HRP20050179A2 - Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof - Google Patents

Abstract

The invention relates to carboxamide compounds of the general formula in which the groups and radicals A, B, W, X, Y, Z, R1, R2, R3 and k have the meanings given in claim 1. The invention also relates to processes for the preparation of the above-mentioned carboxamide compounds and on medicaments containing at least one carboxamide according to the invention. Due to their MCH receptor antagonist activity, the drugs according to the invention are suitable for the treatment of metabolic and / or eating disorders, in particular obesity, bulimia, anorexia, hyperphagia and diabetes.

Description

The subject of the proposed invention are new carboxamide compounds, processes for their preparation and their physiologically tolerable salts as well as their use as MCH-antagonists and their use for the production of a drug that is suitable for the prophylaxis and/or treatment of phenomena and/or diseases caused by MCH or are with MCH in a different causal relationship. A further object of the invention relates to the use of the compound according to the invention for influencing the behavior of mammals when taking food and for reducing the body weight and/or for preventing the increase in the body weight of the mammal. Furthermore, the subject of this invention are compositions and medicines which in any case contain the compound according to the invention, as well as processes for their production.

Background of the invention

Taking food and its transformation in the body plays an important role in the life of all living beings. Because of this, deviations in food intake and food conversion usually lead to disorders and also to diseases. Changes in people's lifestyles and eating habits, especially in industrialized countries in recent decades, have favored obesity. In affected people, obesity leads directly to a limitation of mobility and a reduction in the quality of life. In addition, obesity often results in other diseases, such as diabetes, dyslipidemia, high blood pressure, arteriosclerosis and coronary heart disease. In addition, high body weight itself leads to an increased load on the bearing and movement apparatus, which can lead to chronic ailments and diseases, such as arthritis or osteoarthritis. This is why obesity is a serious health problem for society.

The term obesity means an excess of adipose tissue. In this regard, obesity is generally considered to be an increased amount of fat that leads to health hazards. In the latest analyses, it is not possible to draw an exact line between normal individuals and individuals prone to obesity, however, there is an ever-increasing health hazard that is probably associated with an increase in obesity. For the sake of simplification in relation to the proposed invention, individuals with a body mass index (BMI = body mass index) above 25, especially above 30, and which index is defined as body weight measured in kilograms and divided by height, are considered to be individuals prone to gaining weight. (in meters) per square.

Regardless of physical activity and dietary changes, there is currently no convincing possibility for effective weight loss. However, since obesity represents the main risk factor for the development of serious and even life-threatening diseases, it becomes increasingly important to prepare an active substance for the prophylaxis and/or treatment of obesity. More recently, the therapeutic use of MCH antagonists has been proposed (among others in WO 01/21577, WO 01/82925).

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. In mammals, it is synthesized mainly in the hypothalamus and from there it travels to other parts of the brain via the projections of hypothalamic neurons. Its biological action in humans is mediated through two different glycoprotein-linked receptors (GPCRs) from the rhodopsin-related GPCR family, namely MCH receptors 1 and 2 (MCH-1R and MCH-2R).

Research into the function of MCH in animal models gave good indications for the role of the peptide in the regulation of energy balance, i.e. changes in metabolic activity and food intake [1, 2]. For example, after intraventricular administration of MCH to rats, food intake increased compared to control animals. In addition, genetically altered rats, which produce more MHC than control animals, responded after being fed a high-fat diet with a significantly greater weight gain than animals whose amount of MCH was not experimentally altered. It could also be determined that there is a positive correlation between the stages of increased desire for food and the amount of MCH mRNA in the hypothalamus of rats. However, experiments with MCH knock out mice are particularly important regarding the function of MCH. Loss of the neuropeptide results in lean animals with reduced body mass, which take in significantly less food than control animals.

The anorectic effects of MCH in rodents are mediated by Gons-linked MCH-1Rs [3-6]. Unlike primates, weasels and dogs, no other receptor has been demonstrated in rodents so far. After loss of MCH-1R, knock out mice have less fat mass, increased energy expenditure, and when fed a high-fat diet, they do not gain weight compared to control animals. Further indication for the importance of the MCH-MCH-1R system in the regulation of energy balance comes from experiments with receptor antagonists (SNAP-7941) [3]. In long-term experiments, animals receiving antagonists significantly lost weight.

In addition to its anorectic effect, additional anxiolytic and antidepressant effects are achieved in rat behavioral experiments [3] with the MCH-1R antagonist SNAP-7941. Thus, there is clear evidence that the MCH-MCH-1R system is involved not only in the regulation of energy balance, but also affects 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 hormone are hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.

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

4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002. 143(7): p. 2469-77.

5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci 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.

Certain amine compounds have been proposed in the patent literature as MCH antagonists. Thus, compounds of the formula are described in WO 01/21577 (Takeda).

[image]

in which Ar1 represents a cyclic group, X is a spacer, Y is a bond or spacer, Ar is an aromatic ring, which can be condensed with a non-aromatic ring, R1 and R2 are independently H or a hydrocarbon group, where R1 and R2 together with an adjacent N atom can form a hetero ring containing N, and R2 with Ar can also form a spirocyclic ring, R together with an adjacent N atom and Y can form a hetero ring containing N, as MCH antagonists for the treatment of, among other things, obesity.

In addition, compounds of the formula are also described in WO 01/82925 (Takeda).

[image]

in which Ar' represents a cyclic group, X and Y are spacer groups, Ar is an optionally substituted condensed polycyclic aromatic ring, R1 and R2 are independently H or a hydrocarbon group, whereby R1 and R2 together with the adjacent N atom can form heterocyclic rings containing N, and R2 together with the adjacent N atom and Y can form a hetero ring containing N, as MCH antagonists for the treatment of, among other things, obesity.

Further amine compounds with MCH-antagonistic activity are proposed in WO 02/057233 (Schering Corp.). These compounds fall under the general formula

[image]

in which Ar1, Ar2, Ar3 represent, among others, aryl or heteroaryl, X O, S or N-CN, Y is a single bond or C1-4-alkylene, and R1 and R2 have the indicated meanings.

The MCH-antagonistic effect is also described in WO 02/051809 (Schering Corp.) in connection with piperidine derivatives of the formula

[image]

in which W represents a more closely defined aminocarbonyl or carbonylamino group, X is -CHR8, -CO-, -C(=NOR9)- or -CR8=, Y is CH, C(OH), C(C1-4-Alkoxy) or in the case of a double bond at C, R 2 is a substituted aryl or hetero-aryl group, R 10 is H, C 1-6 -alkyl or aryl, and the remaining radicals have the indicated meanings.

Carboxamides as antagonists of human 11CBy receptors are proposed in WO 02/10146 (Smithkline Beecham). These compounds are examples of ethers of the general structural formula

[image]

in which A represents H, alkyl, alkoxy, alkenyl, acyl, halogen, OH, CN or CF3, R3 is H, methyl or ethyl, R4 is optionally substituted aromatic carbocyclic or heterocyclic ring, Z is O, S, NH, CH2 or a single bond, R5 is optionally substituted aromatic, saturated or unsaturated carbocyclic or heterocyclic ring, and Q is the group -X-Y-NR1(R2), while according to different configurations X can be O, S or N, Y is an alkylene or cycloalkylene group , which may also be substituted, and R 1 and R 2 may be alkyl or phenyl-alkyl, wherein R 1 and R 2 , R 1 and Y or R 1 and X may also be linked together to form a ring system, as described.

Further compounds with MCH-antagonistic properties are proposed in published patent applications WO 03/035055, WO 03/033480, WO02/06245, WO 02/04433, WO 01/87834, WO 01/21169 and JP 2001/226269.

Quinazolinone compounds of the general formula

[image]

are described in WO 01/23365 (Merck), where Z represents a bond or phenylene, and in WO 01/23364 (Merck), where Z represents cyclohexylene. In addition, Y represents a bond or C2-4-alkenyl and R4 is aryl, cycloalkyl, phenylalkyl or a heterocyclic system. These compounds are described as GPIbIX inhibitors, particularly as inhibitors of this receptor with von Willebrand factor (vWF) ligands.

In addition, aromatic compounds that may contain an amide bridge and an amine group have been proposed in the literature for other indications. Thus, in WO 99/01127 (Smithkline Beecham Corp.) compounds of the general formula Ar-A-E are described, in which Ar represents an optionally substituted aromatic mono- or bicyclic group, A is an amide or amine bridge and E is, among other things, a phenyl group, which in the para position it can be substituted via the spacer group B with a substituted aminoalkylene group. These compounds are proposed as CCR5 receptor ligands for the treatment of, among others, asthma, superficial diseases and rheumatoid arthritis.

WO 01/72712 (Cor Therapeutics Inc.) describes isoquinoline compounds of the following formula

[image]

in which A represents an optionally substituted amino or amidino group, Z is a bond or an alkyl, cycloalkyl, alkenyl, alkynyl or aryl spacer group, m and n are 0 to 3, D is a bond or the specified bridge, X is NR12 or CHR12, p is 0 to 3, E is also a bond other than the mentioned ether, amine, amide and carboxyl group, J is a bond, cycloalkylene, phenylene, naphthylene or heteroaryl group, G is a more specifically specified amide, imino or amidino group, and the terminated radicals have the indicated meanings. These compounds are proposed as inhibitors of isolated factor Xa as well as of blood coagulation and thus as antithrombotic and thrombolytic active substances.

DE 197 18 181 A1 (Boehringer Ingelheim) proposes disubstituted bicyclic heterocycles of the formula

Ra-A-Het-Ar-E

in which Ra represents a more precisely specified amino group or, if necessary, also R4-SO2-NR5 or a group R4-SO2, wherein R4 and R5 have the given meanings, A is a phenylene-C1-3-alkylene group, n-C2-6-alkylene group or a C5-7-cycloalkylene-C1-3-alkylene group, which may be substituted as indicated, Het is an optionally substituted benzimidazole, indole, tetrahydro-quinolinone or quinazolinone group, Ar is an optionally substituted phenylene, naphthylene, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, and E is cyano or the group RbNH-C(=NH), wherein Rb represents H, OH, C1-3-alkyl or a residue that can be cleaved in vivo. These compounds are proposed as thrombin inhibitors and thrombin time prolonging agents.

Object of the invention

The proposed invention is based on the task of preparing new carboxamide compounds, especially those that have the effect of MCH antagonists. One task of the present invention is also to prepare new carboxamide compounds that enable an effect on the feeding behavior of mammals, and achieve, especially in mammals, a reduction in body weight and/or prevention of an increase in body weight. The task of the proposed invention is furthermore the preparation of new drugs which are suitable for prophylaxis and/or treatment of phenomena and/or diseases caused by MCH or which are otherwise causally related to MCH. This invention is particularly based on the task of providing drugs for the treatment of metabolic disorders, such as obesity and/or diabetes, as well as diseases and/or disorders associated with obesity and diabetes. A further task of the proposed invention relates to proving the beneficial use of the compounds according to the invention. Also, one object of this invention is to provide a process for the production of carboxamide compounds. Further tasks of the proposed invention are immediately apparent to the expert from the above and following embodiments.

The main subject of the invention

The first object of the proposed invention are carboxamide compounds of the general formula I

[image]

where

R1 and R2 independently of each other represent H, C1-8-alkyl or C3-7-cycloalkyl group which is optionally substituted with the group R11 or a phenyl group optionally mono- or polysubstituted with the group R12 and/or monosubstituted with nitro, or

R1 and R2 form a C2-8-alkylene bridge in which

- one or two -CH2- groups can be replaced independently of each other by -CH=N- or -CH=CH- and/or

- one or two -CH2- groups can be replaced independently of each other by -O-, -S-, -CO-, -C(=CH2)- or -NR13- so that the heteroatoms are not directly connected to each other,

while in the alkylene bridge defined above, one or more H atoms can be replaced by R14, and/or

The alkylene bridge defined above can be substituted with one or two identical or different carbo- or heterocyclic Cy groups in such a way that the bond between the alkylene bridge and the Cy groups is formed

- via single or double connection,

- through a common C atom that forms a spirocyclic ring system,

- over two common, adjacent C and/or N atoms that form a condensed bicyclic ring system or

- over three or more C and/or N atoms that form a bridged ring system,

R3 represents H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl-, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-4-alkyl-, phenyl, phenyl -C1-4-alkyl-, C1-3-Alkoxy-C2-6-alkyl-, amino-C2-6-alkyl-, C1-3-alkyl-amino-C2-6-alkyl- or di-(C1- 3-alkyl)-amino-C2-6-alkyl-,

X represents a single bond or a C1-8-alkylene bridge in which

- one or two -CH2- groups can be replaced independently of each other by -CH=CH- or -C≡C- and/or

- one or two -CH2- groups can be replaced independently of each other by -O-, -S-, -(SO)-, -(SO2)-, -CO- or

- -NR4- in such a way that in each case two O, S or N atoms or one O atom and an S atom are not directly connected to each other,

while one or two C atoms can be independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and/ or in each case with one or two identical or different C 1-6 -alkyl groups, and/or

an alkylene bridge may be attached to R1 so as to include the N atom attached to R1 and X, forming a heterocyclic group,

Z represents a C1-4-alkylene bridge, in which two adjacent C atoms with an additional C1-4-alkylene bridge can be interconnected, while in the Z group the -CH2- group can be replaced by -O- or -NR5-,

and one or two C atoms of the alkylene bridge can be substituted independently of each other with a hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl, C1-3-alkoxy group, amino -C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl and/or with one or two identical or different C1- 6-alkyl groups, and/or

R3 may be linked to Z by including an N atom linked to R3 forming a heterocyclic group,

A and Y independently of each other have one of the meanings given for Cy,

while R1 may be linked to Y so as to include a group X and an N atom linked to R1 and X, forming a heterocyclic group fused to Y, and/or

R 3 may be attached to Y so as to include a group Z and an N atom attached to R 3 and Z, forming a saturated or partially unsaturated heterocyclic group fused to Y, or

A and R 3 can be interconnected in such a way that the group of formula I

[image]

represents a group of partial formula II

[image]

and

Q represents a group selected from partial formulas IIIa to IIIg

[image]

L1, L2 and L3 independently of each other have one of the meanings given for R20,

B represents C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7-cycloalkenyl-C1-3-alkyl-, C3-7- cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups can be mono- or polysubstituted with R20, or

B has one of the meanings given for Cy, while the bond with the group W or, if necessary, directly with the group A goes through the C atom of the carbocyclic unit or, if necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit,

while, if k = 0, group B and group A can be interconnected via a common C atom forming a spirocyclic ring system or

via two shared, neighboring atoms that form a condensed, bicyclic ring system,

W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene-oxy -C1-3-alkylene-, imino, N-(C1-3-alkyl)-imino-, imino-C1-3-alkylene-, N-(C1-3-alkyl)-imino-C1-4-alkylene- , C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino- group,

while one or two C atoms can be independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and/ or with one or two identical or different C1-6-alkyl groups, and/or

W defined as alkylene, oxyalkylene and alkyleneoxy-alkylene may also be linked to B via a double bond,

k represents 0 or 1,

Cy represents a carbo- or heterocyclic group selected from the following meanings:

- saturated 3- to 7-membered carbocyclic group,

- unsaturated 5- to 7-membered carbocyclic group,

- phenyl group,

- saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with N, O or S atom as hetero-atom,

- saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms,

- aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S,

while the above-mentioned 4, 5, 6 or 7-membered groups can be linked via two common, adjacent C atoms, fused to a phenyl or pyridine ring, and

in the above-mentioned 5-, 6- or 7-membered groups, one or two non-adjacent -CH2- groups can be replaced by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and

the aforementioned saturated 6- or 7-membered groups may also be present as bridged ring systems with imino, N-(C1-4-4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1- 4-alkyl)-methylene bridge, i

the above-mentioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, and in the case of phenyl groups they can also additionally be mono-substituted with nitro, and/or they can be substituted with R21 on one or more N atoms,

R4 and R5 independently of each other have one of the meanings given for R16,

R 6 , R 7 , R 8 and R 9 independently represent H, C 1-6 -alkyl, ω-C 1-3 -alkoxy-C 1-3 -alkyl or ω-hydroxy-C 1-3 -alkyl, and R 6 , R 7 , R 8 also independently of each other represent halogen,

R11 represents R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-or Cy-,

R12 has one of the meanings given for R20,

R13 has one of the meanings given for R17,

R14 represents halogen, C1-6-alkyl, R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-, R15-O-C1-3-alkyl-, R15-O-CO-C1-3- alkyl-, R16R17N-C1-3-alkyl-, R18R19N-CO-C1-3-alkyl- or Cy-C1-3-alkyl-,

R15 represents H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl, phenyl-C1-3-alkyl- or pyridinyl,

R16 represents H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, C4-6-cycloalkenyl, C4-7-cycloalkenyl-C1-3-alkyl, ω-hydroxy -C2-3-alkyl-, ω-(C1-3-alkoxy)-C2-3-alkyl-, amino-C1-6-alkyl-, C1-3-alkyl-amino-C1-6-alkyl- or di -(C1-3-alkyl)-amino-C1-6-alkyl-,

R17 has one of the meanings given for R16 or represents phenyl, phenyl-C1-3-alkyl-, pyridinyl, dioxolan-2-yl, C1-3-alkylcarbonyl, hydroxycarbonyl-C1-3-alkyl-, C1-4-alkoxy- carbonyl, C1-3-alkylcarbonylamino-C2-3-alkyl-, C1-3-alkyl-sulfonyl- or C1-3-alkylsulfonylamino-C2-3-alkyl-,

R18 and R19 independently represent H or C1-6-alkyl,

R20 represents halogen, hydroxy, cyano, C1-4-alkyl, C3-7-cycloalkyl, hydroxy-C1-3-alkyl, R22-C1-3-alkyl- or has one of the meanings given for R22,

R21 represents C1-3-alkyl, ω-hydroxy-C2-3-alkyl-, phenyl, phenyl-C1-3-alkyl-, C1-3-alkyl-carbonyl, carboxy, C1-4-alkoxy-carbonyl, C1- 3-alkylsulfonyl, phenylcarbonyl or phenyl-C1-3-alkyl-carbonyl,

R22 represents pyridinyl, phenyl, phenyl-C1-3-Alkoxy-, C1-3-Alkoxy, C1-3-Alkylthio, carboxy, H-CO-, C1-3-Alkyl-carbonyl, C1-4-Alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, C1-3-alkyl-sulfonyl-, C1-3-alkyl-sulfinyl-, C1-3-alkyl-sulfonylamino-, amino, C1 -3-alkylamino-, di-(C1-3-alkyl)-amino-, phenyl-C1-3-alkylamino- or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenyl-carbonylamino-, phenylcarbonylmethylamino-, hydroxy-alkyl-aminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)-carbonyl , (4-methyl-1-piperazinyl)carbonyl, methylenedioxy-, aminocarbonylamino- or alkylaminocarbonylamino-,

while in groups and residues A, B, W, X, Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently mono-substituted with Cl or Br, and/or in any case one or more phenyl rings can have mutually independently and additionally one, two or three substituents selected from the group consisting of F, Cl, Br, I, C1 -4-alkyl, C1-4-Alkoxy, difluoro-methyl, trifluoromethyl, hydroxy, amino, C1-3-alkyl-amino-, di-(C1-3-alkyl)-amino-, acetylamino-, amino-carbonyl, CN, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl-, C1-3-alkylamino-C1-3-alkyl- and di-(C1-3-alkyl)-amino-C1-3-alkyl- and/or can be monosubstituted with nitro, i

The H atom of any carboxy group present or the H atom attached to the N atom can be replaced in each case by a group that can be cleaved in vivo,

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

A further subject of the invention are also the respective compounds in the form of individual optical isomers, mixtures of individual enantiomers or racemates, in the form of tautomers as well as in the form of free bases or corresponding acid addition salts with pharmacologically unmistakable acids. The subject of the invention also includes compounds, including their salts, in which one or more hydrogen atoms have been replaced with deuterium.

A further object of the proposed invention is a process for the production of carboxamide compounds of formula I

[image]

in which A, B, W, X, Y, Z, R1, R2, R3 and k have one of the meanings hereinbefore set forth, wherein

if A represents a group R3 which is not related to the group A:

a) in the event that A represents a heterocyclic group with nitrogen which is connected to a carboxamide group through a nitrogen atom, which may also have, in addition to the nitrogen atom and one or more heteroatoms selected from N, O and S, at least one amine compound of the formula I-1

[image]

wherein R1, R2, R3, X, Y and Z have the meanings given above,

reacts with CDT (1,1'-carbonyldi-(1,2,4-triazole)) and at least one secondary amine compound of formula I-2

[image]

in which A, B, W and k have the meanings given above, and the group A has a secondary amine functional group,

in a solvent or in a mixture of solvents in the presence of at least one base, and

b) in other cases, at least one carboxylic acid of formula I-3

[image]

wherein A, B, W and k have the meanings hereinbefore given,

reacts with TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate) and at least one amine compound of formula I-1

[image]

wherein R1, R2, R3, X, Y and Z have the meanings hereinbefore given,

in a solvent or in a mixture of solvents in the presence of at least one base, and

if B represents the group R3 attached to the group A:

a) in the case of the group Q having the meaning -CR6R7- (IIIa), while R6 and R7 are defined as here before, the amine of formula Ia.1

[image]

in which R1, R2, X, Y and Z have the given meanings,

reacts with the ester derivative of o-bromo-methyl-benzoic acid of formula Ia.2

[image]

wherein R 6 , R 7 , W , B and k have the given meanings,

b) in the case of the group Q having the meaning -CR6=CR7- (IIIb), in which R6 and R7 are defined as here before,

isoquinolinone derivative of formula Ib.2

[image]

wherein R 6 , R 7 , W , B and k have the given meanings,

reacts with an electrophilic compound of formula Ib.3

[image]

in which Y and Z have the given meanings, and OMs represents a suitable leaving group, primarily mesylate, which results in an isoquinoline derivative of formula Ib.4

[image]

in which R6, R7, W, B, Y, Z and k have the indicated meanings, and the isoquinoline derivative of formula Ib.4 is further derivatized by known methods, which results in the compound of formula I,

c) in the case of the group Q having the meaning -N=CR8- (IIIc), in which R8 is defined as here before, the phthalazinon derivative of the formula Ic.4

[image]

wherein R 8 , W, B and k have the given meanings,

reacts with the electrophilic compound of formula Ic.5

[image]

in which Y and Z have the indicated meanings, and OMs represents a leaving group, primarily mesylate, which results in the phthalazinon derivative of formula Ic.6

[image]

in which R8, W, B, Y, Z and k have the indicated meanings, and thus obtained phthalazinone derivative of the formula Ic.6 is further derivatized by known procedures, thereby obtaining the formula I in which Q represents -N=CR8- (IIIc),

d) in the case of group Q, which has the meaning -N=N- (IIId), o-amino-benzamide derivative of formula Id.1

[image]

wherein R1, R2, W, B, X, Y, Z and k have the meanings indicated,

reacts in the presence of a suitable nitrite compound and an acid, resulting in a compound of formula I in which Q represents -N=N-,

e) in the case of the group Q having the meaning -CO-NR9- (IIIe), in which R9 is defined as hereinbefore, an o-amino-benzamide derivative of the formula Ie.1

[image]

in which R1, R2, R9, W, B, X, Y, Z and k have the given meanings, reacts in the presence of CDI (carbonyldiimidazole) to obtain a compound of formula I in which Q represents -CO-NR9-,

f) in the case of the group Q having the meaning -CR8=N- (IIIf), in which R3 is defined as hereinbefore, an o-amino-benzamide derivative of the formula If.1

[image]

in which R1, R2, W, B, X, Y, Z and k have the given meanings, reacts with the carboxylic acid R8COOH in which R9 has the given meaning and/or with the corresponding activated derivative of the same carboxylic acid, thereby obtaining a quinazolinone derivative of formula I in where Q represents -CR8=N-,

g) in the case of group Q, which has the meaning -CO- (IIIg) isobenzofurandione derivative of formula Ig.2

[image]

in which W, B and k have the indicated meanings, reacts with the amine of formula Ig.1

[image]

in which R 1 , R 2 , X, Y and Z have the indicated meanings, thereby obtaining a compound of formula I in which Q represents -CO-.

The invention also includes physiologically tolerable salts of the previous and below described carboxamide compounds according to the invention.

The subject of this invention are also compositions containing at least one carboxamide compound and/or salt according to the invention in addition to one or more physiologically tolerable excipients, if necessary.

Furthermore, the subject of the proposed invention are medicines containing at least one carboxamide compound according to the invention and/or a salt according to the invention, if necessary together with one or more inert carriers and/or diluents.

The subject of this invention is also the use of at least one carboxamide compound according to the invention for influencing the feeding behavior of mammals.

The invention also relates to the use of at least one carboxamide compound and/or salt according to the invention for reducing body weight and/or for preventing body weight gain in a mammal.

Also, the subject of the proposed invention is the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug that acts as an MCH receptor antagonist.

The subject of this invention is furthermore the use of at least one carboxamide compound according to the invention and/or salt for the production of a medicament suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally related to MCH.

A further subject of this invention is the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug, which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, especially obesity, bulimia, neurotic bulimia, cachexia, anorexia, neurotic anorexia and hyperphagia.

The subject of this invention is also the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug, which is suitable for the prevention and/or treatment of obesity-related diseases and/or disorders, especially diabetes, especially type II diabetes, complications related to diabetes, which include 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.

Furthermore, the proposed invention relates to the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug suitable for the prevention 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.

Furthermore, the subject of this invention is the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug suitable for the prevention and/or treatment of urinary disorders, such as for example urinary incontinence, overactive bladder, urgency, nocturia and enuresis.

Furthermore, the subject of this invention relates to a process for the production of a drug according to the invention, which is characterized by the fact that at least one carboxamide compound according to the invention and/or a corresponding salt is non-chemically incorporated into one or more inert carriers and/or diluents.

A further subject of this invention is a medicine containing a first active substance selected from carboxamide compounds and/or corresponding salts, as well as a second active substance selected from active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably different from MCH antagonists, active agents for the treatment of high blood pressure, active agents for the treatment of hyperlipidemia, including arteriosclerosis, active agents for the treatment of arthritis, active agents for the treatment of anxiety and active agents for the treatment of depression, as appropriate together with one or more inert carriers and/or diluents.

Description of the invention in detail

Unless otherwise stated, groups, residues, substituents and indices, in particular A, B, W, X, Y, Z, R1 to R9, R11 to R22, L1, L2, L3 and k have one of the preceding and/or below meanings.

A preferred embodiment of the present invention comprises compounds of formula I, wherein

R3 represents H, C1-6-alkyl, C3-7-cycloalkyl, C1-7-cycloalkyl-C1-4-alkyl-, C1-3-alkoxy-C2-6-alkyl-, amino-C2-6-alkyl- , C1-3-alkyl-amino-C2-6-alkyl- or di-(C1-3-alkyl)-amino-C2-6-alkyl-,

B has one of the meanings given for Cy, while the connection to the group W or, if necessary, directly to the group A goes through the C atom of the carbocyclic unit or, if necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit,

while, if k = 0, group B and group A can be interconnected through one common C atom forming a spirocyclic ring system or

over two common, neighboring atoms forming a condensed, bicyclic ring system,

Cy represents a carbo- or heterocyclic group selected from the following meanings:

- saturated 3- to 7-membered carbocyclic group,

- unsaturated 5- to 7-membered carbocyclic group,

- phenyl group,

- saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with N, O or S atom as hetero-atom,

- saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms,

- aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S,

while the above-mentioned 4, 5, 6 or 7-membered groups can be linked via two common, adjacent C atoms, fused to a phenyl or pyridine ring, and

in the above-mentioned 5-, 6- or 7-membered groups, one or two non-adjacent -CH2- groups can be replaced by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and

the aforementioned saturated 6- or 7-membered groups may also be present as bridged ring systems with imino, N-(C1-4-4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1- 4-alkyl)-methylene bridge, i

the aforementioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, and in the case of the phenyl group also additionally monosubstituted with nitro, and/or substituted with R21 on one or more N atoms,

R15 represents H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl or phenyl-C1-3-alkyl-,

R17 has one of the meanings given for R16 or represents phenyl, phenyl-C1-3-alkyl-, dioxolan-2-yl, C1-3-alkyl-carbonyl, hydroxycarbonyl-C1-3-alkyl-, C1-3-alkylcarbonyl- amino-C2-3-alkyl-, C1-3-alkylsulfonyl- or C1-3-alkyl-sulfonylamino-C2-3-alkyl-,

R 22 represents phenyl, phenyl-C1-3-Alkoxy-, C1-3-Alkoxy, C1-3-Alkylthio, carboxy, C1-3-Alkylcarbonyl, C1-3-Alkoxycarbonyl, aminocarbonyl, C1-3-Alkylaminocarbonyl, di-( C1-3-alkyl)-aminocarbonyl, C1-3-alkylsulfonyl, C1-3-alkylsulfinyl, C1-3-alkyl-sulfonylamino-, amino, C1-3-alkyl-amino-, di-(C1-3-alkyl) -amino-, phenyl-C1-3-alkyl-amino- or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-, acetyl-amino-, propionylamino-, phenylcarbonyl, phenylcarbonyl-amino-, phenylcarbonylmethylamino -, hydroxyalkylamino-carbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonyl -amino- or alkylaminocarbonylamino-,

while in groups A, B, W, X, Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently monosubstituted with Cl or Br,

The H atom of any carboxy group present or the H atom attached to the N atom in any case with a group that can be cleaved in vivo may be replaced,

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

According to the first group of preferred embodiments, group A and the residue R3 are not directly connected to each other. Therefore, group A has one of the meanings given for Cy.

According to another group of preferred embodiments, group A and the residue R3 are interconnected in such a way that the group of formula I

[image]

represents a group of partial formula II

[image]

and

Q represents a group selected from partial formulas IIIa to IIIg

[image] .

The values of group Q are preferably selected from partial formulas IIIb, IIId, IIIe, IIIf and IIIg, especially IIId, IIIe, IIIf and IIIg.

Favorable meanings of the substituents R6, R7, R8 and R9 are independently of each other H and C1-4-alkyl-, especially H, methyl or ethyl.

Substituents L1, L2, L3 primarily independently have the following meanings: H, F, CI, Br, CH3, CHF2, CF3, C2H5, C3H7, CH(CH3)2, OCH3, OCHF2, OCF3, OC2H5, OC3H7 and OCH(CH3 )2.

Preferably, only one of the substituents L1, L2, L3 has a meaning other than H, especially one of the meanings previously mentioned as favorable. Particularly advantageously, all three substituents L1, L2, L3 mean H.

First of all, groups R1, R2 represent mutually independent H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, ω-hydroxy-C2-3-alkyl, ω-(C1- 3-Alkoxy)-C2-3-alkyl-, C1-4-Alkoxy-carbonyl-C1-3-alkyl, amino-C2-4-alkyl-, C1-3-alkyl-amino-C2-4-alkyl- or di-(C1-3-alkyl)-amino-C2-4-alkyl-, phenyl or phenyl-C1-3-alkyl-, while in the above-mentioned groups and residues one or more C atoms can be mono- or polysubstituted with F and/or with one or two C atoms can be mutually independently monosubstituted with Cl or Br, and the phenyl group can be mono- or polysubstituted with the above-defined group R12 and/or monosubstituted with nitro.

It is most favorable that the residues R1 and R2 independently represent H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cyclo-alkyl-C1-3-alkyl-, ω-hydroxy-C2-3-alkyl, ω -(C1-3-Alkoxy)-C2-3-Alkyl-, C1-4-Alkoxy-carbonyl-C1-3-Alkyl, wherein the residues R1 and R2 can also mean H.

Also preferably, R1 and R2 also form an alkylene bridge in such a way that the group R1R2N is selected from the group consisting of azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro -pyridine, 2,3,4,7-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, piperazine, where the free imino functional group can be substituted with R13, morpholine and thiomorpholine, whereby , according to the general definition for R1 and R2, one or more H atoms can be replaced by R14, and/or the previously mentioned groups can be substituted with one or two identical or different carbo- or heterocyclic groups Cy in the manner described in the general definition for R1 and R2.

Especially good, group

[image]

has the meaning defined according to one of the following partial formulas

[image]

[image]

[image]

in which one or more H atoms of the heterocycle formed with the group R1R2N- can be replaced by R14 and the ring connected to the heterocycle formed with the group R1R2N can be mono- or polysubstituted on one or more C atoms with R20, and in the case of a phenyl ring, it can also be additionally monosubstituted with nitro.

The most favorable are the groups R1R2N described above in which R1 and R2 with the N atom of the group R1R2N form a pyrrolidine, piperidine or 2,5-dihydro-1H-pyrrole ring, which can be substituted as indicated.

Favorable meanings for the group R14 are C1-4-alkyl-, C1-4-cycloalkyl-, hydroxy-, C1-4-alkoxy, C1-4-alkoxy-C1-3-alkyl-, hydroxy-C1-3-alkyl, C1-4-Alkyl-carbonyl-, C1-4-Alkoxy-carbonyl-, C1-4-Alkoxy-carbonyl-C1-3-Alkyl-, C1-4-Alkoxy-carbonylamino-, C1-4-Alkoxy-carbonylamino- C1-3-alkyl-, amino, (C1-4-alkyl)-amino-, di-(C1-4-alkyl)-amino-, phenyl, phenyl-oxy-, pyridinyl, pyridinyl-oxy.

A preferred piperidine group is substituted with a Cy group and has the structure

[image]

wherein Cy is preferably phenyl, which may be substituted as indicated.

Preferably, the alkylene bridge X has no or at most one -NR4 group. The position of the NR4 group within the alkylene bridge X is chosen primarily so that it together with the amino group NR1R2 or another adjacent amino group does not form an amine functional group or that two N atoms are adjacent to each other. That is why the alkylene bridge, in the case that one -CH2 group is replaced by -NR4-, primarily has the meaning C2-7-alkylene-NR4-C0-5-alkylene, whereby the bridge X has, in addition to N atoms, a maximum of 7 C atoms of the bridge and whereby the C atoms can be substituted in the specified manner.

X means preferably a single bond or an unbranched bridge selected from the group consisting of C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, C1-6-alkylenoxy, carbonyl, carbonyl-C1-6-alkylene or C1-6 -alkylene-amino-, wherein the amino group may be substituted by R 4 , and wherein one or two C atoms may be substituted as specified according to the general definition for X, and/or an alkylene bridge may be linked to R 1 in the manner specified.

Particularly advantageously, X means a single bond, a carbonyl or an alkylene bridge selected from the group consisting of methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, where one or two C atoms can be mutually independently substituted with hydroxy . 4-alkyl radicals, and in each case one or more C atoms can be mono- or multi-substituted with F and/or in each case one or two C atoms can be independently mono-substituted with Cl or Br.

If in the group X one or two C atoms are substituted with a hydroxy and/or C1-3-alkoxy residue, then the substituted C atom is preferably not immediately adjacent to the amino group, especially -NR1R2 or -NR4-.

It is especially advantageous when the bridge X means a single bond, -CH2- or -CH(CH3)-.

In the event that one -CH2- group is replaced by -NR5- in the Z bridge, the position of the NR5 group within the Z group is chosen primarily so that it together with the amino group -NR3- or another adjacent amino group does not form an aminal functional group or are two N atoms adjacent to each other.

A preferred meaning of the bridge Z is methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy and 1,4-butylenoxy, where one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy radical and/or in any case with one or two identical or different C1-4-alkyl residues, and in each case one or more C atoms can be single or multiple substituted with F and/or in each case one or two C atoms can be mutually independently single substituted with Cl or Br and wherein R3 can be connected to Z with the inclusion of the N atom connected to R3 with the formation of a heterocyclic group.

If in group Z one or two C atoms are substituted with a hydroxy and/or with a C1-3-alkoxy residue, then the substituted C atom is preferably not immediately adjacent to the amino group, especially to -NR3- or -NR5-.

Z is particularly advantageously selected from the group consisting of -CH2-, -CH2-CH2-, -CH2-CH(CH2)-, -CH2-C(CH3)2-, -CH(CH3)-CH2-, -C( CH3)2-CH2- and -CH2-O-, especially -CH2-CH2- or -CH(CH3)-CH2-.

According to a particularly advantageous definition, Z is linked to R 3 so that the group of the partial formula

[image]

has a meaning selected from the group consisting of 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,2,5,6-tetrahydropyridin-1,3-ylene and 3-hydroxy-1,3-piperidinylene.

The residue R3 is selected primarily from the group consisting of methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or 2-hydroxy-1-methyl-ethyl, wherein in the mentioned groups one, two or three H atoms may be replaced by F, or R3 is selected from H, amino-C2-3-alkyl, C1-3-alkyl-amino-C2-3-alkyl or di-(C1-3- alkyl)-amino-C2-3-alkyl.

Particularly favorable meanings of the radical R3 are H, methyl or ethyl, especially H or methyl.

Particularly favorable meanings of the radicals R4 and/or R5 are H, C1-4-alkyl, C3-6-cycloalkyl and C3-6-cycloalkyl-C1-3-alkyl, especially H and C1-4-alkyl.

Favorable meanings of the groups R 11 are C 1-6 -cycloalkyl, hydroxy, C 1-4-4 -alkoxy, amino, C 1-4 -alkyl-amino- and di-(C 1-4 -alkyl)-amino-.

A favorable meaning of the group R20 is halogen, hydroxy, cyano, C1-4-alkyl, C3-7-cycloalkyl and hydroxy-C1-3-alkyl. R 20 is particularly preferably F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.

Group Y is selected primarily from a number of divalent cyclic groups consisting of 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1 ... pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydro-pyridinylene, 2,4- and 2,5-pyridinylene or 1,4-piperazinylene, wherein the previously mentioned 5-, 6- or 7 -membered groups can be connected via two common adjacent C atoms condensed with a phenyl or pyridine ring, whereby the previously mentioned cyclic groups can be single or multiple substituted on one or more C atoms with R2, and in the case of a phenyl group also additionally single with nitro, and/or on one or more N atoms with R 21 , and wherein R 1 may be linked to Y and/or R 3 to Y in the manner described in the general definition.

The group Y, which is selected from a number of cyclic structures that make up:

[image]

wherein the cyclic groups can be singly or doubly, preferably singly substituted with R20, preferably with halogen, CF3, C1-4-alkyl and/or C1-4-alkoxy.

Furthermore, the group Y can also be linked to the residue R1 in such a way that the group of the partial formula

[image]

has a meaning selected from the following partial formulas

[image] and [image] .

A preferred meaning of group A is selected from a series of divalent cyclic groups comprising 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1, 3- and 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1,3-pyrrolinilene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydro-pyridinylene, 2,4- and 2,5-pyridinylene, 1,4-piperazinylene, 7-aza-bicyclo[2.2.1]heptane-2 . or a pyridine ring, and wherein the above-mentioned cyclic groups can be single or multiple substituted on one or more C atoms with R20, and in the case of a phenyl group also additionally single with nitro, and/or on one or more N atoms with R21.

The particularly favorable meaning of group A is selected from a series of cyclic structures that make up:

[image]

wherein the cyclic groups can be singly or doubly, preferably singly substituted with R20, preferably with halogen, CF3, C1-4-alkyl and/or C1-4-alkoxy.

In the divalent cyclic groups, which are listed for Y and/or A, mirror image forms are also included in each case, i.e. forms in which the bond with neighboring groups is exchanged, in the case of Y with X and Z, as well as in the case of A with CO and W. So for example 1,4-cyclohexenylene means how

[image] so also [image] .

The divalent cyclic groups Y and A mentioned above include all possible isomers. The above preferred meanings will be explained in more detail below.

The definition of tetrahydropyridinylene includes the meaning of 1,2,3,4-tetrahydropyridin-1,4- and -3,6-ylene, 1,2,3,6-tetrahydropyridin-1,4-, -2,5- and -3, 6-ylene, 2,3,4,5-tetrahydropyridin-2,5- and -3,6-ylene. A preferred meaning is 1,2,3,6-tetrahydropyridin-1,4-ylene.

The definition of dihydropyridinylene includes the meaning of 1,4- and 1,2-dihydro-pyridin-1,4-ylene as well as 1,2-, 1,4-, 1,6-, 2,3-, 2,5-, 3 ,4-, 4,5- and 5,6-dihydropyridin-2,5-ylene. Here, the preferred meaning is 1,2-dihydropyridin-1,4-ylene.

Preferred groups A and/or B are unsubstituted or mono- or di-substituted with R 20 , particularly preferably they are unsubstituted or mono-substituted with R 20 .

Group B which is preferred according to the first preferred form is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7 -cycloalkenyl-C1-3-alkyl-, C3-7-cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, in which one or more C atoms can be singly or multiply substituted with halogen and/or singly with hydroxy or cyano and/or cyclic groups may be singly or multiply substituted with R20, and

W means a single bond, -O-, C1-4-alkylene-, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene- oxy-C1-3-alkylene-, imino-, N-(C1-3-alkyl)-imino-, imino-C1-4-alkylene-, N-(C1-3-alkyl)-imino-C1-4- alkylene-, C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino group, whereby one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy- by C1-3-alkyl, ω-(C1-3-alkyloxy)-C1-3-alkyl and/or a C1-3-alkyl radical and/or with one or two identical or different C1-4-alkyl radicals, and

k is 0 or 1, especially 1, and

R20 has one of the above meanings.

In the above preferred meanings for B, k preferably has the value 1 and W preferably has the meaning of a single bond, imino- or N-(C1-3-alkyl)-imino-, especially a single bond.

In this case, particularly advantageously, the group B represents C3-6-alkynyl, especially C3-6-alk-1-ynyl, and/or the group W represents a single bond, where k = 1.

The preferred meaning for group B is according to another form derived from the series consisting of the cyclic groups cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydro-pyridinyl, dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl and thienyl, wherein the bond to to the W group or, if necessary, directly to the A group via the C atom of the carbocyclic part or, if necessary, the co-condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic part, or B, together with the W group connected via a double bond, is selected from the group consisting of cyclo-pentylidene-methyl, cyclohexylidene-methyl and cyclohexanone-4-ylidene-methyl, and wherein the aforementioned cyclic s blackberry can be singly or multiply substituted on one or more C atoms with R20, and in the case of a phenyl group also additionally singly substituted with nitro, and/or on one or more N atoms with R21.

A particularly preferred meaning of group B is phenyl, which is singly, doubly or triply, preferably singly or doubly substituted with R 20 .

With the above definitions for B, all possible isomers of the respective groups are included. Thus, the following isomers are included in particular: cyclopenten-1-, 3- and 4-yl, cyclo-hexanon-4-yl, cyclohexen-1-, 3- and 4-yl, cyclohepten-1-, 3-, 4- and 5-yl, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrole-1-yl, piperidin-1- and 4-yl, pyridin-2-, -3 - and -4-yl, azepan-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, quinolin-2-, 3-, 4 -, 5-, 6-, 7- and 8-yl, isoquinolin-1-, 3-, 4-, 5-, 6-, 7- and 8-yl, 1H-benzoimidazol-1-, 2-, 4 -, 5-, 6- and 7-il.

The definition of pyrazole includes the 1H-, 3H- and 4H-pyrazole isomers. Preferably, pyrazolyl means 1H-pyrazol-1-yl.

The definition of imidazole includes the 1H-, 2H- and 4H-imidazole isomers. Imidazolyl is preferably 1H-imidazol-1-yl.

The definition of tetrahydropyridine includes the 1,2,3,4-, 1,2,3,6- and 2,3,4,5-tetrahydropyridine isomers. In particular, tetrahydropyridinyl means 1,2,3,4- and 1,2,3,6-tetrahydro-pyridin-1-yl.

The definition of dihydropyridine includes the isomers 1,2-, 1,4-, 2,3-, 2,5- and 4,5-dihydropyridine. Dihydropyridinyl means primarily 1,2- and 1,4-dihydropyridin-1-yl.

The definition of triazole includes isomers of 1H-, 3H- and 4H-[1,2,4]-triazole as well as 1H-, 2H- and 4H-[1,2,3]-triazole. The definition of triazolyl thus includes 1H-[1,2,4]-triazol-1-, 3- and 5-yl, 3H-[1,2,4]-triazol-3- and 5-yl, 4H-[1, 2,4]-triazol-3-, 4- and 5-yl, 1H-[1,2,3]-triazol-1-, 4- and 5-yl, 2H-[1,2,3]-triazole -2-, 4- and 5-yl as well as 4H-[1,2,3]-triazol-4- and 5-yl.

The term tetrazole includes the 1H-, 2H- and 5H-tetrazole isomers. The definition of tetrazolyl thus includes 1H-tetrazol-1- and 5-yl, 2H-tetrazol-2- and 5-yl as well as 5H-tetrazol-5-yl.

The definition of indole includes the 1H- and 3H-indole isomers. The term indolyl means primarily 1H-indol-1-yl.

The definition of isoindole includes the isomers 1H- and 2H-isoindole. The term isoindolyl means primarily 2H-isoindol-2-yl.

In general, the bond to one of the above-mentioned heterocyclic groups, especially to pyrazolyl, imidazolyl, tetrahydropyridinyl, dihydropyridinyl, triazolyl, tetrazolyl, indolyl or isoindolyl group can go through the C atom or, if necessary, through the N atom of the imine functional group.

