MXPA05002158A - Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof. - Google Patents

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

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Publication number
MXPA05002158A
MXPA05002158A MXPA05002158A MXPA05002158A MXPA05002158A MX PA05002158 A MXPA05002158 A MX PA05002158A MX PA05002158 A MXPA05002158 A MX PA05002158A MX PA05002158 A MXPA05002158 A MX PA05002158A MX PA05002158 A MXPA05002158 A MX PA05002158A
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MX
Mexico
Prior art keywords
phenyl
ethyl
ylmethyl
alkyl
group
Prior art date
Application number
MXPA05002158A
Other languages
Spanish (es)
Inventor
Philipp Lustenberger
Original Assignee
Boehringer Ingelheim Pharma
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Publication date
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
Publication of MXPA05002158A publication Critical patent/MXPA05002158A/en

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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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Abstract

The invention relates to carboxamide compounds of general formula (I), in which the groups and radicals A, B, W, X, Y, Z, R1, R2, R3, and k have the meanings indicated in claim 1. The invention also relates to methods for producing said carboxamide compounds and medicaments containing at least one inventive carboxamide. The inventive medicaments are suitable for treating metabolic disorders and/or eating disorders, especially obesity, bulimia, anorexia, hyperphagia, and diabetes due to the MCH receptor-antagonistic activity thereof.

Description

NEW CARBOXAMIDE COMPOUNDS THAT HAVE MCH ANTAGONISTIC ACTIVITY, PHARMACEUTICAL PREPARATIONS THAT UNDERSTAND THESE COMPOUNDS AND PROCESS FOR THEIR ELABORATION The present invention relates to novel carboxamide compounds, processes for the preparation and physiologically acceptable salts thereof as well as their use as MCH antagonists and their use to prepare a pharmaceutical preparation which is suitable for prevention and / or treatment of symptoms. and / or diseases caused by MCH or causally related to MCH in some other way. The invention is further related to the use of a compound according to the invention to influence the feeding behavior and to reduce body weight and / or to prevent an increase in the body weight of a mammal. The invention also relates to compositions and medicaments that a compound according to the invention, and a process for their preparation.
Background according to the invention The ingestion of food and its transformation in the body play an essential role in the life of all living beings. Therefore, deviations in the ingestion and transformation of foods usually produce disorders and also diseases. Changes in the lifestyle and diet of humans, particularly in industrialized countries, have favored obesity in recent decades. In people affected, obesity automatically generates in those involved a limitation of their mobility and a decrease in their quality of life. There is the additional factor that obesity often leads to other diseases such as, for example, diabetes, dyslipidemia, high blood pressure, arteriesclerosis and coronary heart disease. In addition, the high body weight generates a greater load of the support and motor apparatus, which can produce diseases and chronic disorders such as arthritis or osteoarthritis. In this way, obesity is a serious health problem for society. The term obesity means an excess of adipose tissue. In this connection, obesity is fundamentally to be considered as the increased level of obesity that generates a risk to health. For the purpose of simplicity, in the present invention, individuals with a Body Mass Index (BMI), which are defined as the measure of body weight in kilograms divided by weight. (in meters) squared, previously a value of 25 and more particularly in the above 30 are preferably considered as suffering from obesity. - From physical activity and a change in diet, currently there is no convincing treatment option for effective reduction of body weight. However, since obesity is a high risk factor in the development of serious and even life-threatening diseases, it is all the more important to have access to active pharmaceutical substances for the prevention and / or treatment of obesity. A principle that has been proposed lately is the therapeutic use of MCH antagonists [for example, WO 01/21577, WO 01/82925). The melanin concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. In mammals it is synthesized mostly in the hypothalamus and from there it reaches other areas through the projections of hypothalamic neurons. Its biological activity is transmitted in humans through two different glycoprotein-coupled receptors (GPCs) of the rhodopsin-related GPCR family, mainly MCH receptors 1 and 2 (MCH-1R, MCH-2R). Investigations into the role of MCH in animal models have provided good indications for the representation of the peptide in the regulation of energy balance, that is, modification of metabolic activity and food intake [1, 2] -. For example, - after the intraventricular administration of HCM in rats, it increases the food intake in relation to control animals. Additionally, the transgenic rats that produce a greater amount of HCM than the control animals, have a higher weight gain after a higher fat diet than the animals with an experimentally modified MCH level. It could also be determined that there is a positive correlation between the phases of greater anxiety for food and · the amount of RA m of MCH in the hypothalamus of rats. However, experiments with MCH in unconscious mice are. particularly important in the arrival of the MCH function. A loss of neuropeptide occurs in thin animals with less fat, which ingest significantly less food than control animals. The anorexic effects of MCH are transmitted in rodents through MCH-1 coupled with Gas [3-6]. Unlike the primate, hound and dog, until the moment could not prove the existence of a second receiver. After the loss of MCH-IR, the unconscious mice have a lower amount of fat, a greater energy waste and, compared to control animals, they do not present an increase in weight with a high-fat diet. Another indication of the importance of the MCH-MCH-1R system in the regulation of energy balance is obtained from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term trials, animals treated with the antagonist lose significant amounts of weight. In addition to its anorexic effect, the CH-1R antagonist SNAP-7941 also achieves other anxiolytic and antidepressant effects in behavioral trials with rats [3]. In this way, there are clear indications that the CH-MCH1 system not only intervenes in the regulation of the energy balance, but also in the affectivity.
