monosubstituted with the group R ²⁰ or more times and / or by nitro substituted phenyl or pyridinyl group, wherein the alkyl or cycloalkyl group substituted independently of one another by identical or different radicals R ^11, or may be multiply substituted, and 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 -.

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 hydroxy-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 radical R ^{2 is} preferably 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 alkylamino C _2-4 alkyl, di (C _1-4 alkyl) amino C _2-4 alkyl, cycloC _3-6 alkyleneiminoC _2-4 alkyl, pyrrolidin-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, piperidin-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, phenyl-C _1-3 alkyl, pyridyl or pyridyl-C _1-3 -alkyl-, wherein in the groups and radicals indicated above, one or multiple C atoms independent of one or more times with F, C _1-3 alkyl or hydroxy-C _1-3 alkyl, and / or one or two C atoms may be independently substituted with Cl, Br, OH, CF ₃ or CN independently , and wherein the phenyl or pyridyl radical may be mono- or polysubstituted by identical or different radicals R ²⁰ and / or simply by nitro. 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 radical R ² are selected from the group consisting of H, C _1-4 -alkyl, C _3-5 -alkenyl, C _3-5 -alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl C _1-3 alkyl, ω- (C _1-4 alkoxy) C _2-3 alkyl, pyridyl and benzyl, wherein in said radicals (with the exception of H) one or more C atoms independently of one another mono- or polysubstituted with F, C _1-3 -alkyl or hydroxy-C _1-3 -alkyl, and / or one or two C-atoms independently of one another can be substituted by Cl, Br, OH, CF ₃ or CN.

Very particularly preferred radicals R ² are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl , (1-hydroxycyclopropyl) -methyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl.

According to a second embodiment, the radicals R ¹ , R ² together with the N-atom to which they are attached form a heterocyclic group which is selected from the meanings
Dihydroxy- (cyclo-C _4-7 -alkylene-imino),
(HydroxyC _1-4 alkyl) hydroxycycloC _3-7 alkylene imino,
(Hydroxy-C _1-3 -alkyl) -cyclo-C _3-7 -alkylene-imino, where in the last meaning
the C _1-3 alkyl group may be substituted by one or more identical or different C _1-3 alkyl groups, of which 2 alkyl groups may be linked to form a C _3-7 cycloalkyl group;
wherein said heterocyclic groups may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 - CycloalkylC _1-4 alkyl, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, amino, C _1-4 -Alkyl-amino and di- (C _1-4 -alkyl) -amino, wherein occurring in said Substituenten alkyl, alkoxy or cycloalkyl groups one or more carbon atoms may be mono- or polysubstituted by fluorine, and wherein in the substituents occurring alkyl, alkoxy or cycloalkyl groups one or more carbon atoms can be easily substituted with chlorine, bromine or hydroxy.

According to this second embodiment, preferred heterocyclic groups are 3,4-dihydroxypyr rolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxyC _1-3 alkyl) hydroxypyrrolidinyl, (hydroxyC _1-3 alkyl) hydroxy piperidinyl, (hydroxyC _3-6 - cycloalkyl) -hydroxypyrrolidinyl, (hydroxyC _3-6 -cycloalkyl) -hydroxy-piperidinyl, (C _1-3 -alkylhydroxy-methyl) -pyrrolidinyl, (C _1-3 -alkyl-hydroxy-methyl) -piperidinyl, (Di-C _1-3 -alkyl-hydroxy-methyl) -pyrrolidinyl, (di-C _1-3 -alkyl-hydroxy-methyl) -piperidinyl, (1-hydroxy-C _3-6 -cycloalkyl) -pyrrolidinyl, ( 1-hydroxy-C _3-6 -cycloalkyl) -piperidinyl, wherein said groups may be substituted as indicated above.

In The indicated heterocyclic groups may also be in one or two Hydroxy groups the N atom be replaced by a methyl group.

Preferred substituents of the said heterocyclic groups are fluorine, chlorine, hydroxy, CF ₃ , C _1-3 -alkyl and hydroxy-C _1-3 -alkyl, in particular methyl, ethyl and CF ₃ .

Particularly preferred heterocyclic groups according to this second embodiment are 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxy-piperidinyl, (1-hydroxyethyl) -hydroxy -pyrrolidinyl, (1-hydroxyethyl) -hydroxy-piperidinyl, (1-hydroxy-1-methylethyl) -hydroxy-pyrrolidinyl, (1-hydroxy-1-methylethyl) -hydroxy-piperidinyl, (1-hydroxycyclopropyl) -hydroxy-pyrrolidinyl , (1-Hydroxycyclopropyl) -hydroxy-piperidinyl, (1-hydroxy-cyclopropyl) -pyrrolidinyl, (1-hydroxy-cyclopropyl) -piperidinyl, (1-hydroxyethyl) -pyrrolidinyl, (1-hydroxyethyl) -piperidinyl, (1 Hydroxy-1-methylethyl) pyrrolidinyl, (1-hydroxy-1-methylethyl) piperidinyl, where 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 .

worin X wie zuvor und insbesondere nachfolgend definiert ist, und
worin die angegebenen heterocyclischen Gruppen R¹R²N- 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 sind.Very particularly preferred meanings of the heterocyclic groups

wherein X is as defined previously and in particular below, and
wherein the specified heterocyclic groups R ¹ R ² N- are not further substituted, or
wherein methyl or ethyl groups may be substituted by fluorine mono-, di- or trisubstituted, and wherein one or more carbon-bonded H atoms of the heterocycle formed by the group R ¹ R2N- 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 .

According to a first embodiment, the group X is preferably a C _2-4 -alkylene bridge, particularly preferably ethylene or propylene, where one or two C atoms are monosubstituted by hydroxy, hydroxyC _1-3 -alkyl or C _1-3 . Alkoxy, in particular hydroxy, may be substituted, and wherein the alkylene bridge with C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl C _1-3 Alkyl may be mono-, di- or tri-substituted with the same or different C _1-3 alkyl groups, and wherein two alkyl groups to form a 3- to 7-membered cycloalkyl group or a Alkyl group and an alkenyl group to form a 5 to 7-membered cycloalkenyl group may be joined together. In group X, one or more C atoms may be monosubstituted or polysubstituted by F and / or Cl, preferably F.

According to a second embodiment, the group X is preferably 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 by -CH = CH-, -CC-, -CH ₂ -O-, -CH ₂ -S- or -CH ₂ -NR ⁴ - is replaced, particularly preferably a -CH ₂ -CH = CH-, -CH ₂ -C≡C , -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -S- or -CH ₂ -CH ₂ -NR ⁴ -bridge, 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 al kyl and / or one, 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 7-membered cyclic 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.

Particularly preferred meanings of X are therefore ethylene, propylene, -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -S- or - CH ₂ -CH ₂ -NR ⁴ -.

A particularly preferred meaning of X is unsubstituted propylene or C _1-4 alkylene, in particular propylene, which has one or two identical or different substituents independently of one another selected from fluorine, chlorine, hydroxy and C _1-3 -alkyl and / or a C _{2 -6-} alkenyl or cyclopropyl substituents, wherein two alkyl substituents to form a C _3-6 cycloalkyl group or an alkyl and an alkenyl group to form a C _5-6 cycloalkenyl group together can. Particularly preferably, the alkylene bridge is monosubstituted or disubstituted by identical or different radicals selected from methyl, ethyl and i-propyl, it being possible for two alkyl groups to be linked together as indicated to form a cyclic group.

In the meaning substituted propylene particularly preferred meanings are selected from the group consisting of

In addition, particularly preferred meanings of X are -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -S- or -CH ₂ - CH ₂ -NR ⁴ -, in particular -CH ₂ -CH = CH-, -CH ₂ -CH ₂ -O- or -CH ₂ -CH ₂ -NR ⁴ -, wherein R ^{4 is} H or C _1-4 alkyl wherein the meanings given for X are unsubstituted or have one or two identical or different substituents independently of one another selected from fluorine and C _1-3 -alkyl and / or a cyclopropyl substituent, where two alkyl groups to form a C _3-6 -Cycloalkyl group or if an alkyl group is the radical R ⁴ , may be connected together to form a pyrrolidine or piperidine 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.

A particularly preferred meaning of X is unsubstituted -CH ₂ -CH ₂ -O- or substituted -CH ₂ -CH ₂ -O- selected from the group consisting of

Also, a particularly preferred meaning of X is -CH ₂ -CH ₂ -NH- or -CH ₂ -CH ₂ -NCH ₃ - or substituted -CH ₂ -CH ₂ -NCH ₃ - selected from the group consisting of

Furthermore, a particularly preferred meaning of X is -CH ₂ -CH = CH- or 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.

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

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

In a third embodiment, the group X is a -CH ₂ -bridge which is unsubstituted or substituted by 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, wherein two alkyl substituents may be linked together to form a 3- to 6-membered carbocyclic ring system , According to this embodiment, X in the meaning -CH ₂ - is preferably unsubstituted or monosubstituted or disubstituted by methyl, where two methyl substituents may be bonded together to form a cyclopropyl group. This third embodiment with respect to X is particularly preferred when Y is a bicyclic group, wherein the first ring of the bicyclic group is connected to X and the second ring is connected to Z.

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.

The group Y preferably has a meaning 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, chromanyl, chromen-4-onyl, benzothienyl, or benzofuranyl, more preferably phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein the aforementioned cyclic groups one or more times to one or more carbon atoms with the same or various radicals R ²⁰ , in the case of a phenyl ring may also be additionally substituted with nitro, and / or to one or more N atoms with R ²¹ .

If the group Y is a 6-membered cyclic or heterocyclic group is, are the bridges X and Z are preferably connected in para-position to the group Y.

insbesondere weist Y eine der folgenden Bedeutungen auf

ganz besonders bevorzugt weist Y eine der folgenden Bedeutungen auf

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

In particular, Y has one of the following meanings

most preferably Y has one of the following meanings

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

insbesondere falls Y eine der folgenden Bedeutungen aufweist

wobei die vorstehend aufgeführten bicyclischen Gruppen ein- oder mehrfach an ein oder mehreren C-Atomen mit gleichen oder verschiedenen Resten R²⁰ substituiert sein können, im Falle eines Phenylrings auch zusätzlich einfach mit Nitro, und/oder eine oder mehrere NH-Gruppen mit R²¹ substituiert sein können, bedeutet die Brücke X vorzugsweise eine -CH₂-Gruppe, die gemäß der zuvor beschriebenen dritten Ausführungsform bezüglich X substituiert sein kann.If the group Y is selected from the group of bivalent bicyclic groups

in particular if Y has one of the following meanings

where the abovementioned bicyclic groups may be monosubstituted or polysubstituted by one or more C atoms having the same or different radicals R ²⁰ , in the case of a phenyl ring additionally also simply with nitro, and / or one or more NH groups having R ²¹ Preferably, the bridge X is a -CH ₂ group which may be substituted for X according to the third embodiment described above.

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

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

Very particularly preferred substituents R ^{20 of} the group Y are selected from among fluorine, chlorine, bromine, cyano, C _1-3 -alkyl, C _1-3 -alkoxy, C _1-4 -alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, im Case of a phenyl ring also nitro.