Group B is preferably unsubstituted, or is mono-, di- or tri-substituted with R 20 . Particularly advantageously, B is mono- or doubly substituted with R 20 . In the case that B represents a substituted four-membered ring, the substituent is primarily in the para position relative to the bond with the group

[image]

The index k may have a value of 0 or 1. In the preferred case of k = 1, the bridge W has the indicated meaning, preferably the meaning of a single bond, -CH2- or -CH=. A preferred meaning of the partial formula -A-W-B is selected from the structures listed below, wherein V represents a C or N atom, preferably a C atom, and the said cyclic groups may be mono- or multi-substituted on one or more C atoms with R20, and in in the case of a phenyl or phenylene group also additionally single with nitro:

[image]

[image]

Particular preference is given to compounds of formula I, in which k = 1, and W is a single bond.

The index k can also have a value of 0. According to the first sub-version, group A is connected to group B through a common C atom with the formation of a spirocyclic ring, while group A represents saturated 5- to 7-membered, and group B saturated 4- to 7-membered -membered carbo- or heterocyclic group, and wherein the heterocyclic groups have in each case an N, O or S atom, and wherein a phenyl or pyridine ring can be condensed via two adjacent C atoms on the 5- to 7-membered group B, and whereby the above-mentioned cyclic groups can be singly or multiply substituted on one or more C atoms with R20, and in the case of a condensed phenyl ring also additionally singly substituted with nitro, and/or on one or more N atoms with R21.

The meaning of the partial formula -A-W-B which is preferred according to this second sub-version is selected from the structures listed in the following table, wherein the mentioned cyclic groups can be mono- or multi-substituted on one or more C atoms with R20, and in the case of a fused phenyl ring also additionally single with nitro:

[image]

According to another sub-version in the case that k = 0, group B is connected to group A via two common, adjacent atoms with the formation of a condensed, bicyclic saturated, unsaturated or aromatic, 8- to 12-membered ring system, which may contain one or several identical or different heteroatoms selected from N, O and/or S, and whereby the bicyclic ring system can be singly or multiply substituted on one or more C atoms with R20, and in the case of co-condensed phenyl psten also additionally singly substituted with nitro, and/ or on one or more N atoms with R21.

The meaning of the partial formula -A-W-B which is preferred according to this first sub-version is selected from the structures listed in the following table, whereby the mentioned cyclic groups can be single or multi-substituted on one or more C atoms with R20, and in the case of a phenyl ring also and additionally single with nitro.

[image]

Preferred compounds according to the invention are those in which one or more groups, residues, substituents and/or indices have one of the above preferred meanings.

A preferred meaning of the substituent R20 is selected from the group consisting of fluorine, chlorine, bromine, CF3, C1-4-alkyl, C1-4-alkoxy.

Special preference is given to those compounds according to the invention in which

Y and A are mutually independently selected from the series consisting of bivalent cyclic groups 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2,3,6-tetrahydro- pyridin-1,4-ylene, 2,5-pyridinylene and 1,4-piperazinylene, while A may also be attached to R 3 according to claim 3, and the aforementioned cyclic groups may be mono- or polysubstituted by R 20 at one or more C atoms, in the case of a phenyl group it may additionally be monosubstituted with nitro, and/or may be substituted with R21 on one or more N atoms,

B represents phenyl or cyclohexyl, while the aforementioned groups can be mono- or polysubstituted by R20 and/or the phenyl ring can additionally be monosubstituted by nitro, while R20 has the meaning given in claim 1, and

k has the value 1,

W is a single bond, -CH2- or -CH=, i

Z represents -CH2-CH2-, -CH2-CH(CH3)-, -CH2C(CH3)2-, -CH(CH3)-CH2-, -C(CH3)2-CH2- or -CH2-O- or

is connected to R3 in such a way that the group of the partial formula

[image]

of formula I has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene.

Particular preference is given to compounds according to the invention of the following groups of formulas I.1 to I.14:

[image]

[image]

[image]

in which

U and V independently represent C or N,

R23 and R24 independently represent H, F, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl,

while in formulas 1.1 to 1.6 the radical R24 can be connected to R3 in such a way that the group of the partial formula

[image]

has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene, and

R 25 , R 26 R 27 independently of each other have the meanings given to R 20 according to claim 1 or 2 or in the case of a phenyl group also simply represent nitro, while the groups R 25 , R 26 and R 27 appearing more than once can have the same or different meanings, and

j is 0, 1, 2, 3 or 4 and

m, n represent 0, 1 or 2 independently of each other.

A very special preference is given to compounds according to the invention of the above formulas I.1, I.2, I.8, I.10 and I.12. In particular, a particular advantage can be attributed to the compounds of the following formulas

[image]

[image]

whereby residues and substituents have the meanings defined above and below.

Furthermore, preference is given to compounds according to the invention of the following partial formula:

[image]

where

B is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7-cycloalkenyl-C1-4-alkyl- , C3-7-cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups may be mono- or polysubstituted by R20, i

W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene-oxy -C1-3-alkylene-, imino, N-(C1-3-alkyl)-imino-, imino-C1-4-alkylene-, N-(C1-3-alkyl)-imino-C1-4-alkylene- , C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino group, while one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3 -alkyl, ω-(C1-3-Alkoxy)-C1-3-Alkyl and/or C1-3-Alkoxy group and/or with one or two identical or different C1-4-Alkyl groups, and

k represents 0 or 1.

Furthermore, according to this embodiment, preference is given to such compounds in which group B is selected from the group consisting of C1-6-alkyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl- or C3-7 -cycloalkenyl-C1-4-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups can be mono- or polysubstituted with R20, and/or

W represents a single bond, -O-, imino, N-(C1-3-alkyl)-imino-, while one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω- (C1-3-Alkoxy)-C1-3-Alkyl and/or C1-3-Alkoxy group and/or with one or two identical or different C1-4-Alkyl groups, and

k represents either 1.

Special priority is given to group meanings

-W-B according to this embodiment which is selected from the group consisting of C1-8-alkyl, -C≡C-C1-6-alkyl, -CH=CH-C1-6-alkyl, -O-C1-6-alkyl, -NH(C1-6-alkyl) and -N(C1-6-alkyl)(C1-3-alkyl), especially from the group consisting of C3-8-alkyl, -C≡C-C3-6-alkyl, - CH=CH-C3-6-alkyl, -O-C3-6-alkyl, -NH(C3-6-alkyl) and -N(C3-6-alkyl)(C1-3-alkyl).

Among the compounds according to the invention previously described, particular preference is given to those, especially partial formulas I.1 to I.15, in which the residues R1, R2, R3, L1, L2, L3 and/or the group X have in each case the meanings which is preferred.

In particular, particular preference is given to those compounds according to the invention in which X is selected from -CH2-, -CH(CH3)- or -C(CH3)2-.

Also, special preference is given to those compounds of partial formulas I.1 to I.15 in which

a) group U is an N atom, and group V is a C atom, or

b) group U is a C atom, and group V is an N atom, or

c) both groups U and V represent a C atom in each case.

In the compounds according to the invention which are given particular preference, the substituents R25, R26, R27 have a mutually independent meaning selected from the series consisting of F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso -propyl, methoxy, difluoromethoxy, trifluoro-methoxy, ethoxy, n-propoxy or iso-propoxy, and in the case of substitution of the phenyl group also single nitro, whereby the residues R25, R26, R27, which appear more than once, can have the same or different meanings, j is 0, 1 or 2, m and n are independently 0 or 1.

The meanings of the residues R6, R7, R8 and/or R9, which are preferred in the compounds according to the invention, are independently of each other H, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl, and in the case of R6, R7, also F.

Particular advantage is given to individual compounds that are selected from the group they comprise

(1) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(2) 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one

(3) 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-tri-fluoromethyl-phenyl)-3H-quinazolin-4-one

(4) 7-(4-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(5) 7-(3,4-dichloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(6) 7-(4-fluoro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(7) 7-(4-ethyl-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(8) 2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazolin-4-one

(9) 2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one

(10) 7-(4-chloro-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(11) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1 H-quinazoline-2,4-dione

(12) 7-(4-chloro-phenyl)-3-{2-[4-((S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

(13) 7-(4-chloro-phenyl)-3-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(14) 7-(4-chloro-phenyl)-3-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(15) 7-(4-chloro-phenyl)-3-[2-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(16) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-benzo[d][1,2,3]triazin-4- he

(17) 5-(4-fluoro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-isoindol-1,3-dione

(18) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(19) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-diethyl-aminomethyl-phenyl)-ethyl]-amide

(20) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide

(21) 4'-methoxy-biphenyl-4-carboxylic acid [2-(4-di-ethylaminomethyl-phenyl)-ethyl]-amide

(22) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-diethyl-aminomethyl-phenyl)-ethyl]-methyl-amide

(23) 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(24) 4-methylphenyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(25) 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]amide

(26) 4-(4-chloro-phenyl)-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(27) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide

(28) 4'-chloro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-benzyloxy)-amide

(29) 4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(30) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(31) 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one

(32) 4'-chloro-biphenyl-4-carboxylic acid {2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide

(33) 7-(3-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

(34) 4-(4-oxo-cyclohexyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(35) 4-cyclohexyl-1-cylohexylcarboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(36) 4-benzyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(37) 4-cyclohexyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(38) 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(39) 4-(4-fluoro-phenyl)-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(40) 4-(4-Methoxy-phenyl)-piperazine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(41) 4-phenyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(42) (4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-1-yl]-methanone

(43) 4'-chloro-biphenyl-4-carboxylic acid [2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide

(44) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide

(45) 4-benzyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(46) 4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(47) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(48) 5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one

(49) 4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(50) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][ 1,2,3]-triazin-4-one

(51) 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-quinazolin-4 -he

(52) 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-benzo[d ][1,2,3]triazin-4-one

(53) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

(54) 7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4 -he

(55) 6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one

(56) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(57) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(58) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide

(59) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide

(60) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-aza-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-phenyl]-ethyl}-amide

(61) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1,3-dihydro-isoindol-2-ylmethyl)-phenyl]-ethyl}-amide

(62) 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(di-isopropylamino)-methyl]-phenyl}-ethyl)-amide

(63) 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

(64) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-di-methylaminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

(65) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-di-methylamino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

(66) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(67) 4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(68) 4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide

(69) 4'-chloro-biphenyl-4-carboxylic acid [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide

(70) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(71) 2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(72) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

(73) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-amino-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

(74) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-methyl-2,6-diaza-spiro[3.4]oct-6-ylmethyl)-phenyl]-ethyl}-amide

(75) 4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide

(76) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(77) 4'-bromo-biphenyl-4-carboxylic acid {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

(78) 4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

(79) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(80) 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

(81) 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(82) 4'-ethyl-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(83) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-2-ylmethyl]-carbamate

(84) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-methyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

(85) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-{2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

(86) 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(cyclo-propyl methyl-amino)-methyl]-phenyl}-ethyl)-amide

(87) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethyl}-amide

(88) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-ethyl]-amide

(89) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-3-yl]-carbamate

(90) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

(91) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-azetidin-1-ylmethyl-phenyl)-ethyl]-amide

(92) 3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(93) 4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-yl methyl-phenyl)-ethyl]-amide

(94) 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(95) 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(96) 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(97) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

(98) 4'-bromo-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

(99) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-amide

The above-mentioned individual compounds number (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), ( 11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23) , (24), (25), (25), (26), (27), (28), (29), (30), (47) as well as (50) to (99).

In the following, some terms used above and below to describe compounds according to the invention will be more fully defined.

The term halogen means an atom selected from F, Cl, Br and I.

The term C1-n-alkyl, where n has a value from 3 to 8, means a saturated, branched or unbranched carbon-hydrogen group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C1-n-alkylene, where n can have a value from 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2-CH2-), 1-methyl-ethylene (-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2 -CH2-), n-prop-1,3-ylene (-CH2-CH2-CH2-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop- 1,3-ylene (-CH2-CH(CH3)-CH2-), etc., as well as corresponding mirror-symmetric forms.

The term C2-n-alkenyl, where n has a value of 3 to 6, means a branched or unbranched hydrocarbon group with 2 to n C atoms and at least one C=C double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 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, 2,4-hexadienyl, 5-hexenyl, etc.

The term C 1-n -Alkoxy means an -O-C 1-n -alkyl group, wherein C 1-n -alkyl is defined as 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 C1-n-alkylthio means a -S-C1-n-alkyl group, wherein C1-n-alkyl is defined as above. Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert-pentylthio, n- hexylthio, iso-hexylthio, etc.

The term C1-n-alkylcarbonyl means a -C(=O)-C1-n-alkyl group, wherein C1-n-alkyl is defined as 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-pentyl- carbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C3-n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term C3-n-cycloalkylcarbonyl means a -C(=O)-C3-n-cycloalkyl group, wherein C3-n-cycloalkyl is defined as above.

The term aryl means a carbocyclic, aromatic ring system, such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc.

The term heteroaryl, as used in this application, denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, includes one or more heteroatoms selected from N, O and/or S. Examples of such groups are furanyl, thiophenyl (thienyl) , 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, benz-isoxazolyl, purinyl, quinazolinyl, quinozylinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The term heteroaryl also includes the moiety ohmically hydrogenated heterocyclic, aromatic ring system, partially those listed above. Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.

The terms aryl-C1-n-alkyl, heteroaryl-C1-n-alkyl, etc. refer to C1-n-alkyl, as defined above, which is substituted with an aryl or heteroaryl group. Many of the terms given above may be used more than once in the definition of a formula or group and in each case may have one of the meanings given above independently of each other.

The term "unsaturated carbocyclic group" or "unsaturated heterocyclic group", as used partially in the definition of the group Cy, in addition to fully unsaturated groups, also includes corresponding only partially unsaturated groups, especially mono- and diunsaturated groups.

The term "optionally substituted", which is used in this application, means that the group thus constructed is not substituted or is mono- or polysubstituted with the specified substituents. If the group in question is poly-substituted, the substituents may be the same or different.

The residues and substituents described above may be mono- or polysubstituted with fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups 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, predominantly carboxyl groups, and/or basic groups such as, for example, amino functional groups. The compounds of the general formula I can therefore exist as internal salts, as salts with pharmaceutically useful inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, sulphonic acid, or with organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useful bases such as hydroxides or carbonates of alkali or alkaline earth metals, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, among others.

The compounds according to the invention can be obtained using synthesis methods that are known in principle. Preferred compounds are obtained by the preparation process described above and explained more fully below.

In the preparation process according to the invention for obtaining the first group of embodiments that are given preference, i.e. those compounds in which group A and group R3 are not directly connected to each other, two cases are fundamentally distinguished.

The first case includes those compounds of the formula I in which the group A denotes a heterocyclic group with nitrogen that is connected via a nitrogen atom to a carboxamide group, which, in addition to the nitrogen atom, may additionally contain one or more heteroatoms selected from N, O and S. Reaction of amines of formula 1 -1 with secondary amine of formula I-2 is shown in the following general reaction scheme:

Reaction scheme 1:

[image]

Preferably, the amine compound of formula 1-1 is first reacted with CDT (1,1'-carbonyl-(1,2,4-triazole)) in a solvent or solvent mixture and then the reaction mixture is further reacted with the amine compound of formula I-2, while a minimal amount of base is added to the reaction mixture before and/or after the reaction of the amine compound with CDT. The amine compound of formula 1-1 reacts with CDT favorably in the temperature range from -20°C to 20°C and then this reaction mixture reacts with the amine compound of formula I-2 in the temperature range from 40°C to 100°C in the molar ratio of the amine compound of formula I-1: to the amine compound of formula I-2 : CDT : base of 1±0.25 : 1±0.25 : 1±0.25 : 3±1.5. First of all, a nitrogen-containing base, especially tert, is used as a base. amine, such as for example triethylamine.

The amine compound of formula I-2 can be a saturated N-heterocyclic compound, such as, for example, a piperazine derivative according to the following reaction scheme 2.

Reaction scheme 2

[image]

The second case of the preparation procedure includes other compounds of formula I that are not covered by case 1, whereby group A is not directly connected to R3. The reaction of the carboxylic acid compound of formula I-3 with TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluranium-tetrafluoroborate) and the amine compound of formula I-1 in a solvent or solvent mixture in the presence of at least of one base is shown in reaction scheme 3.

Reaction scheme 3:

[image]

First of all, the carboxylic acid, the compound of formula I-3 is reacted with TBTU in a solvent or solvent mixture and then the reaction mixture is further reacted with the amine compound of formula I-1, while the minimum amount is added to the reaction mixture before and/or after the reaction of the carboxylic acid compound with TBTU amount of base. Suitable activated carboxylic acid derivatives, such as for example esters, ortho-esters, carboxylic acid chlorides or anhydrides, can also be used instead of the carboxylic acid. A nitrogen-containing base, especially a tert-amine, such as triethylamine, is primarily used. The carboxylic acid compound of the formula I-3 reacts favorably with TBTU and then this reaction mixture is used with the amine compound of the formula I-1 in the temperature range from 0°C to 60°C in the molar ratio of the carboxylic acid compound of the formula I-3: amine compound of the formula 1-1 : TBTU : base from 1±0.25 : 1±0.25 : 1+0.25 : 1 to 4.

The starting compound of formula I-3 can be obtained by methods known to the expert. Thus, biaryl compounds can be obtained by Suzuki coupling, for example starting from p-bromoarylcarboxylic acid derivatives and arylboronic acid derivatives in the presence of Pd[0] catalyst.

In the preparation process according to the invention for the second group of preferred embodiments, i.e. those compounds in which group A is connected to group R3, seven cases are distinguished, depending on the meanings of IIIa to IIIg for group Q.

According to the first case, in which Q stands for -CR6R7- (IIIa), the amine compound of formula Ia.1 reacts with the o-bromo-methyl-benzoic acid derivative of formula Ia.2, as shown in the following reaction scheme 4, in which they are omitted for clarity substituents L1, L2, L3 on the phenyl ring.

Reaction Scheme 4:

[image]

Preferably, the o-bromo-methyl-benzoic acid ester derivative of formula Ia.2 is reacted with an amine compound of formula Ia.1 in a solvent or solvent mixture, whereby at least one base is added. Instead of the o-bromo-methyl-benzoic acid ester derivative of formula Ia.2, other suitable o-benzyl-benzoic acid ester derivatives (iodine or mesylate instead of bromine) can also be used. Potassium carbonate or cesium carbonate can be advantageously used as a base, but tert bases are also common. amines such as triethylamine. The o-bromo-methyl-benzoic acid ester derivative of the formula Ia.2 in acetonitrile with the amine of the formula Ia.1 and with potassium carbonate as a base in the temperature range of 40-80°C is used primarily in a molar ratio of the o-bromo-methyl ester derivative -benzoic acids of formula Ia.2: amine of formula Ia.1: potassium carbonate of 1+0.25: 1+0.25: 3+0.50.

According to the second case in which Q denotes -CR8=R7- (IIIb), the isoquinolinone derivative of the formula Ib.3 reacts with the electrophilic compound of the formula Ib.4, resulting in the isoquinoline derivative of the formula Ib.5, which is further derivatized by known procedures, resulting in compound of formula I. The isoquinolinone derivative of formula Ib.3 can be obtained from the cinnamic acid derivative of formula Ib.1 by reaction with (EtO)2P(O)N3. The synthesis of the basic substance was described by M. Becker et al. in Bioorganic & Medicinal Chemistry Letters 9 (1999), 2753-2758. The reaction is shown in the following reaction scheme 5, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.

Reaction Scheme 5:

[image]

A compound of formula Ib.2 is advantageously prepared by the sequential reaction described hereinbelow. The acrylic acid derivative Ib.1 is first reacted with a chlorinating agent such as thionyl chloride, phosphorus pentachloride or oxalyl chloride, without a solvent or, if necessary, in an inert solvent such as dichloromethane, which gives the acid chloride at a temperature between 0°C and 80 °C. By adding sodium azide in a solvent or solvent mixture, it is converted into an acrylic acid azide derivative. For example, dioxane, tetrahydrofuran or water can be used as a solvent. First of all, the isocyanate derivative Ib.2 is synthesized directly by the action of phosphoric acid diphenyl ester azide on the acrylic acid derivative Ib.1 in the presence of a base in a solvent at a temperature between 0oC and 150oC. Suitable solvents include for example toluene or dioxane. Tertiary amines such as for example triethylamine can be used as bases. The time of the above reaction is between one and twelve hours. Advantageously, the reaction of acrylic acid derivative Ib.1 with phosphoric acid diphenyl ester azide and triethylamine in a molar ratio of 1±0.25 : 1±0.25 : 1±0.25 takes place in toluene as a solvent. The isocyanate derivative Ib.2 is heated in a solvent as needed in the presence of a base such as, for example, tributylamine, whereby the isoquinolone derivative of the formula Ib.3 is formed. First of all, the reaction takes place in diphenyl ether in the melting point range. Heat sources that can be used are oil, metal baths or a microwave heater.

The reaction of the isoquinolone derivative of the formula Ib.3 with the mesylate derivative of the formula Ib.4, which gives the isoquinolone derivative of the formula Ib.5, is carried out in a solvent in the presence of a base at a temperature between 0°C and 150°C. Advantageously, the reaction of the isoquinolone derivative Ib.3 with the mesylate derivative of the formula Ib.4 and sodium hydride in a molar ratio of 1±0.25 : 1±0.25 : 1±0.25 takes place in DMF as a solvent. The isoquinolone derivative of formula Ib.5 first reacts in a solvent in the presence of an acid, which converts the acetal into the corresponding aldehyde. It is converted to a compound of formula Ib in the presence of a hybridizing agent, an amine, and an acid in the solvent. Examples of hybrid conversion agents include, for example, sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. Advantageously, the reaction of the aldehyde, released from the isoquinolone derivative Ib.5, with the amine and sodium cyanoborohydride in a molar ratio of 1±0.25 : 1±0.25 : 0.8±0.25 takes place in methanol and acetic acid at a temperature around 20°C.

The synthesis of isoquinolines of formula Ib, including starting compounds and subsequent derivatization to obtain amines, will be shown with the following scheme of the synthesis of a specific compound, while the synthesis of educt 1 can be seen in the following diagram 6 for the preparation of phthalazinone (diagram 8).

Reaction Scheme 6:

[image]

According to the third case in which Q denotes -N=CR8- (IIIc), the phthalazinon derivative of the formula Ic.4 reacts with the electrophilic compound of the formula Ic.5, thereby obtaining the phthalazinon derivative of the formula Ic.6, which is further derivatized by methods known to obtaining a compound of formula Ic. The phthalazinon derivative of formula Ic.4, for R8 = hydrogen, can be obtained starting from the phenyloxazole derivative of formula Ic.1 by acylation, which gives the o-oxazolyl-benzaldehyde derivative of formula Ic.2, and then by cyclization, which gives 3-hydroxy-3H-isobenzofuran -1-one derivative of formula Ic.3. The synthesis of the basic substance is described by M. Napoletano et al., Bioorganic & Medicinal Chemistry Letters 12 (2002), 5-8.

The reaction for obtaining compounds of the general formula Ic is shown in the following reaction scheme 7, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.

Reaction Scheme 7:

[image]

The above reaction sequences are described in more detail below. The oxazoline derivative Ic.1 is metalized using a suitable organometallic reagent and then reacted with a formaldehyde equivalent such as for example dimethylformamide or orthoformate at a temperature between -70°C and 20°C, preferably at a temperature between -20°C and 0°C, thus obtaining the compound of formula Ic.2. Suitable solvents include for example dioxane, tetrahydrofuran or diethyl ether. By the action of aqueous sulfuric acid in a solvent such as, for example, ethanol at a temperature close to the boiling point of the solvent or in a mixture of solvents for a period of one to 24 hours, a compound of the general formula Ic.3 can be obtained. The phthalazinon derivative of formula Ic.4 can be obtained by reacting the compound of formula Ic.3 with hydrazine in acetic acid and, if necessary, in a solvent at a temperature in the range between 20 and 120 degrees Celsius. The synthesis to obtain the phthalazinone derivative of formula Ic is carried out analogously to the reactions described for the synthesis of compounds of general formula Ib.

The synthesis of phthalazinone derivatives of formula Ic, especially the starting compounds and then the derivatization will now be shown using the synthesis scheme 8 for a specific compound in which the abbreviations have the following meanings: LAH stands for lithium aluminum hydride, BuLi is n-butyllithium, DMF is dimethylformamide , MeOH is methanol and Ms-Cl is methanesulfonic acid chloride.

Reaction scheme 8

[image]

According to the fourth case, in which Q stands for -N=N- (IIId), the o-amino-benzamide derivative of formula Id.1 reacts in the presence of a suitable nitrite compound and an acid via a diazonium intermediate, thereby obtaining a benzotri-azinone derivative of formula Id. The reaction is shown in the following reaction scheme 9, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.

Reaction Scheme 9:

[image]

Preferably, the compound of general formula Id.1 is reacted in a solvent, such as for example methanol, in the presence of an inorganic acid, for example hydrochloric acid, and a salt containing nitrite ions at a temperature between -10°C and 30°C. The reaction of the amino compound Id.1 with sodium nitrite in a molar ratio of 1±0.25 : 1.5±0.25 takes place advantageously in methanol as a solvent and in the presence of hydrochloric acid.

According to the fifth case, in which Q stands for -CO-NR9- (IIIe), the o-amino-benzamide derivative of formula Ie.1 is reacted in the presence of CDI to give the quinazolinedione derivative of formula Ie. CDI is added to the benzamide derivative of formula Ie.1 in a molar ratio greater than or equal to 1 and the reaction is carried out at least partially in the temperature range from 35°C to 100°C, preferably in the range of the boiling temperature of the reaction mixture. The reaction is shown in the following reaction scheme 10, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.

Reaction scheme 10:

[image]

According to the sixth case, in which Q denotes -CR8=N- (IIIf), the o-amino-benzamide derivative of formula If.1 reacts with the carboxylic acid R8COOH and/or with the appropriate activated carboxylic acid derivative, thereby obtaining the quinazolinone derivative of formula If. Suitable activated carboxylic acid derivatives are for example esters, ortho-esters, carboxylic acid chlorides and anhydrides. If necessary, the activated carboxylic acid is added to the carboxamide compound of the formula If.1 in a molar ratio greater than 1 or equal to 1, and the reaction takes place at least partially in the temperature range from 35°C to 100°C, preferably in the temperature range of the boiling point of the reaction mixture . The reaction is shown in the following reaction scheme 11, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.

Reaction scheme 11:

[image] I

The synthesis of the quinazolinone derivative of the formula If, especially the starting compounds, will be shown using the synthesis scheme of the specific compound 12, in which the following abbreviations are used: CDI is carbonyldiimidazole, TBTU is 2-(1H-benzo-triazol-1-yl)-1,1 ,3,3-tetramethyluronium tetrafluoroborate and NEt3 is triethylamine. First, the synthesis schemes for the two starting compounds 1 and 2 are presented.

Reaction scheme 12

[image]

[image]

The starting compounds 1 and 2 are connected to each other via an amide bond using TBTU. The nitro group in the ortho position to the amide bond is obtained by reduction, which gives the amine in the presence of PtO2. Cyclization to obtain quinazolinone is carried out using a carboxylic acid, in this case formic acid.

According to the seventh case in which Q denotes -CO- (IIIg), the isobenzofurandione derivative of the formula Ig.2 reacts with the amine compound of the formula Ig.1 to obtain the isoindoledione derivative of the formula Ig. The reaction is shown in the following reaction scheme 13, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.

Reaction Scheme 13:

[image]

The isobenzofurandion derivative Ig.2 reacts in a solvent, such as acetic acid for example, with the amine of the general formula Ig.1 in a molar ratio of 1±0.25 : 1.5±0.25. The temperature during the reaction is primarily the temperature of the boiling point of the solvent.

However, the isoindoledione derivative of the formula Ig can also be obtained according to the following synthesis scheme 14. Any expert can easily apply the synthesis of the individual compound, as shown, to other compounds of the formula Ig, and modify it as necessary. First of all, the isoindoledione functional group is obtained from the isobenzofurandione derivative by amine binding, and then the aryl group is further added by Suzuki coupling in the presence of Pd[0].

Reaction scheme 14

[image]

The above-described possible procedures for the synthesis of the compounds according to the invention can be easily modified and/or supplemented by a person skilled in the art for the individual compounds to be synthesized, at least as far as the breadth of their representation is concerned, using known procedures as described for example in Houben-Weyl, Methoden der organischen Chemistry.

In the reactions described above, any reactive group present, such as a hydroxy, carboxy, amino or imino group, can be protected during the reaction by methods known from the literature with the usual protecting groups being cleaved off again after the reaction; in particular, protecting groups commonly used in peptide chemistry can be used. Information on this can be found, for example, in WO 98/11128.

Stereoisomeric compounds of formula (I) can be separated in principle by usual procedures. Diastereomers can be resolved on the basis of their different physicochemical properties, eg by fractional crystallization from suitable solvents, high pressure liquid chromatography or column chromatography, using a chiral or preferably non-chiral stationary phase.

As already mentioned, the compounds of formula (I) can be translated into their salts, especially for pharmaceutical use into their physiologically and pharmacologically acceptable salts. These salts can be, on the one hand, in the form of physiologically and pharmacologically acceptable acid addition salts of compounds of formula (I) with inorganic or organic acids. On the other hand, in the case of acid-bonded hydrogen, the compound of formula (I) can also be converted by reaction with an inorganic base into physiologically and pharmacologically acceptable salts with cations of alkali or alkaline earth metals as ions of opposite charge. Acid addition salts can be produced, for example, using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, mixtures of the above-mentioned acids can also be used. For the preparation of salts of alkali and alkaline earth metals and compounds of formula (I) with acid-bonded hydrogen, hydroxides and hydrides of alkali and alkaline earth metals are primarily used, with preference being given to hydroxides and hydrides of alkali metals, especially sodium and potassium, and the greatest preference is given to sodium and potassium hydroxide.

The compounds according to the proposed invention, including their physiologically acceptable salts, are effective as antagonists of the MCH receptor, especially the MCH-1 receptor, and they show good affinity in MCH receptor binding studies. Pharmacological test systems for MCH-antagonistic properties are described in the following experimental section.

As MCH receptor antagonists, the compounds according to the invention are advantageously suitable as pharmaceutically active substances for the prevention and/or treatment of symptoms and/or diseases caused by MCH or diseases that are somehow causally related to MCH. In general, the compounds according to the invention have low toxicity, they are well absorbed orally and they have intracerebral transitivity, especially availability to the brain.

Therefore, MCH antagonists containing at least one compound according to the invention are particularly suitable for mammals, such as for example rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys, and also humans, for treatment and/or prevention of symptoms and/or diseases that are caused by MCH or otherwise causally related to MCH.

Diseases caused by MCH or otherwise causally related to MCH are in particular metabolic disorders, such as for example obesity, and eating disorders, such as for example bulimia, including bulimia nervosa. Indications of obesity include especially exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity. These indication areas also include cachexia, anorexia and hyperphagia. The compounds of the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behavior and/or inducing satiety.

Additionally, diseases caused by MCH or otherwise causally related to MCH also include hyper-lipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety states, reproductive disorders, memory disorders, forms of dementia and hormonal disorders.

The compounds according to the invention are also suitable as active substances for the prevention and/or treatment of other diseases and/or disorders, especially those accompanying obesity, such as for example diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia , complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, abnormal glucose tolerance, cardiovascular diseases, especially arteriosclerosis and high blood pressure, and gonitis.

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

Another field of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of micturition disorders, such as for example urinary incontinence, overactive bladder, nocturia, enuresis, while overactive bladder and urinary incontinence may or may not be associated with benign hyperplasia prostate.

The dosage required to achieve such an effect is usual, intravenously or subcutaneously 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, and orally or nasally or by inhalation 0.01 to 50 mg/kg of body weight , preferably 0.1 to 30 mg/kg of body weight, in any case 1 to 3 times a day.

For this purpose, the compounds of formula I produced according to the invention may be formulated, optionally together with other active substances as described below, together with one or more physiologically acceptable excipients, with inert conventional carriers and/or diluents, such as are, for example, corn starch, lactose, glucose, 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 suitable mixtures thereof for the production of conventional galenic preparations such as flat or coated tablets, capsules, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments or suppositories.

In addition to pharmaceutical compositions, the invention also includes compositions containing at least one carboxamide compound according to the invention and/or a salt according to the invention, if necessary together with one or more physiologically acceptable auxiliary agents. Such compositions can also be, for example, foodstuffs which can be solid or liquid, and in which the compound according to the invention is incorporated.

In the above-mentioned combinations, as additional active substances can be used especially those which, for example, enhance the therapeutic effect of the MCH antagonist according to the invention in terms of one of the above-mentioned indications and/or which enable a reduction in the dosage of the MCH antagonist according to the invention. First of all, one or more additional active substances are chosen from the series that make up

- active substances for the treatment of diabetes,

- active substances for the treatment of diabetic complications,

- active substances for the treatment of obesity, preferably different from MCH antagonists,

- active substances for the treatment of high blood pressure,

- active substances for the treatment of hyperlipidemia, including arteriosclerosis,

- active substances for the treatment of arthritis,

- active substances for the treatment of anxiety states,

- active substances for the treatment of depression.

The categories of active substances mentioned above will now be explained in more detail by means of examples.

Examples of active substances for the treatment of diabetes are insulin sensitizers, agents for accelerating insulin secretion, biguanides, insulins, α-glucosidase inhibitors, β3 adreno-receptor agonists.

Insulin sensitizers include pioglitazone and its salts (primarily hydrochlorides), troglitazone, rosiglitazone and its salts (primarily maleate), JTT-501, Gl-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP -297, R-119702, GW-1929.

Agents for accelerating insulin secretion include sulfonylureas, such as for example tolbutamide, chlorpropamide, trazamide, acetohexamide, glidlopyramid and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of agents for accelerating insulin secretion are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.

Biguanides include metformin, buformin and phenformin.

Insulins include those obtained from animals, especially bovine or porcine, semi-synthetic human insulins synthesized enzymatically from animal-derived insulin, human insulin obtained by genetic engineering, eg from Escherichia coli or yeasts. In addition, the term insulin also includes insulin-zinc (containing 0.45 to 0.9 wt. percent zinc) and protamine-insulin-zinc which can be obtained from zinc chloride, protamine sulfate, and insulin. Insulin can also be obtained from insulin fragments or derivatives (eg INS-1, etc.).

Insulin can also include different types, e.g. in terms of time of onset of effect and duration of effect ("ultra immediate action type", "immediate action type", "two phase type", "intermediate type", "prolonged action type", etc.) which are chosen depending on the pathological condition of the patient.

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

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

Active substances for the treatment of diabetes other than those mentioned above include ergocet, pramlintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide .

Active substances for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors and protein kinase C inhibitors.

Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-SOi, AS-3201.

One example of a glycation inhibitor is pimagedin.

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

Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, tiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).

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

An example of a preferred lipase inhibitor is orlistat.

Examples of preferred anorectics are phentermine, mazindole, dexfenfluramine, fluoxetine, sibutramine, baiamin, (S)-sibutramine, SR-141716, NGD-95-1.

Active substances other than those mentioned above for the treatment of obesity include lipstatin.

In addition, for the purpose of this application, active substances from the group of active substances against obesity also include anorectics, which must include β3 agonists, thyromimetic active substances and NPY antagonists. The purpose of the anti-obesity or anorectic active agents preferred herein is exemplified in the following additional list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, cholecystokinin-A (hereinafter referred to as CCK-A) agonist, monoamine reuptake inhibitor (such as sibutramine), sympathomimetic agents, serotonergic agents (such as dexfenfluramine or fenfluramine), dopamine antagonists (such as bromocriptine), melanocyte-stimulating hormone receptor agonist or mimetic, melanocyte-stimulating hormone analog, cannabinoid receptor antagonist, MCH antagonist, OB protein (hereinafter referred to as leptin), leptin analog, leptin receptor agonist, gatanin antagonist, GI lipase inhibitor or reducer (such as orlistat). Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin-binding protein antagonists, glucagon-like peptide 1 receptor agonists, such as exendin, and ciliary neurotrophic factors, such as axokines.

Active agents for the treatment of high blood pressure include angiotensin-converting enzyme inhibitors, calcium antagonists, potassium channel openers, and angiotensin II antagonists.

Angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temokapril, trandolapril, manidipine (hydrochloride).

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

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

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

Active substances for the treatment of hyperlipidemia, 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 salts thereof.

Fibrate compounds include bezafibrate, clinofibrate, clofibrate, and simfibrate.

Active substances for the treatment of arthritis include ibuprofen.

Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.

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

The dosage of these active substances is usually 1/5 of the lowest normally prescribed dose up to 1/1 of the normal prescribed dose.

In another embodiment, the invention also relates to the use of at least one carboxamide compound according to the invention and/or a salt according to the invention for influencing the feeding behavior of a mammal. This use is based in particular on the fact that the compounds of the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and/or inducing satiety. Eating behavior is favorably influenced by reducing food intake. For this reason, the compounds according to the invention are taken primarily for weight reduction. Another use according to the invention is the prevention of weight gain, for example in people who have previously taken steps to reduce weight and are interested in maintaining their lower body weight. According to this embodiment, non-therapeutic use is preferred. Such non-therapeutic use may be a cosmetic use, for example to change the external appearance, or an application to improve general health. The compounds of the invention are preferably used non-therapeutically for mammals, especially humans who do not suffer from any diagnosed eating disorder, who are not diagnosed with obesity, bulimia, diabetes and/or who are not diagnosed with micturition disorders, especially urinary incontinence. In particular, the compounds of the invention are suitable for non-therapeutic use in humans whose BMI (body mass index), defined as their body weight in kilograms divided by their height (in meters) squared, is below 30 , especially under 25.

The following examples are intended to illustrate the invention.

Previous notes:

As a rule, melting points, 1H-NMR and/or mass spectra were obtained for the produced compounds. Unless stated otherwise, Rf values were determined using 60 ready-to-use silica gel TLC plates F254 (E. Merck, Darmstadt, product no. 1.05714) without saturating the chamber. Rf values were obtained using DC ready-made F254 alumina 60 TLC plates (E. Merck, Darmstadt, product no. 1.05713) without saturating the chamber.

The above HPLC data were measured under the following parameters:

Column Zorbax (Agilent Technologies), SB (Stable Bond) - C18; 3.5 μm; 4.6 x 75 mm; column temperature: 30°C; flow rate: 0.8 ml/min; injection volume: 5 μl; detection at 254 nm.

Procedure A: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 for 9 minutes.

Procedure B: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 for 4 minutes, then 6 minutes 1:9:0.01

If no specific configuration information is given, it remains an open question whether these are pure enantiomers or whether partial or even complete racemization has occurred.

The following abbreviations are used above and below:

BOC-anhydride tert-butyloxycarbonyl-anhydride

GDI carbonyldiimidazole

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

DMF dimethylformamide

ethyl acetate/EtOAc ethyl acetate

ether diethyl ether

HOBt 1-hydroxybenzotriazole hydrate

Hünig's base N,N-diisopropyl-ethylamine

conc. concentrated

Me methyl

MeOH methanol

RT room temperature (approx. 20°C)

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

THF tetrahydrofuran

eq. equivalent

calc. calculated

fnd. found

General working procedure I (TBTU connection):

Triethylamine (1.5 eq.) and TBTU (1.0 eq.) were added sequentially to a solution of the carboxylic acid (1.0 eq.) in THF or DMF. Depending on the carboxylic acid, the mixture is stirred for 10 minutes to 12 hours between room temperature and 40°C before the addition of the amine (1.0 eq.). The reaction mixture is stirred for 30 minutes to 2 hours between room temperature and 40°C, and then half-saturated NaHCO3 solution is added. After extraction of the aqueous phase with a suitable solvent (eg ethyl acetate), the organic phase is dried over magnesium sulfate. The solvent was removed on a rotary evaporator; further purification is performed by column chromatography or HPLC. The reaction can also be carried out in a Chemspeed automatic synthesis device.

General working procedure II (CDT connection):

CDT (1 eq.) was added to a solution of the primary amine (1.0 eq.) in DMF (1 mol/ml) at 0 °C and the mixture was stirred at 0 °C for another 30 min. The reaction mixture was heated to 25°C and triethylamine (3 eq.) was added. Secondary amine (1.0 eq.) in DMF (0.25 mol/ml) is then added and the reaction solution is heated for 30 min to 3 days at 60 to 80°C. DMF is removed in vacuo and the residue is taken up with dichloromethane and 5% Na2CO3 solution or with water and tert-butylmethyl ether. The organic phase is extracted with water and the solvent is removed on a rotary evaporator, if necessary after drying over magnesium sulfate; further purification is done by column chromatography or crystallization. The reaction can also be carried out in a Chemspeed automated synthesizer.

Example 1.1:

7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.1.a. 4-bromo-2-nitro-benzoic acid

To the reaction mixture of 82 g (0.379 mol) of 4-bromo-2-nitro-toluene in 700 ml of pyridine and 500 ml of water, 174.5 g (1.104 mol) of potassium permanganate were added in portions over eight hours. The reaction mixture was stirred for 12 hours at 60°C. A further 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are then successively added. The reaction mixture was stirred for 12 hours at 60°C, mixed with 200 ml of ethanol and refluxed for 30 minutes. The reaction mixture is then filtered hot and the filtrate is evaporated on a rotary evaporator. The residue is basified with 10% sodium hydroxide solution and extracted with diethyl ether. The aqueous phase is separated and acidified with dilute hydrochloric acid. The resulting crystals are filtered off, washed with water, azeotropically dried with tetrahydrofuran and mixed with diisopropyl ether.

Yield: 37 g (32.8% of theoretical).

C7H4BrNO4 (M = 246.018)

Calculated: molecular weight (M+Na)+: 268/270

Found: molecular weight (M+Na)+: 268/270

Rf value: 0.46 (silica gel, dichloromethane/methanol/acetic acid 8:2:0.1)

1.1.b. 4'-chloro-3-nitro-biphenyl-4-carboxylic acid

0.288 g (0.25 mmol) of tetrakis-(triphenylphosphine)-palladium, 1.25 g (7.99 mmol) of 4-chloro-phenyl-boronic acid in 30 ml of methanol and 2.31 g (21.7 mmol) of sodium of carbonate in 14 ml of water is added successively to a solution of 1.92 g (7.81 mmol) of 4-bromo-2-nitro-benzoic acid in 30 ml of dioxane. The reaction mixture is heated for one hour at 110°C in a microwave heater at 300 Watts. The reaction mixture is then evaporated on a rotary evaporator, the residue is taken up in water and adjusted to pH 3 with 1 M hydrochloric acid. The aqueous solution was extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off on a rotary evaporator and the residue is mixed with diisopropyl ether.

Yield: 2.04 g (93.9% of theoretical).

C13H8ClNO4 (M = 277.666)

Calculated: molecular weight (M-H)-: 276

Found: molecular weight (M-H)-: 276

Rf value: 0.5 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.1.c. Ethyl 4-cyanomethyl-benzoate

To a solution of 147.5 g (2.263 moles) of potassium cyanide in 250 ml of hot water, a solution of 500 g (2.057 moles) of ethyl 4-bromo-methyl-benzoate in 1000 ml of ethanol is added drop by drop. The reaction mixture is refluxed for one hour and stirred for another 12 hours at room temperature. A further 73.7 g (0.5 mol) of potassium cyanide was added and the mixture was refluxed for two hours. The solids in the reaction mixture are filtered off and the filtrate is filtered through a mixture of silica gel and activated carbon. The resulting filtrate is evaporated and the residue is poured into 1000 ml of water. The aqueous solution was extracted with tert-butylmethyl ether and the organic phase was extracted three times with water. Then the organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator. Purification is performed by chromatography on a silica gel column (petroleum ether/ethyl acetate 8:2).

Yield: 164.46 g (42.2% of theoretical).

C11H11NO2 (M = 189.216)

Calculated: molecular weight (M+H)+: 190

Found: molecular weight (M+H)+: 190

Rf value: 0.3 (silica gel, petroleum ether/ethyl acetate 8:2)

1.1.d. 4-cyanomethyl-benzoic acid

A solution of 10 g (53 mmol) of ethyl 4-cyanomethyl-benzoate and 2.02 ml of a 1 M sodium hydroxide solution in 100 ml of ethanol is refluxed for one hour. The reaction solution was evaporated and the residue was mixed with ice water. Concentrated hydrochloric acid is added drop by drop to the reaction solution until the formation of a precipitate stops. The precipitate is filtered off, washed twice with water and dried.

Yield: 4.7 g (55% of theoretical).

C9H7NO2 (M = 161.162)

Calculated: molecular weight (M-H)-: 160

Found: molecular weight (M-H)-: 160

1.1.e. (4-hydroxymethyl-phenyl)-acetonitrile

5.17 g (32 mmol) of CDI was added to a solution of 4.7 g (29 mmol) of 4-cyanomethyl-benzoic acid in 250 ml of tetrahydrofuran and stirred until gas evolution ceased. This reaction mixture is added drop by drop to a solution of 3.29 g (87 mmol) of sodium borohydride in 200 ml of water in such a way that the temperature does not rise above 30°C. This is stirred for two hours and the reaction mixture is adjusted to pH 3-4 with potassium hydrogen sulfate solution. It is then extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator.

Yield: 2.6 g (60.9% of theoretical).

C9H9NO (M = 147.178)

Calculated: molecular weight (M-H)-: 146

Found: molecular weight (M-H)-: 146

1.1. f. (4-bromo-methyl-phenyl)-acetonitrile

0.86 ml (9 mmol) of phosphorus tribromide was added dropwise at 0°C to a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile in 25 ml of tert-butylmethyl ether. At the end of the reaction, the reaction mixture is mixed with water at room temperature, the organic phase is separated and extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator.

Yield: 2.9 g (78.1% of theoretical).

