WO2005063239A1 - 3-(4-piperidine-1ylmethyl-phenyl)-propion acid-phenylamide-derivatives and related compounds used in the form of mch antagonists (melanine concentrating hormone) for treating eating disorders - Google Patents

Abstract

The invention relates to amid compounds of general formula (I), wherein groups and residuals A, B, b, W, X, Y, Z, R1, R2 and R3 have significances given in a claim 1. In addition, said invention relates to drugs containing at least one type of inventive amid. Because of the antagonist activity of an MCH-receptor, the inventive drugs are suitable for treating metabolic disturbances and/or eating disorders, in particular adiposity, bulimia, anorexia, hyperphagia and diabetes.

Description

 - (4-piperidin-1-yl-methyl-phenyl) -propionic acid phenylamides derivatives and related compounds as MCH (melaninconcentration hormone) antagonists

TREATMENT OF FOODSTUFFS

The present invention relates to novel amide compounds, their physiologically acceptable salts and their use as MCH antagonists and their use for the preparation of a medicament which is used for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or with MCH are in a different causal relationship, is appropriate. Another object of this invention relates to the use of a compound according to the invention for influencing the eating behavior as well as for reducing the body weight and / or for preventing an increase in the body weight of a mammal. Further, compositions and pharmaceutical compositions, each containing a compound of the invention ^ and processes for their preparation are the subject of this invention. Further objects of this invention relate to processes for the preparation of the compounds according to the invention.

Background of the invention

The intake of food and its implementation in the body plays an existential role in life for all living things. Therefore, deviations in the intake and conversion of food usually lead to disorders and diseases. The change in human eating and eating habits, particularly in industrialized countries, has in recent decades favored the development of pathological obesity (obesity or obesity), which directly leads to a reduction in mobility and a reduction in the number of people affected by obesity To make matters worse, obesity often leads to other illnesses, such as diabetes, dyslipidaemia, high blood pressure, atherosclerosis and coronary heart disease, in addition, the high body weight alone leads to an increased burden on the musculoskeletal system, resulting in chronic discomfort Diseases such as arthritis or osteoarthritis, thus obesity is a serious health problem for society.

The term obesity refers to an excess of adipose tissue in the body. In this context, obesity is basically considered to be any elevated level of body fat, leading to a health risk. There is no sharp separation between normal weight and obese individuals, but the health risk associated with obesity is likely to increase continuously with increasing obesity. For reasons of simplification are related Preferably, with the present invention, the individuals having a body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, are above the value of 25, especially above 30, as being obese considered suffering.

Apart from physical activity and dietary changes, there is currently no convincing treatment option for effectively reducing body weight. However, since obesity is a high risk factor in the development of serious and even life-threatening diseases, it is even more important to provide pharmaceutical agents for the prophylaxis and / or treatment of obesity. One recently proposed approach is the therapeutic use of MCH antagonists (inter alia WO 01/21577, WO 01/82925).

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is mainly synthesized in the hypothalamus in mammals and reaches further brain regions via the projections of hypothalamic neurons. Its biological activity is mediated in humans by two distinct G protein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, 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 energy balance, i. Change in 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 to the function of MCH. Loss of the neuropeptide leads to leaner animals with reduced fat mass, which consume significantly less food than control animals.

The anorectic effects of MCH are probably mediated by the G-galpha I coupled MCH-1 R in rodents [3-6], as opposed to primates, ferrets and dogs, no other MCH receptor subtype has been detected in rodents. Loss of MCH-1R results in "knock out" mice to lower fat mass, an increased Energy conversion and high-fat diet to no weight increase compared to control animals. Another indication of the importance of the MCH system in the regulation of the energy balance comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term experiments, the animals treated with this antagonist lose significant weight.

In addition to its anorexic effect, the MCH-1 R antagonist SNAP-7941 provides further anxiolytic and antidepressant effects in behavioral experiments with rats [3]. Thus, there is clear evidence that the MCH-MCH-1R system is involved not only in the regulation of the energy balance but also the affectivity.

Literature:

1. Qu, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature, 1996. 380 (6571): p. 243-7. 2. Shimada, M., et al., Mice Lacking melanin-concentrating hormones are hypophagic and lean. Nature, 1998. 396 (6712): p. 670-4.

3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of melanin-concentrating hormone-1 receptor antagonist. Nat Med, 2002. 8 (8): p. 825-30.

4. Chen, Y., et al., Targeted disruption of melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002.

143 (7): p. 2469-77.

5. Marsh, D., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Be U S A, 2002. 99 (5): p. 3240-5. 6. Takekawa, S., et al., T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438 (3): p. 129-35.

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

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

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

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

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

JP 2000086603 describes propenamide derivatives which have a 2-hydroxypropoxy group in use as 5-HT 1A receptor antagonists.

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

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

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

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

The preparation of [[(benzoxyzolylalkanoyl) amino] phenyl] alkanoates and their suitability as integrin receptor ligands are described in WO 2000049005. It is u.a. the compound 9-methyl-4 - [[3- [2 - [(2-methylphenyl) amino] -6-benzoxazolyl] -1-oxopropylamino] -benzenepropanoic acid.

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

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

International Publication WO 2004/072018 proposes amine derivatives as antagonists of the MCH receptor. In addition to connections made by the

umfasst sind, wird auch einegeneral formula

also includes a

Published a variety of individual links.

Object of the invention

The present invention has for its object to show new amide compounds, especially those that have high activity as MCH antagonists.

It is also an object of this invention to provide novel amide compounds which allow mammalian eating habits to be controlled and, particularly in mammals, to achieve body weight reduction and / or prevent body weight gain.

Furthermore, it is an object of the present invention to provide novel medicaments which are used for the prophylaxis and / or treatment of phenomena and / or diseases which are caused by MCH or are in a different causal relationship with MCH. In particular, it is an object of the present invention to provide medicaments for the treatment of metabolic disorders, such as obesity and / or diabetes, as well as diseases and / or disorders associated with obesity and diabetes. Further objects of the present invention relate to the demonstration of advantageous uses of the compounds of the invention. It is also an object of this invention to provide a process for preparing the amide compounds of the present invention. Other objects of the present invention will become apparent to those skilled in the art directly from the foregoing and following embodiments.

Subject of the invention

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

R \ '

N-X-Y - Z - N - W - A ^ -B

2 / ^"

R 'R °

in the

R ^1, R ² are independently H, an optionally monosubstituted with the group R ¹ or polysubstituted Cι _-8 -AlkyI- or c. _{3 7} -Cycloalkyl group, wherein a -CH ₂ group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S-, -NR ¹³ -, or optionally with the remainder R ¹² mono- or polysubstituted and / or nitro-substituted phenyl or pyridinyl, or

R ¹ and R ² form a C _2-8 alkylene bridge in which

- one or two -CH ₂ groups can be replaced independently of one another by -CH =N- or -CH =CH- and / or - one or two -CH ₂ groups independently of one another by -O-, -S-, - SO-

-, - (SO ₂ ) -, -C = NOR ¹⁸ , -CO-, -C (= CH ₂ ) - or -NR ¹³ - may be replaced such that heteroatoms are not directly connected to each other, and that a group - C = NOR ¹⁸ or -CO- is not directly connected to the group R ¹ R ² N-, wherein in the above-defined alkylene bridge, one or more H atoms may be replaced by R ¹⁴ , and

wherein the previously defined alkylene bridge may be substituted with one or two identical or different carbo- or heterocyclic groups Cy such that the bond between the alkylene bridge and the group Cy

- via a single or double bond,

- via a common carbon atom with the formation of a spirocyclic ring system, - via two common, adjacent C and / or N atoms under

Formation of a fused bicyclic ring system or

- takes place via three or more C and / or N atoms to form a bridged ring system,

R ³ is H, C _-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-4 alkyl or phenyl C _1-3 alkyl,

X is a single bond or a C _-8 alkylene bridge in which

- a -CH ₂ group which is not directly connected to the group R ¹ R ² N-, may be replaced by -CH = CH- or -C≡C- and / or - one or two non-adjacent -CH ₂ Groups that are not with the group

R ¹ R ² N are directly connected, independently of one another by -O-, -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ - may be replaced such that in each case two O, S or N atoms or an O with an S atom are not directly connected to each other,

wherein the bridge X may be connected to R ¹ , including the N atom connected to R ¹ and X to form a heterocyclic group, wherein the bridge X additionally with R ² , including the R ² and X connected to N atom under Formation of a heterocyclic group may be linked, and

wherein two C atoms or one C and one N atom of the alkylene bridge may be linked together by an additional C 1-6 alkylene bridge, and

wherein a carbon atom with R ¹⁰ and / or one or two C atoms in each case with one or two same or different substituents selected from C _-6 - alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C ₃ . ₇ cycloalkyl, C _3-7 -CycloaIkyl-C _-3 alkyl, C _{4- 7} -cycloalkenyl and C- _7- cycloalkenyl-C _1-3 -alkyl- may be substituted, wherein two alkyl and / or alkenyl substituents may be joined together to form a carbocyclic ring system, and

W means a single bond, where

Z -C ≡CC (= O) -, -CR ^7a = CR ^7c -C (= O) - or -CR ^7a R ^7b -CR ^7c R ^7d -C (= O) - means, or

W is -C (= O) -C≡C-, where Z is a single bond; and

Y is one of the meanings given for Cy,

wherein X may be linked to Y to form a carbamoyl or heterocyclic group fused to Y, and / or

wherein optionally R ^{1 may be} linked to Y including the group X and the N atom joined to R ¹ and X to form a heterocyclic group fused to Y, and

A is one of the meanings given for Cy, in which case the index b has the value 0, the group Cy has no amino group as substituent in the ortho position to the bridge W;

B is one of the meanings given for Cy,

b is 0 or 1,

Cy is a carbo or heterocyclic group selected from one of the following meanings

a saturated 3- to 7-membered carbocyclic group,

an unsaturated 4- to 7-membered carbocyclic group,

a phenyl group,

a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having an N, O or S atom as 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 having one or more identical or different heteroatoms selected from N, O and / or S,

wherein the above-mentioned 4-, 5-, 6- or 7-membered groups may be fused via two common, adjacent carbon atoms with a phenyl or pyridine ring, and

where in the abovementioned 5, 6 or 7-membered groups one or two nonadjacent -CH ₂ groups are independently of one another denoted by a --CO--, - C (CHCH ₂ ) -, - (SO) - or - ( SO ₂ ) group can be replaced, and

wherein the above-mentioned saturated 6- or 7-membered groups as bridged ring systems with an imino, N- (C ₁ alkyl) -imino-, methylene, C _1-4 - alkyl-methylene or di- ( C _1-4 alkyl) methylene bridge, and

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

R ^{4 is} one of the meanings given for R ¹⁷ , C _2-6 -alkenyl or C _3-6 -alkynyl,

R ^7a, R ^7c H, F, Cl, Ci- ₄ alkyl or CF _3,

R ^7b , R ^7d H, F, C _1-4 alkyl, wherein R ^7b and R ^7d may be linked together in the meaning of alkyl to form a cyclopropyl group;

R ^{10 is} hydroxy, hydroxyC _1-3 -alkyl, C _1-4 -alkoxy, C _1-4 -alkoxy-C _1-3 -alkyl, carboxy, C _1-4

Alkoxycarbonyl, amino, C _1-4 -alkylamino, di- (C _1-4 -alkyl) -amino, cyclo-C _3-6 -alkylenimino, amino-C _1-3 -alkyl, C _{1 - 4} alkyl-amino-C _1-3 -alkyl, di- (C ₁ -alkyl) - amino-C _1-3 -alkyl, cyclo-C _3-6 -alkylenimino-C _1-3 -alkyl- , Amino C _1-3 alkoxy, C _-4 -

Alkyl-amino-C _1-3 -alkoxy-, di- (C _1-4 -alkyl) -amino-C _1-3 -alkoxy, cyclo-C ₃ . ₆ -alkylenimino-C _1-3 -alkoxy, aminocarbonyl, C 1 -alkyl-aminocarbonyl, di- (C ₁ - alkyl) -aminocarbonyl- or cyclo-C _3-6 -alkylenirinylaminocarbonyl-,

R ¹¹ C _2-6 -AlkenyI, C ^ alkynyl, R ¹⁵ -O-, R ⁵ -O-Cι. _3- alkyl, R ¹⁵ -O-CO-, R ¹⁵ -CO-O-,

R ¹⁶ R ¹⁷ N, cyano, R ¹⁸ R ¹⁹ N-CO- or cy-,

R ^{12 is} one of the meanings given for R ²⁰ ,

R ^{13 is} one of the meanings given for R ¹⁷ , with the exception of carboxy,

R ^{14 is} halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁶ -CO-, R ¹⁵ -

CO-O-, R ¹⁶ R ¹⁷ N-, R ¹⁸ R ¹⁹ N-CO-, R ¹⁵ -OC _1-3 -alkyl, R ¹⁵ -O-CO-C _1-3 -alkyl-, R ¹⁵ - O-CO-NH-, R ¹⁵ -SO ₂ -NH-, R ¹⁵ -O-CO-NH-C 1-6 alkyl, R ¹⁵ -SO ₂ -NH-C _1-3 -alkyl-, R ¹⁵ - CO-C _1-3 -alkyl, R ¹⁵ -CO-OC _1-3 -alkyl, R ¹⁶ R ¹⁷ NC _1-3 -alkyl, R ¹⁸ R ¹⁹ N-CO-C _1-3 -alkyl- or Cy-C _1-3 alkyl,

R ^{15 is} H, C 1-6 -alkyl, C _3-7 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -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, hydroxy C _2-3 alkyl, C 1-6 alkoxy C 1-8 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 cycloC _3-6 -alkyleneimino-C ₂ . _6- alkyl,

R ^{17 is} one of the meanings given for R ¹⁶ or

C _-4-Alkoxycarbonyl-C_1-3-alkyl-, Cι- -Alkylcarbonylamino-C_2-3-alkyI-, N-(C_1-4-Alkylcarbonyl)-N-(C_M-Alkyl)-amino-C₂-₃-alkyl-, C_1-4-Alkylsulfonyl, Ci. 4-Alkylsulfonylamino-C_2-3-alkyl- oder N-(C_w-Alkylsulfonyl)-N(C₁^-Alkyl)- amino-C_2-3-alkyl-Phenyl, phenyl-C _1-3 -alkyl, pyridinyl, dioxolan-2-yl, -CHO, C 1-6 -alkylcarbonyl, carboxy, hydroxycarbonyl-C _1-3 -alkyl,

C _-4 alkoxycarbonyl-C _1-3 alkyl, C _2-3 alkylcarbonylamino Cι- -alkyI-, N- (C _1-4 alkylcarbonyl) -N- (C _M alkyl) amino-C ₂ - ₃ -alkyl-, C _1-4 -alkylsulfonyl, Ci. 4-alkylsulfonylamino-C _2-3 -alkyl- or N- (C _w -alkylsulfonyl) -N (C ₁ -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-Cι _-3 -alkyl, hydroxy-C _1-4 alkyl, R ^ -C ^ alky! - or one of for R ²² given meanings,

R ²¹ is C _1-4 alkyl, hydroxy C _2-3 alkyl, C ^ alkoxy-C ^ e-alkyl, C ₁ _ ₄ -alkyl-amino-C _2-6 alkyl,

Di- _(C1 ^ -alkyl) -amino-C _2-6 -alkyl, cyclo-C. _{3 6} -alkyleneimino-C _2-6 -alkyl-, phenyl-d. 3-alkyl-, C _1-4 -alkyl-carbonyl, C _1-4 -alkoxycarbonyl or C _1-4 -alkylsulfonyl,

R ²² is phenyl-C _1-3 alkoxy, cyclo-C _3-6 -alkyIenimino-C ₂ - ₄ alkoxy, OHC-, HO-N = HC, d. Alkoxy-N = HC, C _1-4 alkoxy, C _1-4 alkylthio, carboxy, C _1-4 alkylcarbonyl, d. 4-alkoxycarbonyl, aminocarbonyl, C ₁ -alkylaminocarbonyl, di- (C _1-4 -alkyl) -aminocarbonyl, cyclo-C _3-6 -alkyl-amino-carbonyl, cyclo-C _3-6 -alkyleneimino-carbonyl , cyclo-C _3-6 -alkylenimino-C _2-4 -alkyl-aminocarbonyl, phenyl-aminocarbonyl, C _1- alkyl-sulfonyl, C _1-4 alkyl sulfinyl, d ^ alkyl-sulfonylamino, Amino, C _1-4 -alkylamino, di- (d ^ -alkyl) -amino, C _1-4 -alkyl-carbonyl-amino, cyclo-C _3-6 -alkyleneimino, phenyl-Cι _-3 alkylamino, N- (C _1-4 alkyl) phenyl, C _1-3 alkylamino, acetylamino, propionylamino, phenylcarbonylamino,

Phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino,

wherein in the aforementioned groups and radicals, in particular in particular A, B, W, X, Y, Z, R ¹ to R ⁴ , R ^7a , R ^7b , R ^7c , R ^7d , R ¹⁰ to R ²² , each one or more C atoms can additionally be mono- or polysubstituted with F and / or in each case one or two C atoms independently additionally simply substituted with CI or Br and / or one or more phenyl rings independently of one another additionally one, two or more three substituents selected from the group F, CI, Br, I, C ^ alkyl, C _1-4 alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, -C. _3- alkylamino, di (C _1-3 alkyl) amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C _1-3 alkyl, Cι. ₃ -alkylamino-C _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 an H atom bound to an N atom can each be replaced by an in-vivo leaving group,

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, the following compounds according to provisos (M1) to (M14) are not included:

(M1) N- [4 - [[(methylamino) sulphonyl] methyl] phenyl] -3- [2- (dimethylamino) ethyl] -1H-indole-5-propanamide oxalate,

(M2) 3- [2- [3- [3,6-dihydro-4- (2-naphthyl) -1 (2H) -pyridinyl] -2-hydroxypropoxy] phenyl] -N-methyl-N-phenyl-2 -propenamid,

(M3) 3- [2- [2-hydroxy-3- [4- (1-naphthyl) -1-piperidinyl] propoxy] phenyl] -N-methyl-N-phenyl-2-propenamide,

(M4) 3- [2- [2-hydroxy-3- [4- (2-naphthyl) -1-piperidinyl] propoxy] phenyl] -N-methyl-N-phenyl-2-propenamide,

(M5) 3- [2- [2-hydroxy-3- [4- (2-naphthyl) -1-piperidinyl] propoxy] phenyl] -N-phenyl-2-propenamide,

(M6) N- [4- [1- (1 H -imidazol-1-yl) -2-methylpropyl] phenyl] -3-phenyl-2-propynamide,

(M7) 2 '- [[3- (dimethylamino) propyl] thio] -3-phenylpropiolanilide,

(M8) 2- (methylthio) -5 - [[3- [4- (octadecylamino) phenyl] -1-oxopropyl] amino] -benzoic acid, including the trifluoroacetate salt,

(M9) 4-amino-N- (4-hydroxy-3,5-dimethylphenyl) -benzenepropanamide,

(M10) 4- (dimethylamino) -N- (4-hydroxy-3,5-dimethylphenyl) -benzenepropanamide,

(M11) ^ -methyl-4 - [[3- [2 - [(2-methylphenyl) amino] -6-benzoxazolyl] -1-oxopropylamino] -benzenepropanoic acid,

(M12) 4- [3 - [[1-oxo-3- [2- (phenylamino) -6-benzoxazolyl] propyl] amino] phenoxy] butanoic acid,

(M13) 2-chloro-5 - [[1-oxo-3- [4 - [(5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid, (M14) 2-Chloro-5 - [[1-oxo-3- [4 - [(5-phenylpentyl) amino] phenyl] propyl] amino] benzoic acid methyl ester.

With regard to the individual compounds disclosed in WO 2004/072018, the following compounds are preferably also not included according to the invention: N- (4-pentyl-phenyl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -propionamide, N - (4-Bromo-phenyl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -propionamide, N- (4'-chloro-biphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl -phenyl) -propionamide, N- (4-bromo-phenyl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide,

N- (4'-chloro-biphenyl-4-yl) -3- (4- pyrrolidin-1-ylmethyl-phenyl) -acrylamide,

N- (4-bromo-2-fluoro-phenyl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -propionamide,

N- (4'-chloro-3-fluoro-biphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -propionamide.

The compounds of the present invention, including the physiologically acceptable salts, have particular activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show very good affinities in MCH receptor binding studies. In addition, the compounds of the invention have a high to very high selectivity with respect to the MCH receptor. In general, the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.

The invention also relates to the respective compounds in the form of the individual optical isomers, mixtures of the individual diastereomers, 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 included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms are replaced by deuterium.

Furthermore, the physiologically acceptable salts of the above and below described amide compounds according to the invention are also an object of this invention.

Also an object of this invention are compositions comprising at least one amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients. Furthermore, medicaments containing at least one amide compound according to the invention and / or an inventive salt in addition to optionally one or more inert carriers and / or diluents are the subject of the present invention.

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

Furthermore, the use of at least one amide compound of the invention and / or a salt of the invention including compounds excluded by provisos (M1) to (M14) for reducing body weight and / or preventing an increase in body weight of a mammal is an object thereof Invention.

Likewise provided by the present invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the compounds excluded by provisos (M1) to (M14), for the preparation of a medicament having MCH receptor antagonistic activity, in particular MCH-1 receptor antagonistic activity.

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

Another object of this invention is the use of at least one amide compound of the invention and / or a salt according to the invention, including the excluded by the provisos (M1) to (M14) compounds for the preparation of a medicament, which for the prophylaxis and / or treatment of metabolic Disorders and / or eating disorders, particularly of obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa or hyperphagia. Likewise an object of this invention is the use of at least one amide compound according to the invention and / or a salt according to the invention, including the compounds excluded by provisos (M1) to (M14), for the preparation of a medicament which is used for the prophylaxis and / or treatment of obesity-associated diseases and / or disorders, in particular diabetes, especially type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular disorders, in particular arteriosclerosis and hypertension, arthritis and gonitis is suitable.

In addition, the present invention has the use of at least one amide compound according to the invention and / or a salt according to the invention, including the excluded by the provisos (M1) to (M14) compounds for the preparation of a medicament, which for the prophylaxis and / or treatment of

The subject of the study is 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.

A further subject matter of this invention is the use of at least one amide compound according to the invention and / or of a salt according to the invention, including the compounds excluded by provisos (M1) to (M14), for the preparation of a medicament which is used for the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia and enuresis.

In addition, an object of this invention relates to processes for the preparation of a medicament according to the invention, characterized in that at least one amide compound according to the invention and / or a salt according to the invention is incorporated into one or more inert carriers and / or diluents by non-chemical means.

Another object of this invention is a pharmaceutical composition containing a first active ingredient selected from the amide compounds of the invention and / or the corresponding salts, including compounds excluded by provisos (M1) to (M14), and a second active ingredient who is from the A group consisting of drugs for the treatment of diabetes, drugs for the treatment of diabetic complications, drugs for the treatment of obesity, preferably other than MCH antagonists, drugs for the treatment of hypertension, drugs for the treatment of hyperlipidemia, including arteriosclerosis, drugs for the treatment of arthritis , Agents for the treatment of anxiety and drugs for the treatment of depression, besides optionally one or more inert carriers and / or diluents.

Detailed description of the invention

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

If groups, radicals and / or substituents in a compound occur several times, these may each have the same or different meanings given.

Preferred embodiments of this invention include compounds which can each be described by the following formulas Ia, Ib, Ic and Id:

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

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

The preferred meanings of the individual groups and substituents listed below refer to compounds of the formula I according to the invention, in particular to the four embodiments described by the formulas Ia, Ib, Ic and Id.

Preferred meanings of the substituent R ³ are H, C ₁ alkyl, C ₃ . ₆ -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl-; in particular H or C _1-3 -alkyl. R ³ particularly preferably denotes H or methyl, in particular H.

The substituents R ¹ and R ² may have a meaning as defined above and below as separate radicals or as a bridge connected to one another. For the sake of clarity, the preferred meanings of R ¹ and R ² are described below as separate radicals and then the preferred meanings of interconnected, bridging radicals R ¹ and R ² . Preferred compounds according to the invention therefore have one of the preferred meanings of R ¹ and R ² described below as separate radicals combined with one of the preferred meanings of R ¹ and R ² described below as interconnected radicals forming a bridge.

If R ¹ and R ^{2 are} not linked to one another via an alkylene bridge, then R ¹ and R ^2, independently of one another, preferably represent a C _1-8 -alkyl or C _3-7 -cycloalkyl radical which is optionally monosubstituted or polysubstituted by the radical R ¹¹ A group in which one -CH ₂ group in position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR ¹³ -, or may optionally be substituted by the radical R ^12. or several times and / or with nitro single substituted phenyl or pyridinyl, and wherein one of the radicals R ¹ and R ^{2 may} also be H.

C_1-4-Alkoxy- carbonyl-d- -alkyl-, Carboxyl-C_1-4-alkyl-, Amino-C^-alkyl-, C_1-4-Alkyl-amino-C_2-4-aIkyl-, Di-(d. ₄-alkyl)-amino-C_2-4-alkyl-, Cyclo-C₃.₆-alkylenimino-C_2- -alkyl-, PyrroIidin-3-yl, wobei die NH- Gruppe mit R¹³ substituiert sein kann, Pyrrolidinyl-C_1-3-alkyl-, wobei die NH-Gruppe mit R¹³ substituiert sein kann, Piperidin-3-yl oder -4-yl, wobei die NH-Gruppe mit R¹³ substituiert sein kann, Piperidinyl-C_1-3-alkyl-, wobei die NH-Gruppe mit R¹³ substituiert sein kann, Tetrahydropyran-3-yl oder -4-yl, Tetrahydropyranyl-C_1-3-alkyl, Tetrahydrofuran-3-yl, Tetrahydrofuranyl-C_1-3-alkyl, Phenyl, Phenyl-C_1-3-alkyl, Pyridyl oder Pyridyl-C_1-3-alkyl-, wobei in den zuvor angegebenen Gruppen und Resten ein oder mehrere C-Atome ein- oder mehrfach mit F und/oder ein oder zwei C-Atome, insbesondere ein C-Atom unabhängig voneinander einfach mit CI oder Br substituiert sein können, und wobei der Phenyl- oder Pyridylrest ein- oder mehrfach mit dem zuvor definierten Rest R¹² und/oder einfach mit Nitro substituiert sein kann, und wobei einer der Reste R¹, R² auch H bedeuten kann. Vorzugsweise können die zuvor angeführten Cycloalkyl-Ringe ein- oder mehrfach mit Substituenten ausgewählt aus Hydroxy, Hydroxy-C_1-3-alkyl, C_1-3-Alkyl oder C_1-3-Alkyloxy, insbesondere Hydroxy, Hydroxymethyl, Methyl und Methoxy substituiert sein. Weiterhin vorzugsweise können die C_2-4-Alkyl-Brücken in den Bedeutungen Hydroxy-C_2- -alkyl- und d. ₄-Alkoxy-C_2-4-alkyl- zusätzlich einfach mit Hydroxy, Hydroxy-C_1-3-alkyl, C_1-3-Alkyl oder C_1-3- Alkyloxy, insbesondere Hydroxy, Hydroxymethyl, Methyl oder Methoxy substituiert sein. Bevorzugte Substituenten R¹² der zuvor genannten Phenyl- oder Pyridylreste sind ausgewählt aus der Gruppe F, CI, Br, I, Cyano, C_1-4-alkyl, C_1- -alkoxy-, Difluormethyl-, Trifluormethyl-, Hydroxy-, Amino-, C_1-3-alkylamino-, Di-(C_1-3-alkyl)-amino-, Acetylamino-, Aminocarbonyl-, Difluormethoxy-, Trifluormethoxy-, Amino-C_1-3-alkyl-, Cι_-3-alkylamino- C_1-3-alkyl- und Di-(C_1-3-Alkyl)-amino-C₁.₃-alkyl-, wobei ein Phenylrest auch einfach mit Nitro substituiert sein kann.Preferably, the radicals R ^1, R ² mutually independently represent C _1-6 alkyl, C _3-7 cycloalkyl, C _{3- 7} cycloalkyl C _1-3 alkyl, hydroxy-C _2-4 alkyl, NC-C _2-4 alkyl,

C _1-4 -alkoxycarbonyl-d-alkyl, carboxyl-C _1-4 -alkyl, amino-C 1-6 -alkyl, C _1-4 -alkyl-amino-C _2-4 -alkyl, di- (d. _4-alkyl) -amino-C _2-4 -alkyl, _{cyclo-C3. 6} -alkylenimino-C ₂ -alkyl-, pyrrolidin-3-yl, where the NH group may be substituted by R ¹³ , pyrrolidinyl-C _1-3 -alkyl-, wherein the NH group may be substituted by R ¹³ , Piperidin-3-yl or 4-yl, where the NH group may be substituted with R ¹³ , piperidinyl-C _1-3 -alkyl, where the NH group may be substituted with R ¹³ , tetrahydropyran-3 yl or -4-yl, tetrahydropyranylC _1-3 alkyl, tetrahydrofuran-3-yl, tetrahydrofuranylC _1-3 alkyl, phenyl, phenylC _1-3 alkyl, pyridyl or pyridylC _1-3 alkyl, where in the abovementioned groups and radicals one or more C atoms may be monosubstituted or polysubstituted with F and / or one or two C atoms, in particular a C atom, independently of one another with CI or Br, and wherein the phenyl or pyridyl radical may be monosubstituted or polysubstituted by the previously defined radical R ¹² and / or may simply be substituted by nitro, and one of the radicals R ¹ , R ^{2 may} also be H. Preferably, the aforementioned cycloalkyl rings may be substituted one or more times with substituents selected from hydroxy, hydroxyC _1-3 alkyl, C _1-3 alkyl or C _1-3 alkyloxy, in particular hydroxy, hydroxymethyl, methyl and methoxy his. Further preferably, the C _2-4 alkyl bridges in the meanings hydroxy-C _2- alkyl- and d. ₄ alkoxy-C _2-4 alkyl additionally be substituted by hydroxy, hydroxy-C _1-3 alkyl, C _1-3 alkyl or C _1-3 alkyloxy, especially hydroxy, hydroxymethyl, methyl or methoxy. Preferred substituents R ^{12 of} the abovementioned phenyl or pyridyl radicals are selected from the group F, Cl, Br, I, cyano, C _1-4 -alkyl, C _1- alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino -, C _1-3 alkylamino, di- (C _1-3 -alkyl) -amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C _1-3 alkyl, Cι _-3 - alkylamino-C _1-3 -alkyl- and di- (C _1-3 -alkyl) -amino-C ₁ . ₃ -alkyl-, wherein a phenyl radical may also be easily substituted with nitro.

Particularly preferred meanings of the radicals R ¹ and / or R ² are selected from the group consisting of C _1-6 -alkyl, C _3- cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, tetrahydropyran-3 - or -4-yl, tetrahydropyranyl Cι _-3 alkyl, piperidin-3- or -4-yl, wherein the NH group may be substituted with R ^13, piperidinyl-C _1-3 alkyl, wherein the NH- group may be substituted with R ^13, phenyl, pyridyl, phenyl-C _1-3 -alkyl, pyridyl-C _1-3 alkyl, hydroxy-C _2-4 alkyl, C _1-4 alkoxy C _2-4 -alkyl, amino-C _2-4 -alkyl, C 1-8 -alkyl-amino-C _2- -alkyl and di- (C _1-4 -alkyl) -amino-C _2-4 -alkyl-, wherein cycloalkyl Single, double or triple rings with substituents selected from hydroxy, Hydroxy C _1-3 alkyl, C _1-3 alkyl or C _1-3 alkyloxy, in particular hydroxy, hydroxymethyl, methyl and methoxy may be substituted, and wherein C ₂ - alkyl bridges in the meanings hydroxy-C _2-4 alkyl and C _1-4 alkoxy-C _2-4 -a! alkyl- additionally be monosubstituted by hydroxy, hydroxy-Cι _-3 alkyl, C _1-3 alkyl or C _1-3 alkyloxy, in particular hydroxy, hydroxymethyl, methyl or methoxy may be substituted, and wherein alkyl groups may be mono- or polysubstituted with F and / or simply substituted with CI, and wherein one of the radicals R and R ^{2 may} also be H.

R ¹³ is preferably H, C _1-6 alkyl, C _1-4 alkylcarbonyl or C _1-4 alkyloxycarbonyl. More preferably R ^{13 is} H or d 1 alkyl, especially H, methyl, ethyl or propyl.

Very particularly preferred meanings of the radicals R ¹ and / or R ² are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, Cyclohexylmethyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, tetrahydropyran-4-yl-methyl, piperidin-4-yl, which may be substituted at the N-atom by R ¹³ , or piperidin-4-yl-methyl which may be substituted at the N atom with R ¹³ , said ethyl, propyl and butyl radicals may be monosubstituted by amino, methylamino or dimethylamino or mono- or di-hydroxy, methoxy or ethoxy, and wherein said cycloalkyl Rings may be mono- or disubstituted by hydroxy, hydroxymethyl or methyl, and wherein methyl radicals may be mono- or polysubstituted by fluorine, and wherein one of R ¹ and R ^{2 may} also be H.

Examples of very particularly preferred meanings of the radicals R ¹ and / or R ² are methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl , 2-methoxyethyl, 3-aminopropyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, (1-hydroxycyclopropyl) methyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methylpiperidin-4-yl, N- (methylcarbonyl) -piperidin-4-yl and N- (tert-butyloxycarbonyl) -piperidin-4-yl, wherein hydroxyalkyl groups may additionally be substituted by hydroxy, and wherein one of the radicals R ¹ , R ^{2 is} also H. can.

If the substituent R ^{1 has} one of the meanings given above as preferred, but not H, then the substituent R ² very particularly preferably denotes H, methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl or 2-methoxyethyl. Compounds according to the invention, in particular those which can be described by the formula Ic or Id, are also preferred in which one or both radicals R ¹ , R ^{2 are} one or more groups selected from 2-hydroxyethyl, 2-hydroxy-2-methyl- propyl, 2-methoxyethyl, 3-aminopropyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, (1-hydroxycyclopropyl) methyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methyl-piperidin-4-yl , N- (methylcarbonyl) -piperidin-4-yl and N- (tert-butyloxycarbonyl) -piperidin-4-yl, in particular selected from 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl, 2-methoxyethyl, tetrahydropyran- 4-yl, cyclopropylmethyl and (I-hydroxycyclopropyl) methyl, wherein hydroxyalkyl groups may be additionally substituted with hydroxy.

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

If R ¹ and R ^{2 form} an alkylene bridge, this is preferably a C ₃ -alkylene bridge in which a -CH ₂ group not adjacent to the N atom of the R ¹ R ² N group can be replaced by -CH = CH- and / or a -CH ₂ group, which is preferably not adjacent to the N atom of the R ¹ R ² N group, by -O-, -S-, -C ( = NOR ¹⁸ ) -, -CO-, -C (= CH ₂ ) - or -NR ¹³ -, more preferably by -O-, -S- or -NR ¹³ -, may be replaced such that heteroatoms not directly and that a group -C = NOR ¹⁸ or

-CO- is not directly connected to the group R ¹ R ² N-,

wherein in the above-defined alkylene bridge, one or more H atoms may be replaced by R ¹⁴ , and

Besonders bevorzugt bedeutet R¹³ H oder C_1-6-Alkyl, insbesondere H, Methyl, Ethyl oder Propyl.wherein the previously defined alkylene bridge having a carbo- or heterocyclic group Cy may be substituted such that the bond between the alkylene bridge and the group Cy - via a single or double bond, via a common carbon atom to form a spiro-cyclic ring system, via two common, adjacent C and / or N atoms to form a fused bicyclic ring system or via three or more C and / or N atoms to form a bridged ring system takes place. R ¹³ is preferably H, C _1-6 -alkyl,

With particular preference R ^{13 is} H or C _1-6 -alkyl, in particular H, methyl, ethyl or propyl.

Further preferably, R ¹ and R ^{2 form} such an alkylene bridge that R ¹ R ² N- is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1, 2,3,6 Tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free imine function is substituted with R ¹³ , piperidine-4 -on, piperidin-4-one oxime, piperidin-4-one-OC _1-4 alkyl oxime, morpholine and thiomorpholine,

in particular selected from pyrrolidine, piperidine, 2,5-dihydro-1H-pyrrole, piperazine, in which the free imine function is substituted by R ¹³ , morpholine and thiomorpholine,

wherein according to the general definition of R ¹ and R ^2, one or more H atoms may be replaced by R ¹⁴ , and / or the abovementioned groups in a manner indicated by the general definition of R ¹ and R ² with one or two identical or different carbo- or heterocyclic groups Cy may be substituted. Particularly preferred groups Cy are phenyl, C ₃ . ₇ -cycloalkyl, aza-C _4-7 -cycloalkyl-, in particular phenyl, C _3-6 -cycloalkyl, cyclo-C _3-5 -alkyleneimino-, and also NC _1-4 -alkyl- (aza-C _4-6 - cycloalkyl) -, wherein the cyclic groups Cy may be substituted as indicated.

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

In the case where the alkylene bridge is connected to a group Cy via a single bond, Cy is preferably selected from the group consisting of C _3-7 -cycloalkyl, cyclo-C _3-6 -alkyleneimino, piperazinyl, 1H-imidazole, thienyl and phenyl, in particular C _3-6 -cycloalkyl, pyrrolidinyl, piperidinyl and piperazinyl, which may be substituted as indicated, in particular wherein the N-atoms may each be substituted by C _1-4 -alkyl.

In the case that the alkylene bridge is connected to a group Cy via a common carbon atom with the formation of a spirocyclic ring system, Cy is preferably selected from the group consisting of C _3-7 -cycloalkyl, aza-C 1 -a-cycloalky-, Oxa-C "- cycloalkyl, 2,3-dihydro-1 H-quinazolin-4-one, in particular cyclopentyl and cyclohexyl, which may be substituted as indicated, in particular wherein the N-atoms in each case substituted by C _1-4 alkyl could be. In the event that the alkylene bridge is connected to a group Cy via two common adjacent C and / or N atoms to form a fused bicyclic ring system, Cy is preferably selected from the group consisting of C _4-7 cycloalkyl, aza -C ^ -cycloalky-, phenyl, thienyl, in particular phenyl and pyrrolidinyl, which may be substituted as indicated, in particular wherein the N atoms may each be substituted by C _1-4 alkyl.

In the event that the alkylene bridge is linked to a group Cy via three or more C- and / or N atoms, a bridged ring system is connected with the formation means Cy preferably C _-8 cycloalkane or aza-C _-8 -cycIoalkan, in particular cyclopentane , Cyclohexane, pyrrolidine or piperidine, where the N atoms may each be substituted by C ₄ alkyl.

eine Bedeutung gemäß einer der folgenden TeilformelnMost preferably, the group has

a meaning according to one of the following sub-formulas

wherein in the heterocycle formed by the group R ¹ R ² N- one or more H atoms by R ¹⁴ and / or an H atom by Cy in the meaning C _3-7 cycloalkyl, the one or more times with R ²⁰ , in particular with F, hydroxy, C _1-3 -alkyl, CF ₃ , C _1-3 -alkyloxy, OCF ₃ or hydroxy-C _1-3 -alkyl may be substituted, and wherein the group represented by R ¹ R ² N- formed heterocycle connected ring one or more times at one or more carbon atoms with R ²⁰ , in the case of a phenyl ring may also be additionally substituted with nitro and additionally easy X ', X "independently of one another a single bond or C _1-3 alkylene and

for the case that the group Y is connected to X or X "via a C atom, also -C _1-3 -alkylene-O-, -C _1-3 -alkylene-NH- or -C _1-3 Alkylene-N (C _1-3 alkyl) -, and

X "additionally also -OC _1-3 -alkylene, -NH-C _1-3 -alkylene or

-N (C _1-3 alkyl) -C _1-3 alkylene and

for the case that the group Y is connected to X "via a C atom, also -NH-,

-N (C _1-3 alkyl) - or -O-,

wherein in the above for X, X "meanings each denote a C atom with R ⁰ , preferably with a hydroxy, ω-hydroxy-C _1-3 alkyl, co- (C _1-4 alkoxy) -C _1-3 alkyl and / or C _1-4 alkoxy radical, and / or one or two C atoms each having one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 -CycIoalkyl, C ₃ _ ₇ cycloalkyl C _1-3 alkyl, C _4-7 - cycloalkenyl, and C _4-7 cycloalkenyl-Cι _-3 -alkyl may be substituted, wherein two alkyl and / or alkenyl substituents may be linked together to form a carbocyclic ring system, and

where in X, X "independently of one another in each case one or more C atoms may be mono- or polysubstituted with F and / or in each case one or two C atoms independently of one another may simply be substituted by CI or Br, and

wherein R ² , R ¹⁰ , R ¹³ , R ¹⁴ , R ¹⁸ , R ²⁰ , R ²¹ and X are those given above and below

Own meanings.