Literature: 1. Qu, D., et al.,? role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature, 1996. 380 (6571): p. 243-7. 2. Shimada, M., et al., Mi ce 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,? . , et al. , Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and jresistance 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 ship altered metabolism. Proc. Nati Acad. Sci. USA, 2002. 99 (5):. 3240-5. 6. Takekawa, S., et al. , T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur. J. Pharmacol., 2002. 438 (3): p. 129-35. In the patent literature certain amino compounds are proposed as MCH antagonists. Thus, in O 01/21577 (Takeda) compounds of the formula are described wherein Ar 1 means, a cyclic group, X means a spacer, Y means a bond or a spacer, Ar means an aromatic ring which may be fused with a non-aromatic ring, R 1 and R 2 independently of each other mean H or a hydrocarbon group, while R1 and R2 together with the adjacent N atom can form a hetero ring containing N and R2 with Ar can also form a spirocyclic ring, R together with the adjacent N atom and? can form a hetero ring containing N, as antagonists of MCH for the treatment of obesity. Also in the. WO 01/82925 (Takeda) also describes compounds of the formula wherein Ar 1 signifies a cyclic group, X and Y represent spacer groups, Ar means an optionally substituted fused polycyclic aromatic ring, R 1 and R 2 independently denote H or a hydrocarbon group, while R 1 and R 2 together with the adjacent N atom. they can form an hetero ring containing N and R2 together with the adjacent one of the N atom and Y can form a hetero ring containing N, as antagonists of MCH for the treatment of obesity. Other amino compounds having MCH antagonistic activity are proposed in WO 02/057233 (Schering Corp.). The compounds are included in the general formula wherein Ar1, Ar2, Ar3 mean inter alia aryl or heteroaryl, X, 0, S or N-CN, Y signifies a single bond or alkylene of Ci_4, and R1 and R2 are as defined herein. Also in WO 02/051809 (Schering Corp.) is described an antagonistic activity of MCH in connection with piperidine derivatives of the formula wherein W means an especially defined aminocarbonyl or carbonylamino group, X means -CHR8, -C0-, -C (= NOR9) or ~ CR8 =, Y means CH, C (OH), C (C1-4 alkoxy) or in the case of a double bond C, R 2 signifies a substituted aryl or heteroaryl group, R 10 signifies H, Ci_s alkyl or aryl and the other groups are as defined herein. Carboxamides are proposed as antagonists of human HCBy receptors in WO 02/10146 (Smithklyne Beecham). The compounds are examples of the general structural formula wherein A means H, alkyl, alkoxy, alkenyl, acyl, halogen, OH, CN or CF3, R3 signifies H, methyl or ethyl, R4 signifies a ring. optionally substituted heterocyclic or carbocyclic aromatic, Z means 0, S, NH, CH2 or a single bond, R5 means an optionally substituted saturated or unsaturated aromatic carbocyclic or heterocyclic ring, Q means the group -XY-NR1 (R2) , while according to different configurations X can mean O, S or N, Y can mean an alkylene or cycloalkylene group which can also be substituted, and R1 and R2 can represent alkyl or phenyl-alkyl, while R1 and R2, R1 and Y or R1 and can also be linked together to form a cyclic system, as described. Other compounds with MCH antagonistic properties are proposed in published applications WO 03/035055, WO 03/033480, WO 02/06245, WO 02/04433, WO 01/87834, WO 01/21169 and JP 2001/226269. Quinazolinone compounds of the general formula are described in WO 01/23365 (Merck), wherein Z means a bond or phenylene, and in WO 01/23364 (Merck), wherein Z means cyclohexylene. In addition Y is equivalent to a C2-4 bond or alkenyl