C9H8BrN (M = 210.075)

Calculated: molecular weight (M+H)+: 209/211

Found: molecular weight (M+H)+: 209/211

1.1.g. (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile

0.446 ml (5.44 mmol) of pyrrolidine and 1.366 g (9.882 mmol) of potassium carbonate were added to 20 ml of dimethylformamide. With stirring, 1.038 g (4.941 mmol) of (4-bromo-methyl-phenyl)-acetonitrile was added and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated on a rotary evaporator and the residue was extracted with ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator.

Yield: 0.732 g (74% of theoretical).

C13H16N2 (M = 200.286)

Calculated: molecular weight (M+H)+: 201

Found: molecular weight (M+H)+: 201

Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.1.h 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine

The reaction mixture of 0.73 g (3.66 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile and 0.1 g of Raney nickel in 25 ml of methanolic ammonia solution is hydrogenated for 9 h at 50oC and 3 bar hydrogen pressure .

Yield: 0.72 g (96.4% of theoretical).

C13H20N2 (M = 204.31)

Calculated: molecular weight (M+H)+: 205

Found: molecular weight (M+H)+: 205

Rf value: 0.23 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.1.i. 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

A solution of 0.4 (1.44 mmol) 4'-chloro-3-nitro-biphenyl-4-carboxylic acid, 0.29 g (1.44 mmol) 2-(4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine, 0.46 g (1.44 mmol) TBTU, 0.19 g (1.44 mmol) HOBT and 0.42 ml (3 mmol) triethylamine in 30 ml tetrahydrofuran were stirred for 14 hours at room temperature. The reaction mixture is evaporated on a rotary evaporator, extracted with water and ethyl acetate and dried over magnesium sulfate. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia = 90:10:1).

Yield: 0.47 g (70.3% of theoretical).

C26H26ClN3O3 (M = 463.96)

Calculated: molecular weight (M+H)+: 464/466

Found: molecular weight (M+H)+: 464/466

Rf value: 0.36 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.1.j. 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl methyl-phenyl)-ethyl]-amide

The reaction mixture of 0.47 g (1.01 mmol) of 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide and 0.1 g of Raney nickel in 50 ml of methanolic ammonia solution is hydrogenated for 24 hours at 20°C and 3 bar of hydrogen pressure. The crude product reacts further without purification.

Yield: 0.46 g, raw.

C26H28ClN3O (M = 433.98)

Calculated: molecular weight (M+H)+: 434/436

Found: molecular weight (M+H)+: 434/436

Rf value: 0.34 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.1.k. 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

0.46 g (1.06 mmol) of 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide and 5 ml of formic acid is mixed for 3 hours at room temperature and 2 hours at 100oC. The reaction mixture is mixed with water, made alkaline with 6N sodium hydroxide solution and the precipitate is filtered off with suction. The precipitate is taken up in dichloromethane and dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator and the residue is triturated with diisopropyl ether.

Yield: 0.3 g (64.6% of theoretical).

Melting point: 178-179°C

C27H26ClN3O (M = 443.98)

Calculated: molecular weight (M+H)+: 444

Found: molecular weight (M+H)+: 444

Rf value: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.2

3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one

[image]

1.2.a. 4'-methyl-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-methyl-phenyl-boronic acid.

Yield: 1.48 g (70.8% of theoretical).

C14H11NO4 (M = 257.24)

Calculated: molecular weight (M-H)-: 256

Found: Molecular Weight (M-H)-: 256

Rf value: 0.54 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.2.b. 4'-methyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.i from 4'-methyl-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.

Yield: 0.51 g (78.3% of theoretical).

C27H29N3O3 (M = 443.55)

Calculated: molecular weight (M+H)+: 444

Found: molecular weight (M+H)+: 444

Rf value: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.2.c. 4'-methyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.j from 4'-methyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.2 g (69.2% of theoretical).

C28H31N3O (M = 413.56)

Calculated: molecular weight (M+H)+: 414

Found: molecular weight (M+H)+: 414

Rf value: 0.36 (silica gel, dichloromethane/methanol/aminoniacin 9:1:0.1)

Example 1.3:

3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoro-methyl-phenyl)-3H-quinazolin-4-one

[image]

1.3.a. 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-trifluoromethyl-phenyl-boronic acid.

Yield: 1.24 g (49% of theoretical).

C14H8F3NO4 (M = 311.21)

Calculated: molecular weight (M-H)-: 310

Found: molecular weight (M-H)-: 310

R1 value: 0.3 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.3.b. 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.i from 4'-trifluoro-methyl-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.

Yield: 0.36 g (49.3% of theoretical).

C27H26F3N3O3 (M = 497.52)

Calculated: molecular weight (M+H)+: 498

Found: molecular weight (M+H)+: 498

R1 value: 0.3 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.3.c. 4'-trifluoromethyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

The reaction mixture of 0.1 g (0.2 mmol) of 4'-trifluoro-methyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide and 0.08 g of platinum oxide in 50 ml of ethyl acetate is hydrogenated for 2.5 h at 20oC. The catalyst is filtered off. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia = 90:10:1).

Yield: 0.06 g (63.8% of theoretical).

C27H28N3N3O (M = 467.53)

Calculated: molecular weight (M+H)+: 468

Found: molecular weight (M+H)+: 468

Rf value: 0.46 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.4:

7-(4-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.4.a. 4'-Methoxy-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-methoxy-phenyl-boronic acid.

Yield: 0.38 g (48.9% of theoretical)

C14H11NO5 (M = 273.24)

Calculated: molecular weight (M-H)-: 272

Found: molecular weight (M-H)-: 272

Rf value: 0.39 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.4.b. 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.j from 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.

Yield: 0.23 g (57% of theoretical).

C27H29N3O4 (M = 459.55)

Calculated: molecular weight (M+H)+: 460

Found: molecular weight (M+H)+: 460

Rf value: 0.48 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.4.c. 4'-methoxy-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.09 g (42% of theoretical).

C27H31N3O2 (M = 429.56)

Calculated: molecular weight (M+H)+: 430

Found: molecular weight (M+H)+: 430

Rf value: 0.44 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.5:

7-(3,4-dichloro-phenyl)-3-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.5.a. 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 3,4-dichloro-phenyl-boronic acid.

Yield: 0.72 g (28.4% of theoretical).

C13H7Cl2NO4 (M = 312.11)

Calculated: molecular weight (M-H)-: 310/312/314

Found: molecular weight (M-H)-: 310/312/314

Rf value: 0.39 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.5.b. 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.1 from 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.

Yield: 0.47 g (64.2% of theoretical).

C26H25Cl2N3O3 (M = 498.41)

Calculated: molecular weight (M+H)+: 498/500/502

Found: molecular weight (M+H)+: 498/500/502

Rf value: 0.24 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.5.c. 3',4'-dichloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide.

Yield: 0.11 g (25% of theoretical).

C26H25Cl2N3O (M = 468.43)

Calculated: molecular weight (M+H)+: 468/470/472

Found: molecular weight (M+H)+: 468/470/472

Rf value: 0.46 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.6:

7-(3-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.6.a. 3'-Methoxy-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 3-methoxy-phenyl-boronic acid.

Yield: 0.39 g (73.6% of theoretical).

C14H11NO5 (M = 273.24)

Calculated: molecular weight (M+H)+: 274

Found: molecular weight (M+H)+: 274

Rf value: 0.35 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.6.b. 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.1 from 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethylamine.

Yield: 0.39 g (57% of theoretical).

C27H29N3O4 (M = 459.55)

Calculated: molecular weight (M+H)+: 460

Found: molecular weight (M+H)+: 460

Rf value: 0.23 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.6.c. 3'-methoxy-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.j from 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.11 g (30.6% of theoretical).

C27H31N3O2 (M = 429.56)

Calculated: molecular weight (M+H)+: 430

Found: molecular weight (M+H)+: 430

Rf value: 0.36 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.7:

7-(4-fluoro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.7.a. 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-fluoro-phenyl-boronic acid.

Yield: 1.3 g (61.2% of theoretical).

C13H8FNO4 (M = 261.21)

Calculated: molecular weight (M-H)-: 260

Found: molecular weight (M-H)-: 260

Rf value: 0.34 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.7.b. 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.i from 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethylamine.

Yield: 0.38 g (57.8% of theoretical).

C26H26FN3O3 (M = 447.51)

Calculated: molecular weight (M+H)+: 448

Found: molecular weight (M+H)+: 448

Rf value: 0.24 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.7.c. 4'-fluoro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.06 g (32% of theoretical).

C26H28FN3O (M = 417.53)

Calculated: molecular weight (M+H)+: 418

Found: molecular weight (M+H)+: 418

Rf value: 0.63 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.8:

7-(4-ethyl-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.8.a. 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid

It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-vinyl-phenyl-boronic acid. Yield: 0.58 g (53% of theoretical).

C15H11NO4 (M = 269.25)

Calculated: molecular weight (M-H)-: 268

Found: molecular weight (M-H)-: 268

Rf value: 0.39 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.8.b. 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.i from 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethylamine.

Yield: 0.38 g (56.8% of theoretical).

C28H29N3O3 (M = 455.56)

Calculated: molecular weight (M+H)+: 456

Found: molecular weight (M+H)+: 456

Rf value: 0.21 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.8.c. 4'-ethyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.15 g (63.9% of theoretical).

C28H33N3O (M = 427.59)

Calculated: molecular weight (M+H)+: 428

Found: molecular weight (M+H)+: 428

Rf value: 0.47 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

The following compounds were produced analogously to example 1.1.k:

[image]

Rf value: A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.9

[image]

1.9.a 7-(4-trifluoromethyl-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

A solution of 0.07 g (0.15 mmol) of 4'-trifluoromethyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide ( see example 1.3.c) in 4 ml of acetic acid and 0.028 ml (0.3 mmol) of acetic anhydride is refluxed for 12 hours. The reaction solution is diluted with water, adjusted to pH 8 with dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia 90:10:1).

Yield: 0.008 g (11% of theory) C29H28F3N3O (M = 491.56)

Calculated: molecular weight (M+H)+: 492

Found: molecular weight (M+H)+: 492

Rf value: 0.36 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

The following compounds were produced analogously to example 1.9.a:

[image]

[image]

Rf value: A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.10:

2-methyl-3-[2-(4-pyralidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one

Example 1.11:

7-(4-chloro-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

Example 1.12

[image]

1.12.a 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1H-quinazolin-2,4-dione

The reaction mixture of 0.3 g (0.69 mmol) of 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]- amide (see example 1.1.j) and 0.1 g (0.65 mmol) of CDI in 50 ml of tetrahydrofuran is refluxed for 24 hours. A further 0.1 g of CDI was then added and the reaction mixture was refluxed for a further 24 hours. The reaction mixture is evaporated on a rotary evaporator. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia 60:1:0.1).

Yield: 0.2 g (62.9% of theoretical).

Melting point: 274-276oC

C27H26ClN3O2 (M = 459.98)

Calculated: molecular weight (M+H)+: 460/462

Found: molecular weight (M+H)+: 460/462

Rf value: 0.1 (silica gel, dichloromethane/methanol/ammonia 50:1:0.1)

Example 1.13:

7-(4-chloro-phenyl)-3-{2-E4-((S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

[image]

1.13.a [4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetonitrile

It is produced analogously to example 1.1.g from 2-(S)-methoxymethyl-pyrrolidine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 0.9 g (51.6% of theoretical).

C15H20N2O (M = 244.33)

Calculated: molecular weight (M+H)+: 245

Found: molecular weight (M+H)+: 245

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

1.13.b 2-[4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethylamine

It was produced analogously to example 1.1.h from [4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetonitrile. Yield: 0.5 g (54.7% of theoretical).

C15H24N2O (M = 248.37)

Calculated: molecular weight (M+H)+: 249

Found: molecular weight (M+H)+: 249

Rf value: 0.3 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)

1.13.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethnyl)-phenyl]-ethyl}-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(2-(S)-methoxy-methyl-pyrrolidin-1-ylmethyl)-phenyl]- ethylamine.

Yield: 0.5 g (54.7% of theoretical).

C28H30ClN3O4 (M = 508.02)

Calculated: molecular weight (M+H)+: 508/510

Found: molecular weight (M+H)+: 508/510

Rf value: 0.6 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)

1.13.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(2-(S)-methoxy-methyl-pyrrolidin-1-ylmethyl)-phenyl] -ethyl}-amide.

Yield: 0.24 g (51% of theoretical).

C28H32VlN3O2 (M = 478.03)

Calculated: molecular weight (M+H)+: 478/480.

Found: molecular weight (M+H)+: 478/480

R1 value: 0.2 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)

Example 1.14:

7-(4-chloro-phenyl)-3-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.14.a (4-dimethylaminomethyl-phenyl)-acetonitrile

It is produced analogously to example 1.1.g from dimethylamine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 1.0 g (30% of theoretical).

C11H14N2 (M = 174.24)

Calculated: molecular weight (M+H)+: 175

Found: molecular weight (M+H)+: 175

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

1.14.b 2-(4-dimethylaminomethyl-phenyl)-ethylamine

It was produced analogously to example 1.1.h from (4-dimethyl-aminomethyl-phenyl)-acetonitrile.

Yield: 1.0 g, raw.

C11H18N2 (M = 178.28)

Calculated: molecular weight (M+H)+: 179

Found: molecular weight (M+H)+: 179

Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)

1.14.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-dimethylamino-methyl-phenyl)-ethylamine.

Yield: 0.5 g (63.4% of theoretical).

C24H24ClN3O3 (M = 437.93)

Calculated: molecular weight (M+H)+: 438/440

Found: molecular weight (M+H)+: 438/440

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

1.14.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-dimethylamino-methyl-phenyl)-ethyl]-amide.

Yield: 0.2 g (43% of theoretical).

C24H26ClN3O (M = 407.94)

Calculated: molecular weight (M+H)+: 408/410

Found: molecular weight (M+H)+: 408/410

Rf value: 0.2 (silica gel, dichloromethane/methanol/ammonia 20:1:0.1)

Example 1.15:

7-(4-chloro-phenyl)-3-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.15.a {4-piperidin-1-ylmethyl-phenyl)-acetonitrile

It was produced analogously to example 1.1.g from piperidine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 1.6 g (39% of theoretical).

C14H18N2 (M = 214.31)

Calculated: molecular weight (M+H)+: 215

Found: molecular weight (M+H)+: 215

Rf value: 0.4 (silica gel, cyclohexane/ethyl acetate 1:1)

1.15.b 2-(4-piperidin-1-ylmethyl-phenyl)-ethylamine

It was produced analogously to example 1.1.h from (4-piperidin-1-ylmethyl-phenyl)-acetonitrile.

Yield: 1.4 g (85.9% of theoretical).

C14H22N2 (M = 218.34)

Calculated: molecular weight (M+H)+: 219

Found: molecular weight (M+H)+: 219

Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)

1.15.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-piperidin-1-yl-methyl-phenyl)-ethylamine.

Yield: 0.07 g (40.7% of theoretical).

C27H28ClN3O3 (M = 477.99)

Calculated: molecular weight (M+H)+: 478/480

Found: molecular weight (M+H)+: 478/480

Rf value: 0.5 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)

1.15.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.05 g (76.4% of theoretical).

C27H30ClN3O (M = 448.01)

Example 1.16:

7-{4-chloro-phenyl)-3-[2-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one

[image]

1.16.a (4-morpholin-4-ylmethyl-phenyl)-acetonitrile

It is produced analogously to example 1.1.g from morpholine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 1.63 g (98.9% of theoretical).

C13H16N2O (M = 216.28)

Calculated: molecular weight (M+H)+: 217

Found: molecular weight (M+H)+: 217

Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate 1:1)

1.16.b 2-(4-morpholin-1-ylmethyl-phenyl)-ethylamine

It was produced analogously to example 1.1.h from (4-morpholin-1-ylmethyl-phenyl)-acetonitrile.

Yield: 1.65 g (99.4% of theoretical).

C13H20N2O (M = 220.31)

Calculated: molecular weight (M+H)+: 221

Found: molecular weight (M+H)+: 221

Rf value: 0.54 (silica gel, dichloromethane/ethanol/ammonia 9:1:0.1)

1.16.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-morpholin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.1.1 from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-morpholin-1-yl-methyl-phenyl)-ethylamine.

Yield: 0.53 g (76.6% of theoretical).

C26H26ClN3O4 (M = 479.97)

Calculated: molecular weight (M+H)+: 480/482

Found: molecular weight (M+H)+: 480/482

Rf value: 0.5 (silica gel, dichloromethane/ethanol/ammonia 90:1:0.1)

1.16.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-morpholin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-morpholin-1-yl-methyl-phenyl)-ethyl]-amide.

Yield: 0.45 g (90.6% of theoretical).

C26H28ClN3O2 (M = 449.98)

Calculated: molecular weight (M+H)+: 450/452

Found: molecular weight (M+H)+: 450/452

Rf value: 0.67 (silica gel, dichloromethane/ethanol/ammonia 90:1:0.1)

The following compounds were produced analogously to example 1.1.k:

[image]

[image]

[image]

Rf value:

A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

C = (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)

D = (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)

Example 1.17

7-(4-chloro-phenyl)-3-{2-[6-(4-metriyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one

[image]

1.17.a (6-chloro-pyridin-3-yl)-acetonitrile

A solution of 7.5 g (41.66 mmol) of 2-chloro-5-chloromethyl-pyridine, dissolved in 100 ml of ethanol, was added dropwise to a solution of 6.91 g (41.66 mmol) of potassium iodide and 2 .24 g (49.01 mmol) of sodium cyanide in 400 ml of a mixture of ethanol and water (9:1). Then the reaction mixture is heated for five hours at 85°C. The solvent is mostly distilled off in vacuo and the residue is extracted with water and ethyl acetate. The organic phase is washed with water three times and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: dichloromethane/ethanol).

Yield: 2.9 g (45.6% of theoretical).

C7H5ClN2 (M = 152.58)

Calculated: molecular weight (M+H)+: 151/153

Found: molecular weight (M+H)+: 151/153

1.17.b [6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-acetonitrile

A solution of 2.9 g (19 mmol) of (6-chloro-pyridin-3-yl)-acetonitrile, 5.27 ml (38 mmol) of triethylamine and 2.1 ml (19 mmol) of N-methylpiperazine in 50 ml of n- butanol is heated for 2 hours at 180°C in a microwave heater. The solvent is distilled off in vacuo, the residue is suspended in water and then extracted with ethyl acetate. The organic phase compounds are extracted three times with water and dried over sodium sulfate. Purification is performed by chromatography on an Alox column (eluent: petroleum ether/ethyl acetate 1:1).

Yield: 1 g (24.6% of theoretical).

Melting point: 58-59°C

C12H16N4 (M = 216.28)

Calculated: molecular weight (M+H)+: 217

Found: molecular weight (M+H)+: 217

Rf value: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1).

1.17.c 2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl-amine

It is produced analogously to example 1.1.i from [6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-acetonitrile.

Yield: 0.94 g (96% of theoretical).

C12H20N4 (M = 220.32)

Calculated: molecular weight (M+H)+: 221

Found: molecular weight (M+H)+: 221

1.17.d 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide

It is produced analogously to example 1.1.j from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethylamine.

Yield: 0.48 g (36.7% of theoretical).

Melting point: 158-159°C

C25H26ClN5O3 (M = 479.97)

Calculated: molecular weight (M+H)+: 480/482

Found: molecular weight (M+H)+: 480/482

1.17.e 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl }-amide.

Yield: 0.12 g (64% of theoretical).

Melting point: 198-199°C

C25H28ClN5O (M = 449.98)

Calculated: molecular weight (M+H)+: 450/452

Found: molecular weight (M+H)+: 450/452

1.17.f 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one

It is produced analogously to example 1,1,1 from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl] -ethyl}-amide and formic acid.

Yield: 0.06 g (53.5% of theoretical).

Melting point: 263-264°C

C26H26ClN5O (M = 459.98)

Calculated: molecular weight (M+H)+: 460/462

Found: molecular weight (M+H)+: 4460/462

Example 1.18

7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-benzo[d][1,2,3]triazin-4-one

[image]

1.18.a 7-(4-chloro-phenyl)-3-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-3H-benzo[d][1,2, 3]triazin-4-one

A solution of 0.09 g (0.93 mmol) of sodium nitrite in 2 ml of water is slowly added drop by drop to a solution of 0.27 g (0.62 mmol) of 4'-chloro-3-amino-biphenyl-4- carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (see example 1.1.j) in 10 ml of methanol and 1N hydrochloric acid at a temperature between 0°C and 5°C. The reaction mixture is then stirred for three hours at room temperature, then diluted with 30 ml of water and made alkaline with an ammonia solution. The aqueous solution was extracted with ethyl acetate. The combined organic phases are washed with water three times, dried over sodium sulfate and filtered through activated carbon. The solvent was removed and the residue was washed with diisopropyl ether.

Yield: 0.09 g (32.5% of theoretical).

Melting point: 151-152°C

C26H25ClN4O (M = 444.96)

Calculated: molecular weight (M+H)+: 445/447

Found: molecular weight (M+H)+: 445/447

Rf value: 0.35 (silica gel, dichloromethane/ethanol = 10:1).

Example 1.19

7-(4-chloro-phenyl)-3-(4-pyrrolidin-1-ylmethyl-benzyl)-3H-benzo[d][1,2,3]triazin-4-one

[image]

1.19.a 4-(1-pyrrolidin-1-yl-ethyl)-benzonitrile

It is produced analogously to example 1.1.g from piperidine and 4-bromo-methyl-benzonitrile.

Yield: 2.4 g (85.9% of theoretical).

C12H14N2 (M = 186.25)

Calculated: molecular weight (M+H)+: 187

Found: molecular weight (M+H)+: 187

Rf value: 0.63 (silica gel, dichloromethane/methanol/ammonia = 8:2:1).

1.19.b 4-(1-pyrrolidin-1-yl-ethyl)-benzylamine

It is produced analogously to example 1.1.h from 4-(1-pyrrolidin-1-yl-ethyl)-benzonitrile.

Yield: 2.42 g (98.7% of theoretical)

C12H18N2 (M = 190.29)

Calculated: molecular weight (M+H)+: 191

Found: molecular weight (M+H)+: 191

Rf value: 0.26 (silica gel, dichloromethane/methanol/ammonia = 90:10:1).

1.19.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide

It is produced analogously to example 1.1.1 from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-4-(1-pyrrolidin-1-yl-ethyl)-benzylamine.

Yield: 0.28 g (28.8% of theoretical).

C25H24ClN3O3 (M = 449.94)

Calculated: molecular weight (M+H)+: 450/452

Found: molecular weight (M+H)+: 450/452

1.19.d 3-amino-4'-chloro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide.

Yield: 0.19 g (72.7% of theoretical).

C25H26ClN3O (M = 419.95)

Calculated: molecular weight (M+H)+: 420/422

Found: molecular weight (M+H)+: 420/422

1.19.e 7-(4-chloro-phenyl)-3-[4-(1-pyrrolidin-1-yl-ethyl)-benzyl]-3H-benzo[d][1,2,3]triazin-4- he

It is produced analogously to example 1.18.a from 3-amino-4'-chloro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide.

Yield: 0.045 g (31.4% of theoretical).

Melting point: 147-148°C

C25H23ClN4O (M = 430.94)

Calculated: molecular weight (M+H)+: 431/433

Found: molecular weight (M+H)+: 431/433

Rf value: 0.3 (silica gel, dichloromethane/ethanol = 10:1).

Example 1.20

5-(4-fluoro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-isoindol-1,3-dione

[image]

1.20.a 5-bromo-2-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione

A solution of 0.8 g (3.52 mmol) of 5-bromo-isobenzofuran-1,3-dione and 0.72 g (3.52 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine ( see example 1.1.h) in 10 ml of acetic acid is heated for 4 hours at 110°C. The reaction mixture is then poured into water, made alkaline with a 2N sodium hydroxide solution and the precipitate is filtered off. The precipitate is washed several times with water and dried.

Yield: 0.5 g (34.3% of theoretical).

C21H21BrN2O2 (M = 413.31)

Calculated: molecular weight (M+H)+: 413/415

Found: molecular weight (M+H)+: 413/415

1.20.b. 5-(4-fluoro-phenyl)-2-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione

It was produced analogously to example 1.1.b from 5-bromo-2-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione and 4-fluoro- phenylboronic acid.

Yield: 0.01 g (4.8% of theoretical).

C27H25FN2O2 (M = 428.51)

Calculated: molecular weight (M+H)+: 429

Found: molecular weight (M+H)+: 429

Example 1.21:

7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

[image]

1.21.a [4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile

It is produced analogously to example 1.1.g from 4-phenyl-piperidine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 3.8 g (98% of theoretical).

C20H22N2 (M = 290.41)

Calculated: molecular weight (M+H)+: 291

Found: molecular weight (M+H)+: 291

Rf value: 0.5 (silica gel, cyclohexane/ethyl acetate 1:1)

1.21.b 2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine

It was produced analogously to example 1.1.h from [4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile.

Yield: 3.6 g, raw.

C20H26N2 (M = 294.44)

Calculated: molecular weight (M+H)+: 295

Found: molecular weight (M+H)+: 295

Rf value: 0.49 (silica gel, dichloromethane/ethanol 20:1)

1.21.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine.

Yield: 1.33 g (70.7% of theoretical).

C33H32ClN3O3 (M = 554.09)

Calculated: molecular weight (M+H)+: 554/556

Found: molecular weight (M+H)+: 554/556

Rf value: 0.58 (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1)

1.21.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide.

Yield: 0.82 g (65.2% of theoretical).

C33H32ClN3O (M = 524.11)

Calculated: molecular weight (M+H)+: 524/526/528

Found: molecular weight (M+H)+: 524/526/528

Rf value: 0.65 (silica gel, dichloromethane/methanol 10:1)

Example 1.22:

7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

[image]

1.22.a [4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-acetonitrile

It is produced analogously to example 1.1.g from 4-phenyl-piperazine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 3.7 g (97% of theoretical).

C19H21N3 (M = 291.39)

Calculated: molecular weight (M+H)+: 292

Found: molecular weight (M+H)+: 292

Rf value: 0.6 (silica gel, cyclohexane/ethyl acetate 1:1)

1.22.b 2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethylamine

It was produced analogously to example 1.1.h from [4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-acetonitrile.

Yield: 1.1 g (28.6% of theoretical).

C19H25N2 (M = 295.43)

Calculated: molecular weight (M+H)+: 296

Found: molecular weight (M+H)+: 296

1.22.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethylamine.

Yield: 0.32 g (18.2% of theoretical).

C32H31ClN4O3 (M = 555.08)

Calculated: molecular weight (M+H)+: 555/557

Found: molecular weight (M+H)+: 555/557

1.22.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide.

Yield: 0.11 g (38.8% of theoretical).

C32H33ClN4O (M = 525.09)

Calculated: molecular weight (M+H)+: 525/527

Found: molecular weight (M+H)+: 525/527

Example 1.23:

7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

[image]

1.23.a [4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile

It is produced analogously to example 1.1.g from 4-hydroxy-4-phenylpiperidine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 3.8 g (98% of theoretical).

C20H22N2O (M = 306.41)

Calculated: molecular weight (M+H)+: 307

Found: molecular weight (M+H)+: 307

Rf value: 0.1 (silica gel, cyclohexane/ethyl acetate 1:1)

1.23.b 2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine

It was produced analogously to example 1.1.h from [4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile.

Yield: 3.36 g (92.1% of theoretical).

C20H26N2O (M = 310.44)

Calculated: molecular weight (M+H)+: 311

Found: molecular weight (M+H)+: 311

Rf value: 0.1 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)

1.23.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine.

Yield: 1.2 g (65.3% of theoretical).

C33H32ClN3O4 (M = 570.09)

Calculated: molecular weight (M+H)+: 570/572

Found: molecular weight (M+H)+: 570/572

Rf value; 0.35 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)

1.23.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl }-amide.

Yield: 1.04 g (91.5% of theoretical).

C33H34ClN3O2 (M = 540.11)

Melting point: 175-180°C

Calculated: molecular weight (M+H)+: 540/542/544

Found: molecular weight (M+H)+: 540/542/544

Rf value: 0.34 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)

1.23.e. 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

It is produced analogously to example 1.1.k. from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide.

Yield: 0.025 g (8.2% of theoretical).

Melting point: 204-205°C

C34H32ClN3O2 (M = 550.10)

Calculated: molecular weight (M+H)+: 550/552

Found: molecular weight (M-HH)+: 550/552

Rf value: 0.46 (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1)

Example 1.24:

7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4- he

[image]

1.24.a. 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4- he

It is produced analogously to example 1.1.k. from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide as a side product in example 123.e.

Yield: 0.08 g (27.1% of theoretical).

Melting point: 166-167°C

C34H30ClN3O (M = 532.09)

Calculated: molecular weight (M+H)+: 532/534

Found: molecular weight (M+H)+: 532/534

Rf value: 0.57 (silica gel, dichloromethane/ethanol/ammonia 10:1)

Example 1.25:

7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one

[image]

1.25.a [4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-acetonitrile

It was produced analogously to example 1.1.g from 3-aza-spiro-[5,5]undecane and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 3.38 g (98% of theoretical).

C19H26N2 (M = 282.43)

Calculated: molecular weight (M+H)+: 283

Found: molecular weight (M+H)+: 283

Rf value: 0.56 (silica gel, cyclohexane/ethyl acetate 1:1)

1.25.b 2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl-amine

It was produced analogously to example 1.1.h from [4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-acetonitrile.

Yield: 3.33 g (96.6% of theoretical).

C19H30N2 (M = 286.46)

Calculated: molecular weight (M+H)+: 287

Found: molecular weight (M+H)+: 287

Rf value: 0.18 (silica gel, dichloromethane/ethanol 20:1)

1.25.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl)-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(3-aza-spiro-[5,5]undec-3-ylmethyl)-phenyl] -ethylamine.

Yield: 1 g (52.5% of theoretical).

C32H36ClN3O3 (M = 546.11)

Calculated: molecular weight (M+H)+: 546/548

Found: molecular weight (M+H)+: 546/548

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

1.25.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl}-amide

It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro-[5,5]undec-3-ylmethyl)-phenyl ]-ethyl}-amide.

Yield: 0.8 g (84.7% of theoretical).

C32H38ClN3O (M = 516.13)

Calculated: molecular weight (M+H)+: 516/518

Found: molecular weight (M+H)+: 516/518

Rf value: 0.38 (silica gel, dichloromethane/methanol 10:1)

Example 1.26:

7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4-one

[image]

1.26.a {4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-acetonitrile

It was produced analogously to example 1.1.g from 2-(piperidin-4-yloxy)-pyridine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 0.91 g (49.8% of theoretical).

C19H21N3O (M = 307.39)

Calculated: molecular weight (M+H)+: 308

Found: molecular weight (M+H)+: 308

Rf value: 0.49 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.26.b 2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethylamine

It was produced analogously to example 1.1.h from {4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-acetonitrile.

Yield: 0.92 g (99.8% of theoretical).

C19H25N30 (M = 311.43)

Calculated: molecular weight (M+H)+: 312

Found: molecular weight (M+H)+: 312

Rf value: 0.16 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.26.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide

It is produced analogously to example 1.1.1 from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}- ethylamine.

Yield: 0.8 g (97.2% of theoretical).

C32H31ClN4O4 (M = 571.08)

Calculated: molecular weight (M+H)+: 571/573

Found: molecular weight (M+H)+: 571/573

Rf value: 0.52 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.26.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide

It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl-phenyl}- ethyl)-amide.

Yield: 0.38 g (50% of theoretical).

C32H33ClN4O2 (M = 541.09)

Calculated: molecular weight (M+H)+: 541/543

Found: molecular weight (M+H)+: 541/543

Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

Example 1.27:

7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4-one

[image]

1.27.a {4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-acetonitrile

It was produced analogously to example 1.1.g from 2-(piperidin-4-ylamino)-pyridine and (4-bromo-methyl-phenyl)-acetonitrile.

Yield: 1.57 g (86.1% of theoretical).

C19H22N4 (M = 306.41)

Calculated: molecular weight (M+H)+: 307

Found: molecular weight (M+H)+: 307

Rf value: 0.43 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.27.b 2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethylamine

It was produced analogously to example 1.1.h from {4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-acetonitrile.

Yield: 1.62 g (99.8% of theoretical).

C19H26N4 (M = 310.44)

Calculated: molecular weight (M+H)+: 311

Found: molecular weight (M+H)+: 311

Rf value: 0.1 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.27.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide

It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}- ethylamine.

Yield: 0.36 g (43.8% of theoretical).

C32H32ClN5O33 (M = 570.09)

Calculated: molecular weight (M+H)++: 570/572

Found: molecular weight (M+H)+: 570/572

Rf value: 0.28 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

1.27.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide

It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl} -ethyl)-amide.

Yield: 0.29g (85.7% of theoretical).

C32H34ClN5O (M = 540.11)

Calculated: molecular weight (M+H)+: 540/542

Found: molecular weight (M+H)+: 540/542

Rf value: 0.27 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

The following compounds were produced analogously to example 1.1.k:

[image]

[image]

Rf value:

A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

E = (silica gel, dichloromethane/ethanol 10:1)

F = (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1)

Example 1.28

7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][1,2,3]triazine -4-he

[image]

1.28.a 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidin-1-yl-methyl)-phenyl]-ethyl}-3H-benzo[d][1, 2,3]triazin-4-one

It is produced analogously to example 1.18.a from 4'-chloro-3-amino-bipenenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide.

Yield: 0.13 g (50.9% of theoretical).

Melting point: 183-184°C

C33H31ClN4O (M = 535.09)

Calculated: molecular weight (M+H)+: 535/537

Found: molecular weight (M+H)+: 535/537

Rf value: 0.66 (silica gel, dichloromethane/ethanol 10:1)

Example 1.29

7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[c/][1, 2,3]triazin-4-one

[image]

1.29.a 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][ 1,2,3]-triazin-4-one

It was produced analogously to example 1.18.a from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl }-amide.

Yield: 0.21 g (68.7% of theoretical).

Melting point: 265-266°C

C33H31ClN4O2 (M = 551.09)

Calculated: molecular weight (M+H)+: 551/553

Found: molecular weight (M+H)+: 551/553

Rf value: 0.53 (silica gel, dichloromethane/ethanol 10:1)

Example 1.30

7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5,5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-benzo[d] [1,2,3]triazin-4-one

[image]

1.30.a 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl}-3H-benzo[d ][1,2,3]triazin-4-one

It was produced analogously to example 1.18.a from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro-[5,5]undec-3-ylmethyl)-phenyl] -ethyl}-amide.

Yield: 0.14 g (54.9% of theoretical).

Melting point: 165-166°C

C32H35ClN4O (M = 527.11)

Calculated: molecular weight (M+H)+: 527

Found: molecular weight (M+H)+: 527

Rf value: 0.56 (silica gel, dichloromethane/ethanol 10:1)

Example 1.31:

6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one

[image]

1.31.a. 2-[2-(4-bromo-phenyl)-ethoxy]-tetrahydro-pyran

0.025 g of p-toluenesulfonic acid and 2.575 ml (28.22 mmol) of dihydropyran were added successively to a solution of 4.83 g (24.02 mmol) of 2-(4-bromo-phenyl)-ethanol in 12 ml of dichloromethane at 0°C. The reaction mixture is then stirred for three hours at room temperature. The reaction mixture is extracted with sodium hydrogen carbonate solution and the organic phase is dried over sodium sulfate. Purification is performed by chromatography on an Alox column (eluent: cyclohexane/ethyl acetate = 8:2).

Yield: 37 g (32.8% of theoretical).

C13H17BrO2 (M = 285.18)

Calculated: molecular weight (M)+: 284/286

Found: molecular weight (M)+: 284/286

1.31.b 4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde

11.5 ml (18.41 mmol) of a 1.6 M solution of n-butyllithium was added dropwise to a solution of 5 g (17.53 mmol) of 2-[2-(4-bromo-phenyl)-ethoxy ]-tetrahydropyran in 80 ml of tetrahydrofuran at -70°C and stirred for one hour at that temperature. Then 2.8 ml (36.46 mmol) of dimethylformamide was added drop by drop and the reaction mixture was stirred for another two hours at -70°C. The reaction mixture was mixed with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are extracted three times with saturated sodium chloride solution and dried over sodium sulfate. Cleaning is done by chromatography on a silica gel column (eluent: cyclohexane/ethyl acetate = 6:4).

Yield: 2.8 g (68.2% of theoretical).

C14H18O3 (M = 234.29)

Calculated: molecular weight (M+H)+: 235

Found: molecular weight (M+H)+: 235

Rf value: 0.57 (silica gel, petroleum ether/ethyl acetate 3:1)

1.31.c 4-(2-hydroxy-ethyl)-benzaldehyde

A solution of 2.8 g (11.95 mmol) of 4-[2-{tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde in a mixture of 48 ml of 1M hydrochloric acid and 60 ml of acetone was stirred for five hours at 5°C. The reaction mixture was mixed with 140 ml of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are extracted three times with water and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: cyclohexane/ethyl acetate = 1:1).

Yield: 1.3 g (72.4% of theoretical).

C9H10O2 (M = 150.17)

Calculated: molecular weight (M+H)+: 151

Found: molecular weight (M+H)+: 151

Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate 1:1)

1.31.d 2-(4-[1,3]dioxan-2-yl-phenyl)-ethanol

A suspension of 9.4 g (62.59 mmol) of 4-(2-hydroxy-ethyl)-benzaldehyde, 15.83 ml (219.07 mmol) of 1,3-propanediol, 0.3 g of p-toluenesulfonic acid and 150 ml of toluene is refluxed for three hours. The reaction mixture is extracted three times with saturated sodium hydrogen carbonate solution and the organic phase is dried over sodium sulfate.

Yield: 8 g (61.4% of theoretical).

C12H16O3 (M = 208.26)

Calculated: molecular weight (M+H)+: 209

Found: molecular weight (M+H)+: 209

1.31.e Methanesulfonic acid-2-(4-[1,3]dioxan-2-yl-phenyl)-ethyl ester

8 g (38.41 mmol) of 2-(4-[1,3]dioxan-2-yl-phenyl)-ethanol and 10.65 ml (42.25 mmol) of triethylamine are dissolved in 300 ml of dichloromethane and at 0° C is mixed with 3.27 ml of methanesulfonic acid chloride dissolved in 50 ml of dichloromethane. The reaction mixture is stirred for one hour at room temperature, extracted three times with water and the organic phase is dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate = 1:1).

Yield: 7.7 g (70% of theoretical).

C13H18O5S (M = 286.34)

Calculated: molecular weight (M+H)+: 287

Found: molecular weight (M+H)+: 287

Rf value: 0.49 (silica gel, petroleum ether/ethyl acetate 1:1)

1.31.f (E)-3-{3-bromo-phenyl)-acryloylazide

A solution of 25 g (111.1 mmol) of (E)-3-(3-bromo-phenyl)-acrylic acid and 15.26 ml (110.10 mmol) of triethylamine in 800 ml of acetone was added dropwise at 0 °C 11.5 ml (121.11 mmol) of ethyl chloroformate. After one hour, 11.45 g (176.16 mmol) of sodium azide, dissolved in 88 ml of distilled water, was also added drop by drop at 0°C. The reaction mixture is allowed to warm to room temperature and then poured into 1.3 l of ice water. The resulting precipitate is filtered off, washed with water and dried at 30°C in a circulating dryer.

Yield: 21.1 g (76.1% of theoretical).

C9H6BrN3O (M = 252.07)

Calculated: molecular weight (M+H)+: 256/258

Found: molecular weight (M+H)+: 256/258

Rf value: 0.85 (silica gel, petroleum ether/ethyl acetate 1:1)

1.31.g 6-bromo-2H-isoquinolin-1-one

150 g of biphenyl ether and 7.08 ml (29.75 mmol) of tributylamine are heated to 100°C. At this temperature, 5 g (19.83 mmol) of (E)-3-(3-bromo-phenyl)-acryloylazide are added and then heated for two hours at 195-205°C. The reaction mixture is then allowed to cool and poured into cooled n-hexane. The precipitate is filtered off and washed with a mixture of cooled n-hexane and diethyl ether. Then the solid substance is dried in a circulating dryer at 50°C. The solid was mixed with a mixture of diisopropyl ether and ethyl acetate and drying was repeated.

Yield: 0.6 g (13.5% of theoretical).

C9H6BrN3O (M = 224.05)

Calculated: molecular weight (M+H)+: 224/226

Found: molecular weight (M+H)+: 224/226

1.31.h 6-(4-chloro-phenyl)-2H-isoquinolin-1-one

A reaction mixture of 0.57 g (2.54 mmol) of 6-bromo-2H-isoquinolin-1-one, 0.398 g (2.54 mmol) of 4-chlorophenylboronic acid, 2.6 ml of a 2M solution of sodium carbonate in 20 ml of dioxane and 5 ml of methanol are heated at 110oC for two hours in a microwave heater. Then the reaction mixture is poured into water, the precipitate is filtered off and dried in a circulating dryer at 40°C.

Yield: 0.42 g (64.6% of theoretical).

C15H10ClNO (M = 255.70)

Calculated: molecular weight (M+H)+: 256/258

Found: molecular weight (M+H)+: 256/258

Rf value: 0.6 (silica gel, dichloromethane/ethanol 10:1)

1.31.i 2-[2-(4-formyl-phenyl)-ethyl]-6-(4-chloro-phenyl)-2H-isoquinolin-1-one

A solution of 0.41 g (1.6 mmol) of 6-(4-chloro-phenyl)-2H-isoquinolin-1-one in 10 ml of dimethylformamide was mixed with 0.18 g (1.6 mmol) of potassium tert-butoxide and stirred for 30 minutes at 50°C. Then 0.46 g (1.6 mmol) of methanesulfonic acid-2-(4-[1,3]dioxan-2-yl-phenyl)-ethyl ester was added. The reaction mixture is heated in a microwave oven for five hours at 180°C and then poured onto a 10% solution of citric acid. This is extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate = 3:1 to 1:1).

Yield: 0.15 g (24.1% of theoretical).

C24H18ClNO2 (M = 387.87)

Calculated: molecular weight (M+H)+: 388/390

Found: molecular weight (M+H)+: 388/390

Rf value: 0.7 (silica gel, petroleum ether/ethyl acetate 1:1)

1.31.j 6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one

0.14 g (0.36 mmol) of 2-[2-(4-formyl-phenyl)-ethyl]-6-(4-chloro-phenyl)-2H-isoquinolin-1-one and 0.03 ml (0 .36 mmol) of pyrrolidine is dissolved in 40 ml of dichloromethane. The pH was adjusted to three with glacial acetic acid. Then 0.076 g (0.36 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred for 48 hours at room temperature. The reaction mixture is then extracted with 2M sodium carbonate solution and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: dichloromethane/ethanol 10:1 to 1:1).

Yield: 0.04 g (25% of theoretical).

Melting point: 136-137oC

C28H27ClN2O (M = 442.99)

Calculated: molecular weight (M+H)+: 443

Found: molecular weight (M+H)+: 443

Rf value: 0.5 (silica gel, dichloromethane/methanol 10:1)

The following compounds were produced analogously to examples 1.1 to 1.31:

[image]

[image]

[image]

[image]

Example 2.1:

4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.1.a 4'-chloro-biphenyl-4-carboxylic acid

5.83 g (29.0 mmol) of 4-bromobenzoic acid are dissolved in 50 ml of dioxane and 29 ml of 2M sodium carbonate solution. 4.5 g (29.0 mmol) of 4-chloro-phenylboronic acid and 1.68 g (1.45 mmol) of tetrakis-(triphenylphosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The hot reaction solution is sucked off through a glass fiber filter. The filtrate is extracted with ethyl acetate. The aqueous phase is acidified with citric acid and stirred for one hour at 0°C. The resulting precipitate is filtered off, washed with water and dried in a vacuum.

Yield: 5.1 g (75.6% of theoretical).

C13H9ClO2 (M = 232.668)

Calculated: molecular weight (M-H)-: 231/233

Found: molecular weight (M-H)-: 231/233

2.1.b. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

471 mg (1.47 mmol) of TBTU and 0.26 ml (1.47 mmol) of Hünig's base are added to a suspension of 251 mg (1.08 mmol) of 4'-chloro-biphenyl-4-carboxylic acid in 5 ml of THF - and at room temperature. The reaction mixture was stirred for 10 min and then 200 mg (0.98 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine was added (see example 1.1.h). The mixture is stirred overnight. The reaction solution is mixed with saturated NaHCO3 solution, the aqueous phase is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator and the residue is mixed with tert-butylmethyl ether under heating. The resulting solid is filtered off, washed with a little tert-butylmethyl ether and air-dried.

Yield: 210 mg (51.2% of theoretical).

C26H27ClN2O (M = 418.971)

Calculated: molecular weight (M-HH)+: 419/421

Found: molecular weight (M+H)+: 419/421

Rf value: 0.57 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1).

Example 2.2:

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-diethylamino-methyl-phenyl)-ethyl]-amide

[image]

2.2.a (4-diethylaminomethyl-phenyl)-acetonitrile

0.88 ml (8.38 mmol) of diethylamine was dissolved in 30 ml of acetone and 2.1 g (15.2 mmol) of potassium carbonate and 1.6 g (7.62 mmol) of (4-bromo-methyl -phenyl)-acetonitrile (see 1.1.f). The reaction mixture was stirred for 2 h at room temperature, filtered through a glass frit and washed with ethyl acetate. The filtrate is evaporated on a rotary evaporator, extracted with water and ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (eluent: dichloromethane/methanol 9:1).

Yield: 900 mg (58.4% of the theoretical).