Preferably, X, X "independently of one another are a single bond or C _1-3 -alkylene and, in the case where the group Y is connected to X or X" via a C atom, also -C _1-3 -alkylene-O -, C _1-3 -alkylene-NH- or -C _1-3 -alkylene-N (C _1-3 -alkyl) -, and X "additionally also -OC _1-3 -alkylene, -NH-C _{1 3-} alkylene or -N (C _1-3 -alkyl) C _1-3 -alkylene, and in the event that the group Y is linked to X "via a C atom, X" also denotes -NH-, -N (C _1-3 -alkyl) - or -O-, more preferably X, X "independently of one another are a single bond or methylene and in the event that the group Y is connected to X or X" via a carbon atom is also -CH ₂ -O-, -CH ₂ -NH- or -CH ₂ -N (Cι_ ₃ -alkyI) -, and in the event that the group Y is connected via a C atom with X ", X "also means -NH-, -N (C _-3 - alkyl) - or -O-.

amino-C_1-3-alkyl, Amino-, C^-Alkyl-amino-, C_3-7-Cycloalkyl-amino-, N-(C_3-7-Cycloalkyl)-N-(d. ₄-alkyl)-amino-, Di-(C_1-4-alkyl)-amino-, Amino-C_1-3-alkyl-, C_1-4-Alkyl-amino-C_1-3-alkyl-, C_3-7- Cycloalkyl-amino-C_1-3-alkyl-, N-(C₃.₇-CycloalkyI)-N-(C_M-alkyl)-amino-C_1-3-alkyl-, Di-(C_1-4-alkyl)- amino-C_1-3-alkyl-, Cyclo-C₃.₆-alkylenimino-C_1-3-alkyl-, Aminocarbonyl-, C_1- -Alkyl-amino- carbonyl-, C^-Cycloalkyl-amino-carbonyl-, N-(C_3-7-Cycloalkyl)-N-(C_1-4-alkyl)-amino-carbonyl-, Di-(C_1-4-alkyl)-amino-carbonyl-, Pyridinyl-oxy-, Pyridinyl-amino-, Pyridinyl-C_1-3-alkyl-amino-. In den genannten Bedeutungen des Rests R¹⁴ können ein oder mehrere C-Atome ein- oder mehrfach mit F und/oder ein oder zwei C-Atome unabhängig voneinander einfach mit CI oder Br substituiert sein, insbesondere Alkyl-Reste ein- oder mehrfach mit Fluor substituiert sein.In the above-mentioned preferred and particularly preferred meanings of R ¹ R ² N, the following definitions of the substituent R ^{14 are} preferred: F, Cl, Br, C _1-4 -alkyl, C _2- alkenyl, C _2-4 -alkynyl, C _5-7 -cycloalkyl-C _1-3 -alkyl, hydroxy, hydroxy-C _1-3 -alkyl, C _1-4 -alkoxy, ω- (C _1-4 -alkoxy) -C-1. _3- alkyl, ^ -alkyl-carbonyl, carboxy, d. _4- alkoxycarbonyl, hydroxy-carbonyl-C _1-3 -alkyl, C _1-4 -alkoxycarbonyl-C _1-3 -alkyl, C _1-4 -alkoxycarbonylamino,

amino-C _1-3 -alkyl, amino, C 1-4 -alkylamino, C _3-7 -cycloalkylamino, N- (C _3-7 -cycloalkyl) -N- (d ₄ -alkyl) amino, di (C _1-4 alkyl) amino, amino C _1-3 alkyl, C _1-4 alkylamino C _1-3 alkyl, C _{3-7 cycloalkyl-amino-C1-3} -alkyl, N- (C _{3 7} -CycloalkyI.) -N- (C _M alkyl) amino-C _1-3 -alkyl, di- (C _1-4 - alkyl) -amino-C _1-3 -alkyl-, cyclo-C ₃ . ₆ -alkylenimino-C _1-3 -alkyl, aminocarbonyl, C _1- alkyl-amino- carbonyl, C ^ -cycloalkyl-amino-carbonyl, N- (C _3-7 -cycloalkyl) -N- ( C _1-4 alkyl) amino carbonyl, di (C _1-4 alkyl) amino carbonyl, pyridinyl oxy, pyridinyl amino, pyridinyl C _1-3 alkyl amino , In the abovementioned meanings of the radical R ¹⁴ , one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another simply substituted with CI or Br, in particular alkyl radicals one or more times with fluorine be substituted.

Very particularly preferred meanings of the substituent R ¹⁴ are F, Cl, C _1-4 alkyl, C _3-6 - cycloalkyl-Cι _-3 alkyl, hydroxy, hydroxy-C _1-3 -alkyl, C _1-4 - Alkoxy, C _1-4 alkoxy-C _1-3 -alkyl, amino-C-ι. ₃ -alkyl-, C _1-4 -alkylamino-C _1-3 -alkyl-, C _3-7 -cycloalkyl-amino-C _1-3 -alkyl-, N- (C _3-7 -cycloalkyl) - N- (C _1-4 -alkyl) -amino-C _1-3 -alkyl, di- (C ₁ alkyl) amino-C _1-3 -alkyl, cyclo-C _3-6 -alkylenimino- C _1-3 alkyl, aminocarbonyl and pyridylamino. In the abovementioned meanings of the radical R ¹⁴ , one or more C atoms, in particular alkyl radicals, may be monosubstituted or polysubstituted by fluorine.

If, in the heterocycle formed by the group R ¹ R ² N-, an H atom is replaced by Cy meaning C _3-7 -cycloalkyl, which may be mono- or polysubstituted by R ²⁰ , then Cy is preferably C _{3 -6} cycloalkyl and R ²⁰ is preferably F, hydroxy, C _1-3 alkyl, CF _3, C _1-3 alkyloxy, OCF _3, or hydroxy-C _1-3 -alkyl, in particular F, hydroxy, methyl, methoxy, CF ₃ , OCF ₃ or hydroxymethyl. Particularly preferred meanings of Cy are C ₃ . ₆ - cycloalkyl and 1-hydroxy-C _3-5 cycloalkyl.

eine Bedeutung gemäß einer der folgenden Teilformeln

Most preferably, the group has

a meaning according to one of the following sub-formulas

wherein in the heterocycle formed by the group R ¹ R ² N- one or more H atoms by R ¹⁴ and / or an H atom by Cy meaning C _3-6 cycloalkyl, the one or more times with R ²⁰ , in particular with F, hydroxy, d. _3- alkyl, CF ₃ , C _1-3 alkyloxy, OCF ₃ or hydroxy-C ₃ alkyl, particularly preferably with F, hydroxy, methyl, methoxy, CF ₃ , OCF ₃ or hydroxymethyl may be substituted , and

wherein the ring connected to the heterocycle formed by the group R ¹ R ² N- may be monosubstituted or polysubstituted, preferably simply substituted on one or more carbon atoms by R ²⁰ , and in the case of a phenyl ring may additionally also be substituted simply by nitro and in which

R 14 are each independently of one another F, Cl, C _1-4 alkyl, C _3-6 cycloalkylC _1-3 alkyl, hydroxy, hydroxyC _1-3 alkyl, C _1-4 alkyloxy, C _1-4 alkoxy-C _1-3 -alkyl, pyridylamino or aminocarbonyl, where in each case one or more C atoms, in particular alkyl radicals may additionally be mono- or polysubstituted by F; most preferably methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methyl-ethyl, 1-hydroxycyclopropyl, methoxy, ethoxy, methoxymethyl, pyridylamino or aminocarbonyl; and

R 13 is as defined above, in particular H or C _1-3 -AlkyI means. Compounds according to the invention, in particular those which can be described by the formula Ic or Id, are also preferred in which the group

a meaning according to one of the following sub-formulas

in which H atoms can be replaced as indicated above and the ring connected to the heterocycle formed by the group R ¹ R ² N- one or more times, preferably simply at one or more C atoms with R ²⁰ , in the case of In addition, phenyl rings may additionally be substituted by nitro, or

in which the group

a meaning according to one of the following sub-formulas

in which at least one H atom of the heterocycle formed by the group R ¹ R ² N- by a substituent selected from hydroxy, hydroxy-C ₃ alkyl, 1-hydroxy-C _3-5 cycloalkyl, C _1-4 -Alkyloxy and Cι _-4 -alkoxy-Cι _-3 -alkyI is substituted, and wherein additionally a or more, preferably one or two, H atoms of the heterocycle formed by the group R ¹ R ² N- through the previously defined substituent R ¹⁴ and / or an H atom of the heterocycle formed by the group R ¹ R ² N- by Cy in the meaning C _3-6 -cycloalkyl which is mono- or polysubstituted with R ²⁰ , in particular with F, hydroxyl, C _1-3 -alkyl, CF ₃ , C _1-3 -alkyloxy, OCF ₃ or hydroxy-C _{1 3-} alkyl, particularly preferably with F, hydroxy, methyl, methoxy, CF ₃ , OCF ₃ or hydroxymethyl may be substituted.

Preferably, X represents a C _1-6 -alkylene bridge in which - a -CH ₂ - group not adjacent to the N atom of the R ¹ R ² N group is replaced by -CH = CH- or -G≡C- may be and / or a not adjacent to the N atom of the R ¹ R ² N group -CH ₂ group by -O-, -S-, -CO- or -NR ⁴ -, more preferably by -O- , -S- or -NR ⁴ -, may be replaced such that in each case two O, S or N atoms or an O with an S atom are not directly connected to one another,

wherein R ⁴ may be linked together with Y to form a heterocyclic ring system,

wherein the bridge X may be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and

wherein two C atoms or one C and one N atom of the alkylene bridge may be linked together by an additional C _1-4 alkylene bridge, and

wherein one C atom with R ¹⁰ and / or one or two C atoms each having one or two identical or different substituents selected from d _-6- alkyl, C _2-6 alkenyl, C ₂ . ₆ alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _4-7 cycloalkenyl and C _4-7 cycloalkenyl C _1-3 alkyl in which two alkyl and / or alkenyl substituents can be bonded together to form a carbocyclic ring system, in particular a cyclopropyl, cyclobutyl or cyclopentyl group.

Preferably, in group X, a -CH ₂ - group immediately adjacent to the group R ¹ R ² N- is not denoted by -O-, -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ - replaced. If, in group X, one or two -CH ₂ groups are independently replaced by -O-, -S-, - (SO) -, - (SO ₂ ) -, -CO- or -NR ⁴ -, these are Preferably, groups are spaced from the group R ¹ R ² N- by an alkylene bridge having at least 2 C atoms.

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

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

Preferably, the alkylene bridge X, X 'or X "has no or at most one imino group The position of the imino group within the alkylene bridge X, X or X" is preferably selected such that 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 each other.

If one C atom is substituted in X, X or X ", preferred substituents are selected from the group of the C ₁ -alkyl, C _2-4 -alkenyl, C _2-4 -alkynyl, C _3-7 -Cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, hydroxy, ω-hydroxy-d _-3 -alkyl, ω- (C _M -alkoxy) C _1-3 -alkyl and C _{1 -4} alkoxy radicals. further, in X, X or X "is a carbon atom doubly and / or one or two carbon atoms mono- or disubstituted, preferred substituents are selected from the group d. _4- alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 cycloalkyl and C _3-7 cycloalkyl-C _1-3 alkyl, and two C 1-6 alkyl and or C _2-4 alkenyl substituents may also be linked together to form a saturated or monounsaturated carbocyclic ring.

Advantageously, the group X in the meaning C ₂ -Alkylenoxy, in particular -CH ₂ - CH ₂ -CH ₂ -O-, no hydroxy substituent on.

Very particularly preferred substituents of one or two C atoms in X, X or X "are selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl, where two alkyl substituents on a C atom also form a carbocyclic ring can be connected to each other. In the meanings of the substituents of the bridges X, X and / or X "listed above and below and the meanings of the bridges X, X 'and / or X" themselves, one or more carbon atoms can additionally be mono- or polysubstituted with F and or in each case one or two C atoms, in each case independently of one another, may additionally be monosubstituted by Cl or Br.

Is in the group X, X or X 'is a more C-atoms or with a hydroxy and / or C ,. ₄ alkoxy radical is substituted, the substituted C atom is preferably not directly adjacent to another heteroatom.

Preferably, X is an unbranched C _1-4 alkylene bridge and

for the case that the group Y is connected to X via a C atom, also -CH ₂ -CH = CH-, -CH ₂ -C≡C-, Q _M -alkyleneoxy or C ₂ -alkylene NR ⁴ -, in particular C ₂ - alkyleneoxy or C _2-4 alkylene-NR ⁴ -,

wherein R may be linked to Y to form a heterocyclic ring system,

wherein the bridge X may be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and

wherein in X is a C atom with R ¹⁰ and / or one or two C atoms each having one or two identical or different substituents selected from d. ₆ -alkyl, C _2-6 -alkenyl, C ₂ . _1-3 alkyl, C ^ cycloalkenyl, and C _4-7 cycloalkenyl Cι _-3 alkyl alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C, in particular selected from C - _{B 1-3} alkyl may be substituted, wherein two alkyl and / or alkenyl substituents may be linked together to form a carbocyclic ring system, and

where one or more C atoms in the abovementioned groups and radicals can be mono- or polysubstituted with F and / or one or two C atoms independently of one another and can be substituted simply by Cl or Br, and

wherein R ¹ , R ⁴ and R ^{10 are} as defined above and below.

The substituent R ¹⁰ is preferably a hydroxy, hydroxy-d. _3- alkyl, C _1-4 alkoxy C _1-3 alkyl and / or C _M alkoxy radical, especially hydroxy, hydroxymethyl or methoxy. Preferred meanings of the substituent R ⁴ are H, d. _6- alkyl and C _3-6 -AIkenyI. More preferably, R ^{4 is} H or C 1-4 alkyl. If R ^{4 is} linked to Y to form a heterocyclic ring system, particularly preferred meanings of R ^{4 are} C _2-6 -alkyl and C _2-6 -alkenyl.

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

Particularly preferably X is -CH ₂ -, -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ - and

in the event that the group Y is connected to X via a C atom (the group Y), also -CH ₂ -CH = CH-, -CH ₂ OC-, -CH ₂ -CH ₂ -O-, - CH ₂ -CH ₂ -CH ₂ -O- or

-CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, in particular -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, - CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -,

wherein R may be linked to Y to form a heterocyclic ring system,

wherein the bridge X may be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and

where in X a C atom with R ¹⁰ and / or one or two C atoms can each independently be substituted by one or two identical or different d ^ -alkyl radicals, two alkyl radicals with formation of a carbocyclic ring system with one another can be connected; preferably wherein in X one or two carbon atoms may each independently be substituted with one or two identical or different C _1-3 -alkyl radicals, two alkyl radicals with formation of a carbocyclic ring system, in particular a cyclopropyl group, with one another can be connected, and

wherein in each case one or more C atoms may be mono- or polysubstituted with F and / or in each case one or two C atoms independently of one another may be substituted by CI or Br, preferably in each case one or more C atoms are mono- or polysubstituted by F may be substituted. It is very particularly preferred for the case that the group Y is connected to X via a C atom (the group Y), -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, 1,1-Cyclopropylene, -CH ₂ - CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, where these groups are unsubstituted or in which the alkylene bridge is as indicated, preferably mono- or disubstituted by methyl and / or fluorine.

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

The group X preferably has no carbonyl group.

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

In the event that the index b is 1, X is more preferably -CH ₂ - or 1,1-cyclopropylene. In this case, X in the meaning -CH ₂ - may be linked together with Y to form a bicyclic ring system as indicated, for which purpose the -CH ₂ -bridge is substituted by C _2-3 -alkyl. The -CH ₂ bridge can be one or two

Substituents independently selected from the group consisting of C _1-3 alkyl, wherein two alkyl radicals may be connected together to form a carbocyclic ring system.

In the event that the index b has the value 0, X is particularly preferably -CH ₂ - CH ₂ -, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, wherein said groups may have one or two substituents independently selected from the group consisting of C _1-3 -alkyl, wherein two Alkyl radicals may be connected together to form a ring system.

The bridge X can also mean a single bond. Preferably, the bridge X forms a single bond only when Y represents a bicyclic ring system. Furthermore, the bridge X may preferably only be a single bond if the compound according to the invention can be described according to one of the partial formulas Ia, Ib or Id, in particular according to one of the partial formulas Ia or Ib, very particularly preferably of the partial formula Ib. The group Y preferably has a meaning which is selected from the group of the bivalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl or benzoxazolyl, the abovementioned cyclic groups may be mono- or polysubstituted to one or more carbon atoms with R ²⁰ , in the case of a phenyl group also additionally simply with nitro, and / or to one or more N atoms with R ²¹ . Here, R ¹ may be connected to Y and / or X to Y as indicated above.

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

Particularly preferred is a meaning of the group Y selected from the group of bivalent cyclic groups

In particular, Y has one of the following meanings

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

The group Y may be linked to the group X to form a carbamoyl or heterocyclic group fused to Y. Here preferred meanings of the interconnected groups -X-Y- are selected from the list consisting of

wobei in den vorstehend aufgeführten bicyclischen Gruppen der Phenyl-Ring ein- oder mehrfach mit R²⁰ oder auch zusätzlich einfach mit Nitro, und der gesättigte carbocyclische Ring ein- oder zweifach mit d^-Alkyl substituiert sein kann.in particular

wherein in the bicyclic groups listed above, the phenyl ring may be monosubstituted or polysubstituted with R ²⁰ or additionally simply with nitro, and the saturated carbocyclic ring may be monosubstituted or disubstituted with d 1-4 -alkyl.

The group Y is preferably unsubstituted or monosubstituted or disubstituted.

Particularly preferred substituents R ^{20 of} the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C 1-6 -alkyl, C _2-6 -alkenyl, hydroxy, hydroxy-C _1-3 -alkyI, C- _M alkoxy, trifluoromethyl, trifluoromethoxy, C ₂ alkynyl, C _1-4 alkoxy carbonyl, Cι_ _{alkoxy! -3} alkyl, _C1-4 alkoxy-carbonylamino, amino, d ^ alkyl-amino, di- (C ₁ alkyl) -amino, aminocarbonyl, C ^ alkyl-amino-carbonyl, di- (Cι _-4 alkyl) amino carbonyl, -CH = N-OH and -CH = NOC _1-4 -alkyl.

Very particularly preferred substituents R ^{20 of} the group Y are selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, C _1-3 -alkyl, C _1-3 -alkoxy, C 1-4 -alkoxycarbonyl, trifluoromethyl, Trifluoromethoxy, amino, in the case of a phenyl ring also nitro.

Most preferably, the group Y represents substituted phenylene

Partial formula wherein L is one of those previously for R ²⁰

meanings indicated, preferably F, CI, Br, I, CH _3, CF _3, OCH _3, OCF, methoxycarbonyl, ethoxycarbonyl, CN, amino, or NO ₂₎ has or H.

A preferred meaning of group A is aryl or heteroaryl.

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

Preferably, the group A does not have a substituent selected from the group consisting of C _1-4 -alkyl-sulfonylamino, C _1-4 -alkyl-carbonyl-amino, C _1- alkyl -sulfonylamino-C _1-3 -alkyl, C _1- alkyl-carbonyl-amino-C _1-3 alkyl, and phenylcarbonylamino on. Further, non-preferred substituents are aminocarbonyl, C ₁ -alkylaminocarbonyl, di- (C _1- -alkyl) -aminocarbonyl, cyclo-C _3-6 -alkyl-amino-carbonyl, cyclo-C _3-6 -alkylenimino-carbonyl, cyclo-C _3-6 -alkyleneimino-C _2-4 -acyl-aminocarbonyl, phenyl -amino-carbonyl, aminocarbonyl-d. 3-alkyl, C _1-4 -alkylaminocarbonyl-Cι _-3 -alkyl, di- (C _1-4 -alkyl) aminocarbonyl-Cι _-3 -alkyl, cyclo-C _3-6 - alkyl-amino-carbonyl-C _3- alkyl, cyclo-C _3-6 -alkylenimino-carbonyl-C _1-3 -alkyl, cyclo-C _3-6 -alkylenimino-C _2-4 -alkyl-aminocarbonyl-C _1-3 -alkyl and phenyl- amino-carbonyl-Cι _-3 -alkyl.

In addition, the group A preferably has no substituent selected from the group consisting of nitro and tert-butyloxycarbonylamino in each case in the ortho position to the bridge W.

If b has the value 0, the group A is preferably monosubstituted, disubstituted or trisubstituted.

If b has the value 1, the group A is preferably unsubstituted or monosubstituted or disubstituted. If b has the value 1 and the group A is monosubstituted, then the substituent is preferably in the ortho position with respect to the group W.

Most preferably, A is one of the groups listed below

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

Particularly preferred substituents R ²⁰ of group A are selected from the group consisting of fluorine, chlorine, bromine, cyano, C _1- alkyl, C _2-6 alkenyl, -CHO, hydroxy, hydroxy-Cι. ₃ -alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, C ₂ alkynyl, carboxy, C, _ ₄ alkoxycarbonyl, C _1-4 alkoxy-C _1-3 alkyl, C ₁ alkoxy carbonylamino, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cyclo C _3-6 alkyleneimino, aminocarbonyl, C _1-4 alkyl amino carbonyl, di (C _1- alkyl) amino carbonyl, -CH = N-OH and -CH = NOC _1-4 alkyl. Very particularly preferred substituents R ²⁰ of group A are selected from among fluorine, chlorine, bromine, cyano, C _1-4 -alkoxy, trifluoromethyl, trifluoromethoxy, carboxy, C _1-4 -alkoxycarbonyl, C ₁ -alkyl amino and di (C _M alkyl) amino

In the event that b has the value 0, a particularly preferred meaning of the group A is substituted phenyl of the partial formula

wherein

has one of the meanings given for R ²⁰ or H, preferably F, CI, Br, I, CH ₃ , CF ₃ , OCH ₃ , OCF _3> CN or NO ₂ ; particularly preferably F, Cl or Br;

has one of the meanings given for R ²⁰ or H, preferably F, Cl, Br, I, CF ₃ , OCF ₃ , CN, NO ₂ , C 1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl- Cι _-3 alkyl, C _1- alkoxy, C _3-7 cycloalkyl-O-, C _3-7 cycloalkyl-C _1-3 -alkoxy, -COO-C _M alkyl or -COOH; particularly preferably F, Cl, Br, C _1-4 alkyl, CF ₃ , methoxy, OCF ₃ , CN or NO ₂ ; most preferably CI, Br, CF ₃ or NO ₂ ;

q has the value 0, 1 or 2.

with the proviso that the phenyl group can only be substituted with nitro at most.

A is particularly preferably substituted phenyl according to the above sub-formula in which q is 1 or 2 and / or at least one substituent L ^{2 is} in the meta position to the substituent L ³ . Furthermore, a preferred sub-formula for A, in particular for the case where b is the value 0

, wobei die Bindung zur Gruppe W über das C-Atom mit der Positionsnummer 2 oder 3 erfolgt und L² und L³ wie zuvor definiert sind.owns, is

in which the bond to the group W is via the C-atom with the position number 2 or 3 and L ² and L ^{3 are} as previously defined.

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

Preferred meanings of group B are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl. Most preferably, the group B is phenyl. The group B in the meanings given may be mono- or polysubstituted with R ²⁰ , a

Phenyl group additionally also be easily substituted with nitro. Preferably, the group B is mono-, di- or trisubstituted, in particular monosubstituted or disubstituted. In the case of a single substitution, the substituent is preferably in ortho or para position, in particular para position to group A.

Particularly preferred substituents R ²⁰ of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, C ₁ -alkyl, hydroxy, hydroxy-C _{3 -3} -alkyl, d. ₄ -alkoxy, trifluoromethyl, trifluoromethoxy, C _2-4 alkynyl, carboxy, C _1-4 alkoxycarbonyl, d. ₄ -alkoxy-Cι _-3 alkyl, C _1-4 alkoxy-carbonylamino, amino, C _1-4 alkyl-amino, di- (C _-4 alkyl) - amino, cyclo-C _3-6 -alkylenimino-, aminocarbonyl, C _1-4 -alkyl-amino-carbonyI- and di- (Cι _-4 - alkyl) -amino-carbonyk

Very particularly preferred substituents R ²⁰ of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF ₃ , C _1-3 -alkyl, C ₁ -alkoxy and trifluoromethoxy or nitro; in particular fluorine, chlorine, bromine, methoxy, CF ₃ and trifluoromethoxy.

In general, R ^{4 has} one of the meanings given for R ¹⁷ , preferably one of R ¹⁶ .

Particularly preferred meanings of the substituent R ⁴ are H, C _1-6 -alkyl and C _3-6 -alkenyl. If R ^{4 is} linked to Y to form a heterocyclic ring system, particularly preferred meanings of R ^{4 are} C _2-6 -alkyl and C _2-6 -alkenyl. When R ^{11 is} a C _2-6 alkenyl or C _2-6 alkynyl group, then the meanings are -CH = CH ₂ , -CH = CH (CH ₃ ), -CH = C (CH ₃ ) ₂ and also -C≡CH, -C≡C-CH ₃ preferred.

The substituent R ²⁰ preferably has none of the following structural elements: a) -CO-aryl or -CO-heteroaryl, in particular -CO-phenyl, where heteroaryl, aryl and phenyl may be substituted, b) -C (= NH) -NH -, Wherein the H atoms may be substituted and / or c) -NH-CO-NH-, wherein the H atoms may be substituted.

Generally preferred meanings of the group R ²⁰ are halogen, hydroxy, cyano, C _1-4 - alkyl, C _3-7 cycloalkyl, Cι _-4 alkoxy, C _1-4 alkoxycarbonyl or amino, wherein, as hereinbefore defined, 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, in each case independently of one another, may additionally be substituted simply by Cl or Br. R ^{20 is} particularly preferably F, CI, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, methoxycarbonyl , Ethoxycarbonyl or amino.

Preferred meanings of the group R ²¹ are C _1- alkyl, C _1-4 -AlkyIcarbonyl, C _1- -

Alkoxycarbonyl, C _1-4 alkylsulfonyl, -SO ₂ -NH ₂ , -SO ₂ -NH-C _1-3 -alkyl, -SO ₂ -N (C _1-3 -alkyl) ₂ and cycloC _3-6 -alkyleneimino-sulfonyl-, where, as defined above, in each case one or more C atoms additionally mono- or polysubstituted with F and / or in each case one or two C-atoms independently can additionally be additionally substituted simply with CI or Br ,

Very particularly preferred meanings of R ²¹ are H, C _1-4 -alkyl, C _1-4 -alkylcarbonyl, C _1-4 -alkoxycarbonyl, in particular H and C _1-3 -alkyl.

Cy preferably denotes a C _3-7 -cycloalkyl, in particular a C _5-7 -cycloalkyl group, a C _5-7 -cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, where aryl or Heteroaryl is preferably a monocyclic or condensed bicyclic ring system, and where the abovementioned cyclic groups are mono- or polysubstituted to one or more C atoms with R ²⁰ , in the case of a phenyl group additionally also simply with nitro, and / or one or more NH- Groups with R ²¹ can be substituted. Those compounds according to the invention are preferred in which one or more of the groups, radicals, substituents and / or indices has one of the meanings given above as being preferred.

In particular, those compounds according to the invention are preferred in which

the bridge X is -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or 1,1-cyclopropylene, and

for the case that the group Y is connected to X via a C atom (the group Y), also -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ - may mean

wherein the groups indicated for X are unsubstituted or in which the alkylene bridge is as indicated, preferably one or two times substituted with methyl and / or fluorine, where two methyl groups may be linked together to form a cyclopropyl ring; and

the group Y has one of the following meanings

or the group Y is connected to the group X to form a carbo or heterocyclic group fused to Y, where the groups -XY-

means

wherein the abovementioned phenyl rings or bicyclic groups having heteroatoms are monosubstituted or polysubstituted by R ²⁰ and phenyl rings are also additionally monosubstituted by nitro, and the saturated carbocyclic ring in the indane skeleton is monosubstituted or disubstituted by C 1-3 -alkyl can be, and

Group A is one of the subformulae listed below

means which may be mono- or polysubstituted with R ²⁰ , wherein in the event that the index b has the value 0, the group A has no amino group as a substituent in the ortho position to the bridge W, and

the group B phenyl, which is mono- or polysubstituted by R ²⁰ , means and

b has the value 0 or 1.

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

Preferred groups of compounds according to this invention can be obtained by the following formulas, more preferably by the formulas la.1, la.2a, la.2b, la.3, la.5, la.6, la.7, la.8, lb.1, lb.2, lc.1 and ld.1 describe

where the bridges X contained in the formulas la.1 to la.8, lb.1, lc.1 and ld.1 in the meanings -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ - NR ⁴ -, -CH ₂ -CH ₂ -CH ₂ -NR ⁴ -, -CH ₂ -CH ₂ -O- and -CH ₂ -CH ₂ -CH ₂ -O- one or two substituents independently selected from the group consisting of C _1-3 -alkyl and C _3-5 -cycloalkyl, wherein two alkyl substituents may be linked together to form a C _3-6 -cycloalkyl group; particularly preferably, the abovementioned bridges X, in particular the meaning -CH ₂ -, may have one or two methyl substituents, where two methyl substituents may be linked together to form a cyclopropyl group; and wherein L ¹ , R ¹ , R ² , R ³ , R ⁴ and R ^{20 have} the meanings given above and multiply occurring substituents may have the same or different meanings; in particular

R ^1, R are alkyl from the group consisting of Cι _-6 alkyl, C ₃ _ ₇ cycloalkyl, C _3-7 cycloalkyl-C _1-3 ² independently selected, tetrahydropyran-3- or -4- yl, tetrahydropyranylC _1-3 alkyl, piperidin-3 or -4-yl, where the NH group may be substituted with R ¹³ , piperidinyl-C _1-3 alkyl, wherein the NH group with R ¹³ may be substituted, phenyl, pyridyl, phenyl C _1-3 alkyl, pyridyl-C _1-3 alkyl, hydroxy-C _2-4 alkyl, d. -Alkoxy-C ₂ ^ .- alkyl, amino-C _2-4 alkyl, C _1- alkyl-amino-C _2-4 alkyl- and di- (C-ι _-4 alkyl) - amino- C _2-4 -alkyl-, wherein cycloalkyl rings one, two or three times with substituents selected from hydroxy, hydroxy-C _{3 -3} alkyl, C _1-3 -alkyl or C _1-3 -alkoxy, in particular hydroxy, Hydroxymethyl, methyl and methoxy may be substituted, and wherein C _2-4 alkyl bridges in the meanings hydroxy-C _2-4 alkyl and C _1-4 alkoxy-C _2-4 alkyl additionally simple with hydroxy hydroxy-Cι _-3 alkyl, C _1-3 alkyl or C especially hydroxy, hydroxymethyl, methyl or methoxy may be substituted _1-3 alkyloxy, and wherein alkyl groups mono- or poly-F and / or simply with may be substituted with CI, and wherein one of R ¹ and R ^{2 may} also be H; or

eine Bedeutung gemäß einer der folgenden TeilformelnR ¹ , R ² are linked together in such a way that the group

a meaning according to one of the following sub-formulas

wherein, in the heterocycle formed by the group R ¹ R ² N- one or more H atoms by R ¹⁴ and / or an H atom by Cy in the meaning C _3-6 - cycloalkyl, the one or more times with R ²⁰ , in particular with F, hydroxy, -C. _3- alkyl, CF ₃ , C _1-3 alkyloxy, OCF ₃ or hydroxy-C _1-3 alkyl, particularly preferably with F, hydroxy, methyl, methoxy, CF ₃ , OCF ₃ or hydroxymethyl may be substituted can, and

wherein the ring connected to the heterocycle formed by the group R ¹ R ² N- may be monosubstituted or polysubstituted, preferably simply substituted on one or more carbon atoms by R ²⁰ , and in the case of a phenyl ring may additionally also be substituted simply by nitro and

R ^{3 is} preferably H or methyl,

R ^{14 are} each independently of one another F, Cl, C _1-4 alkyl, C _3-6 cycloalky [-d _-3 alkyl, hydroxy, hydroxyC _1-3 alkyl, C _1-4 alkoxy, C _1- alkoxy-C _1-3 -alkyl, pyridylamino or aminocarbonyl, where in each case one or more C atoms may additionally be monosubstituted or polysubstituted by F or in each case one C atom may simply be substituted by Cl; very particularly preferably methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxy,

Ethoxy, methoxymethyl, pyridylamino or aminocarbonyl; and

R ¹³ is H, C _1- alkyl, C _1-4 -Alkylcarbonyi or C _1- alkyloxycarbonyl group; particularly preferably H or C _1-3 alkyl; and

Q is CH or N, where CH can be substituted by R 1 ^υ ,

L ^{1 is} preferably fluorine, chlorine, bromine, cyano, C _1-3 -alkyl, d 1-4 -alkyl, trifluoromethyl,

Trifluoromethoxy, C 1-4 alkoxycarbonyl, amino or nitro; particularly preferably fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, methoxycarbonyl,

Ethoxycarbonyl, cyano, amino or nitro; has the value 0 or 1,

Amino-, C_1-4-Alkyl-amino-, Di-(C_1-4-alkyl)-amino-, Aminocarbonyl-, C-_M-Alkyl-amino-carbonyl-, Di-(C_1-4-aIkyl)-amino-carbonyl-, bedeutet, wobei für den Fall, dass der Index b den Wert 0 besitzt, die Gruppe Cy keine Amino-Gruppe als Substituenten in ortho-Stellung zur Brücke W aufweist;R 20 each independently preferably fluoro, chloro, bromo, cyano, nitro, d. 4-alkyl, C _2-6 alkenyl, hydroxy, hydroxyC 1-6 alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _2-4 alkynyl, carboxy, C _1-4 alkoxycarbonyl, C _{1 -4-} alkoxy-C _1-3 -alkyl,

Amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, aminocarbonyl, C- _M alkylamino-carbonyl, di (C _1-4 alkyl) ) -amino-carbonyl-, wherein in the event that the index b has the value 0, the group Cy has no amino group as substituent in the ortho position to the bridge W;

more preferably R ²⁰ is selected from fluorine, chlorine, bromine, cyano, nitro, C ₁ - alkyl, hydroxy, hydroxy-C _1-3 -alkyI, Cι _-4 alkoxy, trifluoromethyl, trifluoromethoxy, C ₂ - alkynyl, Carboxy, C _1-4 alkoxycarbonyl and C, _M alkoxy-ds-alkyl;

most preferably fluorine, chlorine, bromine, cyano, CF ₃ , C _1-3 alkyl, C _1-4 alkoxy and trifluoromethoxy or nitro;

r, s each independently of one another have the value 0, 1, 2 or 3, preferably at least one index r or s does not denote the value 0, and

wherein the compounds according to the provisos (M1) to (M14) are not included.

The groups contained in formulas la.1 to ld.2

und weisen vorteilhaft folgendes

and advantageously have the following

bzw.Substitution pattern on:

respectively.

wherein R ^{20 has} one of the meanings given above, including H, and wherein multiple occurring substituents R ^{20 may have the} same or different meanings, and preferably wherein at least one substituent R ^{20 has} a different meaning from H. The compounds listed in the examples and tables, including their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, are preferred according to the invention. Particularly preferred compounds are listed below, with the example number in question in brackets:

3- (4-piperidin-1-ylmethyl-phenyl) -propynoic acid (4'-methoxy-biphenyl-4-yl) -amide [1-8];

3- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -propynoic acid (4'-methoxy-biphenyl-4-yl) -amide [1-11]; 3- (4-pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4'-chloro-3-fluoro-biphenyl-4-yl) -amide [1.17];

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

[1-18];

3- [4 - ((R) -2-hydroxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-3-fluoro-biphenyl-4-yl) -amide [1-20]; 3- [4- (4-hydroxy-piperidin-1-ylmethyl) -phenyl] -propinsäure- (4'-chloro-3-fluoro-biphenyl-4-yl) -amide

[1-21];

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide [1-23];

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-33];

3- {4- [4- (1-Hydroxy-1-methyl-ethyl) -piperidin-1-ylmethyl] -phenyl} -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-34 ];

3- [4- (4-Methyl-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-35];

3- [4- (4-methoxy-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-36];

3- [4- (4-Hydroxy-4-methylpiperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-37]; 3- (4-piperidin-1-ylmethyl-phenyl) -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-38];

3- {4 - [(Cyclohexyl-ethyl-amino) -methyl] -phenyl} -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [1-

52];

3- {4- [cyclopentyl-methyl-amino) -methyl] -phenyl} -propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide [1-

425]; 3- (1-pyrrolidin-1-yl-indan-5-yl) -propynoic acid (4'-chloro-biphenyl-4-yl) -amide [2-3];

3- (4'-Chloro-biphenyl-4-yl) -propynoic acid (4-piperidin-1-ylmethyl-phenyl) -amide [3-6];

3- (4'-Chlorobiphenyl-4-yl) -propynoic acid [4- (4-methoxy-piperidin-1-ylmethyl) -phenyl] -amide [3

13];

3- (4'-Chloro-biphenyl-4-yl) -propynoic acid [4- (4-methylpiperidin-1-yl-methyl) -phenyl] -amide [3-14]; 3- (4'-Chloro-biphenyl-4-yl) -propynoic acid {4 - [(cyclopropylmethyl-methyl-amino) -methyl] -phenyl} -amide [3-15]; 3- (4'-Chloro-biphenyl-4-yl) -propynoic acid [4- (4-hydroxy-4-trifluoromethyl-piperidin-1-ylmethyl) -phenyl-amide [3-17];

3- (4'-Chloro-biphenyl-4-yl) -propynoic acid [4- (4-hydroxy-1-piperidin-1-ylmethyl) -phenyl] -amide [3

18]; 3- [5- (4-Chloro-phenyl) -pyridin-2-yl] -propynoic acid (4-piperidin-1-ylmethyl-phenyl) -amide [3-25];

3- [5- (4-Chloro-phenyl) -pyridin-2-yl] -propynoic acid [4- (3,5-dimethyl-1-piperidin-1-ylmethyl) -phenyl] -amide [3-29];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (2-diethylamino-ethoxy) -phenyl] -amide [3

38]; 3- (2,4-dichloro-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide [4-1];

3- (2,4-dichloro-phenyl) -propynoic acid [3-methoxy-4- (2-diethylamino-ethoxy) -phenyl] -amide-hydrochloride [4-7];

3- (4-Chloro-phenyl) -propynoic acid [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide [4-10];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide [4-11];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-bromo-4- (2-diethylamino-ethoxy) -phenyl] -amide [4-15];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-nitro-4- (2-diethylamirio-ethoxy) -phenyl] -amide [4-17]; 3- (2-Chloro-4-thifluoromethyl-phenyl) -propynoic acid [3-methoxy-4- (2-diethylamino-ethoxy) -phenyl] -amide-hydrochloride [4-20];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-methyl-4- (2-diethylamino-ethoxy) -phenyl] -amide [4-21];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (3-diethylamino-ethoxy) -3-fluoro-phenyl] -amide [4-25];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl-amino] -phenyl} -amide [4-27] ;

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

[4-31]; 3- (4-Bromo-2-chloro-phenyl) -propionic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide [4-

35];

3- (2-Chloro-4-thifluoromethyl-phenyl) -propynoic acid {3-methoxy-4- [2- (4-methylpiperidin-1-yl) -ethoxy] -phenyl} -amide [4-270] ;

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (3,5-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxyphenyl} -amide [4- 271];

3- (2-Chloro-4-thifluoromethyl-phenyl) -propynoic acid {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxyphenyl} -amide [4- 277]; 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (cyclopropylmethyl-methyl-amino) -ethoxy] -3-methoxyphenyl} -amide-hydrochloride [4-278];

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (cyclopropylmethyl-propyl-amino) -ethoxy] -3-methoxyphenyl} -amide-hydrochloride [4-279]; (E) -Λ / - (4'-Chloro-biphenyl-4-yl) -3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -acrylamide [5-2]; (E) - / V- (4'-chlorobiphenyl-4-yl) -3- [4- (4-methoxy-piperidin-1-ylmethyl) -phenyl] -acrylamide [5-4]; 1- {4 - [(E) -2- (4'-Chloro-biphenyl-4-ylcarbamoyl) -vinyl] -benzyl} -piperidine-4-carboxylic acid amide [5-6]; (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4 - {[methyl- (tetrahydro-pyran-4-yl) -amino] -methyl} -phenyl) -acrylamide [ 5-7]; (E) -Λ / - ^{(4-chloro-biphenyl-4-yl)} -3- [4- (4-hydroxymethyl-piperidin-1-ylmethyl) phenyl] acrylamide [5-8]; (E) -Λ / - (4'-Chloro-biphenyl-4-yl) -3- [4 - ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) phenyl] acrylamides

[5-9];

(E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide [5-13]; (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4-cyclopropylaminomethyl-phenyl) -acrylamide [5-14];

(E) -Λ / - ^{(4-chloro-biphenyl-4-yl)} -3- {4 - [(cyclopropylmethyl-methyl-amino) -methyl] -phenyl} - acrylamide [5-17];

(E) - / V- ^{(4-chloro-biphenyl-4-yl)} -3- {4 - [(cyclohexyl-methyl-amino) -methyl] -phenyl} -acrylamide [5-

19]; (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- {4 - [(cyclohexyl-methyl-amino) -methyl] -phenyl} -acrylamide [5-

21];

(E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- [4- (2,6-dimethyl-morpholin-4-ylmethyl) -phenyl] -acrylamide [5-

23];

(E) -3- [4- (8-aza-spiro [4.5] dec-8-ylmethyl) -phenyl] -Λ / - (4'-chlorobiphenyl-4-yl) -acrylamide [5-25] ; (E) -Λ / - (4'-chloro-biphenyl-4-yl) -3- (4 - {[(2-hydroxy-2-methyl-propyl) - (2-methoxy-ethyl) -amino] - methyl} -phenyl) acrylamide [5-27];

(E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- [4- (3-piperidin-1-yl-pyrrolidin-1-ylmethyl) -phenyl] -acrylamide [5-

28]

/ V- (4'-chlorobiphenyl-4-yl) -3- [4- (4-methylpiperidin-1-ylmethyl) -phenyl] -propionamide [6-2]; Λ / - (4'-chlorobiphenyl-4-yl) -3- [4- (4-methoxy-piperidin-1-ylmethyl) -phenyl] -propionamide [6-3];

Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-morpholin-4-ylmethyl-phenyl) -propionamide [6-4];

1- {4- [2- (4'-Chloro-biphenyl-4-ylcarbamoyl) -ethyl] -benzyl} -piperidine-4-carboxylic acid amide [6-5];

Λ / - (4'-Chlorobiphenyl-4-yl) -3- [4- (4-hydroxymethyl-1-piperidin-1-ylmethyl) -phenyl] -propionamide [6-

6]; Λ / - (4'-chlorobiphenyl-4-yl) -3- [4 - ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) -phenyl] -propionamide [6-

7]; Λ / - (4'-chlorobiphenyl-4-yl) -3- [4 - ((R) -2-hydroxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -propionamide [6-8];

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

[6-9]; Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -propionamide [6-11];

Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4 - {[methyl- (tetrahydro-pyran-4-yl) -amino] -methyl} -phenyl) -propionamide [6-12] ;

/ V- (4'-chloro-biphenyl-4-yl) -3- {4 - [(cyclopropylmethyl-methyl-amino) -methyl] -phenyl} -propionamide [6-13]; Λ / - (4'-Chloro-biphenyl-4-yl) -3- (4 - {[(2-hydroxy-2-methyl-propyl) - (2-methoxy-ethyl) -amino] -methyl} -phenyl ) -propionamide [6-14];

Λ / - (4'-chlorobiphenyl-4-yl) -3- {4 - [(cyclopropyl-methyl-amino) -methyl] -phenyl} -propionamide [6-

15]; tV- (4'-chlorobiphenyl-4-yl) -3- [4- (hexahydro-pyrrolo [1,2-a] pyrazin-2-ylmethyl) -phenyl] -propionamide [6-16];

Λ / - (4'-chlorobiphenyl-4-yl) -3- (4 - {[(2-methoxy-ethyl) -methyl-amino] -methyl} -phenyl) -propionamide [6-17];

3- {4 - [(Benzyl-methyl-amino) -methyl] -phenyl} -W- (4'-chloro-biphenyl-4-yl) -propionamide [6-18];

Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4 - {[methyl- (tetrahydro-pyran-4-ylmethyl) -amino] -methyl} -phenyl) -propionamide [6-19] ;

Λ / - (4'-chlorobiphenyl-4-yl) -3- (4 - {[methyl (2-phenoxyethyl) amino] methyl} phenyl) propionamide [6-20];

A / - (4'-Chlorobiphenyl-4-yl) -3- [4- (2,6-dimethyl-morpholin-4-ylmethyl) -phenyl] -propionamide [6-

21]; - (4'-Chloro-biphenyl-4-yl) -3- {4 - [(cyclohexyl-methyl-amino) -methyl] -phenyl} -propionamide [6-

22];

A / - (4'-Chlorobiphenyl-4-yl) -3- [4- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -phenyl] -propionamide [ 6-23];

W- (4'-chlorobiphenyl-4-yl) -3- [4- (3-piperidin-1-yl-pyrrolidin-1-ylmethyl) -phenyl] -propionamide [6-25];

Λ / - (4'-Chlorobiphenyl-4-yl) -3- [4 - ((3S, 5R) -3,5-dimethyl-piperidin-1-ylmethyl) -phenyl] -propionamide [6-26] ;

3- (4 - {[(3-Amino-propyl) -methyl-amino] -methyl} -phenyl) -Λ / - (4'-chloro-biphenyl-4-yl) -propionamide

[6-27]; 3- [4- (8-aza-spiro [4.5] dec-8-ylmethyl) -phenyl] - / V- (4'-chloro-biphenyl-4-yl) -propionamide [6-28];

A / - (4'-Chlorobiphenyl-4-yl) -3- [4 - ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -phenyl] -propionamide [6-

29]; Λ / - (4'-chlorobiphenyl-4-yl) -3- {4 - [(methylpyridin-3-ylmethylamino) methyl] phenyl} propionamide [6-33];

N- (4'-chlorobiphenyl-4-yl) -3- {4 - [(cyclohexyl-ethyl-amino) -methyl] -phenyl} -propionamide [6-35]; A / - (4'-chlorobiphenyl-4-yl) -3- (4-cyclohexylaminomethyl-phenyl) -propionamide [6-39]; Λ / - (4'-chlorobiphenyl-4-yl) -3- {4 - [(cyclohexyl-isopropyl-amino) -methyl] -phenyl} -propionamide [6-40];

Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-cyclopentylaminomethyl-phenyl) -propionamide [6-41]; Λ / - (4'-chlorobiphenyl-4-yl) -3- (4 - {[ethyl- (2-hydroxy-2-methyl-propyl) -amino] -methyl} -phenyl) -propionamide [6- 42];

including their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

In the following, terms which are used previously and hereinafter for the description of the compounds according to the invention are defined in more detail.