Most notably Preferably, the group Y represents substituted phenylene

worin L¹ eine der zuvor für R²⁰ angegebenen Bedeutungen, vorzugsweise F, Cl, Br, I, Methyl, Ethyl, Ethenyl, Ethinyl, CF₃, OCH₃, OCF₃, -CO-CH₃, -COOCH₃, CN oder NO₂, besitzt oder H bedeutet. Ganz besonders bevorzugte Bedeutungen des Substituenten L¹ sind H, F, Cl, Br, Methyl, Ethyl, Ethenyl, Acetyl oder Methoxy.partial formula

wherein L ^{1 is} one of the meanings given above for R ²⁰ , preferably F, Cl, Br, I, methyl, ethyl, ethenyl, ethynyl, CF ₃ , OCH ₃ , OCF ₃ , -CO-CH ₃ , -COOCH ₃ , CN or NO ₂ , or H means. Very particularly preferred meanings of the substituent L ¹ are H, F, Cl, Br, methyl, ethyl, ethenyl, 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.

ganz besonders bevorzugt

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

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, CF ₃ , amino, 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, aminoC _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 of 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, bromine 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 the same or different 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-, 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 C atoms can additionally be substituted, independently of one another, additionally 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 _3-7 -cycloalkyl, C _1-3 -alkylcarbonyl 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. Very particularly preferably, R ^{20 is} F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, acetyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or isobutyl. 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 _1-3 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 _1-4 -alkylsulphonyl, -SO ₂ -NH ₂ , -SO ₂ -NH-C _1-3 -alkyl, SO ₂ -N (C _1-3 -alkyl) ₂ and cyclo-C _3-6 -alkyleneimino-sulfonyl-, where, as defined above, in each case one or more C atoms additionally one or more times with F and / or in each case one or two carbon atoms can additionally be substituted, independently of one another, additionally simply with Cl or Br. 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
R¹, R², X und Z eine der zuvor genannten bevorzugten Bedeutungen besitzen und
L¹, L², L³, unabhängig voneinander eine der für R²⁰ angegebenen Bedeutungen besitzen, und
m, n, p unabhängig voneinander die Werte 0, 1 oder 2, p auch den Wert 3, bedeuten.Particularly preferred compounds according to the invention can have a general formula IIa, IIb, IIc, IId, in particular IIa and IIb,

be described in the
R ¹ , R ² , X and Z have one of the aforementioned preferred meanings and
L ¹ , L ² , L ³ , independently of one another have one of the meanings given for R ²⁰ , and
m, n, p independently of one another denote the values 0, 1 or 2, p also the value 3.

In particular, in the formulas IIa, IIb, IIc, IId
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,
m is 0 or 1,
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 ₁₄ Alkylamino, di (C _1-4 alkyl) amino, cycloC _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 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 is} prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, (1-hydroxy-C _3-6 -cycloalkyl) -methyl, tetrahydropyran-3-yl, tetrahydropyran-4 -yl, 2,3-dihydroxy-C _3-5 -alkyl, and
R ^{2 is} H, C _1-4 -alkyl, C _3-5 -alkenyl, C _3-5 -alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, ω- ( C _1-4 -alkoxy) C _2-3 -alkyl, pyridyl and benzyl, where in the radicals mentioned (with the exception of H) one or more 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 may be independently substituted with Cl, Br, OH, CF ₃ or CN independently, 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 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, ( Hydroxymethyl) -hydroxy-pyrrolidinyl, (hydroxymethyl) -hydroxypiperidinyl, (1-hydroxyethyl) -hydroxy-pyrrolidinyl, (1-hydroxyethyl) -hydroxy-piperidinyl, (1-hydroxy-1-methylethyl) -hydroxy-pyrrolidinyl, (1- Hydroxy-1-methylethyl) -hydroxy-piperidinyl, (1-hydroxycyclopropyl) -hydroxy-pyrrolidinyl, (1-hydroxy cyclopropyl) -hydroxy-piperidinyl, (1-hydroxy-cyclopropyl) -pyrrolidinyl, (1-hydroxycyclopropyl) -piperidinyl, (1-hydroxyethyl) -pyrrolidinyl, (1-hydroxyethyl) -piperidinyl, (1-hydroxy-1-) methylethyl) -pyrrolidinyl, (1-hydroxy-1-methylethyl) -piperidinyl, where the groups indicated have no further substituents or one or two substituents independently selected from fluorine, hydroxyl, C _1-3 -alkyl, hydroxy-C _{1- 3} -alkyl, CF ₃ ,
X is propylene which is unsubstituted or has one or two identical or different substituents independently selected from fluorine, chlorine, hydroxy and C _1-3 -alkyl and / or a C _2-6 alkenyl or cyclopropyl substituent, where two alkyl Substituents to form a C _3-6 cycloalkyl group or an alkyl and an alkenyl group to form a C _5-6 cycloalkenyl group may be joined together, or
-CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -O- or -CH ₂ -CH ₂ -NR ⁴ -, which 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 to form a C _3-6 cycloalkyl group or if an alkyl group is the radical R ⁴ , under Formation of a pyrrolidine or piperidine group may be linked together.

The compounds listed in the experimental section, including theirs Tautomers, their diastereomers, their enantiomers, their mixtures 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-pen tylcarbonyl, 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, cyclonomenyl, 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 representatives heterocyclic, aromatic ring systems, in particular those above listed Ring systems. Examples of such partially hydrogenated heterocycles are 2,3-dihydrobenzofuranyl, Pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc .. Heteroaryl particularly preferably represents a heteroaromatic mono- or bicyclic ring system.

Terms such as 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 -alkyl-amino, 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 above and below notation, in which a bond of a substituent to the center of this cyclic group is represented in a cyclic group, means, unless otherwise indicated, that this substituent is attached to any free position of the cyclic group carrying an H atom 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 N atom bound to an N atom (imino or amino group) may each be replaced by an in-vivo leaving group. A radical which can be split off from an N atom in vivo is understood as meaning, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C _1-16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert -butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, An undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenylC _1-6 alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C _1-3 -alkylsulfonyl-C _2-4 -alkoxycarbonyl, C _1-3 -alkoxy C _2-4 alkoxy-C _2-4 alkoxycarbonyl or R _e CO-O- (R _f CR _g ) -O-CO- group in which
R _{e is} a C _1-8 -alkyl, C _5-7 -cycloalkyl, phenyl or phenyl-C _1-3 -alkyl group,
R _{f is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{g is} a hydrogen atom, a C _1-3 alkyl or R _e CO-O- (R _f CR _g ) -O- group in which
R _e to R _{g are} as defined above, wherein 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 acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic Amines such as e.g. Diethylamine, triethylamine, triethanolamine, and the like. 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 used.

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 reacted in a suitable solvent. information to suitable 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:

A For this alternative synthesis is shown in Reaction Scheme D. Thereafter, the halogen compound D.2 with the alkyne compound D.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 reacted directly to the product D.3. Again, the information to suitable reaction conditions, including catalysts, bases and solvents, the Explanations to Reaction 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 be converted to the corresponding iodine compound. An advantageous here molar ratio the halogen compound to sodium iodide is 1: 1.8 to 1: 2.3. N, M-dimethyl-ethylenediamine advantageously in a molar ratio of 10 to 30 mol% based 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 a volume ratio of 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 aqueous methane, carefully neutralized and thereby 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 of the compound of the formula (I) with acidic hydrogen are preferably the alkali and alkaline earth hydroxides and hydrides into consideration, wherein the hydroxides and hydrides of the alkali metals, especially of sodium and potassium, sodium and potassium hydroxide particularly preferred are.

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 in another causal relationship with MCH are, in particular, metabolic disorders such as obesity and eating disorders such as bulimia including bulimia nervosa. The indication obesity includes above all exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central Adi Positas. Furthermore, cachexia, anorexia and hyperphagia are to be mentioned in this indication environment.

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 disease, in particular arteriosclerosis and hypertension, arthritis and gonitis suitable is.

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-1929.

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

biguanides include metformin, buformin, phenformin.

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

Agents for the treatment of obesity, preferably other than MCH antagonists, include Li pase 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 sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine, fenfluramine, or a 5-HT2C agonist such as BVT.933), a dopamine agonist (such as bromocriptine or pramipexole), a melanocyte stimulating hormone receptor agonist or mimetic, analogous to melanocyte-stimulating 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 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 expediently 1/5 of the commonly emp foaled 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 are suitable can, reduce hunger, curb appetite, control eating habits and / or to cause a feeling of satiety. The eating behavior is favorably influenced to the effect that the Food intake is reduced. Therefore, find the compounds of the invention advantageous application for reducing body weight. Another use according to the invention is preventing an increase in body weight, for example in people who took action before to reduce weight and then to are interested in maintaining the reduced body weight. According to this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic use may be a cosmetic application, for example, to change the external appearance, or an application to improve the general condition. The Compounds of the invention are preferably for mammals, especially people, non-therapeutically used, no diagnosed disorders eating habits, no diagnosed obesity, bulimia, diabetes and / or no diagnosed voiding disorders, especially urinary incontinence exhibit. Preferably, the compounds of the invention are for non-therapeutic use in humans suitable, their body weight index (BMI = body mass index), which is the body weight measured in kilograms divided by height (in meters) is defined in square, below the value 30, in particular below 25, lies.

The 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 stated, R _f values are determined using GCF Finished Tops Kieselgel 60 F ₂₅₄ (E. Merck, Darmstadt, Article No. 1.05714) with no chamber saturation. The R _f values determined under the name Alox are determined using TLC plates alumina 60 F ₂₅₄ (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation.

For chromatographic purifications, silica gel from Millipore (MATREX ^™ , 35-70 my) or Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 μm, article no: 1.01097.9050) is used. 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. Unless otherwise stated, the acid, base and salt solutions used in the workups of the reaction solutions are aqueous systems of the stated concentrations.

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

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

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

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 .: Molpeak (M + H) ⁺ : 238
Found: Molepeak (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 sulfite 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 means of 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 .: Molpeak (M + H) ⁺ : 276
Found: Molepeak (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: Molpeak (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 5.8 g (24.04 mmol) of 1-benzyl-4-trifluoromethyl-1,2,3,6-tetrahydropyridine 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 .: Molpeak (M + H) ⁺ : 276
Found: Molepeak (M + H) ⁺ : 276
HPLC-MS: 3.70 min (Method A)

A1b (3R, 4S) -4-trifluoromethyl-piperidine-3,4-diol

The product is obtained analogously to Ald starting from 1.09 g (3.96 mmol) of (3R, 4S) -1-benzyl-4-trifluoromethyl-piperidine-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: Molpeak (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 A1b 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 a nitrogen atmosphere, 14 g of AD mix alpha in 50 ml of water and 50 ml of tert-butanol are initially charged 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 sulfate 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 .: Molpeak (M + H) ⁺ : 222
Found: Molepeak (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: Molpeak (M + H) ⁺ : 132
HPLC-MS: 0.93 min (Method C)

Amin A4

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 .: Molpeak (M + H) ⁺ : 222
Found: Molepeak (M + H) ⁺ : 222
R _f value: 0.54 (silica gel, EtOAc / MeON / 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: Molpeak (M + H) ⁺ : 132
R _f value: 0.05 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

Amine A5

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

A5a 1-Benzyl-3-methylpyridinium chloride

The product is obtained analogously to Ala starting from 41.8 ml (430 mmol) of 3-methylpyridine.
Yield: 73.8 g (78% of theory)
C ₁₃ H ₁₄ N · Cl (M = 219,710)
calc .: Molpeak (M) ⁺ : 184
Found: Molpeak (M) ⁺ : 184

A5b 1-Benzyl-5-methyl-1,2,3,6-tetrahydro-pyridine

The product is obtained analogously to Alb starting from 40.0 g (182 mmol) of 1-benzyl-3-methylpyridinium chloride.
Yield: 14.9 g (44% of theory)
C ₁₃ H ₁₇ N (M = 187,281)
Calc .: Molpeak (M + H) ⁺ : 188
Found: Molepeak (M + H) ⁺ : 188
R _f value: 0.32 (silica gel, Cyc / EtOAc 4: 1)

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

The product is obtained analogously to A3b starting from 7.5 g (40.0 mmol) of 1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine and AD-Mix-Alpha.
Yield: 5.73 g (65% of theory)
C ₁₃ H ₁₉ NO ₂ (M = 221,296)
Calc .: Molpeak (M + H) ⁺ : 222
Found: Molepeak (M + H) ⁺ : 222
R _f value: 0.63 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A5d (3R, 4S) -3-methylpiperidine-3,4-diol