C13H22N2 (M = 202.30)

Calculated: molecular weight (M+H)+: 203

Found: molecular weight (M+H)+: 203

Rf value: 0.65 (silica gel, dichloromethane/methanol 9:1).

2.2.b. 2-(4-diethylaminomethyl-phenyl)-ethylamine

A solution of 900 mg (4.45 mmol) of (4-diethylaminomethyl-phenyl)-acetonitrile in 20 ml of methanolic ammonia solution was mixed with 100 mg of Raney nickel and shaken at 50°C and under 5 bar in an autoclave. The catalyst is suctioned off and the solvent is removed on a rotary evaporator.

Yield: 900 mg (98.0% of theoretical).

C13H22N2 (M = 206.334)

Calculated: molecular weight (M+H)+: 207

Found: molecular weight (M+H)+: 207

Rf value: 0.12 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

2.2.c. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-di-ethylaminomethyl-phenyl)-ethyl]-amide

It was produced analogously to example 2.1.b from 4'-chloro-biphenyl-4-carboxylic acid (248 mg, 1.07 mmol) and 2-(4-diethylaminomethyl-phenyl)-ethylamine (200 mg, 0.97 mmol).

Yield: 280 mg (68.6% of theoretical).

C26H29ClN2O (M = 420.987)

Calculated: molecular weight (M+H)+: 421/423

Found: molecular weight (M+H)+: 421/423

Rf value: 0.49 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

Example 2.3:

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.3.a. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-prienyl)-ethyl]-amide

It was produced analogously to example 2.1.b from 4'-chloro-biphenyl-4-carboxylic acid (234 mg, 1.01 mmol) and 2-(4-piperidin-1-ylmethyl-phenyl)-ethylamine (see 1.15.b, 200 mg, 0.92 mmol).

Yield: 260 mg (65.6% of theoretical).

C27H29ClN2O (M = 432.998)

Calculated: molecular weight (M+H)+: 433/435

Found: molecular weight (M+H)+: 433/435

Rf value: 0.57 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

Example 2.4:

4'-methoxy-biphenyl-4-carboxylic acid-[2-(4-diethyl-aminomethyl-phenyl)-ethyl]-amide

[image]

2.4.a 1-(4'-methoxy-biphenyl-4-yl)-ethanone

4-Methoxybiphenyl is added to a solution of 11.3 g (85.0 mmol) of aluminum chloride in 100 ml of carbon disulfide. The mixture is heated to 40°C and then 6.07 ml (81.4 mmol) of acetyl chloride is added very slowly. The reaction mixture is refluxed for one hour. When cooled, the reaction solution is added to 100 g of ice and 25 ml of conc. hydrochloric acid. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is recrystallized from isopropanol.

Yield: 8.8 g (48.0% of theoretical).

C15H14O2 (M= 226.278)

Calculated: molecular weight (M+H)+: 227

Found: molecular weight (M+H)+: 227

2.4.b 4'-methoxy-biphenyl-4-carboxylic acid

6.0 ml (117 mmol) of bromine is slowly added dropwise to a solution of 15.6 g (390.9 mmol) of NaOH in 70 ml of water at 0°C. Then 8.8 g (39.1 mmol) of 1-(4'-methoxy-biphenyl-4-yl)-ethanone in 50 ml of dioxane were added slowly. After three hours, the resulting solid is filtered off, taken up in dichloromethane and filtered again. The filtrate is freed from the solvent on a rotary evaporator.

Yield: 9.0 g (100.0% of theoretical).

C15H14O2 (M = 228.250)

Calculated: molecular weight (M-H)-; 227

Found: molecular weight (M-H)-: 227

2.4.c Chloride of 4'-methoxy-biphenyl-4-carboxylic acid

A solution of 3.0 g (0.013 mol) of 4'-methoxy-biphenyl-4-carboxylic acid in 47.4 ml (0.65 mol) of thionyl chloride was stirred at 50°C for three hours. After removal of thionyl chloride on a rotary evaporator, the product is obtained as a yellowish solid, which is stored in the refrigerator.

Yield: 3.2 g (99.8% of theoretical)

C15H14O2 (M = 246.696)

Calculated: molecular weight (M+H)+: 246/248

Found: molecular weight (M+H)+: 246/248

2.4.d 4'-methoxy-biphenyl-4-carboxylic acid-[2-(4-diethylaminomethyl-phenyl)-ethyl]-amide

287 mg (1.16 mmol) of acid chloride is added at 0°C to a solution of 200 mg (0.97 mmol) of 2-(4-diethylaminomethyl-phenyl)-ethylamine and 0.25 ml (1.45 mmol) of Hünig's base in 5 ml dichloromethane. The reaction mixture was stirred overnight and then mixed with half-saturated NaHCO 3 solution. The aqueous phase is washed with dichloromethane and the combined organic phases are dried over magnesium sulfate. The residue after removal of the solvent on a rotary evaporator is triturated with tert-butylmethyl ether and the resulting solid is filtered off with suction.

Yield: 90 mg (22.3% of theoretical).

C27H32N2O2 (M = 416.568)

Calculated: molecular weight (M+H)+: 417

Found: molecular weight (M+H)+: 417

Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.5.

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-diethylamino-ethyl-phenyl)-ethyl]-methyl-amide

[image]

2.5.a Tert-butyl [2-(4-diethylaminomethyl-phenyl)-ethyl]-carbamate

815 mg (3.73 mmol) of BOC anhydride was added to a solution of 700 mg (3.93 mmol) of 2-(4-diethylaminomethyl-phenyl)-ethylamine in 5.0 ml of dichloromethane and 0.52 ml (3.73 mmol) of triethylamine and stirred overnight at room temperature. The mixture is mixed with saturated NaHCO3 solution. The aqueous phase is washed with dichloromethane, and the organic phase is dried over magnesium sulfate. The residue after removing the solvent on a rotary evaporator is purified by chromatography on a silica gel column (eluent: dichloromethane/methanol/NH3 = 9:1:0.1).

Yield: 600 mg (57.7% of theoretical).

C18H30N2O2 (M = 306.452)

Calculated: molecular weight (M+H)+: 307

Found: molecular weight (M+H)+: 307

2.5.b [2-(4-diethylaminomethyl-phenyl)-ethyl]-methyl-amine

600 mg (1.96 mmol) of tert-butyl [2-(4-diethylaminomethyl-phenyl)-ethyl]-carbamate in THF was added slowly dropwise to a suspension of 250 mg (6.59 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran. The reaction mixture is stirred overnight and heated at 50°C for another hour. The treatment is carried out by successively adding 0.25 ml of water, 0.25 ml of 15% NaOH solution and 0.75 ml of water. After filtration, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator.

Yield: 350 mg (81.1% of theoretical).

C14H24N2 (M = 220.361)

Calculated: molecular weight (M+H)+: 221

Found: molecular weight (M+H)+: 221

2.5.c 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-diethyl-aminomethyl-phenyl)-ethyl]-methyl-amide

It was produced analogously to example 2.1.b from 4'-chloro-biphenyl-4-carboxylic acid (222 mg, 0.95 mmol) and [2-(4-diethylaminomethyl-phenyl)-ethyl]-methyl-amine (175 mg, 0.79 mmol).

Yield: 60 mg (17.4% of theoretical).

C27H31ClN2O (M = 435.014)

Calculated: molecular weight (M+H)+: 435/437

Found: molecular weight (M+H)+: 435/437

Rf value: 0.39 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.6:

[image]

2.6.a. 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure I from 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid (239 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1 .0 mmol).

Yield: 65 mg (15.3% of theoretical).

C26H33ClN2O (M = 425.019)

Calculated: molecular weight (M+H)+: 425/427

Found: molecular weight (M+H)+: 425/427

Rf value: 0.3 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.7:

4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.7.a ethyl 4-piperidin-1-yl-benzoate

0.41 ml of piperidine was added to a suspension of 0.5 ml (4.13 mmol) of ethyl 4-fluorobenzoate and 571 mg (4.13 mmol) of potassium carbonate in 20 ml of DMSO. The reaction mixture was stirred overnight at 70°C, a further 1 ml (2.44 mmol) of piperidine was added and stirring was continued for another 6 h at 70°C. After filtration, water is added, the mixture is extracted with ethyl acetate, the organic phase is separated and the solvent is removed on a rotary evaporator. The product reacts further without cleaning.

Yield: 706 mg (73.2% of theoretical).

C14H19NO2 (M = 233.313)

Calculated: molecular weight (M+H)+: 234

Found: molecular weight (M+H)+: 234

HPLC retention time: 6.2 min (method A)

2.7.b 4-piperidin-1-yl-benzoic acid

0.78 ml (0.74 mmol) of 2N NaOH was added to a solution of 350 mg (1.50 mmol) of ethyl 4-piperidin-1-yl-benzoate in 10 ml of ethanol. The reaction solution was stirred for 2 h at 60°C and then the pH was adjusted to 6-7 with 1N HCl. The resulting precipitate is dried overnight after filtration under high vacuum.

Yield: 158 mg (51.3% of theoretical).

C12H15NO2 (M = 205.259)

Calculated: molecular weight (M+H)+: 206

Found: molecular weight (M+H)+: 206

HPLC retention time: 6.2 min (method A)

2.7.c 4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (157 mg, 0.77 mmol) and 4-piperidin-1-yl-benzoic acid (158 mg, 0.77 mmol).

Yield: 102 mg (33.8% of theoretical).

C25H33N3O (M =391.561)

Calculated: molecular weight (M+H)+: 392

Found: molecular weight (M+H)+: 392

HPLC retention time: 4.4 min (method A)

Example 2.8:

[image]

2.8.a 4-benzyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to the general procedure I described above from diphenylmethane-4-carboxylic acid (104 mg, 0.49 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (100 mg, 0.49 mmol). .

Yield: 66 mg (33.9% of theoretical).

C27H30N2O (M = 398.553)

Calculated: molecular weight (M+H)+: 399

Found: molecular weight (M+H)+: 399

Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.9:

4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide

[image]

2.9.a Ethyl 4-(1,4-dioxa-spiro[4,5]dec-8-ylidenemethyl)-benzoate

350 ml (0.56 mol, 1.6 M in hexane) of n-BuLi solution was added dropwise at -20°C to a solution of 90.0 ml (0.63 mol) of diisopropylamine in 100 ml of THF and the reaction solution is stirred for 30 min at -20oC. 112 g (0.37 mol) of ethyl 4-(diethoxy-phosphorylmethyl)-benzoate in 100 ml of THF are added slowly, dropwise. The reaction solution was stirred for 1 h at –20oC and then 58 g (0.37 mol) of 1,4-dioxa-spiro[4,5]decan-8-one in 200 ml of THF. The reaction solution was stirred for 30 min at -12°C and then warmed to room temperature for 2 h. Water is added and the aqueous phase is extracted with ether, ethyl acetate and dichloromethane. The organic phase is filtered through silica gel. The residue after removal of the solvent on a rotary evaporator is purified by chromatography (silica gel, petroleum ether/ethyl acetate 9:1).

Yield: 80 g (72.0% of theoretical).

2.9.b 4-(1,4-dioxa-spiro[4,5]dec-8-ylidenemethyl)-benzoic acid

20 g of NaOH in 130 ml of water is added to a solution of 35 g (0.12 mol) of ethyl 4-(1,4-dioxa-spiro[4,5]dec-8-ylidene-methyl)-benzoate in 150 ml of ethanol. and the mixture is refluxed for 2 h. The reaction solution is added to 400 g of ice and 60 ml of conc. hydrochloric acid, the aqueous phase is extracted with ethyl acetate and the solvent is removed on a rotary evaporator.

Yield: 32 g (91.4% of theoretical).

Melting point: 164-165°C.

2.9.c 4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 4-(1,4-dioxa-spiro[4,5]dec-8-ylidenemethyl)-benzoic acid (134 mg, 0.49 mmol) and 2-(4-pyrrolidine-1 -ylmethyl-phenyl)-ethylamine (100 mg, 0.49 mmol).

Yield: 57 mg (28.0% of theoretical).

C27H32N2O2 (M = 416.568)

Calculated: molecular weight (M+H)+: 417

Found: molecular weight (M+H)+: 417

Rf value: 0.36 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.10:

[image]

2.10.a 4-(4-oxo-cyclohexyl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 4-(4-oxo-cyclohexyl)-benzoic acid (128 mg, 0.49 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (100 mg, 0 .49 mmol).

Yield: 26 mg (13.1% of theoretical).

C26H32N2O2 (M = 404.557)

Calculated: molecular weight (M+H)+: 405

Found: molecular weight (M+H)+: 405

Rf value: 0.31 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.11:

4-cyclohexyl-1-cyclohexylcarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethnyl]-amide

[image]

2.11.a 4-cyclohexyl-1-cyclohexylcarboxylic acid

0.44 ml conc. of hydrochloric acid and 100 mg of platinum oxide are added to a solution of 500 mg (2.10 mmol) of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid in 10 ml of methanol. The reaction mixture is stirred for 3 hours at 50°C and under 5 bar vacuum pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator.

Yield: 440 mg (99.9% of theoretical).

C13H22O2 (M = 210.319)

Calculated: molecular weight (M-H)-: 209

Found: molecular weight (M-H)-: 209

2.11.b 4-cyclohexyl-1-cyclohexylcarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from bicyclohexyl-4-carboxylic acid (103 mg, 0.49 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (100 mg, 0.49 mmol) .

Yield: 2.0 mg (1.0% of theoretical).

C26H40N2O2 (M = 396.622)

Calculated: molecular weight (M+H)+: 397

Found: molecular weight (M+H)+: 397

Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.12:

[image]

2.12.a 4-methylphenyl-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II described above from 4-methylphenyl-piperidine (175 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.0 mmol).

Yield: 90.0 mg (22.2% of theoretical).

C26H35N3O (M = 405.558)

Calculated: molecular weight (M+H)+: 406

Found: molecular weight (M+H)+: 406

Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.13:

4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.13.a 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine

4-Chloromethylstyrene is added dropwise at 60°C to 100 ml (1.2 mol) of formalin solution (37% in water) and 32.1 g (0.6 mol) of ammonium chloride. The reaction mixture was stirred for 3 h at 60°C and then cooled to room temperature. 100 ml of methanol is added and the mixture is stirred overnight. The residue after evaporation of the solvent on a rotary evaporator is mixed with 150 ml conc. of hydrochloric acid and stirred for 4 h at 100°C. When it cools down to room temperature, it is added to ice and made alkaline with flakes of NaOH. After re-extraction with ether, the organic phase is dried over sodium sulfate. The residue after removing the solvent on a rotary evaporator is purified by chromatography on a silica gel column (eluent: ethyl acetate:methanol:NH3 9:1:0.1).

Yield: 17.0 g (29.3% of theoretical).

C11H12ClN (M = 193.678)

Calculated: molecular weight (M+H)+: 194

Found: molecular weight (M+H)+: 194

Rf value: 0.26 (silica gel, ethyl acetate/methanol/NH3 6:4:0.4).

2.13.b 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine (193 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl- phenyl)-ethylamine (204 mg, 1.0 mmol).

Yield: 40.0 mg (9.4% of theoretical).

C25H30ClN3O (M = 423.990)

Calculated: molecular weight (M+H)+: 424/426

Found: molecular weight (M+H)+: 424/426

Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.14:

[image]

2.14.a 3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 1,2,3,4,5,6-hexahydro-[4,41bipyridinyl (81 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)- ethylamine (102 mg, 0.50 mmol).

Yield: 43.8 mg (22.3% of theoretical).

C24H32N4O (M = 392.549)

Calculated: molecular weight (M+H)+: 393

Found: molecular weight (M+H)+: 393

Rf value: 0.14 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.15:

[image]

2.15.a 4-benzyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-benzyl-piperidine (87.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 33.5 mg (16.5% of theoretical).

C26H35N3O (M = 405.6)

Calculated: molecular weight (M+H)+: 406

Found: molecular weight (M+H)+: 406

Rf value: 0.36 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.16:

[image]

2.16.a 4-(1H-indol-3-yl)-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 3-piperidin-4-yl-1H-indole (100 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).

Yield: 56.5 mg (26.2% of theoretical).

C27H34N4O (M = 430.6)

Calculated: molecular weight (M+H)+: 431

Found: molecular weight (M+H)+: 431

Rf value: 0.36 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.17:

[image]

2.17.a Tert-butyl 1'-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylcarbamoyl]-[4,4']bipiperidinyl-1-carboxylate

It was prepared according to general procedure II from tert-butyl[4,4']bipiperidinyl-1-carboxylate (134 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg , 0.50 mmol).

Yield: 51.0 mg (20.5% of theoretical).

C29H46N4O3 (M = 498.7)

Calculated: molecular weight (M+H)+: 499

Found: molecular weight (M+H)+: 499

Rf value: 0.40 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.18:

4-cyclohexyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.18.a 4-cyclohexyl-piperidine

In a solution of 1.0 g (6.4 mmol) of 4-phenylpyridine in 20 ml of methanol, 1.35 ml of conc. hydrochloric acid and 200 mg of platinum oxide. The reaction mixture is stirred for 2.5 hours at 50°C and 3 bar hydrogen pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator, whereby the product is precipitated as the hydrochloride.

Yield: 1.2 (91.4% of theoretical).

C11H21N·HCl (M = 203.758)

Calculated: molecular weight (M+H)+: 168

Found: molecular weight (M+H)+: 168

2.18.b 4-cyclohexyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-cyclohexyl-piperidine (83.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 38.0 mg (19.1% of theoretical).

C25H39N3O (M = 397.6)

Calculated: molecular weight (M+H)+: 398

Found: molecular weight (M+H)+: 398

Rf value: 0.54 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.19:

4-(4-chloro-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.19.a 4-(4-chloro-phenyl)-piperidine

500 mg of Pd/ C. The reaction mixture was stirred for 7 h at room temperature and 10 psi of hydrogen. After separation of the catalyst, the solvent is removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia = 5:4.9:0.1).

Utilization: 3.2 (75.3% of theoretical).

C11H14ClN (M = 195.694)

Calculated: molecular weight (M+H)+: 196/198

Found: molecular weight (M+H)+: 196/198.

Rf value: 0.37 (silica gel, dichloromethane/methanol/NH3 5:4.9:0.1).

2.19.b 4-(4-chloro-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-chloro-phenyl)-piperidine (97.9 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 9.0 mg (4.2% of theoretical).

C25H32ClN3O (M = 426.0)

Calculated: molecular weight (M+H)+: 426/428

Found: molecular weight (M+H)+: 426/428

Rf value: 0.49 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.20:

[image]

2.20.a 4-hydroxy-4-(4-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-hydroxy-4-(4-trifluoromethyl-phenyl)-piperidine (123 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 35.0 mg (14.7% of theoretical).

C26H32F3N3O2 (M= 475.6)

Calculated: molecular weight (M+H)+: 476

Found: molecular weight (M+H)+: 476

Rf value: 0.45 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.21:

[image]

2.21.a 3-phenyl-8-aza-bicyclo[3,2,1]octane-8-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 3-phenyl-8-aza-bicyclo[3,2,1]octane (93.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).

Yield: 26.0 mg (12.5% of theoretical).

C27H35N3O (M = 417.6)

Calculated: molecular weight (M+H)+: 418

Found: molecular weight (M+H)+: 418

Rf value: 0.51 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.22:

[image]

2.22.a 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-chloro-phenyl)-piperazine (117 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).

Yield: 13.0 mg (6.1% of theoretical).

C24H31ClN4O (M = 427.0)

Calculated: molecular weight (M+H)+: 427/429

Found: molecular weight (M+H)+: 427/429

Rf value: 0.42 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.23:

[image]

2.23.a 4-cyano-4-phenyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-cyano-4-phenyl-piperidine (111 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol ).

Yield: 27.0 mg (13.0% of theoretical).

C26H32N4O (M = 416.6)

Calculated: molecular weight (M+H)+: 417

Found: molecular weight (M+H)+: 417

Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.24:

[image]

2.24.a 3-aza-spiro[5,5]undecane-3-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 3-aza-spiro[5,5]undecane (76.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenylj-ethylamine (102 mg, 0 .50 mmol).

Yield: 24.0 mg (12.5% of theoretical).

C24H37N3O (M = 383.6)

Calculated: molecular weight (M+H)+: 384

Found: molecular weight (M+H)+: 384

Rf value: 0.49 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.25:

[image]

2.25.a 4-(4-fluoro-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-fluoro-phenyl)-piperidine (108 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).

Yield: 32.0 mg (15.6% of theoretical).

C25H32FN3O (M = 409.6)

Calculated: molecular weight (M+H)+: 410

Found: molecular weight (M+H)+: 410

Rf value: 0.50 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.26:

[image]

2.26.a 1,2-dihydro-1-(methylsulfonyl)-spiro[3H-indole-3,4'-piperidine]-1-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl) -ethyl]-amide

It was prepared according to general procedure II from 1,2-dihydro-1-(methylsulfonyl)-spiro[3H-indole-3,4'-piperidine] (133.2 mg, 0.50 mmol) and 2-(4- pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 28.0 mg (11.3% of theoretical).

C27H36N4O3S (M = 496.7)

Calculated: molecular weight (M+H)+: 497

Found: molecular weight (M+H)+: 497

Rf value: 0.42 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.27:

[image]

2.27.a 4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-chloro-phenyl)-4-hydroxy-piperidine (106 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 32.0 mg (14.5% of theoretical).

C25H32ClN3O2 (M = 442.0)

Calculated: molecular weight (M+H)+: 442/444

Found: molecular weight (M+H)+: 442/444

Rf value: 0.44 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.28:

[image]

2.28.a 4-(4-methoxy-phenyl)-piperazine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-methoxy-phenyl)-piperazine (133 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).

Yield: 35.0 mg (16.6% of theoretical).

C25H34N4O2 (M = 422.6)

Calculated: molecular weight (M+H)+: 423

Found: molecular weight (M+H)+: 423

Rf value: 0.47 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.29:

[image]

2.29. 4-(2-Methoxy-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(2-methoxy-phenyl)-piperidine (114 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).

Yield: 20.0 mg (9.5% of theoretical).

C26H35N3O2 (M = 421.6)

Calculated: molecular weight (M+H)+: 422

Found: molecular weight (M+H)+: 422

Rf value: 0.55 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.30:

[image]

2.30.a 1,3-dihydro-isoindole-2-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 1,3-dihydro-isoindole (77.8 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 13.0 mg (7.4% of theoretical).

C22H27N3O (M = 349.48)

Calculated: molecular weight (M+H)+: 350

Found: molecular weight (M+H)+: 350

Rf value: 0.30 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

Example 2.31:

[image]

2.31.a 1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 1,2,4,5-tetrahydro-benzo[d]azepine (73.6 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 12.0 mg (6.4% of theoretical).

C24H31N3O (M = 377.534)

Calculated: molecular weight (M+H)+: 378

Found: molecular weight (M+H)+: 378

Rf value: 0.33 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

Example 2.32:

[image]

2.32.a 4-phenyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-phenyl-piperidine (80.6 mg, 0.50 mmol) and 2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 24.0 mg (12.3% of theoretical).

C25H33N3O (M =391.561)

Calculated: molecular weight (M+H)+: 392

Found: molecular weight (M+H)+: 392

Rf value: 0.35 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

Example 2.33:

4-(4-Dimethylaminomethyl-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.33.a Tert-butyl 4-(4-dimethylaminomethyl-phenyl)-4-hydroxy-piperidine-1-carboxylate

236 ml (0.38 mol, 1.6 M in hexane) of n-BuLi was added dropwise over 35 min at -65°C to a solution of 81 g (0.38 mol) of 4-bromodimethylbenzylamine in 450 ml of THF- And. 75 g (0.38 mol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 150 ml of THF is added dropwise over 60 min so that the temperature does not rise above –60oC. The reaction solution is stirred for 2 hours at -65oC and for a further 17 hours at room temperature. The reaction mixture was mixed with 300 ml of ether, cooled to 5°C and the resulting precipitate was filtered off with suction. The precipitate is mixed with 200 ml of water and 700 ml of ether and stirred for 10 min. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The obtained product is dried in a vacuum.

Yield: 45 g (35.7% of theoretical).

2.33.b Dimethyl-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-amine

70 ml of trifluoroacetic acid is added dropwise to a solution of 45 g (0.14 mol) tert-butyl 4-(4-dimethyl-amino-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylate in 140 ml of dichloromethane at -10°C. The solution is stirred for 1.5 h at room temperature, cooled to -10oC and 30 ml conc. sulfuric acid. After half an hour, a further 10 ml of sulfuric acid is added. After 1 h, the solvent is removed on a rotary evaporator and added to 300 g of ice. The pH was adjusted to 14 with 6 N NaOH solution. The aqueous phase is saturated with potassium carbonate and extracted twice with ether. The combined organic phases are concentrated to dryness on a rotary evaporator.

Yield: 25.2 g (86.9%).

2.33.c Dimethyl-(4-piperidin-4-yl-benzyl)-amine

6 g of Pd/BaSO4 was added to a solution of 16 g (74 mmol) of dimethyl-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-amine in 200 ml of methanol. The solution is stirred for 1 h at room temperature in a hydrogen atmosphere, the catalyst is filtered off and the solvent is removed on a rotary evaporator. The residue is dissolved in methanol, methanolic hydrochloric acid is added and then ether until the mixture becomes cloudy. After keeping at -20°C, the resulting hydrochloride is suctioned off.

Yield: 16 g (84.9%).

2.33.d 4-(4-dimethylaminomethyl-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-(4-dimethylaminomethyl-phenyl)-piperidine (127 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).

Yield: 37.0 mg (16.5% of theoretical).

C28H40N4O (M = 448.657)

Calculated: molecular weight (M+H)+: 449

Found: molecular weight (M+H)+: 449

Rf value: 0.37 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).

Example 2.34:

4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-yl-methyl-phenyl)-piperidin-1-yl]-methanone

[image]

2.34.a 1-(4-bromo-benzyl)-pyrrolidine

20.0 g (0.080 mol) of 4-bromobenzyl bromide in THF is slowly added, dropwise, to a solution of 13.1 ml (0.16 mmol) of pyrrolidine and 200 ml of tetrahydrofuran, so that the temperature does not rise above 20oC. The reaction solution was stirred overnight and then mixed with ice and acidified with concentrated hydrochloric acid. After extraction with ether, the aqueous phase is made alkaline with sodium hydroxide solution and saturated with potassium carbonate. After extraction with ether, the organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator.

Yield: 18.1 g (94.2% of theoretical).

C11H14BrN (M = 240.145)

Calculated: molecular weight (M+H)+: 240/242

Found: molecular weight (M+H)+: 240/242

Rf value: 0.19 (silica gel, petroleum ether/ethyl acetate 8:2).

2.34.b 3-(4-pyrrolidin-1-ylmethyl-phenyl)-pyridine

1.11 g (4.64 mmol) of 1-(4-bromo-benzyl)-pyrrolidine was dissolved in 10 ml of dioxane and 5 ml of 2M sodium carbonate solution. 570 mg (4.64 mmol) of pyridine-3-boronic acid and 270 mg (0.23 mmol) of tetrakis-(triphenyl-phosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The reaction solution is sucked off through a glass fiber filter. The filtrate is extracted several times with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (eluent: ethyl acetate/methanol/NH3 = 8:2:0.1).

Yield: 500 mg (45.2% of the theoretical).

C16H18N2 (M = 238.335)

Calculated: molecular weight (M+H)+: 239

Found: molecular weight (M+H)+: 239

2.34.c 3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine

4 ml of 1M hydrochloric acid and 200 mg of platinum oxide were added to a solution of 500 mg (2.10 mmol) of 3-(4-pyrrolidin-1-ylmethyl-phenyl)-pyridine in 10 ml of ethanol. The reaction mixture is stirred for 4.5 hours at room temperature and under 3 bar hydrogen pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator, the product being precipitated as the hydrochloride.

Yield: 600 mg (100% of theoretical).

C16H24N2·HCl (M = 280.844)

Calculated: molecular weight (M+H)+: 245

Found: molecular weight (M+H)+: 245

2.34.d (4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-1-yl]-methanone

It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (183 mg, 0.78 mmol) and 3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine (200 mg, 0, 71 mmol).

Yield: 20.0 mg (6.1% of theoretical).

C29H31ClN2O (M = 459.036)

Calculated: molecular weight (M+H)+: 459/461

Found: molecular weight (M+H)+: 459/461

Rf value: 0.58 (silica gel, ethyl acetate/methanol/NH3

9:1:0,1).

Example 2.35:

4'-chloro-biphenyl-4-carboxylic acid-[2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide

[image]

2.35.a 2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile

3.4 g (30 mmol) of potassium tert-butoxide was added to a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (see 1.1.g) in 50 ml of tetrahydrofuran at room temperature. The reaction solution was stirred briefly, then mixed with 1.9 ml (30 mmol) of methyl iodide, stirred for a further 2 h at room temperature and then evaporated to dryness on a rotary evaporator. The residue is divided between water and ethyl acetate, the organic phase is washed with water and dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the crude product is further reacted without purification.

Yield: 1.4 g (61.3% of theoretical).

C15H20N22 (M = 228.340)

Calculated: molecular weight (M+H)+: 229

Found: molecular weight (M+H)+: 229

Rf value: 0.40 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

2.35.b 2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine

150 mg of Raney nickel was added to a solution of 1.4 g (6.13 mmol) of 2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile in 20 ml of methanolic ammonia solution. The reaction mixture is stirred overnight at 50°C under a pressure of 5 bar hydrogen atmosphere. When the catalyst is filtered off, the solvent is removed on a rotary evaporator.

Yield: 1.4 g (98.3% of theoretical).

C15H24N2 (M = 232.372)

Calculated: molecular weight (M+H)+: 233

Found: molecular weight (M+H)+: 233

Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

2.35.c 4'-chloro-biphenyl-4-carboxylic acid-[2-methyl-2-(4-pyrrolidin-1-yl methyl-phenyl)-propyl]-amide

It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (233 mg, 1.0 mmol) and 2-methyl-2-(4-pyrrolrdin-1-ylmethyl-phenyl)-propylamine (232 mg, 1.0 mmol).

Yield: 400 mg (89.5% of theoretical).

C28H31ClN2O (M = 447.025)

Calculated: molecular weight (M+H)+: 447/449

Found: molecular weight (M+H)+: 447/449

Rf value: 0.35 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.36:

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide

[image]

2.36.a 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile

1.12 g (10 mmol) of potassium tert-butoxide is added to a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (see 1.1.g) in 50 ml of tetrahydrofuran at room temperature. The reaction solution was stirred for 30 min and then mixed with 0.63 ml (10 mmol) of methyl iodide. The reaction mixture was stirred for 1 h at 50°C and then concentrated to dryness on a rotary evaporator. The residue is divided between water and ethyl acetate, the organic phase is washed twice with water and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the crude product containing approx. 20% of the dimethylated compound reacts further without purification.

Yield: 0.5 g (23.3% of theoretical).

C14H18N2 (M = 214.313)

Calculated: molecular weight (M+H)+: 215

Found: molecular weight (M+H)+: 215

Rf value: 0.40 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

2.36.b 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine

100 mg of Raney nickel was added to a solution of 400 mg (1.87 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile in 20 ml of methanolic ammonia solution. The reaction mixture is stirred overnight at 50°C and 5 bar hydrogen atmosphere. When the catalyst is filtered off, the solvent is removed on a rotary evaporator. Amine, containing approx. 20% of the dimethylated compound, reacts further without any further purification.

Yield: 0.4 g (98.6% of theoretical).

C15H22N2 (M = 218.345)

Calculated: molecular weight (M+H)+: 219

Found: molecular weight (M+H)+: 219

Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

2.36.c 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide

It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (233 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine (218 mg, 1, 0 mmol).

Yield: 10 mg (2.3% of theoretical).

C28H31ClN2O (M = 447.025)

Calculated: molecular weight (M+H)+: 447/449

Found: molecular weight (M+H)+: 447/449

Rf value: 0.35 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.37:

4'-chloro-biphenyl-4-carboxylic acid-(4-pyrrolidin-1-ylmethyl-benzyloxy)-amide

[image]

2.37.a 2-(4-pyrrolidin-1-ylmethyl-benzyloxy)-isoindol-1,3-dione

A mixture of 8.2 g (50 mmol) of N-hydroxyphthalimide and 8.7 ml (50 mmol) of Hünig's base in 125 ml of acetonitrile was added at room temperature to a solution of 13.2 g (50 mmol) of α,α' -dibromo-p-xylene in 125 ml of acetonitrile. The reaction solution was stirred for 10 min, then 4.1 ml (50 mmol) of pyrrolidine was added and the stirring was continued for another hour. When the royal jelly is filtered, it is evaporated to dryness on a rotary evaporator. The residue is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia). This substance reacts further immediately after cleaning.

Yield: 1.0 g (5.9% of theoretical).

Rf value: 0.60 (Alox, ethyl acetate/petroleum ether 1:1).

2.37.b O-(4-pyrrolidin-1-ylmethyl-benzyl)-hydroxylamine

50 ml of a 40% solution of methylamine in water is added to a solution of 1.0 g (2.97 mmol) of 2-(4-pyrrolidin-1-ylmethyl-benzyloxy)-isoindol-1,3-dione in 50 ml of toluene. and the mixture was stirred for 2.5 days at room temperature. After separation of the organic phase, the aqueous phase is extracted twice with tert-butylmethyl ether. The combined organic phases are washed with water and dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the resulting product reacts further without purification.

Yield: 260 mg (42.4% of theoretical).

C12H18N2O (M= 206.290)

Calculated: molecular weight (M+H)+: 207

Found: molecular weight (M+H)+: 207

2.37.c 4'-chloro-biphenyl-4-carboxylic acid-(4-pyrrolidin-1-ylmethyl-benzyloxy)-amide

It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and O-(4-pyrrolidin-1-ylmethyl-benzyl)-hydroxylamine (103 mg, 0, 5 mmol).

Yield: 10.0 mg (4.8% of theoretical).

C29H25ClN2O2 (M = 420.943)

Calculated: molecular weight (M+H)+: 421/423

Found: molecular weight (M+H)+: 421/423

Rf value: 0.38 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.38:

4'-chloro-biphenyl-4-carboxylic acid-[1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.38.a Ethyl (4-pyrrolidin-1-ylmethyl-phenyl)-acetate

3.0 g (15 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (see 1.1.g) is dissolved in ethanolic hydrochloric acid (saturated) and refluxed for 4 hours. The solvent was removed on a rotary evaporator and the residue was taken up with dilute NaHCO3 solution and tert-butylmethyl ether. The organic phase is dried with sodium sulfate, filtered off with suction through activated carbon, and then the solvent is removed on a rotary evaporator.

Yield: 3.4 g (91.6% of theoretical).

C15H21NO2 (M = 247,340)

Calculated: molecular weight (M+H)+: 248

Found: molecular weight (M+H)+: 248

Rf value: 0.25 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

2.38.b 2-methyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-2-ol

3.4 g (13.8 mmol) of ethyl (4-pyrrolidin-1-ylmethyl-phenyl)-acetate in 20 ml of tetrahydrofuran was added dropwise to 13.3 ml (40 mmol) of a 3.0 M solution of methylmagnesium chloride in tetrahydrofuran at room temperature. The temperature rises to 40°C. The reaction mixture was stirred for one hour and then poured onto 100 ml of ammonium chloride solution. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with saturated NaCl solution and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was purified by chromatography on an Alox column (activities 2-3) (eluent: cyclohexane:ethyl acetate 4:1).

Yield: 800 mg (24.9% of theoretical).

C15H23NO (M = 233.357)

Calculated: molecular weight (M+H)+: 234

Found: molecular weight (M+H)+: 234

Rf value: 0.50 (Alox, petroleum ether/ethyl acetate 6:4).

2.38.c N-[1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-formamide

A mixture of 2 ml of sulfuric acid and 1 ml of glacial acetic acid is added drop by drop to a solution of 250 mg (5.0 mmol) of sodium cyanide in 2 ml of glacial acetic acid so that the temperature of the reaction mixture does not rise above 20°C. Then 800 mg (3.43 mmol) of 2-methyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-2-ol in 2 ml of glacial acetic acid was added dropwise. The temperature is kept below 20oC. The reaction solution is stirred for one hour at room temperature and then poured onto ice and neutralized with sodium carbonate solution. The aqueous phase is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the product reacts further without purification.

Yield: 520 mg (58.2% of theoretical).

C16H24N2O (M = 260.382)

Calculated: molecular weight (M+H)+: 261

Found: molecular weight (M+H)+: 261

2.38.d 1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine

25 ml conc. of hydrochloric acid is added to a solution of 520 mg (2 mmol) of N-[1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-formamide in 10 ml of ethanol and the mixture is refluxed overnight . The reaction solution was cooled and then basified with 25% aqueous sodium hydroxide solution and the aqueous phase was extracted several times with tert-butylmethyl ether. The combined organic phases are washed with water, dried over magnesium sulfate and filtered through activated carbon. The solvent was removed on a rotary evaporator.

Yield: 380 mg (81.8% of theoretical).

C15H24N2 (M = 232.372)

Calculated: molecular weight (M+H)+: 233

Found: molecular weight (M+H)+: 233

Rf value: 0.10 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

2.38.e 4'-chloro-biphenyl-4-carboxylic acid-[1,1-di-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and 1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (116 mg, 0.5 mmol).

Yield: 73.0 mg (32.7% of the theoretical.

C28H31ClN2O2 (M = 447.025)

Calculated: molecular weight (M+H)+: 447/449

Found: molecular weight (M+H)+: 447/449

Rf value: 0.48 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.39:

4'-chloro-biphenyl-4-carboxylic acid-4-(2-pyrrolidin-1-yl-ethyl)-benzylamide

[image]

2.39.a 4-(2-pyrrolidin-1-yl-ethyl)-benzonitrile

91 mg (0.56 mmol) of potassium iodide, 453 mg (3.28 mmol) of potassium carbonate and 0.33 ml (2.74 mmol) of 1,4-dibromobutane were added successively to a solution of 500 mg (2, 74 mmol) of 4-(2-amino-ethyl)-benzonitrile in 50 ml of acetonitrile. The reaction mixture was stirred for 6 h at 78°C. Another 0.08 ml (0.66 mmol) of 1,4-dibromobutane was then added and the reaction mixture was stirred overnight at 78°C. After filtration, the filtrate is evaporated to dryness. Further purification is performed by chromatography on a silica gel column (dichloromethane/methanol 8:2).

Yield: 183.0 mg (33.4% of theoretical).

C13H16N2 (M = 200.286)

Calculated: molecular weight (M+H)+: 201

Found: molecular weight (M+H)+: 201

2.39.b 4-(2-pyrrolidin-1-yl-ethyl)-benzylamine

75 mg of Raney nickel was added to a solution of 183 mg (0.91 mmol) of 4-(2-pyrrolidin-1-yl-ethyl)-benzonitrile in 20 ml of ethanolic ammonia solution. The reaction solution is stirred overnight at 50°C and 3 bar hydrogen pressure. Another 75 mg of Raney nickel was added and the mixture was stirred for a further 6 h at 50°C and 3 bar hydrogen pressure. The catalyst is filtered off and the solvent is removed on a rotary evaporator. The raw product can be used without further purification.

Yield: 114.0 mg (61.0% of theory).

C13H20N2 (M = 204.318)

Calculated: molecular weight (M+H)+: 205

Found: molecular weight (M+H)+: 205

2.39.c 4'-chloro-biphenyl-4-carboxylic acid-4-(2-pyrrolidin-1-yl-ethyl)-benzylamide

It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (130 mg, 0.56 mmol) and 4-(2-pyrrolidin-1-yl-ethyl)-benzylamine (114 mg, 0, 56 mmol).

Yield: 75.0 mg (32.1% of theoretical).

C26H27ClN2O (M = 418.971)

Calculated: molecular weight (M+H)+: 419/421

Found: molecular weight (M+H)+: 419/421

Rf value: 0.38 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.40:

[image]

2.40.a [1,4']bipiperidinyl-1'-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-piperidinopiperidine (84.1 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).

Yield: 3.0 mg (1.5% of theoretical).

C24H38N4O (M = 398.597)

Calculated: molecular weight (0.5 M+H)+: 200

Found: Molecular Weight (0.5 M+H)+: 200

HPLC retention time: 1.59 min (method A)

Example 2.41:

[image]

2.41.a 4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was prepared according to general procedure I from 4-cyclohexylbenzoic acid (102 mg, 0.50 mmol) and 4-(2-pyrrolidin-1-yl-ethyl)-benzylamine (102 mg, 0.50 mmol). Yield: 2.0 mg (1.0% of theoretical).

C26H34N2O (M= 390.574)

Calculated: molecular weight (M+H)+: 391

Found: molecular weight (M+H)+: 391

Rf value: 0.38 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.42:

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide

[image]

2.42.a 2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethylamine

1.52 ml conc. hydrochloric acid and 300 mg of platinum oxide are added to a solution of 500 mg (2.45 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (see example 1.1.h) in 10 ml of methanol. The reaction mixture was stirred for 50 h at 50°C and under 5 bar hydrogen pressure. After coating the catalyst, the solvent is removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (dichloromethane/methanol/ammonia 8:2:0.2).

Yield: 130 mg (25.3% of theoretical).

C13H26N2 (M = 210.366)

Calculated: molecular weight (M+H)+: 211

Found: molecular weight (M+H)+: 211

Rf value: 0.14 (silica gel, dichloromethane/methanol/NH3 8:2:0.2).

2.42.b 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide

It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (116 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethylamine (105 mg, 0, 50 mmol).

Yield: 53.0 mg (24.9% of theoretical).

C26H33ClN2O (M = 425.019)

Calculated: molecular weight (M+H)+: 425/427

Found: molecular weight (M+H)+: 425/427

Rf value: 0.16 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).

Example 2.43:

4'-chloro-biphenyl-4-carboxylic acid-[2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.43.a 4-cyanomethyl-2-methoxy-benzoic acid

It is produced analogously to example 1.1.d from methyl 4-cyanomethyl-2-methoxy-benzoate.

Yield: 6.5 g (69.8% of theoretical).

C10H9NO3 (M = 191.18)

Calculated: molecular weight (M+H)+: 192

Found: molecular weight (M+H)+: 192

Rf value: 0.64 (silica gel, dichloromethane/ethanol 10:1).

2.43.b (4-hydroxymethyl-3-methoxy-phenyl)-acetonitrile

It is produced analogously to example 1.1.e from 4-cyano-methyl-2-methoxy-benzoic acid.

Yield: 4.81 g (81% of theoretical).

C10H11NO2 (M = 177.20)

Calculated: Molecular Weight (M)+: 177

Found: Molecular Weight (M)+: 177

2.43.c (4-bromo-methyl-3-methoxy-phenyl)-acetonitrile

It was produced analogously to example 1.1.f from (4-hydroxy-methyl-3-methoxy-phenyl-acetonitrile.

Yield: 4.2 g (64.6% of theoretical).

C10H10BrNO (M = 240.10)

Calculated: molecular weight (M)+: 239/241

Found: molecular weight (M)+: 239/241

Rf value: 0.84 (silica gel, dichloromethane/ethanol 50:1).

2.43.d (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile

It was produced analogously to example 1.1.g from (4-bromo-methyl-3-methoxy-phenyl)-acetonitrile and piperidine.

Yield: 0.95 g (24.2% of theoretical).

C14H18N2O (M = 230.31)

Calculated: molecular weight (M+H)+: 231

Found: molecular weight (M+H)+: 231

2.43.e (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine

It was produced analogously to example 1.1.h from (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile. The crude product further reacts directly without cleaning.

2.43.f 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It is produced according to general procedure I from 2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 4'-chloro-biphenyl-4-carboxylic acid.

Yield: 0.5 g (86.2% of theoretical).

Melting point: 162-163oC

C27H29ClN2O2 (M = 448.99)

Calculated: molecular weight (M+H)+: 449/451

Found: molecular weight (M+H)+: 449/451

Rf value: 0.85 (silica gel, dichloromethane/ethanol/ammonia 5:1:0.1).

Example 2.44:

4'-chloro-biphenyl-4-carboxylic acid-[2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.44.a (E)-3-(4-cyano-2-fluoro-phenyl)-acrylic acid

2.75 g (10 mmol) of palladium acetate and 7.0 g (25 mmol) of tri-o-tolylphosphane were added to a solution of 20.0 g (100 mmol) of 4-bromo-3-fluoro-benzonitrile in 200 ml of DMF. -And. Then 50 ml of triethylamine and 30 ml (30 mmol) of ethyl acrylate are added. The reaction mixture was stirred for 3 h at 100°C. When it cools down, it is diluted with 400 ml of dichloromethane and washed twice with water. The solvent was removed on a rotary evaporator and the residue was taken up in 250 ml of methanol with heating. The insolubles are suctioned off by filtration through diatomaceous earth and the filtrate is evaporated to half on a rotary evaporator. After repeated filtration, it is mixed with 150 ml of THF, 100 ml of MeOH and 43 ml of 2N NaOH and stirred for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was mixed with 100 ml of water. After extraction with ether, the aqueous phase was acidified with conc. hydrochloric acid. The crystalline precipitate is dissolved in 300 ml of warm ethyl acetate, and the aqueous phase is separated. Ethyl acetate is distilled off and the resulting crystals are suspended in ether and filtered off with suction.

Yield: 11.5 g (60.2% of theoretical).

Melting point: 214-218°C.