The term halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular 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. Substituted alkyl radicals such as the C _2-4 alkyl group in hydroxyC _2-4 alkyl or C _1-4 alkoxyC _2-4 alkyl may also be branched or unbranched.

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, where 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, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and an O≡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 denotes a C ₁ . _n -Alkyl-S group, wherein Cι- _n- alkyl is as defined above. Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, tert-pentylthio, n-butylthio Hexylthio, iso-hexylthio, etc.

The term C _1-n -alkylcarbonyl refers to a C _1-n -alkyl-C (= O) group, wherein C _1-n -alkyl is as defined above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso -propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-butyl Hexylcarbonyl, iso-hexylcarbonyl, etc.

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

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

The term C _3-n -cycloalkylcarbonyl refers to a C _3-n -cycloalkyl-C (= O) group in which C ₃ . _n - cycloalkyl as defined above. The term aryl refers to a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. A particularly preferred meaning of "aryl" is phenyl.

The term cyclo-C _3-7 -alkyleneimino- refers to a 4- to 7-membered ring containing 3 to 7

Having methylene units and an imino group, wherein the bond to the rest of the

Molecule takes place via the imino group.

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

The term heteroaryl used in this application denotes a heterocyclic aromatic ring system which, in addition to at least one C atom, has one or more

Heteroatoms selected from N, O and / or S includes. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- Oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,

Tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl , etc. The term heteroaryl also includes the partially hydrogenated heterocyclic aromatic ring systems, in particular the ring systems listed above. Examples of such partially hydrogenated heterocycles are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc. Particularly preferred heteroaryl means a heteroaromatic mono- or bicyclic ring system.

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

Some 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. The term "unsaturated", for example in "unsaturated carbocyclic group" or "unsaturated heterocyclic group", as used in particular in the definition of the group Cy, in addition to the mono- or polyunsaturated groups also includes the corresponding fully unsaturated groups, but especially mono- and diunsaturated groups.

The term "optionally substituted" used in this application means that the group so designated is either unsubstituted or monosubstituted or polysubstituted by the specified substituents. If the group in question is substituted several times, the substituents may be the same or different.

The notation used above and below 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 bonds to any free position of the cyclic group carrying an H atom can be.

jede der freien Positionen des Phenylrings gebunden sein; im Fall s = 2 können unterschiedlich voneinander ausgewählte Substituenten R²⁰ an unterschiedliche, freie Positionen des Phenylrings gebunden sein.Thus, in the example, the substituent R in the case s = 1 on

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

The H atom of an existing carboxy group or an H atom bound to an N atom (imino or amino group) can each be replaced by a residue which can be split off in vivo. Under a cleavable by a N-atom in vivo radical is understood to mean, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a Cι _-16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or Hexanoyl, an allyloxycarbonyl, a -C ι ₆ alkoxycarbonyl such as

Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl groups, a phenyl-Cι. 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 Cι _-8 alkyl, C _5-7 alkyl cycloalkyl, phenyl or phenyl C _1-3,

R _{f is} a hydrogen atom, a d ^ -Alky! -, 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,

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 radicals and substituents described above may be mono- or polysubstituted by fluorine in the manner described. Preferred fluorinated alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.

The compounds of the general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups, e.g. Amino functions. Compounds of general formula I can therefore be used as internal salts, as salts with pharmaceutically acceptable 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 Diethylamine, triethylamine, triethanolamine, and the like. available.

The compounds according to the invention can be obtained using synthesis methods known in principle. The compounds are preferably obtained in analogous application to the production process explained in more detail below, which likewise

Represent subject of this invention. The abbreviations used below are defined in the introduction to the experimental part or are familiar to the person skilled in the art as such.

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

O

R \

N - X - Y - IHCCC - - - | -B] _fc

R 2 /

ib

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

Scheme 2:

Hai: Br, I when R = alkyne, Y = H when R = aryl, Y = B (OH) ₂

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

Scheme 3a:

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

Scheme 3b:

A5

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

Scheme 3c:

A8 A5

la

la

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

Scheme 4:

Ic

ic

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

Scheme 5:

A18

T = CI, MeSO ₂ 0-A20

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

The compounds according to the invention are also advantageously accessible by the processes described in the following examples, these being combined with processes known to those skilled in the art, for example from the literature, for example from WO 04/024702, WO 04/039780 and WO 04/039764 can.

In principle, stereoisomeric compounds of the formula (I) can be separated by customary methods. The separation of the respective diastereomers is possible due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.

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 contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which, when reacted with an optical 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.

According to a conventional isomer separation method, the racemate of a compound of the general formula (I) is reacted with one of the above-mentioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, 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 the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used. Then, each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.

In each case only the (R) - or (S) -enantiomer or a mixture of two optically active diastereomeric compounds falling under the general formula (I) is also obtained by reacting the syntheses described above with in each case one suitable (R) - or (S) - configured reaction component.

As mentioned above, the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen by reaction with inorganic bases, the compound of formula (I) can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid come into consideration for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used. For the preparation of the alkali metal and alkaline earth metal salts of the compound of the formula (I) with acidically bonded 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 are preferred, sodium and potassium hydroxide are particularly preferred.

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

As antagonists of the MCH receptor, the compounds of the invention are advantageously useful as pharmaceutical agents for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or in another causal relationship with MCH. In general, the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.

Therefore, MCH antagonists having at least one compound of the invention are particularly useful in mammals, such as rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys, and especially in humans, for treatment and / or Prophylaxis of symptoms and / or diseases caused by MCH or in another causal relationship with MCH.

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 indications of obesity include especially 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 obesity. Furthermore, cachexia, anorexia and hyperphagia are to be mentioned in this indication environment.

In particular, compounds of the invention may be useful in reducing hunger, curbing appetite, controlling eating behavior, and / or inducing satiety. In addition, diseases caused by MCH or otherwise causally related to MCH may also include 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 useful as agents for the prophylaxis and / or treatment of other diseases and / or disorders, in particular those with

Obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, heart failure, cardiovascular disease , especially arteriosclerosis and hypertension, arthritis and gonitis is suitable.

MCH antagonists and formulations according to the invention can advantageously be used in combination with an alimentary therapy, such as, for example, an alimentary diabetes therapy, and exercise.

Another area of indication for which the compounds of the invention are advantageously useful is the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.

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

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

In addition to medicaments, the invention also encompasses compositions comprising at least one amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients. Such compositions may, for example, also be foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.

For the abovementioned combinations, suitable further active substances are, in particular, those which, for example, enhance the therapeutic effectiveness 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 - active ingredients for the treatment of diabetes,

- agents for the treatment of diabetic complications,

Active ingredients 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,

Active ingredients for the treatment of anxiety,

- agents for the treatment of depression.

The aforementioned classes of active compounds are explained in more detail below by means of examples.

Examples of drugs for the treatment of diabetes are insulin sensitizers, insulin secretagogues, biguanides, insulins, α-glucosidase inhibitors, β3 adreno receptor agonists.

Insulin sensitizers include glitazones, especially 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, gliclazides, glimepirids. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608.

Biguanides include metformin, buformin, phenformin.

Insulins include insulins derived from animals, particularly cattle or swine, semi-synthetic human insulins enzymatically synthesized from animal-derived insulin, human insulin obtained by genetic engineering, for example from Escherichia coli or yeasts. Further, as insulin insulin zinc

(containing 0.45 to 0.9 weight percent zinc) and protamine insulin zinc available from zinc chloride, protamine sulfate and insulin. In addition, insulin can be obtained from insulin fragments or derivatives (e.g., INS-1, etc.).

Insulin may also include different types, for example with respect to

Entry and duration of action ("ultra-immediate action type", "immediate action type", "two-phase type", "intermediate type", "prolonged action type", etc.), which are selected depending on the pathological condition of the patients ,

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

β3 adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.

Other than the aforementioned agents for the treatment of diabetes include

Ergoset, Pramlintide, Leptin, BAY-27-9955 and Glycogen Phosphorylase Inhibitors, Sorbitol Dehydrogenase Inhibitors, Protein Tyrosine Phosphatase 1B Inhibitors, Dipeptidyl Protease Inhibitors, Giipizide, Glyburide.

Agents for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-1 analogs, SGLT-2 inhibitors. Aldose reductase inhibitors include, for example, Tolrestat, Epalrestat, Imirestat, Zenarestat, SNK-860, Zopolrestat, ARI-50i, AS-3201.

An example of a glycation inhibitor is pimagedine.

Protein kinase C inhibitors are, for example, NGF, LY-333531.

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

GLP-1 analogs include Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin).

SGLT-2 inhibitors are, for example, AVE-2268 (Aventis) and T-1095 (Tanabe,

Johnson & Johnson).

Alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711), other than the aforementioned drugs for the treatment of diabetic complications.

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

A preferred example of a lipase inhibitor is orlistat.

Examples of preferred anorectic agents are phentermine, mazindol, fluoxetine, sibutramine, baiamine, (S) -sibutramine, SR-141716, NGD-95-1.

Other than 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 ß ₃ agonists, thyromimetic agents and NPY antagonists are highlighted. The scope of the substances which are suitable here as preferred anti-obesity or anorectic active substances is given by way of example by the following list: Phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic drug, a serotonergic drug (such as dexfenfluramine, fenfluramine, or a 5-HT2C agonist such as BAT.933 or APD356), a dopamine

Agonist (such as bromocriptine or pramipexole), a melanocyte-stimulating hormone receptor agonist or mimetic, an analog of melanocyte-stimulating hormone, a cannabinoid receptor antagonist (rimonabant, ACOMPLIA ™), an MCH antagonist, OB protein (hereinafter referred to as leptin ), a leptin analog, a leptin receptor agonist, a galanin antagonist, a

Gl 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.

Agents for the treatment of hypertension include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists.

Inhibitors of the angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochlorides), lisinopril, imidapril, benazepril, cilazapril,

Temocapril, trandolapril, manidipine (hydrochloride).

Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.

Potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121.

Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.

Agents for the treatment of hyperipidemias, including arteriosclerosis, include HMG-CoA reductase inhibitors, fibrate compounds. HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and their salts.

Fibrate compounds include bezafibrates, clinofibrates, clofibrates, simfibrates.

Agents for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), in particular COX2 inhibitors such as meloxicam or ibuprofen.

Agents for the treatment of anxiety include chlordiazepoxides, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.

Agents for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.

The dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage.

In a further embodiment, the invention also relates to the use of at least one alkyne compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal. This use is based in particular on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing satiety. The eating behavior is favorably influenced so that the food intake is reduced. Therefore, find the inventive

Compounds beneficial application for reducing body weight. Another use of the invention is to prevent an increase in body weight, for example, in people who have previously taken weight-loss measures and are subsequently interested in maintaining the reduced body weight. In accordance with this embodiment, it is preferably a non-therapeutic use. Such a non-therapeutic use may be a cosmetic application, for example, for altering the appearance or an application for improving the general condition. The compounds according to the invention are preferably used non-therapeutically for mammals, in particular humans, who have no diagnosed disorders of eating behavior, no diagnosed obesity, bulimia, diabetes and / or no diagnosed micturition disorders, in particular urinary incontinence. Preferred are the Compounds of the invention are suitable for non-therapeutic use in humans whose body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, is below the value of 30, especially below 25, lies.

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

Preliminary remarks:

For prepared compounds, IR, ^" 1 H-NMR and / or mass spectra are usually present, unless otherwise stated, R _r values are determined using DC precast plates silica gel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714 The R _r values determined under the name Alox are determined using TLC finished plates alumina 60 F254 (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation The ratios stated for the flow agents are based on The volume units given for NH ₃ are based on a concentrated solution of NH ₃ in water For chromatographic purifications, silica gel from Millipore (MATREX ™, 35-70 my) is used for chromatographic purifications. Merck, Darmstadt, alumina 90 standardized, 63-200 μm, Article No.: 1.01097.9050) The indicated HPLC data are listed below measured parameters measured:

Analytical columns: Zorbax column (Agilent Technologies), SB (stable bond) - C18; 3.5 μm; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 μL; Detection at 254 nm (methods A and B) Symmetry 300 (Waters), 3.5 μm; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 μL; Detection at 254 nm (Method C) Method A: Water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 over 9 min Method B: water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 4 min, then 6 min 1: 9: 0.01 Method C: Water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 over 4 min, then 6 min 1: 9: 0.01 Preparative column: Zorbax column (Agilent Technologies), SB (Stable Bond) - C18; 3.5 μm; 30 x 100 mm; Column temperature: room temperature; Flow: 30 mL / min; Detection at 254 nm. Preparative HPLC purifications generally use the same gradients used in the collection of analytical HPLC data.

The collection of products is mass-controlled, the product-containing fractions are combined and freeze-dried. If further information on the configuration is missing, it remains unclear whether they are pure enantiomers or whether partial or even complete racemization has occurred.

The following abbreviations are above and below

Section. made absolute

Boc tert-butoxycarbonyl

Cbz benzyloxycarbonyl

CDI N, N'-carbonyldiimidazole

CDT 1, 1'-carbonyldi (1, 2,4-triazole)

DMF N, N-dimethylformamide

Et ethyl

Ether diethyl ether

EtOAc ethyl acetate

EtOH ethanol

Fmoc 9-fluorenylmethoxycarbonyl sat. saturated half semi focused

HCI hydrochloric acid

HOAc acetic acid

HOBt 1-hydroxybenzotriazole hydrate

Hünig base N-ethyldiisopropylamine

HV high vacuum i. vac. in vacuo (in vacuum)

KOH potassium hydroxide conc. concentrated

Me methyl

MeOH methanol

MTBE methyl tert-butyl ether

NaCl sodium chloride

NaOH sodium hydroxide org. organic

Ph phenyl

RT room temperature (about 20 ° C)

TBTU 2- (1H-Benzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate

TEBAC triethylbenzylammonium chloride TFA trifluoroacetic acid

THF tetrahydrofuran

- ** denotes the binding site of a residue

Above and below, in structural formulas, in addition to the H atoms on C atoms, the H atoms at O and N atoms, such as, for example, in hydroxyl or amino groups, for the sake of clarity are generally not explicitly depicted.

Example 1.1:

3- (4-pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4-prop-1-ynyl-phenyl) -amide

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

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

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

1.2 g (5.86 mmol) of DCC are added to a solution of 375 mg (5.35 mmol) of propynoic acid in 10 ml of dichloromethane at 0 ° C. and the mixture is stirred for 30 minutes. Subsequently, 0.7 g

(5.35 mmol) 4-prop-1-ynyl-phenylamine, dissolved in dichloromethane, slowly added dropwise and two

Stirred at 0 ° C continued. The reaction mixture is then filtered through Celite and the filtrate is concentrated. The purification is carried out by column chromatography on silica gel

(Eluent: dichloromethane / ethanol = 40: 1). Yield: 0.7 g (71.4% of theory)

C ₁₂ H ₉ NO (M = 183.21) calc .: Mol peak (M + H) ⁺ : 184 found: Mol peak (M + H) ⁺ : 184

Rr value: 0.65 (silica gel, dichloromethane / ethanol / acetic acid 20: 1)

1.1.c. 1 - (4-iodobenzyl) -pyrrolidine

A solution of 5 g (16.83 mmol) of 4-iodobenzylbromide, 1.41 ml (17 mmol) of pyrrolidine and 4.8 ml (34.43 mmol) of triethylamine in 50 ml of dichloromethane are added during 14 hours Room temperature stirred. The reaction mixture is mixed with water, the organic phase separated and dried over sodium sulfate. Yield: 4 g (82.7% of theory) C ₁ H ₄ IN (M = 287.14) calc .: Mole peak (M + H) ⁺ : 288 f: Mol peak (M + H) ⁺ : 288

1.1.d. 3- (4-Pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4-prop-1-ynyl-phenyl) -amide

10 ml of acetonitrile are degassed and washed with 0.35 ml (2 mmol) of ethyldiisopropylamine and 0.2 g

(0.69 mmol) of 1- (4-iodo-benzyl) -pyrrolidine was added. It is then degassed again and there are successively added 13 mg of copper (I) iodide, 34 mg Tetrakistriphenylphosphinpalladium and 137 mg (0.75 mmol) of propynoic acid (4-prop-1-ynyl-phenyl) -amide added. The reaction mixture is stirred for 24 hours at room temperature and then admixed with 60 mg of propynoic acid (4-prop-1-ynyl-phenyl) -amide. After 24 hours, the batch is concentrated. The purification is carried out by column chromatography on silica gel (dichloromethane / methanol / ammonia = 30: 1: 0.1 to 20: 1: 0.1). Yield: 24 mg (10% of theory) of C23H22N2O (M = 342.44) .: Mol peak (M + H) ⁺ : 343 f: Mol peak (M + H) ⁺ : 343

R _r value: 0.2 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.2:

3- (4-piperidine-1-ylmethyl-phenyl) -propynoic acid (4-prop-1-ynyl-phenyl) -amide

1.2.a. 3- (4-hydroxymethyl-phenyl) -propynoic acid (4-prop-1-ynyl-phenyl) -amide 40 ml of THF are degassed, admixed with 2.62 g (8.03 mmol) of cesium carbonate and 4-iodobenzyl alcohol and again degassed. 138 mg (0.12 mmol) of tetrakistriphenylphosphine palladium, 53 mg (0.28 mmol) of copper (I) iodide and 0.7 g (3.2 mmol) of propynoic acid (4-prop-1-ynyl) are successively added to this reaction mixture. phenyl) -amide. It is stirred for 24 hours at room temperature and the reaction mixture is subsequently concentrated. The cleaning of the residue is carried out by column chromatography on silica gel (eluent: dichloromethane / ethano 60: 1). Yield: 0.5 g (57.8% of theory) C ₉ H ₁₅ NO ₂ (M = 289.33) calc .: Mol peak (M + H) ⁺ : 290 F: Mol peak (M + H) ⁺ : 290

Rr value: 0.21 (silica gel, dichloromethane / ethanol = 50: 1)

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

To a solution of 0.5 g (1.72 mmol) of 3- (4-hydroxymethyl-phenyl) -propynoic acid (4-prop-1-ynyl-phenyl) -amide and 0.49 ml (3.6 mmol) 0.14 ml (1.8 mmol) of methanesulfonyl chloride are slowly added dropwise at room temperature to triethylamine in 20 ml of dichloromethane and the reaction mixture is stirred at room temperature for two hours. It is extracted three times with water and the organic phase dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether. Yield: 0.48 g (75.6% of theory) of C20H17NO4S (M = 367.42) calc .: Mol peak (M + H) ⁺ : 368 f: Mol peak (M + H) ⁺ : 368

Rr value: 0.48 (silica gel, dichloromethane / ethanol = 20: 1)

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

A reaction mixture of 0.5 mg (0.13 mmol) of methanesulfonic acid 4 - [(4-prop-1-ynyl-phenylcarbamoyl) -ethynyl] -benzyl ester, 0.028 ml (0.28 mmol) of piperidine in 5 ml of THF becomes 14 Stirred hours at room temperature. The reaction mixture is concentrated. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol = 25: 1 to 15: 1).

Yield: 13 mg (26.8% of theory) Melting point: 180-181 ° C C24H24N2O (M = 356.47) calc .: Mol peak (M + H) ⁺ : 357 F: Mol peak (IV1 + H) ⁺ : 357 Rr value: 0.21 (silica gel, dichloromethane / ethanol = 20: 1)

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

Rr value: A = (silica gel, dichloromethane / ethanol / 20: 1)

Example 1.8:

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

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

Prepared analogously to Example 1.1. b from propionic acid and 4'-methoxy-biphenyl-4-ylamine. Yield: 1.3 g (17.2% of theory) of C ₁₆ H ₁₃ NO ₂ (M = 251.28) calc .: Mol peak (M + H) ⁺ : 252 f: Mol peak (M + H) ⁺ : 252

Rr value: 0.6 (silica gel, dichloromethane / ethanol = 20: 1)

1.8.b. 3- (4-hydroxymethyl-phenyl) -propynoic acid (4'-methoxy-biphenyl-4-yl) -amide Prepared analogously to Example 1.2.a from iodobenzyl alcohol and propynoic acid (4'-methoxy-biphenyl-4-yl) - amide. Yield: 0.21 g C (22.9% theory d.) ₂ 3 H ₁₉ NO ₃ (M = 357.41) calc .: molecular peak (M + H) ^+: 358 Found .: molecular peak (M + H) ⁺ : 358

Rr value: 0.35 (silica gel, dichloromethane / ethanol = 20: 1)

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

R_rWert: 0.58 (Kieselgel, Dichlormethan/ Ethanol = 20:1 )Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propinsäure- (4'-methoxy-biphenyl-4-yl) -amide and methanesulfonyl chloride. Yield: 0.18 g (70.3% of theory)

R _r value: 0.58 (silica gel, dichloromethane / ethanol = 20: 1)

1.8.d. 3- (4-piperidin-1-ylmethyl-phenyl) -propynoic acid (4'-methoxy-phenyl) -amide Prepared analogously to Example 1.2.c from methanesulfonic acid 4 - [(4'-methoxy-biphenyl-4-ylcarbamoyl) - ethynyl] benzyl ester and piperidine. Yield: 5 mg (18.8% of theory). Melting point: 28 ^N 2 ° 2 ⁽⁼ 424.54) calc .: molecular peak (M + H) ⁺ 170 ° C C28 ^H: Found 425: molecular peak (M + H ) ⁺ : 425

Rr value: 0.28 (silica gel, dichloromethane / ethanol = 20: 1)

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

Rr value: A = (silica gel, dichloromethane / ethanol / ammonia 20: 1)

B = (silica gel, dichloromethane / ethanol / ammonia 5: 1)

Example 1.17:

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

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

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

Rr value: 0.41 (silica gel, cyclohexane / ethyl acetate 3: 1)

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

Prepared analogously to Example 1.1.b from 4'-chloro-3-fluoro-biphenyl-4-ylamine and propynic acid.

Yield: 0.16 g (43.7% of theory)

C ₅ H ₉ CIFNO (M = 273.69) calc .: Mol peak (M + H) ⁺ : 274/276 f: Mol peak (M + H) ⁺ : 274/276

Rr value: 0.3 (silica gel, cyclohexane / ethyl acetate 3: 1)

1.17.c. 3- (4-Pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4'-chloro-3-fluoro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1. d of 1- (4-iodobenzyl) -pyrrolidine and propynoic acid (4'-chloro-3-fluoro-biphenyl-4-yl) -amide.

Yield: 20 mg (13% of theory)

Melting point: 136 ° C C26H22CIFN2O (M = 432.92) calc .: Mol peak (M + H) ⁺ : 433/435/437 found: Mol peak (M + H) ⁺ : 433/435/437

Rr value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1) Example 1.18:

3- [4- (4_lvlethyl-piperidin-1-ylmethyl) -phenyl] -propinsäure- ^{(4, -chloro-2} -fluoro-biphenyl-4-yl) -amide

1.18.a. 3- (4-hydroxymethyl-phenyl) -propynoic acid (4'-chloro-2'-fluorobiphenyl-4-yl) -amide Prepared analogously to Example 1.2.a from propynoic acid (4'-chloro-3-fluoro) biphenyl-4-yl) -amide and 4-iodobenzyl alcohol. Yield: 0.4 g (41% of theory) of C ₂ H ₂ 5CIFNO ₂ (M = 379.82) Calculated: Mol peak (M + H) ⁺ : 380/382 Found: Mol peak (M + H) ⁺ : 380 / 382

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 20: 1: 0.1)

1.18.b. Methanesulfonic acid 4 - [(4'-chloro-2'-fluorobiphenyl-4-ylcarbamoyl) ethynyl] benzyl ester Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propynoic acid (4'-methyl) chloro-2'-fluoro-biphenyl-4-yl) -amide and methanesulfonyl chloride. Yield: 0.23 g (50% of theory) C23H1 CIFN2O2S (M = 457.91) calc .: Mol peak (M + H) ⁺ : 456/458 F: Mol peak (M + H) ⁺ : 456/458 Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 20: 1: 0.1)

1.18.C. 3- [4- (4-Methyl-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-2'-fluoro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.2.c from methanesulfonic acid 4 - [(4'-chloro-2'-fluorobiphenyl-4-ylcarbamoyl) ethynyl] benzyl ester and 4-methylpiperidine.

Yield: 13 mg (21% of theory)

Melting point: 149-150 ° C

^C 28 26 ^{C! FN} 2 ° ( ^{M =} 460.98) calc .: Mol peak (M + H) ⁺ : 461/463 found: Mol peak (M + H) ⁺ : 461/463 Rr value: 0.3 (silica gel, dichloromethane / Methanol / ammonia = 20: 1: 0.1)

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

Rr value: A = (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) B = (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1)

Example 1.23:

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

1.23.a. Propinsäure-(4'-chlor-biphenyl-4-yl)-amid

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

Prepared analogously to Example 1.1.b from 4'-chloro-biphenyl-4-ylamine and propynic acid. Yield: 0.4 g (29.2% of theory) C ₁₅ H ₁₀ CINO (M = 255.70) calc .: Mol peak (M + H) ⁺ : 256/258 f: Mol peak (M + H) ⁺ : 256/258 R _r value: 0.35 (silica gel, dichloromethane / ethanol 20: 1) 23.1. b. Propinsäure- (4'-chloro-biphenyl-4-yl) -methyl-amide

To a solution of 0.4 g (1.56 mmol) of propynoic acid (4'-chloro-biphenyl-4-yl) -amide in 10 ml of THF at 0 ° C 75 mg (1.72 mmol) of sodium hydride (55 %) and stirred for one hour at this temperature. Subsequently, 0.098 ml (1.56 mmol) of methyl iodide are added dropwise and the mixture is stirred for 14 hours, during which the reaction mixture is allowed to warm to room temperature. Subsequently, the reaction mixture is extracted with water and ethyl acetate and the organic phase dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 3: 1).

ber.: Molpeak (M+H)⁺: 270/272 gef.: Molpeak (M+H)⁺: 270/272Yield: 0.15 g (35.6% of theory)

Calcd .: Mol peak (M + H) ⁺ : 270/272 Found: Mol peak (M + H) ⁺ : 270/272

Rr value: 0.61 (silica gel, cyclohexane / ethyl acetate 1: 1

23.1. c. 3- (4-Pyrrolidin-1-ylmethyl-phenyl) -propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide Prepared analogously to Example 1.1. d of 1- (4-iodo-benzyl) -pyrrolidine and propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide. Yield: 38 mg (25.4% of theory) Melting point: 161-164 ° C C27H25CIN2O (M = 428.96) calc .: Mole peak (M + H) ⁺ : 429/431 mf: Molepeak (M + H) ⁺ : 429/431

Rr value: 0.41 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.24:

3- [4- (4-Pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide-ditrifluoroacetate

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

Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-pyrrolidin-1-yl-piperidine. Yield: 0.57 g (51% of theory) of C ₁₆ H ₂ 3 LN ₂ (M = 370.28) calc .: Mol peak (M + H) ⁺ : 371 f: Mol peak (M + H) ⁺ : 371

Rr value: 0.3 (silica gel, dichloromethane / ethanol 20: 1)

1.24.b. 3- [4- (4-Pyrrolidin-1-yl-piperidin-1-yl-methyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide-ditrifluoroacetate

Prepared analogously to Example 1.1. d of 1- (4-iodobenzyl) -4-pyrrolidin-1-yl-piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide. Yield: 5 mg (4% of theory) Melting point: 161-164 ° C C 32 H 34 CIN ₃ O X 2 CF ₃ CO ₂ H (M = 740.14) calc .: Mole peak (M + H) ⁺ : 512/514 mf: Mol peak (M + H) ⁺ : 512/514

Rr value: 0.41 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.25:

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

1.25.a. 3-(4-Hydroxymethyl-phenyl)-propinsäure-(4'-chlor-biphenyl-4-yl)-methyl-amid

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

Prepared analogously to Example 1.2.a from 4-iodo-benzyl alcohol and propynoic acid (4'-chloro-biphenyl)

4-yl) -methyl-amide.

Yield: 0.52 g (90% of theory)

C ₂ 3H _{1 8} CINO ₂ (M = 375.85) calc .: Mol peak (M + H) ⁺ : 376/378 F: Mol peak (M + H) ⁺ : 376/378

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

1.25.b. Methanesulfonic acid 4 - {[(4'-chloro-biphenyl-4-yl) -methyl-carbamoyl] -ethynyl} -benzyiester Prepared analogously to Example 1.2.b from 3- (4-hydroxymethyl-phenyl) -propynoic acid (4 '). -chloro-biphenyl-4-yl) -methyl-amide.

Yield: 0.54 g (100% of theory) of C ₂ 4H ₂ oCINO ₄ S (M = 453.94 calc .: Molpeak (M + Hf: 454/456 found: Molpeak (M + H) ⁺ : 454/456

1.25.C. 3- [4- (4-Methyl-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -methyl-amide

Prepared analogously to Example 1.2.c from methanesulfonic acid 4 - {[(4'-chloro-biphenyl-4-yl) -methyl-carbamoyl] -ethynyl} benzyl ester and 4-methylpiperidine. Yield: 8 mg (16% of theory) C29H29CIN2O (M = 457.02) Calculated: Mol peak (M + H) ⁺ : 457/459 F: Mol peak (M + H) ⁺ : 457/459

Rr value: 0.41 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

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

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

Example 1.33:

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

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

A reaction mixture of 1 g (3.48 mmol) of 1- (4-iodobenzyl) pyrrolidine, 5 ml of piperidine, 105 mg (0.091 mmol) of tetrakistriphenylphosphine palladium and 10 mg (0.053 mmol) of copper (I) iodide is brought to 0 ° C cooled. At this temperature, 0.59 ml (4.18 mmol) of trimethylsilylacetylene are added dropwise and then removed the cooling bath. It is stirred for three hours at room temperature, then treated with a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 1: 1). Yield: 0.75 g (83.6% of theory) of C ₁₆ H ₂ 3Si (M = 257.45) calc .: Mol peak (M + H) ⁺ : 258 f: Mol peak (M + H) ⁺ : 258

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

A solution of 0.75 g (2.91 mmol) of 1- (4-trimethylsilanylethynyl-benzyl) -pyrrolidine in 10 ml of dichloromethane and 10 ml of methanol is added 2.4 ml of a 1 M sodium hydroxide solution and stirred for three hours at room temperature. The reaction mixture is concentrated and the residue treated with water and ethyl acetate. The organic phase is stirred with activated charcoal, filtered and then dried over sodium sulfate. Yield: 0.4 g (74.1% of theory.) C-i3H ₁₅ N (M = 185.27) calc .: molecular peak (M + H) ^+: 186 Found: molecular peak (M + H) ^+: 186

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

To a solution of 2.3 g (12.41 mmol) of 1- (4-ethynyl-benzyl) -pyrrolidine in 50 ml of THF at -78 ° C 5.98 ml (14.85 mmol) of a 1, 6 M Butyllithiumlösung added dropwise in n-hexane and stirred for one hour at this temperature. Subsequently, dry ice is added to the reaction mixture. Thereafter, the reaction mixture is allowed to rise

Room temperature and stir for 14 hours. The reaction mixture is treated with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is separated and dried over sodium sulfate. The sodium sulfate is separated and the solvent removed. Yield: 0.3 g (10.5% of theory) C ₁₄ H ₁₅ NO ₂ (M = 229.28) calc .: Mol peak (M + H) ⁺ : 230 F: Mol peak (M + H) ⁺ : 230

Rr value: 0.15 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

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

A solution of 0.3 g (1.30 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -propynoic acid, 0.27 g (1.32 mmol) of 4'-chlorobiphenyl-4-ylamine, O, 42 g (1.32 mmol) of TBTU and 0.18 ml (1.32 mmol) of triethylamine in 30 ml of DMF are stirred for 14 hours at room temperature. The reaction mixture is concentrated and the residue extracted with water and dichloromethane. The organic phase is dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluant: dichloromethane / ethano 10: 1). Yield: 0.095 g (17.5% of theory) Melting point: from 180 ° C. C26H23CIN2O (M = 414.93) Calculated: Molepeak (M + H) ⁺ : 415/417 F: Mol peak (M + H) ⁺ : 415/417

Rr value: 0.3 (silica gel, dichloromethane / ethanol = 5: 1)

Example 1.34: 3- {4- [4- (1-Hydroxy-1-methyl-ethyl) -piperidin-1-ylmethyl] -phenyl} -propynoic acid (4'-chloro-biphenyl-4-yl) -amide

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

Prepared analogously to Example 1.1. c from 4-iodobenzylbromide and 2-piperidin-4-yl-propan-2-ol. Yield: 1.01 g (67% of theory) C ₁₅ H ₂ .2NNO (M = 359.25) calc .: Mol peak (M + H) ⁺ : 360 F: Mol peak (M + Hf: 360

Rr value: 0.4 (silica gel, dichloromethane / ethanol 20: 1)

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

Prepared analogously to Example 1.1. d of 2- [1- (4-iodobenzyl) -piperidin-4-yl] -propan-2-ol and

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

Yield: 45 mg (30% of theory)

Melting point: 194-195 ° C C30H31 CIN ₂ O ₂ (M = 487.04) calc .: Mol peak (M + H) ⁺ : 487/489 found: Mol peak (M + H) ⁺ : 487/489

Rr value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.35:

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

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

Prepared analogously to Example 1.1. c from 4-iodobenzylbromide and 4-methylpiperidine.

Yield: 0.95 g (71.6% of theory)

C ₁₃ H _{1 8} IN (M = 315.20) calc .: Mol peak (M + H) ⁺ : 316 Found: Mol peak (M + H) ⁺ : 316

R f value: 0.6 (silica gel, dichloromethane / ethanol 20: 1) 1.35.b. 3- [4- (4-Methylpiperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide Prepared analogously to Example 1.1. d of 1- (4-iodo-benzyl) -4-methyl-piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -amide. Yield: 50 mg (27% of theory) C ₂₈ H ₂ 7CIN ₂ O (M = 442.99) calc .: Mole peak (M + H) ⁺ : 443/445 found: mol peak (M + H) ⁺ : 443/445

Rr value: 0.45 (silica gel, dichloromethane / methanol = 10: 1)

Example 1.36:

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

1.36.a. 1- (4-iodo-benzyl) -4-methoxy-piperidine Prepared analogously to Example 1.1. c from 4-iodobenzyl bromide and 4-methoxy-piperidine. Yield: 0.93 g (66.7% of theory.) C _{1 3} H _{1 8} INO (M = 331, 19) calc .: molecular peak (M + H) ^+: 332. Found: molecular peak (M + H) ⁺ : 332

Rr value: 0.55 (silica gel, dichloromethane / ethanol 20: 1)

1.36.b. 3- [4- (4-Methoxy-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.1.d from 1- (4-iodobenzyl) -4-methoxy-piperidine and propynoic acid

(4'-chloro-biphenyl-4-yl) -amide. Yield: 25 mg (13% of theory)

Melting point: 145-146 ° C

C ₂₈ H27CIN θ2 ₂ (M = 458.99) calc .: molecular peak (M + H) ^+: 459/461 Found: molecular peak (M + H) ^+: 459/461

Rr value: 0.4 (silica gel, dichloromethane / methanol = 10: 1) BeipieM.37:

3- [4- (4-Hydroxy-4-methylpiperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide

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

Prepared analogously to Example 1.1. c from 4-iodobenzylbromide and 4-methyl-piperidin-4-ol.

Yield: 0.22 g (30% of theory)

C ₃ H _{1 8} INO (M = 331, 19) calc .: Mol peak (M + H) ⁺ : 332 f: Mol peak (M + H) ⁺ : 332

Rr value: 0.45 (silica gel, dichloromethane / ethanol 20: 1)

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

4-yl) -amide

Prepared analogously to Example 1.1. d of 1- (4-iodo-benzyl) -4-methyl-piperidin-4-ol and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.

Yield: 25 mg (13% of theory)

Melting point: 192-193 ° C

^C 28 27 ^CIN 2 ° 2 ( ^{M =} 458.99) calc .: Mol peak (M + H) ⁺ : 459/461 f: Mol peak (M + H) ⁺ : 459/461 Rr value: 0.2 (silica gel, dichloromethane / methanol = 10: 1)

Example 1.38:

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

1.38.a. 3- [4- (4-Pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -propynoic acid (4'-chloro-biphenyl-4-yl) -amide Prepared analogously to Example 1.1. d of 1- (4-iodo-benzyl) -4-pyrrolidin-1-yl-piperidine and

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

Yield: 15 mg (7% of theory)

Melting point: 191-192 ° C

^C 31 ^H 32 ^C1N 3 ° ( ^{M =} 498.07) calc .: Mol peak (M + H) ⁺ : 498/500 f: Mol peak (M + H) ⁺ : 498/500

Rr value: 0.45 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1.39:

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

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

Prepared analogously to Example 1.1. c from 4-iodobenzyl bromide and pipiridine.

Yield: 0.85 g (67% of theory)

C ₁₂ H ₁₆ IN (M = 301, 17) calc .: Mol peak (M + H) ⁺ : 322 f: Mol peak (M + H) ⁺ : 302

Rr value: 0.55 (silica gel, dichloromethane / ethanol 20: 1)

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

Prepared analogously to Example 1.1. d of 1- (4-iodobenzyl) piperidine and propynoic acid (4'-chloro-biphenyl-4-yl) -amide.

Yield: 6 mg (4% of theory)

Melting point: 179.5 ° C C27H25CIN2O (M = 428.96) calc .: Mol peak (M + H) ⁺ : 429/431 mf: Mol peak (M + H) ⁺ : 429/431

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example 1:40: 3- {4- [cyclopropylmethyl-methyl-amino) -methyl] -phenyl} -propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} - amide

1.40.a. Propinsäure- (4 ^{'chloro-biphenyl-4-yl)} -amide

To a solution of 4.9 g (70 mmol) of propionic acid in 120 ml of dichloromethane are added at -10 ° C

36 ml of a 1 molar DCC solution in dichloromethane was added dropwise and stirred for 30 min.

Then 7 g (34.37 mmol) of 4 ^' -chloro-biphenyl-4-ylamine, dissolved in dichloromethane, are slowly added dropwise and stirred at -8 ° C for 2 h. The reaction mixture is then filtered through Celite, washed with methanol and the filtrate was concentrated. The cleaning is done by

Column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 6: 1 to 2: 1)

Yield: 7.6 g (95% of theory)

C ₁₅ H ₁₀ CINO (M = 255.70) calc .: Mole peak (M + H) ⁺ : 256/8 (CI) Fc: Molepeak (M + H) ⁺ : 256/8 (CI)

Rr value: 0.2 (silica gel, cyclohexane / ethyl acetate 1: 1)

1.40.b 3- (4-hydroxymethyl-phenyl) -propynoic acid-4'-chloro-biphenyl-4-yl) -amide 10 g (30.69 mmol) cesium carbonate and 2.4 g (10.26 mmol) 4 Iodobenzyl alcohol are introduced into 120 ml of THF and cooled in the ice / methanol bath to -15 ° C, purged with argon and degassed. 660 mg (0.57 mmol) of tetrakistriphenylphosphine palladium and 240 mg (1.26 mmol) of copper (I) iodide are successively added to this reaction mixture and degassed again. 3.2 g (12.52 mmol) of propynoic acid (4'-chloro-biphenyl-4-yl) -amide were added last. It is stirred for 24 hours at room temperature and the reaction mixture is subsequently concentrated. The residue is extracted between water and ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the residue is purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 30: 1). Yield: 2 g (54% of theory) C22 16 ^CIN ° 2 ( ^M = 361.82) calc .: Mol peak (M + H) ⁺ : 362/4 (CI) Found: Mol peak (M + H) ⁺ : 362/4 (CI)

Rr value: 0.35 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)

1.40.C. 3- (4-chloromethyl-phenyl) -propinsäure- (4'chlor-biphenyl-4-yl) -amide To a solution of 2 g (3.87 mmol) of 3- (4-hydroxymethyl-phenyl) -propinsäure-4 ^'chloro- biphenyl-4-yl) -amide and 1, 56 ml (1, 1 2 mmol) of triethylamine 0.45 ml (5.81 mmol) of methanesulfonyl chloride are slowly added dropwise at room temperature in 100 ml of dichloromethane and the reaction mixture is stirred at room temperature for 24 hours. It is extracted three times with water and the organic phase dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether and filtered off with suction. Yield: 0.8 g (54% of theory) C22H15Cl2NO (M = 380.27) calc .: Mole peak (M + H) ⁺ : 380/2/4 (CI2) Fc: Mole peak (M + H) ⁺ : 380/2/4 (CI2) Rr value: 0.7 (silica gel, dichloromethane / ethanol = 50: 1)

1.40.d. 3- {4- [cyclopropylmethyl-methyl-amino) -methyl] -phenyl} -propinsäure- (4 ^'chloro- biphenyl-4-yl) -amide

A reaction mixture of 70 mg (0.18 mmol) of 3- (4-chloromethyl-phenyl) -propinsäure- (4 ^{'chloro-biphenyl-4-yl)} -amide, 19 mg (0.19 mmol), cyclopropylmethyl-methyl amine and 51 mg

(0.37 mmol) of potassium carbonate in 5 ml of acetone are shaken under reflux for 24 hours.