and R4 means aryl, cycloalkyl, phenylalkyl or a heterocyclic system. These compounds are described as GPIblX inhibitors, especially as inhibitors of this receptor with the Willebrand factor ligand (vWF). Aromatic compounds that may contain an amide bridge and an amide group and are also proposed in the literature for other indications. Thus, compounds of the general formula Ar-AE are described, wherein Ar is an optionally substituted mono or bicyclic aromatic group, A means an amide or amino bridge and E means inter alia a phenyl group is substituted in the para position through a spacer B with a substituted aminoalkylene group, in WO 99/01127 (Smithklyne Beechara Corp.) These compounds are proposed as ligands of the CCR5 receptor for the treatment among other things of asthma, diseases Atopic and rheumatoid arthritis. In WO 01/72712 (Cor Therapeutics Inc.) isoquinoline compounds of the following formula are described wherein A means an optionally substituted amino or amidino group, Z means a bond or an alkyl, cycloalkyl, alkenyl, alkenyl or aryl spacer group, m and n mean from 0 to 3, D means a specified bond or bridge, X means NR12 or CHR12, p means from 0 to 3, E also means a bond, in addition, to the specified ether, amino, amide and carboxyl, J means a bond, a cycloalkylene, phenylene, naphthylene or heteroaryl group, G means more in detail, a amido, imino or amidino group and the other groups as defined in the above. These compounds are proposed as inhibitors of the isolated factor Xa, as well as of blood coagulation and thus as antithrombotic and thrombolytic active ingredients. In DE 197 18 181 Al (Boehringer Ingelheim) proposes disubstituted bicyclic heterocycles of the formula ¾-A-Het-Ap-E wherein Ra can mean one of the most specified amino groups or optionally also a group R4-S02-NR5 or a group R -S02 having the meanings specified for R4 and R5, A means a phenylene alkylene group of C1-3, an n-alkylene group of C2-s or a cycloalkylene group of C5_7-alkylene of Ci_3, which can be substituted specified mode, Het means an optionally substituted benzoimidazole group, indole, tetrahydroquinolinone or quinazolinone, Ar means a phenylene, naphthylene, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted and E means a cyano or bNH-C group ( = NH), where R means H, OH, Ci_3 alkyl or a group that can be divided in vivo. These compounds are proposed as active substances of thrombin inhibitors and thrombin time extension agents.
OBJECT OF THE INVENTION The object of the present invention is to provide novel carboxamide compounds, particularly those which are effective as MCH antagonists. The invention also establishes to provide novel compounds of. carboxamide "that can be used to influence the behavior of food ingestion in mammals and achieve a reduction in body weight, particularly in mammals and / or prevent an increase in body weight, The present invention further establishes to provide novel pharmaceutical compositions which are suitable for the prevention and / or treatment of symptoms and / or diseases caused by HCM or otherwise casually connected to HCM In particular, the object of this invention is to provide pharmaceutical compositions for the treatment of metabolic disorders such as obesity and / or diabetes, as well as diseases and / or disorders related to obesity and diabetes Other objects of the present invention relate to demonstrating advantageous uses of the compounds according to the invention The invention is also established for provide a process for preparing the carboxamide compounds according to with the invention Other objects of the present invention will be apparent to the expert of the above remarks and those that follow.