2.44.b 3-(4-cyano-2-fluoro-phenyl)-propionic acid

A solution of 11.5 g (60 mmol) of (E)-3-(4-cyano-2-fluoro-phenyl)-acrylic acid in 200 ml of water was mixed with 4.0 g of 5% Pd/C and 24.4 g of potassium carbonate. The mixture is shaken for 6 h at room temperature and under normal hydrogen pressure in an autoclave. When the catalyst is sucked off, the mother liquor is acidified with conc. hydrochloric acid. The precipitated crystals are dissolved in 250 ml of warm ethyl acetate and dried, and the ethyl acetate is distilled off. The resulting crystals are mixed with ether/hexane and suctioned off.

Yield: 900 mg (98.0% of theoretical).

Melting point: 102-106°C.

2.44.c Tert-butyl [2-(4-cyano-2-fluoro-phenyl)-ethyl]-carbamate

1.25 ml of triethylamine and 0.61 ml (2.8 mmol) of diphenyl-phosphoryl azide were added to a solution of 500 mg (2.6 mmol) of 3-(4-cyano-2-fluoro-phenyl)-propionic acid in 5 ml tert-butanol. The reaction mixture was refluxed overnight and then the solvent was removed on a rotary evaporator. Purification is performed by chromatography on a silica gel column (dichloromethane/methanol 9:1).

Yield: 138 mg (20.2% of theoretical).

C14H17FN2O2 (M = 264.302)

Calculated: molecular weight (M+H)+: 265

Found: molecular weight (M+H)+: 265

2.44.d Tert-butyl [2-(4-aminomethyl-2-fluoro-phenyl)-ethyl]-carbamate

A solution of 138 mg (0.52 mmol) of tert-butyl [2-(4-cyano-2-fluoro-phenyl)-ethyl]-carbamate in 15 ml of ethanolic ammonia solution was mixed with 75 mg of Raney nickel and the mixture was shaken over overnight at 50°C and under 3 bar hydrogen pressure in an autoclave. Then the catalyst is sucked off, and the solvent is removed on a rotary evaporator.

Yield: 137 mg (97.8% of theoretical).

C14H21FN2O2 (M = 268.334)

Calculated: molecular weight (M+H)+: 269

Found: molecular weight (M+H)+: 269

2.44.e Tert-butyl [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-carbamate

To a solution of 300 mg (1.12 mmol) of tert-butyl [2-(4-aminomethyl-2-fluoro-phenyl)-ethyl]-carbamate in 15 ml of acetonitrile, 42 mg (0.25 mmol) are added successively of potassium iodide, 180 mg (1.30 mmol) of potassium carbonate and 0.13 ml (1.11 mmol) of 1,4-dibromobutane. The reaction mixture was stirred for 6 h at 78°C. Another 0.08 ml (0.66 mmol) of 1,4-dibromobutane was then added and the reaction mixture was stirred overnight at 78°C. The solvent is removed on a rotary evaporator and the product reacts further without cleaning.

Yield: 320 mg (88.8% of theoretical).

C18H27FN2O2 (M = 322.426)

Calculated: molecular weight (M+H)+: 323

Found: molecular weight (M+H)+: 323

2.44.f 2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine

1.5 ml of trifluoroacetic acid was added to a solution of 232 mg (0.72 mmol) of tert-butyl [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-carbamate in 5 ml of dichloromethane. The reaction mixture was stirred for 2 h at room temperature. The solvent is removed on a rotary evaporator and the crude product is further reacted without purification.

Yield: 160 mg (100% of theoretical).

C13H19FN2 (M = 222.308)

Calculated: molecular weight (M+H)+: 223

Found: molecular weight (M+H)+: 223

2.44.g 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure I from 2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (160 mg, 0.72 mmol) and 4'-chloro-biphenyl-4-carboxylic acid (168 mg, 0.72 mmol).

Yield: 49 mg (15.6% of theoretical).

C26H26ClFN2O (M = 436.961)

Calculated: molecular weight (M+H)+: 437/439

Found: molecular weight (M+H)+: 437/439

HPLC retention time: 6.6 min (method A)

Example 2.45:

4-pyridin-4-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.45.a Methyl 4-pyridin-4-yl-benzoate

3.0 g (15 mmol) of 4-bromopyridine is dissolved in 50 ml of dioxane and 15 ml of 2M sodium carbonate solution. 2.7 g (15 mmol) of 4-methoxycarbonylphenylboronic acid and 1.73 g (2 mmol) of tetrakis-(triphenylphosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The hot reaction solution is sucked off through a glass fiber filter. The solvent is removed on a rotary evaporator and cleaning is performed by chromatography on a silica gel column (dichloromethane/methanol 9:1).

Yield: 845 mg (26.4% of theoretical).

C13H11NO2 (M = 213.238)

Calculated: molecular weight (M+H)+: 214

Found: molecular weight (M+H)+: 214

HPLC retention time: 4.1 min (method A)

2.45.b 4-pyridin-4-yl-benzoic acid

0.37 ml (0.74 mmol) of 2N NaOH was added to a solution of 150 mg (0.70 mmol) of methyl 4-pyridin-4-yl-benzoate in 10 ml of ethanol. The reaction solution is stirred for 2 h at 60oC and then the pH is adjusted to 6-7 with 1N HCl. After filtration, the resulting precipitate is dried overnight under high vacuum.

Yield: 84 mg (60.0% of theoretical).

C12H9NO2 (M = 199.211)

Calculated: molecular weight (M+H)+: 200

Found: molecular weight (M+H)+: 200

HPLC retention time: 2.5 min (method A)

2.45.c 4-pyridin-4-yl-W-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (86 mg, 0.42 mmol) and 4-pyridin-4-yl-benzoic acid (84 mg, 0.42 mmol).

Yield: 65 mg (40.0% of theoretical).

C25H27N3O (M = 385.513)

Calculated: molecular weight (M+H)+: 386

Found: molecular weight (M+H)+: 386

HPLC retention time: 4.7 min (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 91:9:0.01).

Example 2.46:

5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one

[image]

2.46.a Ethyl 4-bromo-2-methyl-benzoate

A solution of 5.0 g (23.3 mmol) of 4-bromo-2-methyl-benzoic acid in 50 ml of ethanolic hydrochloric acid was stirred for 8 h at 45°C. The reaction solution was cooled to room temperature overnight and then the solvent was removed on a rotary evaporator. The residue is taken up in ether, filtered and the solvent removed on a rotary evaporator. The residue reacts further without cleaning.

Rf value: 0.88 (silica gel, dichloromethane/ethanol 95:5).

2.46.b ethyl 4'-chloro-3-methyl-biphenyl-4-carboxylate

1.66 g (6.83 mmol) of ethyl 4-bromo-2-methylbenzoate was dissolved in 70 ml of dioxane and 7 ml of 2M sodium carbonate solution. 1.07 g (6.83 mmol) of 4-chloro-phenylboronic acid and 0.40 g (0.34 mmol) of tetrakis-(triphenylphosphine)-palladium are added successively. The reaction mixture was refluxed for 6 h and stirred for a further 60 h at room temperature. The hot reaction solution is sucked off through a glass fiber filter. The solvent was removed on a rotary evaporator. The residue was mixed with water and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Purification is performed by chromatography on a silica gel column (petroleum ether/ethyl acetate 8:2).

Yield: 1.3 g (69.3% of theoretical).

C16H15ClO2 (M = 274.750)

Calculated: molecular weight (M+H)+: 275/277

Found: molecular weight (M+H)+: 275/277

Rf value: 0.67 (silica gel, petroleum ether/ethyl acetate 8:2).

2.46.c Ethyl 3-bromo-methyl-4'-chloro-biphenyl-4-carboxylate

78 mg (0.47 mmol) of 2,2'-azobis(isobutyronitrile) was added to a solution of 1.3 g (4.73 mmol) of ethyl 4'-chloro-3-methyl-biphenyl-4-carboxylate and 0.84 g (4.73 mmol) of N-bromosuccinimide in 10 ml of carbon tetrachloride. The reaction mixture is refluxed overnight. After filtration, the solvent is evaporated on a rotary evaporator. Purification is performed by chromatography on a silica gel column (petroleum ether/ethyl acetate 8:2).

Yield: 1.6 g (62.1% of theoretical).

C16H14BrClO2 (M = 353.646)

Calculated: molecular weight (M+H)+: 353/355/357

Found: molecular weight (M+H)+: 353/355/357

Rf value: 0.57 (silica gel, petroleum ether/ethyl acetate 8:2).

2.46.d 5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one

375 mg (1.47 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine was slowly added dropwise at room temperature to a suspension of 800 mg (1.47 mmol) of ethyl 3-bromo-methyl- 4'-chloro-biphenyl-4-carboxylate and 508 mg (3.68 mmol) of potassium carbonate in 7.5 ml of acetonitrile. The reaction mixture was refluxed for 5 hours. The residue after removal of the solvent on a rotary evaporator is taken up in water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. The residue after removing the solvent on a rotary evaporator is dissolved in DMF and purified by HPLC chromatography (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 in 9 min).

Yield: 82 mg (12.9% of theoretical).

C27H27ClN2O2 (M = 430.982)

Calculated: molecular weight (M+H)+: 431/433

Found: molecular weight (M+H)+: 431/433

HPLC retention time: 6.13 min (method A)

Example 2.47:

4-piperidin-1-ylmethyl-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.47.a 4-piperidin-1-ylmethyl-pyridine

242 ml of piperidine (2.44 mol) were added dropwise to a solution of 100 g (0.61 mol) of 4-chloromethyl-pyridine in 600 ml of dry methanol and the reaction mixture was stirred for one hour at 50°C. The solvent was removed on a rotary evaporator. The residue is made alkaline with a 40% sodium hydroxide solution and the aqueous phase is extracted with ether. The organic phase is dried over sodium sulfate and after filtration through activated carbon, the solvent is removed on a rotary evaporator. The crude product reacts further without purification.

Yield: 106 g (98% of theoretical).

2.47.b 4-piperidin-1-ylmethyl-piperidine

A solution of 106 g (0.6 mol) of 4-piperidin-1-ylmethyl-pyridine in 1.0 l of glacial acetic acid was mixed with 7 g of platinum oxide and shaken in an autoclave at room temperature and 3 bar hydrogen pressure. When the catalyst is sucked off, the solvent is removed on a rotary evaporator. The crude product reacts further without purification.

Yield: 48 g (43.9% of theoretical).

2.47.c 4-piperidin-1-ylmethyl-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 4-piperidin-1-ylmethyl-piperidine (182 mg, 1.00 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.00 mmol ).

Yield: 160.0 mg (38.8% of theoretical).

C25H40N4O (M = 412.624)

Calculated: molecular weight (M+H)+: 413

Found: molecular weight (M+H)+: 413

HPLC retention time: 1.75 min (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01 to 4:6:0.01 in 8 min).

Example 2.48:

[image]

2.48.a 4-(1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid-[2-{4-pyrrolidin-1-yl]ethyl-phenyl)-ethyl]-amide

It was prepared according to general procedure II from 2-piperidin-4-yl-1H-benzoimidazole (164 mg, 1.00 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1, 00 mmol).

Yield: 80.0 mg (18.5% of theoretical).

C26H33N5O (M = 431.586)

Calculated: molecular weight (M+H)+: 432

Found: molecular weight (M+H)+: 432

HPLC retention time: 2.80 min (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01 to 4:6:0.01 in 8 min).

Example 2.49:

4-(1-methyl-piperidin-4-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.49.a methyl 4-piperidin-4-yl-benzoate

4.0 ml of 1M hydrochloric acid and 200 mg of platinum oxide are added to a solution of 695 mg (3.26 mmol) of methyl 4-pyridin-4-yl-benzoate (see example 2.45.a) in 10 ml of ethanol. The reaction mixture is stirred for 2 h at room temperature and 3 bar hydrogen pressure. When another 300 mg of platinum oxide and 6.0 ml of 1M hydrochloric acid were added to the reaction mixture, the mixture was stirred for another 16 h at room temperature and 3 bar hydrogen pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator. The crude product reacts further without purification.

Yield: 589 mg (82.4% of theoretical).

C13H17NO2 (M = 219.286)

Calculated: molecular weight (M+H)+: 220

Found: molecular weight (M+H)+: 220

HPLC retention time: 3.5 min (method A)

2.49.b methyl 4-(1-methyl-piperidin-4-yl)-benzoate

48 mg (2.00 mmol) of sodium hydride was added portionwise to a solution of 429 mg (1.96 mmol) of methyl 4-piperidin-4-yl-benzoate in 10 ml of DMF under a nitrogen atmosphere at 0°C. The reaction mixture was stirred for 1 h at room temperature. 0.13 ml (2.10 mmol) of methyl iodide was added drop by drop and the solution was stirred for two hours at room temperature. The reaction solution is mixed with water, the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. Purification is performed by column chromatography (silica gel; dichloromethane/methanol 8:2).

Yield: 70 mg (15.3% of theoretical).

C14H19NO2 (M = 233.313)

Calculated: molecular weight (M+H)+: 234

Found: molecular weight (M+H)+: 234

HPLC retention time: 2.7 min (method A)

2.49.c 4-(1-methyl-piperidin-4-yl)-benzoic acid

0.37 ml (0.74 mmol) of 2N NaOH was added to a solution of 70 mg (0.30 mmol) of methyl 4-(1-methyl-piperidin-4-yl)-benzoate in 10 ml of ethanol. The reaction solution was stirred for 2 h at 60oC and then adjusted to pH 6-7 using 1N HCl. The precipitate formed after filtration is dried overnight under high vacuum.

Yield: 50 mg (76.0% of theoretical).

C13H17NO2 (M = 219.286)

Calculated: molecular weight (M+H)+: 220

Found: molecular weight (M+H)+: 220

HPLC retention time: 1.5 min (method A)

2.49.d 4-(1-methyl-piperidin-4-yl)-W-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (47 mg, 0.23 mmol) and 4-(1-methyl-piperidin-4-yl)-benzoic acid ( 50 mg, 0.23 mmol).

Yield: 22 mg (23.8% of theoretical).

C26H35N3O (M = 405.588)

Calculated: molecular weight (M+H)+: 406

Found: molecular weight (M+H)+: 406

HPLC retention time: 2.4 min (method A)

Example 2.50:

[image]

1.21.a 4'-chloro-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide

It is produced analogously to example 1.1.i from 2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethylamine and 4'-chloro-bi-phenyl-4-carboxylic acid.

Yield: 0.94 g (96% of theoretical).

Melting point: 211-213oC

C25H27ClN4O (M = 434.97)

Calculated: molecular weight (M+H)+: 435/437

Found: molecular weight (M+H)+: 435/437

Example 2.51:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide

[image]

2.51.a [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-acetonitrile

A solution of 2 g (12.41 mmol) 4-cyanomethyl-benzoic acid, 1.25 g (12.5 mmol) N-methylpiperazine, 4.01 g (12.5 mmol) TBTU and 3.48 ml (25 mmol ) of triethylamine in 40 ml of DMF was stirred for 12 hours at room temperature. The reaction mixture is then evaporated to a certain extent and mixed with water. This mixture is extracted with ethyl acetate and the solvent is distilled off on a rotary evaporator. The aqueous phase is also evaporated and the organic phase is mixed with the residue. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/ethanol/ammonia 30:1:0.1).

Yield: 2.6 g (86% of theoretical).

C14H14N3O (M = 243.31)

Calculated: molecular weight (M+H)+: 244

Found: molecular weight (M+H)+: 244

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

2.51.b [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone

It is produced analogously to example 1.1.i from [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-acetonitrile.

Yield: 2.9 g (90% of theoretical).

C14H21N3O x HCl (M = 283.80)

Rf value: 0.25 (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1).

2.51.c 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide

It was produced according to general procedure I from [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone and 4'-chloro-biphenyl-4-carboxylic acid.

Yield: 0.18 g (48.4% of theoretical).

Melting point: 217-218°C

C27H28ClN3O2 (M = 461.99)

Calculated: molecular weight (M+H)+: 462/464

Found: molecular weight (M+H)+: 462/464

Rf value: 0.25 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1).

Example 2.52:

4'-bromo-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.52.a methyl 4'-bromo-biphenyl-4-carboxylate

0.54 g (2.5 mmol) of methyl 4-bromobenzoate is dissolved in 10 ml of dioxane and 2.5 ml of 2M sodium carbonate solution. 0.6 g (3 mmol) of 4-bromophenylboronic acid and 0.12 g (0.1 mmol) of tetrakis-(triphenylphosphine)-palladium are added successively and the reaction mixture is refluxed for 5 hours. The reaction mixture was mixed with water and EtOAc, filtered and the phases separated. The aqueous phase was extracted with EtOAc and the combined organic phases were dried over MgSO4. After removal of drying agent and solvent, the residue is triturated with acetonitrile, suction and dried in air.

Yield: 100 mg (13.7% of the theoretical).

C14H11BrO2 (M = 291.15)

Calculated: molecular weight (M+H)+: 291/293

Found: molecular weight (M+H)+: 291/293

Rf value: 0.68 (silica gel, petroleum ether/EtOAc 8:2).

2.52.b 4'-bromo-biphenyl-4-carboxylic acid

A solution of 100 mg (0.34 mmol) of methyl 4'-bromo-biphenyl-4-carboxylate in 3 ml of THF was mixed with 3 ml of a 1M NaOH solution in water and refluxed for 3 h. The reaction mixture is evaporated in vacuo, the aqueous residue is acidified with 1 M HCl, the precipitated product is filtered off and dried in air.

Yield: 60 mg (63.1% of theoretical).

C13H9BrO2 (M = 277.19)

Calculated: molecular weight (M-H)-: 275/277

Found: molecular weight (M-H)-: 275/277

HPLC retention time: 8.48 min (method A)

2.52.c 4'-bromo-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 45 mg (0.22 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 60 mg (0.22 mmol) of 4'-bromo-biphenyl-4-carboxylic acid.

Yield: 28 mg (27.5% of theoretical).

C26H27BrN2O (M = 463.42)

Calculated: molecular weight (M+H)+: 463/465

Found: molecular weight (M+H)+: 463/465

HPLC retention time: 6.46 min (method A)

Example 2.53:

4'-ethyl-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 113 mg (0.5 mmol) of 4'-ethyl-biphenyl-4-carboxylic acid (Lancaster).

Yield: 65 mg (31.5% of theoretical).

C28H32N2O (M = 412.58)

Calculated: molecular weight (M+H)+: 463

Found: molecular weight (M+H)+: 463

HPLC retention time: 6.64 min (method A)

Example 2.54:

Biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 99 mg (0.5 mmol) of biphenyl-4-carboxylic acid.

Yield: 46 mg (23.9% of theoretical).

C26H28N2O (M = 384.53)

Calculated: molecular weight (M+H)+: 385

Found: molecular weight (M+H)+: 385

HPLC retention time: 5.70 min (method A)

Example 2.55:

4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.55a. 4'-fluoro-biphenyl-4-carboxylic acid

14.27 g (71 mmol) of 4-bromobenzoic acid are dissolved in 120 ml of dioxane and 70 ml of 2M Na2CO3 solution. 10 g (71 mmol) of 4-fluorophenylboronic acid and 4.1 g (4 mmol) of tetrakis-(triphenylphosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The catalyst is sucked off and washed with hot water. The reaction mixture was mixed with EtOAc, the phases were separated and the aqueous phase was acidified with citric acid. The resulting precipitate is suctioned off, washed with water and dried at 45oC in a vacuum.

Yield: 4.9 g (31.9% of theoretical).

C13H9FO2 (M = 216.21)

Calculated: molecular weight (M-H)-: 215

Found: molecular weight (M-H)-: 215

2.55.b. 4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 108 mg (0.5 mmol) of 4'-fluoro-biphenyl-4-carboxylic acid.

Yield: 12 mg (6.0% of theoretical).

C26H27FN2O (M = 402.52)

Calculated: molecular weight (M+H)+: 403

Found: molecular weight (M+H)+: 403

HPLC retention time: 5.83 min (method A)

Example 2.56:

4'-hydroxy-3'-nitro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 130 mg (0.5 mmol) of 4'-fluoro-3'-nitro- biphenyl-4-carboxylic acids.

Yield: 9 mg (4.0% of theoretical).

C26H27N3O4 (M = 445.52)

Calculated: molecular weight (M+H)+: 446

Found: molecular weight (M+H)+: 446

HPLC retention time: 5.83 min (method A)

Example 2.57:

3'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.57.s. 3'-chloro-biphenyl-4-carboxylic acid

It was produced analogously to example 2.55.a from 9.64 g (47.96 mmol) of 4-bromobenzoic acid and 7.5 g (47.96 mmol) of 3-chlorophenylboronic acid.

Yield: 6.2 g (55.6% of theoretical).

C13H9ClO2 (M = 232.67)

Calculated: molecular weight (M-H)-: 231/233

Found: molecular weight (M-H)-: 231/233

2.57.b. 3'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 116 mg (0.5 mmol) of 3'-chloro-biphenyl-4-carboxylic acid.

Yield: 63 mg (30.1% of theoretical).

C26H27ClN2O (M = 418.97)

Calculated: molecular weight (M+H)+: 419/421

Found: molecular weight (M+H)+: 419/421

HPLC retention time: 6.20 min (method A)

Example 2.58:

3',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.58.a. 3',4'-dichloro-biphenyl-4-carboxylic acid

It was produced analogously to example 2.55.a from 5.27 g (26.20 mmol) of 4-bromo-benzoic acid and 5.0 g (26.20 mmol) of 3',4'-dichloro-phenylboronic acid.

Yield: 4.05 g (57.9% of theoretical).

C13H18Cl2O2 (M = 267.11)

Calculated: molecular weight (M-H)-: 265/267/269

Found: molecular weight (M-H)-: 265/267/269

2.58.b. 3',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 134 mg (0.5 mmol) of 3',4'-dichloro-biphenyl- 4-carboxylic acids.

Yield: 45 mg (19.8% of theoretical).

C26H26Cl2N2O (M = 453.42)

Calculated: molecular weight (M+H)+: 453/455/457

Found: molecular weight (M+H)+: 453/455/457

HPLC retention time: 6.45 min (method A)

Example 2.59:

2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.59.a. 2',4'-dichloro-biphenyl-4-carboxylic acid

It was produced analogously to example 2.55.a from 5.23 g (26.0 mmol) of 4-bromobenzoic acid and 10.0 g (52.0 mmol) of 2,4-dichlorophenylboronic acid, by refluxing the reaction mixture for 48 h.

Yield: 1.5 g (21.6% of theoretical).

C13H8Cl2O2 (M = 267.11)

Calculated: molecular weight (M-H)-: 265/267/269

Found: molecular weight (M-H)-: 265/267/269

2.59.b 2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 134 mg (0.5 mmol) of 2',4'-dichloro-biphenyl- 4-carboxylic acids.

Yield: 72 mg (31.8% of theoretical).

C26H26Cl2N2O (M = 453.42)

Calculated: molecular weight (M+H)+: 453/455/457

Found: molecular weight (M+H)+: 453/455/457

HPLC retention time: 6.84 min (method A)

Example 2.60:

2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.60.a 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid

It was produced analogously to example 2.55.a from 0.52 g (2.5 mmol) of 1-bromo-4-chloro-2-fluorobenzene and 0.5 g (3.0 mmol) of 4-carboxyphenyl-boronic acid.

Yield: 0.5 g (79.8% of theoretical).

C13H8ClFO2 (M = 250.66)

Calculated: molecular weight (M-H)-: 249/251

Found: molecular weight (M-H)-: 249/251

HPLC retention time: 8.39 min (method A)

2.60.b. 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 125 mg (0.5 mmol) of 2'-fluoro-4'-chloro- biphenyl-4-carboxylic acids.

Yield: 36 mg (16.5% of theoretical).

C26H26ClFN2O (M = 436.96)

Calculated: molecular weight (M+H)+: 437/439

Found: molecular weight (M+H)+: 437/439

HPLC retention time: 6.32 min (method A)

Example 2.61:

3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.61.a. 3,4'-dichloro-biphenyl-4-carboxylic acid

It was produced analogously to example 2.55a from 0.59 g (2.5 mmol) of 4-bromo-2-chloro-benzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.

Yield: 0.55 g (82.4% of theoretical).

C13H8Cl2O2 (M = 267.11)

Calculated: molecular weight (M-H)-: 265/267/269

Found: molecular weight (M-H)-: 265/267/269

HPLC retention time: 8.83 min (method A)

2.61.b. 3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 134 mg (0.5 mmol) of 3,4'-dichloro-biphenyl-4 -carboxylic acids.

Yield: 24 mg (10.6% of theoretical)

C26H26Cl2N2O (M = 453.42)

Calculated: molecular weight (M+H)+: 453/455/457

Found: molecular weight (M+H)+: 453/455/457

HPLC retention time: 6.41 min (method A)

Example 2.62:

4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.62a. 4'-chloro-3-fluoro-biphenyl-4-cart)oxylic acid

It was produced analogously to example 2.55.a from 0.55 g (2.5 mmol) of 4-bromo-2-fluoro-benzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.

Yield: 0.60 g (95.7% of theoretical).

C13H8ClFO2 (M = 250.66)

Calculated: molecular weight (M-H)-: 249/251

Found: molecular weight (M-H)-: 249/251

HPLC retention time: 8.22 min (method A)

2.62.b. 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethnylamine and 125 mg (0.5 mmol) of 4'-chloro-3-fluoro- biphenyl-4-carboxylic acids.

Yield: 37 mg (16.9% of theoretical).

C26H26ClFN2O (M = 436.96)

Calculated: molecular weight (M+H)+: 437/439

Found: molecular weight (M+H)+: 437/439

HPLC retention time: 6.45 min (method A)

Example 2.63:

4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.63.a 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid

It was produced analogously to example 2.55.a from 0.66 g (3.0 mmol) of 4-bromo-3-fluoro-benzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.

Yield: 0.60 g (79.8% of theoretical).

C13H8ClFO2 (M = 250.66)

Calculated: molecular weight (M-H)-: 249/251

Found: molecular weight (M-H)-: 249/251

HPLC retention time: 8.50 min (method A)

2.63.b. 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 163 mg (0.8 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 201 mg (0.8 mmol) of 4'-chloro-2-fluoro-biphenyl -4-carboxylic acids.

Yield: 74 mg (21.2% of theoretical).

C26H26ClFN2O (M = 436.96)

Calculated: molecular weight (M+H)+: 437/439

Found: molecular weight (M+H)+: 437/439

HPLC retention time: 6.61 min (method A)

Example 2.64:

3-nitro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.64.a. 3-nitro-biphenyl-4-carboxylic acid

150 mg (0.13 mmol) of tetrakis-(triphenylphosphine)-palladium is added to a solution of 1.0 g (4.07 mmol) of 4-bromo-2-nitro-benzoic acid in 20 ml of toluene and stirred for 10 min at room temperature. Then a solution of 0.5 g (4.10 mmol) of phenylboronic acid in 10 ml of MeOH and a solution of 1.0 g of Na2CO3 in 10 ml of water are added. The reaction mixture was refluxed for 5 h and stirred at room temperature over the weekend. Solvents are removed under vacuum, the residue is mixed with water, acidified with conc. HCl, extracted with EtOAc, the organic phase was dried over Na2SO4 and then the solvent was removed.

Yield: 0.87 g (87.5% of theoretical).

Rf value: 0.40 (silica gel, dichloromethane/ethanol 3:1).

2.64.b. 3-nitro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 122 mg (0.5 mmol) of 3-nitro-biphenyl-4-carboxylic acid .

Yield: 100 mg (46.6% of the theoretical).

C26H27N3O3 (M = 429.52)

Calculated: molecular weight (M+H)+: 430

Found: molecular weight (M+H)+: 430

HPLC retention time: 5.83 min (method A)

Example 2.65:

5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.65.a. 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid

It was produced analogously to example 2.55a from 0.51 g (2.5 mmol) of 5-bromo-pyridine-2-carboxylic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.

Yield: 0.23 g (39.4% of theoretical).

C12H8ClNO2 (M = 233.66)

Calculated: molecular weight (M-H)-: 232/234

Found: molecular weight (M-H)-: 232/234

HPLC retention time: 5.89 min (method A)

2.65.b. 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 116 mg (0.5 mmol) of 5-(4-chloro-phenyl)- pyridine-2-carboxylic acids.

Yield: 7 mg (3.3% of theoretical).

C25H26ClN3O (M = 419.96)

Calculated: molecular weight (M+H)+: 420/422

Found: molecular weight (M+H)+: 420/422

HPLC retention time: 6.40 min (method A)

Example 2.66:

N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-3-yl-benzamide

[image]

2.66.a. Ethyl 4-thiophen-3-yl-benzoate

It was produced analogously to example 2.46.b from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophene-3-boronic acid.

Yield: 348 mg (100% of theoretical).

C13H12O2S (M = 232.30)

Calculated: molecular weight (M+H)+: 233

Found: molecular weight (M+H)+: 233

HPLC retention time: 6.20 min (method B)

2.66.b. 4-thiophen-3-yl-benzoic acid

It was produced analogously to example 2.7.b from 280 mg (1.5 mmol) of ethyl 4-thiophen-3-yl-benzoate.

Yield: 146 mg (59.3% of theoretical).

C11H8O2S (M = 204.25)

Calculated: molecular weight (M-H)-: 203

Found: molecular weight (M-H)-: 203

HPLC retention time: 7.60 min (method A)

2.66.c. N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-3-yl-benzamide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 102 mg (0.5 mmol) of 4-thiophen-3-yl-benzoic acid. .

Yield: 103 mg (53.0% of theoretical).

C24H26N2OS (M = 390.55)

Calculated: molecular weight (M+H)+: 391

Found: molecular weight (M+H)+: 391

HPLC retention time: 6.10 min (method A)

Example 2.67:

N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-2-yl-benzamide

[image]

2.67a. Ethyl 4-thiophen-2-yl-benzoate

It was produced analogously to example 2.46.b from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophene-2-boronic acid.

Yield: 348 mg (100% of theoretical).

C13H12O2S (M = 232.30)

Calculated: molecular weight (M+H)+: 233

Found: molecular weight (M+H)+: 233

HPLC retention time: 6.29 min (method B)

2.67.b. 4-thiophen-2-yl-benzoic acid

It was produced analogously to example 2.7.b from 280 mg (1.5 mmol) of ethyl 4-thiophen-2-yl-benzoate.

Yield: 126 mg (51.2% of theoretical).

C11H8O2S (M = 204.25)

Calculated: molecular weight (M-H)-: 203

Found: molecular weight (M-H)-: 203

HPLC retention time: 7.60 min (method A)

2.67.c. N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-2-yl-benzamide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 102 mg (0.5 mmol) of 4-thiophen-2-yl-benzoic acid. .

Yield: 112 mg (57.5% of theoretical).

C24H26N2OS (M = 390.55)

Calculated: molecular weight (M+H)+: 391

Found: molecular weight (M+H)+: 391

HPLC retention time: 6.05 min (method A)

Example 2.68:

4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.68a. 4-(5-chloro-thiophen-2-yl)-benzoic acid

It was produced analogously to example 2.55.a from 300 mg (1.52 mmol) of 2-bromo-5-chlorothiophene and 277 mg (1.67 mmol) of 4-carboxyphenyl-boronic acid using KHSO4 solution for acidification during processing of the reaction mixture.

Yield: 76 mg (21.0% of theoretical).

C11H7ClO2S (M = 238.69)

Calculated: molecular weight (M-H)-: 237/239

Found: molecular weight (M-H)-: 237/239

HPLC retention time: 8.75 min (method A)

2.68.b. 4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 61 mg (0.3 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 71 mg (0.3 mmol) of 4-(5-chloro-thiophene-2 -yl)-benzoic acid.

Yield: 29 mg (22.9% of theoretical).

C24H25ClN2OS (M = 425.0)

Calculated: molecular weight (M+H)+: 425/427

Found: molecular weight (M+H)+: 425/427

HPLC retention time: 6.65 min (method A)

Example 2.69:

4-furan-2-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.69.a. 4-furan-2-yl-benzoic acid

It was produced analogously to example 2.68a from 302 mg (1.5 mmol) of 4-bromo-benzoic acid and 201 mg (1.8 mmol) of furan-2-boronic acid.

Yield: 166 mg (58.8% of theoretical).

C11H8O3 (M = 188.19)

Calculated: molecular weight (M-H)-: 187

Found: molecular weight (M-H)-: 187

HPLC retention time: 6.82 min (method A)

2.69b. 4-furan-2-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 94 mg (0.5 mmol) of 4-furan-2-yl-benzoic acid .

Yield: 91 mg (48.4% of theoretical).

C24H26N2O2 (M = 374.49)

Calculated: molecular weight (M+H)+: 375

Found: molecular weight (M+H)+: 375

HPLC retention time: 6.48 min (method A)

Example 2.70:

4-(5-methyl-pyridin-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.70a. 4-(5-methyl-pyridin-2-yl)-benzoic acid

It was produced analogously to example 2.55.a from 430 mg (2.50 mmol) of 2-bromo-5-methylpyridine and 498 mg (3.00 mmol) of 4-carboxyphenyl-boronic acid.

Yield: 300 mg (56.3% of the theoretical).

C13H11NO2 (M = 213.24)

Calculated: molecular weight (M+H)+: 214

Found: molecular weight (M+H)+: 214

HPLC retention time: 4.55 min (method A)

2.70.b. 4-(5-methyl-pyridin-2-yl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl-benzamide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 107 mg (0.5 mmol) of 4-(5-methyl-pyridin-2 -yl)-benzoic acid.

Yield: 53 mg (26.5% of theoretical).

C26H29N3O (M = 399.54)

Calculated: molecular weight (M+H)+: 400

Found: molecular weight (M+H)+: 400

HPLC retention time: 3.98 min (method A)

Example 2.71:

4-(6-methyl-pyridin-3-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.71.a. 4-(6-Methyl-pyridin-3-yl)-benzoic acid

It was produced analogously to example 2.55.a from 430 mg (2.50 mmol) of 5-bromo-2-methylpyridine and 498 mg (3.00 mmol) of 4-carboxyphenylboronic acid.

Yield: 300 mg (56.3% of the theoretical).

C13H11NO2 (M = 213.24)

Calculated: molecular weight (M+H)+: 214

Found: molecular weight (M+H)+: 214

HPLC retention time: 2.66 min (method A)

2.71.b. 4-(6-methyl-pyridin-3-yl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 107 mg (0.5 mmol) of 4-(6-methyl-pyridin-3 -yl)-benzoic acid.

Yield: 48 mg (24.0% of theoretical).

C26H29N3O (M = 399.54)

Calculated: molecular weight (M+H)+: 400

Found: molecular weight (M+H)+: 400

HPLC retention time: 3.06 min (method A)

Example 2.72:

4-(4-chloro-phenyl)-thiophene-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.72.a. Methyl 4-(4-chloro-phenyl)-thiophene-2-carboxylate

420 mg (1.25 mmol) of methyl 4-bromo-thiophene-2-carboxylate are dissolved in 10 ml of dioxane and 5 ml of 2M Na2CO3 solution. 196 mg (0.06 mmol) of 4-chloro-phenyl-boronic acid and 72 mg (0.06 mmol) of tetrakis-(triphenylphosphine)-palladium are successively added, the reaction mixture is refluxed for 6 h and stirred for a further 60 h at room temperature. temperature. When rewarmed, the hot reaction solution was filtered off with suction through a glass fiber filter, washed with dioxane, mixed with semi-saturated NaHCO 3 solution, and extracted with EtOAc. The combined organic phases are dried over MgSO4. The residue after removing the drying agent and solvent is purified by chromatography on a silica gel column (petroleum ether/ethyl acetate 9:1).

Yield: 150 mg (47.3% of theoretical).

C12H9ClO2S (M = 252.72)

Calculated: molecular weight (M+H)+: 253/255

Found: molecular weight (M+H)+: 253/255

HPLC retention time: 6.21 min (method B)

2.72.b. 4-(4-Chloro-phenyl)-thiophene-2-carboxylic acid

2 ml of 1M NaOH solution was added to a solution of 150 mg of methyl 4-(4-chloro-phenyl)-thiophene-2-carboxylate in 10 ml of EtOH and the reaction solution was stirred at room temperature over the weekend. The solvent is evaporated in a vacuum, the residue is mixed with 2 ml of 1N hydrochloric acid and cooled to 0°C. The precipitated product is sucked off, washed with water and dried at 50°C.

Yield: 140 mg (98.7% of theoretical).

C11H7ClO2S (M = 238.69)

Calculated: molecular weight (M+H)+: 239/241

Found: molecular weight (M+H)+: 239/241

HPLC retention time: 8.31 min (method A)

2.72.c. 4-(4-chloro-phenyl)-thiophene-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 144 mg (0.70 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 140 mg (0.59 mmol) of 4-(4-chloro-phenyl)- thiophene-2-carboxylic acids.

Yield: 78 mg (31.3% of theoretical).

C26H29N3O (M = 425.00)

Calculated: molecular weight (M+H)+: 425/427

Found: molecular weight (M+H)+: 425/427

HPLC retention time: 3.90 min (method A)

Example 2.73:

4-(5-acetyl-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.73a. 4-iodo-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 2.04 g (10.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 2.48 g (10.0 mmol) of 4-iodo-benzoic acid .

Yield: 1.91 g (44.0% of theoretical).

C20H23IN2O (M = 434.32)

Calculated: molecular weight (M+H)+: 435

Found: molecular weight (M+H)+: 435

HPLC retention time: 5.40 min (method A)

2.73b. 4-(5-acetyl-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide

It was produced analogously to example 2.46b from 250 mg (0.58 mmol) of 4-iodo-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benz-amide and 118 mg (0.69 mmol ) of 5-acetyl-2-thiophene-boronic acid, by refluxing the reaction mixture for 15 h.

Yield: 50 mg (20.2% of theoretical).

C26H28N2O2S (M = 432.59)

Calculated: molecular weight (M+H)+: 433

Found: molecular weight (M+H)+: 433

HPLC retention time: 3.91 min (method B)

Example 2.74:

4-(5-formyl-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

It was produced analogously to example 2.46.b from 250 mg (0.58 mmol) of 4-iodo-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benz-amide and 107 mg (0.69 mmol) of 5-formyl-2-thiophene-boronic acid, by refluxing the reaction mixture for 15 h.

Yield: 22 mg (9.1% of theoretical).

C25H26N2O2S (M = 418.56)

Calculated: molecular weight (M+H)+: 419

Found: molecular weight (M+H)+: 419

HPLC retention time: 3.82 min (method B)

Example 2.75:

4'-chloro-biphenyl-4-carboxylic acid [2-(4-aminomethyl-phenyl)-ethyl]-amide

[image]

2.75.a. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate

20 ml of thionyl chloride and 1 ml of DMF were added dropwise to 9.31 g (40 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. The reaction mixture is heated for 2 h at 60°C. Then excess thionyl chloride is removed in vacuo at 50°C and the residue is taken up in 200 ml of CH2Cl2. 9.19 g (40 mmol) of ethyl 4-(2-amino-ethyl)-benzoate, used in the form of hydrochloride, in 100 ml of a 10% aqueous Na2CO3 solution were added dropwise to that solution and the reaction mixture was further stirred hour at room temperature. After adding water and CH2Cl2, the organic phase is separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are washed with half-saturated NaHCO3 solution and water and dried over MgSO4. After removing the drying agent, the solution is filtered through activated carbon, evaporated in vacuo and the residue recrystallized from tert-butylmethyl ether.

Yield: 11.93 g (73.1% of theoretical)

C24H22ClNO3 (M = 407.90)

Calculated: molecular weight (M+H)+: 408

Found: molecular weight (M+H)+: 408

HPLC retention time: 9.8 min (method A)

2.75.b. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid

50 ml of 2M NaOH solution is added to a solution of 11.93 g (29.25 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate in 150 ml EtOH and stirred for 2 h at room temperature. The reaction solution is adjusted to pH 6-7 with 1N HCl solution, the precipitated product is filtered off and dried in a vacuum oven.

Yield: 10.74 g (96.7% of theoretical).

C22H22ClNO3 (M = 379.85)

Calculated: molecular weight (M+H)+: 380/382

Found: molecular weight (M+H)+: 380/382

HPLC retention time: 8.0 min (method A)

2.75c. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-hydroxymethyl-phenyl)-ethyl]-amide

4.82 g (29.69 mmol) of CDI was added to a solution of 10.74 g (28.28 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]- of ethyl}-benzoic acid in 150 ml of dry THF and the reaction mixture is heated for 2 h at 50°C. This solution was added to a suspension of 2.14 g (56.56 mmol) of NaBH 4 in 5 ml of water and stirred vigorously for a further hour at room temperature. The pH of the solution was adjusted to 6 using 1N HCl solution, and this was then mixed with EtOAc and filtered. The filtrate was washed with half-saturated NaHCO3 solution and water and dried over MgSO4. As the residue still contains unreacted 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid after removal of drying agent and solvent, the above reduction procedure is repeated. The obtained product is dried at 40°C.

Yield: 9.3 g (89.9% of theoretical)

C22H20ClNO2 (M = 365.86)

Calculated: molecular weight (M+H)+: 366/368

Found: molecular weight (M+H)+: 366/368

HPLC retention time: 8.11 min (method A)

2.75 d. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-bromo-methyl-phenyl)-ethyl]-amide

1.22 ml of PBr3 was added dropwise to a solution of 7.9 g (21.59 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-phenyl)-ethyl]-amide in 300 ml of CH2Cl2. The reaction mixture was stirred overnight at room temperature. The resulting precipitate is suctioned off and the filtrate is evaporated. The residue is triturated with a little acetonitrile and CH2Cl2, filtered off with suction, mixed with the first precipitate obtained and dried in air.

Yield: 8.6 g (92.9% of theoretical).

C22H19BrClNO (M = 428.76)

Calculated: molecular weight (M+H)+: 428/430/432

Found: molecular weight (M+H)+: 428/430/432

Rf value: 0.40 (silica gel, CH2Cl2).

2.75.e. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-aminomethyl-phenyl)-ethyl]-amide

3 ml of a 0.5 M solution of NH3 in dioxane is added to a solution of 150 mg (0.35 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl] -amide in 10 ml of acetonitrile and stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is purified by column chromatography (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

Yield: 8 mg (6.3% of theoretical).

C22H21ClN2O (M = 364.88)

Calculated: molecular weight (M+H)+: 365/367

Found: molecular weight (M+H)+: 365/367

HPLC retention time: 5.97 min (method A)

Example 2.76:

4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(diisopropyl-amino)-methyl]-phenyl}-ethyl)-amide

[image]

47 μl (0.33 mmol) of diisopropylamine was added to a suspension of 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]- amide and 55 mg (0.4 mmol) of K2CO3 in 20 ml of acetonitrile and the reaction mixture was stirred overnight at room temperature. This is diluted with CH 2 Cl 2 , filtered to remove undissolved inorganic salts and the filtrate is evaporated. The residue is triturated with acetonitrile, suction and dried in air.

Yield: 75 mg (55.7% of theoretical).

C28H33ClN2O (M = 449.04)

Calculated: molecular weight (M+H)+: 449/451

Found: molecular weight (M+H)+: 449/451

Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.77:

4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-oxo-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 33 mg (0.33 mmol) of piperazin-2-one.

Yield: 23 mg (17.1% of theoretical).

C26H26ClN3O2 (M = 447.97)

Calculated: molecular weight (M+H)+: 448/450

Found: molecular weight (M+H)+: 448/450

Rf value: 0.10 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.78:

Ethyl [(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-methyl-aminoj-acetate

[image]

It was produced analogously to example 2.76 from 257 mg (0.6 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 193 mg of K2CO3 and 101 mg (0.66 mmol) of ethyl methylaminoacetate (used in the form of hydrochloride).

Yield: 152 mg (54.5% of theoretical).

C27H29ClN2O3 (M = 465.0)

Calculated: molecular weight (M+H)+: 465/467

Found: molecular weight (M+H)+: 465/467

Rf value: 0.40 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.79:

[(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-methyl-amino]-acetic acid

[image]

0.3 ml of 1M NaOH solution was added to a solution of 80 mg (0.17 mmol) ethyl [(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl) -methyl-amino]-acetate in 3 ml of EtOH and refluxed for 1 h. The solvent was evaporated in vacuo and the residue was mixed with water and 0.3 ml of 1 M HCl. The precipitate is sucked off and dried at 40°C.

Yield: 76 mg (100% of theoretical).

C25H25ClN2O3 (M = 436.94)

Calculated: molecular weight (M+H)+: 437/439

Found: molecular weight (M+H)+: 437/439

HPLC retention time: 6.35 min (method A)

Example 2.80:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 42 mg (0.33 mmol) of 1-piperazin-1-yl-ethanone.

Yield: 60 mg (42.0% of theoretical).

C28H30ClN3O2 (M = 476.02)

Calculated: molecular weight (M+H)+: 476/478

Found: molecular weight (M+H)+: 476/478

Rf value: 0.15 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.81:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-aza-bicyclo[2,2,1]hept-5-en-2-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 31 mg (0, 33 mmol) of 2-aza-bicyclo[2,2,1]hept-5-ene.

Yield: 100 mg (75.2% of theoretical).

C28H27ClN2O (M = 442.99)

Calculated: molecular weight (M+H)+: 443/445

Found: molecular weight (M+H)+: 443/445

Rf value: 0.08 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.82:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(1,3-dihydro-isoindol-2-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethnyl]-amide, 97 mg of K2CO3 and 51 mg (0.33 mmol) of 2,3-dihydro-1H-isoindole (used as hydrochloride).

Yield: 80 mg (57.1% of theoretical).

C30H27ClN2O (M = 467.02)

Calculated: molecular weight (M+H)+: 467/469

Found: molecular weight (M+H)+: 467/469

Rf value: 0.40 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.83:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(7-methyl-2,7-diaza-spiro[4,4]non-2-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 46 mg (0.33 mmol) of 2-methyl-2,7-diaza-spiro[4,4]nonane.