The reaction mixture is concentrated. The residue between water and

Extracted ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the residue is purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 100: 0 to 50:50).

Yield: 30 mg (38% of theory)

Melting point: 181 ° C C27 ^H 25 ^N 2 ° ^{C (M =} 428.95) calc .: molecular peak (M + H) ^+: 429/31 (CI) Found: molecular peak (M + H) ^+: 429/31 ( CI) Rr value: 0.5 (silica gel, dichloromethane / ethanol / ammonia = 20: 1: 0.1)

The following compounds are prepared analogously to Example 1.40.d .:

Rr value: A = (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) B = (silica gel, dichloromethane / ethanol / ammonia 50: 1: 0.1)

Example 1.54:

3- (4 - {[(2-Hydroxy-2-methyl-propyl) - (2-methoxy-ethyl) -amino] -methyl} -phenyl) -propionic acid (4'-chloro-biphenyl-4-yl) -amide trifluoroacetate

A reaction mixture of 7O mg (0.18 mmol) of 3- (4-chloromethyl-phenyl) -propynoic acid (4'-chloro-biphenyl-4-yl) -amide, 19 mg (0.19 mmol) of 1- (2 Methoxy-ethylamino) -2-methyl-propan-2-ol and 51 mg (0.37 mmol) of potassium carbonate in 5 ml of acetone are shaken under reflux for 24 hours. The reaction mixture is concentrated. The residue is extracted between water and ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the residue is purified by column chromatography first on silica gel (eluent: dichloromethane / methanol = 100: 0 to 50:50) and then on RP-18 (eluent: water + 0.1% trifluoroacetic acid / acetonitrile + 0.1% trifluoroacetic acid = 100: 0 to 50:50).

Yield: 11 mg (11% of theory.) C29 ^H 3lCIN2θ3 * C ₂ HF3θ ₂ (M = 605.04) calc .: molecular peak (M + H) ^+: 491/93 (CI) Found .: molecular peak (M + H) ⁺ : 491/93 (CI)

The following compounds are prepared analogously to Example 1.54:

Example 1.58:

3- {4 - [(Methyl-pyridin-2-ylmethyl-amino) -methyl-phenyl} -propinsäure- (4 ^{'chloro-biphenyl-4-yl)} amide

A reaction mixture of 55 mg (0.15 mmol) of 3- (4-chloromethyl-phenyl) -propinsäure- (4 ^{'chloro-biphenyl-4-yl)} -amide, 18.3 mg (0.159 mmol) of methyl pyridine-2 -ylmethylamine and 51 mg (0.37 mmol) of potassium carbonate in 5 ml of acetone are shaken under reflux for 24 hours. The reaction mixture is concentrated. The residue is triturated with water and diisopropyl ether and the product is filtered off with suction and dried in air. Yield: 20 mg (30% of theory) Melting point: 217-218 ° C C29H24CIN3O (M = 465.97) calc .: Mol peak (M + H) ⁺ : 466/468 (CI) Found: Molepeak (M + H) ⁺ : 466/468 (CI)

The following compound is prepared analogously to Example 1.58:

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

Example 1.422:

3- [4- (1-amino-cyclopropyl) -phenyl] -propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide trifluoroacetate

1,422.a: 1- (4-Bromo-phenyl) -cyclopropyl] -carbamic acid-tert-butyl ester 10 g (29.04 mmol) 1- (4-bromobenzene) 1-cyclopropanecarboxylic acid and 6.07 ml (43.55 mmol) Triethylamine was dissolved in 63 ml of ferf-butanol. At RT 9.68 ml (43.55 mmol) of diphenylphosphoryl azide (DPPA) were added dropwise and refluxed for 15 h. Subsequently, 14.69 g (65.27 mmol) of di-tert-butyl pyrocarbonic acid were added and refluxed again for 15 h. The solvent was distilled off and the residue was taken up in ethyl acetate, washed successively with 5% citric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase dried with magnesium sulfate, filtered and the solvent distilled off. Yield: 6.00 g (66% of theory) C ₁₄ H ₈ BrNO ₂ (M = 312.20) Calc .: Mol peak (M + H) ⁺ : 312/14 (Br) Fe: Mol peak (M + H) ⁺ : 312/14 (Br)

Rr value: 0.8 (silica gel, dichloromethane / ethanol = 20: 1)

1, 422.b. [1- (4-iodo-phenyl) -cyclopropyl] -carbamic acid-ferf-butyl ester To a reaction mixture of 0.4 g (2 mmol) copper (I) iodide, 6.2 g (19.86 mmol) of [1- ( 4-bromo-phenyl) -cyclopropyl] -carbamic acid tert-butyl ester and 6 g (40 mmol) of sodium iodide in 15 ml of 1,4-dioxane were added 0.43 ml (4, N ^{'dimethylethylenediamine} added mmol) and N under nitrogen for 24 h boiled under reflux. Subsequently, the cooled suspension with 30% ammonia solution was added, distilled to. Water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent distilled off. Yield: 6.60 g (93% of theory.) C ₁₄ H ₁₈ INO ₂ (M = 359,20) calc .: molecular peak (M + H) ^+: 360 Found: molecular peak (M + H) ^+: 360 R f value : 0.8 (silica gel, dichloromethane / ethanol = 50: 1)

1.422.C. 3- [4- (1-te / butoxycarbonyl-amino-cyclopropyl) -phenyl] -propinsäure- (4 ^'chloro- biphenyl-4-yl) amide

1, 4 g (4.2 mmol) of cesium carbonate and 0.5 g (1, 4 mmol) of [1- (4-iodo-phenyl) - cyclopropyl] carbamic acid te / f-butyl ester are placed in 20 ml of THF and in Cooled ice / methanol bath to -15 ° C, purged with argon and degassed. To this reaction mixture are successively added 160 mg (0.14 mmol)

Tetrakistriphenylphosphinepalladium and 30 mg (0.158 mmol) of copper (I) iodide and degassed again. 0.5 g (1.4 mmol) Propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} amide were added to the end. It was stirred for 24 hours at room temperature and the reaction mixture was subsequently concentrated. The residue was triturated with water and ethyl acetate, filtered off with suction, washed with ethyl acetate and dried in air. Yield: 0.4 g (59% of theory) C29H27CIN2O3 (M = 486.99) Calculated: Molepeak (M + H) ⁺ : 487/89 (CI) Fc: Molepeak (M + H) ⁺ : 487 / 89 (CI)

Rr value: 0.62 (silica gel, cyclohexane / ethyl acetate 1: 1)

1.422.d. 3- [4- (1-amino-cyclopropyl) phenyl] propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide trifluoroacetate To a solution of 0.24 g (0.49 mmol) of 3- [4- (1-fe / t-butoxycarbonyl-amino-cyclopropyl) - phenyl] -propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} Amide in 20 ml of dichloromethane was added 1 ml (12.92 mmol) of trifluoroacetic acid and stirred for 24 h. The solvent was then removed by rotary evaporation and the residue was admixed with toluene and then removed by rotary evaporation. This residue was then triturated with dichloromethane, filtered off with suction and dried in air. Yield: 0.22 g (89% of theory) of C 24 H 19 Cl ₂ O * C ₂ HF ₃ O ₂ (M = 500.90) Calculated: Mol peak (M + H) ⁺ : 387 (CI) Fc: Mol peak (M + H) ⁺ : 387 (CI)

F _D = 160-164 ° C

Example 1.423:

3- [4- (1-methylamino-cyclopropyl) phenyl] propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide trifluoroacetate

1.423.a: [1- (4-iodo-phenyl) -cyclopropyl] -methyl-carbamic acid-tert-butyl ester To a solution of 1 g (2.78 mmol) of [1- (4-iodo-phenyl) -cyclopropyl] carbamic acid -terf-butyl ester in 20 ml of DMF are added at RT 131 mg (3 mmol) of sodium hydride (55%) and stirred at RT for 30 min. Subsequently, 0.287 ml (4.4 mmol) of methyl iodide are added dropwise and stirred for 24 hours. The solvent was spun off. The residue was extracted between water and ethyl acetate and the organic phase dried over sodium sulfate. The solvent was again spun off. Yield: 1 g (96% of theory) C ₁₅ H ₂ olNO ₂ (M = 373.23) calc .: Mol peak (M + H) ⁺ : 374 f: Mol peak (M + H) ⁺ : 374

Rr value: 0.68 (silica gel, cyclohexane / ethyl acetate 3: 1)

1.423.b: 3- [4- (1-tert-butoxycarbonyl-methyl-amino-cyclopropyl) -phenyl] -propinsäure- (4 ^'chloro- biphenyl-4-yl) amide 2.28 g (7 mmol) of cesium carbonate and 1 g (2.68 mmol) of [1- (4-iodo-phenyl) -cyclopropyl] - Methylcarbaminsäure-te / f-butyl ester are placed in 20 ml of THF and cooled in ice / methanol bath to -15 ° C, purged with argon and degassed. 180 mg (0.16 mmol) of tetrakistriphenylphosphinepalladium and 50 mg (0.263 mmol) of copper (I) iodide are successively added to this reaction mixture and degassed again. 0.75 g (2.9 mmol) of propynoic acid (4'-chloro-biphenyl-4-yl) -amide were added last. It was stirred for 24 hours at room temperature and the reaction mixture was subsequently concentrated. The residue was extracted between water and ethyl acetate, the organic phase was dried with sodium sulfate and the solvent was removed by rotary evaporation. The purification was carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). Yield: 0.75 g (56% of theory) C30H29CIN2O3 (M = 501.02) calc .: Mole peak (M + H) ⁺ : 501/3 (CI) Fc: Molepeak (M + H) ⁺ : 501 / 3 (CI)

Rr value: 0.75 (silica gel, cyclohexane / ethyl acetate 1: 1)

1.423.c: 3- [4- (1-methylamino-cyclopropyl) phenyl] propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide Prepared analogously to Example 1.422.d from 3- [4- (1-tert -butoxycarbonyl-methyl-amino-cyclopropyl) -phenyl] -propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide yield: 0.43 g (56% of theory) C25H21 CIN2O ^* C ₂ HF ₃ O _2. (M = 514.92) calc .: Mole peak (M + H) ⁺ : 401/3 (CI) Fc: Molepeak (M + H) ⁺ : 401/3 (CI)

F _p = 217.3 ° C

Example 1.424:

3- {4- [1- (4-methyl-piperidin-1-yl) -cyclopropyl] -phenyl} -propinsäure (4 ^{'-chloro-biphenyl-4-yl)} amide

1 24.a: 1- (4-iodo-phenyl) -cyclopropylamine To a solution of 1 g (2.78 mmol) of tert-butyl [1- (4-iodo-phenyl) -cyclopropyl-carbamate in 40 ml of dichloromethane 3 ml (38.76 mmol) of trifluoroacetic acid were added and Stirred for 24 h. The solvent was then removed by rotary evaporation and the residue was admixed with toluene and then removed by rotary evaporation. This residue was then added to a solution of 0.39 g (2.8 mmol) of potassium carbonate in 20 ml of water and stirred at RT for 30 min. With dichloromethane, the aqueous phase was extracted, the organic was dried with sodium sulfate and the solvent was removed by rotary evaporation. Yield: 0.7 g (97% of theory) CgH ₀ IN (M = 259.09) calc .: Mol peak (M + H) ⁺ : 260 f: Mol peak (M + H) ⁺ : 260

1.424.b: 1 [1-1- (4-iodo-phenyl) cyclopropyl] -4-methylpiperidine

To a reaction mixture of 0.5 g (1.93 mmol) of 1- (4-iodo-phenyl) -cyclopropylamine and 0.89 g (2 mmol) of 1, 5-dibromo-3-methylpentane in 20 ml of N, N- Dimethylformamide are added to 0.55 g (4 mmol) of potassium carbonate and stirred at 80 ° C for 24 h. The solvent was then concentrated and the residue extracted between ethyl acetate and water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography (eluent: cyclohexane / ethyl acetate 3: 1). Yield: 0.065 g (10% of theory) C ₁₅ H ₂ olN (M = 341.23) calc .: Mol peak (M + H) ⁺ : 342 F: Mol peak (M + H) ⁺ : 342 R _r value : 0.65 (silica gel, cyclohexane / ethyl acetate 3: 1)

1.424.c: 3- {4- [1- (4-Methyl-piperidin-1-yl) -cyclopropyl] -phenyl} -propynoic acid (4'-chloro-biphenyl-4-yl) -amide

Prepared analogously to Example 1.424.b from 1 [1-1- (4-iodo-phenyl) -cyclopropyl] -4-methylpiperidine and propynoic acid (4'-chloro-biphenyl-4-yl) amide. Yield: 20 mg (24% of theory) Theory) C30H29CIN2O (M = 469.02) calc .: Mole peak (M + H) ⁺ : 469/71 (CI) Fc: Mole peak (M + H) ⁺ : 469/71 (CI)

R _r value: 0.3 (silica gel, cyclohexane / ethyl acetate 3: 1) F _P = 128-129 ° C

Example 1.425:

3- {4- [cyclopentyl-methyl-amino) -methyl] -phenyl} -propinsäure- (4 ^{'-chloro-biphenyl-4-yl)} -amide

Prepared analogously to Example 1:40 d of 3- (4-chloromethyl-phenyl) -propinsäure- (4 ^{'chloro-biphenyl-4-yl)} -amide and methyl-cyclopentylamine.

Yield: 10 mg (316% of theory)

Melting point: 217-219 ° C

^C 28 ^H 27 ^CIN 2 ° ( ^M = 442.98) calc .: Mol peak (M + H) ⁺ : 443/45 (CI) f: Mol peak (M + H) ⁺ : 443/45 (CI)

Example 2.1 .:

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

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

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

2.1.b. MethansuIfonsäure-2- (4-iodo-phenyl) -ethyIester

ber.: Molpeak (M)⁺: 326 gef: Molpeak (M)⁺: 326Prepared analogously to Example 1.2.b from 2- (4-iodo-phenyl) -ethanol and methanesulfonyl chloride. Yield: 5.7 g (77.4% of theory)

Calc .: Molpeak (M) ⁺ : 326 f: Mol peak (M) ⁺ : 326

2.1.c. 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine To a solution of 2 g (6.13 mmol) of methanesulfonic acid 2- (4-iodo-phenyl) -ethyl ester in 30 ml of DMF is added 1 ml ( 12.26 mmol) of pyrrolidine and the reaction solution stirred at 70 ° C for six hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The sodium sulfate is separated and the solvent removed.

Yield: 1.28 g (69.3% of theory) C ₂ H ₁₆ IN (M = 301, 17) calc .: Mole peak (M + H) ⁺ : 302 F f: Mole peak (M + H) ⁺ : 302

Rr value: 0.4 (silica gel, dichloromethane / methanol = 10: 1)

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

To a solution of 2.89 g (41.36 mmol) of propionic acid in 100 ml of dichloromethane 9.38 g (45.5 mmol) of DCC are added in portions at -15 ° C and stirred for one hour. Then a -15 ° C cold solution of 7 g (41.36mmol) of biphenyl-4-ylamine in 30 ml of dichloromethane is added dropwise and stirred for two hours. After this time, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. To the reaction mixture, 20 g of Celite are added and then filtered. The filtrate is concentrated in vacuo. The residue is treated with acetonitrile and stirred. The suspension is filtered, the filtrate is concentrated and the residue is stirred with petroleum ether and pentane. The solid is isolated by filtration. Yield: 5.5 g (60.1% of theory) C ₁₅ H _{1 1} NO (M = 221, 26) calc .: Mol peak (M + H) ⁺ : 222 f: Mol peak (M + H) ⁺ : 222

Rr value: 0.7 (silica gel, dichloromethane / methanol = 10: 1)

2.1.e. 3- [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -propynoic-biphenyl-4-ylamide 25 ml of THF are degassed and treated with 0.25 g (0.83 mmol) of 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine, 0.81 g (2.49 mmol) of cesium carbonate, 16 mg of 0.083 mmol) of copper (I) iodide and 38 mg (0.033 mmol) tetrakistriphenylphosphine palladium. It is then degassed again, and there are added 184 mg (0.83 mmol) of propynoic acid biphenyl-4-ylamide. The reaction mixture is stirred at room temperature for 3 hours, poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. Purification by column chromatography on silica gel (dichloromethane / methanol / ammonia = 10: 1: 0.1) Yield: 90 mg (27.5% of theory) Melting point: 180-189 ° C C27 ^H 26 ^N 2 ° (= 394.52) calc .: Mol peak (M + H) ⁺ : 395 f: Mol peak (M + H) ⁺ : 395

Example 2.2 .:

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

2.2.a. Propynoic acid (4-chlorophenyl) amide Prepared analogously to Example 1.1.b from propionic acid and 4-chloroaniline. Yield: 0.56 g (31.2% of theory) of C ₉ H ₆ CINO (M = 179.60) calc .: Mol peak (MH) ^" : 178/180 f: Mol peak (MH) ^" : 178/180

Rr value: 0.53 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

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

Prepared analogously to Example 2.1.e from propynoic acid (4-chloro-phenyl) -amide and 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine.

Yield: 80 mg (34.1% of theory) Melting point: 153-154 ° C c21 ^H 2lCIN2θ (M = 352.86) Calcd .: Mol peak (M + H) ⁺ : 353/355 f: Mol peak (M + H) ⁺ : 353/355

Example 2.3 .:

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

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

To a solution of 5 g (22.98 mmol) of 5-bromo-1-indanone in 100 ml of isopropanol, 0.9'87 g (23 mmol) of sodium borohydride are added at room temperature and the reaction mixture is stirred for five hours. Then, an acidic pH is adjusted by careful addition of potassium bisulfate solution and the reaction mixture with part. Butyl methyl ether extracted. The organic phase is extracted with saturated sodium chloride solution and then dried with magnesium sulfate. The filtrate is concentrated after separation of the magnesium sulfate in vacuo. The residue is dissolved in tert-butyl methyl ether and successively diluted

Sodium bicarbonate solution and water extahed. It is then dried over magnesium sulfate and filtered through activated charcoal. The filtrate is concentrated in vacuo. Yield: 3.6 g (73.5% of theory) CgHgBrO (M = 213.07).

Rr value: 0.6 (silica gel, petroleum ether / ethyl acetate = 6: 4)

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

To a solution of 3.8 g (17.83 mmol) of 5-bromo-indan-1-ol in 200 ml of dichloromethane at -10 ° C 3.09 ml (37.45 mmol) of thionyl chloride, dissolved in cooled dichloromethane, dropwise. The reaction mixture is allowed to warm slowly to room temperature and stirred for 14 hours at room temperature. Subsequently, successively ice and 100 ml of dilute sodium bicarbonate solution are added. The organic phase is washed twice with 50 ml Extracted water. The combined organic phases are dried over magnesium sulfate, filtered and the solvent distilled off. Yield: 3.7 g (90% of theory) CgH ₈ BrCl (M = 231, 52) R _r value: 0.91 (silica gel, petroleum ether / ethyl acetate = 6: 4)

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

To a solution of 3.71 g (16.92 mmol) of 5-bromo-1-chloro-indane in 250 ml of dichloromethane at 0 ° C is added 7 ml (85.23 mmol) of pyrrolidine. The reaction mixture is allowed to warm to room temperature and stirred for 24 hours. It is then extracted once with water and the organic phase extracted with potassium bisulfate solution. The aqueous phase is extracted once with dichloromethane. Subsequently, the aqueous phase is basified with sodium carbonate solution to liberate the product. This solution is extracted with dichloromethane, the organic phase extracted with water and dried over magnesium sulfate.

Yield: 1.81 g (42.4% of theory) of C ₃ H ₁₆ BrN (M = 266.18) calc .: Mole peak (M + H) ⁺ : 266/268 m: Mole peak (M + H) ⁺ : 266/268

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

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

2.3. e. (1-pyrrolidin-1-yl-indan-5-yl) -propynoic acid

Under an argon atmosphere, 0.5 g (1.59 mmol) of 1- (5-iodo-indan-1-yl) -pyrrolidine and 123 mmol (2 mmol) of propynoic acid are dissolved in 25 ml of acetonitrile at 0 ° C. To this solution, 0.66 ml (4.79 mmol) of triethylamine, 30 mg (0.16 mmol) of copper (I) iodide and 80 mg (0.1 1 mmol) of ditriphenylphosphine palladium dichloride are added and the mixture is stirred for two hours, whereupon the solution to room temperature. Purification is by preparative HPLC (eluent: dichloromethane / methanol / ammonia = 8: 2: 0.2). Yield 0.1 g (24.5% of theory) of C ₁₆ H ₁₇ NO ₂ (M = 255.31) Calc .: Molpeak (M + H) ⁺ : 256 Found: Molepeak (M + H) ⁺ : 256 2.3.f. 3- (1-pyrrolidin-1-yl-indan-5-yl) -propin- (4'-chloro-biphenyl-4-yl) -amide

A solution of 0.1 g (0.39 mmol) of (1-pyrrolidin-1-yl-indan-5-yl) -propynoic acid and 47 mmol (0.43 mmol) of N-methylmorpholine in 5 ml of absolute THF is added at - 15 ° C with 56 microliters (0.43 mmol) of isobutyl chloroformate and stirred for ten minutes. in the

Subsequently, 87 mg (0.43 mmol) of 4'-chlorobiphenyl-4-ylamine are added at room temperature and the reaction mixture is stirred for 14 hours. Subsequently, 3 ml

Dichloromethane to the reaction mixture and stirred for 48 hours. After that, the

The reaction mixture was filtered, the filtrate was concentrated, treated with water and extracted with dichloromethane. The organic phase is concentrated. Purification is by preparative

HPLC (eluent: dichloromethane / methanol / ammonia = 8: 2: 0.2)

Yield: 9 mg (5.7% of theory)

^C 28 ^H 25 ^CIN 2 ° ( ^{M =} 440.97) calc .: Mol peak (M + H) ⁺ : 441/443 f: Mol peak (M + H) ⁺ : 441/443

Example 2.4 .:

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

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

Prepared analogously to Example 2.1.e from propynoic acid (4'-chloro-biphenyl-4-yl) -amide and 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine.

Yield: 70 mg (32.8% of theory)

Melting point: 217-218 ° C c27H25CIN O (M = 428.96) calc .: Mole peak (M + H) ⁺ : 429/431 mf: Mol peak (M + H) ⁺ : 429/431

Rr value: 0.3 (silica gel, dichloromethane / methanol = 10: 1) Example 2.5 .:

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

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

Prepared analogously to Example 2.1.e from propynoic acid (4-prop-1-ynyl-phenyl) -amide and 1- [2- (4-iodo-phenyl) -ethyl] -pyrrolidine.

Yield: 20 mg (11% of theory)

Melting point: 198-199 ° C

C24H24N2O (M = 356.47)

Rr value: 0.1 (silica gel, dichloromethane / methanol = 10: 1)

Example 3.1 .:

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

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

To a suspension of 71.7 g (515.41 mmol) of p-nitrophenol and 284.94 g (2.061 mol) of potassium carbonate in 600 ml of DMF at room temperature 88.7 g (515.41 mmol) (2-chloroethyl ) -diethylamine hydrochloride and the reaction mixture heated at 80 ° C for eight hours. The reaction mixture is concentrated and the residue is poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the filtrate is concentrated. Yield: 110.52 g (90% of theory) C ₁₂ H ₈ N ₂ O 3 (M = 238.28)

Rr value: 0.52 (silica gel, dichloromethane / methanol = 10: 1) 3.1.B. 4- (2-diethylamino-ethoxy) -phenylamine

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

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

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

Rr value: 0.62 (alumina, ethyl acetate / petroleum ether = 3: 1)

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

To a suspension of 10.68 g (281.59 mmol) of lithium aluminum hydride in 600 ml of absolute THF are added 30 g (112.63 mmol) of [4- (2-diethylamino-ethoxy) -phenyl] -carbamic acid methyl ester dissolved in 300 ml of absolute THF, slowly added dropwise with ice cooling and nitrogen atmosphere. The mixture is subsequently stirred for 14 hours, during which the reaction mixture is allowed to warm to room temperature. Then, after reaction control, 7 g of lithium aluminum hydride are added and stirred for 14 hours. By adding 60 ml of 20% sodium hydroxide solution, the reaction is stopped. The precipitate is filtered off and rinsed with diisopropyl ether. The filtrate is dried over sodium sulfate and the solvent is distilled off. Yield: 24.7 g (98.6% of theory)

0 | ₃ H ₂ 2N 2θ (M = 222.33) calc .: Mol peak (M + H) ⁺ : 223 f: Mol peak (M + H) ⁺ : 223 Rr value: 0.44 (silica gel, dichloromethane / methanol / ammonia = 10: 1)

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

A solution of 0.29 g (2 mmol) phenylpropynoic acid, 0.44 g (2 mmol) of [4- (2-diethylaminoethoxy) phenyl] methylamine, 0.7 g (2.2 mmol ) TBTU 0.29 g (2.2 mmol) HOBT and 0.51 ml (3 mmol) Hünig base in 30 ml THF and 2 ml DMF is stirred for 14 hours at room temperature.

The reaction mixture is concentrated. Purification by column chromatography on silica gel (dichloromethane / methanol = 80:20)

Yield: 130 mg (18.5% of theory)

C22 ^H 26 ^N 2 ° 2 ^{(M =:} 350.46) Calc .: molecular peak (M + H) ^+: 351 Found .: molecular peak (M + H) ^+: 351

Rr value: 0.39 (silica gel, dichloromethane / methanol = 80:20)

Example 3.2 .:

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

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

Prepared analogously to Example 3.1.e from [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine and (4-

Methoxy-phenyl) -propynoic acid in dichloromethane as solvent.

Yield: 300 mg (46.3% of theory)

C23H28 ^N 2 ° 3 (M = 380.49) calc .: Mol peak (M + H) ⁺ : 381 f: Mol peak (M + H) ⁺ : 381

Rr value: 0.42 (silica gel, dichloromethane / methanol = 80:20)

Example 3.3:

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

3.3.a. 3- (4-Chloro-phenyl) -propynoic acid [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide Prepared analogously to Example 3.1.e from [4- (2-diethylamino-ethoxy) -phenyl] - methyl-amine and (4-chloro-phenyl) -propynoic acid in dichloromethane as solvent. Yield: 36 mg (5% of theory)

^C 22 ^H 25 ^CIN 2 ° 2 ( ^{M = 38} , 91) calc .: Mol peak (M + H) ⁺ : 385/387 f: Mol peak (M + H) ⁺ : 385/387

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 3.4:

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

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

To a suspension of 11.67 g (53.76 mmol) of 2,6-dichlorocinnamic acid in 500 ml

Carbon tetrachloride at 0 ° C 9.45 g (59.14 mmol) of bromine, dissolved in 20 ml

Carbon tetrachloride, added dropwise and stirred for three hours at room temperature. Subsequently, the solvent is distilled off and the residue is treated with petroleum ether. The solid is filtered off and dried in a convection oven at 50 ° C.

Yield: 19.22 g (94.9% of theory)

Melting point: 184-185 ° C

C9H ₆ Br ₂ Cl ₂ θ2 (M = 376,86)

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

Rr value: 0.5 (silica gel, dichloromethane / ethanol / glacial acetic acid = 10: 1: 0.1)

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

Prepared analogously to Example 2.3.f from 4- (2-diethylamino-ethoxy) -phenylamine and (2,4-dichloro-phenyl) -propynoic acid.

Yield: 0.62 g (85% of theory)

Melting point: 107-109 ° C

^C 21 ^H 22 ^Cl 2 ^N 2 ° 2 ( ^M = 405.32) calc .: Mol peak (M + H) ⁺ : 405/407/409 f: Mol peak (M + H) ⁺ : 405/407/409

Rr value: 0.6 (silica gel, dichloromethane / methanol / ammonia = 5: 1: 0.1)

Example 3.5:

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

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

Prepared analogously to Example 3.4.c from 4- (2-diethylamino-propoxy) -phenylamine and (2,4-

Dichloro-phenyl) -propinsäure.

Yield: 0.41 g (65.2% of theory)

Melting point: 70-72 ° C

^C 22 ^H 24 ^C! 2 ^N 2 ° 2 ( ⁼ 419,35) Calc .: Mol peak (M + H) ⁺ : 419/421/423 mf: Mol peak (M + H) ⁺ : 419/421/423

Rr value: 0.4 (silica gel, dichloromethane / ethanol / ammonia = 5: 1: 0.01)

Example 3.6:

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

3.6.a. (E) -3- (4'-Chloro-biphenyl-4-yl) -acrylic acid ethyl ester To a solution of 1.124 g (4.04 mmol) of ethyl (E) -3- (4-bromo-phenyl) -acrylate in At room temperature, 173 mg (0.15 mmol) of tetrakistriphenylphosphine palladium and 4.4 ml (8.8 mmol) of a 2M sodium carbonate solution are added to 50 ml of dioxane at room temperature. To this reaction mixture are added 0.689 g (4.404 mmol) of 4-chlorophenylboronic acid dissolved in 10 ml of methanol and heated to reflux for five hours. The reaction mixture is concentrated, the residue taken up in dichloromethane and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 9: 1). Yield: 0.94 g (74.4% of theory) C ₁₇ H _{1 5} CIO ₂ (M = 286.76) calc .: Mole peak (M + H) ⁺ : 287/289 m: Mole peak (M + H ) ⁺ : 287/289

Rr value: 0.44 (silica gel, petroleum ether / ethyl acetate = 40:10)

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

To a solution of 0.9 g (3.13 mmol) of ethyl (E) -3- (4'-chlorobiphenyl-4-yl) acrylate in 30 ml of ethanol is added 6.27 ml of a 1 M sodium hydroxide solution and three Stirred hours at room temperature. The reaction is stopped by adding 6.27 ml of 1 N hydrochloric acid and the reaction mixture is stirred for two hours. The mixture is then concentrated, the residue is mixed with water and the precipitate is filtered off. The precipitate is repeatedly rinsed with water and dried in a vacuum oven at 80 ° C.

Yield: 0.68 g (67% of theory) C ₁₅ H ₁ - | CIO ₂ (M = 258.70) calc .: molecular peak (M-HV: 257/259 Found: molecular peak (MH) ^": 257/259

Rr value: 0.5 (silica gel, dichloromethane / methanol = 90:10)

3.6.c. (E) -3- (4'-Chlorobiphenyl-4-yl) - / V- (4-piperidin-1-ylmethyl-phenyl) -acrylamide

Prepared analogously to Example 3.1.e from [(E) -3- (4'-chlorobiphenyl-4-yl) -acrylic acid and 4-piperidin-1-ylmethyl-phenylamine. Yield: 0.57 g (62.9% of theory) Melting point: 265-270 ° C C27H27CIN2O (M = 430.98) calc .: Mole peak (M + H) ⁺ : 431/433 mf: Mol peak (M + H) ⁺ : 431/433

Rr value: 0.31 (silica gel, dichloromethane / methanol = 90:10)

3.6.d. 2,3-Dibromo-3- (4'-chlorobiphenyl-4-yl) -Λ- ^, - (4-piperidin-1-ylmethylphenyl) -propionamide A suspension of 150 mg (0.348 mmol) (E) -3- (4'-Chlorobiphenyl-4-yl) -Λ- (4-piperidin-1-ylmethyl-phenyl) -acrylamide in 15 ml of dichloromethane is added 0.02 ml (0.383 mmol) of bromine and three Stirred hours at room temperature. Subsequently, the

Concentrated reaction mixture, the residue recrystallized from petroleum ether and in

Vacuum drying oven dried at 70 ° C. Yield: 0.19 g (92.4% of theory)

Melting point: 145-150 ° C

C27H27Br ₂ CIN ₂ O I (M = 590.79) calc .: Mol peak (M + H) ⁺ : 589/591/593/595 F: Mol peak (M + H) ⁺ : 589/591/593/595 Rr value: 0.47 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

3.6.e. 3- (4'-Chloro-biphenyl-4-yl) -propynoic acid (4-piperidin-1-ylmethyl-phenyl) -amide Prepared analogously to Example 3.4.b from 2,3-dibromo-3- (4'-chloro -biphenyl-4-yl) -Λ- (4-piperidin-1-ylmethyl-phenyl) -propionamide. Yield: 26 mg (23.9% of theory) c27 25 ^{c |} N2O1 (M = 428.96) calc .: Mole peak (M + H) ⁺ : 429/431 mf: Mol peak (M + H) ⁺ : 429/431

Rr value: 0.42 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 3.7: 3- (4'-Chloro-biphenyl-4-yl) -propynoic acid (4-piperidin-1-ylmethyl-phenyl) -methyl-amide

3.7.a. 2,3 Dibromo-3- (4'-chloro-biphenyl-4-yl) propynoic acid To a suspension of 15 g (58 mmol) of 3- (4'-chlorobiphenyl-4-yl) acrylic acid in 370 ml

Carbon tetrachloride is added dropwise at room temperature with 3.3 ml (64.22 mmol) of bromine and stirred for three hours at room temperature. The precipitate is filtered off, washed with petroleum ether and dried in a convection oven at 70 ° C. Yield: 24 g (99% of theory) Melting point: 230-234 ° C

^C 15 ^H 11 Br ₂ CIO ₂ (M = 418.51)

Rr value: 0. 2 (silica gel, dichloromethane / methano 90:10)

3.7.b. (4'-Chloro-biphenyl-4-yl) -propinsäure A solution of 24 g (57.35 mmol) of 2,3-dibromo-3- (4 ^{'-chloro-biphenyl-4-yl)} propionic in 270 ml of THF is added in portions with 25.74 g (229.39 mmol) of potassium tert-butylate, so that the temperature does not exceed 40 ° C. The mixture is then stirred for 3.5 hours at this temperature. The reaction mixture is poured onto ice-water / conc. Hydrochloric acid and the precipitate taken up in ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. The desiccant is filtered off and the solvent distilled off. The residue is stirred with petroleum ether and filtered with suction. Yield: 14.2 g (97% of theory) C ₁₅ H ₉ ClO 2 (M = 256.68)

Rr value: 0.45 (silica gel, dichloromethane / methanol / glacial acetic acid = 90: 10: 0.1)

3.7.c. 3- (4 ^{'-Chloro-biphenyl-4-yl)} -propinsäure- (4-piperidin-1-ylmethyl-phenyl) -methyl-amide A solution of 0.26 g (1 mmol) of (4 ^{"-chloro-biphenyl} -4-yl) -propynoic acid and 0.12 ml (1.1 mmol) of N-methylmorpholine in 20 ml of absolute THF at -15 ° C with 0.14 ml (1.1 mmol) of isobutyl chloroformate and stirred for ten minutes. Thereafter, 0.225 g (1.1 mmol) of methyl (4-piperidin-1-ylmethyl-phenyl) -amine dissolved in 10 ml of THF are added and the reaction mixture is stirred for 2 hours until it reaches room temperature. The reaction mixture is concentrated and the residue is dissolved in dichloromethane. The organic phase is washed twice with water and then dried over sodium sulfate. The desiccant is filtered off and the solvent distilled off. The residue is triturated with ether, filtered off with suction and dried at 80 ° C. in a vacuum drying oven. Yield: 220 mg (50% of theory) Melting point: 237-239 ° CC ₂₈ H27CIN ₂ O (M = 442.98) calc .: Mole peak (M + H) ⁺ : 443/445 (CI) Fc: Molepeak (m.p. M + Hf: 443/445 (CI)

Rr value: 0.5 (silica gel, dichloromethane / methanol = 90:10)

Example 3.8: 3- (4'-Chloro-biphenyl-4-yl) -propynoic acid [4- (4-methylpiperazin-1-ylmethyl) -phenyl] -amide

Eine Lösung aus 0,26 g (1 mmol) (4'-ChIor-biphenyl-4-yl)-propinsäure und 0,12 ml (1,1 mmol) N-Methylmorpholin in 20 ml absolutem THF wird bei -15°C mit 0,14 ml (1,1 mmol)

A solution of 0.26 g (1 mmol) of (4'-chlorobiphenyl-4-yl) propynoic acid and 0.12 ml (1.1 mmol) of N-methylmorpholine in 20 ml of absolute THF is kept at -15 ° C with 0.14 ml (1.1 mmol)

Isobutyl chloroformate was added and stirred for ten minutes. Thereafter, 0.226 g (1.1 mmol) of 4- (4-methylpiperazin-1-ylmethyl) -phenylamine dissolved in 7 ml of THF are added and the reaction mixture is stirred for 2 hours until it reaches room temperature. The reaction mixture is concentrated and the residue is dissolved in dichloromethane. The organic phase is washed twice with water and then dried over sodium sulfate. The desiccant is filtered off and the solvent distilled off. The residue is triturated with ether and filtered with suction. Purification by column chromatography on silica gel (dichloromethane / methanol / ammonia = 90/10 / 0.1) Yield: 60 mg (14% of theory) Melting point: 182-185 ° C C27H26CIN3O (M = 443.97). Mole peak (M + H) ⁺ : 444/446 (CI) F: Molepeak (M + H) ⁺ : 444/446 (CI)

Rr value: 0.4 (silica gel, dichloromethane / methanol ammonia = 90: 10: 0.1)

Example 3.9. 3- (4 ^{'-Chloro-biphenyl-4-yl)} -propinsäure- [4- (2,6-dimethyl-piperidin-1-ylmethyl) - phenyl] -amide

Prepared analogously to Example 3.8. from (4 ^{'-Chloro-biphenyl-4-yl)} -propinsäure and 4- (2,6-dimethyl- piperidin-1-ylmethyl) -phenylamine.

Yield: 100 mg (22% of theory)

Melting point: 158-163 ° C

C29H29CIN2O (M = 457.01) calc .: Mol peak (M + H) ⁺ : 458/460 (CI) Fc: Mol peak (M + H) ⁺ : 458/460 (CI)

Rr value: 0.50 (silica gel, dichloromethane / methanol ammonia = 90: 10: 0.1)

Example 3.10: 3- (4 ^{'-Chloro-biphenyl-4-yl)} -propinsäure- {4 - [(cyciohexyl-methyl-amino) -methyl] - phenyl} -amide

Prepared analogously to Example 3.8. -propinsäure from (4 ^{'-Chloro-biphenyl-4-yl)} and 4 - [(cyclohexyl methyl-amino) -methyl] -phenylamine hydrochloride Chlord Yield: 60 mg (13% of theory). Melting point: 205-210 ° C C29H29CIN2O (M = 457.01) calc .: Mole peak (M + H) ⁺ : 457/459 (CI) Fc: Mole peak (M + H) ⁺ : 457/459 (CI) Rr value: 0.60 (silica gel, dichloromethane / Methanol = 90:10)

Example 3.11: BI00017862

3- (4 ^{'-ChIor-biphenyl-4-yl)} propinsäure- (4 - {[(2-methoxy-ethyl) -methyl-amino] -methyl} -phenyl) - amide

Prepared analogously to Example 3.8. from (4'-chloro-biphenyl-4-yl) -propynoic acid and 4 - {[(2-methoxy-ethyl) -methyl-amino] -methyl} -phenylamine.

Yield: 150 mg (35% of theory)

Melting point: 130-133 ° C

^C 26 ^H 25 ^CIN 2 ° 2 ( ^M = 432.94) calc .: Mol peak (M + H) ⁺ : 433/435 (CI) f: Mol peak (M + H) ⁺ : 433/435 (CI)

Rr value: 0.50 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 3.12:

3- (4'-chloro-biphenyl-4-yl) -propinsäure- [4- (3,5-dimethyl-piperidin-1-ylmethyl) -phenyl] -amide

A solution of 0.26 g (1 mmol) (4 ^{'-Chloro-biphenyl-4-yl)} -propinsäure and 0.12 ml (1.1 mmol) of N-methylmorpholine in 20 ml of absolute THF at -15 ° C 0.14 ml (1.1 mmol) of isobutyl chloroformate and stirred for ten minutes. Thereafter, 0.240 mg (1.1 mmol) of 4 - [(3,5-dimethylcyclohexylamino) -methyl] -phenylamine, dissolved in 7 ml of THF, are added and the reaction mixture is stirred for 16 hours. The reaction mixture is concentrated. Purification is carried out by column chromatography on silica gel (dichloromethane / methanol = 90/10). Yield: 300 mg (66% of theory) Melting point: 209-214 ° C. c29 29 ^clN 2 ° ( ^{M =} 457.01) calc .: Molpeak (M + H) ⁺ : 457/459 (CI) Fc: Molepeak (M + H) ⁺ : 457/459 (CI) Rr value: 0.60 (silica gel, dichloromethane / methanol = 90:10) Analogously to Example 3.12. the following compounds are prepared:

Rr value: A = (silica gel, dichloromethane / methanol / ammonia 90: 10: 0.1)

B = (silica gel, dichloromethane / methanol 90:10) Example 3.18: 3- (4'-Chlorobiphenyl-4-yl) -propynoic acid [4- (4-hydroxy-piperidin-1-ylmethyl) -phenyl] - amide

3.18.a 4-(4-Nitro-benzyl)-piperidin-4-ol

3.18.a 4- (4-nitro-benzyl) -piperidin-4-ol

To a solution of 41.5 g (0.410 mol) of 4-hydroxypiperidine in 500 ml of dichloromethane is added 137 ml (0.983 mol) of triethylamine. Subsequently, 56.28 g (0.328 mol) of 4-nitrobenzyl chloride are added slowly. The reaction mixture is boiled for 12 hours. The resulting solid is filtered off, the filtrate is washed twice with water and dried over magnesium sulfate. The solvent is concentrated. Yield: 66.45 g (86% of theory) of C ₁₂ H ₁₆ N ₂ O 3 (M = 236.27) calc .: Mol peak (M + H) ⁺ : 237 f: Mol peak (M + H) ⁺ : 237

3.18. b. 4- (4-amino-benzyl) -piperidin-4-ol

To a solution of 66.45 g (0.281 mol) of 4- (4-nitro-benzyl) -piperidin-4-ol in 660 ml of methanol is added 6.6 g of Raney nickel. The reaction mixture is hydrogenated for 13 hours at room temperature and 3 bar of hydrogen. The catalyst is filtered off and the filtrate is concentrated.