Subject matter according to the invention A first object of the present invention comprises general formula I wherein R1, R2 independently from each other mean H, an alkyl group of Ci_8 or C3-7 cycloalkyl 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 an alkylene bridge of C2.8, wherein one or two -C¾ groups can be independently replaced with -CH = N- or -CH = CH- and / or one or two -CH2 groups can be independently replaced with each other with -OR-, -S-, -C0-, -C (= C¾) - or -NR13 so that the heteroatoms are not directly bonded together, while the alkylene bridge defined above can be replaced by one or more H atoms by R14, and / or the alkylene bridge defined above can be replaced by one or two Cy- or heterocyclic groups identical or different such that the bond between the alkylene bridge and the group Cy is carried out - through a single or double bond, - through a common C atom forming a ring system , spirocyclic, - through two adjacent common C and / or N atoms forming a combined bicyclic ring system or - through "three or more atoms of C and / or N, forming a bridged ring system." R3_ means H, C3_7 cycloalkyl, C3_7 cycloalkyl, Ci-4 alkyl, C3-7 cycloalkenyl. , C3_7 cycloalkenyl-Ci_4 alkyl / phenyl, C 1-4 phenylalkyl, Ci_ 3 -alkyl-C 2 -alkyl, C 2 -e aminoalkyl, C 1 -alkylamino-C 2 -o-di- (alkyl) of C1-3) -amino-C2-s alkyl, X means a single bond or a C1-8 alkylene bridge, wherein one or two -CH2 groups can be independently substituted with -CH = CH- or -C = C- and / or - one or two -CH2 groups can be independently replaced with -O-, -S-, - (SO) -, - (S02) -, -CO- or -NR4- in such a way that two O, S or N atoms or an O atom are not directly linked to each other with an S atom, while one or two C atoms can be independently substituted with an idroxy, co-hydroxy-Ci_3 alkyl group ,? - (Ci_3 alkoxy) -Ci_3 alkyl and / or alkoxy of Ci-3 and / or in each case with one or two identical or different alkyl groups of 01-6,. / or the alkylene bridge can be linked to R1 such that it includes the N atom bound to R1 and X forming a heterocyclic group, Z means an alkylene bridge of Ci_4, where two adjacent C atoms can be linked together with an alkylene bridge Additional C1-4, while in group Z a -CH2 group can be replaced by -O- or -NRS-, and one or two C atoms of the alkylene bridge can be independently replaced with a hydroxy, co-hydroxy- group. C3_3alkyl- (Ci_3 alkoxy) -C1_3alkyl, 0_3_alkoxy, C1-3 aminoalkyl, C1-3 alkylaminoC1_3 alkyl, or di- (C1_4alkyl) ) -aminoalkyl of Ci_3 and / or with one or two identical or different Ci_6 alkyl groups, and / or R3 can be bonded with Z, so that it includes the N atom attached to R3, forming a heterocyclic group, A, Y have independently of each other one of the meanings specified for Cy, while R1 can join with? so that it includes the -X group and the N atom bonded with R1 and X, forming a heterocyclic group fused in Y, and / or R3 can be attached to Y so as to include the group Z and the N atom bonded to R3 and Z, forming a saturated or partially unsaturated heterocyclic group fused to Y, or. A and R3 can be linked together in such a way that the group of formula I means' a group of partial formula II and Q means a selected group of the partial formulas Illa to Illg - CR '- CRS = CR7 - N = N CO NR 9 CR¾ = N -CO- L 1, L 2, L 3 independently of each other means one of the meanings specified for R 20, B means C 1-6 alkyl (C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl-alkyl) from ¾-3, C3_7 cycloalkenyl-Ci_3 alkyl, C3-7 cycloalkyl-C1-3 alkenyl or C3_7-C3_3 alkynyl cycloalkyl, wherein one or more C atoms may be mono- or polysubstituted by halogen and / or monosubstituted by hydroxy or cyano and / or cyclic groups mono- or polysubstituted by R20, or one of the meanings specified for Cy, while the bonding with the group W or optionally directly with group A is carried out by a C atom of the carbocyclic part or of the phenyl or pyridine ring optionally fused or through a N or C atom of the heterocyclic part, where for the case that k = 0 the group E can be linked with the group A a ' through a common C atom forming a spirocyclic ring system or through two adjacent common atoms forming a fused bicyclic ring system, W means a simple bond, -O-, an alkylene