Yield: 42 mg (28.7% of theoretical).

C30H34ClN3O (M = 488.08)

Calculated: molecular weight (M+H)+: 488/490

Found: molecular weight (M+H)+: 488/490

Rf value: 0.05 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.84:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3-diethyl-amino-azetidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 138 mg of K2CO3 and 66 mg (0.33 mmol) of azetidin-3-yl-diethylamine (used in the form of bis-hydrochloride); the product is purified by column chromatography.

Yield: 15 mg (10.5% of theoretical).

C29H34ClN3O (M = 476.07)

Calculated: molecular weight (M+H)+: 476/478

Found: molecular weight (M+H)+: 476/478

Rf value: 0.10 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.1).

Example 2.85:

Ethyl (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylate

[image]

It was produced analogously to example 2.76 from 257 mg (0.6 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 193 mg of K2CO3 and 119 mg (0.66 mmol) ethyl (S)-pyrrolidine-2-carboxylate (used as hydrochloride); the product is purified by column chromatography.

Yield: 160 mg (54.3% of theoretical).

C29H31ClN2O3 (M = 491.04)

Calculated: molecular weight (M+H)+: 491/493

Found: molecular weight (M+H)+: 491/493

Rf value: 0.60 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.86:

(S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylic acid

[image]

It was produced analogously to example 2.79 from 130 mg (0.27 mmol) ethyl (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl )-pyrrolidine-2-carboxylate.

Yield: 120 mg (97.8% of theoretical).

C27H27ClN2O3 (M = 462.98)

Calculated: molecular weight (M+H)+: 463/465

Found: molecular weight (M+H)+: 463/465

HPLC retention time: 6.20 min (method A)

Example 2.87:

Tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-3-yl]-carbamate

[image]

It was produced analogously to example 2.76 from 429 mg (1.0 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 205 mg (1.10 mmol) of tert-butyl pyrrole idin-3-yl-carbamate.

Yield: 500 mg (93.6% of the theoretical).

C31H36ClN3O3 (M = 534.10)

Calculated: molecular weight (M+H)+: 534/536

Found: molecular weight (M+H)+: 534/536

Rf value: 0.33 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.88:

4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl)-amide

[image]

1 ml of trifluoroacetic acid is added to a solution of 500 mg (0.94 mmol) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl )-pyrrolidin-3-yl]-carbamate in 15 ml of CH2Cl2 and the reaction mixture was stirred overnight. This is then evaporated and the residue taken up in a little CH2Cl2 and mixed with half-saturated NaHCO3 solution. The precipitated product is filtered off with suction, triturated with acetonitrile and dried at 40°C.

Yield: 240 mg (59.1% of theoretical).

C26H28ClN3O (M = 433.99)

Calculated: molecular weight (M+H)+: 434/436

Found: molecular weight (M+H)+: 434/436

Rf value: 0.22 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

Example 2.89:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3-dimethyl-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

0.12 ml of a 37% aqueous solution of formaldehyde, 28 mg (0.45 mmol) of NaBH3CN and one drop of glacial acetic acid were added to a solution of 60 mg (0.14 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide in 5 ml of acetonitrile. The reaction mixture was stirred overnight at room temperature and then treated with a dilute solution of NaOH and EtOAc. The phases are separated, the organic phase is dried over MgSO4 and then freed from the drying agent and solvent. The residue is purified by column chromatography.

Yield: 10 mg (15.7% of theoretical).

C28H32ClN3O (M = 462.04)

Calculated: molecular weight (M+H)+: 462/464

Found: molecular weight (M+H)+: 462/464

HPLC retention time: 5.16 min (method A)

Example 2.90:

Tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-2-ylmethyl]-carbamate

[image]

It was produced analogously to example 2.76 from 230 mg (0.54 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 116 mg (1 .10 mmol) of tert-butyl pyrrolidin-2-ylmethyl-carbamate.

Yield: 230 mg (78.3% of theoretical).

C32H38ClN3O3 (M = 548.13)

Calculated: molecular weight (M+H)+: 548/550

Found: molecular weight (M+H)+: 548/550

Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).

Example 2.91:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-aminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.88 from 230 mg (0.42 mmol) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine -2-ylmethyl]-carbamate.

Yield: 188 mg (100% of theoretical).

C27H30ClN3O (M = 448.01)

Calculated: molecular weight (M+H)+: 448/450

Found: molecular weight (M+H)+: 448/450

Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

Example 2.92:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-dimethyl-aminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.89 from 40 mg (0.09 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-aminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}- amide, 0.08 ml of 37% aqueous formaldehyde solution and 19 mg (0.30 mmol) of NaBH3CN.

Yield: 10 mg (23.6% of theoretical).

C29H34ClN3O (M = 476.07)

Calculated: molecular weight (M+H)+: 476/478

Found: molecular weight (M+H)+: 476/478

Rf value: 0.12 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

Example 2.93:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-methyl-2,6-diaza-spiro[3,4]oct-6-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.76 from 250 mg (0.58 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 97 mg of K2CO3 and 81 mg (0.64 mmol) of 2-methyl-2,6-diaza-spiro[3,4]octane; the product is purified by HPLC.

Yield: 20 mg (7.2% of theoretical).

C29H32ClN3O (M = 474.05)

Calculated: molecular weight (M+H)+: 474/476

Found: molecular weight (M+H)+: 474/476

Rf value: 0.20 (silica gel, CH2Cl3/MeOH/NH3 9:1:0.1).

Example 2.94:

3-[(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-ethyl-amino]-propionic acid

[image]

A suspension of 257 mg (0.6 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 166 mg (1.2 mmol) of K2CO3 and 138 mg of 3-ethylamino-propionic acid (0.9 mmol, used in the form of hydrochloride) in 20 ml of acetonitrile was stirred for 3 days at room temperature. 5 ml of DMF was added and the mixture was heated for 3 h at 50°C. The reaction mixture is filtered, the filtrate is evaporated and the residue is purified by HPLC.

Yield: 50 mg (17.9% of theoretical).

C27H29ClN2O3 (M = 465.0)

Calculated: molecular weight (M+H)+: 465/467

Found: molecular weight (M+H)+: 465/467

HPLC retention time: 5.85 min (method A)

Example 2.95:

Methyl (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylate

[image]

2.95.a. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate

It was produced according to general procedure I from 10.0 g (42.98 mmol) of 4'-chloro-biphenyl-4-carboxylic acid and 9.87 g (42.98 mmol) of ethyl 4-(2-amino-ethyl) -benzoate.

Yield: 10.64 g (60.7% of theoretical).

C24H22ClNO3 (M = 407.90)

Calculated: molecular weight (M+H)+: 408/410

Found: molecular weight (Mt-H)+: 408/410

Rf value: 0.87 (silica gel, CH2Cl2/MeOH 95:5).

2.95.b. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid

14 ml of 2 M NaOH solution was added to a solution of 10.64 g (26.08 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate in 100 ml of EtOH and the reaction mixture is heated overnight at 60°C. Then a further 30 ml of NaOH solution is added and the mixture is kept at this temperature for a further 3 h. The reaction mixture is adjusted to pH 6-7 with 1M HCl solution, the precipitated product is filtered off and dried in a vacuum.

Yield: 7.65 g (77.2% of theoretical).

C22H18ClNO3 (M = 379.85)

Calculated: molecular weight (M+H)+: 380/382

Found: molecular weight (M+H)+: 380/382

HPLC retention time: 8.1 min (method A)

2.95.c. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-hydroxymethyl-phenyl)-ethyl]-amide

3.24 g (20 mmol) of CDI was added to a solution of 7.2 g (18.97 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoin acid in 150 ml of dry THF and the reaction mixture is heated for 2 h at 50°C. This solution was added to a suspension of 1.44 g (38 mmol) of NaBH 4 in 5 ml of water and stirred for another hour. The reaction mixture was adjusted to pH 6-7 with 1M HCl solution and extracted exhaustively with EtOAc. The organic phase is washed with NaHCO3 solution and with water and dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography (silica gel, CH2Cl2/MeOH 9:1). Since there is still an educt in the product, the procedure described above is repeated with 50% of the reagents used.

Yield: 2.85 g (41.0% of theoretical).

C22H20ClNO2 (M = 365.86)

Calculated: molecular weight (M+H)+: 366/368

Found: molecular weight (M+H)+: 366/368

HPLC retention time: 8.0 min (method A)

2.95 d. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate

1.25 ml (9 mmol) of triethylamine was added to a solution of 1.0 g (2.73 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-phenyl)-ethyl]- of the amide in 100 ml of dry THF and the mixture was cooled to -20°C. Then, 0.64 ml (8.2 mmol) of methanesulfonic acid chloride was added drop by drop and the mixture was stirred for a further 2 h at this temperature. A 5% NaHCO3 solution was added and the mixture was exhaustively extracted with EtOAc. The organic phase is dried over Na2SO4, the drying agent and the solvent are removed and the residue is dried at 30°C in a vacuum.

Yield: 1.21 g (99.7% of theoretical).

C23H22ClNO4S (M = 443.95)

Calculated: molecular weight (M+H)+: 444/446

Found: molecular weight (M+H)+: 444/446

HPLC retention time: 8.8 min (method A)

2.95.e. Methyl {S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylate

Under a nitrogen atmosphere, a solution of 50 mg (0.3 mmol) of methyl (2S)-pyrrolidine-2-carboxylate (used in the form of hydrochloride) and 0.7 ml (0.5 mmol) of triethylamine in 4 ml of DMF was mixed for 20 min at room temperature. Then 111 mg (0.25 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate was added and the mixture was heated for 2 h at 60°C. The reaction mixture was evaporated in vacuo and the residue was purified by HPLC.

Yield: 4 mg (3.4% of theoretical).

C28H29ClN2O3 (M = 477.01)

Calculated: molecular weight (M+H)+: 477/479

Found: molecular weight (M+H)+: 477/479

HPLC retention time: 6.51 min (method A)

Example 2.96:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-methyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[{4-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 35 μl (0.3 mmol ) 2-methyl-piperidine without the use of triethylamine.

Yield: 7 mg (6.3% of theoretical).

C28H31ClN2O (M = 447.03)

Calculated: molecular weight (M+H)+: 447/449

Found: molecular weight (M+H)+: 447/449

HPLC retention time: 6.4 min (method A)

Example 2.97:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 32 μl (0.3 mmol) of 2-methylpyrrolidine without the use of triethylamine.

Yield: 2 mg (1.8% of theoretical).

C27H29ClN2O (M= 433.0)

Calculated: molecular weight (M+H)+: 433/435

Found: molecular weight (M+H)+: 433/435

HPLC retention time: 6.3 min (method A)

Example 2.98:

4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(cyclopropyl-methyl-amino)-methyl]-phenyl}-ethyl)-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 26 μl (0.3 mmol) of cyclopropylmethylamine without the use of triethylamine.

Yield: 4 mg (3.8% of theoretical).

C26H27ClN2O (M = 418.97)

Calculated: molecular weight (M+H)+: 418/420

Found: molecular weight (M+H)+: 418/420

HPLC retention time: 6.4 min (method A)

Example 2.99:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3,4-dihydro-1H-isoquinolin-2-yl methyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 40 mg (0.3 mmol) of 1,2,3,4-tetrahydroisoquinoline without the use of triethylamine.

Yield: 21 mg (17.5% of theoretical).

C26H27ClN2O (M = 481.04)

Calculated: molecular weight (M+H)+: 481/483

Found: molecular weight (M+H)+: 481/483

HPLC retention time: 6.8 min (method A)

Example 2.100:

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-{[(2-hydroxy-ethyl}-methyl-amino]-methyl}-phenyl)-ethyl]-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 24 μl (0.3 mmol) of 2-methylamino-ethanol without the use of triethylamine.

Yield: 13 mg (12.3% of theoretical).

C25H27ClN2O2 (M = 422.96)

Calculated: molecular weight (M+H)+: 423/425

Found: molecular weight (M+H)+: 423/425

HPLC retention time: 5.8 min (method A)

Example 2.101:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 41 μl (0.3 mmol) of 2,6-dimethyl-piperidine without the use of triethylamine.

Yield: 8 mg (6.9% of theoretical).

C29H33ClN2O (M = 461.05)

Calculated: molecular weight (M+H)+: 461/463

Found: molecular weight (M+H)+: 461/463

HPLC retention time: 6.6 min (method A)

Example 2.102:

4'-chloro-biphenyl-4-carboxylic acid-[2-(4-azetidin-1-yl-methyl-phenyl)-ethyl]-amide

[image]

It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 20 μl (0.3 mmol) of azetidine without the use of triethylamine.

Yield: 3 mg (3.0% of theoretical).

C25H25ClN2O (M = 404.94)

Calculated: molecular weight (M+H)+: 405/407

Found: molecular weight (M+H)+: 405/407

HPLC retention time: 5.9 min (method A)

Example 2.103:

4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

It was produced analogously to example 2.95.e from 50 mg (0.11 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 11 μl (0, 14 mmol) of 2,5-dihydro-1H-pyrrole without the use of triethylamine.

Yield: 18 mg (38.2% of theoretical).

C26H25ClN2O (M = 416.95)

Calculated: molecular weight (M+H)+: 417/419

Found: molecular weight (M+H)+: 417/419

HPLC retention time: 6.2 min (method A)

Example 2.104:

4'-bromo-biphenyl-4-carboxylic acid-{2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

[image]

2.104.a. Ethyl 4'-bromo-biphenyl-4-carboxylate

It was produced analogously to example 2.46.b from 1.22 ml (7.47 mmol) of ethyl 4-bromobenzoate and 1.8 g (8.96 mmol) of 4-bromophenylboronic acid by refluxing for 72 h. The product crystallizes from acetonitrile.

Yield: 293 mg (12.8% of theoretical).

C15H13BrO2 (M = 305.17)

Calculated: molecular weight (M+H)+: 304/306

Found: molecular weight (M+H)+: 304/306

Rf value: 0.9 (silica gel, petroleum ether/EtOAc 6:4).

2.104.b. 4'-bromo-biphenyl-4-carboxylic acid

1.24 ml of 2M NaOH solution was added to a solution of 270 mg (0.89 mmol) of ethyl 4'-bromo-biphenyl-4-carboxylate in 10 ml of EtOH and the reaction mixture was stirred for 2 h at room temperature. The pH is adjusted to 6-7 with 1 M HCl, the precipitated product is filtered off and dried.

Yield: 205 mg (83.6% of theoretical).

C13H9BrO2 (M = 277.12)

Calculated: molecular weight (M-H)-: 275/277

Found: molecular weight (M-H)-: 275/277

HPLC retention time: 8.5 min (method A)

2.104.c. [4-(2-amino-ethyl)-phenyl]-methanol

580 mg of Raney nickel was added to 5.8 g (39.41 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile (see Example 1.1e.) in 116 ml of methanolic NH 3 solution and the reaction mixture was hydrogenated under 50 psi H 2 . At the end of the reaction, the catalyst is filtered off, the solvent is removed and the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 7:3:0.3)

Yield: 3.9 g (65.4% of theoretical).

C9H13NO (M = 151.21)

Calculated: molecular weight (M+H)+: 152

Found: molecular weight (M+H)+: 152

Rf value: 0.18 (silica gel, EtOAc/MeOH/NH3 8:2:0.2).

2.104.d Tert-butyl [2-(4-hydroxymethyl-phenyl)-ethyl]-carbamate

17.36 ml of 1M BOC anhydride in CH2Cl2 was added at room temperature to a solution of 2.5 g (16.53 mmol) [4-(2-amino-ethyl)-phenyl]-methanol in 50 ml of CH2Cl2 and the reaction mixture was stir overnight at room temperature. 100 ml of KHSO4 solution is added, the organic phase is separated, washed with diluted NaHCO3 solution and water and dried over MgSO4. After removing the drying agent and solvent, the desired product is obtained.

Yield: 4.06 g (97.7% of theoretical).

C14H21NO3 (M = 251.33)

Calculated: molecular weight (M+H)+: 252

Found: molecular weight (M+H)+: 252

HPLC retention time: 6.4 min (method A)

2.104.e. Tert-butyl [2-(4-chloromethyl-phenyl)-ethyl]-carbamate

1 ml of pyridine is added to a solution of 2.6 g (10.35 mmol) of tert-butyl [2-(4-hydroxymethyl-phenyl)-ethyl]-carbamate in 50 ml of CH2Cl2, cooled to 0°C and added 1.03 ml (12.41 mmol) of thionyl chloride. The mixture is kept for 1 h at 0°C and then allowed to warm to room temperature. The reaction mixture is washed with water, with a dilute solution of KHSO4 and again with water, dried with MgSO4 and filtered through activated carbon. After removing the solvent, the product is obtained as an oil, which reacts further without cleaning.

Yield: 1.8 g (64.5% of theoretical).

C14H20ClNO2 (M = 269.77)

Calculated: molecular weight (M-H)-: 268/270

Found: molecular weight (M-H)-: 268/270

Rf value: 0.62 (silica gel, petroleum ether/EtOAc 7:3).

2.104.f. Tert-butyl {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate

2.37 g (17.13 mmol) of K2CO3 and 0.8 ml (10.38 mmol) of 2,5-dihydro-1H-pyrrole were added to a solution of 1.4 g (5.19 mmol) of tert-butyl [ of 2-(4-chloromethyl-phenyl)-ethyl]-carb-aminate in 50 ml of acetonitrile and the mixture was stirred overnight at room temperature. The reaction mixture is diluted with CH2Cl2, washed with water and dried over MgSO4. After removing the drying agent and solvent, the desired product is obtained.

Yield: 1.46 g (93.0% of theory).

C18H26N2O2 (M = 302.42)

Calculated: molecular weight (M+H)+: 303

Found: molecular weight (M+H)+: 303

Rf value: 0.15 (silica gel, petroleum ether/EtOAc 7:3).

2.104.g 2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine

5 ml of trifluoroacetic acid is added to a solution of 1.21 g (4 mmol) of tert-butyl {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate in 50 ml of CH2Cl2 and stirred for 2 h at room temperature. The reaction mixture is evaporated in vacuo, the residue is mixed with water and CH2Cl2 and basified with K2CO3 solution. The organic phase is separated, washed with water and dried over MgSO4. After removing the drying agent and solvent, the desired product is obtained.

Yield: 0.35 g (43.3% of theoretical).

C13H18N2 (M = 202.30)

Calculated: molecular weight (M+H)+: 203

Found: molecular weight (M+H)+: 203

Rf value: 0.05 (silica gel, EtOAc/MeOH/NH3 9:1:0.1).

2.104.h 4'-bromo-biphenyl-4-carboxylic acid-{2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide

It was produced according to general procedure I from 139 mg (0.50 mmol) of 4'-bromo-biphenyl-4-carboxylic acid and 101 mg (0.50 mmol) of 2-[4-(2,5-dihydro-pyrrole- 1-ylmethyl)-phenyl]-ethylamine.

Yield: 21 mg (9.1% of theoretical).

C26H25BrN2O (M = 461.41)

Calculated: molecular weight (M+H)+: 461/463

Found: molecular weight (M+H)+: 461/463

HPLC retention time: 6.46 min (method A)

Example 2.105:

4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide

[image]

2.105.a. (4-pyridin-2-yl-phenyl)-acetonitrile

It was produced analogously to example 2.46.b from 0.52 ml (5.40 mmol) of 2-bromopyridine and 1.0 g (5.96 mmol) of 4-cyanomethylphenylboronic acid. The residue after removal of drying agent and solvent is triturated with diisopropyl ether and dried in air.

Yield: 0.76 g (72.5% of theoretical).

C13H10N2 (M = 194.24)

Calculated: molecular weight (M+H)+: 195

Found: molecular weight (M+H)+: 195

HPLC retention time: 3.56 min (method B)

2.105.b. 2-(4-Cyanomethyl-phenyl)-1-ethyl-pyridinium iodide

0.38 ml (4.7 mmol) of ethyl iodide was added to a solution of 760 mg (3.91 mmol) of (4-pyridin-2-yl-phenyl)-acetonitrile in 5 ml of DMF and stirred overnight at room temperature. To complete the reaction, the solution is placed in a microwave oven at 120°C for 20 minutes. The solvent was evaporated in vacuo, the residue was mixed with water and extracted with EtOAc. The aqueous phase is evaporated, the residue is triturated with THF and the suspension is cooled to 0°C. The product is sucked off and dried at 50°C.

Yield: 800 mg (58.4% of theoretical).

C15H15JN2 (M = 350.21)

Calculated: Molecular Weight (M)+: 223

Found: Molecular Weight (M)+: 223

HPLC retention time: 1.76 min (method A)

2.105.c. 2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethylamine

100 mg of Raney nickel is added to a solution of 800 mg (2.28 mmol) of 2-(4-cyanomethyl-phenyl)-1-ethyl-pyridinium iodide in 10 ml of methanolic NH3 and the reaction mixture is hydrogenated for 24 h under 20 psi and at room temperature in an autoclave. The catalyst is sucked off, the reaction solution is mixed with 100 mg of PtO2 and hydrogenated again for 30 h at room temperature and under 20 psi. After removing the catalyst, a product (as hydroiodide) is obtained, which reacts further without further purification.

Yield: 700 mg (85.1% of theoretical).

C15H24IN2 (M = 360.28)

Calculated: Molecular Weight (M)+: 233

Found: Molecular Weight (M)+: 233

HPLC retention time: 0.93 min (isocratic water:acetonitrile:formic acid 95:5:0.01 for 8 min).

2.105.d. 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide

It was produced according to general procedure I from 480 mg (1.33 mmol) of 2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethylamine (used in the form of hydroiodide) and 310 mg (1.33 mmol) 4'-chloro-biphenyl-4-carboxylic acids.

Yield: 20 mg (3.4% of theoretical).

C28H31ClN2O (M = 447.03)

Calculated: molecular weight (M+H)+: 447/449

Found: molecular weight (M+H)+: 447/449

HPLC retention time: 6.68 min (method A)

Example 2.106:

4'-chloro-biphenyl-4-carboxylic acid [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide

[image]

2.106.a. Ethyl (E)-3-(1-oxo-indan-5-yl)-acrylate

5.96 ml (55 mmol) of ethyl acrylate, 275 mg (1.21 mmol) of Pd(OAc)2 and 704 mg (2.31 mmol) of tri-o-tolylphosphine were added to a solution of 4.64 g (21, 99 mmol) of 5-bromo-indan-1-one in 110 ml of triethylamine under N2 and the reaction mixture is heated for 4 h at 100oC. The solvent is distilled off, the residue is mixed with 150 ml of EtOAc and 100 ml of ice water, acidified with conc. HCl, the organic phase is washed with 100 ml of water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography (silica gel, hexane/EtOAc 9:1 to 8:2).

Yield: 4.0 g (79.0% of theoretical).

Melting point: 100-102oC

2.106.b. (E)-3-(1-oxo-indan-5-yl)-acrylic acid

10 ml of 2 N NaOH was added to a solution of 4.0 g (17.0 mmol) of ethyl (E)-3-(1-oxo-indan-5-yl)-acrylate in 50 ml of MeOH and the reaction mixture was refluxed for 30 min. This is then mixed with 11 ml of 2 N HCl solution, the MeOH is distilled off, the crystals are filtered off with suction and dried.

Yield: 3.0 g (87.3% of theoretical).

Melting point: 240-244oC

2.106.c. 3-(1-oxo-indan-5-yl)-propionic acid

150 mg of 10% Pd/C was added to a solution of 1.6 g (7.91 mmol) of (E)-3-(1-oxo-indan-5-yl)-acrylic acid in 50 ml of MeOH and the reaction the mixture is shaken in a Parr autoclave at room temperature and 3 bar H2 pressure until the theoretical hydrogen consumption is reached. 10 ml of 1 N NaOH was added and the solvent was removed. The residue was acidified with dilute HCl, exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. The residue after removal of drying agent and solvent is triturated with tert-butylmethyl ether, the precipitate is filtered off with suction and dried.

Yield: 500 mg (31.0% of theoretical).

C12H12O3 (M = 204.23)

Calculated: molecular weight (M-H)-: 203

Found: molecular weight (M-H)-: 203

Rf value: 0.45 (silica gel, CH2Cl2/MeOH 9:1).

2.106.d. Tert-butyl [2-(1-oxo-indan-5-yl)-ethyl]-carbamate

1.6 g (7.83 mmol) of 3-(1-oxo-indan-5-yl)-propionic acid was added to 25 ml of tert-butanol and 2.5 ml of triethylamine under an argon atmosphere. 2.22 ml (10.0 mmol) of diphenyl azido-phosphate was added to this solution and heated for 3 h at 80°C. The reaction mixture was evaporated in vacuo and the residue was purified by chromatography on silica gel.

Yield: 750 mg (34.8% of theoretical).

C16H21NO3 (M = 275.35)

Calculated: Molecular Weight (M)+: 275

Found: Molecular Weight (M)+: 275

Rf value: 0.65 (silica gel, CH2Cl2/MeOH 95:5).

2.106.e Tert-butyl [2-(1-hydroxy-indan-5-yl)-ethyl]-carbamate

700 mg (18.5 mmol) NaBH4 is added portionwise to a solution of 700 mg (2.54 mmol) tert-butyl [2-(1-oxo-indan-5-yl)-ethyl]-carbamate in 70 ml MeOH and stirred overnight at room temperature. The reaction solution is carefully mixed with 10% KHSO4 solution, diluted with water and exhaustively extracted with tert-butylmethyl ether. The organic phase is washed with water and dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography on silica gel.

Yield: 350 mg (49.7% of theoretical).

C16H23N03 (M = 277.37)

Calculated: Molecular Weight (M)+: 277

Found: Molecular Weight (M)+: 277

Rf value: 0.30 (silica gel, petroleum ether/EtOAc 6:4).

2.106.f Tert-butyl [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-carbamate

109 ml (1.5 mmol) of thionyl chloride (dissolved in a little CH2Cl2) was added slowly, dropwise, to a solution of 350 mg (1.26 mmol) of tert-butyl [2-(1-hydroxy-indan-5- yl)-ethyl]-carbamate in 7.5 ml of CH2Cl2 cooled to 0°C. Mixing was continued for another 30 min at 10oC. The reaction solution is mixed with an ice-cold NaHCO3 solution, the organic phase is separated, washed with cold water and dried over MgSO4. After removing the drying agent, the filtrate is cooled to 0°C, 417 μl (5.0 mmol) of pyrrolidine is added dropwise and the reaction mixture is stirred overnight at room temperature. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel.

Yield: 120 mg (28.8% of theoretical).

C20H30N2O2 (M = 330.47)

Calculated: molecular weight (M+H)+: 331

Found: molecular weight (M+H)+: 331

HPLC retention time: 5.6 min (method A)

2.106.g. 2-(1-pyrrolidin-1-yl-indan-5-yl)-ethylamine

100 μl of trifluoroacetic acid is added with slight cooling to a solution of 100 mg (0.3 mmol) of tert-butyl [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-carbamate in 10 ml of CH2Cl2 and it is stirred for 1 h at room temperature. To complete the reaction, a further 500 μl of trifluoroacetic acid was added with cooling and the mixture was stirred for another 2 h at room temperature. The reaction mixture is evaporated in vacuo and the product (as bis-trifluoroacetate) is further reacted without purification.

Yield: 100 mg (72.7% of theoretical).

C19H24F6N2O4 (M = 458.51)

Calculated: molecular weight (M+H)+: 231

Found: molecular weight (M+H)+: 231

Rf value: 0.3 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

2.106 h. 4'-chloro-biphenyl-4-carboxylic acid-[2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide

It was produced according to general procedure I from 100 mg (0.29 mmol) of 2-(1-pyrrolidin-1-yl-indan-5-yl)-ethylamine (used in the form of bis-trifluoroacetate) and 70 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid.

Yield: 40 mg (30.0% of theoretical).

C28H29ClN2O (M = 445.01)

Calculated: molecular weight (M+H)+: 445/447

Found: molecular weight (M+H)+: 445/447

HPLC retention time: 6.65 min (method A)

Example 2.107:

4'-chloro-biphenyl-4-carboxylic acid [2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.107.a. Methyl 2-bromo-4-cyanomethyl-benzoate

A solution of 98.55 g (0.32 mol) of methyl 2-bromo-4-bromo-methnyl-benzoate in 60 ml of EtOH is added to a solution of 24.51 g (0.5 mol) of NaCN in 40 ml of water and the reaction the mixture is refluxed for 5 h. 1 l of tert-butylmethyl ether and 500 ml of water are added, the organic phase is separated, washed several times with water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (petroleum ether/EtOAc 8:2).

Yield: 15.0 g (16.6% of theoretical).

C10H8BrNO2 (M = 254.09)

Calculated: molecular weight (M-H)-: 252/254

Found: molecular weight (M-H)-: 252/254

2.107.b. 2-bromo-4-cyanomethyl-benzoic acid

35 ml of 1M NaOH solution was added to a solution of 7.9 g (31.0 mmol) of methyl 2-bromo-4-cyanomethyl-benzoate in 100 ml of EtOH, the reaction mixture was refluxed for 1 h and then stirred overnight at room temperature. Ice water is added and the mixture is acidified with dilute KHSO4 solution. The precipitate is suctioned off, washed with water and dried at 50°C.

Yield: 6.2 g (83.3% of theoretical).

C9H6BrNO2 (M = 240.06)

Calculated: molecular weight (M-H)-: 238/240

Found: molecular weight (M-H)-: 238/240

HPLC retention time: 3.99 min (method B)

2.107.c. (3-Bromo-4-hydroxymethyl-phenyl)-acetonitrile

1.78 g (11 mmol) of CDI was added to a solution of 2.4 g (10 mmol) of 2-bromo-4-cyanomethyl-benzoic acid in 50 ml of THF and the water bath was heated until gas evolution ceased. This is then added to a solution of 0.76 g (20 mmol) of NaBH4 in 50 ml of water, but the temperature must not rise above 30°C. Stirring is continued for a further 2 h at room temperature, the reaction mixture is carefully acidified with a dilute solution of KHSO4, extracted exhaustively with tert-butylmethyl ether, the organic phase is washed with water and dried over MgSO4. This is filtered through activated carbon and the solvent is removed in vacuo.

Yield: 2.2 g (97.3% of theoretical).

C9H8BrNO (M = 226.07)

Calculated: molecular weight (M-H)-: 224/226

Found: molecular weight (M-H)-: 224/226

Rf value: 0.6 (silica gel, CH2Cl2/MeOH 9:1).

2.107.d. (3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile

1.25 ml (9 mmol) of triethylamine was added to a solution of 1.9 g (8.4 mmol) of (3-bromo-4-hydroxymethyl-phenyl)-acetonitrile in 50 ml of CH2Cl2, cooled to 0°C. and added dropwise a solution of 0.66 ml (8.5 mmol) of methanesulfonic acid chloride in 10 ml of CH2Cl2. The mixture was stirred for 1 h at 0°C and then a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH2Cl2 was added dropwise while cooling with ice. The reaction mixture is heated overnight at room temperature, mixed with water, the organic phase is separated, washed twice with water, filtered through activated carbon and evaporated in a vacuum. The residue is co-evaporated twice with toluene and the resulting product is further reacted without purification.

Yield: 2.25 g (95.9% of theoretical).

C13H15BrN2 (M = 279.18)

Calculated: molecular weight (M+H)+: 279/281

Found: molecular weight (M+H)+: 279/281

Rf value: 0.5 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

2.107.e. 2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine

20 mg of Raney nickel was added to a solution of 225 mg (0.81 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile in 5 ml of methanolic NH3 and 5 ml of EtOAc and shaken in a Parr autoclave for 1 h at room temperature and under 5 psi H2, the catalyst is filtered off, the solvent is evaporated in vacuo and the product is further reacted without purification.

Yield: 225 mg (98.1% of theoretical).

C13H19BrN2 (M = 283.21)

Calculated: molecular weight (M+H)+: 283/285

Found: molecular weight (M+H)+: 283/285

Rf value: 0.08 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

2.107.f. 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide hydrochloride

It was produced according to general procedure I from 220 mg (0.78 mmol) of 2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl-amine and 186 mg (0.8 mmol) of 4'-chloro -biphenyl-4-carboxylic acids. The residue after removal of drying agent and solvent is taken up in isopropanol/tert-butylmethyl ether, mixed with ethereal HCl and evaporated in vacuo. The residue is taken up again in 20 ml of isopropanol, triturated, suctioned off, washed with a little isopropanol and dried at 50°C.

Yield: 165 mg (39.6% of theoretical)

C26H27BrCl2N2O (M = 534.33)

Calculated: molecular weight (M+H)+: 497/499/501

Found: molecular weight (M+H)+: 497/499/501

Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).

Example 2.108:

4'-chloro-biphenyl-4-carboxylic acid-[2-(3-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

17.3 mg (0.28 mmol) of methylboric acid, 2.5 ml of 2M Na2CO3 solution and 32 mg (0.03 mmol) of tetrakis-(triphenyl-phosphine)-palladium are added to a suspension of 150 mg (0.28 mmol ) 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide hydrochloride in 5 ml of dioxane and the reaction mixture was refluxed for 5 h. The hot suspension was filtered off with suction through a glass fiber filter, the filtrate was mixed with half saturated NaHCO 3 solution, extracted exhaustively with EtOAc and dried over MgSO 4 . The residue after removal of drying agent and solvent was purified by chromatography on silica gel (CH2Cl2/MeOH 8:2).

Yield: 20 mg (16.4% of theoretical).

C27H29ClN2O (M = 433.0)

Calculated: molecular weight (M+H)+: 433/435

Found: molecular weight (M+H)+: 433/435

HPLC retention time: 6.47 min (method A)

Example 2.109:

4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.109.a. Ethyl 4-(2-amino-ethyl)-3-nitro-benzoate

5.78 g (57 mmol) of KNO3 was added in portions to a solution of 12.0 g (52 mmol) of ethyl 4-(2-amino-ethyl)-benzoate in 80 ml of conc. H2SO4 cooled to -5°C and stirred for 1 h at that temperature. Add the reaction solution slowly, drop by drop, to ice water (the temperature must not rise above 0°C) and mix for 1 h. The precipitate is suctioned off, washed with water and dried at 50°C.

Yield: 8.2 g (66.2% of theoretical).

C11H14N2O4 (M = 238.25)

Calculated: molecular weight (M+H)+: 239

Found: molecular weight (M+H)+: 239

HPLC retention time: 3.64 min (method A)

2.109.b. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoate

It was produced according to general procedure I from 8.2 g (34 mmol) of ethyl 4-(2-amino-ethyl)-3-nitro-benzoate and 7.91 g (34 mmol) of 4'-chloro-biphenyl-4- carboxylic acids.

Yield: 7.7 g (50.0% of theoretical).

C24H22ClN2O5 (M = 452.90)

Calculated: molecular weight (M+H)+: 452/454

Found: molecular weight (M+H)+: 452/454

HPLC retention time: 6.14 min (method B)

2.109.c. Ethyl 3-amino-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate

0.5 g of Raney Nickel is added to a solution of 7.7 g (17 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoate in 200 ml EtOAc and the reaction mixture is shaken overnight in an autoclave at room temperature and under 10 psi H2. To complete the reaction, 50 ml of THF was added and the mixture was shaken for a further 2 h. The catalyst is filtered off with suction, washed thoroughly with THF, the solvent is evaporated in vacuo, the residue is triturated with EtOAc, filtered again with suction and dried in air.

Yield: 5.0 g (69.5% of theoretical).

C24H23ClN2O3 (M = 422.92)

Calculated: molecular weight (M+H)+: 423/425

Found: molecular weight (M+H)+: 423/425

HPLC retention time: 5.71 min (method B)

2.109.d. Ethyl 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate

20 ml of 48% HBr is added to a solution of 5.0 g (7.69 mmol) ethyl 3-amino-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl }-benzoate in 20 ml of water and cool to 0°C. Then a solution of 0.9 g (13 mmol) of NaNO2 in 5.2 ml of water is added drop by drop so that the temperature does not rise above 5oC and the mixture is stirred for another 10 min at 0oC. Then, immediately at that temperature, a solution of 1.87 g (13 mmol) CuBr in 6.65 ml of 48% HBr is added drop by drop. The reaction mixture is then heated for 1 h at 60°C. Water was added and the mixture was extracted exhaustively with EtOAc. The organic phase is washed with water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (petroleum ether/EtOAc 6:4).

Yield: 1.3 g (34.7% of theoretical).

C24H21BrClNO3 (M = 486.80)

Calculated: molecular weight (M+H)+: 486/488/490

found: molecular weight (M+H)+: 486/488/490

Rf value: 0.55 (silica gel, petroleum ether/EtOAc 6:4).

2.109.e. 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid

6 ml of 1N NaOH solution was added to a suspension of 1.3 g (2.67 mmol) of ethyl 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}- benzoate in 20 ml of EtOH and 5 ml of THF and the reaction mixture was stirred overnight at room temperature. This is evaporated in vacuo, the residue is mixed with water and neutralized with 1 N HCl, after which the product is precipitated. Mixing is continued for another hour with cooling on ice, the mixture is sucked off, washed with water and the product is dried at 50°C.

Yield: 1.2 g (97.9% of theoretical).

C22H27BrClNO3 (M = 458.74)

Calculated: molecular weight (M+H)+: 456/458/460

Found: molecular weight (M+H)+: 456/458/460

HPLC retention time: 5.51 min (method B)

2.109.f. 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-hydroxymethyl-phenyl)-ethyl]-amide

0.64 g (3.92 mmol) of CDI was added to a solution of 1.2 g (2.62 mmol) of 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino ]-ethyl}-benzoic acid in 10 ml of DMF and the mixture is heated at 50°C until gas evolution stops. The reaction mixture was added to a solution of 0.3 g (7.85 mmol) of NaBH 4 in 10 ml of water, stirred for 1 h at room temperature, acidified with dilute KHSO 4 , and extracted exhaustively with EtOAc. The organic phase is washed with half-saturated NaHCO3 solution and dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.

Yield: 0.87 g (74.8% of theoretical).

C22H19BrClNO2 (M = 444.76)

Calculated: molecular weight (M+H)+: 444/446/448

Found: molecular weight (M+H)+: 444/446/448

HPLC retention time: 8.07 min (method A)

2.109.g. 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-chloromethyl-phenyl)-ethyl]-amide

0.24 ml (2.93 mmol) of pyridine is added to a solution of 0.87 g (1.96 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-hydroxymethyl- phenyl)-ethyl]-amide in 20 ml of CH2Cl2 and cooled to 0°C. 0.21 ml (2.93 mmol) of thionyl chloride was added, the mixture was stirred for 1 h at that temperature and then allowed to warm to room temperature. Then water is added and the mixture is filtered through Celite, the aqueous phase is extracted with CH2Cl2 and the combined organic phases are dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.

Yield: 0.66 g (72.8% of theoretical).

C22H18BrCl2NO (M = 463.21)

Calculated: molecular weight (M+H)+: 462/464/466

Found: molecular weight (M+H)+: 462/464/466

HPLC retention time: 6.37 min (method B)

2.109.h 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

0.59 g (4.28 mmol) of K2CO3 and 0.24 ml (2.85 mmol) of pyrrolidine were added to a solution of 0.66 g (1.43 mmol) of 4'-chloro-biphenyl-4-carboxylic acid- [2-(2-bromo-4-chloromethyl-phenyl)-ethyl]-amide in 20 ml of acetonitrile and 6 ml of DMF and stirred for 5 h at room temperature. Water is added, the mixture is extracted exhaustively with EtOAc, the organic phase is washed several times with water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (CH2Cl2/MeOH 9:1).

Yield: 0.2 g (28.2% of theoretical).

C26H26BrClN2O (M = 497.87)

Calculated: molecular weight (M+H)+: 497/499/501

Found: molecular weight (M+H)+: 497/499/501

HPLC retention time: 4.39 min (method B)

Example 2.110:

4'-chloro-biphenyl-4-carboxylic acid-[2-(2-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

It is produced analogously to example 2.108. from 200 mg (0.40 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide and 27.3 mg ( 0.44 mmol) of methylboric acid by refluxing for only 2 h and purifying the product by HPLC.

Yield: 62 mg (35.6% of theoretical).

C27H29ClN2O (M = 433.0)

Calculated: molecular weight (M+H)+: 433/435

Found: molecular weight (M+H)+: 433/435

HPLC retention time: 6.15 min (method A)

Example 2.111:

4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.111.a. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoic acid

2 ml of 1N NaOH solution was added to a solution of 200 mg (0.44 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoate ( example 2.109.b) in 10 ml of EtOH and the reaction mixture is stirred for 1 h at room temperature. The mixture is evaporated in a vacuum, water and 2 ml of 1N HCl solution are added to the residue and the suspension is stirred for 30 min in an ice bath. The product is sucked off, washed with water and dried at 50°C.

Yield: 180 mg (95.9% of theoretical).

C22H17ClN2O5 (M = 424.84)

Calculated: molecular weight (M+H)+: 425/427

Found: molecular weight (M+H)+: 425/427

Rf value: 0.07 (silica gel, EtOAc/MeOH/NH3 9:1:0.1).

2.111.b. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-2-nitro-phenyl)-ethyl]-amide

It was produced analogously to example 2.109.f from 180 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoic acid.

Yield: 110 mg (63.1% of theoretical).

C22H19ClN2O4 (M = 410.86)

Calculated: molecular weight (M+H)+: 411/413

Found: molecular weight (M+H)+: 411/413

HPLC retention time: 8.27 min (method A)

2.111.c. 4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

23 μl of methanesulfonic acid chloride is added slowly, dropwise, to a solution of 110 mg (0.27 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-{4-hydroxymethyl-2-nitro-phenyl) -ethyl]-amide and 48 μl of triethylamine in 5 ml of CH2Cl2 cooled to 5oC. The solution is heated for 1 h at 40°C, 5 ml of DMF and 115 μl (1.34 mmol) of pyrrolidine are added and the mixture is heated at 80°C for another hour, during which the CH2Cl2 is evaporated. The reaction mixture is evaporated in vacuo, the residue is mixed with water, extracted exhaustively with EtOAc and the organic phase is dried over MgSO4. The residue after removal of drying agent and solvent is purified by HPLC.

Yield: 11 mg (8.8% of theoretical).

C26H26ClN3O3 (M = 463.97)

Calculated: molecular weight (M+H)+: 464/466

Found: molecular weight (M+H)+: 464/466

HPLC retention time: 6.44 min (method A)

Example 2.112:

4'-chloro-biphenyl-4-carboxylic acid [2-(2-methanesulfonyl-amino-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.112.a. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylamino-benzoate

44 μl (0.57 mmol) of methanesulfonic acid chloride was added slowly, dropwise, to a solution of 200 mg (0.47 mmol) of ethyl 3-amino-4-{2-[(4'-chloro-biphenyl-4 -carbonyl)-amino]-ethyl}-benzoate (example 2.109.c) in 5 ml of pyridine cooled to 0°C and the reaction mixture was stirred for 1 h at room temperature. This was mixed with ice water, extracted exhaustively with EtOAc, the organic phase was washed several times with water and dried over MgSO 4 . The residue after removal of desiccant and solvent continues to react without cleaning.

Yield: 230 mg (97.1% of theoretical).

C25H25ClN2O5S (M = 501.01)

Calculated: molecular weight (M+H)+: 501/503

Found: molecular weight (M+H)+: 501/503

HPLC retention time: 5.66 min (method B)

2.112.b. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylamino-benzoic acid

It was produced analogously to example 2.111.a from 230 mg (0.46 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylaminobenzoate.

Yield: 180 mg (82.9% of theoretical).

C23H21ClN2O5S (M = 472.95)

Calculated: molecular weight (M-H)-: 471/473

Found: molecular weight (M-H)-: 471/473

HPLC retention time: 7.67 min (method A)

2.112.c. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-2-methanesulfonylamino-phenyl)-ethyl]-amide

It was produced analogously to example 2.109.f from 180 mg (0.38 mmol) of 4-{2-[{4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylamino-benzoic acid.

Yield: 150 mg (85.8% of theoretical).

C23H23ClN2O4S (M = 458.97)

Calculated: molecular weight (M+H)+: 459/461

Found: molecular weight (M+H)+: 459/461

HPLC retention time: 7.53 min (method A)

2.112.d. 4'-chloro-biphenyl-4-carboxylic acid [2-(2-methanesulfonylamino-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced analogously to example 2.111c from 150 mg (0.33 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-{4-hydroxymethyl-2-methanesulfonylamino-phenyl)-ethyl]-amide and 140 μl ( 1.64 mmol) of pyrrolidine. After purification by HPLC, the product is obtained as a formate salt.

Yield: 18 mg (9.9% of theoretical).