Yield: 64.5 g (111% of theory) of C ₁₂ H ₁₈ N 2 O (M = 206.28) calc .: Mol peak (M + H) ⁺ : 207 f: Mol peak (M + H) ⁺ : 207

3.18.C. 4- [4- (Fatty-Butyl-dimethyl-silanyloxy) -piperidin-1-ylmethyl] -phenylamine To a solution of 4.13 g (20 mmol) of 4- (4-amino-benzyl) -piperidin-4-ol and 3.4 g (50 mmol) of imidazole in 30 ml of dimethylformamide are 3.3 g (22 mmol) of tert. Butyldimethylchlorosilane added. The reaction mixture is stirred for 16 hours at room temperature. Then the solvent is concentrated and extracted between ether and water. The organic phase is dried over sodium sulfate and concentrated. The purification is carried out by column chromatography on aluminum oxide (eluent: petroleum ether / ethyl acetate 90:10). Yield: 1.65 g (26% of theory) C ₈ H ₃₂ N ₂ OSi (M = 320.55) calc .: Mol peak (M + H) ⁺ : 321 f: Mol peak (M + H) ⁺ : 321

Rr value: 0.80 (aluminum oxide, petroleum ether / ethyl acetate = 1: 1)

3.18.d. 3- (4 ^' -Chlorobiphenyl-4-yl) propynoic acid {4 - [(4-hydroxy-cyclohexylamine) -methyl] -phenyl} -amide A solution of 0.26 g (1 mmol) (4 ^' ) Chloro-biphenyl-4-yl) -propynoic acid and 0.12 ml (1, 1 mmol) of N-methylmorpholine in 20 ml of absolute THF is added at -15 ° C with 0.14 ml (1, 1 mmol) of isobutyl chloroformate and ten Stirred for minutes. Following will be Add 0.350 g (1.1 mmol) of 4- [4- (fet-butyl-dimethyl-silanyloxy) -piperidin-1-ylmethyl] -phenylamine dissolved in 7 ml of THF and stir the reaction mixture for four hours. The reaction mixture is concentrated. The residue is dissolved in 30 ml of tetrahydrofuran and treated with 0.95 g (3 mmol) of tetrabutylammonium fluoride hydrate. The reaction mixture is stirred for 16 h at room temperature. Then another 0.5 g (1, 5 mmol)

Tetrabutylammonium fluoride hydrate added and stirred for another 16 h at room temperature. The last step is repeated twice more. The solvent is then concentrated and the residue is extracted between dichloromethane and water. The organic phase is dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. Purification by column chromatography on silica gel (dichloromethane / methanol = 90/10)

Yield: 100 mg (23% of theory) Melting point: 243-247 ° C C27 25 ^CIN 2 ° 2 ( ⁼ 444.95) Calculated: Mol peak (M + H) ⁺ : 445/447 (CI) Fc: Molpeak (M + H) ⁺ : 445/447 (CI)

Rr value: 0.40 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 19.3: 3- (4 ^{'-Chloro-biphenyl-4-yl)} propinsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1f indol-5-yl] - amide

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

A reaction mixture of 16.22 g (0.1 mol) of 5-nitroindole, 35 g (0.205 mol) of 1- (2-chloroethyl) pyrrolidine hydrochloride and 51 g (0.369 mol) of potassium carbonate in 500 ml of DMF becomes 48 Stirred at room temperature for hours and then filtered. The filtrate is concentrated, the residue dissolved in dichloromethane and dried over sodium sulfate. The desiccant is filtered off and the filtrate is concentrated. Yield: 25 g (96.3% of theory) of Ci4H ₁₇ N ₃ O ₂ (M = 259.31) calc .: Mol peak (M + H) ⁺ : 260 f: Mol peak (M + H) ⁺ : 260 Rr value : 0.65 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1) 3.19.b. 5-Amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole

Prepared analogously to Example 3.1.b from 5-nitro-1- (2-pyrrolidin-1-yl-ethyl) -1 -indole in THF as

Solvent.

ber.: Molpeak (M+H)⁺: 230 gef: Molpeak (M+H)⁺: 230Yield: 0.83 g (93.9% of theory)

Calc .: Mol peak (M + H) ⁺ : 230 f: Mol peak (M + H) ⁺ : 230

Rr value: 0.37 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

3.19.C. 3- (4 ^{'-Chloro-biphenyl-4-yl)} propinsäure- [1- (2-pyrrolidin-1-yl-ethyl) -1 / - indol-5-yl] -amide Prepared analogously to Example 3.7.C. from 5-amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole and (4 ^' - chlorobiphenyl-4-yl) -propynoic acid in THF as solvent. Yield: 230 mg (49% of theory) C29H26CIN3O (M = 467.99)

Melting point: 224-227 ° C calc .: Mole peak (M + H) ⁺ : 468/470 (CI) Fc: Molepeak (M + H) ⁺ : 468/470 (CI)

Rr value: 0.4 (silica gel, dichloromethane / methanol = 90:10)

Example 3.20: 3- (4 ^{'-Chloro-biphenyl-4-yl)} -propinsäure- (3-chloro-4-piperidin-1 -yimethyl-phenyl) - amide

3.20.a: (2-Chloro-4-nitrophenyl) -methanol To a solution of 41.1 g (0.2 mol) of 2-chloro-4-nitrobenzoic acid in 400 ml of tetrahydrofuran is added slowly 35.9 g (0 , 22 mol) 1, 1'-carbonyldiimidazole added. The reaction mixture is stirred for 1.5 h at 35 ° C. Subsequently, the green reaction mixture is cooled down by means of ice and at max. 20 ° C added dropwise with a solution of 26.5 g (0.7 mol) of sodium borohydride in 400 ml of water. After stirring for 1.5 hours, the reaction mixture is diluted with 200 ml of water and then neutralized with 250 ml of half-concentrated hydrochloric acid. It is stirred for one hour, then extracted twice with ethyl acetate and the organic phase dried over sodium sulfate. The desiccant is filtered off and the solvent is concentrated. The residue is crystallized with petroleum ether, filtered off and dried at 50 ° C in a drying oven. Yield: 37.66 g (100% of theory) Melting point: 62-64 ° CC ₇ H ₆ CINO ₃ (M = 187.58) calc .: Mole peak (M + H) ⁺ : 187/189 (CI) : Molepeak (M + H) ⁺ : 187/189 (CI)

Rr value: 0.70 (silica gel, dichloromethane / methanol = 90:10)

3.20.b. 2-Chloro-1-chloromethyl-4-nitro-benzene To a solution of 15 g (80 mmol) of 2-chloro-4-nitro-phenyl) -methanol in 300 ml

Dichloromethane, 11, 6 ml (160 mmol) of thionyl chloride and 1 ml of dimethylformamide are added and all together heated under reflux for 2 hours. The solvent is then concentrated and the residue is dissolved in ethyl acetate and washed with water. The organic phase is dried over Natriumsaulfat, the desiccant filtered off and the filtrate was concentrated. Oily product. Yield: 16.8 g (102% of theory) C 7 H 5 Cl 2 N 2 O (M = 206.03) calc .: Mole peak (M + Hf: 205/7/9 (CI 2) Fc: Mole peak (M + H) ⁺ : 205 / 7/9 (CI2)

Rr value: 0.90 (silica gel, dichloromethane / methanol = 90:10)

3.20.C. 1- (2-chloro-4-nitro-benzyl) -piperidin

2 g (9.71 mmol) of 2-chloro-1-chloromethyl-4-nitro-benzene are slowly added at room temperature

Add 4 ml (40.04 mmol) of piperidine. After 15 min, the reaction mixture is washed with

Ethyl acetate and washed twice with water. The organic phase is dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. Oily product.

Yield: 2.39 g (97% of theory)

C ₁₂ Hi5CIN ₂ O ₂ (M = 254.71)

Rr value: 0.30 (silica gel, petroleum ether / ethyl acetate = 6: 1)

3.20.d 3-Chloro-4-piperid-1-ylmethyl-phenylamine

To a solution of 2.37 g (9.31 mmol) of 1- (2-chloro-4-nitro-benzyl) -piperidine in 100 ml of tetrahydrofuran are added 0.4 g of Raney nickel and hydrogenated at room temperature and 3 bar of hydrogen , After completion of the hydrogen uptake, the catalyst is filtered off and the filtrate is concentrated.

Yield: 1.88 g (90% of theory) Ci2H <i7CIN ₂ (M = 224.73) calc .: molecular peak (M + H) ^+: 255/7 (CI) Found: molecular peak (M + H) ^+: 255/7 (CI)

Rr value: 0.20 (silica gel, dichloromethane / methanol = 90:10)

3.20.e 3- (4'-chloro-biphenyl-4-yl) -propinsäure (3-chloro-4-piperidin-1-ylmethyl-phenyl) -amide Prepared analogously to Example 3.7.c from (4 ^{'-Chloro-biphenyl} -4-yl) -propynoic acid and 3-chloro-4-piperidn-1-ylmethyl-phenylamine. Yield: 0.1 g (22% of theory) Melting point: 277-281 ° C C27H24Cl2N2 O (M = 463.4) calc .: Mol peak (M + H) ⁺ : 463/5/7 (CI2) Molepeak (M + H) ⁺ : 463/5/7 (CI2)

Rr value: 0.50 (silica gel, dichloromethane / methanol = 90:10)

The following compounds are prepared analogously to Example 3.20:

Rr value: A = (silica gel, dichloromethane / methanol 90:10)

B = (silica gel, dichloromethane / methanol / ammonia 90: 10: 0.1) Example 3.24: 3- (4 ^{'chloro-biphenyl-4-yl)} -propinsäure- [3-chloro-4- (2-dimethylamino-ethoxy ) - phenyl] -amide hydrochloride CIH

Prepared analogously to Example 3.7.c from (4'-chloro-biphenyl-4-yl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethoxy) -phenylamine.

Yield: 0.28 g (58% of theory)

Melting point: 226-233 ° C

^C 27 ^H 26 ^Cl 2 ^N 2 ° 2 ( ⁼ 481, 41) ^* HCI calc .: Mol peak (M + H) ⁺ : 481/3/5 (CI 2) f: Mol peak (M + H) ⁺ : 481/3 / 5 (CI2)

Rr value: 0.45 (silica gel, dichloromethane / methanol = 90:10)

Example 3.25:

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

3.25.a. 5-Bromo-2-trimethylsilanylethynylpyridine To a solution of 20 g (81.89 mmol) of 2,5-dibromopyridine in 250 ml of absolute THF in an argon atmosphere are added 1.15 g (1.63 mmol) of tetrakistriphenylphosphinepalladium, 0.311 g ( 1.63 mmol) of copper (I) iodide and 50 ml of triethylamine were added. At 17 ° C., a solution of 13 ml (90.14 mmol) of trimethylsilylacetylene in 20 ml of THF is added dropwise rapidly to this reaction mixture. After ten minutes, the cooling is removed. After 20 minutes the temperature is 30 ° C. It is then cooled to 20 ° C and stirred for a short time. The

The reaction mixture is concentrated, the residue taken up in ethyl acetate and extracted twice with Natriumhydrogencarbonatlösunge. The combined organic phases are dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether). Yield: 20.4 g (98% of theory) of C ₁₀ H ₁₂ BrNSi (M = 254.20) Calc .: Mol peak (M + H) ⁺ : 254/256 F: Mol peak (M + H) ⁺ : 254/256

Rr value: 0.72 (silica gel, petroleum ether)

3.25. b. 5- (4-Chloro-phenyl) -2-trimethylsilanylethynylpyridine In an argon atmosphere, to a solution of 20.4 g (80.25 mmol) of 5-bromo-2-trimethylsilanylethynyl-pyridine and 26.33 g (160 mmol ) 4-chlorophenylboronic acid in 350 ml of dioxane 6.93 g (6 mmol) of tetrakistriphenylphosphine palladium and 17 ml of a 2M sodium carbonate solution and the reaction mixture was stirred at 90 ° C for five hours, with 7 ml of 2M sodium carbonate solution added every 30 minutes. Subsequently, 1000 ml of ethyl acetate are added at room temperature, and it is extracted twice with 400 ml of sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether to petroleum ether / ethyl acetate = 9: 1). Yield: 7.9 g (34.4% of theory) of dHCl ₆ CINSi (M = 285.85) calc .: Mol peak (MH) ^" : 286/288 F: Mol peak (MH) ^' : 286/288

Rr value: 0.6 (silica gel, petroleum ether / ethyl acetate = 8: 2)

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

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

To a solution of 0.5 g (2.34 mmol) of 5- (4-chlorophenyl) -2-ethynyl-pyridine in 30 ml of absolute THF are added at -10 ° C 1.6 ml (2.46 mmol) Butyllithiumlösung (1.6M in hexane) was added dropwise and stirred at -8 ° C for five minutes. The reaction mixture is added in portions at -70 ° C with dry ice, stirred for one hour at room temperature and concentrated. The residue is suspended in 5 ml of water and treated with 1.6 ml of 1 N hydrochloric acid, whereupon a precipitate is formed. Following is ethyl acetate added and the suspension filtered. The solid is dried in a vacuum oven at 70 ° C.

Yield: 0.25 g (41.5% of theory) Melting point: 210 ° C. CC ₁₄ H ₈ CINO ₂ l (M = 257.67) Calculated by: Mole peak (M + H) ⁺ : 258/260 F o: mole peak (M + H) ⁺ : 258/260

3.25.e. 3- [5- (4-Chloro-phenyl) -pyridin-2-yl] -propynoic acid (4-piperidin-1-yl-yl-phenyl) -amide Prepared analogously to Example 2.3.f from [5- (4-chloro) phenyl) -pyridin-2-yl] -propynoic acid and 4-piperidin-1-ylmethyl-phenylamine. Yield: 0.2 g (48% of theory) of C26H24CIN3Ol (M = 429.95) calc .: Mol peak (M + H) ⁺ : 430/432 f: Mol peak (M + H) ⁺ : 430/432 Rr value : 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

The following compounds are prepared analogously to Example 3.25:

RrWert: A= (Kieselgel, Dichlormethan/Methanol 90:10)

Rr value: A = (silica gel, dichloromethane / methanol 90:10)

B = (silica gel, dichloromethane / methanol / ammonia 90: 10: 0.1)

The following compounds are prepared analogously to Example 3.25:

Rr value: A = (silica gel, dichloromethane / methanol / ammonia 90: 10: 0.1)

Example 3.32: 3- (3-Chloro-biphenyl-4-yl) -propynoic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide hydrochloride

3.32.a. Trifluor-methansulfonsäure 3-chlor-biphenyl-4-yI ester

3.32.a. Trifluoro-methanesulfonic acid 3-chloro-biphenyl-4-yl ester

To a solution of 7.5 g (36.65 mmol) of 3-chloro-biphenyl-4-ol and 6.1 ml (44 mmol) of triethylamine in 100 ml of dichloromethane are added between -10 to -5 ° C 6.7 ml (40.32 mmol) Trifluormethansulfonsäureanhydrid, dissolved in 5 ml of dichloromethane, added dropwise. Subsequently is stirred for 30 minutes. The reaction solution is then extracted with water, the organic phase separated and filtered through an Aloxfritte. The filtrate is evaporated. Yield: 12 g (97% of theory) of C ₁₃ H ₈ ClF ₃ O ₃ S (M = 336.72) calc .: Mol peak (M + H) ⁺ : 336/338 (CI) Fc: mol peak (M + H) ⁺ : 336/338 (CI)

Rr value: 0.7 (silica gel, petroleum ether / ethyl acetate = 5: 1)

3.32.b. tert-butyl (3-chloro-biphenyl-4-yIethinyl) -dimethyl-silane

To a solution of 8.1 g (24 mmol) trifluoromethanesulfonic acid 3-chloro-biphenyl-4-yl ester in 50 ml of absolute dimethylformamide and 13.31 ml (96 mmol) of triethylamine in an argon atmosphere 0.84 g (1 , 2 mmol) of bis (triphenylphosphine) palladium (II) chloride, 0.23 g (1.2 mmol) of copper (I) iodide and 6.28 ml (33.6 mmol) of (fatty-butyldimethylsilyl) acetyΙen added , At room temperature, the reaction mixture is stirred for 24 hours. The reaction mixture is then concentrated, the residue taken up in ethyl acetate and extracted with water. The organic phase is dried. Purification is carried out by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate 4: 1). Yield: 8.4 g (107% of theory.) C ₂ oH23CISi (M = 326.94) calc .: molecular peak (M + H) ^+: 327/329 (CI) Found: molecular peak (M + H) ^+: 327/329 (CI) Rr value: 0.7 (silica gel, petroleum ether / toluene 9: 1)

3.32.C. 3-chloro-4-ethinyl-biphenyl

7.85 g (24 mmol) of tert-butyl (3-chloro-biphenyl-4-yl-ethynyl) -dimethyl-silane are dissolved in 150 ml of absolute tetrahydrofuran and at 5 ° C in portions with 11, 4 g (36 mmol) of tetrabutylammonium fluoride * 3H2θ offset. The reaction mixture reaches after 30 minutes

Room temperature. The solvent is then concentrated and the residue is extracted between ether and water. The organic phase is dried, treated with activated charcoal and filtered through Celite. The filtrate is concentrated. Purification is effected by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate 20: 1) Yield: 4.7 g (92% of theory.) C ^«| ₄ HgCl (M = 212.67)

Rr value: 0.6 (silica gel, petroleum ether / toluene 5: 1)

3.32.d. (3-Chloro-biphenyl-4-yl) -propynoic acid To a solution of 4.7 g (22.1 mmol) of 3-chloro-4-ethynylbiphenyl in 100 ml of absolute tetrahydrofuran at -10 to -20 ° C 13.8 ml (22.1 mmol) of butyl lithium solution (1, 6 M in Hexane) and cooled to -60 ° C after five minutes. At this temperature, dry ice is added in portions to the reaction mixture and slowly allowed to come to room temperature. The solvent is then concentrated and the residue extracted between ethyl acetate and 1 M hydrochloric acid. The organic phase is dried, the drying agent is filtered off and the solvent is evaporated. The residue is stirred with petroleum ether, filtered off and dried in a convection oven at 80 ° C.

Yield: 4.8 g (85% of theory) C ₁₅ H ₉ ClO 2 (M = 256.68) calc .: Mole peak (M + Hf: 257/259 (CI)) f: Mol peak (M + H) ⁺ : 257/259 (CI)

Rr value: 0.2 (kieselgei, dichloromethane / methanol / glacial acetic acid 90: 10: 0.1)

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

Hydrochloride Prepared analogously to Example 3.8.a from (3-chloro-biphenyl-4-yl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethoxy) -phenylamine.

Yield: 0.35 g (68% of theory)

Melting point: 195-200 ° C

^C 27 ^H 26 ^Cl 2 ^N 2 O ₂ ^* HCl (M = 517.87) calc .: Mol peak (M + Hf: 481/3/5 (CI 2) Fc: Molepeak (M + H) ⁺ : 481/3 / 5 (CI2)

Rr value: 0. 6 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

Example 3.33: 3- (3-Chloro-biphenyl-4-yl) -propynoic acid (4-piperidin-1-ylmethyl-phenyl) -amide hydrochloride

Prepared analogously to Example 3.8. from (3-chloro-biphenyl-4-yl) -propynoic acid and 4-piperidin-1-ylmethyl-phenylamine. Yield: 0.35 g (75% of theory) Melting point: 260-265 ° C C27H25CIN2 O * HCl (M = 465.41) Calcd .: Mol peak (M + H) ⁺ : 429/31 (CI) Fc: Molepeak (M + H) ⁺ : 429/31 (CI)

Rr value: 0. 6 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

Example 3.34:

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

3.34.a. 3- (2,4-dichloro-phenyl) -propionic acid [4- (2-diethylamino-ethyl) -phenyl] -amide-hydrochloride

Prepared analogously to Example 2.3.f from 4- (2-diethylamino-ethyl) -phenylamine and (2,4-dichloro-phenyl) -propynoic acid.

Yield: 0.3 g (47% of theory)

Melting point: 204-208 ° CC ₂ 1 H22CI2N2O (M = 425.78) Calculated by: Molepeak (M + H) ⁺ : 389/391/393 f: Mol peak (M + H) ⁺ : 389/391/393

Rr value: 0.6 (silica gel, dichloromethane / ethanol / ammonia = 5: 1: 0.01)

Example 3.35.

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

Prepared analogously to Example 2.3.f from 90 mg (0.44 mmol) of 4- (2-diethylamino-ethyl) -phenylamine and 99 mg (0.40 mmol) of 2-chloro-4-trifluoromethyl-phenyl) -propynoic acid. Yield: 71 mg (42% of theory) Melting point: 145-150 ° C C22H22CIF3N2O (M = 422.88) calc .: Mol peak (M + H) ⁺ : 423/425 Found: Mol peak (M + H) ⁺ : 423/425

Rr value: 0.30 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.36

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [N- (2-dimethylamino-ethyl) -methylamino] -phenyl} -amide-formate

Prepared analogously to Example 2.3.f. from 90 mg (0.44 mmol) of 4- [N- (2-dimethylamino-ethyl) -methylamino] -phenylamine (preparation see international patent application WO 01/27081) and 99 mg (0.40 mmol) of 2-chloro-4 -trifluoromethyl-phenyl) -propinsäure. Yield: 64 mg (38% of theory) C21H21 CIF3N3O x CH ₂ O ₂ (M = 469.89) calc .: molecular peak (M + H) ^+: 424/426 Found: molecular peak (M + H) ^+: 424 / 426

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.37

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

Prepared analogously to Example 2.3.f from 67 mg (0.3 mmol) of 4- (2-diethylamino-propoxy) - phenylamine and 75 mg (0.3 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid. Yield: 71 mg (52% of theory) Melting point: 172-176 ° C c23H24CIF ₃ N ₂ θ2 (M = 452.90) Calc .: Mol peak (M + H) ⁺ : 453/455 f: Mol peak (M + H) ⁺ : 453/455

Rr value: 0.30 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.38

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

Prepared analogously to Example 2.3.f from 69 mg (0.33 mmol) 4- (2-diethylamino-ethoxy) - phenylamine and 75 mg (0.30 mmol) (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.

Yield: 70 mg (53% of theory)

Melting point: 194-197 ° C C22 ^H 22 ^CIF 3N2θ2 (M = 438.88) calc .: molecular peak (M + H) ^+: 439/441 Found: molecular peak (M + H) ^+: 439/441 R f value: 0, 35 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.39

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

Prepared analogously to Example 2.3.f from [4- (2-diethylamino-ethoxy) -phenyl] -methyl-amine and (2-

Chloro-4-trifluoromethyl-phenyl -propinsäure).

Yield: 60 mg (22% of theory)

Melting point: 135-138 ° C ₃ N c23H24CIF θ2 (M = 452,90) calc .: molecular peak (M + H) ^+: 453/455 Found: molecular peak (M + H) ^+: 453/455 Rr value: 0.4 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.40

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

Prepared analogously to Example 2.3.f from 4-diethylaminomethyl-phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid. Yield: 72 mg (59% of theory) of C21H20CIF3N2O (M = 408.85) calc .: Mole peak (M + H) ⁺ : 409/411 mf: Mol peak (M + H) ⁺ : 409/411

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.41 3- (2-Chloro-4-trifluoromethylphenyl) propynoic acid (4-piperidin-1-ylmethyl-phenyl) -amide Hydrochloride

Prepared analogously to Example 2.3.f from 4-piperidin-1-ylmethyl-phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid. Yield: 170 mg (40% of theory) C22H20CIF3N2O (M = 420.86)

Melting point: 193-195 ° C calc .: Molepeak (MH) ^' : 419/421 (CI) F: Molepeak (MH) ^' : 419/421 (CI)

Rr value: 0.5 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.42

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

Prepared analogously to Example 2.3.f from 4- (2-imidazol-1-yl-ethoxy) -phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.

Yield: 78 mg (60% of theory)

Melting point: 182-186 ° C

C2lH ₁₅ CIF ₃ N ₃ O 2 (M = 433.82) calc .: Mol peak (M + H) ⁺ : 434/436 f: Mol peak (M + H) ⁺ : 434/436

Rr value: 0.33 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.43

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

Prepared analogously to Example 2.3.f from 4- (2-pyrazol-1-yl-ethoxy) -phenylamine and (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.

Yield: 56 mg (43% of theory)

Melting point: 120-125 ° C

C21H15CIF3N3O2 (M = 433.82) calc .: Mol peak (M + H) ⁺ : 434/436 F: Mol peak (M + H) ⁺ : 434/436

Rr value: 0.6 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.44

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

Prepared analogously to Example 2.3.f from 4- (2- [1,2,4] triazol-4-yl-ethoxy) -phenylamine and (2-chloro

4-trifluoromethyl-phenyl) -propinsäure.

Yield: 51 mg (39.4% of theory)

Melting point: 223-227 ° C

C20H14CIF3N4O2 (M = 434.80) calc .: Mole peak (M + Hf: 435/437 mf: Mol peak (M + Hf: 435/437

Rr value: 0.31 (silica gel, dichloromethane / methanol = 9: 1)

Example 3.45 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (4-methylpiperidin-1-yl) -ethoxy] -phenyl} -amide hydrochloride

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

To a solution of 0.54 g (3.83 mmol) of 1-fluoro-4-nitrobenzene and 0.6 g (4.2 mmol) of 2- (4-methylpiperidin-1-yl) ethanol in 10 ml Dimethylformamide at 0 ° C under an argon atmosphere 200 mg (4.2 mmol) of sodium hydride (55%) was added. The reaction mixture is stirred at 0 ° C for two hours and then a further 1.5 hours at room temperature. The reaction mixture is concentrated and the residue is extracted between water and ethyl acetate. The organic phase is dried, the drying agent is filtered off and the filtrate is concentrated. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol 9: 1). Yield: 700 mg (69% of theory) of C14H20 2O3 (M = 264.32) calc .: Mole peak (M + Hf: 265 Fem: mole peak (m.p. M + Hf: 265

Rr value: 0.7 (silica gel, dichloromethane / methanol = 9: 1) 3.45.b. 4- [2- (4-methylpiperidin-1-yl) ethoxy] -phenylamine

A reaction mixture of 680 mg (2.57 mmol) of 4-methyl-1- [2- (4-nitro-phenoxy) -ethyl] -piperidine and 80 mg of palladium (10% on carbon) in 10 ml of methanol is added at room temperature and Hydrogenated 3 bar hydrogen for 4.5 hours. The catalyst is filtered off with suction and the filtrate is concentrated.

Yield: 540 mg (90% of theory)

C-14H22N2O (M = 234.34) calc .: Mol peak (M + Hf: 235 fc: Mol peak (M + Hf: 235

Rr value: 0.33 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

3.45.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (4-methylpiperidin-1-yl) -ethoxy] -phenyl} -amide hydrochloride

Prepared analogously to Example 3.7.c. from 4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine and

(2-Chloro-4-trifluoromethyl-phenyl) -propinsäure.

Yield: 230 mg (49% of theory)

C24H24 CIF ₃ N ₂ O ₂ (M = 464.91) * HCI

Melting point: 240-245 ° C calc .: Mol peak (M + Hf: 465/467 (CI) F f: Mol peak (M + Hf: 465/467 (CI)

Rr value: 0.6 (silica gel, dichloromethane / methanol = 9: 1)

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

Table 1

The following compounds are prepared analogously to Example 3.20:

R _f value: A = (silica gel, dichloromethane / methanol 90:10)

B = (silica gel, dichloromethane / methanol / ammonia 90: 10: 0.1)

Example 3.168:

3- [5- (4-Chloro-phenyl) -pyridin-2-yl] -propionic acid [4- (4-hydroxy-piperidin-1-ylmethyl) -phenyl] -amide

Prepared analogously to Example 2.3.f from [5- (4-chloro-phenyl) -pyridin-2-yl] -propynoic acid and 4- [4- (tert-butyl-dimethyl-silanyloxy) -piperidin-1-ylmethyl] -phenylamine , The splitting off of Silyl group is made by adding tetrabutylammonium fluoride to a solution of the silyl ether in THF.

Yield: 0.25 g (43% of theory)

Melting point: 186-190 ° C

^C 26 ^H 24 ^CIN 3 ° 2 ( ^M = 445.94) calc .: Mole peak (M + Hf: 446/448 F o: mol peak (M + Hf: 446/448

Rr value: 0.6 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

Example 4.1:

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

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

To a solution of 35 g (0.202 mol) of 2-chloro-4-nitro-phenol in 350 ml of DMF is added 112 g (0.81 mol) of potassium carbonate. Subsequently, the reaction mixture is mixed with 35 g (0.203 mol) of (2-chloroethyl) -diethyl-amine hydrochloride and stirred for three hours at 80 ° C and 14 hours at room temperature. The reaction mixture is concentrated and the residue poured into 1000 ml of water and this mixture with three times

Extracted ethyl acetate. The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. Yield: 49.6 g (90% of theory) of C ₁₂ H ₁ 7CIN ₂ O 3 (M = 272.73) Calculated: Mol peak (M + Hf: 273 f: Mol peak (M + Hf: 273

Rr value: 0.36 (silica gel, dichloromethane / methanol = 90:10)

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

Prepared analogously to Example 3.1. b from [2- (2-chloro-4-nitro-phenoxy) -ethyl] -diethyl-amine in methanol in a reaction time of 4.5 hours. Yield: 36.12 g (81.8% of theory) of C ₁₂ H ₁₉ CIN ₂ O (M = 242.75) Calc .: Molpeak (M + Hf: 243/245 F: Mol peak (M + Hf: 243/245

Rr value: 0.36 (silica gel, dichloromethane / methanol = 90:10)

4.1.C (2,4-dichloro-phenyl) -propionic acid chloride

A reaction mixture of 0.34 g (1, 58 mmol) of (2,4-dichloro-phenyl) -propynoic acid and 0.14 ml (1.9 mmol) of thionyl chloride in 15 ml of absolute toluene is stirred for three hours at 70 ° C and then concentrated. The residue is taken up in absolute toluene and the solution is concentrated to dryness. This process is then repeated again and the residue is reacted further raw.

4.1. d. 3- (2,4-dichloro-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amϊd 0.37 g (1, 58 mmol) (2,4-dichloro) phenyl) -propionic chloride are dissolved in 15 ml of absolute toluene and cooled with ice with 0.77 g (3.16 mmol) of [2- (2-chloro-4-amino-phenoxy) -ethyl] -diethyl-amine, dissolved in 10 ml of absolute toluene, added and four hours

Room temperature stirred. Subsequently, the reaction mixture is extracted with ethyl acetate and dilute aqueous ammonia solution. The organic phase is extracted with water and dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol = 9: 1). The product obtained is recrystallized from petroleum ether and dried in a vacuum oven at 50 ° C.

Yield: 0.21 g (30.2% of theory). Melting point: 98-100 ° C C21 ^H 21 ^CI 3 ^N 2 over ° 2 (= 439.77) .: molecular peak (M + Hf 439/441 / 443 F: Molepeak (M + Hf: 439/441/443

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.2: 3- (2-Chloro-4-trifluoromethylphenyl) propynoic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

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

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

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

Prepared analogously to Example 4.1.d from (2-chloro-4-trifluoromethyl-phenyl) -propionyl chloride and

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

Yield: 0.26 g (27.5% of theory)

C22H21CI2F3N2O2 (M = 473.32) calc .: Mol peak (M + Hf: 473/475 Fc: Mol peak (M + Hf: 473/475

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.3:

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

4.3.a. Pyridin-2-yl-propynoic

6.3 ml of n-butyllithium solution (1.6 M in hexane) are added dropwise at -10 ° C. to a solution of 1 g (9.7 mmol) of 2-ethynylpyridine in 30 ml of absolute THF and the mixture is stirred for 30 minutes. Dry ice is added in portions at -78 ° C. and the reaction mixture is allowed to warm to room temperature. After about one hour, the reaction mixture is concentrated and the residue taken up under ice-cooling in 10 ml of 1N hydrochloric acid. The rainfall is filtered off, rinsed with isopropanol and diethyl ether and in a vacuum oven at 70

° C dried.

Yield: 0.6 g (42% of theory)

Melting point: 130 ° C

C ₈ H ₅ NO ₂ (M = 147.13) calc .: Mole peak (M + Hf: 148 F o: mol peak (M + Hf: 148

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

Prepared analogously to Example 2.3.f from pyridin-2-yl-propric acid and [2- (2-chloro-4-amino-phenoxy) ethyl] -d ethyl-amine.

Yield: 0.37 g (53.3% of theory)

^C 20 22 ^CIN 3 ° 2X ^CI ( ^M = 408.33) calc .: Mole peak (M + Hf: 372/374 mf: Mol peak (M + Hf: 372/374

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.4:

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

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

Prepared analogously to Example 3.4.a from 3-biphenyl-4-yl-acrylic acid.

Yield: 5 g (91.2% of theory)

Melting point: 200-203 ° C c15Hl2 ^B r2Ö2 ( ^{M = 384} .07)

Rr value: 0.4 (silica gel, dichloromethane / methanol / acetic acid = 90: 10: 1)

4.4.b. Biphenyl-4-yl-propynoic

Prepared analogously to Example 3.4.b from 3-biphenyl-4-yl-2,3-dibromo-propane carboxylic acid.

Yield: 2.8 g (96.8% of theory) C ₁₅ H ₁₀ O ₂ (M = 222.24)

Melting point: 170 ° C calc .: Mole peak (M + Hf: 223 F: Mol peak (M + Hf: 223

Rr value: 0.4 (silica gel, dichloromethane / methanol / acetic acid = 90: 10: 1)

4.4.c. Biphenyl-4-yl-propinsäurechlorid

Prepared analogously to Example 4.1. c from biphenyl-4-yl-propric acid. The connection is continued raw.

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

Prepared analogously to Example 4.1.d from biphenyl-4-yl-propric acid chloride and [2- (2-chloro-4-amino-phenoxy) ethyl] -diethyl-amine. Yield: 0.28 g (31.3% of theory) Melting point: 105-108 ° C. C27H27CIN2O2 (M = 446.98) Calculated by: Mole peak (M + Hf: 447/449 Fc: Mole peak (M + Hf: 447/449

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.5:

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

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

In an argon atmosphere, 9 g (34.6 mmol) of 1-bromo-2,4,6-trichlorobenzene, 9.8 g (34.45 mmol) of triphenylsilylacetylene and 15 ml of triethylamine are dissolved in 100 ml of absolute dioxane and at 90 ° C. with 0.2 g (1, 04 mmol) of copper (I) iodide and 1, 2 g (1, 04 mmol) Tetrakistriphenylphosphinpalladium and stirred for 20 hours. The reaction mixture is filtered through Celite and the filtrate is concentrated. The residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: Petroleum ether / toluene = 5: 1). The product is recrystallized from petroleum ether and dried in a vacuum oven at 70 ° C. Yield: 6.9 g (43% of theory) Melting point: 115-120 ° CC ₂ 6Hi7Cl ₃ Si (M = 463.87) calc .: Mole peak (M + Hf: 463/465/467/469 m.p. (M + Hf: 463/465/467/469 Rr value: 0.6 (silica gel, petroleum ether / toluene = 4: 1)

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

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

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

Prepared analogously to Example 4.3.a from triphenyl (2,4,6-trichloro-phenyIethynyl) silane and

Dry ice.

Yield: 3.3 g (77.7% of theory)

Melting point: 170-175 ° C C9H3Cl3O2 (M = 249.48) calc .: Mol peak (M + Hf: 249/251/253 Found: Mol peak (M + Hf: 249/251/253

Rr value: 0.4 (silica gel, dichloromethane / methanol / acetic acid = 50: 10: 1)

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

Prepared analogously to Example 2.3.f from (2,4,6-trichloro-phenyI) -propinic acid and [2- (2-chloro-4-amino-phenoxy) -ethyl] -diethyl-amine.

Yield: 0.72 g (82.9% of theory)

Melting point: 188-191 ° CC ₂ ιH2θCi4N2θ ₂ X HCI (M = 510.67) calc .: Mole peak (M + Hf: 473/475/477/479/481 m: Mole peak (M + Hf: 473/475/477 / 479/481 Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

Example 4.6:

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

4.6.a. [2- (2-Chloro-4-nitro-phenoxy) -propyl] -diethyl-amine To a solution of 5.3 g (30 mmol) of 3-chloro-4-fluoro-nitrobenzene and 4.3 g (33 mmol ) 3-diethylaminopropan-1-ol in 50 ml of DMF are added at 0 ° C 1.6 g (33 mmol) of sodium hydride (50% in oil) and stirred for two hours. The mixture is then warmed to room temperature and stirred for one hour. The reaction mixture is concentrated, treated with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia = 9: 1: 0.1). Yield: 8 g (93% of theory) of C-13H19CIN2O3 (M = 286.76)

Rr value: 0.3 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 0.1)

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

Prepared analogously to Example 3.1. b from [2- (2-chloro-4-nitro-phenoxy) -propyl] -diethyl-amine in

Methanol in a reaction time of 8 hours.

Yield: 6.7 g (93.5% of theory) C | 3H21 CIN ₂ O (M = 256.77) calc .: Mole peak (M + Hf: 257/259 mf: Mol peak (M + Hf: 257/259

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

4.6.C. 3- (2,4-dichloro-phenyl) -propionic acid [3-chloro-4- (2-diethylamino-propoxy) -phenyl] -amide-hydrochloride Prepared analogously to Example 3.4.c from [2- (2-chloro-4-amino-phenoxy) -propyl] -diethyl-amine and

(2,4-dichloro-phenyl) -propinsäure

Yield: 0.62 g (84.3% of theory)

Melting point: 180-185 ° C

^C 22 ^H 23 ^Cl 3 ^N 2 ° 2 HCl (M = 490.26) calc .: Mole peak (M + Hf: 453/455/457/459 F o: mol peak (M + Hf: 453/455/457/459

Rr value: 0.7 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

Example 4.7:

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

4.7.a. 3-(2,4-Dichlor-phenyl)-propinsäure-[3-methoxy-4-(2-diethylamino-ethoxy)-phenyl]-amid- hydrochlorid

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

Prepared analogously to Example 2.3.f from (2,4-dichloro-phenyl) -propionyl chloride and [2- (2-

Methoxy-4-amino-phenoxy) -ethyl] -diethyl-amine.

Yield: 0.25 g (31.2% of theory) Melting point: 205-207 ° C

C22H24CI2N2O3 X HCI (M = 471.81) calc .: Molpeak (M + Hf: 435/437/439 found: Molpeak (M + Hf: 435/437/439

Rr value: 0.6 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

Example 4.8:

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

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

Prepared analogously to Example 4.1. a from 3-chloro-4-nitro-phenol and (2-chloroethyl) -diethyl-amine hydrochloride.

Yield: 1.25 g (79.5% of theory)

C-12H-I 7CIN2O3 (M = 272.73) calc .: Mole peak (M + Hf: 273/275 mf: Mol peak (M + Hf: 273/275

Rr value: 0.44 (silica gel, dichloromethane / methanol = 90:10)

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

Prepared analogously to Example 3.1. b from [2- (3-chloro-4-nitro-phenoxy) -ethyl] -diethyl-amine in ethyl acetate. Yield: 1.05 g (95.4% of theory) C <| ₂ H- _{j 9} CIN ₂ O (M = 242.75) calc .: Mole peak (M + Hf: 243/245 f: Mol peak (M + Hf: 243/245

Rr value: 0.41 (silica gel, dichloromethane / methanol = 90:10)

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

Prepared analogously to Example 2.3.f from (2,4-dichloro-phenyl) -propionyl chloride and [2- (3-chloro)

4-amino-phenoxy) -ethyl] -diethyl-amine.

Yield: 0.53 g (65.5% of theory)

Melting point: 128-130 ° CC ₂ 1 H ₂ 1 CI 3 N ₂ O ₂ X HCI (M = 476.23) calc .: Mole peak (M + Hf: 439/441/443 f: Mol peak (M + Hf: 439/441/443

Rr value: 0.7 (silica gel, dichloromethane / methanol / ammonia = 50: 10: 0.1)

Example 4.9:

3- (4-Chloro-phenyl) -propynoic acid [1- (2-pyrrolidin-1-yl-ethyl) -1-W-indol-5-yl] -amide

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

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

Rr value: 0.65 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

4.9.b. 5-Amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole Prepared analogously to Example 3.1. b from 5-nitro-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole in THF as solvent.

ber.: Molpeak (M+Hf: 230 gef: Molpeak (M+Hf: 230 RrWert: 0.37 (Kieselgel, Dichlormethan/ Methanol/Ammoniak = 90:10:1)Yield: 0.83 g (93.9% of theory)

calc .: Mole peak (M + Hf: 230 F f: mol peak (M + Hf: 230 Rr value: 0.37 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

4.9.c. 3- (4-Chloro-phenyl) -propicarboxylic acid [1- (2-pyrrolidin-1-yl-ethyl) -1 / - / - indol-5-yl] -amide Prepared analogously to Example 3.1. e from 5-amino-1- (2-pyrrolidin-1-yl-ethyl) -1r-indole and (4-chloro-phenyl) -propynoic acid in THF as solvent. Yield: 186 mg (47.5% of theory) of C23H22CIN3O (M = 391.90)

Melting point: 135-144 ° C ber .: Molpeak (M + Hf: 393/394 Found: Molpeak (M + Hf: 393/394

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Beipiel 6.1:

Example 6.1:

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

A reaction mixture of 60 mg (0.14 mmol) of (E) - / V- (4'-methoxy-biphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide and 10 mg of Raney Nickel in 30 ml of methanol is hydrogenated for four hours. The catalyst is filtered off and the filtrate is evaporated to dryness. Yield: 56 mg (93.2% of theory) Melting point: 185-188 ° C. CC ₂₇ H ₃ θN ₂ θ ₂ (M = 414.55) Calculated by: Mole peak (M + Hf: 415 mf: mol peak (M + Hf: 415

Rr value: 0.29 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 6.2:

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

A reaction mixture of 80 mg (0.18 mmol) of (E) -Λ- (4'-chlorobiphenyl-4-yl) -3- [4- (4-methylpiperidine-1-ylmethyl) -phenyl] acrylamide and 20 mg Raney nickel in 15 ml

Ethyl acetate and 15 ml of methanol are hydrogenated for one hour at 50 psi and room temperature. The catalyst is filtered off, the filtrate is evaporated to dryness and washed with

Stirred diisopropyl ether.