group of Ci-4, alkenylene of C2- 4, C2-4 alkynylene, alkyleneoxy C1-4, Ci-4-oxyalkylene, Cx ^ -oxi-alkylene-C1-3-alkylene, imino, N- (Ci_3-alkyl) -imino, Ci-4-alkyleneimino, N- (Ci-3-alkyl) Ci_4 -imino alkylene, Ci_4 alkyleneimino, or 4,4-? - (Ci_3 alkyl) -imino alkylene, while one or two C atoms can be independently substituted with a hydroxy, co-hydroxy-alkyl group of C1-3,? - (Cx_3 alkoxy) -C 1-3 alkyloxy- and / or Ci-3 alkoxy and / or with one or two identical or different 0-6 alkyl groups, and / or W with the definitions of alkylene, oxyalkylene and alkyleneoxyalkylene can be bonded to B through a double bond, means 0 or 1, Cy means a carbo- or heterocyclic group selected from one of the following meanings: a saturated carbocyclic group of 3 to 7 members, 5 to 7 membered unsaturated carbocyclic group, - a phenyl group, - a 4 to 7 membered saturated or unsaturated 4 to 7 membered saturated heterocyclic group with an N, O or S atom as the heteroatom mo, - a saturated or unsaturated 5-7 membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, - a 5- or 6-membered heterocyclic aromatic group with one or more identical or different heteroatoms selected from N, 0 and / or S, while the groups of 5, 6 or 7 members mentioned in the above can be joined through two adjacent common C atoms in a fused manner with a ring phenyl or pyridine, and the groups of 5, 6 or 7 members mentioned in the foregoing, one or two non-adjacent -CH2 groups can be replaced by a group -CO-, -C (= CH2), - (SO) or - ( S02), and the 6 or 7 membered saturated groups mentioned above may also be present as bridged ring systems with an imino bridge, N- (Ci_4 alkyl) -imino, methylene, Ci-4_methylene alkyl or di- (Ci_4 alkyl) -methylene, and the cyclic groups mentioned in the above may be mono or polysusti in one or more C atoms with R20, in the case of a "phenyl" group additionally also monosubstituted with nitro, and / or in one or more N atoms with R21, R4, R5 independently have one of the meanings specified for R1S, R6, R7, R8, R9 independently of each other means H, an alkyl, Cis,? -3-C3-3 alkoxy- Ci_3 alkyl or co-hydroxyCi-3 alkyl group and R6, R7, R8 also independently of one another means halogen, R11 is R15-0-, R15-0-CO-, R16R17N-, R16R19N-CO- or Cy-, R12 has one of the meanings specified for R20, 'R13 have one of the meanings specified for Rl7 'R14 means halogen, Ci_s alkyl, R15 ~ 0-, R15-0-CO-, RI6R17N-, R18R19N-CO-,. R15-0-C1-3 alkyl, R15 -O-C0- C1-3 alkyl, R1SR17N- C1-3 alkyl, R18R19N-CO-CX-3 alkyl or Cy-C1-3 alkyl, R15 means H, alkyl of Q1.-4, cycloalkyl of C3_7, cycloalkyl of C3.7-alkylb of Ci_3, phenyl, phenyl-alkyl of Ci_3 or pyridinyl, R16 means H, alkyl of Ci_6, cycloalkyl of C3_7, cycloalkyl of C3-7 -alkyl Ci_3, C4_7 cycloalkenyl, C4_7 cycloalkenyl-Ci_3 alkyl,? -hydroxyC2-3 alkyl,? - (C1-3 alkoxy) -C2_3 alkyl, Ci_6 amino-alkyl, C1-3-aminoC1-6alkyl or di- (C3-alkyl) -amino-Ci-6alkyl, R17 has one of the meanings specified for R16 or phenyl, phenyl-C1-3alkyl, pyridinyl, dioxolan- 2-yl, Ci_3 alkylcarbonyl / hydroxycarbonyl-Ci_3 alkyl, C 1 alkoxycarbonyl, C 1_ 3 alkylcarbonylamino, C 3_3 alkylsulfonyl or alkylsulfonylamino alkyl, C 2_ 3 alkyl, R 18, R 1 S independently from each other mean H or alkyl of Ci-S, R20 meant to halogen, hydroxy,. cyano, Ci_4 alkyl, C3_7 cycloalkyl, Ci_3 hydroxy-alkyl, R22-Ci_3 alkyl or has one of the meanings specified for R22, R21 means 0? _3 alkyl,? -hydroxy-C2 alkyl- 3, phenyl, phenylC1-3alkyl, alkylcarbonyl of (3C, carboxy, C1-4 alkoxycarbonyl, C1-3 alkylsulfonyl, phenylcarbonyl or phenylC1 -carbonyl alkyl, R22 means pyridinyl, phenyl, phenyl- Ci_3 alkoxy, Ci_3 alkoxy / Ci_3 alkylthio, carboxy, H-CO-, Ci_3 alkylcarbonyl, CL_4 alkoxycarbonyl, aminocarbonyl, Ci_3 alkylaminocarbonyl, di- (Ci_3 alkyl) -aminocarbonyl, alkyl of Ci_3-sulfonyl, C3_3- 'sulphinyl, C1_3-sulfonylamino, amino, C1-3 alkylamino, di- (Ci_3 alkyl) -amino, phenyl-CX-3 alkylamino or N- alkyl (alkyl of Ca_3) -phenyl-C1-3 alkylamino, acetylamino, propionyl mino, · phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrole) idinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino, while in the groups and residues A, B, W, X , Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms may be mono or polysubstituted