The product is obtained analogously to Ald starting from 5.73 g (25.9 mmol) of (3R, 4S) -1-benzyl-3-methylpiperidine-3,4-diol.
Yield: 3.4 g (quant.
C ₆ H ₁₃ NO ₂ (M = 131.173)
calc .: Molpeak (M + H) ⁺ : 132
Found: Molpeak (M + H) ⁺ : 132
R _f value: 0.05 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

Amine A6

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

A6a (3S, 4R) -1-Benzyl-3-methylpiperidine-3,4-diol

The product is obtained analogously to A3b starting from 7.5 g (40.0 mmol) of 1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine and AD-Mix-Beta.
Yield: 7.42 g (84% of theory)
C ₁₃ H ₁₉ NO ₂ (M = 221,296)
Calc .: Molpeak (M + H) ⁺ : 222
Found: Molepeak (M + H) ⁺ : 222
R _f value: 0.63 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A6b (3S, 4R) -3-methylpiperidine-3,4-diol

The product is obtained analogously to Ald starting from 8.86 g (40.0 mmol) of (3S, 4R) -1-benzyl-3-methylpiperidine-3,4-diol.
Yield: 5.03 g (96% of theory)
C ₆ H ₁₃ NO ₂ (M = 131.173)
calc .: Molpeak (M + H) ⁺ : 132
Found: Molpeak (M + H) ⁺ : 132
R _f value: 0.17 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A7

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

A7a 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 .: Molpeak (M + H) ⁺ : 198
Found: Molepeak (M + H) ⁺ : 198
R _f value: 0.12 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A1b 1-Benzyl-4-ethyl-1,2,3,6-tetrahydropyridine

The product is obtained analogously to A1b 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: Molpeak (M + H) ⁺ : 202
R _f value: 0.91 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A7c (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)

A7d (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 A8

cis-pyrrolidine-3,4-diol

A8a 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 with suction 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 .: Molpeak (M + H) ⁺ : 160
Found: Molepeak (M + H) ⁺ : 160
R _f value: 0.60 (silica gel, EtOAc / MeOH / NH ₃ 19: 1: 0.1)

A8b 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)

A8c 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 .: Molpeak (M + H) ⁺ : 104
Found: Molepeak (M + H) ⁺ : 104
R _f value: 0.05 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A9

A9a (3R, 4S) -1-Benzyl-piperidine-3,4-diol

The product is obtained analogously to A3b starting from 8.0 g (46.17 mmol) of 1-benzyl-1,2,3,6-tetrahydropyridine and AD-Mix-Alpha.
Yield: 6.40 g (67% of theory)
C ₁₂ H ₁₇ NO ₂ (M = 207,269)
Calc .: Molpeak (M + H) ⁺ : 208
Found: Molepeak (M + H) ⁺ : 208
R _f value: 0.24 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A9b (3R, 4S) -piperidine-3,4-diol

The product is obtained analogously to Ald starting from 6.4 g (30.86 mmol) of (3R, 4S) -1-benzylpiperidine-3,4-diol.
Yield: 3.83 g (quant.
C ₅ H ₁₁ NO ₂ (M = 117,146)
Calc .: Molpeak (M + H) ⁺ : 118
Found: Molepeak (M + H) ⁺ : 118
R _f value: 0.13 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A10

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

A10a (3S, 4R) -1-Benzyl-piperidine-3,4-diol

The product is obtained analogously to A3b starting from 8.0 g (46.17 mmol) of 1-benzyl-1,2,3,6-tetrahydropyridine and AD-Mix-Beta.
Yield: 6.13 g (64% of theory)
C ₁₂ H ₁₇ NO ₂ (M = 207,269)
Calc .: Molpeak (M + H) ⁺ : 208
Found: Molepeak (M + H) ⁺ : 208
R _f value: 0.35 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1)

A10b (3S, 4R) -piperidine-3,4-diol

The product is obtained analogously to Ald starting from 6.13 g (29.56 mmol) of (3S, 4R) -1-benzyl-piperidine-3,4-diol.
Yield: 3.75 g (quant.
C ₅ H ₁₁ NO ₂ (M = 117,146)
Calc .: Molpeak (M + H) ⁺ : 118
Found: Molepeak (M + H) ⁺ : 118
R _f value: 0.12 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A11

4-hydroxymethyl-piperidin-4-ol

A11a 1-Benzyl-4-hydroxymethyl-piperidin-4-ol

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

A11b 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: Molpeak (M + H) ⁺ : 132
R _f value: 0.06 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A12

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

A12a 1 - ((S) -1-Benzyl-pyrrolidin-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) of ethyl magnesium bromide are added dropwise 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 N ₁₉ NO (M = 217,307)
Calc .: Molpeak (M + H) ⁺ : 218
Found: Molepeak (M + H) ⁺ : 218
R _f value: 0.17 (silica gel, EtOAc)

A12b (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 .: Molpeak (M + H) ⁺ : 128
Found: Molepeak (M + H) ⁺ : 128
R _f value: 0.10 (silica gel, EtOAc / MeOH / NH ₃ 5: 5: 0.5)

Amine A13

(2S, 4R) -2-hydroxymethyl-pyrrolidin-4-ol

A13a (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a cooled to 0 ° C solution of 5.0 g (21.62 mmol) (2S, 4R) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 25 mL dry THF 54 mL (54.0 mmol) Borane THF complex was added dropwise, the reaction mixture stirred for a further 15 min at 0 ° C and then for 4 h at RT. It is combined with 60 ml of MeOH while cooling with ice, stirred for a further 62 h at RT and then concentrated i. vac. one. The residue obtained is purified by chromatography (silica gel, EtOAc / MeOH 19: 1).
Yield: 4.53 g (96% of theory)
C ₁₀ H ₁₉ NO ₄ (M = 217,262)
Calc .: Molpeak (M + H) ⁺ : 218
Found: Molepeak (M + H) ⁺ : 218
R _f value: 0.50 (silica gel, EtOAc / MeOH 19: 1)

A13b (2S, 4R) -2-hydroxymethylpyrrolidin-4-ol

To a cooled to 0 ° C solution of 4.53 g (20.85 mmol) (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 200 mL DCM are added 16.0 mL of TFA and the reaction mixture stirred overnight at RT. You narrow it down i. vac. and subjects the product to a freeze-drying. The product is obtained as trifluoroacetate salt.
Yield: 4.73 g (96% of theory)
C ₅ H ₁₁ NO ₂ .C ₂ HF ₃ O ₂ (M = 231.170)
Calc .: Molpeak (M + H) ⁺ : 118
Found: Molepeak (M + H) ⁺ : 118
R _f value: 0.68 (silica gel, EtOAc / MeOH 9: 1)

example 1

(3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -4-trifluoromethyl-piperidin-3, 4-diol

1a 2- (4-iodo-2-methyl-phenoxy) -ethanol

Under N ₂ atmosphere to a cooled to 0 ° C suspension of 0.48 g (11 mmol) of NaH in 50 mL of THF 2.34 g (10 mmol) of 4-iodo-2-methyl-phenol added in portions and another 30 min at this temperature stirred. Then 0.85 ml (12 mmol) of 2-bromoethanol dissolved in 5 ml of THF are added dropwise and the mixture is stirred at RT for 18 h. 5 ml of DMF are added and the reaction mixture is heated at 70 ° C. for 8 h. You narrow it down i. vac. , the residue is taken up in water, extracted exhaustively with EtOAc and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, Cyc / EtOAc 7: 3).
Yield: 0.39 g (14% of theory)
C ₉ H ₁₁ IO ₂ (M = 278,091)
Calc .: Molpeak (M + H) ⁺ : 279
Found: Molepeak (M + H) ⁺ : 279
R _f value: 0.28 (silica gel, Cyc / EtOAc 2: 1)

1b 2- (2-methyl-4-trimethylsilanylethynyl-phenoxy) -ethanol

To a degassed solution of 2.23 g (8.00 mmol) of 2- (4-iodo-2-methyl-phenoxy) -ethanol, 1.22 mL (8.80 mmol) of trimethylsilylacetylene, 185 mg (0.160 mmol) of tetrakis-triphenylphosphine-palladium and 2.38 mL ( 24.00 mmol) of piperidine in 50 ml of THF are added under argon 31 mg (0.160 mmol) of Cul and the mixture is stirred for 1 h at RT. The reaction mixture is diluted with water and the aqueous phase exhaustively extracted with EtOAc. The combined organic phases are washed with saturated NaCl solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, Cyc / EtOAc 2: 1).
Yield: 1.70 g (86% of theory)
C ₁₄ H ₂₀ O ₂ Si (M = 248,393)
Calc .: Molpeak (M + H) ⁺ : 249
Found: Molepeak (M + H) ⁺ : 249
R _f value: 0.24 (silica gel, Cyc / EtOAc 2: 1)

1c 2- (4-ethynyl-2-methyl-phenoxy) -ethanol

20.8 g (74.4 mmol) of TBAF are added at RT to a solution of 16.8 g (67.6 mmol) of 2- (2-methyl-4-trimethylsilanylethynyl-phenoxy) -ethanol in 500 ml of THF, and the mixture is stirred at RT for 3 h. The reaction mixture is i. vac. concentrated and the residue dissolved in EtOAc. The organic phase is washed with water and saturated NaCl solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is reacted further without purification.
Yield: 12.0 g (quant.
C ₁₁ H ₁₂ O ₂ (M = 176,212)
Calc .: Molpeak (M) ⁺ : 176 Found: Molpeak (M) ⁺ : 176
R _f value: 0.24 (silica gel, Cyc / EtOAc 2: 1)

1d 2- [4- (5-Bromo-pyridin-2-yl-ethynyl) -2-methyl-phenoxy] -ethanol

To a degassed solution of 11.98 g (68.0 mmol) of 2- (4-ethynyl-2-methyl-phenoxy) -ethanol, 16.11 g (68.0 mmol) of 2,5-dibromopyridine, 0.96 g (1.36 mmol) of bis-triphenylphosphine-palladium (II) chloride and 19.22 ml (136.0 mmol) of diisopropylamine in 500 ml of THF are added 0.26 g (1.36 mmol) of CuI and the mixture is stirred at RT for 4 h. The reaction mixture is i. vac. concentrated and the residue taken up in 800 mL EtOAc. The organic phase is washed with water and saturated NaCl solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, gradient DCM / EtOAc 90:10 → 80:20).
Yield: 13.20 g (58% of theory)
C ₁₆ H ₁₄ BrNO ₂ (M = 332,192)
calc .: Molpeak (M + H) ⁺ : 332/334 (Br)
Found: Molpeak (M + H) ⁺ : 332/334 (Br)
R _f value: 0.39 (silica gel, Cyc / EtOAc 1: 1)

1e 2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethanol

To a suspension of 13.20 g (39.74 mmol) of 2- [4- (5-bromo-pyridin-2-yl-ethynyl) -2-methyl-phenoxy] -ethanol, 9.32 g (59.60 mmol) of 4-chlorophenylboronic acid and 2.30 g (1.99 g mmol) of tetrakis-triphenylphosphine-palladium in 400 ml of 1,4-dioxane are added 40 ml of 2N NaHCO ₃ solution and the mixture is refluxed for 12 hours. Another 4.66 g of 4-chlorophenylboronic acid and 1.14 g of tetrakis-triphenylphosphinepalladium are added and the mixture is heated under reflux for a further 8 hours. The reaction mixture is i. vac. concentrated and the residue stirred with EtOAc and water. The precipitate is filtered off, washed with diethyl ether and i. vac. dried.
Yield: 10.70 g (74% of theory)
C ₂₂ H ₁₈ ClNO ₂ (M = 363,837)
calc .: Molpeak (M + H) ⁺ : 364/366 (Cl)
Found: Molpeak (M + H) ⁺ : 364/366 (Cl)
R _f value: 0.47 (silica gel, DCM / EtOAc 2: 1)