Yield: 40 mg (49.7% of theory) Melting point: 150-151 ° C. c28 ^H 3lCIN ₂ O (M = 447.02) Calculated by: Mole peak (M + Hf: 447/449 m.p .: Mol peak (M + Hf: 447/449

RrWert: A, B wie zuvor angegebenRr value: 0.5 (silica gel, dichloromethane / methanol = 10: 1) Analogous to example 6.2. the following compounds are prepared:

Rr value: A, B as previously stated

C = (silica gel, dichloromethane / ethanol / ammonia 20/1 / 0.1) Example 6.12:

Λ / - (4'-Chloro-biphenyl-4-yl) -3- (4 - {[methyl- (tetrahydro-pyran-4-yl) -amino] -methyl} -phenyl) -propionamide

A reaction mixture of 60 mg (0.13 mmol) of (E) -Λ / - (4'-chlorobiphenyl-4-yl) -3- (4 - {[methyl-

(tetrahydro-pyran-4-yl) -amino] -methyl} -phenyl) -acrylamide and 20 mg Raney nickel in 10 ml

N, N-dimethylformamide is hydrogenated for three hours at 50 psi and room temperature. Of the

Catalyst is filtered off and the filtrate is evaporated to dryness. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia

20/1 / 0.1)

Yield: 22 mg (29% of theory)

Melting point: 167-173 ° C

C ₂₈ H ₃₁ CIN ₂ O ₂ (M = 463.01) calc .: Mole peak (M + Hf: 463/65 (CI) F f: Mole peak (M + Hf: 463/65 (CI)

Analogously to Example 6.12. the following compounds are prepared:

Beispiel 6.29

Example 6.29

N- (4'Chlor-biphenyl-4-yl) -3- [4- (R) -3-hydroxy-pyrrolidin-1-yImethyl) -phenyl] -propionamide

A reaction mixture of 40 mg (0.09 mmol) of 3- [4 - ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) - phenyl] -propinsäure (4 ^{'-chloro-biphenyl-4-yl)} amide and 10 mg Raney nickel in 10 ml N, N-

Dimethylformamide is hydrogenated at 50 psi and room temperature for three hours. The catalyst is filtered off and the filtrate is evaporated to dryness. The cleaning is done by

Column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 15/1 / 0.1)

Yield: 20 mg (50% of theory)

Melting point: 169-170 ° C

C ₂ 6H27CIN ₂ O ₂ (M = 434.96) calc .: Mole peak (M + Hf: 435/37 (CI) F f: Mole peak (M + Hf: 435/37 (CI)

Analogously to Example 6.29. the following compounds are prepared:

Beispiel 6.32:

Example 6.32:

Λ / - (4'-Chloro-biphenyl-4-yl) -3- {4 - [(methylpyridin-4-ylmethyl-amino) -methyl] -phenyl} -propionamide

6.32.a Λ / - (4'-Chloro-biphenyl-4-yl) -3- (4-cyano-phenyl) -propionamide

To a reaction mixture of 7.5 g (42.81 mmol) of 4-cyano-phenylpropionic acid in 150 ml of N, N-dimethylformamide are added 6 ml (43.04 mmol) of triethylamine and 13.73 g (42.75 mmol) of TBTU and stirred at RT for 30 min. Subsequently, an additional 6 ml (43.04 mmol) of triethylamine and 8.72 g (42.83 mmol) of 4 ^k chloro-biphenyl-4-ylamine were added and stirred for 24 h at RT. The solution is treated with water and the precipitated A / - (4 ^{'-Chloro-biphenyl-4-yl)} -3- (4-cyano-phenyl) -propionamide is suction filtered, washed with water and finally with diisopropyl ether. The yellow solid is dried at 50 ° C and 20 mbar in a vacuum oven for 6 h. Yield: 14.22 g (92% of theory.) C22 17CIN ^H ₂ O (M = 360.84) calc .: molecular peak (M + Hf: 361/63 (CI) Found: molecular peak (M + Hf: 361 / 63 (CI)

Rr value: 0.5 (silica gel, dichloromethane / ethanol = 20: 1)

6.32.b Λ / - (4 ^{'-Chloro-biphenyl-4-yl)} -3- (4-formyl-phenyl) -propionamide

To a reaction mixture of 3 g of water wet Raney nickel and 14.22 g (39.41 mmol) of A / - (4'-chlorobiphenyl-4-yl) -3- (4-cyanophenyl) -propionamide become 100 ml of formic acid and boiled under reflux for 20 h. The catalyst is then filtered off with suction and the filtrate is diluted with plenty of water. The precipitated Λ / - (4'-chloro-biphenyl-4-yl) -3- (4-formyl-phenyl) -propionamide is filtered off with suction and dissolved in ethyl acetate. The organic phase is first washed with 2 molar sodium hydroxide solution, then with water and finally with saturated sodium chloride solution, dried over sodium sulfate and activated charcoal and evaporated off from the solvent. Yield: 11.7 g (57% of theory) c22 ^H 1δCINO ₂ (M = 363.84) calc .: Mol peak (M + Hf: 364/66 (CI) F f: mol peak (M + Hf: 364/66 (CI)

Rr value: 0.5 (silica gel, cyclohexane / ethyl acetate = 1: 1) 6.32.c / V- (4'-Chloro-biphenyl-4-yl) -3- (4-hydroxymethyl-phenyl) -propionamide. To a reaction solution of 11.7 g (22.51 mmol) Λ / - (4 ^'). -Chloro-biphenyl-4-yl) -3- (4-formyl-phenylpropionamide in 200 ml of tetrahydrofuran are first added 8 ml of glacial acetic acid and then added 15.1 g (67.53 mmol) of sodium triacetoxyborohydride and stirred at RT for 20 h reaction mixture is poured onto a lot of water and the precipitate filtered off with suction This is purified by column chromatography on silica gel.. (eluent: dichloromethane / acetone 01/15 to 01/10) yield: 5.46 g (66% of theory.) C22 ^H 20 ^CIN ° 2 ( ⁼ 365.85) calc .: Mole peak (M + Hf: 366/68 (CI) Fc: Mole peak (M + Hf: 366/68 (CI)

Rr value: 0.35 (silica gel, dichloromethane / acetone = 10: 1)

6.32.d./ - (4'-Chloro-biphenyl-4-yl) -3- (4-chloromethyl-phenyl) -propionamide

To a solution of 2 g (5.47 mmol) of Λ / - (4 ^{'-Chloro-biphenyl-4-yl)} -3- (4-hydroxymethyl-phenyl) - propionamide and 1.56 ml (11.2 mmol) Triethylamine in 50 ml of dichloromethane are slowly added dropwise at room temperature 0.43 ml (5.6 mmol) of methanesulfonyl chloride and the reaction mixture is stirred for 24 hours at room temperature. It is extracted with water and the organic phase dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether and filtered off with suction. Yield: 1.45 g (69% of theory) of C ₂ H ₂ H 9 Cl ₂ NO (M = 384.3) calc .: Mole peak (M + H) ⁺ : 384/86/88 (CI 2) m: Mole peak (M + H) ⁺ : 384/86/88 (CI2) Rr value: 0.45 (silica gel, dichloromethane / ethanol = 50: 1)

6.32.e / V- (4 ^{'-Chloro-biphenyl-4-yl)} -3- {4 - [(methyl-pyridin-4-ylmethyl-amino) -methyl] -phenyl} - propionamide

A reaction mixture of 70 mg (0.18 mmol) of A / - (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenyl) propionamide, 18 mg (0.15 mmol) of methylpyridin-4-ylmethylamine and 41 mg (0.3 mmol)

Potassium carbonate in 5 ml of acetone are shaken under reflux for 24 hours. The

Reaction mixture is concentrated. The residue is triturated with water and diisopropyl ether, filtered off with suction and dried in air.

Yield: 52 mg (87% of theory) Melting point: 102 ° C

^C 29H28 ^CIN 3 ° ( ^M = 470.01) Calcd .: Mol peak (M + H) ⁺ : 470/72 (CI) F f: Mol peak (M + H) ⁺ : 470/72 (CI)

The following compounds are prepared analogously to Example 6.32.e:

Example 6.38.

3- [4- (benzylamino-methyl) -phenyl] - / V- (4'-Chloro-biphenyl-4-yl) -propionamide

A reaction mixture of 70 mg (0.18 mmol) - (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenyl) -propionamide, 16 mg (0.15 mmol) benzylamine and 41 mg ( 0.3 mmol) of potassium carbonate in 5 ml of acetone are shaken under reflux for 24 hours. The reaction mixture is concentrated. The residue is triturated with water and diisopropyl ether, filtered off with suction and on air dried. The residue is purified by column chromatography on silica gel (eluant: dichloromethane / ethanol / ammonia 30/1 / 0.1). Yield: 23 mg (40% of theory) Melting point: 176 ° C. C29H27CIN2O (M = 454.99) : Mol peak (M + H) ⁺ : 455/57 (CI) f: Mol peak (M + H) ⁺ : 455/57 (CI)

The following compounds are prepared analogously to Example 6.38:

Rr value: A = (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)

Example 6.43.

Λ / - (4'-Chloro-biphenyl-4-yl) -3- (4-cyclopropylaminomethyl-phenyl) -propionamide trifluoroacetate

A reaction mixture of 70 mg (0.18 mmol) of Λ- (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenyl) propionamide, 16 mg (0.15 mmol) of cyclopropylamine and 41 mg (0, 3 mmol) of potassium carbonate in 5 ml of acetone were shaken under reflux for 24 hours.The reaction mixture is concentrated.The residue is triturated with water and diisopropyl ether, filtered off with suction and dried in air Column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia 30/1 / 0.1) and then by column chromatography on RP-18 (eluent: water + 0.1% trifluoroacetic acid / acetonitrile + 0.1% trifluoroacetic acid 100/0 to 50/50) Yield: 24 mg (36% of theory) Melting point: 208 ° C. C25H25CIN2O * C2HF3O2 (M = 518.96) Calcd .: Mol peak (M + H) ⁺ : 405/07 (CI) Fc: Molpeak (M + H) ⁺ : 405/07 (Cl)

The following compound was prepared analogously to Example 6.43:

Example: 6.45

3- [4- (8-aza-spiro [4.5] dec-8-ylmethyl) phenyl] -Λ / - (4 ^{'-chloro-biphenyl-4-yl)} -Λ / -methyl-propionamide

Prepared analogously to Example 29.6, from 3- [4- (8-aza-spiro [4.5] dec-8-ylmethyl) -phenyl] - propionic (4 ^{'-chloro-biphenyl-4-yl)} methyl-amide

Yield: 43 mg (86% of theory) Melting point: 119 ° C. C32H37CIN2O (M = 501, 10) Calculated: Molepeak (M + H) ⁺ : 501/07 (CI) Fc: Molepeak (M + H) ⁺ : 501/03 (CI)

The following compounds are prepared analogously to Example 6.2: R

Example R, R ₂ NX L,

Example 6.217: 2- (4-morpholin-4-ylmethyl-phenyl) -cyciopropancarbonsäure (4 ^{'-chloro-biphenyl-4-yl)} -amide

Preparation of diazomethane: 0.15 g (1.48 mmol) of N-nitroso-N-methylurea are added with manual shaking to 10 ml of diethyl ether, layered with 3 ml of 40% potassium hydroxide solution, at 5 to 0 ° C. The reaction mixture is allowed to stand for ten minutes and then the yellow ether solution is decanted off and dried over potassium hydroxide. The yellow diazomethane solution prepared is added to a suspension of 80 mg (0.19 mmol) (E) -A- (4 ^{'-Chloro-biphenyl-4-yl)} -3- (4-morpholin-4-ylmethyl-phenyl) - acrylamide (preparation see 6.4) and 202 mg (0.001 mmol) of palladium (II) acetate in 20 ml of diethyl ether at 0 ° C slowly added dropwise. The dark reaction mixture was stirred for 30 min. Then the reaction mixture is used twice more with twice the amount of a diazomethane solution. After completion of the reaction, 10 ml of glacial acetic acid are added dropwise to the suspension and extracted several times with a sodium bicarbonate solution. The organic phase is dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. Further purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia 30: 1: 0.1). Yield: 32 mg (82.6% of theory) of C27H27CIN2O2 (M = 446.97) Melting point: 187-188 ° Calcd .: Mol peak (M + Hf: 447/449 (CI) F f: Mol peak (M + Hf: 447/449 (CI)

Rr value: 0.3 (silica gel, dichloromethane / ethanol / ammonia = 20: 1: 0.1)

Example 7.1:

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

7.1.a. 6-Amino-2-piperidin-2-yl-quinoline Prepared analogously to 3.1.b from 6-nitro-2-piperidin-2-yl-quinoline. Yield: 0.79 g (59.6% of theory) C ₁₄ H ₁₇ N ₃ (M = 227.31) calc .: Mole peak (M + Hf: 228 F o: mol peak (M + Hf: 228

Rr value: 0.37 (silica gel, dichloromethane / methanol 19: 1)

7.1.b. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid (2-piperidin-1-yl-quinolin-6-yl) -amide Prepared analogously to Example 2.3.f from (2-chloro-4-trifluoromethyl-phenyl ) -propynoic acid and 6-amino-2-piperidin-2-yl-quinoline. Yield: 170 mg (37.1% of theory) Melting point: 176-179 ° C C24H.19CIF3N3O (M = 457.88) Calculated: Mol peak (M + Hf: 456/458 F o: mol peak (M + Hf: 456 / 458

Rr value: 0.62 (silica gel, dichloromethane / methanol = 19: 1)

Example 7.2:

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

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

2.55 ml (29.96 mmol) of isopropylamine are added to a solution of 1.25 g (5.99 mmol) of 2-chloro-6-nitro-quinoline in 50 ml of ethanol and stirred at room temperature for 18 hours. Subsequently, the reaction mixture is heated in the microwave for two hours at 65 ° C. Thereafter, the reaction mixture is concentrated, the residue taken up in 20 ml of DMF, with 2.55 ml (29.96 mmol) of isopropylamine and 18 hours at room temperature touched. The reaction mixture is concentrated and the residue is combined with ethyl acetate and water. The organic phase is extracted twice with water. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is then removed.

Yield: 0.75 g (54.1% of theory)

C ₁₂ H ₁₃ N ₃ O ₂ (M = 221, 25) Calcd .: Mol peak (M + Hf: 232 f: Mol peak (M + Hf: 232

Rr value: 0.48 (silica gel, petroleum ether / ethyl acetate 2: 1)

7.2.b Λ / -silyl-quinoline-2,6-diamine

Made analog 3.1. b from isopropyl (6-nitro-quinolinyl-2-yl) amine.

Yield: 0.51 g (78.1% of theory)

C ₁₂ H ₁₅ N ₃ (M = 201.27) calc .: Mol peak (M + Hf: 202 f: Mol peak (M + Hf: 202

Rr value: 0.25 (silica gel, dichloromethane / methanol 19: 1)

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

Prepared analogously to Example 2.3.f from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and / V ² - isopropyl-quinoline-2,6-diamine.

Yield: 140 mg (46.3% of theory) Melting point: 57-60 ° C C22H17CIF3N3O (M = 431, 84) Calculated by: Mole peak (M + Hf: 432/434 mf: Mol peak (M + Hf: 432/434 Rr value: 0.49 (silica gel, petroleum ether / ethyl acetate 2: 1)

Analogously to Example 7.1, the following compounds are prepared:

7.22 .

7.22.

-CI -CF ₃ -Me

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

MCH-1 receptor binding test

Method: MCH binding to hMCH-1 R transfected cells

Species: Human

Test cell: hMCH-1 R stably transfected in CHO / Galpha16 cells. Results: IC50 values

Membranes from human hMCH-1R stably transfected CHO / Galpha16 cells are resuspended by syringe (0.6 x 25 mm needle) and assay buffer (50 mM HEPES, 10 mM MgCl ₂ , 2 mM EGTA, pH 7.00, 0.1% bovine serum Albumin (protease-free), 0.021% bacitracin, 1 μg / mL aprotinin, 1 μg / mL leupeptin, and 1 μM phosphoramidone) to a concentration of 5 to 15 μg / mL.

200 microliters of this membrane fraction (containing 1 to 3 μg of protein) are incubated for 60 to 120 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 Microliter incubated. After incubation, the reaction is filtered using 0.5% PEI-treated glass fiber filters (GF / B, Unifilter Packard) using a cell strainer. 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). 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 based on the assumption of a receptor binding site. Default:

Unlabeled MCH competes with labeled ¹²⁵ I-MCH for receptor binding with one

IC50 value between 0.06 to 0.15 nM.

The KD value of the radioligand is 0.156 nM.

MCH-1 receptor-coupled Ca ²⁺ mobilization test

Method: Calcium mobilization test with human MCH (FLIPR ³⁸⁴ )

Species: Human

Test Cells: Stably-transfected CHO / Galpha 16 cells with hMCH-R1

Results: 1st measurement:% stimulation of the reference (MCH 10 ^"6 M)

2nd measurement: pKB value

Reagents: HBSS (10x) (GIBCO)

HEPES buffer (1M) (GIBCO)

Pluronic F-127 (Molecular Probes)

Fluo-4 (Molecular Probes)

Sample sathy (Sigma)

MCH (Bachern)

Bovine Serum Albumin (Serva) (Protease Free)

DMSO (Serva)

Ham's F12 (BioWhittaker)

FCS (BioWhittaker)

L-Glutamine (GIBCO)

Hygromycin B (GIBCO)

PENStrep (BioWhittaker)

Zeocin (invitrogen)

Clonal CHO / Galpha16 hMCH-R1 cells are 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 sampleicid are added at 37 ° C for 45 minutes. After loading with fluorescent dye, the cells are washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which is mixed 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 as a peak of the relative fluorescence minus the background and measured as a percentage of the maximum signal of the reference (MCH 10 ^"6 M, signal is standardized to 100%) expressed the EC50 values of the MCH dosage. - Effect curve with and without test substance (defined concentration) are graphically determined by the GraphPad Prism 2.01 curve program MCH antagonists cause a right shift in the generated graph of the MCH stimulation curve.

The inhibition is expressed in pKB value: pKB = lθg (EC residual substance + MCH) / Cδo (CH) -1) "IC JC (τ _es substance)

The compounds according to the invention, including their salts, exhibit an MCH receptor antagonistic action in the abovementioned tests. Using the MCH-1 receptor binding test described above is ^"to 10 ^{9" 6} M, obtain an antagonistic activity in a dose range of about 10 ^"10 to ^{10" 5} M, in particular of 10 degrees. The following IC 50 values were determined using the previously described MCH-1 receptor binding assay:

In the following, examples of dosage forms are described in which the term "active ingredient" denotes one or more compounds according to the invention, including their salts.

Example A

Capsules for powder inhalation with 1 mq active substance

Composition:

1 capsule for powder inhalation contains:

Active ingredient 1.0 mg

Lactose 20.0 mg

Hard gelatine capsules 50.0 mq

71.0 mg Production method:

The active ingredient is ground to the particle size required for inhalation. 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 mq active substance

Composition:

1 hub contains:

Active ingredient 1.0 mg

Benzalkonium chloride 0.002 mg

Disodium edetate 0.0075 mg water purified ad 15.0 μl

Production method:

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

Example C

Inhalation solution for nebulizers with 1 mq active substance

Composition:

1 vial contains:

Active ingredient 0.1 g

Sodium chloride 0.18 g

Benzalkonium chloride 0.002 g water purified ad 20.0 ml

Production method:

Active substance, sodium chloride and benzalkonium chloride are dissolved in water.

Example D

Treibqas metered dose inhaler with 1 mq active substance Composition: 1 stroke contains:

Active ingredient 1.0 mg

Lecithin 0.1% propellant ad 50.0 μl

Production method:

The micronized drug is homogeneously suspended in the mixture of lecithin and propellant. The suspension is filled into a pressure vessel with metering valve.

Example E

Nasalsprav with 1 mg of active ingredient

Composition: active ingredient 1.0 mg

Sodium chloride 0.9 mg

Benzalkonium chloride 0.025 mg

Disodium edetate 0.05 mg

Water cleaned ad 0.1 ml

Production method:

The active substance and the excipients are dissolved in water and in a corresponding

Bottled container.

Example F

Injection solution with 5 mg of active substance per 5 ml

Composition: active substance 5 mg glucose 250 mg

Human serum albumin 10 mg

Glykofurol 250 mg

Water for injections ad 5 ml

production: Glykofurol and glucose in water for injection dissolve (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; Fill into ampoules under nitrogen fumigation.

Example G

Injection solution with 100 mq active substance per 20 ml

Composition: active substance 100 mg monopotassium dihydrogen phosphate = KH2PO4 12 mg

Disodium hydrogen phosphate = Na 2 HP 4 .2H 2 O 2 mg

Sodium chloride 180 mg

Human Serum Albumin 50 mg Polysorbate 80 20 mg Water for Injection ad 20 ml

production:

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

Example H Lyophilisate with 10 mg active substance

Composition: Active substance 10 mg

Mannitol 300 mg human serum albumin 20 mg

production:

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

Solvent for lyophilisate: Polysorbate 80 = Tween 80 20 mg

Mannitol 200 mg

Water for injections ad 10 ml

production:

Dissolve polysorbate 80 and mannitol in water for injections (Wfl); 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

Preparation: Mix active substance, lactose and corn starch homogeneously; granulate with an aqueous solution of povidone; mix with magnesium stearate; press on a 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

Preparation: Mix active substance, corn starch and silica homogeneously; mix with magnesium stearate; Fill mixture on a capsule filling machine into hard gelatin capsules size 3. Example K

Suppository with 50 mg active substance

Composition: active substance 50 mg

Hard fat (Adeps solidus) q.s. ad 1700 mg

production:

Melt hard fat at approx. 38 ° C; homogeneously disperse the ground active substance in the molten hard fat; after cooling to approx. 35 ° C pour into pre-cooled molds.

Example L

Injection solution with 10 mq active substance per 1 ml

Composition:

Active substance 10 mg

Mannitol 50 mg

Human serum albumin 10 mg

Water for injections ad ml

production:

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

Example 4.10:

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

Prepared analogously to Example 3.1.e from 5-amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole and (2,4-

Dichloro-phenyl) -propynoic acid in THF as solvent.

Yield: 133 mg (31.2% of theory)

^C 23 ^H 21 ^CI 2 ^N 3 ° (= 426.34)

Melting point: 127-129 ° C calc .: Mole peak (M + H) ⁺ : 426/428/430 mf: Mol peak (M + Hf: 426/428/430

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

Example 4.11:

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

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

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

0.65 g (1.175 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propinsäureethylester are dissolved in 20 ml of ethanol, treated with 2 ml of 2M sodium hydroxide solution and stirred for three hours at room temperature. The reaction mixture is concentrated, the residue taken up in water and extracted with ethyl acetate. The aqueous phase is mixed with 2 mM M hydrochloric acid and stirred for one hour at room temperature. Subsequently, with three times

Extracted ethyl acetate. The combined organic phases are dried over sodium sulfate. Yield: 0.14 g (48% of theory) of C-ιoH4CIF ₃ O ₂ (M = 248.59) calc .: Mole peak (MH) ^" : 247/249 m: Mole peak (MH) ^" : 247/249

Rr value: 0.09 (silica gel, petroleum ether / ethyl acetate = 4: 1)

4.11.c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propicarboxylic acid [1- (2-pyrrolidin-1-yl-ethyl) -1H-indol-5-yl] -amide Prepared analogously to Example 2.3.f from 5 -Amino-1- (2-pyrrolidin-1-yl-ethyl) -1H-indole and (2-chloro-4-trifluorophenyl) -propynoic acid. Yield: 160 mg (66.5% of theory) of C 24 H 21 CIF 3 N 3 O (M = 459.90)

Melting point: 200-205 ° C calc .: molecular peak (M + Hf: 460/462 Found: molecular peak (M + H) ^"": 460/462

Rr value: 0.45 (silica gel, dichloromethane / methanol = 90:10)

Example 4.12: 3- (2,4-Dichloro-phenyl) -propynoic acid [2- (2-pyrrolidin-1-yl-ethyl) -benzooxazol-5-yl] -amide

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

A reaction mixture of 1.54 g (10 mmol) 2-amino-4-nitrophenol, 1.36 g (10 mmol) 3-

Chloropropionic acid ethyl ester and 20 g of polyphosphoric acid is stirred for two hours at 170 ° C. Subsequently, the approach by addition of saturated

Sodium bicarbonate solution neutralized at room temperature. The aqueous phase is extracted with dichloromethane. The organic phase is dried over Natriurnsulfat. The

Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol

= 20: 1).

Yield: 0.3 g (15.8% of theory)

CgH ₆ N ₂ O ₃ (M = 190.16) calc .: Mol peak (M + Hf: 191 fc: Mol peak (M + Hf: 191

Rr value: 0.8 (silica gel, dichloromethane / ethanol = 20: 1)

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

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

Rr value: 0.2 (silica gel, dichloromethane / ethanol / ammonia = 20: 1: 0.1)

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

A reaction mixture of 0.74 g (2.83 mmol) of 5-nitro-2- (2-pyrrolidin-1-yl-ethyl) -benzoxazole and 0.1 g of palladium (on charcoal 10%) in 20 ml of ethanol three hours at 3 bar and

Hydrogenated at 20 ° C. The catalyst is filtered off and the filtrate is concentrated.

Yield: 0.6 g (91.6% of theory)

C ₁₃ H ₁₇ N ₃ O (M = 231.30) calc .: Mol peak (M + Hf: 232 found: Mol peak (M + Hf: 232

Rr value: 0.3 (silica gel, dichloromethane / ethanol / ammonia = 20: 1: 0.1) 4.12.d. 3- (2,4-dichloro-phenyl) -propynoic acid [2- (2-pyrrolidin-1-yl-ethyl) -benzooxazol-5-yl] -amide

Prepared analogously to Example 3.1.e from 5-amino-2- (2-pyrrolidin-1-yl-ethyl) -benzoxazole and (2,4-chlorophenyl) -propynoic acid.

Yield: 43 mg (33.1% of theory)

C22H19CI2N3O2 (M = 428.32)

Melting point: 130 ° C calc .: Mole peak (M + Hf: 428/430/432 mf: Mol peak (M + Hf: 428/430/432

C ₁₃ H ₁₇ N ₃ O (M = 231.30) calc .: Mol peak (M + Hf: 232 f: Mol peak (M + Hf: 232

Rr value: 0.21 (silica gel, dichloromethane / methanol / ammonia = 10: 1: 0.1)

Example: 4.133- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid (2-pyrrolidin-1-ylmethyl-benzoxazol-5-yl) -amide

4.13.a 2-chloromethyl-5-nitro-benzoxazole

To a solution of 12 g (77.86 mmol) of 2-amino-4-nitrophenol in 110 ml of ethanol is added 10.5 ml (77.87 mmol) of 2-chloro-orthoacetic acid and boiled together at 80 ° C for 3 h. Thereafter, the reaction mixture is poured onto water, the precipitate was filtered off with suction and washed several times with water. The product is included

80 ° C dried in a convection oven.

Yield: 14.2 g (86% of theory)

C ₈ H ₅ CIN ₂ O ₃ (M = 212.59) calc .: Mol peak (M + Hf: 213/215 (CI) F f: Mol peak (M + Hf: 213/215 (CI)

4.13.b. 5-nitro-2-pyrrolidin-1-ylmethyl-benzoxazol

ber.: Molpeak (M+Hf: 248 gef: Molpeak (M+Hf: 248A reaction mixture of 3 g (14.11 mmol) of 2-chloromethyl-5-nitro-benzoxazole, 1.5 ml (17.97 mmol) of pyrrolidine and 3.9 g (28.22 mmol) of potassium carbonate in 30 ml of dimethylformamide becomes 4 Stirred at 50 ° C h. Then the reaction mixture is diluted with water and overlaid with diisopropyl ether. The precipitated yellow solid is filtered off, washed and dried in a convection oven at 60 ° C. Yield: 1.8 g (52% of theory)

calc .: Mole peak (M + Hf: 248 F: Mol peak (M + Hf: 248

Rr value: 0.4 (silica gel, dichloromethane / ethanol = 20: 1)

4.13.C. 2-pyrrolidin-1-ylmethyl-benzoxazol-5-ylamine

Prepared analogously to Example 4.12.C from 5-nitro-2-pyrrolidin-1-ylmethyl-benzoxazole.

Yield: 1.1 g (70% of theory)

C ₁₂ Hi5N ₃ O (M = 217.27) calc .: Mol peak (M + Hf: 218 F o: mol peak (M + Hf: 218

Rr value: 0.6 (alumina, dichloromethane / ethanol = 20: 1)

4.13.d. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid (2-pyrrolidin-1-ylmethylbenzoxazol-5-ylfamide Prepared analogously to Example 2.3.f from 0.2 g (0.92 mmol) of 2-pyrrolidine 1-ylmethyl-benzoxazol-5-ylamine and 0.2 g (0.8 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid.

Yield: 290 mg (81% of theory)

C22H17 CIF3N3O2 (M = 447.84)

Melting point: 218-223 ° C calc .: Mol peak (M + H) ⁺ : 448/450 (CI) Fc: Mol peak (M + Hf: 448/450 (CI)

Rr value: 0.33 (silica gel, dichloromethane / methanol = 19: 1)

Example 4.14

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-ethoxycarbonyl-4- (2-diethylamino-ethoxy) -phenyl-amide

4.14.a. 2- (2-diethylamino-ethoxy) -5-nitro-benzoic acid ethyl ester 1.06 g (5.00 mmol) of ethyl 2-fluoro-5-nitrobenzoate and 0.58 ml (5.00 mmol) of 2-diethylaminoethanol are dissolved in 20 ml of dimethylformamide and 0.36 g (7 , 45 mmol) sodium hydride (50 percent). The mixture is stirred for 45 minutes at 0 ° C, poured onto ice-water and finally extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is stripped off and the residue is purified on a silica gel column with petroleum ether / ethyl acetate 4.1 as eluent. Yield: 0.30 g (19% of theory) C ₁₅ H ₂ 2 2θ5 (M = 310.35) calc .: Mole peak (M + Hf: 311 fc: mol peak (M + Hf: 311 R r value: 0, 1 ( Silica gel, petroleum ether / ethyl acetate 4: 1)

4.14.b.5-amino-2- (2-diethylamino-ethoxy) -benzoic acid ethyl ester

Prepared analogously to Example 3.1.b. from 0.30 g of 2- (2-diethylamino-ethoxy) -5-nitro-benzoic acid ethyl ester in ethyl acetate. Yield: 0.27 g (100% of theory) C ₁₅ H 24 N ₂ O 3 (M = 280.37) calc .: Mole peak (M + Hf: 281 F o: mol peak (M + Hf: 281

Rr value: 0.40 (silica gel, dichloromethane / methanol / ammonia = 39: 1: 0.1)

4.14.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-ethoxycarbonyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 99 mg (0.40 mmol) of (2-chloro-4-trifluoromethyl-phenyl) propionic acid and 120 mg (0.44 mmol) of 5-amino-2- (2-diethylamino-ethoxy) benzoic acid ethyl ester. Yield: 44 mg (22% of theory)

C25H26CIF3N2O4 (M = 510.94) calc .: Mole peak (M + Hf: 511/513 mf: Mol peak (M + Hf: 511/513

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.15

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-bromo-4- (2-diethylamino-ethoxy) -phenyl] -amide

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

Prepared analogously to regulation 4.13.a. starting from 0.66 g (2.00 mmol) of 2-bromo-1-fluoro-4-nitrobenzene and 0.40 ml (3.00 mmol) of 2-diethylamino-ethanol.

Yield: 0.95 g (100% of theory)

C ₁₂ H ₁₇ BrN ₂ O ₃ (M = 317.185) calc .: Mole peak (M + Hf: 317/319 mf: Mol peak (M + Hf: 317/319

Rr value: 0.50 (silica gel, dichloromethane / methanol 9: 1).

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

Prepared analogously to Example 3.1. b. from 1.10 g (3.47 mmol) of [2- (2-bromo-4-nitrophenoxy) ethyl] -diethylamine in ethyl acetate.

Yield: 0.58 g (58% of theory)

C ₂ H ₁₉ BrN ₂ O (M = 287.202) calc .: Mole peak (M + Hf: 287/289 f: Mol peak (M + Hf: 287/289

Rr value: 0.30 (silica gel, dichloromethane / methanol 9: 1).

4.15.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-bromo-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 450 mg (1.80 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propionic acid and 550 mg (1.92 mmol) of 3-bromo-4- (2-diethylamino-ethoxy) -phenylamine.

Yield: 370 mg (40% of theory)

C22H2lBrCIF ₃ N ₂ θ2 (M = 517.77) calc .: Mole peak (M + Hf: 517/519/521 mf: Mol peak (M + Hf: 517/519/521

Rr value: 0.45 (silica gel, dichloromethane / methanol = 19: 1)

Example 4.16 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-bromo-4- (2-morpholin-4-yl-ethoxy) -phenyl] -amide

4.16.a. 4- [2- (2-bromo-4-nitro-phenoxy) -ethyl] -morpholine

To a solution of 0.3 g (1.27 mmol) of 3-bromo-4-chloro-nitrobenzene and 0.15 ml (1.27 mmol) in 20 ml of dimethylformamide is added at 0 ° C. under argon atmosphere 92 mg (1, 9 mmol) sodium hydride (55%) was added. The reaction mixture is stirred at 0 ° C for two hours and then poured onto ice-water. The aqueous phase is extracted three times with ethyl acetate. The organic phase is dried, the drying agent is filtered off and the filtrate is concentrated. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol 19: 1). Yield: 230 mg (55% of theory) of C ₂ H ₁ 5BrN ₂ O 4 (M = 331.16) calc .: Mole peak (M + Hf: 331/333 (Br) gef: Molpeak (M + Hf: 331/333 (Br)

4.16.b. 3-Bromo-4- (2-morpholin-4-yl-ethoxy) -phenylamine A reaction mixture of 220 mg (0.66 mmol) of 4- [2- (2-bromo-4-nitro-phenoxy) -ethyl] - morpholine and 100 mg of Raney nickel in 50 ml of ethyl acetate is hydrogenated at room temperature and 3 bar of hydrogen. The catalyst is filtered off with suction and the filtrate is concentrated. The

Purification by column chromatography on aluminum oxide (eluent:

Petroleum ether / ethyl acetate 1: 1). Yield: 100 mg (50% of theory) C12 ^H 17 ^BrN 2 ° 2 ^{(M =} 301.18) calc .: molecular peak (M + Hf: 301/303 (Br) Found: molecular peak (M + Hf: 301/303 (Br)

4.16.c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-bromo-4- (2-morpholin-4-yl-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f from 100 mg (0.33 mmol) of 3-bromo-4- (2-morpholin-4-yl-ethoxyfphenylamin and 75 mg (0.3 mmol) (2-chloro-4-trifluoromethyl-phenyl ) -propinsäure.

Yield: 130 mg (82% of theory)

^C 22 ^H 19 BrCIF ₃ N ₂ O ₃ (M = 531.75) calc .: Mol peak (M + Hf: 529/531/533 (Br, CI) Fc: Mol peak (M + Hf: 529/531/533 ( Br, CI)

Rr value: 0.33 (aluminum oxide, petroleum ether / ethyl acetate = 1: 1) Example 4.17

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-nitro-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.17.a. N- [4- (2-Diethylamino-ethoxy) -3-nitro-phenyl] -acetamide To a solution of 1, 52 g (6.07 mmol) of N- [4- (2-diethylamino-ethoxy) -phenyl] acetamide in 25 mL conc. Sulfuric acid are added at -10 ° C in portions 0.74 g (7.29 mmol) of potassium nitrate and the mixture stirred at -10 ° C for 1 hour. The reaction mixture is poured onto a mixture of ice and concentrated aqueous ammonia and the aqueous

Phase extracted exhaustively with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated.

Yield: 1.8 g (100% of theory)

C ₁₄ H ₂₁ N ₃ O ₄ (M = 295.34) calc .: Mole peak (M + Hf: 296 f: Mol peak (M + Hf: 296

Rr value: 0.50 (Alox, dichloromethane / methanol 39: 1).

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

A solution of 1.85 g (6.26 mmol) of N- [4- (2-diethylamino-ethoxy) -3-nitro-phenyl] -acetamide in half-concentrated aqueous hydrochloric acid is stirred at 100 ° C. for 2 hours

Cooled room temperature, basified with ice and concentrated aqueous ammonia and extracted the aqueous phase with ethyl acetate exhaustively. The combined organic

Phases are washed with water and dried over sodium sulfate.

Yield: 1.38 g (87% of theory)

C ₁₂ H ₁₉ N ₃ O ₃ (M = 253.30) calc .: Mole peak (M + Hf: 254 F f: Mol peak (M + Hf: 254 Rr value: 0.68 (Alox, dichloromethane / methanol 39: 1). 4.17.c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-nitro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 450 mg (1.80 mmol) of (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 500 mg (1.98 mmol) of 4- (2-diethylamino-ethoxy) -3-nitro-phenyl-amine.

Yield: 590 mg (68% of theory)

C22H21CIF3N3O4 (M = 483.87) calc .: Mole peak (M + Hf: 484/486 mf: Mol peak (M + Hf: 484/486

Rr value: 0.40 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.18:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (3-diethylamino-propoxy) -phenyl] -amide-formate

Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 110 mg (0.44 mmol) of [2- (2-chloro-4-amino-phenoxy) -propyl] -diethyl amine.

Yield: 49 mg (25% of theory)

Melting point: 112-116 ° C

C23H22CI2F3N2O2 CH ₂ O ₂ (M = 533.37) calc .: Mole peak (M + Hf: 487/489/491 mf: Mol peak (M + Hf: 487/489/491

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.19:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methyl-amide

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

Prepared analogously to Regulation 3.1. c. starting from 3.00 g (12.4 mmol) of 3-chloro-4- (2-diethylamino-ethoxyfphenylamine and 2.97 g (13.6 mmol) of di-tert-butyl-pyrocarbonate in

Dichloromethane.

Yield: 2.85 g (67% of theory)

C ₁₇ H ₂₇ CIN ₂ O ₃ (M = 342.86) calc .: Mole peak (M + Hf: 343/345 m: Mole peak (M + Hf: 343/345

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

Prepared analogously to Example 3.1. d. of 2.85 g (8.31 mmol) of [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -carbamic acid tert -butyl ester with 10.63 ml (24.9 mmol) of 10 percent strength

Lithium aluminum hydride solution in tetrahydrofuran.

Yield: 0.72 g (34% of theory)

C ₁₃ H ₂ iCIN ₂ O (M = 256.77) calc .: Mole peak (M + Hf: 257/259 mf: Mol peak (M + Hf: 257/259

Rr value: 0.80 (silica gel, ethyl acetate / methanol / ammonia 9: 1: 0.1).

4.19.c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methylamide

Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 110 mg (0.44 mmol) of [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -methylamine ,

Yield: 54 mg (28% of theory) Melting point: 97-100 ° C

C23H23CI2F3N2O2 (M = 487.35) calc .: Mole peak (M + Hf: 487/489/491 mf: Mol peak (M + Hf: 487/489/491

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1) Example 4.20:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-methoxy-4- (2-diethylamino-ethoxy) -phenyl] -amide-hydrochloride

Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 79 mg (0.33 mmol) of [2- (2-methoxy-4-amino-phenoxy) -ethyl] -diethyl amine. Yield: 14 mg (10% of theory) C23H24CIF3N2O3 (M = 468.90) calc .: Mole peak (M + Hf: 469/471 mf: Mol peak (M + Hf: 469/471

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.21: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propionic acid [3-methyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

4.21.a. Diethyl [2- (2-methyl-4-nitro-phenoxy) -ethyl] -amine To a solution of 2.70 g (17.4 mmol) of 2-fluoro-5-nitro-toluene and 2.54 ml ( 19.2 mmol) of 2-diethylaminoethanol in 50 mL of DMF under argon atmosphere at 0 ° C 0.92 g (19.2 mmol) of sodium hydride (50 percent in oil) was added and the mixture for 2 hours at 0 ° C and 1 hour stirred at room temperature. The solvent is stripped off, the residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate and i. vac. concentrated. The mixture is then purified by silica gel column chromatography with dichloromethane / methanol 9: 1 as eluent. Yield: 3.1 g (71% of theory) C ₁₃ H ₂₀ N ₂ O ₃ (M = 252.31) calc .: Mol peak (M + Hf: 253 f: Mol peak (M + Hf: 253

Rr value: 0.60 (silica gel, dichloromethane / methanol 9: 1)

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

3.10 g (12.3 mmol) of diethyl [2- (2-methyl-4-nitro-phenoxy) -ethyl] -amine are dissolved in 250 ml

Dissolved ethyl acetate, added 0.55 g of Raney nickel and the mixture hydrogenated for 36 hours at 50 psi and room temperature. The catalyst is filtered off and the filtrate i. vac. concentrated.

Yield: 2.70 g (99% of theory)

C ₁₃ H ₂₂ N ₂ O (M = 222.33) calc .: Mol peak (M + Hf: 223 f: Mol peak (M + Hf: 223

Rr value: 0.35 (silica gel, dichloromethane / methanol 9: 1)

21.4. c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-methyl-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 73 mg (0.33 mmol) of 4- (2-diethylamino-ethoxy) -3-methyl-phenylamine.

Yield: 134 mg (99% of theory)

C23H24CIF3N2O2 (M = 452.90) calc .: Mole peak (M + Hf: 453/455 f: Mol peak (M + Hf: 453/455

Rr value: 0.40 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.22 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-amino-4- (2-diethylamino-ethoxy) -phenyl] -amide

To a solution of 250 mg (0.52 mmol) of 3- (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-nitro-4- (2-diethylamino-ethoxy) -phenyl] -amide in 50 ml Ethyl acetate are added

Room temperature 870 mg (10.3 mmol) of sodium bicarbonate and 1.17 g (5.17 mmol) Tin (II) chloride dihydrate. The mixture is heated to reflux for twelve hours.

After cooling, water is added and the organic phase is separated off. The watery

Phase is extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent removed. The cleaning of the

Residue is carried out by column chromatography on Alox (eluent: dichloromethane / methanol

= 39: 1).