with F and / or in each case one or two C atoms may be monosubstituted independently of each other, with Cl or Br, and In each case, one or more phenyl rings independently additionally have one, two or three substituents selected from the group F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, difluoromethyl, trifluoromethyl, idroxy, amino, alkylamino of ¾_3, di- (C! -3) alkyl-amino, acetyla ino, aminocarbonyl, CN, difluoromethoxy, trifluoromethoxy, amino-alkyl of _3, alkylamino of C ^ -alkyl of C1-3 and di- (C 1-3 alkyl) -amino-C! _3 alkyl and / or can be monosubstituted by nitro, and the H atom of an existing carboxy group or an H atom attached to an N atom can be replaced by a group cleavable in vivo, the tautomers, enantiomers, mixtures thereof and salts thereof. The invention also relates to the compounds in the form of individual optical isomers, mixtures of the enantiomers or racemates, in the. tautomeric form and in the form of free bases or the corresponding acid addition salts with pharmacologically acceptable acids. The object according to the invention also includes the compounds according to the invention, including their salts, wherein one or more hydrogen atoms are replaced by deuterium. The invention is further related to a process for preparing carboxamide compounds of the formula I where A, B, W, X, Y, Z, R1, R2, R3 and k have one of the meanings specified in the above, where if A means a group R3 which does not join the group A: a) in the fact that A means. a nitrogen-heterocyclic group connected to the carboxamide group via a nitrogen atom which also have in addition to the nitrogen atom one or more heteroatoms selected from N, 0 and S, at least one amine compound of the formula 1-1 where R1, R2, R3, X, Y and Z have the meanings specified in the foregoing, it is reacted with CDT (1,1'-carbonyldi- (1, 2, 4-triazole)) and at least one secondary amine compound of Formula 1-2 A- -W-j ^ B-2 wherein Av B, W and k have the meanings specified in the above and group A has the function amine sec in a solvent or mixture of solvents in the presence of at least one base, and b) in the other cases at least one compound of carboxylic acid of the formula 1-3 where A, B, W and k have the meanings specified in the above; is reacted with TBTU (2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate) and at least one amine compound of the formula 1-1 wherein R1, R2, R3, X, y and Z have the meanings specified in the above, in a solvent or mixture of solvents in the presence of at least one base, and if B is a group R3 connected to group A: a) in the fact that a group Q has the meaning -CRSR7- (Illa), while R6 and R7 are as defined in the above, an amine compound of the formula wherein R1, R2, X, Y and Z having the specified meanings is reacted with an o-bromomethyl-benzoic acid ester of the formula la.2 where R6, R7, W, B and k have the specified meanings, b) in the fact of a group Q having the meaning -CR6 = CR7- (Illb), where R6 and R7 are as defined in the above, an isoquinolinone derivative of the formula Ib.2 wherein Rs, R7, W, B and k have the specified meanings, is reacted with an electrophilic compound of the formula Ib.3 where ? and Z have the specified meanings and OMs means an appropriate leaving group, preferably mesylate, to obtain an isoquinoline derivative of the formula Ib.4 wherein R6, R7, W, B, Y, Z and k have the specified meanings, and the isoquinoline derivative of the formula Ib. it is further derivatized by known methods to form the compound of formula I, c) in the fact of a group Q having the meaning -N = CR8- (lile), wherein R8 is as defined above, a derivative of phthalazinone of the formula Ic.4 where R, W, B and k have the specified meanings, is reacted with an electrophilic compound of the formula lc.5 wherein Y and Z have the specified meanings and OMs means a leaving group, preferably mesylate, to form a phthalazinone derivative of the formula Ic.6 wherein R, W, B, Y, Z and k have the specified meanings, and the phthalazinone derivative of the formula Ic.6 is thus obtained is further derivatized by known methods to form the compounds of the formula I, wherein Q means -N = CR8- (lile), d) in the fact of a group Q having the meaning -N = N- (Illd), an