1f Methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester

To a solution of 10.70 g (29.41 mmol) of 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethanol and 4.08 mL (29.41 mmol) of triethylamine in 500 mL of THF are added dropwise at 0 ° C 2.74 mL (35.29 mmol) of methanesulfonyl chloride and the mixture then stirred for 2 h at RT. The reaction mixture is filtered and the filtrate i. vac. concentrated. The residue is stirred with diethyl ether and water, the precipitate is filtered off and i. vac. dried.
Yield: 11.00 g (85% of theory)
C ₂₃ H ₂₀ ClNO ₄ S (M = 441.928) calc .: Mol peak (M + H) ⁺ : 442/444 (Cl)
Found: Molepeak (M + H) ⁺ : 442/444 (Cl)
R _f value: 0.73 (silica gel, DCM / EtOAc 1: 1)

1g (3S, 4R) -1- (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -4-trifluoromethyl-piperidine-3 , 4-diol

A mixture of 82.6 mg (0.187 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester, 69.2 mg (0.374 mmol) ( 3S, 4R) -4-trifluoromethyl-piperidine-3,4-diol (amine A1) and 0.13 mL (0.748 mmol) of N-ethyldiisopropylamine in 1.7 mL of DMF is shaken for 40 h at 60 ° C. After filtration through a syringe filter, the crude product is purified via HPLC. The product containing fractions are i.vac. The residue was stirred with 20 mL EtOAc and 10 mL saturated NaHCO ₃ solution, the organic phase separated and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is stirred with DIPE, filtered off with suction and dried.
Yield: 39.2 mg (39% of theory)
C ₂₈ H ₂₆ ClF ₃ N ₂ O ₃ (M = 530,966) calc .: Mol peak (M + H) ⁺ : 531/533 (Cl)
Found: Molepeak (M + H) ⁺ : 531/533 (Cl)
HPLC-MS: 8.2 min. (Method A)

The following examples are prepared analogously starting from methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester (Example 1f) and the corresponding amines:

Example 1.15

(S) -3 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amino] -propane-1, 2-diol

1.15a (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amine

A mixture of 1.00 g (2.26 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester, 0.99 mL (11.32 mmol) C -Cyclopropyl-methylamine and 1.92 mL (11.32 mmol) of N-ethyldiisopropylamine in 15 mL of DMF is stirred at 60 ° C for 72 h. You narrow down i.vac. and the residue is purified by chromatography (silica gel, EtOAc / MeOH / NH ₃ 19: 1: 0.1).
Yield: 0.27 g (29% of theory)
C ₂₆ H ₂₅ ClN ₂ O (M = 416,942)
Calc .: Molpeak (M + H) ⁺ : 417/419 (Cl)
Found: Molpeak (M + H) ⁺ : 417/419 (Cl)
R _f value: 0.39 (silica gel, DCM / MeOH / NH ₃ 9: 1: 0.1)

1.15b (S) -3 - [(2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amino] -propane 1,2-diol

A mixture of 70 mg (0.168 mmol) (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amine, 56 μL ( 0.672 mmol) of (R) -3-chloropropane-1,2-diol and 0.12 ml (0.672 mmol) of N-ethyldiisopropylamine in 1.7 ml of DMF are shaken at 80 ° C. for 20 h. Then another 100 μL (1.12 mmol) of (R) -3-chloropropane-1,2-diol are added and the reaction mixture is kept at this temperature for a further 6 days. You narrow down i.vac. , the residue is partitioned between 10 mL semisaturated NaHCO ₃ solution and 20 mL EtOAc, the organic phase is separated and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, DCM / MeOH / NH ₃ 98: 2: 0.2).
Yield: 10 mg (12% of theory)
C ₂₉ H ₃₁ ClN ₂ O ₃ (M = 491,021)
calc .: Molpeak (M + H) ⁺ : 491/493 (CI)
Found: Molpeak (M + H) ⁺ : 491/493 (Cl)
R _f value: 0.30 (silica gel, DCM / MeOH / NH ₃ 19: 1: 0.1)

Example 1.16

(R) -3 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amino] -propane-1, 2-diol

The product is prepared analogously to Example 1.15b starting from 70 mg (0.168 mmol) (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) - cyclopropylmethylamine and 0.28 mL (3.35 mmol) of (S) -3-chloropropane-1,2-diol.
Yield: 29.6 mg (36% of theory) of C ₂₉ H ₃₁ ClN ₂ O ₃ (M = 491.021)
calc .: Molpeak (M + H) ⁺ : 491/493 (CI)
Found: Molpeak (M + H) ⁺ : 491/493 (Cl)
R _f value: 0.24 (silica gel, DCM / MeOH / NH ₃ 19: 1: 0.1)

Example 1.17

(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-prop-2-ynyl-amine

To a solution of 60 mg (0.144 mmol) (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopropylmethyl-amine in 2 mL DMF 39.8 mg K ₂ CO ₃ and 17 .mu.L (0.16 mmol, 80% in toluene) of 3-bromo-propyne and the reaction mixture stirred for 2 h at RT. You narrow down i.vac. , the residue is partitioned between 20 mL water and 40 mL EtOAc, the organic phase is separated and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (Alox, Cyc / EtOAc 9: 1).
Yield: 46.1 mg (70% of theory)
C ₂₉ H ₂₇ ClN ₂ O (M = 454,990)
calc .: Mole peak (M + H) ⁺ : 455/457 (Cl)
Found: Molpeak (M + H) ⁺ : 455/457 (Cl)
R _f value: 0.90 (Alox, Cyc / EtOAc 2: 1)

Example 1.18

Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentyl-amine

1.18a (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentyl-amine

A mixture of 1.33 g (3.0 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester, 1.49 mL (15.0 mmol) of cyclopentylamine and 2.57 mL (15.0 mmol) N-ethyldiisopropylamine in 30 mL DMF is stirred at 60 ° C for 36 h. You narrow down i.vac. , the residue is stirred with water and EtOAc, filtered off with suction, the precipitate is dissolved in DCM, the organic phase is washed with half-saturated K ₂ CO ₃ solution and the organic phase is dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is stirred with diethyl ether, filtered off with suction and dried.
Yield: 0.82 g (63% of theory)
C ₂₇ H ₂₇ ClN ₂ O (M = 430,969)
calc .: Mole peak (M + H) ⁺ : 431/433 (Cl)
Found: Molpeak (M + H) ⁺ : 431/433 (Cl)
R _f value: 0.21 (silica gel, DCM / MeOH 9: 1)

1.18b Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentyl-amine

The product is prepared analogously to Example 1.17 starting from 86.2 mg (0.20 mmol) (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentyl -amine and 42 μL (0.48 mmol) of 3-bromo-propene.
Yield: 5.1 mg (5% of theory)
C ₃₀ H ₃₁ ClN ₂ O (M = 471.033)
Calc .: Molpeak (M + H) ⁺ : 471/473 (Cl)
Found: Molpeak (M + H) ⁺ : 471/473 (Cl)
HPLC-MS: 6.4 min (Method B)

Example 1.19

Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) cyclopentylmethyl-amine

1.19a (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentylmethyl-amine

A mixture of 1.33 g (3.0 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester, 595 mg (6.0 mmol) of cyclopentylmethylamine and 2.57 mL (15.0 mmol) of N-ethyldiisopropylamine in 30 mL of DMF is stirred at 60 ° C for 20 h. You narrow down i.vac. , the residue is taken up in half-concentrated K ₂ CO ₃ solution, 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, DCM / MeOH 95: 5). cleaned.
Yield: 0.57 g (42% of theory)
C ₂₈ H ₂₉ ClN ₂ O (M = 444,995)
Calc .: Molpeak (M + H) ⁺ : 445/447 (Cl)
Found: Molpeak (M + H) ⁺ : 445/447 (Cl)
R _f value: 0.21 (silica gel, DCM / MeOH 95: 5)

1.19b Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentylmethyl-amine

The product is prepared analogously to Example 1.17 starting from 89.0 mg (0.20 mmol) (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -cyclopentylmethylamine and 21 μL (0.24 mmol) of 3-bromo-propene.
Yield: 37.4 mg (39% of theory)
C ₃₁ H ₃₃ ClN ₂ O (M = 485,059)
calc .: Mole peak (M + H) ⁺ : 485/487 (CI)
Found: Molpeak (M + H) ⁺ : 485/487 (Cl)
HPLC-MS: 6.6 min (Method B)

Example 1.20

Allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxy} -ethyl) -amine

The product is prepared analogously to Example 1.19a starting from 400 mg (0.91 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester and 0.2 mL (2.72 mmol) allylamine.
Yield: 228 mg (63% of theory)
C ₂₅ H ₂₃ ClN ₂ O (M = 402.916) calc .: Mol peak (M + H) ⁺ : 403/405 (Cl)
Found: Molpeak (M + H) ⁺ : 403/405 (Cl)
HPLC-MS: 5.4 min (Method B)

Example 2

(3S, 4R) -1- (2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -4-trifluoromethyl-piperidine-3,4-diol

2a 2- (4-iodo-phenoxy) -ethanol

A suspension of 11 g (50 mmol) of 4-iodophenol, 3.88 mL (55 mmol) of 2-bromoethanol and 8.3 g (60 mmol) of K ₂ CO ₃ in 60 mL of acetone is refluxed for 24 h. The solvent is i.vac. removed, the residue is mixed with water, extracted exhaustively with EtOAc and the organic phase dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, Cyc / EtOAc 7: 3).
Yield: 2.9 g (22% of theory)
C ₈ H ₉ IO ₂ (M = 264,064) calc .: Molpeak (M) ⁺ : 264
Found: Molpeak (M) ⁺ : 264
R _f value: 0.24 (silica gel, Cyc / EtOAc 2: 1)

2b 2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethanol

Under argon atmosphere to a solution of 2.9 g (11 mmol) of 2- (4-iodo-phenoxy) ethanol and 2.35 g (11 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-pyridine in 50 mL piperidine 253 mg (0.22 mmol) of tetrakis-triphenylphosphine-palladium and 42 mg (0.22 mmol) of Cul and the reaction mixture stirred for 30 min at RT. The solvent is i.vac. removed, the residue mixed with water and stirred with EtOAc. The precipitated product is filtered off with suction and dried.
Yield: 2.1 g (55% of theory)
C ₂₁ H ₁₆ ClNO ₂ (M = 349.820) calc .: Mol peak (M + H) ⁺ : 350/352 (Cl)
Found: Molepeak (M + H) ⁺ : 350/352 (Cl)
R _f value: 0.42 (silica gel, Cyc / EtOAc 1: 1)

2c Methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} ethyl ester

The product is obtained analogously to Example 1f starting from 4.40 g (12.58 mmol) of 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethanol.
Yield: 4.50 g (84% of theory)
C ₂₂ H ₁₈ ClNO ₄ S (M = 427.901)
Calc .: Molpeak (M + H) ⁺ : 428/430 (CI)
Found: Molpeak (M + H) ⁺ : 428/430 (Cl)
R _f value: 0.88 (silica gel, EtOAc)

2d (3S, 4R) -1- (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl) -4-trifluoromethyl-piperidine-3,4-diol

The product is prepared analogously to Example 1 g starting from 80 mg (0.187 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethinyl] -phenoxy} -ethylester and 69.2 mg (0.374 mmol) (3S, 4R) -4-trifluoromethyl-piperidine-3,4-diol (amine A1).
Yield: 43.6 mg (45% of theory)
C ₂₇ N ₂₄ ClF ₃ N ₂ O ₃ (M = 516,939)
Calc .: Molpeak (M + H) ⁺ : 517/519 (Cl)
Found: Molpeak (M + H) ⁺ : 517/519 (Cl)
HPLC-MS: 7.7 min (Method A)

The following examples are prepared analogously starting from methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl) -phenoxy} -ethyl ester (Example 2c):