Yield: 100 mg (43% of theory)

Melting point: 127-130 ° C

C22H23CIF3N3O2 (M = 453.89) calc .: Mole peak (M + Hf: 454/456 Fc: Mole peak (M + Hf: 454/456

Rr value: 0.60 (Alox, dichloromethane / methanol = 39: 1)

Example 4.23:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (3-diethylamino-ethoxy) -3-methanesulfonyl-amino-phenyl] -amide

To a solution of 0.1 g (0.22 mmol) of 3- (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-amino-4- (2-diethylamino-ethoxy) -phenyl] -amide in 5 ml of pyridine are added dropwise at 0 ° C 0.019 ml (0.242 mmol) of methanesulfonyl chloride. The reaction mixture is slowly warmed to room temperature and stirred for three hours. Subsequently, the reaction mixture is poured into ice-water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent distilled off. The residue is freeze-dried. Yield: 101 mg (86.3% of theory) Melting point: 57-60 ° C. c23H25CIF ₃ N ₃ O ₄ S (M = 531.98) Calculated by: Mole peak (M + Hf: 532/534 mf: Mol peak (M. + Hf: 532/534

Rr value: 0.32 (silica gel, dichloromethane / methanol = 9: 1) Example 4.24:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (3-diethylamino-ethoxy) -3-methoxyphenyl] -methyl-amide

4.24.a. [4- (3-Diethylamino-ethoxy) -3-methoxy-phenyl] -carbamic acid tert-butyl ester Prepared analogously to 3.1.c from 4- (3-diethylamino-ethoxy) -3-methoxyphenylamine. Yield: 0.26 g (91.6% of theory) of C ₈ H ₃ oN ₂ O ₄ (M = 338.45) calc .: Mole peak (M + Hf: 339 F o: mol peak (M + Hf: 339

Rr value: 0.45 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

4.24.b. [4- (3-diethylamino-ethoxy) -3-methoxy-phenyl] -methylamine Prepared analogously to 3.1. d of [4- (3-diethylamino-propoxy) -3-methoxy-phenyl] -carbamic acid tert-butyl ester.

Yield: 0.08 g (44.7% of theory)

C ₄ H24N ₂ θ2 (M = 252.36) calc .: Mol peak (M + Hf: 253 fc: Mol peak (M + Hf: 253

24.4. c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (3-diethylamino-ethoxy) -3-methoxyphenyl] -methyl-amide

Prepared analogously to Example 2.3.f from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and [4- (3

Diethylamino-propoxy) -3-methoxy-phenyl] -methyl-amine. Yield: 33 mg (30% of theory) c24H26 3N2θ ^CIF ₃ (M = 482.93) calc .: molecular peak (M + Hf: 483/485 Found: molecular peak (M + Hf: 483/485

Rr value: 0.43 (silica gel, dichloromethane / methanol = 9: 1) Example 4.25:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (3-diethylamino-ethoxy) -3-fluoro-phenyl] -amide

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

Prepared analogously to 4.6.a from 3,4-difluoro-nitrobenzene and 2-DiethyIaminoethanol.

Yield: 6.94 g (87.4% of theory)

C ₁₂ H ₁ 7FN ₂ O 3 (M = 256.27) calc .: Mol peak (M + Hf: 257 fc: Mol peak (M + Hf: 257

Rr value: 0.46 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

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

Made analog 3.1. b from [diethyl [3- (2-fluoro-4-nitro-phenoxy) -ethyl] -amine.

Yield: 5.93 g (97.1% of theory)

C ₂ H _{1 9} FN ₂ O (M = 226.29) calc .: Mole peak (M + Hf: 229 fc: mole peak (M + Hf: 227

Rr value: 0.33 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

4.25.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [4- (3-diethylamino-ethoxy) -3-fluoro-phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 4- (3

Diethylamino-ethoxy) -3-fluoro-phenylamine.

Yield: 0.14 g (33.5% of theory)

Melting point: 85-88 ° C C22H2 CIF4N2O2 (M = 456.87) calc .: Mole peak (M + Hf: 455/457 mf: Mol peak (M + Hf: 455/457

Rr value: 0.35 (silica gel, dichloromethane / methanol = 9: 1) Example 4.26:

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

4.26.a. 1- [2- (2-Chloro-4-nitro-phenoxy) -ethyl] -4-methyl-piperidine

A reaction mixture of 7.8 g (27.81 mmol) of 1- (2-bromoethoxy) -2-chloro-4-nitrobenzene and 10.14 mL (84 mmol) of 4-methylpiperidine in 100 mL of dichloromethane is added 18 hours at

Room temperature stirred. Subsequently, the solution by column chromatography on

400 g Alox Akt. Il-Ill (eluent: dichloromethane / methanol = 49: 1).

Yield: 6.9 g (83% of theory)

C- | 4H _{1 9} CIN ₂ θ3 (M = 298.77) calc .: Mole peak (M + Hf: 209/301 mf: Mol peak (M + Hf: 209/301

Rr value: 0.48 (Alox, petroleum ether / ethyl acetate = 3: 1)

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

Prepared analogously to 3.1.b from 1- [2- (2-chloro-4-nitro-phenoxy) ethyl] -4-methyl-piperidine. Yield: 3.66 g (59% of theory) of C ₁₄ H ₂ ClN ₂ O (M = 268.78) calc .: Mole peak (M + Hf: 269/271 F o: mol peak (M + Hf: 269/271 R r value: 0 , 52 (silica gel, dichloromethane / methanol = 9: 1)

4.26.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethoxy] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-

Chloro-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine.

Yield: 0.33 g (66% of theory) c24 ^H 23 Cl ₂ F 3 N ₂ O ₂ (M = 499.36) calc .: Mole peak (M + Hf: 499/501/503 f: Mol peak (M + Hf: 499/501 / 503

Rr value: 0.68 (Alox, dichloromethane / methanol = 49: 1) Example 4.27:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethylamino] -phenyl} -amide

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

A solution of 12.02 g (32.45 mmol) 2- (4-methyl-piperidin-1-yl) -ethylamine in 100 ml of DMF is added with 17.94 g (64.82 mmol) of potassium carbonate and 15 minutes at Room temperature stirred. Subsequently, 5.81 g (32.45 mmol) of 3-chloro-4-fluoro-nitrobenzene are added and the reaction mixture is stirred for 18 hours. Subsequently, the reaction mixture in

Poured ice water and the crystalline residue filtered off.

Yield: 8.85 g (91.6% of theory)

^C 14 20 ^CIN 3 ° 2 ( ^M = 297.78) calc .: Mol peak (M + H) ⁺ : 298/300 f: Mol peak (M + Hf: 298/300

4.27.b. 2-Chloro-Λ / ¹ - [2- (4-methylpiperidin-1-yl) ethyl] benzene-1,4-diamine

Prepared analogously to 3.1.b from (2-chloro-4-nitrophenyl) - [2- (4-methyl-piperidin-1-yl) -ethyl] -amine.

Yield: 7 g (89.3% of theory)

C-14H22CIN3 (M = 267.80) calc .: Mol peak (M + H) ⁺ : 268/270 f: Mol peak (M + Hf: 268/270

Rr value: 0.6 (Alox, dichloromethane / methanol = 49: 1)

4.27.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethylamino] -phenyl} -amide

Prepared analogously to Example 2.3.f from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 2-

Chloro-Λ / ¹ - [2- (4-methyl-piperidin-1-yl) -ethyl] -benzene-1,4-diamine. Yield: 0.35 g (70.2% of theory) of C 24 H 24 Cl 2 F 3 N 3 O (M = 498.38) calc .: Mole peak (M + H) ⁺ : 455/457 F o: Mole peak (M + Hf: 455/457 Example 4.28:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethylamino) -phenyl] -amide-formate

4.28.a. Λ / '- (2-chloro-4-nitro-phenyl) - / V, Λ / diethyl-ethane-1,2-diamine

Prepared analogously to 4.25.a from N ', N-diethyi-ethane-1,2-diamine and 3-chloro-4-fluoronitrobenzene.

Yield: 9.2 g (99.1% of theory)

C ₁₂ H ₁₈ CIN ₃ O ₂ (= 271.74) calc .: Mole peak (M + Hf: 272/274 F: Mol peak (M + Hf: 272/274

Rr value: 0.72 (Alox, dichloromethane / methanol = 49: 1)

28.4. b. 2-Chloro-Λr - (2-diethylamino-ethyl) -benzene-1,4-diamine

Made analog 3.1. b from / V- (2-chloro-4-nitrophenyl) -Λ /, / V-diethyl-ethane-1,2-diamine. Yield: 6.15 g (78% of theory) C ₁₂ H ₂ oCIN ₃ (M = 241, 76) calc .: Mole peak (M + Hf: 242/244 F o: mol peak (M + Hf: 242/244

Rr value: 0.62 (Alox, dichloromethane / methanol = 49: 1)

4.28.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethylamino) -phenyl] -amide-formate Prepared analogously to Example 2.3.f from (2-chloro-4 trifluoromethyl-phenyl) -propynoic acid and 2-

Chloro-Λ / ¹ - (2-diethylamino-ethyl) -benzene-1,4-diamine. Yield: 0.17 g (32.8% of theory) of C22H22CI2F3N3O x HCOOH (M = 518.36) calc .: Mole peak (M + Hf: 472/474/476 mf: Mol peak (M + Hf: 472/474 / 476 Example 4.29:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (4-methylpiperidin-1-ylmethyl) -phenyl] -amide

4.29.a. 1 - (2-Chloro-4-nitro-benzyl) -4-methyl-piperidine

To 2 ml (16.22 mmol) of 4-methylpiperidine at room temperature, 1 g (4.85 mmol 2-chloro

4-nitrobenzyl chloride was slowly added dropwise and stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate and extracted twice with water. The organic phase is dried over sodium sulfate and concentrated.

Yield: 1.3 g (99.7% of theory)

Ci ₃ H <| ₇ CIN O ₂ (M = 268.74) calc .: Mole peak (M + Hf: 269/271 f: Mol peak (M + Hf: 269/271

Rr value: 0.4 (Alox, petroleum ether)

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

Made analog 3.1. b from 1- (2-chloro-4-nitro-benzyl) -4-methyl-piperidine. Yield: 0.93 g (80% of theory) C ₂ H ₂ oCIN ₃ (M = 241.76) calc .: Mole peak (M + Hf: 242/244 f: Mol peak (M + Hf: 242/244 Rr value): 0.59 (Alox, petroleum ether / ethyl acetate = 3: 1)

4.29.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -amide

Prepared analogously to Example 2.3.f from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-

Chloro-4- (4-methyl-piperidin-1-ylmethyl) -phenylamine.

Yield: 25 mg (5.3% of theory)

C23H21CI2F3N2O (M = 469.33) calc .: Mole peak (M + Hf: 469/471/473 mf: Mol peak (M + Hf: 469/471/473

Rr value: 0.59 (Alox, petroleum ether / ethyl acetate = 3: 1) Example 4.30: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid (3-chloro-4-piperidin-1-ylmethyl-phenyl) -amide

4.30.a. 1 - (2-Chloro-4-nitro-benzyl) -piperidine Prepared analogously to Example 4.29.a. from 4 ml (40 mmol) piperidine and 2 g (9.71 mmol) 2-chloro-4-nitrobenzyl chloride. Yield: 2.39 g (97% of theory) C ₁₂ H ₁₅ CIN 2 O 2 (M = 254.71) calc .: Mole peak (M + Hf: 255/257 (CI) F f: Mol peak (M + Hf: 255/257 (CI) Rr value: 0.32 (silica gel, petroleum ether / ethyl acetate = 6: 1)

4.30.b. 3-Chloro-4-piperidin-1-ylmethyl-phenylamine Prepared analogously to Example 3.1. b from 1- (2-chloro-4-nitro-benzyl) -piperidine. Yield: 1.88 g (90% of theory) C ₁₂ H ₁₇ CIN 2 (M = 224.73) calc .: Mole peak (M + Hf: 225/227 (CI) F f: mol peak (M + Hf: 225/227 (CI)

Rr value: 0.2 (silica gel, dichloromethane / methanol = 9: 1)

4.30.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid (3-chloro-4-piperidin-1-yl-methylphenyl) -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-chloro-4-piperidin-1-ylmethyl-phenylamine. Yield: 200 mg (44% of theory) of C22H19CI2F3N2O (M = 455.3) x HCI calc .: Mol peak (M + Hf: 455/457/459 (CI) F: mol peak (M + Hf: 455/457/459 (CI)

Rr value: 0.49 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.31:

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

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

Prepared analogously to 4.1.c from (2-chloro-4-nitro-phenyl) -acetic acid. The product is reacted further without further purification.

Yield: 8.8 g (100% of theory)

C ₈ H ₅ Cl ₂ N03 (M = 234.04)

4.31.b. 2- (2-chloro-4-nitro-phenyl) -Λ /, Λ / diethyl-acetamide

Made analog 4.1. d of (2-chloro-4-nitro-phenyl) -acetic acid chloride and diethylamine in

Ethyl acetate.

Yield: 3.7 g (100% of theory)

C ₁₂ H ₁₅ CIN 2 O 3 (M = 270.71) calc .: Mole peak (M + Hf: 271/273 f: Mol peak (M + Hf: 271/273

Rr value: 0.45 (silica gel, petroleum ether / ethyl acetate = 1: 1)

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

To a solution of 3.7 g (13.67 mmol) 2- (2-chloro-4-nitro-phenyl) -Λ /, A / -diethyl-acetamide in

130 ml of THF are added dropwise at room temperature 65 ml (65 mmol) of a 1M borane-THF solution and stirred for four hours. The reaction mixture is then concentrated and the residue is combined with 15 ml of methanol and 15 ml of dilute hydrochloric acid. Thereafter, the mixture is stirred for 15 minutes at 100 ° C, cooled and diluted with water. in the

The mixture is made alkaline with sodium carbonate solution and washed twice with

Extracted ethyl acetate. The combined organic phases are washed twice

Water and once with saturated brine and dried over sodium sulfate. Purification by column chromatography on Alox, neutral, Akt.ll-III

(Eluent: petroleum ether / ethyl acetate = 4: 1).

Yield: 2.1 g (59.8% of theory)

C ₁₂ H ₁₇ CIN 2 O 2 (M = 256.73)

Rr value: 0.63 (Alox, petroleum ether / ethyl acetate = 3: 1) 4.31.d. 3-Chloro-4- (2-diethylamino-ethyl) -phenylamine Prepared analogously to 3.1. b from [2- (2-chloro-4-nitrophenyl) -ethyl] -diethyl-amine. Yield: 1.8 g (100% of theory) of C ₁₂ Hi9CIN ₂ (M = 226.75) calc .: Mole peak (M + Hf: 227/229 m.p .: Mol peak (M + Hf: 227/229

Rr value: 0.63 (Alox, petroleum ether / ethyl acetate = 1: 1)

4.31. e. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-chloro-4- (2-diethylamino-ethyl) -phenyl] -amide

Prepared analogously to Example 2.3.f from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and chloro-4- (2-diethylamino-ethyl) -phenylamine. Yield: 0.21 g (46.8% of theory) of C 22 H 21 Cl 2 F 3 N 2 O (M = 457.32) calc .: Mole peak (M + Hf: 457/459/461 F o: mol peak (M + Hf: 457/459/461

Rr value: 0.63 (Alox, petroleum ether / ethyl acetate = 1: 1)

Example 4.32:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethyl] -phenyl} -amide

ber.: Molpeak (M+Hf: 253/255 gef: Molpeak (M+Hf: 253/2554.32.a. 3-Chloro-4- [2- (4-methylpiperidin-1-yl) ethyl] -phenylamine Prepared analogously to 4.28.a to c from (2-chloro-4-nitro-phenyl) -acetic acid chloride. Yield: 0.71 g (99.3% of theory)

calc .: Mole peak (M + Hf: 253/255 F: Mol peak (M + Hf: 253/255

4.32.b. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -phenyl} -amide Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethyl] -phenylamine. Yield: 0.21 g (45.3% of theory) C 24 H 23 Cl 2 F 3 N 2 O (M = 483.36) calc .: Mole peak (M + Hf: 483/485/487 F o: mole peak (M + Hf: 483/485/487

Rr value: 0.65 (Alox, petroleum ether / ethyl acetate = 1: 1)

Example 4.33: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenyl} -amide

4:33. a. [(E) -2- (2-chloro-4-nitro-phenyl) -vinyl] -dimethyl-amine

A reaction mixture of 8.49 g (48 mmol) of 2-chloro-4-nitrotoluene and 15.03 ml (72.8 mmol) of tert-butoxybut (dimethylamino) methane in 200 ml of THF is refluxed for eight hours. The reaction solution is concentrated and the residue is treated with petroleum ether. The precipitate is filtered off, rinsed with petroleum ether and dried under high vacuum at room temperature. The product is reacted further without further purification. Yield: 11g Ci ₀ H- | -I CIN ₂ O ₂ (M = 226.66) calc .: Mole peak (M + Hf: 227/229 mf: Mol peak (M + Hf: 227/229

Rr value: 0.55 (silica gel, petroleum ether / ethyl acetate = 3: 1)

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

Rr value: 0.62 (silica gel, petroleum ether / ethyl acetate = 1: 1)

4.33.C [2- (2-Chloro-4-nitro-phenyl) -ethyl] -cyclopropyl-methyl-amine To a solution of 1 g (5.01 mmol) (2-chloro-4-nitro-phenyl) - Acetaldehyde in 50 ml of THF are added to 1, 07 g (10 mmol) of N-methyl-cyclopropylamine and then added 4.46 g (20 mmol) of sodium triacetoxyborohydride (95%). The reaction mixture becomes 120

Stirred at room temperature for hours and then in a saturated

Sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. Purification by column chromatography on Alox, neutral, Akt.ll-III (eluent: petroleum ether /

Acetic acid ethyl ester = 5: 1).

Yield: 0.75 g (58.8% of theory)

C ₁₂ Hi 5CIN ₂ θ2 (M = 254.71) calc .: Mol peak (M + Hf: 255/257 f: Mol peak (M + Hf: 255/257

Rr value: 0.61 (Alox, petroleum ether / ethyl acetate = 5: 1)

4.33.d. 3-Chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenylamine Prepared analogously to 3.1. b from [2- (2-chloro-4-nitro-phenyl) -ethyl] -cyclopropyl-methyl-amine. Yield: 0.6 g (100% of theory) C ₁₂ H ₇ CIN ₂ (M = 224.73) calc .: Mole peak (M + Hf: 225/227 f: Mol peak (M + Hf: 225/227

Rr value: 0.57 (Alox, petroleum ether / ethyl acetate = 1: 1)

4.33.e. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-

Chloro-4- [2- (cyclopropyl-methyl-amino) -ethyl] -phenylamine.

Yield: 15 mg (3.4% of theory) of C22H1.9CI2F3N2O (M = 455.31) calc .: Mole peak (M + Hf: 455/457/459 F o: mol peak (M + Hf: 455/457/459

Rr value: 0.3 (Alox, petroleum ether / ethyl acetate = 3: 1)

Example 4.34:

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

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

Prepared analogously to 4.11.a from 3-chloro-4-iodo-nitrobenzene and propynoic acid ethyl ester. Yield: 1.6 g (46.5% of theory) C ₁₁ H ₈ CINO ₄ (M = 253.64) calc .: Molpeak (M. + Hf: 254/256 gef: Molpeak (M + Hf: 254/256

Rr value: 0.6 (silica gel, petroleum ether / ethyl acetate = 6: 1)

4.34.b. (2-Chloro-4-nitro-phenyl) -propynoic acid Prepared analogously to 4.11.b from (2-chloro-4-nitro-phenyl) -propionic acid ethyl ester. Yield: 0.76 g (66.8% of theory) of C9H4CINO4 (M = 225.59) calc .: Mole peak (M + Hf: 225/227 F o: mol peak (M + Hf: 225/227

4:34. c. 3- (2-Chloro-4-nitro-phenyl) -propionic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-nitro-phenyl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethoxy-5-phenylamine.

Yield: 0.49 g (54.4% of theory) C21 H ₂ 1 CI2N3O4 (M = 450.32) calc .: molecular peak (M + Hf: 448/450/452 Found: molecular peak (M + Hf: 448 / 450/452

Rr value: 0.36 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.35:

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

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

Prepared analogously to 4.1 La from 3-chloro-4-iodo-bromobenzene and ethyl propoxide. Yield: 0.97 g (48.2% of theory) of C- | -I H ₈ BrCIO ₂ (M = 287.54) calc .: Molpeak (M + Hf: 287/289/291 F: Mol peak (M + Hf: 287/289/291

Rr value: 0.62 (silica gel, petroleum ether / ethyl acetate = 6: 1)

4.35.b. (4-bromo-2-chloro-phenyl) -propynoic acid Prepared analogously to 4.11.b from (4-bromo-2-chloro-phenyl) -propionic acid ethyl ester. Yield: 0.8 g (93.4% of theory) C ₉ H ₄ BrClO ₂ (M = 259.48) Calculated: Mol peak (M + Hf: 258/260/262 f: Mol peak (M + Hf: 258 / 260/262

4.35.C 3- (4-Bromo-2-chloro-phenyl) -propionic acid [3-chloro-4- (2-diethylamino-ethoxy) -phenyl] -amide

Prepared analogously to Example 2.3.f. from (4-bromo-2-chloro-phenyl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethoxy-5-phenylamine.

Yield: 0.25 g (64.5% of theory) of C ₂ H ₂ 1 BrCl ₂ N ₂ O ₂ (M = 484.22) calc .: Mole peak (M + Hf: 483/485/487/489 F: Molepeak (M + Hf: 483/485/487/489

Rr value: 0.86 (silica gel, dichloromethane / methanol = 49: 1)

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

Example 4.270:

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

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

Prepared analogously to regulation 1.1. c is 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and 4-

Methylpiperidine. Yield: 0.7 g (88.2% of theory) C ₁₅ H ₂₂ N ₂ O ₄ (M = 294.35) calc .: Mole peak (M + Hf: 295 F o: mol peak (M + Hf: 295

Rr value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

4.270.b. 3-Methoxy-4- [2- (4-methylpiperidin-1-yl) ethoxy] -phenylamine Prepared analogously to Example 3.1.b. from 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -4-methylpiperidine.

Yield: 0.51 g (81.1% of theory) of C-i 5H24N2O2 (M = 264.37) calc .: Mole peak (M + Hf: 265 F: mole peak (M + Hf: 265

Rr value: 0.3 (silica gel, dichloromethane / methanol 9: 1).

4.270.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {3-methoxy-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-

Methoxy-4- [2- (4-methyl-piperidin-1-yl) -ethoxy] -phenylamine.

Yield: 70 mg (23.5% of theory)

Melting point: 207-209 ° C C25H26CIF3N2O3 (M = 494.94) Calculated by: Mol peak (M + Hf: 495/497 mf: Mol peak (M + Hf: 495/497

Rr value: 0.45 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.271:

3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (3,5-dimethylpiperidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

4.271.a. 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -3,5-dimethyl-piperidine Prepared analogously to regulation 1.1. c is 1- (2-bromo-ethoxy) -2-methoxy-4-nitro-benzene and 3,5-dimethylpiperidine.

Yield: 0.4 g (48.1% of theory) of C ₁₆ H ₂₄ N ₂ O ₄ (M = 308.38) calc .: Mole peak (M + Hf: 309 F o: mol peak (M + Hf: 309

Rr value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

4271. b. 4- [2- (3,5-Dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenylamine Prepared analogously to Example 3.1. b. from 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -3,5-dimethyl-piperidine.

Yield: 0.35 g (96.9% of theory) C ₁₅ H 24 N ₂ O ₂ (M = 264.37) calc .: Mole peak (M + Hf: 279 F o: mol peak (M + Hf: 279

Rr value: 0.3 (silica gel, dichloromethane / methanol 9: 1).

4.271.c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (3,5-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 4- [2-

(3,5-Dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenylamine. Yield: 160 mg (52.1% of theory)

Melting point: 196-201 ° C

C26H28CIF3N2O3 (M = 508.97) calc .: Mole peak (M + Hf: 509/511 mf: Mol peak (M + Hf: 509/511

Rr value: 0.5 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.272:

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

4.272.a. {(S)-1-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidin-2-yl}-methanol Hergestellt analog Vorschrift L c aus 1-(2-Brom-ethoxy)-2-methoxy-4-nitro-benzol und (S)- 1 -Pyrrolidin-2-yl-methanol. Ausbeute: 0,2 g (25 % der Theorie) C₁₄H₂₀N₂O₅(M= 296,32) ber.: Molpeak (M+Hf: 297 gef: Molpeak (M+Hf: 297

4.272.a. {(S) -1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -pyrrolidin-2-yl} -methanol Prepared analogously to method L c from 1- (2-bromo-ethoxy) -2 -methoxy-4-nitro-benzene and (S) -1-pyrrolidin-2-yl-methanol. Yield: 0.2 g (25% of theory) C ₁₄ H ₂₀ N ₂ O ₅ (M = 296.32) calc .: Mole peak (M + Hf: 297 F o: mol peak (M + Hf: 297

Rr value: 0.55 (silica gel, dichloromethane / methanol 9: 1).

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

Prepared analogously to Example 3.1. b. of {(S) -1- [2- (2-methoxy-4-nitrophenoxy) ethyl] pyrrolidine

2-yl} -methanol.

Yield: 0.15 g (83.4% of theory)

C ₁ H ₂ 2N 2θ ₃ (M = 266.34) calc .: Mol peak (M + Hf: 267 fc: Mol peak (M + Hf: 267

Rr value: 0.15 (silica gel, dichloromethane / methanol 9: 1).

4.272.C 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2 - ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and {(S) -1- [2- (4-amino-2-methoxy-phenoxy) -ethyl] -pyrrolidin-2-yl} -methanol. Yield: 140 mg (58.9% of theory) Melting point: Decomposition at 300 ° C. C24H24CIF3N2O4 (M = 496.91) Calculated by: Mole peak (M + Hf: 497/499 F o: mol peak (M + Hf: 497/499

Rr value: 0.2 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.273: 3- (2-Chloro-4-trifluoromethylphenyl) propynoic acid [3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenyl] -amide

4.273.a. 4- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -morphoIin

Prepared analogously to H.c from 1- (2-bromo-ethoxy) -2-methoxy-4-nitrobenzoyl and

Morpholine.

Yield: 0.3 g (39.4% of theory)

C ₁₃ H ₁₈ N ₂ O ₅ (M = 282.29) calc .: Mol peak (M + Hf: 283 f: Mol peak (M + Hf: 283

Rr value: 0.6 (silica gel, dichloromethane / methanol 9: 1).

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

Prepared analogously to Example 3. Lb. 4- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -morphoIin.

Yield: 0.23 g (85.8% of theory)

C ₁₃ H2θN ₂ θ3 (M = 252.31) calc .: Mol peak (M + Hf: 253 fc: mol peak (M + Hf: 253

Rr value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

4.273.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid [3-methoxy-4- (2-morpholino-4-yl-ethoxy) -phenyl] -amide Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-phenyl) -propynoic acid and 3-

Methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamine.

Yield: 20 mg (6.9% of theory)

Melting point: 209-211 ° C C23 ^H 22 ^CIF 3N2θ4 (M = 482.89) calc .: molecular peak (M + Hf: 483/485 Found: molecular peak (M + Hf: 483/485

Rr value: 0.5 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.274: 3- (2-Chloro-4-trifluoromethylphenyl) propynoic acid {3-methoxy-4- [2- (4-methoxy-piperidin-1-yl) -ethoxy] -phenyl} -amide

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

Prepared analogously to Example 1.1. c from 1g (3.62 mmol) of 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and 1.25 g (10.87 mmol) of 4-methoxypiperidine.

Yield: 1 g (89% of theory)

C ₁₅ H ₂₂ N ₂ θ ₅ (M = 310.35) calc .: Mol peak (M + Hf: 311 fc: Mol peak (M + Hf: 311

Rr value: 0.5 (silica gel, dichloromethane / methanol 9: 1).

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

Prepared analogously to Example 3. Lb. from 1 g (3.22 mmol) of 4-methoxy-1- [2- (2-methoxy-4-nitro-phenoxy) ethyl] piperidine. Yield: 0.85 g (94% of theory)

C ₅ H24N ₂ θ3 (M = 280.36) calc .: Mol peak (M + Hf: 281 fc: Mol peak (M + Hf: 281

Rr value: 0.6 (silica gel, dichloromethane / methanol 9: 1)

4.274.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propanoic acid {3-methoxy-4- [2- (4-methoxy-piperidin-1-yl) -ethoxy] -phenyl} -amide Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 186 mg (0.66 mmol) of 3-methoxy-4- [2- (4-methoxy-piperidin-1-yl ) -ethoxy] - phenylamine. Yield: 20 mg (7% of theory) Melting point: 195-197 ° C c25H26 ^CIF 3N2O4 (M = 510.93) Calculated: Mol peak (M + Hf: 511/513 (CI) Fc: Mole peak (M + Hf: (M + Hf: 511/513 (CI) Rr value: 0.3 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.275: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethoxy] -3-methoxy-phenyl } -amide formate

4.275.a. 2- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -1,3,3,4-tetrahydro-isoquinoline

Prepared analogously to Example LLc from 1 g (3.622 mmol) of 1- (2-bromo-ethoxy) -2-methoxy-4-nitrobenzene and 1.36 ml (10.87 mmol) of 1,2,3,4-tetrahydro -isoquinolin.

Yield: 1.4 g (77% of theory)

C ₁₈ H ₂₀ N ₂ O ₄ (M = 328.36) calc .: Mole peak (M + Hf: 329 F o: mol peak (M + Hf: 329

Rr value: 0.7 (silica gel, dichloromethane / methanol 9: 1).

4.275.b. 4- [2- (3,4-Dihydro-1H-isoquinolin-2-yl) -ethoxy] -3-methoxy-phenylamine Prepared analogously to Example 3. Lb. from 1.4 g (2.77 mmol) 2- [ 2- (2-Methoxy-4-nitrophenoxy) ethyl] -1,3,3,4-tetrahydroisoquinoline (65%). Yield: 1.2 g (94% of theory) Cj ₈ H ₂ 2N ₂ O ₂ (M = 298.38) calc .: Mol peak (M + Hf: 299 F o: mol peak (M + Hf: 299

Rr value: 0.5 (silica gel, dichloromethane / methanol 9: 1)

4,275.C 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethoxy] -3-methoxy-phenyl} amide formate

Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 304 mg (0.66 mmol) of 4- [2- (3,4-dihydro-1H-isoquinolin-2-one yl) -ethoxy] -3-methoxy-phenylamine (65%).

Yield: 17 mg (5% of theory) Melting point: 92-95 ° C

C2 ₈ H24CIF ₃ N ₂ θ3 (M = 528.96) * CH ₂ O ₂ calc .: Mole peak (M + Hf: 529/531 (CI) Fc: Mol peak (M + Hf: 529/531 (CI)

Rr value: 0.55 (silica gel, dichloromethane / methanol = 9: 1)

Example 4.276: 1- (2- {4- [3- (2-Chloro-4-trifluoromethylphenyl) -propinoylamino] -2-methoxyphenoxy} -ethyl) -piperidine-4-carboxylic acid amide

4.276.a. 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -piperidine-4-carboxylic acid amide

Prepared analogously to Example 1.1. c from 1 g (3.622 mmol) of 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and 1.4 g (10.87 mmol) of piperidine-4-carboxylic acid amide.

Yield: 1.05 g (90% of theory)

C ₁₅ H ₂₁ N ₃ O ₅ (M = 323.34) calc .: Mol peak (M + Hf: 324 f: Mol peak (M + Hf: 324

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1).

4.276.b. 1- [2- (4-amino-2-methoxy-phenoxy) -ethyl] -piperidine-4-carboxylic acid amide Prepared analogously to Example 3.1. b. from 1 g (3.1 mmol) of 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -piperidine-4-carboxylic acid amide. Yield: 0.8 g (88% of theory) of C 5 H 23 N 3 O 3 (M = 298.38) calc .: Mole peak (M + Hf: 294 F o: mol peak (M + Hf: 294

Rr value: 0.3 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

4.276.C 3- (1- (2- {4- [3- (2-Chloro-4-trifluoromethylphenyl) -propinoylamino] -2-methoxy-phenoxy} -ethyl) -piperidine-4-carboxylic acid amide

Prepared analogously to Example 2.3.f from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethyl-phenyl) - propionic acid and 194 mg (0.66 mmol) of 1- [2- (4-amino-2-methoxy -phenoxy) -ethyl] -piperidine-4-carboxylic acid amide.

Yield: 310 mg (98% of theory) Melting point: 150 ° C

C25H25CIF3N3O4 (M = 523.93) calc .: Mol peak (M + Hf: 524/526 (CI) Fc: Mol peak (M + Hf: 524/526 (CI)

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 4.277: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxyphenyl} -amide

4.277.a. 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -2,6-dimethyl-piperidine

Prepared analogously to Example 1.1. c from 1 g (3.622 mmol) of 1- (2-bromo-ethoxy) -2-methoxy-4-nitrobenzene and 1.5 ml (10.87 mmol) of 2,6-dimethyl-piperidine.

Yield: 0.85 g (76% of theory)

C ₁₆ H ₂₄ N ₂ O ₄ (M = 308.37) calc .: Mole peak (M + Hf: 309 F o: mol peak (M + Hf: 309

Rr value: 0.55 (silica gel, dichloromethane / methanol 9: 1).

4.277.b. 4- [2- (2,6-Dimethyi-piperidin-1-yl) -ethoxy] -3-methoxy-phenylamine Prepared analogously to Example 3.1.b. from 0.84 g (2.72 mmol) of 1- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -2,6-dimethyl-piperidine. Yield: 0.65 g (86% of theory) of C 6 H 26 ^N 2 O 2 ( ^{M =} 278.39) calc .: Mole peak (M + Hf: 279 F o: mol peak (M + Hf: 279

Rr value: 0.1 (silica gel, dichloromethane / methanol 9: 1)

4.277.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethoxy] -3-methoxy-phenyl} -amide

Prepared analogously to Example 2.3.f from 150 mg (0.6 mmol) (2-chloro-4-trifluoromethyl-phenyl) - propionic acid and 185 mg (0.663 mmol) 4- [2- (2,6-dimethyl-piperidine-1 -yl) ethoxy] -3-methoxy-phenylamine.

Yield: 150 mg (49% of theory) Melting point: 225-227 ° C c26 28 ^CIF 3N2θ (M = 508.96) Calculated by: Mole peak (M + Hf: 509/511 (CI) Fc: Mole peak (M + Hf : 509/511 (CI)

Rr value: 0.2 (silica gel, dichloromethane / methanol 9: 1)

Example 4.278: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (cyclopropylmethyl-methyl-amino) -ethoxy] -3-methoxy-phenyl} -amide-hydrochloride

4.278.a. Cyclopropylmethyl- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -methyl-amine

Prepared analogously to Example 1.1. c from 1 g (3.62 mmol) of 1- (2-bromoethoxy) -2-methoxy-4-nitrobenzene and 900 mg (10.57 mmol) of cyclopropylmethylamine.

Yield: 0.95 g (94% of theory)

C ₁₄ H ₂₀ N ₂ O ₄ (M = 280.32) calc .: Mol peak (M + Hf: 281 f: Mol peak (M + Hf: 281

Rr value: 0.4 (silica gel, dichloromethane / methanol 9: 1).

4.278.b. 4- [2- (Cyclopropylmethyl-methyl-amine) -ethoxy] -3-methoxy-phenylamine Prepared analogously to Example 3. Lb. from 950 mg (3.4 mmol) of cyclopropylmethyl- [2- (2-methoxy-4-nitro phenoxy) -ethyl] -methyl-amine. Yield: 0.68 g (80% of theory) C ₁₄ H ₂ 2N ₂ O ₂ (M = 250.34) calc .: Mole peak (M + Hf: 251 F o: mol peak (M + Hf: 251

Rr value: 0.35 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

4.278.C. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (cyclopropylmethyl-methyl-amino) -ethoxy] -3-methoxy-phenyl} -amide-hydrochloride

Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 166 mg (0.66 mmol) of 4α [2- (cyclopropylmethyl-methyl-amine) -ethoxy] -3-methoxy -phenylamine.

Yield: 130 mg (45% of theory) Melting point: 173-176 ° C

C24H24CIF3N2O3 (M = 480.91) ΗCI calc .: Mole peak (M + Hf: 481/483 (CI) Fc: Mole peak (M + Hf: 481/483 (CI) Rr value: 0.2 (silica gel, dichloromethane / methanol 9 :1)

Example 4.279: 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (cyclopropylmethyl-propyl-amino) -ethoxy] -3-methoxy-phenyl} -amide hydrochloride

4.279.a. Cyclopropylmethyl- [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -propyl-amine

Prepared analogously to Example LLc from 1 g (3.62 mmol) of 1- (2-bromo-ethoxy) -2-methoxy-4-nitro-benzene and 1, 51 ml (10.57 mmol) of cyclopropyl-methyl-propyl-amine ,

Yield: 0.95 g (85% of theory)

C ₁₆ H ₂₄ N ₂ O ₄ (M = 308.37) calc .: Mole peak (M + Hf: 309 F o: mol peak (M + Hf: 309

Rr value: 0.4 (silica gel, dichloromethane / methanol 9: 1).

4.279.b. 4- [2- (Cyclopropylmethyl-propyl-amino) -ethoxy] -3-methoxy-phenylamine Prepared analogously to Example 3.1. b. from 950 mg (3.1 mmol) of cyclopropylmethyl [2- (2-methoxy-4-nitro-phenoxy) -ethyl] -propyl-amine. Yield: 0.74 g (86% of theory) of C ₆ H ₂ 6N ₂ O ₂ (M = 278.39) calc .: Mole peak (M + Hf: 279 F o: mol peak (M + Hf: 279

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

4279. c. 3- (2-Chloro-4-trifluoromethyl-phenyl) -propynoic acid {4- [2- (cyclopropylmethyl-propyl-amino) -ethoxy] -3-methoxy-phenyl} -amide-hydrochloride

Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl) propenoic acid and 185 mg (0.66 mmol) of 4- [2- (cyclopropylmethyl-propyl-amino) -ethoxy] -3-methoxy -phenylamine.

Yield: 180 mg (59% of theory) Melting point: 185-188 ° C c26H28 ^CIF 3N2θ3 (M = 508.96) ΗCI calc .: Mole peak (M + Hf: 509/511 (CI) Fc: Mole peak (M + Hf : 509/511 (CI) Rr value: 0.35 (silica gel, dichloromethane / methanol 9: 1) Example 4.281:

3- (3-Bromo-biphenyl-4-yl) -propynoic acid {3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethyl] -phenyl} -amide

4.281a. 3-bromo-biphenyl-4-ylamine

To a solution of 13.008 g (76.8 mmol) of biphenyl-4-ylamine in 60 ml of DMSO are added dropwise at room temperature 8.7 ml (76.8 mmol) of a 48 percent hydrogen bromide solution and stirred for 14 hours. The mixture is then heated for one hour at 100 ° C, the approach is subsequently cooled and poured onto water. By adding ammonia solution, the reaction mixture is made alkaline and the precipitate which has precipitated out is filtered off, washed with water. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane). Yield: 11.3 g (60% of theory) C ₁₂ H ₁₀ BrNO (M = 248.19) calc .: Mole peak (M + Hf: 248/250 (CI) Fc: mol peak (M + Hf: 248/250 (CI)

4.281b. 3-iodo-biphenyl-4-ylamine A solution of 7.3 g (29.4 mmol) of 3-bromo-biphenyl-4-ylamine in 120 ml of acetic acid is added 6 ml of concentrated hydrochloric acid at room temperature, cooled to 15 ° C and Stirred for 30 minutes. To this reaction mixture, a solution of 2 g (28.9 mmol) of sodium nitrite in 7 ml of water is slowly added dropwise at 15 ° C and stirred for 30 minutes. Subsequently, a solution of 5.4 g (32.5 mmol) of potassium iodide in 28 ml of water is slowly added dropwise at 5 ° C and stirred. After 30 minutes, 2.95 g of sodium thiosulfate are added and stirred for a further 30 minutes. Subsequently, the reaction mixture is concentrated, treated with water / ethyl acetate. The aqueous phase is extracted again with ethyl acetate, the combined aqueous phases are extracted once with water and dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether). Yield: 6.6 g (85% of theory) C ₁₂ H ₈ Brl (M = 359.00) calc .: Molpeak (Mf: 358/360 (Br) Fe: Mol peak (Mf: 358/360 (Br)

4,281 c. (3-Bromo-biphenyl-4-yl-ethynyl) -te / f-butyl-dimethyl-silane Prepared analogously to 1.1. d of 3-iodo-biphenyl-4-ylamine and ferf-butyl-ethynyl-dimethyl-silane. Yield: 0.52 g (72% of theory) c20 ^H 23 ^BrS '(= 371.38) calc .: Mol peak (M + Hf: 371/373 (Br) Fem: Mol peak (M + Hf: 371/373 ( Br)

4.281.d 3-bromo-4-ethynylbiphenyl

To a solution of 495 mg (1.33 mmol) of (3-bromo-biphenyl-4-ylethynyl) -fert-butyl-dimethyl-silane in 8 ml of anhydrous THF at 5 ° C 1, 99 ml (1, 99 mmol ) was added portionwise to a 1 M tetrabutylammonium fluoride solution in THF. The reaction mixture is stirred for a further 30 minutes at room temperature and concentrated. The residue is mixed with diethyl ether and water and the organic phase dried over Natriumsufat. Yield: 0.34 g (99% of theory) C ₁₄ H ₉ Br (M = 257.12) calc .: Mol peak (M-Hf 255/257 (Br) F f: Mol peak (MH) ^" : 255/257 (m.p. br

4.281 e. (3-Bromo-biphenyl-4-yl) -propinsäure

Prepared analogously to 4.3.a from 3-bromo-4-ethynyl-biphenyl and carbon dioxide.

Yield: 2.5 g (89% of theory)

Ci5H BrO ₂ (M = 301, 13) calc .: Mole peak (M + Hf: 301/303 (Br) Fem: Mol peak (M + Hf: 301/303 (Br) Rr value: 0.3 (silica gel, dichloromethane / methanol 90: 10)

4281. f. 3- (3-Bromo-biphenyl-4-yl) -propynoic acid {3-chloro-4- [2- (4-methylpiperidin-1-yl) -ethyl] -phenyl} -amide

Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl) -propynoic acid and 3-chloro-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -phenylamine. Yield: 0.24 g (50% of theory) of C29H ₂₈ BrCIN ₂ O (M = 535.90) Calculated by: Mole peak (M + Hf: 535/37/39 m.p .: Mol peak (M + Hf: 535/37 / 39

Rr value: 0.48 (silica gel, dichloromethane / methanol 90:10) Example 4.282:

3- (3-Bromo-biphenyl-4-yl) -propynoic acid [3-chloro-4- (2-diethylamino-ethyl) -phenyl] -amide hydrochloride

Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl) -propynoic acid and 3-chloro-4- (2-diethylamino-ethyl) -phenylamine. Yield: 95 mg (23.8% of theory) C ₂ 7H26BrCIN ₂ O * HCl (M = 546.32) calc .: Mole peak (M + Hf: 509/11/13 f: mol peak (M + Hf: 509 / 11/13

Rr value: 0.3 (silica gel, dichloromethane / methanol 90:10)

Example 4.283:

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

Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl) -propynoic acid and 3-chloro-4- (2-pyrrolidin-1-yl-ethyl) -phenylamine. Yield: 140 mg (27.2% of theory) of C ₂ 7H24BrCIN ₂ O 1 (M = 507.84) calc .: Mole peak (M + Hf: 507/09/11 f e: mol peak (M + Hf: 507/09 / 11 Example 4.284:

3- (3-Bromo-biphenyl-4-yl) -propynoic acid {3-chloro-4- [2- (4-hydroxy-4-trifluoromethyl-piperidin-1-yl) -ethyl] -phenyl} -amide

Prepared analogously to Example 2.3.f from (3-bromo-biphenyl-4-yl) -propynoic acid and 1- [2- (4-amino)

2-chloro-phenyl) -ethyl] -4-trifluoromethyl-piperidin-4-ol.