o-amino-benzamide derivative of the formula Id.l wherein R1, R2, W, B, X, Y, · z and k have the specified meanings, is reacted in the presence of an appropriate nitrite compound and an acid to form the compound of the formula I, wherein Q means -N = N-, e) in the fact of a group Q having the meaning -CO-NR9- (lile), wherein R9 is as defined above, an o-amino-benzamide derivative of the formula Ie.l wherein R1, R2, R9, W, B, X, Y, Z and k have the specified meanings, is reacted in the presence of CDI (carbonyldiimidazole) to form the compound of formula I, wherein Q -CO- NR9-, f) in the fact of a group Q having the meaning -CR8 = N- (Illf), wherein R8 is as defined above, an o-amino-benzamide derivative of the formula If .1 wherein R1, R2, W, B, X, Y, Z and k have the specified meanings, is reacted with a carboxylic acid R8COOH having the specified meaning for R8 and / or a corresponding activated carboxylic acid derivative for the derivative of quinazolinone of the formula I, wherein Q means -CR8 = N-, g) in the fact of a group Q having the meaning of -CO- (Illg) an isobenzofurandione derivative of the formula Ig.2 - wherein W, B and k have the specified meanings, is reacted with an amine of the formula Ig.l wherein R1, R2, X, Y and Z have the specified meanings, to form the compound of the formula I, wherein Q means -C0-. This invention also includes physiologically acceptable salts of the carboxamide compounds according to the invention as described above and below. Also subject of this invention are compositions containing at least one carboxamide compound according to the invention and / or a salt according to the invention optionally together with one or more excipients of physiological tolerance. Also subject of the present invention are pharmaceutical compositions containing at least one carboxamide compound according to the invention and / or a salt according to the invention optionally together with one or more inert carriers and / or diluents. 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. 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 to reduce body weight and / or to prevent an increase in the body weight of a mammal. 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 preparing a pharmaceutical composition with MCH receptor antagonist activity. Furthermore, it is an object of this invention to use at least one carboxamide compound according to the invention and / or a salt according to the invention to prepare a pharmaceutical composition. which is suitable for the prophylaxis and / or treatment of symptoms and / or diseases caused by HCM or which are causally related to HCM. 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 preparing a pharmaceutical composition which is suitable for the prophylaxis and / or treatment of metabolic disorders and / or food, especially obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia. This invention also relates to the use of at least one carboxamide compound according to the invention and / or a salt according to the invention to prepare a pharmaceutical composition which is suitable for the prophylaxis and / or treatment of diseases and / or disorders that accompany obesity, especially diabetes, especially type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological tolerance to glucose, encephalogram, heart failure, cardiocirculatory diseases , especially arteriosclerosis and hypertension, arthritis and gonitis. In addition, the invention relates to the use of at least one carboxamide compound according to the invention and / or a salt according to the invention to prepare a pharmaceutical composition that is suitable for the prophylaxis and / or treatment of hyperlipidemia, cellulitis , accumulation of fat, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depressions, states of anguish, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders. Another object of the invention is the use of at least one carboxamide compound according to the invention and / or a salt according to the invention to prepare a pharmaceutical composition which is suitable for the prophylaxis and / or treatment of voiding disorders such as, for example, urinary incontinence, overactive urinary bladder, urination, nocturia and enuresis.