Example 2.14

(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl- (tetrahydro-pyran-4-yl) -amine

2.14a (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl-cyclopropyl-methyl-amine

The product is prepared analogously to Example 1.19a starting from 1.71 g (4.0 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl ester and 2.02 ml (20.0 mmol) C-cyclopropyl-methylamine.
Yield: 0.70 g (43% of theory)
C ₂₅ H ₂₃ ClN ₂ O (M = 402.916)
calc .: Mole peak (M + H) ⁺ : 403/405 (Cl)
Found: Molpeak (M + H) ⁺ : 403/405 (Cl)
HPLC-MS: 5.1 min (Method B)

2.14b (2- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl) -cyclopropylmethyl- (tetrahydro-pyran-4-yl) -amine

To a solution of 80.6 mg (0.2 mmol) of (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -pheno xy} -ethyl) -cyclopropylmethyl-amine in 10 mL THF are added 37 μL (0.4 mmol) tetrahydropyran-4-one and 1 drop of glacial acetic acid and the reaction mixture stirred for 15 min at RT, before the addition of 170 mg (0.8 mmol) NaBH (OAc) ₃ takes place. The mixture is stirred at RT for a further 16 h, diluted with water, extracted exhaustively with EtOAc and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, DCM / MeON 95: 5).
Yield: 9 mg (9% of theory)
C ₃₀ H ₃₁ ClN ₂ O ₂ (M = 487.032)
Calc .: Molpeak (M + H) ⁺ : 487/489 (Cl)
Found: Molpeak (M + H) ⁺ : 487/489 (Cl)
R _f value: 0.52 (silica gel, DCM / MeOH 95: 5)

Example 2.15

1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethylamino) -methyl] -cyclopropanol

The product is prepared analogously to Example 1.19a starting from 1.71 g (4.0 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl ester and 0.54 g (4.8 mmol) of 1-aminomethyl-cyclopropanol.
Yield: 0.55 g (33% of theory)
C ₂₅ H ₂₃ ClN ₂ O ₂ (M = 418,915)
calc .: Molpeak (M + H) ⁺ : 419/421 (Cl)
Found: Molpeak (M + H) ⁺ : 419/421 (Cl)
R _f value: 0.18 (silica gel, EtOAc / MeOH / NH ₃ 95: 5: 0.5)
HPLC-MS: 4.9 min (Method B)

Example 2.16

1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - (tetrahydro-pyran-4-yl) -amino] -methyl} - -cyclopropanol

The product is prepared analogously to Example 2.14b starting from 83.8 mg (0.2 mmol) of 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl-amino) -methyl ] -cyclopropanol and 37 μL (0.4 mmol) of tetrahydropyran-4-one.
Yield: 2.1 mg (2% of theory)
C ₃₀ N ₃₁ ClN ₂ O ₃ (M = 503.032)
Calc .: Molpeak (M + H) ⁺ : 503/505 (Cl)
Found: Molepeak (M + H) ⁺ : 503/505 (Cl)
R _f value: 0.47 (silica gel, DCM / MeOH 9: 1)

The following examples are prepared analogously from 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl-amino) -methyl] -cyclopropanol (Example 2.15):

Example 2.20

1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) - (3-hydroxy-propyl) -amino] -methyl} -cyclopropanol

To a solution of 83.8 mg (0.2 mmol) of 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl-amino) -methyl] -cyclopropanol (Example 2.15 ) in 2 mL DMF are added 55.3 mg (0.4 mmol) K ₂ CO ₃ and 36 μL (0.4 mmol) 3-bromo-1-propanol and the reaction mixture is stirred at RT for 24 h. Another 36 μL (0.4 mmol) of 3-bromo-1-propanol are added and the reaction mixture is heated at 50 ° C. for 8 h. You narrow down i.vac. , the residue is taken up in water, extracted exhaustively with DCM and the combined organic phases are dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, EtOAc / MeOH / NH ₃ 95: 5: 0.5).
Yield: 22 mg (23% of theory)
C ₂₈ H ₂₉ ClN ₂ O ₃ (M = 476,994)
Calc .: Molpeak (M + H) ⁺ : 478/480 (CI)
Found: Molpeak (M + H) ⁺ : 478/480 (Cl)
R _f value: 0.34 (silica gel, EtOAc / MeOH 4: 1)

Example 2.21

1 - {[(2- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenoxy} -ethyl) -propyl-amino] -methyl} -cyclopropanol

The product is prepared analogously to Example 2.20 starting from 83.8 mg (0.2 mmol) of 1 - [(2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -phenoxy} -ethyl-amino) -methyl]. -cyclopropanol (Example 2.15) and 23 μL (0.25 mmol) of 1-bromo-propane.
Yield: 22 mg (24% of theory)
C ₂₈ H ₂₉ ClN ₂ O ₂ (M = 460,995)
calc .: Molpeak (M + H) ⁺ : 461/463 (Cl)
Found: Molpeak (M + H) ⁺ : 461/463 (Cl)
R _f value: 0.56 (silica gel, DCM / MeOH 95: 5)

Example 3

2 - ((E) -3- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} allylamino) propane-1,3-diol

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

Under argon atmosphere is added to a solution of 49.90 g (201.0 mmol) of 2,5-dibromopyridine and 43.0 mL (225.6 mmol) of tert-butyl-ethynyl-dimethyl-silane in 500 mL of dry THF and 120 mL of triethylamine at -7 ° C 0.80 g (4.20 mmol) Cul and 2.90 g (4.13 mmol) of bis-triphenylphosphine-palladium (II) chloride were added and the mixture stirred at 0 ° C for 30 min. The reaction mixture is stirred for a further 3.5 h at RT, then filtered and the filtrate i. vac. concentrated. The residue is dissolved in 1 L EtOAc, the organic phase washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ and i. vac. concentrated. The crude product is reacted further without purification.
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)

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

To a solution of 59.5 g (201.0 mmol) of 5-bromo-2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -pyridine and 36.5 g (233.4 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 ₃ 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)
Calc .: Molpeak (M + H) ⁺ : 328/330 (Cl)
Found: Molpeak (M + H) ⁺ : 328/330 (Cl)
R _f value: 0.60 (silica gel, Cyc / EtOAc 8: 1)

3c 5- (4-Chloro-phenyl) -2-ethynyl-pyridine

To a solution of 46.50 g (142.0 mmol) of 2 - [(tert-butyl-dimethyl-silanyl) -ethynyl] -5- (4-chlorophenyl) -pyridine in 1 L DCM are added at RT 43.66 g (156.0 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) calc .: Mol peak (M + H) ⁺ : 214/216 (Cl)
Found: Molepeak (M + H) ⁺ : 214/216 (Cl)
R _f value: 0.30 (silica gel, Cyc / EtOAc 4: 1)

3d (E) -3- (4-iodo-phenyl) -prop-2-en-1-ol

Under a nitrogen atmosphere, to a solution of 4.26 g (20.0 mmol) of (E) -3- (4-bromo-phenyl) -prop-2-en-1-ol and 762 mg (4 mmol) Cul in 20 mL of 1.4 Dioxane 12.0 g (80.0 mmol) of Nal and 0.85 mL (8.0 mmol) of N, N'-dimethylethylenediamine and the reaction mixture shaken at 110 ° C for 17 h. The reaction mixture is cooled to RT, combined with 200 mL EtOAc and 100 mL half-concentrated NH ₃ solution, stirred vigorously, the organic phase is separated off and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is reacted further without purification.
Yield: 4.69 g (90% of theory)
C ₉ H ₉ IO ₂ (M = 260,072)
Calc .: Molpeak (M + H) ⁺ : 261 Found: Molepeak (M + H) ⁺ : 261
HPLC-MS: 7.9 min (Method A)

3e (E) -3- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -phenyl} -prop-2-en-1-ol

A solution of 3.12 g (12.0 mmol) of (E) -3- (4-iodo-phenyl) -prop-2-en-1-ol, 3.33 g (15.0 mmol) of 5- (4-chloro-phenyl) -2 -ethynylpyridine and 4.31 mL (24 mmol) of diisopropylamine in 120 mL of dry THF is evacuated three times and then sparged with argon. Then, 45 mg (0.24 mmol) of Cul and 196 mg (0.24 mmol) of PdCl ₂ (dppf) are added. The reaction mixture is stirred for 18 h at RT, the solvent i.vac. concentrated, the residue with 100 mL DCM and 50 mL semisaturated NaHCO ₃ solution and stirred vigorously. The precipitate is separated, washed with water and a little DCM, slurried in DIPE, again filtered off and dried at 50 ° C to constant weight in a convection oven.
Yield: 4.23 g (quant.
C ₂₂ H ₆ ClNO (M = 345.821)
calc .: Molpeak (M + H) ⁺ : 346/348 (CI))
Found: Molpeak (M + H) ⁺ : 346/348 (Cl)
R _f value: 0.24 (silica gel, Cyc / EtOAc 2: 1)

3f 5- (4-Chloro-phenyl) -2- [4 - ((E) -3-chloro-propenyl) -phenylethynyl] -pyridine

To a cooled to 0 ° C solution of 6.1 g (17.64 mmol) of (E) -3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethinyl] -phenyl} -prop-2-en-1 -ol in 80 ml DCM, a solution of 2.56 mL (35.28 mmol) of thionyl chloride in 10 mL DCM is slowly added dropwise and the reaction solution stirred for a further 2 h at 0 ° C and 14 h at RT. It is cooled again to 0 ° C, carefully added dropwise 150 mL semisaturated NaHCO ₃ solution, the organic phase is separated and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, Cyc / EtOAc 4: 1).
Yield: 3.2 g (50% of theory)
C ₂₂ H ₅ Cl ₂ N (M = 364,267)
calc .: Mole peak (M + H) ⁺ : 364/366/368 (2CI))
Found: Molepeak (M + H) ⁺ : 364/366/368 (2Cl)
R _f value: 0.60 (silica gel, Cyc / EtOAc 2: 1)

3g 2 - ((E) -3- {4- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -phenyl} -allylamino) -propane-1,3-diol

A solution of 70 mg (0.192 mmol) of 5- (4-chlorophenyl) -2- [4 - ((E) -3-chloro-propenyl) -phenylethynyl] -pyridine, 70 mg (0.768 mmol) of 2-amino 1,3-Propanediol and 0.13 mL (0.768 mmol) N-ethyldiisopropylamine in 1.7 mL DMF are shaken for 3.5 h at 60 ° C. The reaction mixture is filtered through a syringe filter and purified directly via HPLC.
Yield: 37.6 mg (47% of theory)
C ₂₅ H ₂₃ ClN ₂ O ₂ (M = 418,915)
Calc .: Molpeak (M + H) ⁺ : 419/421 (Cl))
Found: Molpeak (M + H) ⁺ : 419/421 (Cl)
HPLC-MS: 4.9 min (Method B)

Example 3.1

2 - ((E) -3- {4- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -phenyl} allylamino) -2-methyl-propane-1,3-diol

Prepared analogously to Example 3g from 70 mg (0.192 mmol) of 5- (4-chloro-phenyl) -2- [4 - ((E) -3-chloro-propenyl) -phenylethynyl] -pyridine and 80.7 mg (0.768 mmol) of 2 amino-2-methyl-1,3-propanediol
Yield: 38.2 mg (46% of theory)
C ₂₆ H ₂₅ ClN ₂ O ₂ (M = 432,942) Calc .: molecular peak (M + H) ^+: 433/435 (Cl))
Found: Molpeak (M + H) ⁺ : 433/435 (Cl)
HPLC-MS: 4.9 min (Method B)

The following compounds are prepared according to the method described in Example 3g:

Following the procedure described in Example 2.14b, the following compounds are prepared starting from Example 3:

Example 4

(3R, 4S) -1- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -benzo [b] thiophen-2-ylmethyl} -4-methyl-piperidine-3,4- diol