C27H30ClN3O3S*CH2O2 (M = 558.10) ;Calculated: molecular weight (M+H)+: 512/514 ;Found: molecular weight (M+H)+: 512/514 ;Retention time HPLC: 6.13 min ( method A) ;Example 2.113: ;4'-chloro-biphenyl-4-carboxylic acid-[2-(3-pyridin-4-yl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide ;[image ] ;It was produced analogously to example 2.108 from 200 mg (0.40 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]- amide and 74 mg (0.60 mmol) of pyridine-4-boronic acid, by purifying the product by HPLC. ;Utilization: 13 mg (6.5% of theoretical). ;C31H30ClN3O (M = 496.06) ;Calculated: molecular mass (M+H)+: 496/498 ;Found: molecular mass (M+H)+: 496/498 ;Retention time HPLC: 6.37 min (method A) ;Example 2.114: ;Methyl 5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoate ;[image] ;2.114a. Methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl-benzoate; 0.5 ml triethylamine (3.58 mmol), 40 mg (0.18 mmol) Pd(OAc)2 and 99 mg (0.18 mmol) 1 ,1'-diphenylphosphino-ferrocene is added to a solution of 500 mg (1.79 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (Example 2.107.d) in 10 ml of MeOH and 10 ml of of DMF. The reaction mixture was stirred for 15 h at 50°C in an autoclave under 2 bar CO. To complete the reaction, a further 0.5 ml of triethylamine, 40 mg of Pd(OAc)2 and 99 mg of 1,1'-diphenylphosphino-ferrocene are added and the mixture is stirred for a further 10 h at 50°C and under 2 bar CO and overnight under 4 bar CO and at 70oC. The solvents were evaporated in vacuo, the residue was mixed with EtOAc and extracted twice with water. The aqueous phase was saturated with K2CO3, exhaustively extracted with EtOAc and dried over MgSO4. After removing the desiccant and solvent, the product remains as a black oil that reacts further without cleaning. ;Utilization: 380 mg (82.1% of theoretical). ;C15H18N2O2 (M = 258.32) ;Calculated: molecular weight (M+H)+: 259 ;Found: molecular weight (M+H)+: 259 ;Retention time HPLC: 2.49 min (method B) ;2.114 .b. Methyl 5-(2-amino-ethyl)-2-pyrrolidin-1-ylmethyl-benzoate; 100 mg Raney nickel is added to a solution of 380 mg (1.47 mmol) methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl -benzoate in 20 ml of methanolic NH3 and the reaction mixture is hydrogenated for 27 hours under 20 psi H2 at room temperature. The catalyst is sucked off, the solvent is removed and the residue reacts further without cleaning. ;Utilization: 330 mg (85.5% of theoretical). ;C15H22N2O2 (M = 262.36) ;Calculated: molecular mass (M+H)+: 263 ;Found: molecular mass (M+H)+: 263 ;Retention time HPLC: 1.40 min (method A) ;2.114 c. Methyl 5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoate; It was produced according to general procedure I from 330 mg (1.26 mmol) of methyl 5-(2-amino-ethyl)-2-pyrrolidin-1-ylmethyl-benzoate and 293 mg (1.26 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 315 mg (52.5% of theoretical). ;C28H29ClN2O3 (M = 477.01) ;Calculated: molecular mass (M+H)+: 477/479 ;Found: molecular mass (M+H)+: 477/479 ;Retention time HPLC: 6.82 min (method A) ;Example 2.115: ;5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoic acid ;[image] ;It is produced analogously to example 2.111.a from 310 mg (0.65 mmol) of methyl 5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoate. ;Utilization: 85 mg (28.2% of theoretical). ;C27H27ClN2O3 (M = 462.98) ;Calculated: molecular mass (M+H)+: 463/465 ;Found: molecular mass (M+H)+: 463/465 ;Retention time HPLC: 6.30 min (method A) ; Example 2.116: ; Tert-butyl (5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-phenyl)-carbamate ;[ image]; 0.27 ml (1.92 mmol) of triethylamine and 0.41 ml (1.92 mmol) of diphenyl azido-phosphate are added to a solution of 740 mg (1.6 mmol) of 5-{2-[(4 '-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoic acid in 10 ml of tert-butanol and the reaction mixture is refluxed for 5 h. This is evaporated in vacuo, the residue is mixed with CH2Cl2, extracted with 1N NaOH solution and the organic phase is dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography on silica gel. ;Utilization: 85 mg (28.2% of theoretical). ;C31H36ClN3O3 (M = 534.10) ;Calculated: molecular weight (M+H)+: 534/536 ;Found: molecular weight (M+H)+: 534/536 ;Retention time HPLC: 4.82 min (method B) ;Example 2.117: ;4'-chloro-biphenyl-4-carboxylic acid-[2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide ;[image] ;2.117.a . (4-pyrrolidin-1-ylmethyl-3-trimethylsilanylethynyl-phenyl)-acetonitrile; A suspension of 0.36 g (1.29 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (example 2.107 .d), 0.36 ml (2.58 mmol) trimethylsilylacetylene, 0.36 ml (2.58 mmol) triethylamine, 25 mg (0.13 mmol) CuI and 0.15 g (0.13 mmol) tetrakis- (triphenylphosphine)-palladium in 3 ml of DMF is stirred in a microwave heater (CEM) for 15 min at 100°C and 200 Watts. When cooled, saturated NaCl solution was added to the reaction mixture, the mixture was exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (EtOAc). ;Utilization: 50 mg (13.1% of theoretical). ;C18H24N2Si (M = 296.49) ;Calculated: molecular weight (M+H)+: 297 ;Found: molecular weight (M+H)+: 297 ;Retention time HPLC: 6.39 min (method A) ;2.117 .b 2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine; 20 mg Raney nickel is added to a solution of 50 mg (0.17 mmol) (4-pyrrolidin-1-ylmethyl-3- of trimethylsilanylethynyl-phenyl)-acetonitrile in 5 ml of methanolic NH3 and the reaction mixture was shaken for 22 h at room temperature and under 3 bar H2. The catalyst is sucked off and the solvent is removed in vacuo. The crude product reacts further without purification. ;Utilization: 39 mg (100% of theoretical). ;C15H24N2 (M = 232.37) ;Calculated: molecular mass (M+H)+: 233 ;Found: molecular mass (M+H)+: 233 ;2.117.c 4'-chloro-biphenyl-4-carboxylic acid [2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide; It was produced according to the general procedure I from 40 mg (0.17 mmol) of 2-(3-ethyl-4-pyrrolidine) -1-ylmethyl-phenyl)-ethyl-amine and 48 mg (0.21 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 2 mg (2.6% of theoretical). ;C28H31ClN2O (M = 447.03) ;Calculated: molecular mass (M+H)+: 447/449 ;Found: molecular mass (M+H)+: 447/449 ;Retention time HPLC: 6.87 min (method A) ;Example 2.118: ;4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide ;[image] ;2.118a. Methyl 6-dibromo-methyl-nicotinate; 53.4 g (0.3 mol) of NBS and 2 g of dibenzoyl peroxide are added to a solution of 38.96 g (0.25 mol) of methyl 6-methyl-nicotinate in 1 l CCl4 and the reaction mixture is refluxed overnight. Another 26.7 g (0.15 mol) of NBS and 1 g of dibenzoyl peroxide were then added and the mixture was refluxed again for 24 h. When the reaction mixture is cooled, the precipitate is filtered off with suction, the solvent is removed and the residue is purified by chromatography. Yield: 15.0 g (19.4% of theoretical). ;C8H7Br2NO2 (M = 308.96) ;Calculated: molecular weight (M+H)+: 308/310/312 ;Found: molecular weight (M+H)+: 308/310/312 ;Rf value: 0.6 (silica gel, petroleum ether/EtOAc 8:2). ; 2.118.b. Methyl 6-dimethoxymethyl-nicotinate; 13.9 ml NaOMe in MeOH (30%, 75 mmol) in 100 ml MeOH was heated to boiling. A solution of 11.0 g (34.1 mmol) of methyl 6-dibromo-methyl-nicotinate in 10 ml of MeOH was added dropwise to the boiling solution and refluxed overnight. To complete the reaction, a further 1.5 ml (8.1 mmol) of NaOMe solution was added and the mixture was refluxed again for 24 h. The reaction mixture is evaporated in vacuo, the residue is mixed with dilute KHSO4 solution, neutralized with dilute NaHCO3 solution, exhaustively extracted with EtOAc, the organic phase is washed with water and dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning. Yield: 5.0 g (69.5% of theoretical). ;C10H13NO4 (M = 211.22) ;Calculated: molecular weight (M+H)+: 212 ;Found: molecular weight (M+H)+: 212 ;Rf value: 0.44 (silica gel, petroleum ether/EtOAc 6:4). ; 2.118.c. 6-dimethoxymethyl-nicotinic acid; 15 ml of 1N NaOH solution is added to a solution of 2.8 g (13.26 mmol) of methyl 6-dimethoxymethyl-nicotinate in 50 ml of MeOH and stirred for 24 h at room temperature. The reaction mixture is neutralized with 15 ml of 1N HCl, evaporated in vacuo, the residue is triturated with MeOH/THF, the precipitate is filtered off with suction and the filtrate is evaporated. The resulting product reacts further without cleaning. Yield: 2.6 g (99.4% of theoretical). ;C9H11NO4 (M = 197.19) ;Calculated: molecular weight (M+H)+: 198 ;Found: molecular weight (M+H)+: 198 ;Retention time HPLC: 3.65 min (method A) ;2.118 .d. (6-dimethoxymethyl-pyridin-3-yl)-methanol; It was produced analogously to example 2.109.f from 2.7 g (13.7 mmol) of 6-dimethoxymethyl-nicotinic acid using THF as a solvent and tert-butylmethyl ether for extraction. Yield: 2.1 g (83.7% of theoretical). ;C9H13NO3 (M = 183.21) ;Calculated: molecular weight (M+H)+: 184 ;Found: molecular weight (M+H)+: 184 ;Retention time HPLC: 2.85 min (method A) ;2.118 .e. 5-chloromethyl-2-dimethoxymethyl-pyridine; 0.3 ml (4.14 mmol) of thionyl chloride, dissolved in a little CH2Cl2, is added slowly, dropwise, to a solution of 500 mg (2.73 mmol) (6- of dimethoxymethyl-pyridin-3-yl)-methanol in 10 ml of CH2Cl2 cooled to 0°C and stirred for a further 30 min at that temperature. The reaction mixture is diluted with CH2Cl2, washed with cold NaHCO3 solution and dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning. ;Utilization: 500 mg (90.8% of the theoretical). ;C9H12ClNO2 (M = 201.65) ;Calculated: molecular weight (M+H)+: 202/204 ;Found: molecular weight (M+H)+: 202/204 ;Rf value: 0.3 (silica gel, petroleum ether/EtOAc 6:4). ; 2.118. f. (6-dimethoxymethyl-pyridin-3-yl)-acetonitrile; 20 ml of DMSO is added to 5.21 g (80 mmol) of KCN in 5.2 ml of water and at 80°C a solution of 500 mg (2.48 mmol) of 5-chloro-methyl-2-dimethoxymethyl-pyridine in 10 ml of DMSO and the reaction mixture is kept for another hour at 80°C. This is poured into 200 ml of water, saturated with NaCl, extracted exhaustively with EtOAc, the organic phase is dried over MgSO4 and filtered through activated carbon. The filtrate was evaporated and the residue was purified by chromatography on silica gel (CH 2 Cl 2 /MeOH 9:1). ;Utilization: 330 mg (69.2% of theoretical). ;C10H12N2O2 (M = 192.22) ;Calculated: molecular weight (M+H)+: 193 ;Found: molecular weight (M+H)+: 193 ;Rf value: 0.48 (silica gel, CH2Cl2/MeOH 9 :1). 2.118. 2-(6-dimethoxymethyl-pyridin-3-yl)-ethylamine; 50 mg of Raney nickel is added to a solution of 330 mg (1.72 mmol) of (6-dimethoxymethyl-pyridin-3-yl)-acetonitrile in 10 ml of methanol NH3 and the reaction mixture is hydrogenated in a Parr autoclave for 15 h at 30°C and under 3 bar H2. The catalyst is filtered off, the solvent is evaporated under vacuum and the residue is further reacted without purification. ;Utilization: 340 mg (100% of theoretical). ;C10H16N2O2 (M = 196.25) ;Calculated: molecular weight (M+H)+: 197 ;Found: molecular weight (M+H)+: 197 ;Retention time HPLC: 1.3 min (method A) ;2.118 .h. 4'-Chloro-biphenyl-4-carboxylic acid [2-(6-;dimethoxymethyl-pyridin-3-yl)-ethyl]-amide; It was produced according to general procedure I from 340 mg (1.73 mmol) of 2- (6-dimethoxymethyl-pyridin-3-yl)-ethylamine and 419 mg (1.80 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 210 mg (28.4% of theoretical). ;C23H23ClN2O3 (M = 410.90) ;Calculated: molecular weight (M+H)+: 411/413 ;Found: molecular weight (M+H)+: 411/413 ;Rf value: 0.4 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1). ; 2.118.i. 4'-chloro-biphenyl-4-carboxylic acid [2-(6-formyl-pyridin-3-yl)-ethyl]-amide; 5 ml of 12% HCl is added to a solution of 205 mg (0.5 mmol ) 4'-chloro-biphenyl-4-carboxylic acid-[2-(6-di-methoxymethyl-pyridin-3-yl)-ethyl]-amide in 10 ml of MeOH and the reaction mixture is stirred for 4 h at room temperature and heated at 80°C overnight. Another 2.5 ml of 12% HCl is added, the mixture is heated for a further 8 hours at 80°C and overnight at 100°C. The reaction mixture is mixed with 50 ml of water, adjusted to pH 8 with Na2CO3 solution, extracted exhaustively with CH2Cl2 and the organic phase is dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning. ;Utilization: 180 mg (98.7% of theoretical). ;C21H17ClN2O2 (M = 364.84) ;Calculated: molecular weight (M+H)+: 365/367 ;Found: molecular weight (M+H)+: 365/367 ;Retention time HPLC: 5.25 min (method A) ; 2.118 k. 4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide; 50 μl (0.6 mmol) pyrrolidine, 37.7 mg ( 0.6 mmol) of NaBH3CN and 2 ml of MeOH was added to a solution of 180 mg (0.49 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(6-formyl-pyridin-3-yl)- ethyl]-amide in 5 ml of acetonitrile. The pH value is adjusted to 5-6 with glacial acetic acid and the mixture is stirred for 5 h at room temperature. The reaction mixture is acidified with a 1M KHSO4 solution, basified with a 2M Na2CO3 solution, exhaustively extracted with CH2Cl2 and the organic phase is dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (CH2Cl2/MeOH/NH3 9:1:0.1). ;Utilization: 25 mg (12.1% of theoretical). ;C25H26ClN3O (M = 419.96) ;Calculated: molecular weight (M+H)+: 420/422 ;Found: molecular weight (M+H)+: 420/422 ;Rf value: 0.2 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1). ;Example 2.119: ;4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide ;[image] ;2.119.a. Methyl 6-hydroxymethyl-nicotinate; It was produced analogously to example 2.109.f from 5.0 g (27.6 mmol) of 5-methyl pyridine-2,5-dicarboxylate, using THF as a solvent and tert-butyl methyl ether for extraction. Yield: 2.0 g (43.3% of theoretical). ;C8H9NO3 (M = 167.17) ;Calculated: molecular weight (M+H)+: 168 ;Found: molecular weight (M+H)+: 168 ;Rf value: 0.2 (silica gel, CH2Cl2/MeOH 95 :5). ; 2.119.b. Methyl 6-chloromethyl-nicotinate; In a solution of 2.0 g (11.96 mmol) of methyl 6-hydroxy-methyl-nicotinate in 100 ml of CH2Cl2 cooled to OoC, 1.06 ml (13 mmol) of pyridine is added and then slowly, drop by drop, 1.08 ml (13 mmoles) of thionyl chloride. This is further stirred for one hour at 0oC and then slowly warmed to room temperature. To complete the reaction, 1 ml (12 mmol) of thionyl chloride was added and the mixture was stirred for 1 h at room temperature. Water is added to the reaction mixture, the organic phase is separated, washed with diluted NaHCO3 solution and water and dried over MgSO4. This is filtered through activated carbon and the solvent is evaporated in vacuo. The resulting product reacts further without cleaning. Yield: 1.7 g (65.1% of theoretical). ;C8H8ClNO2 (M = 185.61) ;Calculated: molecular weight (M+H)+: 186/188 ;Found: molecular weight (M+H)+: 186/188 ;Retention time HPLC: 6.7 min (method A) ; 2.119.c. Methyl 6-cyanomethyl-nicotinate; It was produced analogously to example 2.118.f from 1.5 g (8.08 mmol) of methyl 6-chloromethyl-nicotinate and 5.2 g (80 mmol) of KCN, using cyclohexane/EtOAc 8: 2 as eluents for purification using silica gel chromatography. ;Utilization: 220 mg (15.5% of the theoretical). ;C9H9N2O2 (M = 176.18) ;Calculated: molecular weight (M+H)+: 177 ;Found: molecular weight (M+H)+: 177 ;Rf value: 0.6 (silica gel, petroleum ether/EtOAc 1:1). 2.119.d. Methyl 6-(2-amino-ethyl)-nicotinate; 20 mg of Raney nickel is added to a solution of 75 mg (0.43 mmol) of methyl 6-cyanomethyl-nicotinate in 5 ml of methanolic NH3 and the reaction mixture is hydrogenated in Parr's autoclave for 6 h at 30oC under 3 bar H2, the catalyst is filtered off, the solvent is evaporated in a vacuum and the residue reacts further without cleaning. ;Utilization: 70 mg (90.3% of theoretical). ;C9H12N2O2 (M = 180.21) ;Calculated: molecular weight (M+H)+: 181 ;Found: molecular weight (M+H)+: 181 ;Retention time HPLC: 2.5 min (method A) ;2.119 .e. Methyl 6-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinate; It was produced according to the general procedure I from 70 mg (0.39 mmol) of methyl 6-(2- aminoethyl)-nicotinate and 100 mg (0.43 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 150 mg (88.3% of theoretical). ;C22H19ClN2O3 (M = 394.86) ;Calculated: molecular weight (M+H)+: 395/397 ;Found: molecular weight (M+H)+: 395/397 ;Retention time HPLC: 8.6 min (method A) ; 2.119.f. 6-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinic acid; 0.8 ml of 1 M NaOH solution is added to a solution of 150 mg (0.38 mmol) methyl of 6-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinate in 25 ml of MeOH and the reaction mixture was refluxed for 1 h. This is neutralized with 0.8 ml of 1 N HCl, evaporated in vacuo, the residue mixed with water and the precipitate removed with suction. This was dissolved in THF, the solution was dried over MgSO4, filtered and evaporated in vacuo. The rest reacts further without cleaning. ;Utilization: 90 mg (62.2% of theoretical). ;C21H17ClN2O3 (M = 380.83) ;Calculated: molecular weight (M+H)+: 381/383 ;Found: molecular weight (M+H)+: 381/383 ;Retention time HPLC: 6.9 min (method A) ; 2.119. 4'-chloro-biphenyl-4-carboxylic acid {2-(5-hydroxymethyl-pyridin-2-yl)-ethyl]-amide; It was produced analogously to example 2.109.f from 90 mg (0.24 mmol) 6-{ 2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinic acid, using THF as solvent and tert-butylmethyl ether for extraction. ;Utilization: 50 mg (56.8% of theoretical). ;C21H19ClN2O2 (M = 366.85) ;Calculated: molecular weight (M+H)+: 367/369 ;Found: molecular weight (M+H)+: 367/369 ;Rf value: 0.5 (silica gel, CH2Cl2/MeOH 9:1). 2.119 h. 4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide; 22 μl of thionyl chloride is added dropwise to a solution of 50 mg ( 0.14 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(5-hydroxymethyl-pyridin-2-yl)-ethyl]-amide in 5 ml of CH2Cl2 cooled to 0°C and the reaction mixture was slowly let it warm to room temperature. After 1 h at room temperature, a further 22 μl of thionyl chloride was added drop by drop to complete the reaction and stirring was continued for 1 h. The reaction mixture is diluted with 30 ml of CH2Cl2, mixed with ice water, made alkaline with NaHCO3 solution, the organic phase is separated, washed with water and dried over MgSO4. After removing the drying agent, 50 μl (0.6 mmol) of pyrrolidine was added to this solution and the reaction mixture was stirred overnight at room temperature. This was evaporated in vacuo and the residue was purified by HPLC chromatography. ;Utilization: 2.4 mg (4.1% of theoretical). ;C25H26ClN3O (M = 419.96) ;Calculated: molecular weight (M+H)+: 420/422 ;Found: molecular weight (M+H)+: 420/422 ;Rf value: 0.3 (silica gel, CH2Cl2/MeOH 9:1). ; HPLC retention time: 6.0 min (method A) ; Example 2.120: ; 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]- ethyl}-amide ; [image] ; 2.120.a. Tert-butyl [2-(4-acetyl-phenyl)-ethyl]-carbamate; 5.46 g (25 mmol) of BOC-anhydride is added to a solution of 4.99 g (25 mmol) of 1-[4-{2 -amino-ethyl)-phenyl]-ethanone (used in the form of hydrochloride) in 100 ml of CH2Cl2 and at room temperature slowly add, drop by drop, 25 ml of 1N NaOH solution and after the addition is complete, the mixture is stirred for 2 h at room temperature. The reaction mixture is filtered through Celite, washed twice with water and dried over MgSO4. This is filtered through activated carbon, evaporated under vacuum and the product is further reacted without purification. Yield: 6.4 g (97.2% of theoretical). ;C12H21NO3 (M = 263.34) ;Calculated: molecular weight (M+H)+: 262 ;Found: molecular weight (M+H)+: 262 ;Rf value: 0.88 (silica gel, CH2Cl2/MeOH/ NH3 9:1:0.1). ; 2.120.b. Tert-butyl {2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-carbamate; 4.72 g (125 mmol) of NaBH4 was added portionwise at room temperature to a solution of 6.58 g (25 mmol) of tert-butyl [2-(4-acetyl-phenyl)-ethyl]-carbamate in 250 ml of MeOH and the reaction mixture was stirred over the weekend. This is carefully acidified with KHSO4 solution, extracted exhaustively with tert-butylmethyl ether, the organic phase is washed with saturated NaCl solution and dried over MgSO4. After removing the drying agent and solvent, the product remains as a slightly yellowish oil which crystallizes on standing. Yield: 5.4 g (81.4% of theoretical). ;C15H23NO3 (M = 265.36) ;Calculated: molecular weight (M+H)+: 266 ;Found: molecular weight (M+H)+: 266 ;Rf value: 0.4 (silica gel, petroleum ether/EtOAc 6:4). ; 2.120.c. Tert-butyl {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-carbamate; 0.66 ml (8.5 mmol) of methanesulfonic acid chloride, dissolved in 10 ml of CH2Cl2, added was added dropwise to a solution of 2.89 g (10.89 mmol) of tert-butyl {2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-carbamate in 50 ml of CH2Cl2 and 1.25 ml of triethylamine cooled to 0oC. Stirring was continued for 1 h at this temperature and then a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH2Cl2 was slowly added dropwise. The reaction mixture is stirred overnight at room temperature, mixed with dilute KHSO4 solution, the organic phase is separated, washed twice with dilute KHSO4 solution, the combined aqueous phases are made alkaline with K2CO3 solution and exhaustively extracted with tert-butylmethyl ether. The combined organic phases are washed several times with a little water and dried over MgSO4. After removing the desiccant and solvent, the product reacts further without cleaning. Yield: 0.3 g (8.7% of theoretical). ;C19H30N2O2 (M = 318.46) ;Calculated: molecular weight (M+H)+: 319 ;Found: molecular weight (M+H)+: 319 ;Rf value: 0.22 (silica gel, CH2Cl2/MeOH/ NH3 9:1:0.1). 2.120 d. 2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethylamine; 0.72 ml of trifluoroacetic acid is added to a solution of 300 mg (0.94 mmol) tert-butyl {2-[4- (1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-carbamate in 20 ml of CH2Cl2 and stirred for 1 h at room temperature. to complete the reaction, a further 0.72 ml of trifluoroacetic acid was added and the reaction mixture was kept for 1 h at room temperature. The solvent is evaporated in vacuo, the residue is taken up in water, basified with 2 N NaOH, extracted exhaustively with EtOAc and the organic phase is dried over MgSO4. After removing the desiccant and solvent, the product reacts further without cleaning. ;Utilization: 150 mg (72.9% of theoretical). ;C14H22N2 (M = 218.35) ;Calculated: molecular weight (M+H)+: 219 ;Found: molecular weight (M+H)+: 219 ;Rf value: 0.15 (silica gel, CH2Cl2/MeOH/ NH3 8:2:0.2). ; 2.120.e. 4'-Chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-amide; It was produced according to general procedure I from 150 mg (0, 69 mmol) of 2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethylamine and 176 mg (0.76 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 150 mg (88.3% of theoretical). ;C27H29ClN2O (M = 433.0) ;Calculated: molecular weight (M+H)+: 433/435 ;Found: molecular weight (M+H)+: 433/435 ;Retention time HPLC: 6.33 min (method A) Example 2.121: 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide; [image] ; 2.121.a. [4-(2-amino-ethyl)-2-bromo-phenyl]-methanol; 100 mg of Raney nickel is added to a solution of 4 g (17.68 mmol) of (3-bromo-4-hydroxymethyl-phenyl)-acetonitrile (see example 2.107.c) in 100 ml of THF and 50 ml of methanolic NH3 and the reaction mixture is shaken in a Parr autoclave for 5 h at room temperature and under 5 psi of H2. The catalyst is filtered off, the solvent is removed and the product reacts further without cleaning. Yield: 3.8 g (93.4% of theoretical). ;C9H12BrNO (M = 230.11) ;Calculated: molecular weight (M+H)+: 230/232 ;Found: molecular weight (M+H)+: 230/232 ;Retention time HPLC: 1.85 min (method A) ; 2.121.b. Tert-butyl [2-(3-bromo-4-hydroxymethyl-phenyl)-ethyl]-carbamate; 17 ml of a 1 M solution of BOC-anhydride in CH2Cl2 is added to a solution of 3.8 g (16.51 mmol) [4 -(2-amino-ethyl)-2-bromo-phenyl]-methanol in 50 ml of CH2Cl2 and the reaction mixture was stirred overnight at room temperature. This is diluted with 100 ml of dilute KHSO4 solution, the organic phase is separated, washed with dilute NaHCO3 solution and water and dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography on silica gel. ;Yield: 2.3 g (42.2% of theory) ;C14H20BrNO3 (M = 330.22) ;Rf value: 0.44 (silica gel, petroleum ether/EtOAc 6:4). ; 2.121.c. Tert-butyl [2-(3-bromo-4-chloromethyl-phenyl)-ethyl]-carbamate; 0.54 ml (6.5 mmol) of thionyl chloride was slowly added dropwise to a solution of 1.98 g (6.0 mmol) of tert-butyl [2-(3-bromo-4-hydroxymethyl-phenyl)-ethyl]-carbamate in 50 ml of CH2Cl2 and 0.53 ml of pyridine cooled to 0°C, stirred for a further hour at 0 °C and then warmed to room temperature. Water is added to the reaction mixture, the organic phase is washed with diluted KHSO4 solution and water and dried over MgSO4. After filtration through activated carbon and removal of the solvent, the product reacts further without cleaning. Yield: 2.0 g (95.6% of theoretical). ;C14H19BrClNO2 (M = 348.67) ;Calculated: molecular weight (M+H)+: 348/350/352 ;Found: molecular weight (M+H)+: 348/350/352 ;Rf value: 0.6 (silica gel, petroleum ether/EtOAc 6:4). 2.121.d. Tert-butyl {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate; 0.84 ml (11 mmol) 2,5-dihydro-1H -pyrrole is added to a suspension of 1.9 g (5.45 mmol) of tert-butyl [2-(3-bromo-4-chloromethyl-phenyl)-ethyl]-carbamate and 2.5 g (18.1 mmol) K2CO3 in 50 ml of acetonitrile and the reaction mixture was stirred overnight at room temperature. The suspension is filtered, the filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel. Yield: 0.5 g (24.1% of theoretical). ;C18H25BrN2O2 (M = 381.32) ;Calculated: molecular weight (M+H)+: 381/383 ;Found: molecular weight (M+H)+: 381/383 ;Rf value: 0.58 (silica gel, CH2Cl2/MeOH 8:2). ; 2.121.e. 2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine; 5 ml of trifluoroacetic acid is added to a solution of 500 mg (1.31 mmol) of tert-butyl {2 -[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate in 50 ml of CH2Cl2 and the reaction mixture was stirred for 2 h at room temperature. This is evaporated in a vacuum. It is mixed with water and CH2Cl2, adjusted to alkaline pH with K2CO3 solution, the organic phase is separated and washed again with water. This is evaporated in vacuo and the product is purified by silica gel chromatography. ;Utilization: 350 mg (95.0% of theoretical). ;C13H17BrN2 (M =281.20) ;calculated: molecular weight (M+H)+: 281/283 ;Found: molecular weight (M+H)+: 281/283 ;Rf value: 0.08 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5). ;2.121.f 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide ;It is produced according to by general procedure I from 141 mg (0.5 mmol) of 2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine and 116 mg (0.5 mmol) 4 '-chloro-biphenyl-4-carboxylic acids. ;Utilization: 140 mg (56.5% of theoretical). ;C26H24BrClN2O (M= 495.85) ;Calculated: molecular mass (M+H)+: 495/497/499 ;Found: molecular mass (M+H)+: 495/497/499 ;Retention time HPLC: 6, 6 min (method A) ; Example 2.122: ; 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)- phenyl]-ethyl}-amide ; [image] ; 2.122.a. 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid; 1.04 g (5 mmol) of 4-bromophenylboronic acid, 115 mg (0.1 mmol) of tetrakis-(triphenylphosphine)-palladium and 2 ml of 2M Na2CO3 solution added are successively added to a solution of 1.1 g (5 mmol) of 4-bromo-2-fluorobenzoic acid in 5 ml of DMF and 5 ml of dioxane and the reaction mixture is refluxed for 2 h. To complete the reaction, a further 250 mg (1.25 mmol) of 4-bromophenylboronic acid was added and the mixture was refluxed for a further 2 h. The reaction mixture is filtered hot through a glass fiber filter, washed with water, acidified with a dilute solution of KHSO4, the resulting precipitate is suctioned off and washed with water. The residue is triturated with acetonitrile and a little MeOH, filtered to remove undissolved material, the filtrate is evaporated, the residue is triturated with MeOH and the product is filtered off with suction. ;Utilization: 140 mg (9.5% of theoretical). ;C13H8BrFO2 (M = 295.11) ;Calculated: molecular weight (M+H)+: 293/295 ;Found: molecular weight (M+H)+: 293/295 ;Rf value: 0.5 (silica gel, CH2Cl2/MeOH 9:1). ;2.122.b 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide ;It was produced according to general procedure I from 141 mg (0.5 mmol) of 2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine and 140 mg (0.47 mmol) of 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid. ;Utilization: 10 mg (3.8% of theoretical). ;C26H23Br2FN2O (M = 558.29) ;Calculated: molecular weight (M+H)+: 557/559/561 ;Found: molecular weight (M+H)+: 557/559/561 ;HPLC retention time: 7, 0 min (method A) ;Example 2.123: ;4'-chloro-biphenyl-4-carboxylic acid E2-(3-amino-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide ;[image] ;0 .12 ml of trifluoroacetic acid is added to a solution of 40 mg (0.08 mmol) tert-butyl (5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidine -1-ylmethyl-phenyl)-carbamate (see Example 2.116) in 3 ml of CH2Cl2 and the reaction mixture was stirred at room temperature over the weekend. This was evaporated in vacuo, mixed with half saturated NaHCO3 solution, extracted with EtOAc and the organic phase dried over MgSO4. The residue after removal of drying agent and solvent is purified by HPLC. ;Yield: 3 mg (7.3% of theory).;C26H28ClN3O*C2HF3O2 (M = 548.01)

Calculated: molecular weight (M+H)+: 434/436

Found: molecular weight (M+H)+: 434/436

HPLC retention time: 5.35 min (Stable Bond C18; 3.5 μM; water:acetonitrile:formic acid 6:4:0.015)

Example 2.124:

4'-chloro-biphenyl-4-carboxylic acid-ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.124.a. Ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine

A solution of 89 μl (1.1 mmol) of ethyl iodide in 1 ml of THF was added dropwise to a solution of 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 0.17 ml of triethylamine in 5 ml of THF and the reaction mixture was stirred for 24 h at room temperature. This was mixed with saturated NaHCO3 solution, extracted with EtOAc and the organic phase dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.

Yield: 70 mg (30.1% of theoretical).

2.124.b. 4'-chloro-biphenyl-4-carboxylic acid-ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 70 mg (0.3 mmol) of ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 81 mg (0.35 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.

Yield: 20 mg (14.9% of theoretical).

C28H31ClN2O (M = 447.03)

Calculated: molecular weight (M+H)+: 447/449

Found: molecular weight (M+H)+: 447/449

HPLC retention time: 6.92 min (method A)

Example 2.125:

4'-chloro-biphenyl-4-carboxylic acid-isobutyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.125.a. Isobutyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine

A solution of 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 91 μl (1.0 mmol) of isobutyraldehyde in 20 ml of THF was slightly acidified with glacial acetic acid , mixed with 253 mg (1.2 mmol) of NaBH(OAc)3 and stirred overnight at room temperature. The reaction mixture was mixed with half-saturated NaHCO3 solution, extracted exhaustively with EtOAc; the aqueous phase is saturated with K2CO3 and extracted with EtOAc. The combined organic phases are dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.

Yield: 250 mg (96.0% of theoretical).

C17H28N2 (M = 260.43)

Calculated: molecular weight (M+H)+: 261

Found: molecular weight (M+H)+: 261

Rf value: 0.4 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).

2.125.b. 4'-chloro-biphenyl-4-carboxylic acid-isobutyl-

[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 250 mg (0.96 mmol) of isobutyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 244 mg (1.05 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.

Yield: 67 mg (14.7% of theoretical).

C30H35ClN2O (M = 475.08)

Calculated: molecular weight (M+H)+: 475/477

Found: molecular weight (M+H)+: 475/477

HPLC retention time: 7.67 min (method A)

Example 2.126:

4'-chloro-biphenyl-4-carboxylic acid-cyclohex-3-enyl-methyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.126.a. Cyclohex-3-enylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine

It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 114 μl (1.0 mmol) of 1,2,3,6-tetrahydrobenzaldehyde.

Yield: 100 mg (33.5% of the theoretical).

C20H30N2 (M = 298.48)

Rf value: 0.2 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).

2.126.b 4'-chloro-biphenyl-4-carboxylic acid-cyclohex-3-enylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 100 mg (0.34 mmol) of cyclohex-3-enylmethyl-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amine and 86 mg (0.37 mmol) of 4'-chloro-biphenyl-4-carboxylic acid.

Yield: 46 mg (26.8% of theoretical).

C33H37ClN2O (M = 513.13)

Calculated: molecular weight (M+H)+: 513/515

Found: molecular weight (M+H)+: 513/515

HPLC retention time: 8.20 min (method A)

Example 2.127:

4'-chloro-biphenyl-4-carboxylic acid-benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.127a. Benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine

It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 102 μl (1.0 mmol) of benzaldehyde.

Yield: 160 mg (54.3% of theoretical).

C20H26N2 (M = 294.44)

Rf value: 0.28 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).

2.127.b. 4'-chloro-biphenyl-4-carboxylic acid-benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 160 mg (0.54 mmol) of benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 140 mg (0.60 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.

Yield: 16 mg (5.8% of theoretical).

C33H33ClN2O (M = 509.10)

Calculated: molecular weight (M+H)+: 509/511

Found: molecular weight (M+H)+: 509/511

HPLC retention time: 7.51 min (method A)

Example 2.128:

4'-chloro-biphenyl-4-carboxylic acid-cyclohexylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.128.a Cyclohexylmethyl-[2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine

It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 121 μl (1.0 mmol) of cyclohexanecarbaldehyde.

Yield: 100 mg (33.3% of theoretical).

C20H32N2 (M = 300.49)

Rf value: 0.18 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).

2.128.b. 4'-chloro-biphenyl-4-carboxylic acid-cyclohexylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 100 mg (0.33 mmol) of cyclohexylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 86 mg (0.37 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.

Yield: 70 mg (40.8% of theoretical).

C33H33ClN2O (M = 515.15)

Calculated: molecular weight (M+H)+: 515/517

Found: molecular weight (M+H)+: 515/517

HPLC retention time: 8.63 min (method A)

Example 2.129:

4'-chloro-biphenyl-4-carboxylic acid-cyclopropylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

[image]

2.129.a Cyclopropylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine

It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 75 μl (1.0 mmol) of cyclopropanecarbaldehyde.

Yield: 100 mg (38.7% of theoretical).

C17H26N2 (M = 258.41)

Rf value: 0.30 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).

2.129.b. 4'-chloro-biphenyl-4-carboxylic acid-cyclo-propylmethyl-[2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide

It was produced according to general procedure I from 100 mg (0.39 mmol) of cyclopropylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 100 mg (0.43 mmol) of 4'-chloro -biphenyl-4-carboxylic acid.

Yield: 23 mg (12.6% of theoretical).

C30H33ClN2O (M = 473.06)

Calculated: molecular weight (M+H)+: 473/475

Found: molecular weight (M+H)+: 473/475

HPLC retention time: 7.45 min (method A)

Example 2.130:

4-pentyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 4-pentyl-benzoic acid (96 mg, 0.50 mmol).

Yield: 75 mg (39.6% of theoretical).

C25H34N2O (M = 378.56)

Calculated: molecular weight (M+H)+: 379

Found: molecular weight (M+H)+: 379

HPLC retention time: 6.5 min (method A)

Example 2.131:

4-butyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 4-butyl-benzoic acid (89 mg, 0.50 mmol).

Yield: 60 mg (32.9% of theoretical).

C24H32N2O (M = 364.54)

Calculated: molecular weight (M+H)+: 365

Found: molecular weight (M+H)+: 365

HPLC retention time: 6.0 min (method A)

Example 2.132:

4-butylamino-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benz-amide

[image]

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.0 mmol) and 4-butylamino-benzoic acid (155 mg, 0.80 mmol).

Yield: 30 mg (9.9% of theoretical).

C24H33N3O (M = 379.55)

Calculated: molecular weight (M+H)+: 380

Found: molecular weight (M+H)+: 380

HPLC retention time: 6.0 min (method A)

Example 2.133:

4-(1-methyl-butyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

It was produced according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (82 mg, 0.40 mmol) and 4-(1-methyl-butyl)-benzoic acid (75 mg, 0 .39 mmol).

Yield: 40 mg (27.1% of theoretical).

C24H32N2O (M = 378.56)

Calculated: molecular weight (M+H)+: 379

Found: molecular weight (M+H)+: 379

HPLC retention time: 4.3 min (method B)

Example 2.134:

N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-(4,4,4-trifluorobutoxy)-benzamide

[image]

2.134.a. Methyl 4-(4,4,4-trifluorobutoxy)-benzoate

608 mg (4.4 mmol) of K2CO3 is added to a solution of 304 mg (2.0 mmol) of methyl 4-hydroxybenzoate in 10 ml of DMF and then 382 mg (2.0 mmol) of 1-bromo-4,4, 4-trifluorobutane. The mixture was stirred overnight at room temperature, mixed again with 1-bromo-4,4,4-trifluorobutane and stirred for a further 24 h at room temperature. The reaction solution was diluted with water and exhaustively extracted twice with EtOAc. United org. the extracts are dried over MgSO4 and evaporated in vacuo. The crude product is used without further purification in the next step of the reaction.

Yield: 500 mg (95.3% of the theoretical).

C12H13F3O3 (M = 262.23)

Calculated: molecular weight (M+H)+: 263

Found: molecular weight (M+H)+: 263

Rf value: 0.9 (silica gel, petroleum ether/EtOAc 6:4).

2.134.b. 4-(4,4,4-trifluorobutoxy)-benzoic acid

10.0 ml (10.0 mmol) of 1 M sodium hydroxide solution was added to a solution of 500 mg (1.9 mmol) of methyl 4-(4,4,4-trifluoro-butoxy)-benzoate in 7 ml of THF. The mixture was stirred for 8 h under reflux. The THF was removed in vacuo and the residue acidified with hydrochloric acid. After filtration, the resulting precipitate is air-dried.

Yield: 350 mg (73.9% of theoretical).

C11H11F3O3 (M = 248.20)

Calculated: molecular weight (M-H)-: 247

Found: molecular weight (M-H)-: 247

HPLC retention time: 7.5 min (method A)

2.134.c N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-(4,4,4-trifluoro-butoxy)-benzamide

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 4-(4,4,4-trifluoro-butoxy)-benzoic acid ( 124 mg, 0.50 mmol).

Yield: 37 mg (17.0% of theoretical).

C24H29F3N2O2 (M = 434.51)

Calculated: molecular weight (M+H)+: 435

Found: molecular weight (M+H)+: 435

HPLC retention time: 5.8 min (method A)

Example 2.135:

3-methyl-4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.135.a. Methyl 3-methyl-4-pent-1-ynyl-benzoate

0.39 ml (4.0 mmol) pentyne, 0.56 ml (4.0 mmol) triethylamine, 70 mg (0.1 mmol) bis-(triphenylphosphine)-palladium(II) chloride and 19 mg (0.1 mmol) of copper(I) iodide was added successively to a solution of 458 mg (2.0 mmol) of methyl 4-bromo-3-methyl-benzoate in 3.0 ml of DMF. The reaction solution is stirred in a microwave heater for 10 min at 200 Watts and 65°C. A further 0.20 ml (2.0 mmol) of pentyne was added and the reaction solution was stirred for a further 20 min in a microwave oven at 200 Watts and 70°C. The mixture was diluted with 30 ml of EtOAc, filtered through Celite and the filtrate was washed three times with 50 ml of water. The combined organic extracts were dried over MgSO4, filtered through activated carbon and the solvent was removed in vacuo. Purification is performed using chromatography on a silica gel column (cyclohexane and then cyclohexane/ethyl acetate 9:1).

Yield: 200 mg (46.2% of the theoretical).

C14H16O2 (M = 216.28)

Calculated: molecular weight (M+H)+: 217

Found: molecular weight (M+H)+: 217

HPLC retention time: 6.8 min (method B)

2.135.b. 3-methyl-4-pent-1-ynyl-benzoic acid

3.0 ml (3.0 mmol) of 1 M sodium hydroxide solution is added to a solution of 200 mg (0.93 mmol) of methyl 3-methyl-4-pent-1-ynyl-benzoate in 3 ml of methanol. The mixture is refluxed for 3 h . The reaction solution was diluted with water and extracted once with 40 ml of EtOAc. The aqueous phase is acidified with 1M KHSO4 solution and extracted twice with 40 ml of EtOAC. The combined organic phases are dried over MgSO4. After removing the drying agent and solvent, the crude product is used in the next step of the reaction without further purification.

Yield: 50 mg (26.7% of theoretical).

C13H14O2 (M = 202.26)

Calculated: molecular weight (M-H)-: 201

Found: molecular weight (M-H)-: 201

HPLC retention time: 5.6 min (method B)

2.135.c. 3-methyl-4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was produced according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (51 mg, 0.25 mmol) and 3-methyl-4-pent-1-ynyl-benzoic acid (50 mg , 0.25 mmol).

Yield: 22 mg (22.9% of theoretical).

C26H32N2O (M = 388.558)

Calculated: molecular weight (M+H)+: 389

Found: molecular weight (M+H)+: 389

HPLC retention time: 6.9 min (method A)

Example 2.136:

4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.136.a. Ethyl 4-pent-1-ynyl-benzoate

0.39 ml (4 mmol) of 1-pentyne, 0.56 ml of triethylamine, 70 mg (0.1 mmol) of bis-(triphenylphosphine)-palladium(II) chloride and 19 mg (0.1 mmol) of CuI were added successively. in a solution of 552 mg (2.0 mmol) of ethyl 4-iodobenzoate in 3 ml of DMF. The reaction solution was stirred for 4 h at 80°C. The mixture is diluted with 30 ml of EtOAc, filtered through Celite, the filtrate is washed three times with 50 ml of water in each case and dried over MgSO4. After filtration through activated carbon, the solvent is removed under vacuum. Purification is performed using chromatography on a silica gel column (cyclohexane and then cyclohexane/ethyl acetate 9:1).

Yield: 150 mg (34.7% of theoretical).

C14H16O2 (M = 216.282)

Calculated: molecular weight (M+H)+: 217

Found: molecular weight (M+H)+: 217

HPLC retention time: 6.8 min (method B)

2.136.b. 4-pent-1-ynyl-benzoic acid

5.0 ml (5.0 mmol) of 1 M sodium hydroxide solution was added to a solution of 150 mg (0.69 mmol) of ethyl 4-pent-1-ynyl-benzoate in 3 ml of methanol. The mixture was stirred for 3 h under reflux. The reaction solution was diluted with water and extracted once with 40 ml of EtOAc. The aqueous phase was acidified with 1M KHSO4 solution and extracted twice with 40 ml of EtOAc. The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product is used for the next step of the reaction without further purification.

Yield: 150 mg (115% of the theoretical).

C12H12O2 (M = 188.23)

Calculated: molecular weight (M-H)-: 187

Found: molecular weight (M-H)-: 187

Rf value: 0.2 (silica gel, petroleum ether/EtOAc 8:2).

2.136.c. 4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (163 mg, 0.80 mmol) and 4-pent-1-ynyl-benzoic acid (150 mg, 0.80 mmol).

Yield: 122 mg (40.9% of theoretical).

C25H30N2O (M = 374.53)

Calculated: molecular weight (M+H)+: 375

Found: molecular weight (M+H)+: 375

Rf value: 0.35 (silica gel, EtOAc/methanol/NH3

9:1:0,1).