Yield: 36 mg (10.5% of theory) C29 ^H 25BrCIF3N ₂ O ₂ (M = 605.87) calc .: molecular peak (M + Hf: 605/07/09 Found: molecular peak (M + Hf: 605/07 / 09

Example 4.285:

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

Hergestellt analog Beispiel 2.3.f aus Pyridin-3-yl-propinsäure und [2-(2-Chlor-4-amino- phenoxy)-ethyl]-diethyl-amin.

Prepared analogously to Example 2.3.f from pyridin-3-yl-propynoic acid and [2- (2-chloro-4-amino-phenoxy) ethyl] -diethyl-amine.

Yield: 0.42 g (66.4% of theory)

Melting point: 118-120 ° C

C20H22CIN3O2 (M = 371.86) calc .: Mole peak (M + Hf: 372/374 mf: Mol peak (M + Hf: 372/374

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 9: 1: 0.1)

Example 5.1: (E) -Λ / - (4'-Methoxybiphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide

5.1.A. Ethyl (E) -3- (4-pyrrolidin-1-ylmethylphenylfacrylate To a suspension of 0.69 ml (8.2 mmol) of pyrrolidine and 2.05 g (14.86 mmol) of potassium carbonate in 40 ml of DMF is added 2 g ( 7.43 mmol) of ethyl (E) -3- (4-bromomethylphenyl) acrylate and stirred at room temperature for 18 hours The reaction mixture is concentrated and the residue is extracted with water and ethyl acetate The organic phase is dried over sodium sulfate and concentrated and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia = 90: 10: 1) Yield: 0.3 g (15.6% of theory) of C ₁₆ H ₂ iNO ₂ (M = 259, 35) calc .: Mol peak (M + H) ⁺ : 260 f: Mol peak (M + H) ⁺ : 260

Rr value: 0.5 (silica gel, dichloromethane / methanol / ammonia 90: 10: 1)

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

A reaction mixture of 0.3 g (1.15 mmol) of ethyl (E) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylate and 0.4 g (9.53 mmol) of lithium hydroxide monohydrate in 20 ml of a 1: 1 mixture of methanol, THF and water is stirred for 48 hours at room temperature. The reaction mixture is then concentrated, the residue is diluted with water and acidified with hydrochloric acid. The mixture is concentrated, treated with methanol and dichloromethane, filtered and the filtrate evaporated to dryness. Yield: 0.27 g C ₁₄ Hi7NO ₂ (M = 231, 29) Calculated by: Mol peak (M + Hf: 232 F o: mol peak (M + Hf: 232

Rr value: starting spot (silica gel, dichloromethane / methanol / ammonia 90: 10: 1)

5.1.C. (E) -Λ / - (4'-Methoxybiphenyl-4-yl) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylamide Prepared analogously to 3.1. e from (E) -3- (4-pyrrolidin-1-ylmethyl-phenyl) -acrylic acid and 4'-methoxy-biphenyl-4-yl-amine.

Yield: 74 mg (15.4% of theory) Melting point: 199-200 ° C. C27H28 ^N 2 ° 2 ( ^M = 412.53) calc .: Mole peak (M + Hf: 413 mf: Mol peak (M + Hf: 413

Rr value: 0.77 (silica gel, dichloromethane / methanol / ammonia = 80: 20: 1)

Example 5.2:

(E) -Λ / - (4'-chloro-biphenyl-4-yl) -3- [4- (4-methyl-piperidin-1-ylmethyl) -phenyl] -acryIamid

5.2.a. (E) -3- (4-Dimethoxymethyl-phenyl) -acrylic acid To a suspension of 25 g (0.141 mol) of (E) -3- (4-formyl-phenyl) -acrylic acid in 350 ml

Methanol is added 38.81 ml (0.354 mmol) of trimethyl orthoformate and heated to reflux for 48 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in 500 ml of dichloromethane and filtered through Celite. The filtrate is concentrated to 150 ml and cooled to 0 ° C. The precipitate is filtered off, washed with dichloromethane / petroleum ether (1: 1) and dried at 60 ° C in a convection oven. Yield: 12.05 g (31.5% of theory) of C ₁₂ H ₁₄ O ₄ (M = 222.24) calc .: Mol peak (M + H) ⁺ : 245 f: Mol peak (M + H) ⁺ : 245 Rr value: 0.6 (silica gel, petroleum ether / ethyl acetate = 1: 1)

5.2.b. (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4-dimethoxymethyl-phenyl) -acrylamide Prepared analogously to 3.1.e from (E) -3- (4-dimethoxymethyl-phenyl) acrylic acid and 4'-chlorobiphenyl-4-yl-amine. Yield: 9.8 g

C ₂ 4H ₂ 2CINO ₃ (M = 407.90) calc .: Mole peak (M + Hf: 408/410 mf: Mol peak (M + Hf: 408/410

R _r value: 0.3 (silica gel, dichloromethane / ethanol 20: 1)

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

To a suspension of 9.8 g (24.02 mmol) of (E) -Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-dimethoxymethyl-phenylfacrylamide in 280 ml of chloroform are added 70 ml of water and 21 ml of trifluoroacetic acid and the reaction mixture for eight hours at room temperature touched. It is diluted with chloroform and water, the organic phase separated and extracted with water. The organic phase is dried, filtered through silica gel and the solvent distilled off. Yield: 5.5 g of C22H16CINO2 (M = 361, 83) calc .: Mole peak (M + Hf: 362/364 f: Mol peak (M + Hf: 362/364

R _r value: 0.6 (silica gel, cyclohexane / ethyl acetate 1: 1)

5.2.d. (E) -Λ / - ^{(4-chloro-biphenyl-4-yl)} -3- [4- (4-methyl-piperidin-1-ylmethyl) phenyl] acrylamide Prepared analogously 4.30.C from (E) -Λ / - (4'-chloro-biphenyl-4-yl) -3- (4-formyl-phenyl) -acrylamide and

4-methyl-piperidine.

Yield: 80 mg (21.7% of theory)

Melting point: 207-208 ° C

^C 28 ^H 29 ^CIN 2 ° (M = 445.00) calc .: Mole peak (M + Hf: 445/447 F: Mol peak (M + Hf: 445/447

Rr value: 0.76 (silica gel, dichloromethane / methanol = 10: 1)

Example 5.3: (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- [4- (cis-3,5-dimethyl-piperidin-1-ylmethyl) -phenyl] -acrylamide

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

A solution of 4.4 g (12.16 mmol) of (E) -Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-formyl-phenyl) -acrylamide in 200 ml of THF is washed with Adjusted glacial acetic acid to a pH of three, with 8.14 g (36.48 mmol) of sodium triacetoxyborohydride and stirred for 18 hours at room temperature. Then the reaction mixture is poured into water and the precipitate is filtered off. The filtrate is extracted with ethyl acetate, washed with water and dried over sodium sulfate. The solvent is removed and the residue combined with the filtered solid. The cleaning is done by

Column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia = 30: 1: 0.1). Yield: 3.2 g (72.4% of theory) of C ₂ H ₂ H ₁₈ CINO ₂ (M = 363.84) Calc .: Mol peak (M + H) ⁺ : 364/366 F: Mol peak (M + H) ⁺ : 364/366

R _r value: 0.2 (silica gel, dichloromethane / ethanol = 20: 1)

5.3.b. (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4-chloromethyl-phenyl) -acrylamide A suspension of 2.1 g (5.77 mmol) of (E) - / V - (4'-Chloro-biphenyl-4-yl) -3- (4-hydroxymethyl-phenyl) -acrylamide in 100 ml of dichloromethane is treated with 1.7 ml (12.19 mmol) of triethylamine and then with 0.46 ml ( 5.88 mmol) of methanesulfonyl chloride. The reaction mixture is stirred at room temperature for three hours, diluted with water and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered through silica gel and the filtrate is concentrated. Yield: 0.4 g (18.1% of theory) of C ₂ H ₂ 7CI ₂ NO (M = 382.29) calc .: Mole peak (M + Hf: 381/383/385 mpt: mole peak (M + Hf: 381 / 383/385

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

Prepared analogously to 1.2.c from (E) -Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-chloromethyl-phenyl) -acrylamide and cis-3,5-dimethylpiperidine.

Yield: 30 mg (30% of theory)

Melting point: 217-218 ° C

C29H ₃₁ CIN ₂ O (M = 459.03) Calcd .: Mol peak (M + Hf: 459/461 f: Mol peak (M + Hf: 459/461

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

Rr value: A = (silica gel, dichloromethane / methanol (10: 1)

B = (silica gel, dichloromethane / methanol / ammonia (10: 1: 0.1)

Example 5.14.

(E) -Λ / - (4 ^{'-Chloro-biphenyl-4-yl)} -3- (4-cyclopropylaminomethyl-phenyl) -acrylamide

A reaction mixture of 100 mg (0.26 mmol) of (E) -A / - (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenyl) acrylamide, 70 mg (0.77 mmol ) 2-methoxy-ethyl-methylamine and 140 mg (1 mmol) of potassium carbonate in 10 ml of acetone are shaken under reflux for 24 hours. The reaction mixture is concentrated. The residue is purified by column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia 20/1 / 0.1). Yield: 92 mg (81% of theory) Melting point: 222-223 ° C. c26 ^H 27 ^CIN 2θ2 (M = 434.96) calc .: Mole peak (M + H) ⁺ : 435/37 (CI) Fc: Molepeak (M + H) ⁺ : 435/37 (0)

Rr value: 0.4 (silica gel, dichloromethane / methanol / ammonia = 20: 1: 0.1)

The following compounds are prepared analogously to Example 5.14:

Rr value: A = (silica gel, dichloromethane / ethanol / ammonia (20: 1: 0.1) B = (silica gel, dichloromethane / methanol / ammonia (10: 1: 0.1)

Example 5.29: (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4 - {[methyl- (4-methyl-cyclohexyl) -amino] -methyl} -phenyl) -acryloamide

5.29.a. Methanesulfonic acid 4 - [(E) -2- (4'-chloro-biphenyl-4-ylcarbamoyl) -vinyl] -benzyl ester A suspension of 2.3 g (6.3 mmol) of (E) -Λ / - (4 ' -Chloro-biphenyl-4-yl) -3- (4-hydroxymethylphenyl) -acrylamide in 200 ml of dichloromethane is treated with 1.94 ml (13.9 mmol) of triethylamine and then with 0.54 ml (6.92 mmol ) Methanesulfonsäurechlorid added. The Reaction mixture is stirred for 18 hours at room temperature, diluted with water and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered through silica gel and the filtrate is concentrated. Yield: 1.85 g (67% of theory) C23H20CINO4S (M = 441, 93) calc .: Mole peak (M + Hf: 442/444 (CI) Fc: Mole peak (M + Hf: 442/444 (CI)

Rr value: 0.73 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

5.29.b. (E) -Λ / - (4'-Chloro-biphenyl-4-yl) -3- (4 - {[methyl- (4-methyl-cyclohexyl) -amino] -methyl} -phenylfacryamide

A reaction mixture of 100 mg (0.226 mmol) methanesulfonic acid 4 - [(E) -2- (4 ^'-chIor- biphenyl-4-ylcarbamoyl) -vinyl] -benzyl ester, 37.34 mg (0.29 mmol) MethyI- ( 4-methylcyclohexylfamine and 0.1 ml of triethylamine in 10 ml of dichloromethane are stirred for 18 hours at room temperature, then the reaction mixture is extracted between water and dichloromethane, the organic phase is separated off, dried and concentrated, the residue is purified by column chromatography on silica gel ( Eluent: dichloromethane / methanol / ammonia 90: 10: 1) Yield: 52 mg (49% of theory) C30H33CIN2O (M = 473.05) Melting point: 227-258 ° C calc .: Mole peak (M + Hf: 473 / 475 (CI) F f: Mol peak (M + Hf: 473/475 (CI)

Rr value: 0.48 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1)

The following compounds are prepared analogously to Example 5.29.b.

Rr value: A = (silica gel, dichloromethane / methanol / ammonia (90: 10: 1)

Example 5.33:

(E) -A / - (4 ^{'chloro-biphenyl-4-yl)} -3- (4-Cyclohexylaminomethyl-phenyl) -acrylamide

To a suspension of 150 mg (0.39 mmol) of (E) -Λ- (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenylfacryamide in 5 ml of tetrahydrofuran is added 0.082 ml (0, 72 mmol) cyclohexylamine were added and the mixture was refluxed for 18 h, then the reaction mixture was poured into water and the resulting precipitate was filtered off with suction, then purified by column chromatography on silica gel (eluent: dichloromethane / methanol 95: 5-50: 50) mg (40% of th.) _C28 H29CIN ₂ O (M = 444.99)

Melting point: 247-248 ° C calc .: Mole peak (M + Hf: 445/447 (CI) Fc: Molepeak (M + Hf: 445/447 (CI)

Example 5:34: (E) -Λ / - (4 ^{'-Chloro-biphenyl-4-yl)} -3- (4 - {[(2-hydroxy-cyclohexyl) -methyl-amino] - methyl} -phenyl) -acrylamide

Prepared analogously to Example 5.33. from (E) -Λ / - (4'-chlorobiphenyl-4-yl) -3- (4-chloromethyl-phenyl) -acrylamide and 2-methylamino-cyclohexanol. Yield: 90 mg (48% of theory) of C ₂ H 9 C ₃₁ H ₂ O ₂ (M = 475.02).

Melting point: 210-211 ° C calc .: Mole peak (M + Hf: 475/477 (CI) Fc: Molepeak (M + Hf: 475/477 (CI)

Example 5.35: 4 - ({- [(E) -2- (4 ^{'-Chloro-biphenyl-4-ylcarbamoyl)} -vinyl] -benzyl} -methyl-amino) - piperidine-1 -carboxylic acid fe / butyl

To a suspension of 300 mg (0.79 mmol) of (E) - / V- (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenyl) acrylamide in 5 ml of dimethylformamide is added 0, 5 g (2.34 mmol) of 4-methylaminopiperidine-1-carboxylic acid fe / f-butyl ester added and stirred at 80 ° C for 18 h. The reaction mixture is then poured onto water and the precipitate is filtered off with suction. Further purification is carried out by stirring out a little methanol. Yield: 200 mg (45% of theory) of C33H38CIN3O3 (M = 560.13)

Melting point: 168-169 ° C calc .: Mole peak (M + Hf: 560/562 (CI) Fc: Molepeak (M + Hf: 560/562 (CI)

Example 5:36: (E) - / V- (4 ^{'chloro-biphenyl-4-yI)} -3- {4 [(methyl-piperidin-4-yl-amino) -methyl] - phenyl} -acrylamide x Trifluoressigsäureacetat F ₃ CCOOH

To a suspension of 170 mg (0.3 mmol) 4 - ({- [(E) -2- (4 ^{'-Chloro-biphenyl-4-ylcarbamoyl)} - vinyl] -benzyl} -methyl-amino) -piperidine 1-Fatty acid carboxylic acid (Example 5.35) in 25 ml of dichloromethane, 1 ml of trifluoroacetic acid are added and stirred for 18 h at room temperature. The solvent is then concentrated and the residue is crystallized from ethyl acetate / diisopropyl ether 1: 1. The precipitated solid is filtered off and dried at 60 ° C in a convection oven. Yield: 70 mg (40% of theory) C28 30 ^CIN 3 ° ( ^{M =} 460.02) ^* trifluoroacetic acid acetate Melting point: 207-208 ° C calc .: Mole peak (M + Hf: 460/462 (CI) F: Mol peak (M + Hf: 460/462 (CI)

Example 5.37:

(E) -3- (4 - {[(1-Acetyl-piperidin-4-yl) -methyl-amino] -methyl} -phenyl) - / V- (4'-chloro-biphenyl-4-yl) - acrylamide

To a solution of 50 mg (0.087 mmol) of (E) - / V- (4 ^{'chloro-biphenyl-4-yl)} -3- {4 [(methyl-piperidin-

4-yl-amino) -methyl] -phenyl} -acrylamide x trifluoroacetic acid acetate in 4 ml of acetic acid

0.017 ml (0.18 mmol) of acetic anhydride was added and stirred for 18 hours at room temperature.

Then the reaction mixture is poured onto water and basified with ammonia. The precipitate is filtered off and washed with water.

The product is dried at 60 ° C in a convection oven.

Yield: 20 mg (46% of theory)

C30H32CIN3O2 (M = 502.05)

Melting point: 225-226 ° C calc .: Mole peak (M + Hf: 502/504 (CI) Fc: Molepeak (M + Hf: 502/504 (CI)

Example 5.38: (E) -Λ / - (4'-Chlorobiphenyl-4-yl) -3- (4 - {[cyclohexyl-2- (2-hydroxy-ethyl) -amino] -methyl} -phenyl) -acrylamide

To a suspension of 130 mg (0.34 mmol) of (E) -Λ- (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenyl) -acrylamide in 10 ml of dimethylformamide is added 0, 24 g (1.7 mmol) of 2-cyclohexylamino-ethanol was added and stirred at 80 ° C for 48 hours. Subsequently, the reaction mixture is poured onto water and the precipitate was filtered off with suction and washed with water. The solid is dried in a convection oven at 50 ° C. Yield: 20 mg (10% of theory) C30H33Cl2O2 (M = 489.05) Melting point: 178-179 ° C calc .: Mol peak (M + Hf: 489/491 (CI) Fc: Mole peak (M + Hf: 489/491 (CI)

Example 5.39:

(E) - / V- (4'-chloro-biphenyl-4-yl) -3- {4 - [(cyclopentyl-methyl-amino) -methyl] -phenyl} -acryIamid

A reaction mixture of 200 mg (0.523 mmol) of (E) - / V- (4'-chlorobiphenyl-4-yl) -3- (4-chloromethylphenylfacrylamide, 295 mg (1.56 mmol) of cyclopentylmethyl- oxalic acid acetate and 0.44 ml (3.12 mmol) of triethylamine in 5 ml of tetrahydrofuran are refluxed for 18 hours, then the reaction mixture is poured into water and the precipitate is filtered off with suction. methanol 10: 1). yield: 10 mg (4% of theory) C ₂₈ H29CIN ₂ O (M = 445.0).

Melting point: 209-210 ° C calc .: Mole peak (M + Hf: 445/447 (CI) _Ge : Molepeak (M + Hf: 445/447 (CI) The following compounds are prepared analogously to Example 5.3.c:

Claims

Claims Amide compounds of the general formula I in which R1, R2 are independently H, a C^-alky! or C3-7-cycloalkyl group optionally substituted one or more times with the radical R11, where a -CH2 group in Position 3 or 4 of a 5, 6 or 7-membered cycloalkyl group can be replaced by -O-, -S- or -NR13-, or a phenyl or monosubstituted with the radical R12 and/or monosubstituted with nitro Pyridinyl radical, or R1 and R2 form a C2-8 alkylene bridge in which - one or two -CH2 groups can be independently replaced by -CH=N- or -CH=CH- and/or - one or two -CH2 groups can be independently replaced by -O-, -S-, -SO, -(SOzh -C=NO-R18, -CO-, -C(=CH2)- or -NR13- in such a way that heteroatoms are not directly connected to each other, and that a group -C=NO-R18 or -CO- is not directly connected to the group R1R2N-, whereby one or more H atoms can be replaced by R14 in the previously defined alkylene bridge, and wherein the previously defined alkylene bridge can be substituted with one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy - via a single or double bond, - via a common C- Atom to form a spirocyclic ring system, - via two common, neighboring C and/or N atoms to form a fused bicyclic ring system or - via three or more C and/or N atoms to form a bridged ring system, R3 H , C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyI- or phenyl-C1-3-alkyl, X is a single bond or a C1-8-alkylene bridge, in which - a -CH2 group that is not directly connected to the group R1R2N- can be replaced by -CH=CH- or -C≡C- and/or - one or two non-adjacent -CH2 groups that are not connected to the Group R1R2N- are directly connected, can be independently replaced by -O-, -S-, -(SO)-, -(SO2)-, -CO- or -NR4- in such a way that two O-, S- or N atoms or an O and an S atom are not directly connected to one another, whereby the bridge can also be connected to R2 including the N atom connected to R2 and can be connected to each other, and wherein a carbon atom with R10 and / or one or two carbon atoms each with one or two identical or different substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6 -Alkynyl-, Cs-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyI-, C4-7-cycloalkenyl and C4-7-cycloalkenyl-C1-3-alkyl- can be substituted, where two alkyl and / or Alkenyl substituents can be connected to each other to form a carbocyclic ring system, and W means a single bond, where Z -C ≡€-C(=O)-, -CR7a=CR7c-C(=O)- or -CR7aR7b-CR7cR7d- C(=O)- means, or W means -C(=O)-C ≡C-, where Z means a single bond; and Y one of the meanings given for Cy, where can be connected to form a heterocyclic group fused to Y, and / or A one of the meanings given for Cy, whereby in the case that the index b has the value 0, the group Cy does not have an amino group as a substituent in the ortho position to the bridge W; B one of the meanings given for Cy, b the value 0 or 1, Cy a carbo- or heterocyclic group selected from one of the following meanings - a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic Group, - a phenyl group, - a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as a heteroatom, - a saturated or unsaturated 5- to 7-membered group -membered heterocyclic group with two or more N atoms or with one or two N atoms and one O or S atom as heteroatoms, -an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms is selected from N, O and/or S, whereby the previously mentioned 4-, 5-, 6- or 7-membered groups can be fused to a phenyl or pyridine ring via two common, adjacent carbon atoms, and where in the aforementioned 5-, 6- or 7-membered groups, one or two non-adjacent -CH2 groups are independently replaced by a -CO-, -C(=CH2)-, -(SO)- or -(SO )-group can be replaced, and where the saturated 6- or 7-membered groups listed above can also be used as bridged ring systems with an imino, N-(C1-4-alkyl)-imino-, methylene, C1--alkyl-methylene or Di-(C1-4-alkyl)-methylene bridge can be present, and where the aforementioned cyclic groups are connected one or more times on one or more carbon atoms with R20, in the case of a phenyl group also simply with nitro, and / or one or more NH groups can be substituted with R21, R4 one of the meanings given for R17, C2-6-alkenyl or C3.6-alkynyl, R7a, R7c H, F, CI, C1-4-alkyl or CF3, R7b , R7d H, F, C1-4-alkyl, where R7 and R7d in the meaning alkyl can be connected to one another to form a cyclopropyl group; R10 hydroxy, hydroxy-Cι-3-alkyl, C^-alkoxy, C1-4-alkoxy-Cι-3-alkyl-, carboxy, C1-4-Alkoxycarbonyl, amino, C^-alkyl-amino-, di-( Cι-4-alkyl)-amino-, cyclo-C3-6-alkylenimino-, amino-C1-3-alkyl-, C1-4-alkyl-amino-C1-3-alkyl, di-(C1.4-alkyl )-amino-C1.3-alkyl, cyclo-C3.6-alkylenimino-Cι-3-alkyl-, amino-Cι-3-alkoxy-, C1-4-alkyl-amino-C1-3-alkoxy-, Di -(C1-4-alkyl)-amino-Cι-3-alkoxy-, cyclo-C3-6-alkyIenimino-C1-3-alkoxy-, aminocarbonyl-, C1-4-alkyl-aminocarbonyl-, di-(C1^ -alkyl)-aminocarbonyl- or cyclo-C3.6-alkylenimino-carbonyl-, R11 C2.6-alkenyl, C2.6-alkynyl, R15-O-, R15-O-C1-3-alkyl-, R15-O -CO-, R15-CO-O-, Cyano, R16R17N-, R18R19N-CO- or Cy-, R12 one of the meanings given for R20, R13 one of the meanings given for R17, excluding carboxy, R14 halogen, C1-6- Alkyl, C2-6-alkenyl, C2.6-alkynyl, R15-O-, R15-0-CO-, R 5-C0-, R15-CO-O-, R16R17N-, R18R19N-CO-, R15-O -C1-3-alkyl-, R15-O-CO-C1-3-alkyl-, R15-O-CO-NH-, R15-SO2-NH-, R15-O-CO-NH-C1-3-alkyl -, R15-SO2- NH-C1-3-alkyl-, R^-CO-C^-alky!-, R15-CO-O-C1-3-alkyl-, R16R17N-C1-3- alkyl-, R18R19N -CO-C1-3-alkyl- or Cy-C1-3-alkyl-, R15 H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl, phenyl - C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, R16 H, Cι-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7 - Cycloalkenyl, C4-7-cycloalkenyl-Cι-3-alkyl, hydroxy-C2-3-alkyl, Cμ 4-alkoxy-C2-3-alkyl, amino-C2-6-alkyl, Cι-alkyl -amino-C2-6-alkyl-, di-(C1-4-alkyl)-amino-C2-6-alkyl- or cyclo-C3-6-alkyIenimino-C2-δ-alkyl-, R17 one of those specified for R16 Meanings or phenyl, phenyl-C1-3-alkyl, pyridinyl, dioxolan-2-yl, -CHO, C^-alkyl-carbonyl, carboxy, hydroxycarbonyl-C1-3-alkyl-, C1-4-alkoxycarbonyl-, C1- -Alkoxycarbonyl-C1-3-alkyl-, C1-4-alkylcarbonylamino-C2-3-alkyl-, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2-3-alkyl -, C1- -alkylsulfonyl, C1-4-alkylsulfonylamino-C2-3-alkyl or N-(C1-4-alkylsulfonyl)-N(C1^t-alkyl)-amino-C2-3-alkyl-, R18, R19 independently H or C1-6-alkyl, R20 halogen, hydroxy, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3 -alkyl-, hydroxy-C1-4-alkyl, R22-C-3-alkyl or one of the meanings given for R22, R21 C1-4-alkyl, hydroxy-C2-3-alkyl, C1-4-alkoxy-C2- 6-alkyl, C1-4-alkyl-amino-C2-6-alkyl, di-(Cι^-aikyl)-amino-C2-6-alkyl, cyclo-C3-6-alkylenimino-C -6-alkyl -, phenyl-C1-3-alkyl, d^-alkyl-carbonyl, CM-alkoxy-carbonyl or CM-alkylsulfonyl, R22 phenyl-C1-3-alkoxy, cyclo-C3-6-alkylenimino-C2.4-alkoxy -, OHC-, HO- N=HC-, C1- -alkoxy-N=HC-, C1-4-alkoxy, C -alkylthio, carboxy, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, CM- Alkylamino- carbonyl, di-(C1- -alkyl)-aminocarbonyl, cyclo-C3-6-alkyl-amino-carbonyl-, cyclo-C3-6-alkyleneimino-carbonyl, cyclo-C3-6-alkyleneimino-C2- -aIkyl - aminocarbonyl, phenyl-amino-carbonyl, C1-4-Alkyl-sulfonyl, CM-alkyl-sulfinyl, C1-4-alkyl-sulfonylamino-, amino-, C1- -alkyiamino-, di-(C1-4-alkylfamino- , C^-alkyl-carbonyl-amino-, cyclo-C3-6-alkylenimino-, phenyl-C1-3-alkylamino-, N-(C-4-alkyl)-phenyl-C1-3-alkylamino-, Acetylamino-, propionylamino-, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-carbonyl, (I-piperidinyl)carbonyl, (hexahydro-l-azepinyl)carbonyl, (4-methyl-1- piperazinyl) carbonyI, methylenedioxy, aminocarbonylamino- or alkylaminocarbonylamino-, where in the aforementioned groups and radicals, in particular in A, B, W, X, Y, Z, R1 to R4, R7a, R7b, R7c, R7d, R10 to R22, each one or more C atoms can additionally be substituted once or multiple times with F and/or each one or two C atoms independently of one another can additionally be substituted simply by CI or Br and/or each one or more phenyl rings can be independently additionally substituted one, two or three substituents selected from the group F, CI, Br, I, C1-4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C-3-alkylamino, Di-(Cι.3-alkyl)-amino-, acetylamino-, aminocarbonyl-, cyano, difluoromethoxy-, trifluoromethoxy-, amino-C1-3-alkyl-, C1-3-alkylamino-C1-3-alkyl- and di -(C -3-Alkyl)- amino-C1-3-alkyl- can have and / or can be simply substituted with nitro, and the H atom of an existing carboxy group or an H atom bonded to an N atom in each case can be replaced by a residue that can be split off in vivo, mean their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, the following compounds according to the provisions (M1) to (M14) not being included: (M1) N-[4-[[(Methylamino)sulphonyl]methyl]phenyl]-3-[2-(dimethylamino)-ethyl]-1-H-indole-5-propanamide oxalate, (M2) 3-[2-[3-[3,6-dihydro-4-(2-naphthyl)-1(2H)-pyridinyl]-2-hydroxypropoxy]phenyl]-N-methyl-N-phenyI-2 -propenamide, (M3) 3-[2-[2-hydroxy-3-[4-(1-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-N-phenyl-2-propenamide, (M4) 3-[2-[2-hydroxy-3-[4-(2-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-N-phenyl-2-propenamide, (M5) 3-[2-[2-hydroxy-3-[4-(2-naphthyi)-1-piperidinyl]propoxy]phenyl]-N-phenyl-2-propenamide, (M6) N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-3-phenyl-2-propinamide, (M7) 2'-[[3-(dimethylamino)propyl]thio]-3-phenyl-propiolanilide (M8) 2-(Methylthio)-5-[[3-[4-(octadecylamino)phenyl]-1-oxopropyl]amino]-benzoic acid, including the trifluoroacetate salt, (M9) 4-Amino-N-(4-hydroxy-3,5-dimethylphenyl)-benzenepropanamide, (M10) 4-(dimethylamino)-N-(4-hydroxy-3,5-dimethylphenyl)-benzenepropanamide, (M11) /?-methyl-4-[[3-[2-[(2-methylphenyl)amino]-6-benzoxazolyl]-1-oxopropylamino]-benzenepropanoic acid, (M12) 4-[3-[[1 -Oxo-3-[2-(phenylamino)-6-benzoxazolyl]-propyl]amino]phenoxy]-butanoic acid, (M13) 2-Chloro-5-[[1 -oxo-3-[4-[(5-phenylpentyl)amino]phenyl]propyl]amino]-benzoic acid; (M14) 2-Chloro-5-[[1-oxo-3-[4-[(5-phenylpentyl)amino]phenyl]propyl]amino]-benzoic acid methyl ester. 2. Amide compounds according to claim 1 characterized by the formulas la or Ib

wherein R ¹ , R ² , R ³ , X, Y, A, B and b have the meaning according to claim 1. 3. Amide compounds according to claim 1 characterized by the formulas Ic or Id

wherein R ¹ , R ² , R ³ , R ^7a , R ^7b , R ^7c , R ^7d , X, Y, A, B and b have the meaning according to claim 1. 4. Amide compounds according to one or more of the preceding claims, characterized in that R ¹ , R ² are independently C^-alkyl, C _3-7 - Cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, hydroxy-C _2-4 -alkyl-, NC-C ₂ ^-alkyl-, C _1- -alkoxy- C _2-4 -alkyl-,

Amino-C _2-4 -alkyl-, d. 4-Alkyl-amino-C _-4 -alkyl-, di-(C _1-4 -alkyl)-amino-C ₂ ^-alkyl-, cyclo-C _3-6 -alkyleneimino-C ₂ . 4-alkyl-, pyrrolidin-3-yl, where the NH group can be substituted with R ¹³ , pyrrolidinyl-C^-alkyl-, where the NH group can be substituted with R ¹³ , piperidin-3-yl or - 4-yl, where the NH group can be substituted with R ¹³ , piperidinyl-C _1-3 - alkyl-, where the NH group can be substituted with R ¹³ , tetrahydropyran-3-yl or -4-yl, tetrahydropyranyl -C _1-3 -alkyl, tetrahydrofuran-3-yl, tetrahydrofuranyl-Cι _-3 -alkyl, phenyl, phenyl-C _1-3 -alkyl, pyridyl or pyridyl-C _1-3 -alkyI- mean, wherein in the groups and radicals specified above, one or more carbon atoms can be substituted one or more times with F and/or one or two carbon atoms, in particular one carbon atom, can be independently substituted with CI or Br, and where the phenyl or pyridyl radical is one or more times as defined above Rest R ¹² and/or can be simply substituted with nitro, and where cycloalkyl rings can be substituted one or more times with substituents selected from hydroxy, hydroxy-C _1-3 alkyl, C _1-3 alkyl or C _1-3 alkyloxy, and where C _2-4 alkyl bridges have the meanings hydroxy-C ₂ . ₄ -alkyl- and C-ι. ₄ -Alkoxy-C _2- -alkyl- can additionally be simply substituted with hydroxy, hydroxy-C _1-3 -alkyl, C _1-3 -alkyl or Cι _-3 -alkyloxy, and where one of the radicals R ¹ , R ² can also mean H, and where R ¹³ is as defined in claim 1. 5. Amide compounds according to one or more of claims 1 to 3, characterized in that R ¹ and R ² form an alkylene bridge according to claim 1 such that R ¹ R ² N- is a group selected from azetidine, pyrrolidine, piperidine , azepane, 2,5-dihydro-1 H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1 H-azepine, 2,3,6,7-tetrahydro -1 H-azepine, piperazine, in which the free imine function with R ¹³ is substituted, piperidin-4-one-oxime, piperidin-4-one-OC _M -alkyI-oxime, morpholine and thiomorpholine forms, wherein according to claim 1 one or more H atoms can be replaced by R ¹⁴ , and / or which can be substituted in the manner specified in claim 1 with one or two identical or different carbo- or heterocyclic groups Cy, where R ¹³ , R ¹⁴ and Cy have the meaning given in claim 1. Amide compounds according to one or more of the preceding claims, characterized marked that the group

has a meaning according to one of the following partial formulas

where in the heterocycle formed by the group R ¹ R ² N- one or more H atoms through R ¹⁴ and / or an H atom through Cy in the meaning C _3-7 -cycloalkyl, which is one or more times with R ²⁰ can be substituted, can be replaced and where the ring connected to the heterocycle formed by the group R ¹ R ² N- has one or more carbon atoms with R ²⁰ , in the case of a phenyl ring also with one or more carbon atoms Nitro can be substituted, and X', X" independently represent a single bond or C _1-3 alkylene and _{in the} event that the group Y is connected _to X or -Alkylene-N(C _1-3 -alkyl)-, and X" also includes -OC _1-3 -alkylene, -NH-Ci-rAlkylene or -N(C _1-3 -alkyl)-C _1-3 -alkylene and in the case that the group Y is connected to "X" via a carbon atom -NH-, -N(C _1-3 -alkyl)- or -O- means, where _{in the} meanings ^given above for X, _-3 -alkyl- and/or C _1-4 -alkoxy radical, and/or one or two C- Atoms each with one or two identical or different substituents selected from C _1-6 -alkyl-, C _2-6 -alkenyl-, C _2-6 -alkynyl-, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl- C _1-3 -alkyl-, C _4-7 -cycloalkenyl and C ^ -cycloalkenyl-C _1-3 -alkyl- can be substituted, whereby two alkyl and / or alkenyl substituents can be connected to one another to form a carbocyclic ring system , and where in X, wherein R ² , R ¹⁰ , R ¹³ , R ¹⁴ , R ²⁰ , R ²¹ and X have the meanings given in claim 1. 7. Amide compounds according to one or more of the preceding claims, characterized in that X is an unbranched C-u-alkylene bridge and in the event that the group Y is connected to X via a C atom, also a single bond, -CH ₂ -CH=CH-, -CH ₂ -C≡C-, C _2-4 -alkylenoxy or C _{2- 4} -Alkylene-NR ⁴ - means wherein the bridge X can be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and where ⁱⁿ ₆ -alkyl-, C _2- e-alkenyl-, C _2-6 -alkynyl-, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-Cι_ ₃ -alkyl-, C _-7 -cycloalkenyl and C _{4- 7} -Cycloalkenyl-C _1-3 -alkyl- can be substituted, whereby two alkyl and/or alkenyl substituents can be linked together to form a carbocyclic ring system, and where in the above-mentioned groups and residues one or more carbon atoms can be substituted one or more times with F and/or one or two carbon atoms can be independently substituted with CI or Br and wherein R ¹ , R ⁴ and R ¹⁰ are as defined in claim 1. Amide compounds according to claim 7, characterized in that X -CH ₂ -, -CH ₂ - CH ₂ - or -CH ₂ -CH ₂ -CH ₂ - and in the event that the group Y is connected to X via a C atom, also a single bond, -CH ₂ -CH=CH-, -CH ₂ -C=C-, -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -NR ⁴ - or -CH ₂ -CH ₂ -CH ₂ -NR ⁴ - means, wherein the bridge X can be connected to R ¹ including the N atom connected to R ¹ and X to form a heterocyclic group, and ^where _{in _ _} /or one or two carbon atoms each with one or two identical or different substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C ₂ . ₆ -alkynyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _4-7 -cycloalkenyl and C _4-7 -cycloalkenyl-C _1-3 -alkyl can be substituted , where two alkyl and/or alkenyl substituents can be linked together to form a carbocyclic ring system, and where one or more carbon atoms are substituted once or multiple times with F and/or one or two carbon atoms are independently substituted with CI or Br can be and wherein R ¹ , R ⁴ and R ¹⁰ have one of the meanings given in claim 1. 9. Amide compounds according to one or more of the preceding claims, characterized in that the group Y is selected from the group of divalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl , tetrahydro-isoquinolinyl and benzoxazolinyl, where the aforementioned cyclic groups can be substituted one or more times on one or more carbon atoms with R ²⁰ , in the case of a phenyl group also simply with nitro, and/or on one or more N atoms with R ²¹ , where X can be connected to Y as specified in claim 1, and X, R ²⁰ and R ²¹ have the meanings given in claim 1. 10. Amide compounds according to one or more of the preceding claims, characterized in that the group Y is selected from the group of divalent cyclic groups

where the aforementioned cyclic groups can be substituted one or more times on one or more carbon atoms with R ²⁰ , in the case of a phenyl group also simply with nitro, and/or one or more NH groups with R ²¹ , in which R ²⁰ and R ²¹ are as defined in claim 1. 11. Amide compounds according to one or more of the preceding claims, characterized in that the group Y is connected to the group X to form a carbocyclic group fused to Y, the carbocyclic group -X-Y- formed being selected from

where in the bicyclic groups listed above the phenyl ring. one or more times with R ²⁰ or also simply with nitro, and the saturated carbocyclic ring can be substituted once or twice with C _1-3 alkyl. 12. Amide compounds according to one or more of the preceding claims, characterized in that group A means phenyl, pyridyl or naphthyl, wherein the aforementioned cyclic groups can be substituted one or more times on one or more carbon atoms with R ²⁰ , in the case of a phenyl ring also simply with nitro, and/or one or more NH groups with R ²¹ , whereby for the Case that the index b has the value 0, the group A has no amino group as a substituent in the ortho position to the bridge W, and R ²⁰ and R ²¹ have the meanings given in claim 1. 13. Amide compounds according to one or more of the preceding claims, characterized in that b has the value 0. 14. Amide compounds according to one or more of the preceding claims, characterized in that b has the value 1 and B has a meaning selected from the group consisting of phenyl, furanyl, thienyl and pyridyl, where the aforementioned cyclic groups can be substituted one or more times on one or more carbon atoms with R ²⁰ , and in the case of a phenyl ring also simply with nitro, and R ²⁰ has the meaning given in claim 1. 15. Amide compounds according to one or more of the preceding claims, characterized in that Y has a meaning according to claim 9 or 10 and 11, A a meaning according to claim 12, B a meaning according to claim 14 and b has the value 0 or 1. 16. Amide compounds according to claim 15, characterized in that R ¹ , R ² are as defined in claims 4 and 5 or 4 and 6, X is as defined in claim 7 or 8, W and Z are as defined in claims 2 or 3. 17. Amide compounds according to one or more of the preceding claims, characterized in that R ²⁰ F, CI, Br, I, OH, cyano, C^-alkyl, C _1-4 -alkoxy, difluoromethyl, Trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, C _1-3 -alkyl-amino-, di-C _1-3 -alkyl-amino-, carboxy or C _1- -alkoxy-carbonyl, where multiple substituents R ²⁰ are the same or different Can have meanings and in the case of a phenyl ring this can also simply be substituted with nitro. 18. Physiologically tolerable salts of the amide compounds according to one or more of claims 1 to 17. 19. Composition containing at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18 in addition to optionally one or more physiologically tolerated auxiliary substances. 20. Medicament containing at least one amide compound according to one or more of claims 1 to 17 and/or a salt according to claim 18 in addition to optionally one or more inert carriers and/or diluents. 21. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, to influence the eating behavior of a mammal . 22. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for reducing body weight and / or to prevent one Increase in body weight of a mammal. 23. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for the production of a medicament with MCH -Receptor antagonistic activity. 24. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for the production of a medicament which is suitable for the prophylaxis and/or treatment of phenomena and/or diseases that are caused by MCH or have another causal connection with MCH. 25. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for the production of a medicament which is suitable for the prophylaxis and/or treatment of metabolic disorders and/or eating disorders, in particular obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia. 26. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for the production of a medicament which for the prophylaxis and/or treatment of diseases associated with obesity and/or Disorders, especially diabetes, especially type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, heart failure, cardiovascular diseases, especially arteriosclerosis and high blood pressure, arthritis and gonitis. 27. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for the production of a medicament which 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. 28. Use of at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, for the production of a medicament which for prophylaxis and/or Treatment of micturition disorders such as urinary incontinence, overactive urinary bladder, urinary urgency, nocturia, enuresis. 29. A method for producing a composition or a medicament according to one or more of claims 19 to 28, characterized in that at least one amide compound according to one or more of claims 1 to 17 and / or a salt according to claim 18 is prepared non-chemically one or more inert carriers and/or diluents are incorporated. 30. Medicines containing a first active ingredient consisting of the amide compounds according to one or more of claims 1 to 17 and / or a salt according to claim 18, including the compounds excluded by the provisions (M1) to (M14) according to claim 1, is selected and a second active ingredient selected from the group consisting of Active ingredients for the treatment of diabetes, active ingredients for the treatment of diabetic complications, active ingredients for the treatment of obesity, preferably other than MCH antagonists, active ingredients for the treatment of high blood pressure, active ingredients for the treatment of hyperiipidemia, including arteriosclerosis, active ingredients for the treatment of arthritis, active ingredients for the treatment of anxiety and active ingredients for the treatment of depression, in addition to optionally one or more inert carriers and/or diluents.