4a 5-iodo-benzo [b] thiophene-2-carboxylic acid methyl ester

Under Argonatmophäre are added to a solution of 5.0 g (18.4 mmol) of 5-bromo-benzo [b] thiophene-2-carboxylic acid methyl ester in 18 mL of 1,4-dioxane 0.35 g (1.84 mmol) Cul, 5.53 g (36.88 mmol) Nal and 0.39 mL (3.67 mmol) of N, N'-dimethylethylenediamine was added and, after rinsing again with argon, the reaction mixture was heated at 110 ° C. overnight. After cooling, the reaction mixture with 30% NH ₃ solution and water was added, extracted exhaustively with EtOAc, the combined organic phases washed twice with water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is triturated with DIPE and MTBE, filtered off with suction and dried in air.
Yield: 3.4 g (58% of theory)
C ₁₀ H ₇ IO ₂ S (M = 318.132)
calc .: Molpeak (M) ⁺ : 318)
Found: Molpeak (M) ⁺ : 318
HPLC-MS: 6.4 min (Method B)

4b 5- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophene-2-carboxylic acid methyl ester

Under Argonatmophäre be to a solution of 3.4 g (10.69 mmol) of 5-iodo-benzo [b] thiophene-2-carboxylic acid methyl ester and 2.48 g (10.69 mmol) 5- (4-chloro-phenyl) -2-ethynyl-pyridine in 20 mL of THF 3.7 mL (26.72 mmol) of triethylamine, and the reaction mixture was evacuated three times and sparged with argon. Then, 195 mg (0.267 mmol) of PdCl ₂ (dppf) * DCM complex and 51 mg (0.267 mmol) of Cul are added and the reaction mixture is stirred at RT for 70 h. It is mixed with EtOAc, the precipitated product is filtered off with suction, washed with a little EtOAc and dried in air.
Yield: 3.0 g (70% of theory)
C ₂₃ H ₁₄ CINO ₂ S (M = 403.881)
calc .: Molpeak (M + H) ⁺ : 404/406 (Cl))
Found: Molpeak (M + H) ⁺ : 404/406 (Cl)
HPLC-MS: 7.3 min (Method B)

4c 5- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophene-2-carboxylic acid

To a suspension of 3.0 g (7.43 mmol) of 5- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophene-2-carboxylic acid methyl ester in 100 mL EtOH is added 22.3 mL 1N NaOH and the reaction mixture stirred at RT overnight. The reaction solution is cooled to 0 ° C and brought to pH 6 by dropwise addition of 1N HCl. The precipitated product is filtered off with suction, washed with EtOH and dried in air. Since the product still contained educt, the hydrolysis described above is repeated.
Yield: 2.7 g (93% of theory)
C ₂₂ H ₁₂ CINO ₂ S (M = 389,855)
Calc .: Molpeak (M + H) ⁺ : 390/392 (Cl))
Found: Molpeak (M + H) ⁺ : 390/392 (Cl)
R _f value: 0.89 (silica gel, PE / EtOAc 1: 1)

4d {5- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophen-2-yl} -methanol

To a suspension of 1.9 g (4.87 mmol) of 5- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophene-2-carboxylic acid in 40 mL of DMF are added 2.37 g (14.62 mmol) CDI and the reaction mixture heated to 50 ° C overnight. After cooling to RT, the reaction solution is added to a solution of 552 mg (14.62 mmol) of NaBH ₄ in 5 ml of water so that the temperature does not exceed 30 ° C. The mixture is stirred for 2 h at RT, treated carefully with KHSO ₄ solution until acidic reaction, basic with saturated Na ₂ CO ₃ solution, extracted exhaustively with DCM, the combined organic phases are washed twice with water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is triturated with PE, filtered off with suction and dried in air.
Yield: 1.1 g (60% of theory)
C ₂₂ H ₁₄ CINOS (M = 375,871)
calc .: Molpeak (M + H) ⁺ : 376/378 (CI))
Found: Molpeak (M + H) ⁺ : 376/378 (Cl)
HPLC-MS: 6.2 min (Method B)

4e 2- (2-Chloromethyl-benzo [b] thiophen-5-ylethynyl) -5- (4-chloro-phenyl) -pyridine

To a cooled to 0 ° C solution of 1.1 g (2.93 mmol) of {5- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophen-2-yl} -methanol in 20 1 ml of DCM, 1.07 ml (15 mmol) of thionyl chloride are added and the reaction mixture is stirred at RT for 70 h. You narrow down i.vac. a, the residue is mixed with semisaturated NaHCO ₃ solution, exhaustively extracted with DCM, the combined organic phases are washed twice with water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, PE / EtOAc 7: 3).
Yield: 0.65 g (56% of theory)
C ₂₂ H ₁₃ Cl ₂ NS (M = 394,317)
calc .: Mole peak (M + H) ⁺ : 394/396/398 (2CI))
Found: Molepeak (M + H) ⁺ : 394/396/398 (2Cl)
HPLC-MS: 7.6 min (Method B)

4f (3R, 4S) -1- {5- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -benzo [b] thiophen-2-ylmethyl} -4-methyl-piperidine-3,4 diol

To a solution of 60 mg (0.15 mmol) of 2- (2-chloromethylbenzo [b] thiophen-5-ylethynyl) -5- (4-chlorophenyl) -pyridine in 2 ml of DMF are added 39.9 mg (0.30 mmol) (3R, 4S) -4-methyl-piperidine-3,4-diol (amine A3) and the reaction mixture stirred at 70 ° C overnight. After filtration through a syringe filter, the reaction mixture is purified via HPLC.
Yield: 30 mg (40% of theory)
C ₂₈ H ₂₅ ClN ₂ O ₂ S (M = 489,029)
calc .: Molpeak (M + H) ⁺ : 489/491 (CI))
Found: Molepeak (M + H) ⁺ : 489/491 (Cl)
HPLC-MS: 5.4 min (Method A)

Following the procedure described in Example 4f, the following compounds are prepared:

Example 5 (3R, 4S) -1- (2- {4- [5- (4-Chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethyl) -4-methyl-piperidine 3,4-diol

5a 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 concentrated 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 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. PE (100-140 ° C) is heated to 90 ° C, the diazonium salt is added in portions and the mixture is 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 (2Br))
Found: Molpeak (M + H) ⁺ : 253/255/257 (2Br)
R _f value: 0.63 (silica gel, PE / EtOAc 9: 1)

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

Under argon atmosphere at 15 ° C to a solution of 3.20 g (12.56 mmol) of 2,5-dibromo-3-fluoropyridine in 30 mL of dry THF 5.22 mL (37.67 mmol) of triethylamine, 2.62 mL (13.81 mmol) tert-butyl -ethynyl-dimethyl-silane, 59.8 mg (0.31 mmol) of Cul and 220.3 mg (0.31 mmol) of bis-triphenylphosphine-palladium (II) chloride were added and the mixture was stirred for 2 h at RT. Then another 1 mL of tert-butyl-ethynyldimethyl-silane is added and the mixture is 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: Molpeak (M + H) ⁺ : 314/316 (Br)
HPLC-MS: 7.85 min (Method B)

5c 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 CIFNSi (M = 345,913)
calc .: Mole peak (M + H) ⁺ : 346/348 (Cl)
Found: Molpeak (M + H) ⁺ : 346/348 (Cl)
HPLC-MS: 8.83 min (Method B)

5d 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) calc .: Mol peak (M + H) ⁺ : 232/234 (Cl))
Found: Molpeak (M + H) ⁺ : 232/234 (Cl)
HPLC-MS: 5.81 min (Method B)

5e 2- {4- [5- (4-Chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethanol

Under argon atmosphere is added to a solution of 0.82 g (3.11 mmol) of 2- (4-iodo-2-methyl-phenoxy) -ethanol, 0.72 g (2.11 mmol) of 5- (4-chloro-phenyl) -2-ethynyl-3 Fluoropyridine, 57 mg (0.078 mmol) PdCl ₂ (dppf) and 0.86 mL (6.22 mmol) triethylamine in 20 mL THF 14.8 mg (0.08 mmol) Cul was added and the mixture stirred at RT for 16 h. The reaction mixture is mixed with EtOAc, the precipitate is filtered off and washed with EtOAc. The filtrate and the organic washings are washed with 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 / EtOAc 1: 1).
(Silica gel, petroleum ether / EtOAc 1: 1)
Yield: 0.20 g (18% of theory)
C ₂₁ H ₁₅ CIFNO ₂ (M = 367,800)
calc .: Molpeak (M + H) ⁺ : 368/370 (Cl))
Found: Molpeak (M + H) ⁺ : 368/370 (Cl)
HPLC-MS: 5.9 min (Method B)

5f Methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethyl ester

To a solution of 0.20 g (0.54 mmol) 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethanol and 0.11 mL (0.82 mmol) triethylamine in At 0 ° C., 63 μL (0.82 mmol) of methanesulfonyl chloride are added dropwise to 10 mL of DCM, and the mixture is stirred at RT for 16 h. Another 0.11 mL (0.82 mmol) of triethylamine and 63 μL (0.82 mmol) of methanesulfonyl chloride are added and the mixture is stirred for 8 h. The reaction mixture is diluted with DCM, the organic phase washed with water and dilute NaHCO ₃ solution, dried over MgSO ₄ and concentrated i. vac. concentrated.
Yield: 0.24 g (99% of theory)
C ₂₂ H ₁₇ ClFNO ₄ S (M = 445,892)
Calc .: Molpeak (M + H) ⁺ : 446/448 (Cl)
Found: Molpeak (M + H) ⁺ : 446/448 (Cl)
HPLC-MS: 6.2 min (Method B)

5g (3R, 4S) -1- (2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl) -phenoxy} -ethyl) -4-methyl-piperidine-3 , 4-diol

The product is prepared analogously to Example 4f starting from 60 mg (0.135 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethylester and 35.3 mg (0.269 mmol) of (3R, 4S) -4-methyl-piperidine-3,4-diol (amine A3).
Yield: 47 mg (73% of theory)
C ₂₇ H ₂₆ ClFN ₂ O ₃ (M = 480.958)
calc .: Mole peak (M + H) ⁺ : 481/483 (Cl)
Found: Molpeak (M + H) ⁺ : 481/483 (Cl)
HPLC-MS: 5.2 min (Method A)

Following the procedure described in Example 5g, the following compounds are prepared:

Example 5.7 1 - [(S) -1- (2- {4- [5- (4-Chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethyl) -pyrrolidin-2-yl ] -cyclopropanol

The product is prepared analogously to Example 4f starting from 60 mg (0.135 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethylester and 34.2 mg (0.269 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12).
Yield: 12 mg (19% of theory)
C ₂₈ H ₂₆ ClFN ₂ O ₂ (M = 476.969) calc .: Mole peak (M + H) ⁺ : 477/479 (Cl)
Found: Molpeak (M + H) ⁺ : 477/479 (Cl)
HPLC-MS: 5.6 min (Method A)

Example 6 1 - [(S) -1- (2- {2-Bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethyl) -pyrrolidine -2-yl] -cyclopropanol

6a 2- (2-bromo-4-iodo-phenoxy) -ethanol

The product is prepared analogously to Example 1a from 30.8 g (103 mmol) of 2-bromo-4-iodophenol.
Yield: 18.5 g (52% of theory)
C ₈ H ₈ BrIO ₂ (M = 342,956)
R _f value: 0.18 (silica gel, PE / EtOAc 4: 1)

6b 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethanol

The product is prepared analogously to Example 5e starting from 1.5 g (4.37 mmol) of 2- (2-Bom-4-iodo-phenoxy) -ethanol and 1.01 g (4.37 mmol) of 5- (4-chloro-phenyl) -2-ethynyl- 3-fluoro-pyridine.
Yield: 1.60 g (82% of theory)
C ₂₁ H ₁₄ BrClFNO ₂ (M = 446.697)
Calc .: Molpeak (M + H) ⁺ : 446/448/450 (BrCl)
Found: Molpeak (M + H) ⁺ : 446/448/450 (BrCl)
HPLC-MS: 6.4 min (Method B)