Example 2.137:

(4-pent-1-enyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

2.137a. methyl 4-pent-1-enyl-benzoate

246 mg (2.2 mmol) of potassium tert-butoxide was added at 0°C to a solution of 1.08 g (2.2 mmol) of (4-methoxycarbonyl-benzyl)-triphenyl-phosphonium bromide in 20 ml of THF under argon atmosphere. The orange solution was stirred for a further 15 min at 0°C and then mixed with 0.18 ml (2.0 mmol) of butyraldehyde. The reaction solution was refluxed for 3 h and then diluted with EtOAc. The organic phase is washed twice with water, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with diisopropyl ether, filtered and the filtrate is evaporated. Further purification is carried out by chromatography on a silica gel column (petroleum ether/EtOAc 6:4). Methyl 4-pent-1-enyl-benzoate is obtained as a 2:1 mixture of E/Z isomers.

Yield: 350 mg (56.5% of theoretical).

C13H16O2 (M = 204.27)

Calculated: molecular weight (M+H)+: 204

Found: molecular weight (M+H)+: 204

Rf value: 0.90 (silica gel, petroleum ether/EtOAc 6:4).

2.137.b. 4-pent-1-enyl-benzoic acid

5.0 ml (5.0 mmol) of 1 M sodium hydroxide solution was added to a solution of 350 mg (1.71 mmol) of ethyl 4-pent-1-enyl-benzoate in 4 ml of methanol. The mixture is refluxed for 2 h. The solvent was removed in vacuo and the residue was mixed with 6M hydrochloric acid solution. The resulting precipitate is sucked off and dried at 35°C in a dryer with circulating air. Further purification is performed by filtration through a column of silica gel (petroleum ether/EtOAc 6:4).

Yield: 300 mg (92.1% of theoretical).

C12H14O2 (M = 190.24)

Calculated: molecular weight (M-H)-: 189

Found: molecular weight (M-H)-: 189

Rf value: 0.4 (silica gel, petroleum ether/EtOAc 6:4).

2.137.c. (4-pent-1-enyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (306 mg, 1.50 mmol) and 4-pent-1-enyl-benzoic acid (300 mg, 1.56 mmol) as a 2:1 mixture of E/Z isomers.

Yield: 130 mg (23.0% of theoretical).

C25H32N2O (M = 376.547)

Calculated: molecular weight (M+H)+: 377

Found: molecular weight (M+H)+: 377

HPLC retention time: 6.9 min (method A)

Example 2.138:

3-chloro-4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide

[image]

It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 3-chloro-4-cyclohexyl-benzoic acid (119 mg, 0.50 mmol).

Yield: 46 mg (21.6% of theoretical).

C26H33ClN2O (M = 425.019)

Calculated: molecular weight (M+H)+: 425/427

Found: molecular weight (M+H)+: 425/427

HPLC retention time: 4.7 min (method B).

Some procedures for determining the antagonistic activity towards the MCH-receptor will now be described. In addition, other test methods known to those skilled in the art were used, eg inhibition of cAMP production by inhibition of the MCH-receptor, 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 by biologically sensitive measurement of MCH binding to the MCH receptor in the presence of antagonists using plasmon resonance, as described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Application in Surface Plasmon Resonance Biosensors", Anal. Biochem. 300 (2002), 132-138. Other methods of testing antagonistic activity towards MCH receptors are found in the literature and patent documents previously mentioned herein, and the description of the testing methods is hereby incorporated into this application.

MCH-1 receptor binding attempt

Procedure: Binding of MCH to cells transfected with hMCH-1R Species: human

Experimental cells: hMCH-1R stably transfected into CHO/Galpha16 cells

Results: IC50 values

Membranes of CHO/Galpha16 cells stably transfected with human hMCH-1R were resuspended using a syringe (0.6 x 25 mm needle) and diluted in assay buffer (50 mM HEPES, 10 mM MgCl2, 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 phosphoramidon) at a concentration of 5 to 15 μg/ml. 200 microliters of this membrane fraction (containing 1 to 3 μg of protein) was incubated for 60 minutes at room temperature with 100 pM of 125I-tyrosyl melanin-concentrating hormone (125I-MCH can be obtained commercially from NEN) and increasing concentrations of the test compound in the final volume of 250 microliters. After incubation, the reaction mixture was filtered using a cell harvesting agent through glass fiber filters treated with 0.5% PEI (GF/B, Unifilter Packard). Then, the radioactivity bound to the membranes that remained on the filter was determined after the addition of scintillation substance (Packard Microscint 20) to the measuring device (TopCount of Packard).

Nonspecific binding was defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.

The analysis of the concentration and binding curve was performed assuming a single receptor binding site.

Standard:

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

The KD value of the radioligand is 0.156 nM.

An attempt to mobilize Ca2+ associated with the MCH-1 receptor

Procedure: Calcium mobilization experiment with human MCH (FLIPR384)

Species: human

Experimental cells: CHO/Galpha 16 cells stably transfected with hMCH-R1

Results: first measurement: % stimulation of comparison (MCH 10-6 M)

second measurement: pKB value

Reagents:

HBSS (10x) (GIBCO)

HEPES buffer (1M) (GIBCO)

Pluronic F-127 (Molecular Probes)

Fluo-4 (Molecular Probes)

Probenecid (Sigma)

MCH (Bachem)

bovine serum albumin (protease-free) (Serva)

DMSO (Serva)

Ham's F12 (BioWhittaker)

FCS (BioWhittaker)

L-glutamine (GIBCO)

hygromycin B (GIBCO)

PENStrep (BioWhittaker)

Zeocin (Invitrogen)

Clonal CHO/Galpha16 hMCH-R1 cells were grown in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; cat. no. BE12-615F). It contains in 500 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 before the experiment, cells were plated in 384-well microtiter plates (black walls with clear bottom, manufactured by Costar) at a density of 2500 cells per well and grown in the above medium overnight at 37°C, 5% CO2 and 95% relative humidity. On the day of the experiment, the cells were incubated with the culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid were added, for 45 minutes at 37oC. After the addition of the fluorescent dye, the cells were washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which was mixed with 0.07% probenicid. Test substances were diluted in a solution of Hanks buffer mixed with 2.5% DMSO. Baseline fluorescence of unstimulated cells was measured in the presence of substance in 384-well microtiter plates five minutes after the last wash in a FLIPR384 apparatus (Molecular Devices; excitation wavelength: 488 nm; emission wavelength: band band 510 to 570 nm). To stimulate cells, MCH was diluted in Hanks' buffer with 0.1% BSA, 384-well culture plates were pipetted 35 minutes after the last wash, and MCH-stimulated fluorescence was then measured in a FLIPR384 apparatus.

Data analysis:

First measurement: Cellular Ca2+ mobilization was measured as peak relative fluorescence minus baseline fluorescence and expressed as a percentage of the maximum signal of the comparator (MCH 10-6 M). This measurement serves to identify any possible agonistic effect of the test substance.

Second measurement: Cellular Ca2+ mobilization was measured as peak relative fluorescence minus baseline fluorescence and was expressed as a percentage of the maximum signal of the comparator (MCH 10-6 M, signal standardized to 100%). EC50 values were determined graphically from the action curve and MCH dosing with and without the test substance (defined concentration) using the GraphPad Prism 2.01 curve program. In the graphic representation, MCH antagonists cause a shift of the MCH stimulation curve to the right.

Inhibition is expressed as a pKB value:

pKB = log(EC50(test substance + MCH)/EC50(MCH) -1) –log c(test substance)

In the experiments described above, the compounds according to the invention, including their salts, show antagonistic action against the MCH-receptor. Using the MCH-1 receptor binding experiment described above, antagonistic action was obtained in the dosage range of approx. 10-10 to 10-5 M, especially from 10-9 to 10-6 M.

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

[image]

In the following, some examples of formulations will be described, whereby the term "active substance" means one or more compounds according to the invention, including their salts. In case of combination with one or more described active substances, the term "active substance" also includes additional active substances.

Example 3

Capsules with powder for inhalation containing 1 mg of active substance

Composition:

1 capsule with powder for inhalation contains:

active substance 1.0 mg

lactose 20.0 mg

hard gelatin capsules 50.0 mg

71.0 mg

Preparation process:

The active substance is ground to the particle size required for inhalation. The crushed active substance is homogeneously mixed with lactose. The mixture is packed in hard gelatin capsules.

Example 4

Inhalation solution for Respimat® containing 1 mg of active substance

Composition:

1 spray contains:

active substance 1.0 mg

benzalkonium chloride 0.002 mg

disodium edetate 0.0075 mg

purified water ad 15.0 μl

Preparation process:

The active substance and benzalkonium chloride are dissolved in water and packed in Respimat® inserts.

Example 5

Inhalation solution for atomizer containing 1 mg of active

substances

Composition:

1 vial contains:

active substance 0.1 g

sodium chloride 0.18 g

benzalkonium chloride 0.002 g

purified water ad 20.0 ml

Preparation process:

The active substance, sodium chloride and benzalkonium chloride dissolve in water.

Example 6

Aerosol with propellant gas and dose measurement containing 1 mg of active substance

Composition:

1 spray contains:

active substance 1.0 mg

lecithin 0.1%

propellant gas up to 50.0 μl

Preparation process:

The micronized active substance is homogeneously suspended in a mixture of lecithin and pressure gas. The suspension is transferred to a pressure tank with a metering valve.

Example 7

Nasal spray containing 1 mg of active substance

Composition:

active substance 1.0 mg

sodium chloride 0.9 mg

benzalkonium chloride 0.025 mg

dinate edetate 0.05 mg

purified water up to 0.1 ml

Preparation process:

The active substance and auxiliary agents are dissolved in water and transferred to a suitable container.

Example 8

Injection solution containing 5 mg of active substance in 5 ml

Composition:

active substance 5 mg

glucose 250 mg

albumin from human serum 10 mg

glycofurol 250 mg

water for injections up to 5 ml

Preparation:

Glycofurol and glucose are dissolved in water for injections (Wfl); human serum albumin is added; the active ingredient dissolves with heating; the specified volume is supplemented with Wfl; transfer to ampoules under nitrogen gas.

Example 9

Injection solution containing 100 mg of active substance in 20 ml

Composition:

active substance 100 mg

monopotassium dihydrogen phosphate (KH2PO4) 12 mg

disodium hydrogen phosphate (Na2HPO4·2H2O) 2 mg

sodium chloride 180 mg

albumin from human serum 50 mg

Polysorbate 80 20 mg

water for injections up to 20 ml

Preparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; the active ingredient dissolves with heating; replenish to the specified volume with Wfl; transferred to ampoules.

Example 10

Lyophilisate containing 10 mg of active substance

Composition:

active substance 10 mg

mannitol 300 mg

albumin from human serum 20 mg

Preparation:

Mannitol dissolves in water for injections (Wfl); human serum albumin is added; the active ingredient dissolves with heating; replenish to the specified volume with Wfl; transfer to vials; freeze dry.

Solvent lyophilisate:

Polysorbate 80 = Tween 80 20 mg

mannitol 200 mg

water for injections up to 10 ml

Preparation:

Polysorbate 80 and mannitol are dissolved in water for injections (Wfl); transferred to ampoules.

Example 11

Tablets containing 20 mg of active substance

Composition:

active substance 20 mg

lactose 120 mg

corn starch 40 mg

magnesium stearate 2 mg

Povidone K25 18 mg

Preparation:

Homogeneously mix the active substance, lactose and corn starch; it is granulated with an aqueous solution of Povidone; mixed with magnesium stearate; it is pressed on a tablet press; the mass of the tablet is 200 mg.

Example 12

Capsules containing 20 mg of active substance

Composition:

active substance 20 mg

corn starch 80 mg

highly dispersed silicic acid 5 mg

magnesium stearate 2.5 mg

Preparation:

Homogeneously mix the active substance, corn starch and silicic acid; it is mixed with magnesium stearate; the mixture is packed into hard gelatin capsules on a capsule filling machine.

Example 13

Suppositories containing 50 mg of active substance

Composition:

active substance 50 mg

hard fat (Adeps solidus) q.s. up to 1700 mg

Preparation:

The hard fat melted at approx. 38°C; the crushed active substance is homogeneously dispersed in melted hard fat; when it cools down to approx. 35°C is poured into cooled molds.

Example 14

Injection solution containing 10 mg of active substance in 1 ml

Composition:

active substance 10 mg

mannitol 50 mg

albumin from human serum 10 mg

water for injections up to 1 ml

Preparation:

Mannitol dissolves in water for injections (Wfl); human serum albumin is added; the active substance is dissolved with heating; replenish to the specified volume with Wfl; transfer to ampoules under nitrogen gas.

Claims (44)

1. Carboxamide compounds of general formula I [image] indicated by that R1 and R2 independently of each other represent H, C1-8-alkyl or C3-7-cycloalkyl group which is optionally substituted with the group R11 or a phenyl group optionally mono- or polysubstituted with the group R12 and/or monosubstituted with nitro, or R1 and R2 form a C2-8-alkylene bridge in which - one or two -CH2- groups can be replaced independently of each other by -CH=N- or -CH=CH- and/or - one or two -CH2- groups can be replaced independently of each other by -O-, -S-, -CO-, -C(=CH2)- or -NR13- so that the heteroatoms are not directly connected to each other, while in the alkylene bridge defined above, one or more H atoms can be replaced by R14, and/or The alkylene bridge defined above can be substituted with one or two identical or different carbo- or heterocyclic Cy groups in such a way that the bond between the alkylene bridge and the Cy groups is formed - via single or double connection, - through a common C atom that forms a spirocyclic ring system, - over two common, adjacent C and/or N atoms that form a condensed bicyclic ring system or - over three or more C and/or N atoms that form a bridged ring system, R3 represents H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl-, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-4-alkyl-, phenyl, phenyl-C1-4-alkyl-, C1-3-alkoxy-C2-6-alkyl-, amino-C2-6-alkyl-, C1-3-alkyl-amino-C2-6-alkyl- or di-(C1 -3-alkyl)-amino-C2-6-alkyl-, X represents a single bond or a C1-8-alkylene bridge in which - one or two -CH2- groups can be replaced independently of each other by -CH=CH- or -C≡C- and/or - one or two -CH2- groups can be replaced independently of each other by -O-, -S-, -(SO)-, -(SO2)-, -CO- or -NR4- in such a way that in each case two O , S or N atoms or one O atom and an S atom are not directly connected to each other, while one or two C atoms can be independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and/ or in each case with one or two identical or different C 1-6 -alkyl groups, and/or an alkylene bridge may be attached to R1 so as to include the N atom attached to R1 and X, forming a heterocyclic group, Z represents a C1-4-alkylene bridge, in which two adjacent C atoms with an additional C1-4-alkylene bridge can be interconnected, while in the Z group the -CH2- group can be replaced by -O- or -NR5-, and one or two C atoms of the alkylene bridge can be substituted independently of each other with a hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl, C1-3-alkoxy group, amino -C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl and/or with one or two identical or different C1- 6-alkyl groups, and/or R3 may be linked to Z by including an N atom linked to R3 forming a heterocyclic group, A and Y independently of each other have one of the meanings given for Cy, while R1 may be linked to Y so as to include a group X and an N atom linked to R1 and X, forming a heterocyclic group fused to Y, and/or R 3 may be attached to Y so as to include a group Z and an N atom attached to R 3 and Z, forming a saturated or partially unsaturated heterocyclic group fused to Y, or A and R 3 can be interconnected in such a way that the group of formula I [image] represents a group of partial formula II [image] and Q represents a group selected from partial formulas IIIa to IIIg [image] L1, L2 and L3 independently of each other have one of the meanings given for R20, B represents C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7-cycloalkenyl-C1-3-alkyl-, C3-7- cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups can be mono- or polysubstituted with R20, or B has one of the meanings given for Cy, while the bond with the group W or, if necessary, directly with the group A goes through the C atom of the carbocyclic unit or, if necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit, while, if k = 0, group B and group A can be interconnected via a common C atom forming a spirocyclic ring system or via two shared, neighboring atoms that form a condensed, bicyclic ring system, W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene-oxy -C1-3-alkylene-, imino, N-(C1-3-alkyl)-imino-, imino-C1-3-alkylene-, N-(C1-3-alkyl)-imino-C1-4-alkylene- , C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino- group, while one or two C atoms can be independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and/ or with one or two identical or different C1-6-alkyl groups, and/or W defined as alkylene, oxyalkylene and alkyleneoxy-alkylene may also be linked to B via a double bond, k represents 0 or 1, Cy represents a carbo- or heterocyclic group selected from the following meanings: - saturated 3- to 7-membered carbocyclic group, - unsaturated 5- to 7-membered carbocyclic group, - phenyl group, - saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with N, O or S atom as hetero-atom, - saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, - aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, while the above-mentioned 4, 5, 6 or 7-membered groups can be linked via two common, adjacent C atoms, fused to a phenyl or pyridine ring, and in the above-mentioned 5-, 6- or 7-membered groups, one or two non-adjacent -CH2- groups can be replaced by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and the aforementioned saturated 6- or 7-membered groups may also be present as bridged ring systems with imino, N-(C1-4-4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1- 4-alkyl)-methylene bridge, i the above-mentioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, and in the case of phenyl groups they can also additionally be mono-substituted with nitro, and/or they can be substituted with R21 on one or more N atoms, R4 and R5 independently of each other have one of the meanings given for R16, R 6 , R 7 , R 8 and R 9 independently represent H, C 1-6 -alkyl, ω-C 1-3 -alkoxy-C 1-3 -alkyl or ω-hydroxy-C 1-3 -alkyl, and R 6 , R 7 , R 8 also independently of each other represent halogen, R11 represents R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-or Cy-, R12 has one of the meanings given for R20, R13 has one of the meanings given for R17, R14 represents halogen, C1-6-alkyl, R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-, R15-O-C1-3-alkyl-, R15-O-CO-C1-3- alkyl-, R16R17N-C1-3-alkyl-, R18R19N-CO-C1-3-alkyl- or Cy-C1-3-alkyl-, R15 represents H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl, phenyl-C1-3-alkyl- or pyridinyl, R16 represents H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, C4-6-cycloalkenyl, C4-7-cycloalkenyl-C1-3-alkyl, ω-hydroxy -C2-3-alkyl-, ω-(C1-3-alkoxy)-C2-3-alkyl-, amino-C1-6-alkyl-, C1-3-alkyl-amino-C1-6-alkyl- or di -(C1-3-alkyl)-amino-C1-6-alkyl-, R17 has one of the meanings given for R16 or represents phenyl, phenyl-C1-3-alkyl-, pyridinyl, dioxolan-2-yl, C1-3-alkylcarbonyl, hydroxycarbonyl-C1-3-alkyl-, C1-4-alkoxy- carbonyl, C1-3-alkylcarbonylamino-C2-3-alkyl-, C1-3-alkyl-sulfonyl- or C1-3-alkylsulfonylamino-C2-3-alkyl-, R18 and R19 independently represent H or C1-6-alkyl, R20 represents halogen, hydroxy, cyano, C1-4-alkyl, C3-7-cycloalkyl, hydroxy-C1-3-alkyl, R22-C1-3-alkyl- or has one of the meanings given for R22, R21 represents C1-3-alkyl, ω-hydroxy-C2-3-alkyl-, phenyl, phenyl-C1-3-alkyl-, C1-3-alkyl-carbonyl, carboxy, C1-4-alkoxy-carbonyl, C1- 3-alkylsulfonyl, phenylcarbonyl or phenyl-C1-3-alkyl-carbonyl, R22 represents pyridinyl, phenyl, phenyl-C1-3-Alkoxy-, C1-3-Alkoxy, C1-3-Alkylthio, carboxy, H-CO-, C1-3-Alkyl-carbonyl, C1-4-Alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, C1-3-alkyl-sulfonyl-, C1-3-alkyl-sulfinyl-, C1-3-alkyl-sulfonylamino-, amino, C1 -3-alkylamino-, di-(C1-3-alkyl)-amino-, phenyl-C1-3-alkylamino- or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenyl-carbonylamino-, phenylcarbonylmethylamino-, hydroxy-alkyl-aminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)-carbonyl , (4-methyl-1-piperazinyl)carbonyl, methylenedioxy-, aminocarbonylamino- or alkylaminocarbonylamino-, while in groups and residues A, B, W, X, Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently mono-substituted with Cl or Br, and/or in any case one or more phenyl rings can have mutually independently and additionally one, two or three substituents selected from the group consisting of F, Cl, Br, I, C1 -4-alkyl, C1-4-Alkoxy, difluoro-methyl, trifluoromethyl, hydroxy, amino, C1-3-alkyl-amino-, di-(C1-3-alkyl)-amino-, acetylamino-, amino-carbonyl, CN, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl-, C1-3-alkylamino-C1-3-alkyl- and di-(C1-3-alkyl)-amino-C1-3-alkyl- and/or may be monosubstituted with nitro, i The H atom of any carboxy group present or the H atom attached to the N atom can be replaced in each case by a group that can be cleaved in vivo, their tautomers, diastereomers, enantiomers, their mixtures and their salts. 2. Carboxamide compounds according to claim 1, characterized in that R3 represents H, C1-6-alkyl, C3-7-cycloalkyl, C1-7-cycloalkyl-C1-4-alkyl-, C1-3-alkoxy-C2-6-alkyl-, amino-C2-6-alkyl- , C1-3-alkyl-amino-C2-6-alkyl- or di-(C1-3-alkyl)-amino-C2-6-alkyl-, B has one of the meanings given for Cy, while the connection to the group W or, if necessary, directly to the group A goes through the C atom of the carbocyclic unit or, if necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit, while, if k = 0, group B and group A can be interconnected through one common C atom forming a spirocyclic ring system or over two common, neighboring atoms forming a condensed, bicyclic ring system, R15 represents H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl or phenyl-C1-3-alkyl-, R17 has one of the meanings given for R16 or represents phenyl, phenyl-C1-3-alkyl-, dioxolan-2-yl, C1-3-alkyl-carbonyl, hydroxycarbonyl-C1-3-alkyl, C1-3-alkylcarbonyl-amino -C1-3-3-alkyl-, C2-3-alkylsulfonyl- or C1-3-alkyl-sulfonylamino-C2-3-alkyl-, R 22 represents phenyl, phenyl-C1-3-Alkoxy-, C1-3-Alkoxy, C1-3-Alkylthio, carboxy, C1-3-Alkylcarbonyl, C1-3-Alkoxycarbonyl, aminocarbonyl, C1-3-Alkylaminocarbonyl, di-( C1-3-alkyl)-aminocarbonyl, C1-3-alkylsulfonyl, C1-3-alkylsulfinyl, C1-3-alkyl-sulfonylamino-, amino, C1-3-alkyl-amino-, di-(C1-3-alkyl) -amino-, phenyl-C1-3-alkyl-amino- or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-, acetyl-amino-, propionylamino-, phenylcarbonyl, phenylcarbonyl-amino-, phenylcarbonylmethylamino -, hydroxyalkylamino-carbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonyl -amino- or alkylaminocarbonylamino-, while in groups A, B, W, X, Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently monosubstituted with Cl or Br, i groups A, W, X, Y, Z, R1, R2, R4 to R9, R11 to R14, R16 and R18 to R21 and k have the meanings according to claim 1, and The H atom of any carboxy group present or the H atom attached to the N atom, in each case with a group that can be cleaved in vivo, may be replaced, their tautomers, diastereomers, enantiomers, their mixtures and their salts. 3. Carboxamide compounds according to claim 1 or 2, characterized in that group A has the meaning given for Cy in claim 1. 4. Carboxamide compounds according to one or more claims 1 to 3, characterized in that A and R3 are interconnected in such a way that the group of formula I [image] represents a group of partial formula II [image] and Q represents a group selected from partial formulas IIIa to IIIg [image] and L1, L2, L3, R6, R7, R8 and R9 have the meanings given in claim 1. 5. Carboxamide compounds according to one or more claims 1 to 4, characterized in that R1 and R2 independently of each other represent H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, ω-Hydroxy-C2-3-alkyl, ω-(C1-3-Alkoxy)-C2-3-Alkyl-, C1-4-Alkoxy-carbonyl-C1-3-Alkyl, Amino-C2-4-Alkyl-, C1-3-alkyl-amino-C2-4-alkyl- or di-(C1-3-alkyl)-amino-C2-4-alkyl-, phenyl or phenyl-C1-3-alkyl-, while in the above-mentioned groups and residues, one or more C atoms can be mono- or polysubstituted with F and/or one or two C atoms can be mutually independently mono-substituted with Cl or Br, and the phenyl group can be mono- or polysubstituted with the group R14 defined in claim 1 and/or mono-substituted with nitro. 6. Carboxamide compounds according to one or more claims 1 to 4, characterized in that R1 and R2 form an alkylene bridge according to claim 1 in such a way that R1R2N- forms 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-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, morpholine, thiomorpholine and piperazine, whereby the free imino functional group can be substituted with R13, while according to claim 1 one or more H atoms can be replaced by R14, and/or can be substituted in the manner described in claim 1 with one or two identical or different carbo- or heterocyclic groups Cy, while R 13 , R 13 and Cy have the meaning given in claim 1 or 2. 7. Carboxamide compounds according to claim 6, characterized in that the group [image] has meaning according to one of the following partial formulas [image] [image] [image] in which one or more H atoms of the heterocycle formed with the group R1R2N- can be replaced by R14 and the ring connected to the heterocycle formed with the group R1R2N can be mono- or polysubstituted on one or more C atoms with R20, and in the case of a phenyl ring, it may also be additionally monosubstituted with nitro i wherein R13, R14, R20, R21 and X have the meanings given in claim 1 or 2. 8. Carboxamide compounds according to one or more claims 1 to 7, characterized in that X represents a single bond or an unbranched bridge selected from C1-alkylene, C2-6-alkenylene, C2-6-alkynylene, C1-6-alkylenoxy, carbonyl, carbonyl-C1-6-alkylene or C1-6-alkylene-amino, wherein the amino group can be substituted with R4, while one or two C atoms can be substituted as specified in claim 1 and/or the alkylene bridge can be connected with R1 as set forth in claim 1. 9. Carboxamide compounds according to claim 8, characterized in that X represents a single bond, carbonyl or alkylene bridge selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, wherein one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and /or in any case may be substituted with one or two identical or different C1-4-alkyl groups, and in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently mono-substituted with Cl or Br. 10. Carboxamide compounds according to one or more claims 1 to 9, characterized in that Z represents methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3 -propyleneoxy or 1,4-butylenoxy, wherein one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and /or in any case may be substituted with one or two identical or different C1-4-alkyl groups, and in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently mono-substituted with Cl or Br and R 3 may be linked to Z so as to include N atoms linked to R 3 forming a heterocyclic group. 11. Carboxamide compounds according to claim 10, characterized in that Z is selected from the bridge groups -CH2-, -CH2-CH2-, -CH2-CH(CH3)-, -CH2-C(CH2)2-, -CH( CH2)-CH2-, -C(CH2)2-CH2- and -CH2-O- or Z is attached to R3 in such a way that the group of the partial formula [image] has a meaning selected from 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,2,5,6-tetrahydropyridin-1,3-ylene and 3-hydroxy-1,3-piperidinylene. 12. Carboxamide compounds according to one or more of the preceding claims, characterized in that R3 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl and 2-hydroxy- 1-methyl-ethyl-, while in the aforementioned groups one, two or three H atoms can be replaced by F, or is selected from the group consisting of H, amino-C2-3-alkyl-, C1-3-alkyl-amino -C2-3-alkyl- and di-(C1-3-alkyl)-amino-C2-3-alkyl-. 13. Carboxamide compounds according to one or more of the preceding claims, characterized in that the group Y is selected from the group consisting of divalent cyclic groups 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1,3-phenylene, 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cyclo-heptylene, 1,4-cycloheptenylene, 1, 3-pyrrolidinylene, 1,3-pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene or 1,4 -piperazinylene, while the above-mentioned 5-, 6- or 7-membered groups can be connected to two common, adjacent C atoms condensed with a phenylene or pyridine ring, the aforementioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, in the case of a phenyl group they can also be additionally mono-substituted with nitro, and/or can be substituted with R21 on one or more N atoms, while R1 may be linked to Y, and/or R3 to Y as mentioned in claim 1, i R1, R3, R20 and R21 have the meanings given in claim 1 or 2. 14. Carboxamide compounds according to claim 13, characterized in that R1 is connected to Y in such a way that the group of the partial formula [image] has the meaning selected from the following partial formulas [image] 15. Carboxamide compounds according to one or more claims 1, 2, 3 and 5 to 13, characterized in that group A is selected from the following divalent cyclic groups: 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene , 1,3-cyclopentenylene, 1,3- and 1,4-cyclonexylene, 1,3- and 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4- cycloheptenylene, 1,3-pyrrolidinylene, 1,3-pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydro-pyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene , 1,4-piperazinylene, 7-aza-bicyclo[2.2.1]heptane-2,7-diyl and 8-aza-bicyclo[3.2.1]acetane-3,8-diyl, while the aforementioned 5-, 6-, or 7-membered groups may be linked to two common, adjacent C atoms fused to a phenylene or pyridine ring, and the aforementioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, in the case of the phenyl ring they can also be additionally monosubstituted with nitro, and/or they can be substituted on one or more N atoms with R21, and R20, R21 and Y have the meanings given in claim 1 or 2. 16. Carboxamide compounds according to one or more of the preceding claims, characterized in that group B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl , pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl and thienyl, while the connection to group W or, as necessary, directly to group A goes through the C atom of the carbocyclic unit or, as necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit, or B, together with the group W attached to the double bond, is selected from the group consisting of cyclopentylidene-methyl, cyclohexylidenemethyl and cyclohexanone-4-ylidene-methyl, and the above-mentioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, in the case of phenyl groups they can also be additionally mono-substituted with nitro, and/or they can be substituted with R21 on one or more N atoms, and R20 and R21 have the meanings given in claim 1 or 2. 17. Carboxamide compounds according to one or more claims 1 to 15, characterized in that group B is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C1-6-cycloalkyl-C1-6-alkyl-, C3-7-cycloalkenyl-C1-3-alkyl -, C3-7-cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups can be mono- or polysubstituted with R20, i W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkylenoxy, oxy-C1-4-alkylene-, C1-3-alkylene-oxy-C1-3-alkylene-, imino, N-(C1-3 -alkyl)-imino-, imino-C1-4-alkylene-, N-(C1-3-alkyl)-imino- C1-4-alkylene-, C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino- group, while one or two C atoms can be mutually independently substituted with hydroxy, by ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or by a C1-3-alkyl group and/or by one or two identical or different C1-4-alkyl groups , i k represents 0 or 1 and R20 has the meaning given in claim 1 or 2. 18. Carboxamide compounds according to one or more claims 1 to 15, characterized in that k = 0 and group A is connected to group B via a common C atom forming a spirocyclic ring system, while group A represents a saturated 5- to 7-membered carbo- or heterocyclic group, and group B represents a saturated 4- to 7-membered carbo- or heterocyclic group, and the heterocyclic groups in each case contain an N, O or S atom, and the phenyl or pyridine ring may be fused to the 5- to 7-membered group B via two adjacent C atoms, and the above-mentioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, in the case of a condensed phenyl ring it can additionally be monosubstituted with nitro, and/or they can be substituted with R21 on one or more N atoms, while R20 and R21 have the meaning given in claim 1 or 2. 19. Carboxamide compounds according to one or more claims 1 to 15, characterized in that k = 0 and group B is connected to group A via two common, adjacent atoms forming condensed, bicyclic saturated, unsaturated or aromatic, 8- to 12-membered carbo- or heterocyclic ring system, while the heterocyclic ring system has one or more identical or different heteroatoms selected from N, O and/or S, and The bicyclic ring system can be mono- or polysubstituted on one or more C atoms with R20, in the case of a condensed phenyl ring it can also be additionally monosubstituted with nitro, and/or can be substituted with R21 on one or more N atoms, while R20 and R21 have the meanings given in claim 1 or 2. 20. Carboxamide compounds according to one or more claims 1 to 16, characterized in that W is a single bond, -CH2- or -CH=. 21. Carboxamide compounds according to one or more of the preceding claims, characterized in that Y and A are mutually independently selected from the series consisting of bivalent cyclic groups 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2,3,6-tetrahydro- pyridin-1,4-ylene, 2,5-pyridinylene and 1,4-piperazinylene, while A may also be attached to R 3 according to claim 3, and the aforementioned cyclic groups may be mono- or polysubstituted by R 20 at one or more C atoms, in the case of a phenyl group it may additionally be monosubstituted with nitro, and/or may be substituted with R21 on one or more N atoms, B represents phenyl or cyclohexyl, while the aforementioned groups can be mono- or polysubstituted by R20 and/or the phenyl ring can additionally be monosubstituted by nitro, while R20 has the meaning given in claim 1 or 2, and W is a single bond, -CH2- or -CH=, i Z represents -CH2-CH2-, -CH2-CH(CH3)-, -CH2C(CH3)2-, -CH(CH3)-CH2-, -C(CH3)2-CH2- or -CH2-O- or is connected to R3 in such a way that the group of the partial formula [image] from formula I has the meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene, and R3, R20 and R21 have the meanings given in claims 1, 2 and/or 12. 22. Carboxamide compounds according to one or more of the preceding claims, characterized in that they are selected from compounds of formulas 1.1 to 1.14 [image] [image] [image] in which U and V independently represent C or N, R23 and R24 independently represent H, F, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl, while R24 in formulas 1.1 to 1.6 can be connected to R3 in such a way that the group of the partial formula [image] has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene, and R 25 , R 26 R 27 independently of each other have the meanings given to R 20 according to claim 1 or 2 or in the case of a phenyl group also simply represent nitro, while the groups R 25 , R 26 and R 27 appearing more than once can have the same or different meanings, and j is 0, 1, 2, 3 or 4 and m and n independently represent 0, 1 or 2 i L1, L2, L3, R1, R2, R3, R6, R7, R8, R9, R20 and X have the meanings given in claims 1, 2, 5 to 9 and/or 12. 23. Carboxamide compounds according to one or more of the preceding claims, characterized in that they have the formula 1.15 [image] where B is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7-cycloalkenyl-C1-4-alkyl- , C3-7-cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups may be mono- or polysubstituted by R20, i W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene-oxy-C1-3-alkylene-, imino, N-(C1- 3-alkyl)-imino-, imino-C1-4-alkylene-, N-(C1-3-alkyl)-imino- C1-4-alkylene-, C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino group, while one or two C atoms can be mutually independently substituted with hydroxy, ω -hydroxy- C1-3-alkyl, ω-(C1-3-Alkoxy)-C1-3-Alkyl and/or C1-3-Alkoxy group and/or with one or two identical or different C1-4-Alkyl groups, and k represents 0 or 1 and U, V, R23, R24, R26, R27, m, n, L1, L2, L3, R1, R2, R3, R6, R7, R8, R9, R20 and X have the meanings given in claim 22. 24. Carboxamide compounds according to claim 22 or 23, characterized in that U and V in each case represent a C atom. 25. Carboxamide compounds according to claim 21, 22, 23 or 24, characterized in that R1 and R2 independently of each other have the meaning according to claim 5 and/or 6 and R3 has the meaning according to claim 12 and X has the meaning according to claim 8 or 9, while the group R1R2-N-X- can also have the meaning according to claim 7. 26. Carboxamide compounds according to one or more claims 21 to 25, characterized in that X is -CH2-, -CH(CH3)- or -C(CH3)2-. 27. Carboxamide compounds according to one or more claims 21 to 26, characterized in that R25, R26, R27 independently represent F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso- propoxy, in the case of substitution of the phenyl group they can also represent nitro, while the groups R25, R26, R27 that are repeated several times can have the same or different meanings, and j is 0, 1 or 2, i m and n are independently 0 or 1. 28. Carboxamide compounds according to one or more of the preceding claims, characterized in that R6, R7, R8 and/or R9 independently represent H, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl, if R6 and R7 also represent F . 29. Carboxamide compounds according to claim 1 or 2, characterized in that they are selected from the group of compounds consisting of (1) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (2) 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one (3) 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-tri-fluoromethyl-phenyl)-3H-quinazolin-4-one (4) 7-(4-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (5) 7-(3,4-dichloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (6) 7-(4-fluoro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (7) 7-(4-ethyl-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (8) 2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazolin-4-one (9) 2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one (10) 7-(4-chloro-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (11) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1 H-quinazoline-2,4-dione (12) 7-(4-chloro-phenyl)-3-{2-[4-((S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one (13) 7-(4-chloro-phenyl)-3-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-3H-quinazolin-4-one (14) 7-(4-chloro-phenyl)-3-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (15) 7-(4-chloro-phenyl)-3-[2-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (16) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-benzo[d][1,2,3]triazin-4- he (17) 5-(4-fluoro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-isoindol-1,3-dione (18) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (19) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-diethyl-aminomethyl-phenyl)-ethyl]-amide (20) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide (21) 4'-methoxy-biphenyl-4-carboxylic acid [2-(4-di-ethylaminomethyl-phenyl)-ethyl]-amide (22) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-diethyl-aminomethyl-phenyl)-ethyl]-methyl-amide (23) 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (24) 4-methylphenyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (25) 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]amide (26) 4-(4-chloro-phenyl)-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (27) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide (28) 4'-chloro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-benzyloxy)-amide (29) 4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (30) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (31) 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one (32) 4'-chloro-biphenyl-4-carboxylic acid {2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide (33) 7-(3-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one (34) 4-(4-oxo-cyclohexyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (35) 4-cyclohexyl-1-cylohexylcarboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (36) 4-benzyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (37) 4-cyclohexyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (38) 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (39) 4-(4-fluoro-phenyl)-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (40) 4-(4-Methoxy-phenyl)-piperazine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (41) 4-phenyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (42) (4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-1-yl]-methanone (43) 4'-chloro-biphenyl-4-carboxylic acid [2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide (44) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide (45) 4-benzyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (46) 4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (47) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (48) 5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (49) 4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (50) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][ 1,2,3]-triazin-4-one (51) 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-quinazolin-4 -he (52) 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-benzo[d ][1,2,3]triazin-4-one (53) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one (54) 7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4 -he (55) 6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one (56) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (57) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (58) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide (59) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide (60) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-aza-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-phenyl]-ethyl}-amide (61) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1,3-dihydro-isoindol-2-ylmethyl)-phenyl]-ethyl}-amide (62) 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(di-isopropylamino)-methyl]-phenyl}-ethyl)-amide (63) 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide (64) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-di-methylaminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide (65) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-di-methylamino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide (66) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (67) 4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (68) 4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide (69) 4'-chloro-biphenyl-4-carboxylic acid [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide (70) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (71) 2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (72) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide (73) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-amino-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide (74) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-methyl-2,6-diaza-spiro[3.4]oct-6-ylmethyl)-phenyl]-ethyl}-amide (75) 4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide (76) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (77) 4'-bromo-biphenyl-4-carboxylic acid {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide (78) 4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide (79) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (80) 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide (81) 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (82) 4'-ethyl-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (83) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-2-ylmethyl]-carbamate (84) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-methyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide (85) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-{2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide (86) 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(cyclo-propyl methyl-amino)-methyl]-phenyl}-ethyl)-amide (87) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethyl}-amide (88) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-ethyl]-amide (89) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-3-yl]-carbamate (90) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide (91) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-azetidin-1-ylmethyl-phenyl)-ethyl]-amide (92) 3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (93) 4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-yl methyl-phenyl)-ethyl]-amide (94) 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (95) 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (96) 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (97) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide (98) 4'-bromo-biphenyl-4-carboxylic acid [2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (99) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-amide 30. Carboxamide compounds according to claim 29, characterized in that they are selected from compounds number (1), (2), (3), (4), (5), (6), (7), (8), ( 9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21) , (22), (23), (24), (25), (25), (26), (27), (28), (29), (30), (47) and (50) to ( 99). 31. Process for the preparation of carboxamide compounds of formula I [image] wherein A, B, W, X, Y, Z, R1, R2, R3 and k have one of the meanings set forth in claims 1 to 28, characterized in that if A represents a group R3 which is not related to the group A: a) in the event that A represents a heterocyclic group with nitrogen which is connected to a carboxamide group through a nitrogen atom, which may also have, in addition to the nitrogen atom and one or more heteroatoms selected from N, O and S, at least one amine compound of the formula I-1 [image] wherein R1, R2, R3, X, Y and Z have the meanings given above, reacts with CDT (1,1'-carbonyldi-(1,2,4-triazole)) and at least one secondary amine compound of formula I-2 [image] in which A, B, W and k have the meanings given above, and the group A has a secondary amine functional group, in a solvent or in a mixture of solvents in the presence of at least one base, and b) in other cases, at least one carboxylic acid of formula I-3 [image] wherein A, B, W and k have the meanings hereinbefore given, reacts with TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate) and at least one amine compound of formula I-1 [image] wherein R1, R2, R3, X, Y and Z have the meanings hereinbefore given, in a solvent or in a mixture of solvents in the presence of at least one base, and if B represents the group R3 attached to the group A: a) in the case of the group Q having the meaning -CR6R7- (IIIa), while R6 and R7 are defined as here before, the amine of formula Ia.1 [image] in which R1, R2, X, Y and Z have the given meanings, reacts with the ester derivative of o-bromo-methyl-benzoic acid of formula Ia.2 [image] wherein R 6 , R 7 , W , B and k have the given meanings, b) in the case of the group Q having the meaning -CR6=CR7- (IIIb), in which R6 and R7 are defined as here before, isoquinolinone derivative of formula Ib.2 [image] wherein R 6 , R 7 , W , B and k have the given meanings, reacts with an electrophilic compound of formula Ib.3 [image] in which Y and Z have the given meanings, and OMs represents a suitable leaving group, primarily mesylate, which results in an isoquinoline derivative of formula Ib.4 [image] in which R6, R7, W, B, Y, Z and k have the indicated meanings, and the isoquinoline derivative of formula Ib.4 is further derivatized by known methods, which results in the compound of formula I, c) in the case of the group Q having the meaning -N=CR8- (IIIc), in which R8 is defined as here before, the phthalazinon derivative of the formula Ic.4 [image] wherein R 8 , W, B and k have the given meanings, reacts with the electrophilic compound of formula Ic.5 [image] in which Y and Z have the indicated meanings, and OMs represents a leaving group, primarily mesylate, which results in the phthalazinon derivative of formula Ic.6 [image] in which R8, W, B, Y, Z and k have the indicated meanings, and thus obtained phthalazinone derivative of the formula Ic.6 is further derivatized by known procedures, thereby obtaining the formula I in which Q represents -N=CR8- (IIIc), d) in the case of group Q, which has the meaning -N=N- (IIId), o-amino-benzamide derivative of formula Id.1 [image] wherein R1, R2, W, B, X, Y, Z and k have the meanings indicated, reacts in the presence of a suitable nitrite compound and an acid, resulting in a compound of formula I in which Q represents -N=N-, e) in the case of the group Q having the meaning -CO-NR9- (IIIe), in which R9 is defined as hereinbefore, an o-amino-benzamide derivative of the formula Ie.1 [image] in which R1, R2, R9, W, B, X, Y, Z and k have the given meanings, reacts in the presence of CDI (carbonyldiimidazole) to obtain a compound of formula I in which Q represents -CO-NR9-, f) in the case of the group Q having the meaning –CR8=N- (IIIf), in which R3 is defined as hereinbefore, the o-amino-benzamide derivative of the formula If.1 [image] in which R1, R2, W, B, X, Y, Z and k have the given meanings, reacts with the carboxylic acid R8COOH in which R9 has the given meaning and/or with the corresponding activated derivative of the same carboxylic acid, thereby obtaining a quinazolinone derivative of formula I in where Q represents -CR8=N-, g) in the case of group Q, which has the meaning -CO- (IIIg) isobenzofurandione derivative of formula Ig.2 [image] in which W, B and k have the indicated meanings, reacts with the amine of formula Ig.1 [image] in which R 1 , R 2 , X, Y and Z have the indicated meanings, thereby obtaining a compound of formula I in which Q represents -CO-. 32. Physiologically acceptable salts, characterized by the fact that they are salts of carboxamide compounds according to one or more claims 1 to 30. 33. Composition, characterized in that it contains at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, if necessary together with one or more physiologically acceptable auxiliary agents. 34. Pharmaceutical composition, characterized in that it contains at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, if necessary together with one or more inert carriers and/or diluents. 35. Use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used to influence the behavior of mammals when taking food. 36. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for reducing body weight and/or for preventing the increase in body weight of a mammal. 37. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for the preparation of a pharmaceutical composition that acts as an MCH-receptor antagonist. 38. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for the preparation of a pharmaceutical composition suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or are otherwise causally related to MCH. 39. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for the preparation of a pharmaceutical composition suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders , especially obesity, bulimia, neurotic bulimia, cachexia, anorexia, neurotic anorexia and hyperphagia. 40. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for the preparation of a pharmaceutical composition suitable for the prevention and/or treatment of diseases and/or disorders associated with obesity, especially diabetes, especially type II diabetes, diabetes-related complications including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, abnormal glucose tolerance, encephalorrhagia, heart failure, cardiovascular disease, especially arteriosclerosis and high blood pressure, arthritis and gonitis . 41. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for the preparation of a pharmaceutical composition suitable for the prevention 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. 42. The use of at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32, characterized in that it is used for the preparation of a pharmaceutical composition suitable for the prevention and/or treatment of urinary disorders, such as on example urinary incontinence, overactive bladder, urgency, nocturia and enuresis. 43. Process for the preparation of a pharmaceutical composition according to one or more claims 33 to 38, characterized in that at least one carboxamide compound according to one or more claims 1 to 30 and/or a salt according to claim 32 is non-chemically incorporated into one or more inert carriers and / or dilution agents. 44. Pharmaceutical composition, characterized in that it contains the first active substance selected from carboxamide compounds according to one or more claims 1 to 30 and/or salts according to claim 32, and another active substance selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably different from MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety and active substances for the treatment of depression, if necessary together with one or more inert carriers and/or diluents.