6c Methanesulfonic acid 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethyl ester

The product is prepared analogously to Example 5f starting from 1.6 g (3.58 mmol) of 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethanol produced.
Yield: 1.00 g (53% of theory)
C ₂₂ H ₁₆ BrClFNO ₄ S (M = 524.788)
Calc .: Molpeak (M + H) ⁺ : 524/526/528 (BrCl)
Found: Molpeak (M + H) ⁺ : 524/526/528 (BrCl)
HPLC-MS: 6.6 min (Method B)

6d 1 - [(S) -1- (2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} -ethyl) -pyrrolidine 2-yl] -cyclopropanol

The product is prepared analogously to Example 4f starting from 60.0 mg (0.114 mmol) of methanesulfonic acid 2- {2-bromo-4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -phenoxy} ethyl ester and 29.1 mg (0.229 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12).
Yield: 11 mg (17% of theory)
C ₂₈ H ₂₅ BrClFN ₂ O ₂ (M = 555,865)
Calc .: Molpeak (M + H) ⁺ : 555/557/559 (BrCl)
Found: Molepeak (M + H) ⁺ : 555 / q57 / 559 (BrCl)
HPLC-MS: 5.7 min (Method A)

Following the procedure described in Example 6d, the following compounds are prepared:

Example 7 1 - [(S) -1- (2- {4- [5- (4-Chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -pyrrolidine -2-yl] -cyclopropanol

7a 2- (4-iodo-2-methyl-phenoxy) -ethanol

The product is prepared analogously to Example 1 a starting from 10 g (42.7 mmol) of 4-iodo-2-methyl-phenol.
Yield: 11.4 g (96% of theory)
C ₉ H ₁₁ IO ₂ (M = 278,087)
R _f value: 0.40 (silica gel, PE / EtOAc 3: 2}

7b 2- {4- [5- (4-Chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethanol

The product is prepared analogously to Example 5e starting from 1.5 g (5.39 mmol) of 2- (4-iodo-2-methyl-phenoxy) -ethanol and 1.25 g (5.39 mmol) of 5- (4-chloro-phenyl) -2-ethynyl- 3-fluoro-pyridine.
Yield: 1.40 g (68% of theory)
C ₂₂ H ₁₇ ClFNO ₂ (M = 381,827)
calc .: Mole peak (M + H) ⁺ : 382/384 (Cl)
Found: Molpeak (M + H) ⁺ : 382/384 (Cl)
HPLC-MS: 6.3 min (Method B)

7c Methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ester

The product is prepared analogously to Example 5f starting from 1.4 g (3.67 mmol) 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethanol produced.
Yield: 0.77 g (46% of theory)
C ₂₃ H ₁₉ ClFNO ₄ S (M = 459,918)
Calc .: Molpeak (M + H) ⁺ : 460/462 (Cl)
Found: Molpeak (M + H) ⁺ : 460/462 (Cl)
HPLC-MS: 6.5 min (Method B)

7d 1 - [(S) -1- (2- {4- [5- (4-Chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl) -pyrrolidine 2-yl] -cyclopropanol

The product is prepared analogously to Example 4f starting from 60.0 mg (0.130 mmol) of methanesulfonic acid 2- {4- [5- (4-chloro-phenyl) -3-fluoro-pyridin-2-yl-ethynyl] -2-methyl-phenoxy} ethyl ester and 33.2 mg (0.261 mmol) of (S) -1-pyrrolidin-2-yl-cyclopropanol (amine A12).
Yield: 22 mg (34% of theory)
C ₂₉ H ₂₈ ClFN ₂ O ₂ (M = 490,996)
calc .: Molpeak (M + H) ⁺ : 491/493 (CI)
Found: Molpeak (M + H) ⁺ : 491/493 (Cl)
HPLC-MS: 5.8 min (Method A)

The following compounds are prepared according to the method described in Example 7d:

Example 8

(3R, 4S) -1 - ((E) -3- {5- [5- (4-chloro-phenyl) -pyridin-2-ylethynyl] -pyridin-2-yl} -allyl) -4-methyl- iperidin-3,4-diol

8a (E) -3- (5-Bromo-pyridin-2-yl) -prop-2-en-1-ol

A solution of 1.0 g (4.71 mmol) of 3- (5-bromo-pyridin-2-yl ) -prop-2-yn-1-ol in 5 mL THF is added dropwise so that the temperature does not exceed 0 ° C. After completion of the addition, stirring is continued for 2 h at 0 ° C. Excess lithium aluminum hydride is decomposed by careful addition of 0.13 mL water, 0.13 mL 15% NaOH, and 0.38 mL water. The precipitate is filtered and the organic phase dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is reacted further without purification.
Yield: 0.91 g (63% of theory)
C ₈ H ₈ BrNO (M = 214,059)
Calc .: Molpeak (M + H) ⁺ : 214/216 (Br)
Found: Molepeak (M + H) ⁺ : 214/216 (Br)
HPLC-MS: 4.2 min (Method B)

8b (E) -3- (5-iodopyridin-2-yl) -prop-2-en-1-ol

Under argon atmosphere to a solution of 910 mg (4.25 mmol) of (E) -3- (5-bromo-pyridin-2-yl) -prop-2-en-1-ol in 4.5 mL of 1,4-dioxane 81 mg (0.43 mmol) Cul, 1.27 g (8.5 mmol) of Nal and 90 μL of N, N'-dimethylethylenediamine and the reaction mixture heated under reflux overnight. After cooling, water is added, the mixture is extracted exhaustively with EtOAc and the combined organic phases are dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is reacted further without purification.
Yield: 870 mg (78% of theory)
C ₈ H ₈ INO (M = 261,060)
Calc .: Molpeak (M + H) ⁺ : 262
Found: Molepeak (M + H) ⁺ : 262
HPLC-MS: 4.2 min (Method B)

8c (E) -3- {5- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -pyridin-2-yl} -prop-2-en-1-ol

A solution of 870 mg (3.33 mmol) of (E) -3- (5-iodopyridin-2-yl) -prop-2-en-1-ol, 712 mg (3.33 mmol) of 5- (4-chloro) phenyl) -2-ethynylpyridine and 0.97 mL (7.0 mmol) of triethylamine in 10 mL of dry acetonitrile is evacuated three times and then sparged with argon. Then, 70 mg (0.37 mmol) of Cul and 300 mg (0.37 mmol) of PdCl ₂ (dppf) are added. The reaction mixture is stirred overnight at RT. The precipitated product is filtered, washed with a little acetonitrile and dried at 50 ° C to constant weight in a convection oven.
Yield: 980 mg (85% of theory)
C ₂₁ H ₁₅ ClN ₂ O (M = 346,809)
calc .: Molpeak (M + H) ⁺ : 347/349 (CI)
Found: Molpeak (M + H) ⁺ : 347/349 (Cl)
HPLC-MS: 5.6 min (Method B)

8d (E) -3- {5- [5- (4-Chloro-phenyl) -pyridin-2-yl-ethynyl] -pyridin-2-yl} -allyl) -chloride

To a cooled to -10 ° C solution of 450 mg (1.30 mmol) of (E) -3- {5- [5- (4-chlorophenyl) -pyridin-2-ylethinyl] -pyridin-2-yl} -prop- 2-en-1-ol in 25 mL DCM, a solution of 160 μL thionyl chloride in 5 mL DCM is added dropwise. The reaction solution is stirred at 0 ° C. for a further 30 min and at RT overnight. The reaction mixture is mixed with 50 mL semisaturated NaHCO ₃ solution, exhaustively extracted with DCM, the combined organic phases were washed twice with water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is reacted further without purification.
Yield: 450 mg (95% of theory)
C ₂₁ H ₁₄ Cl ₂ N ₂ (M = 365.255) calc .: Mol peak (M + H) ⁺ : 365/367/369 (2CI)
Found: Molpeak ((M + H) ⁺ : 365/367/369 (2Cl)
HPLC-MS: 6.8 min (Method B)

The following compounds are prepared according to the method described in Example 3g:

following Become a test method for the determination of an MCH receptor antagonist Activity described. About that can out also further test methods known to the person skilled in the art, for example via the Inhibition of the MCH receptor mediated inhibition of cAMP production as described by Hoogduijn M et al. in "Melanin-concentrating Hormones and their receptors are expressed and functional in human skin ", Biochem. Biophys. Res Commun. 296 (2002) 698-701 as well as over the biosensing measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by plasmon resonance, as reported 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 described, are used. Further test methods on MCH receptor antagonistic activity are in the introductory references and patent documents Their description of the test methods is hereby incorporated into this Registration is received.

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.

Of the KD value of the radioligand is 0.156 nM.

MCH-1 receptor-coupled Ca ²⁺ mobilization test

Clonal CHO / Galpha16 hMCH-R1 cells are cultured in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat. No .: BE12-615F). This contains per mL mL 10% FCS, 1% PENStrep, 5 mL L-Glutamine (200 mM stock solution), 3 mL Hygromycin B (50 mg / mL in PBS) and 1.25 mL Zeocin (100 μg / mL stock solution). One day prior to the experiment, the cells are plated on 384-well microtiter plate (black-walled with transparent bottom, manufacturer: Costar) at a density of 2500 cells per well and in the above-described medium overnight at 37 ° C, 5% CO ₂ and 95% relative humidity cultured. On the day of the experiment, the cells are incubated with cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid are added at 37 ° C for 45 minutes. After loading with fluorescent dye, the cells are washed four times with Hanks buffer solution (1 × HBSS, 20 mM HEPES) supplemented with 0.07% Probenicid. The test substances are diluted in Hanks buffer solution, mixed with 2.5% DMSO. The background fluorescence of unstimulated cells is measured in the presence of substance in the 384-well microtiter plate five minutes after the last wash in the FLIPR ³⁸⁴ device (Molecular Devices, excitation wavelength: 488 nm, emission wavelength: bandpass 510 to 570 nm). For cell stimulation, MCH is diluted in Hanks buffer with 0.1% BSA, pipetted 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 MCN receptor antagonistic action in the abovementioned tests. Using the MCH-1 receptor binding assay described above, antagonist activity is obtained in a dose range of about 10 ^-10 to 10 ^-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 active ingredient Composition: 1 capsule for powder inhalation contains: active substance 1.0 mg lactose 20.0 mg Hard gelatin capsules 50.0 mg 71.0 mg

Production method:

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

Example B

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

Production method:

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

Example C

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

Production method:

agent Sodium chloride and benzalkonium chloride are dissolved in water.

Example D

Propellant gas metered dose inhaler with 1 mg active ingredient 1 hub contains: active 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 active ingredient Composition: active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg

disodium edetate 00:05 mg water cleaned ad 0.1 ml

Production method:

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

Example F

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

production:

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

Example G

Injection solution with 100 mg active substance per 20 ml Composition: active substance 100 mg Monopotassium dihydrogenphosphate = KH ₂ PO ₄ 12 mg Disodium hydrogen phosphate = Na ₂ HPO ₄ .2H ₂ O 2 mg sodium chloride 180 mg Human serum albumin 50 mg Polysorbate 80 20 mg Water for injections ad 20 ml

production:

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:

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

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

production:

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

Example I

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

production:

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

Example J

Capsules with 20 mg active substance Composition: Active substance 20 mg Corn starch 80 mg Silica. highly dispersed 5 mg Magnesium stearate 2.5 mg

production:

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

Example K

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

production:

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

Example L

Infectious solution with 10 mg 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 C _3-6 alkenyl, C _3-6 alkynyl, (hydroxyC _3-7 cycloalkyl) C _1-3 alkyl, oxaC _4-7 cycloalkyl, dihydroxy C _{3- 7} -alkyl, wherein the angegenben groups may be mono- or polysubstituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl, C _{3 -7-} Cycloalkyl-C _1-3 -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, C _1-4 -alkoxy, C _1-4 -alkenyl, C _1-4 -alkynyl, amino, C _1-4 -alkyl-amino and di- (C _1-4 alkyl) amino, wherein the alkyl, alkoxy, Cylcoalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy; and R ² independently of R ^{1 has} one of the meanings given above for R ¹ or R ² has one meaning from the group consisting of H, C _1-8 -alkyl, C _3-7 -cycloalkyl or an optionally identical or different Radicals R ²⁰ mono- or polysubstituted and / or nitro-substituted phenyl or pyridinyl, wherein the alkyl or cycloalkyl group may be mono- or polysubstituted by 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 may be replaced by -O-, -Soder -NR ¹³ -, or the radicals R ¹ , R ² together with the N-atom to which they are attached , a heterocyclic group which is selected from the meanings - dihydroxy-cyclo-C _4-7 -alkylene-imino, - (hydroxy-C _1-4 -alkyl) -hydroxy-cyclo-C _3-7 -alkylene-imino, - (hydroxy-C _1-3 -alkyl) -cyclo-C _3-7 -alkylene-imino, wherein in the last meaning the C _1-3 alkyl group by one or more the same or different C _1-3 -alkyl groups are substituted, which may be linked together to form a C _3-7 -cycloalkyl group; wherein said heterocyclic groups may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 - CycloalkylC _1-3 alkyl, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkenyl, C _1-4 alkynyl, amino, C _1-4 -Alkyl-amino and di- (C _1-4 -alkyl) -amino, wherein alkyl, alkoxy, cycloalkyl groups may have one or more identical or different substituents selected from halogen and hydroxy; 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 by -CH = CH-, -C≡C-, -CH ₂ -O-, -CH ₂ -S- or -CH ₂ -NR ⁴ -, 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 / or one, two or three identical or different C _1-4 alkyl substituents, where two alkyl groups to form a 3 to 7-membered or an alkyl and an alkenyl Group may be linked together to form a 5- to 7-membered cyclic group, and W, Z are independently a single bond or a C _1-2 alkylene bridge, wherein two adjacent C 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 in which two alkyl radicals may be linked together to form a carbocyclic ring, and Y, A are independently selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl , Tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, thienyl, furanyl, benzothienyl or benzofuranyl, where said cyclic groups are mono- or polysubstituted by one or more carbon atoms or different radicals R ²⁰ , in the case of a phenyl ring also additionally simply with nitro, u or one or more NH groups can be substituted by R ²⁰ , B has one of 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 C _3-7 -cycloalkyl-C _1-3 -alkynyl- wherein one or more C atoms independently of one another or more with halogen and / or simply with hydroxy or cyano and / or cyclic groups or may be substituted several times 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 one N, O or S atom as heteroatom, one saturated Te or unsaturated 5- to 7-membered heterocyclic group having two or more N atoms or having one or two N atoms and an O or S atom as heteroatoms, - an aromatic heterocyclic 5- or 6-membered group having a or a plurality of identical or different heteroatoms selected from N, O and / or S, wherein the previously mentioned saturated 6- or 7-membered groups also as bridged ring systems with an imino, (C _1-4 alkyl) -imino-, methylene -, (C _1-4 alkyl) methylene or di (C _1-4 alkyl) methylene bridge may be present, and wherein the aforementioned cyclic groups one or more times to one or more C atoms with identical or different radicals R ²⁰ , in the case of a phenyl group may also be additionally substituted with nitro, and / or one or more NH groups with R ²¹ , R ^{4 is} H, C _1-4 alkyl, C _3-7 cycloalkyl or C _3-7 -cycloalkyl-C _1-3 -alkyl, R ¹⁰ -hydroxy, ω-hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy or C _1-4 -alko xy C _1-3 alkyl, R ¹¹ halo, 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 halogen, OH, CN, CF ₃ , C _1-3 -alkyl, hydroxy-C _1-3 -alkyl may be mono- or polysubstituted; R ^{13 is} one of the meanings given for R ¹⁷ , R ^{15 is} H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, phenyl, phenyl-C _1-6 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 -alkyl) -amino-C _2-6 -alkyl or cyclo-C _3-6 -alkyleneimino- C _2-6 -alkyl-, R ^{17 is} one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl, pyridinyl, 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 -alkyl-amino-C _2-6 -alkyl, ω-di - (C _1-4 alkyl) amino C _2-6 alkyl, ω-cyclo C _3-6 alkylene-C _2-6 alkyl, phenyl, 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 imino-sulfonyl, R ^{22 is} pyridinyl, phenyl, phenylC _1-3 -alkoxy, cycloC _3-6 -alkyleneimino-C _2-4 -alkoxy, OHC-, HO-N = HC-, C ₁₄ -alkoxy -N = HC-, C _1-4 -alkoxy, C _1-4 -alkylthio, carboxy, C _1-4 -alkylcarbonyl, C _1-4 -alkoxycarbonyl, aminocarbonyl, C _1-4 -alkylaminocarbonyl, di (C _{1 4-} alkyl) -aminocarbonyl, cyclo-C _3-6 -alkyl-amino-carbonyl- , Cyclo-C _3-6 -alkylenimino-carbonyl, 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 alkylcarbonylamino , Cyclo-C _3-6 -alkyleneimino, phenylC _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, where in the abovementioned groups and radicals, in particular in W, X, Z, R ⁴ , R ¹⁰ , R ¹³ and R ¹⁵ 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 additionally simply with Cl or Br and / or in each case one or more phenyl rings independently additionally one, two or three substituents selected from the group ppe 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, aminoC _1-3 alkyl, C _1-3 alkylaminoC _1-3 alkyl and di ( C _1-3 alkyl) -amino-C _1-3 -alkyl- and / or may be monosubstituted by nitro, and the H atom of an existing carboxy group or bound to an N atom H by in each case by a residue cleavable in vivo, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, wherein the following compounds are not included: (2- {4- [5- (4-chloro-phenyl) -pyridine -2-ylethynyl] -2-methyl-phenoxy} -ethyl) -methyl-prop-2-ynyl-amine, (2- {5- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] - indol-1-yl} -ethyl) -cyclopropylmethyl-prop-2-ynyl-amine, {4- [6- (4-chloro-phenyl) -quinolin-2-yl-ethynyl] -benzyl} -methyl- (tetrahydropyran) 4-yl) amine, allyl (2- {4- [5- (4-chloro-phenyl) -pyridine 2-ylethynyl] -phenoxy} -ethyl) -cyclopropylmethyl-amine, allyl (2- {4- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -2-methyl-phenoxy} -ethyl ) -cyclopropylmethyl-amine, allyl (2- {5- [5- (4-chloro-phenyl) -pyridin-2-yl-ethynyl] -indol-1-yl} -ethyl) -cyclopropylmethyl-amine. Alkyne compounds according to claim 1, characterized in that R ^{1 is} selected from the group of the meanings C _3-6 alkenyl, C _3-6 alkynyl, (hydroxy-C _3-7 cycloalkyl) C _1-3 alkyl , Oxa-C _5-7 -cycloalkyl, dihydroxy-C _3-7- alkyl, wherein the angegenben groups may be mono- or polysubstituted with substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylC _1-3 alkyl, C _1-4 alkoxyC _1-4 alkyl, C _1-4 alkoxy, C _{1 4-} alkenyl, C _1-4 alkynyl, amino, C _1-4 alkylamino and di (C _1-4 alkyl) amino wherein alkyl, alkoxy, cycloalkyl groups independently of one another are one or more identical or R ² independently of R ^{1 has} one of the meanings given above for R ¹ or HC _1-6 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, C _3-7 -cycloalkyl, hydroxy-C _3-7 -cycloalkyl, C _3-7 -cycloalky 1-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 alkoxycarbonyl 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-, pyrrolidin-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, piperidin-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, phenyl-C _1-3 alkyl, pyridyl or pyridyl-C _1-3 alkyl-, wherein in the groups and radicals mentioned above, one or more C Atoms independently of one another one or more times with F, C _1-3 -alkyl or hydroxy-C _1-3 -alkyl, and / or one or two C atoms independently einfac h may be substituted by Cl, Br, OH, CF ₃ or CN, and where the phenyl or pyridyl radical may be mono- or polysubstituted by identical or different radicals R ²⁰ and / or simply by nitro, and the radicals R ²⁰ and R ^{21 have} the meaning given in claim 1. Alkyn 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 3,4-dihydroxypyrrolidinyl, 3,4- Dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxyC _1-3 alkyl) hydroxypyrrolidinyl, (hydroxyC _1-3 alkyl) hydroxypiperidinyl, (hydroxyC _3-6 cycloalkyl) hydroxypyrrolidinyl, (hydroxy) C _3-6 -cycloalkyl) -hydroxy-piperidinyl, (C _1-3 -alkyl-hydroxy-methyl) -pyrrolidinyl, (C _1-3 -alkyl-hydroxy-methyl) -piperidinyl, (Di-C _1-3 - alkylhydroxy-methyl) -pyrrolidinyl, (di-C _1-3 -alkyl-hydroxy-methyl) -piperidinyl, (1-hydroxy-C _3-6 -cycloalkyl) -pyrrolidinyl, (1-hydroxy-C _3-6 -cycloalkyl) -piperidinyl, wherein said heterocyclic groups may be mono- or polysubstituted with substituents independently selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _3-7 cycloalkyl , C _3-7 -cycloalkyl-C _1-3 -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, C _1-4 -alkoxy, C _1-4 -alkenyl, C _1-4 -alkynyl, amino, C _1-4 -alkyl- amino and di (C _1-4 alkyl) -amino, wherein alkyl, alkoxy, Cylcoalkyl groups independently of one another can have one or more identical or different substituents selected from halogen and hydroxy. Alkyne compounds according to one or more of the preceding claims, characterized in that X is selected from the meanings -CH ₂ -, ethylene, propylene, -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -S-, -CH ₂ -CH ₂ -NR ⁴ - and C _2-4 -alkylene, which have one or two identical or different substituents independently selected from fluorine, Chlorine, hydroxy and C ₁ _ ₃ alkyl and / or a C _2-6 alkenyl or cyclopropyl substituent, wherein two alkyl substituents to form a C _3-6 cycloalkyl group or an alkyl and an alkenyl Group to form a C _5-6 cycloalkenyl group, and -CH ₂ -CH = CH-, -CH ₂ -C = C-, -CH ₂ -CH ₂ -O-, -CH ₂ - CH ₂ -S- or -CH ₂ -CH ₂ -NR ⁴ - which have one or two identical or different substituents independently selected from fluorine and C _1-3 -alkyl and / or a cyclopropyl substituent, where two alkyl Groups under training ng a C _3-6 cycloalkyl group or if an alkyl group is the radical R ⁴ , may be connected together to form a pyrrolidine or piperidine group, wherein R ^{4 has} the meaning given in claim 1, preferably H or C. _1-3 alkyl. 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 bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl , Dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, benzothienyl or benzofuranyl, where the abovementioned cyclic groups are mono- or polysubstituted by one or more C atoms having identical 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 N atoms with R ²⁰ , where R ²⁰ and R ^{20 have} the meanings given 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 meanings given in claim 1. Alkyne compounds according to one or more of the preceding claims, characterized in that the group B is selected from the group phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, and wherein the abovementioned cyclic groups are mono- or polysubstituted to one or more carbon atoms. Atoms with the same 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 Y is selected from

owns, and A is selected from a meaning

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 mono-, di- or trisubstituted independently of one another with R ²⁰ , in the case of In addition, phenyl rings may additionally be substituted by 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 R ^{20 is} F, Cl, Br, I, OH, cyano, amino, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, 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 a drug which is used for prophylaxis and / or treatment of apparitions and / or diseases caused by MCH be in another causal relationship with MCH, suitable 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 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 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 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. 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 micturition, 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 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. 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.