Furthermore, the invention relates to processes for the preparation of a pharmaceutical composition according to the invention, characterized in that, by a non-chemical route, at least one carboxamide compound according to the invention and / or a salt according to the invention is prepared in accordance with the invention. one or more carriers and / or inert diluents. The invention further relates to a pharmaceutical composition containing a first active substance, which is selected from the carboxamide compounds according to the invention and / or the corresponding salts, as well as a second active substance, which is 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 the antagonists of HCM, active substances for the treatment of hypertension, active substances for the treatment of hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of states of distress and active substances for the treatment of depressions, as well as optionally one or more carriers and / or inert diluents.
DETAILED DESCRIPTION OF THE INVENTION Unless otherwise indicated, the groups, substituent residues and indices, especially A, B, W, X, Y, Z, R1 to R9, R11 to R22, L1, L2, L3 and k, have one of the meanings specified in the above and / or below. A preferred embodiment of this invention comprises compounds of the formula I, wherein R3 is H, Ci_6 alkyl, C3_7 cycloalkyl, C3.7 cycloalkyl-4-alkyl, C2-alkoxy C2_6 alkyl, C2-s aminoalkyl , Ci-3-alkylamino of C2_6 alkyl or di- (Ci-3 alkyl) -aminoalkyl of C2-s, B has one of the meanings specified for Cy, where the binding with the group W or optionally directly with the group A is carried out through a C atom of the carbocyclic part or the phenyl or pyridine ring optionally fused or through an N or C atom of the heterocyclic part while if k = 0, the group B can join with the group A through a common C atom forming a system of spirocyclic ring or 'through two adjacent common atoms forming a system of fused bicyclic rings, Cy is a carbocyclic or heterocyclic group selected from one of the following meanings: a saturated carbocyclic group of 3 to 7 members, an unsaturated carbocyclic group of 5 to 7 members, a phenyl group, a saturated heterocyclic group of 4 to 7 members or unsaturated from 5 to 7 members with one atom of N, O or S as heteroatom, a saturated or unsaturated heterocyclic group of 5 to 7 members with two or more N atoms or with one or two N and O atoms or S as heter oatoms, a 5- or 6-membered heterocyclic aromatic group with one or more identical or different heteroatoms selected from N, O and / or S, while the 5, 6 or 7-membered groups mentioned in the above may be attached through two adjacent common C atoms in a fused manner with a phenyl or pyridine ring, and the groups of 5, 6 or 7 members mentioned in the above a -CH2 group can be substituted with a group -CO-, -C (= C¾) -, . - (SO) - or - (S02) -, and the saturated groups of 6 or 7 members detailed in the above may also be present as bridged ring systems with an imino bridge, N- (C1-3 alkyl) -imino , methylene, Ci_3 alkylmethylene, or di- (C 1-3 alkyl) -methylene, and the cyclic groups mentioned in the above may be mono or polysubstituted in one or more C atoms with 20, or in the case of a group phenyl additionally also monosubstituted with nitro, and / or can be substituted on one or more N atoms with R21, R15 is H, Ci-4 alkyl, C3-7 cycloalkyl, C3_7 cycloalkyl-Cx_3 alkyl, phenyl or phenyl- alkyl of R17 has one of the meanings specified for R16 or phenyl, phenyl-C1-3alkyl, dioxolan-2-yl, alkylcarbonyl of ¾_3, hydroxycarbonyl-Ci-3alkyl, Ci -3-alkylcarbonylamino of C2-3alkyl, alkylsulfonyl of C1-3 or alkylsulfonylamino of Ci- 3-C2-3 alkyl, R22 is phenyl, Ci_3 phenyl-alkoxy, Ci_3 alkylthio alkyloxy, carboxy, Ci_3 alkylcarbonyl, Ci_3 alkoxycarbonyl, aminocarbonyl, Ci_3 alkylaminocarbonyl, di- ( ¾_3-) -aminocarbonyl alkyl, Ci-3 alkylsulfonyl, C1-3 alkylsulfinyl, Ci_3 alkylsulfonylamino, amino, Ci-3 alkylamino, di- (Ci_3 alkyl) -amino, phenyl-C1-3 alkylamino or N- (Ci-3 alkyl) -phenyl-C1-3 alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) -carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino while the groups and residues A, B, W, X, Y, Z, R1 to R9 and R11 to R22, in each case one or more C atoms may be mono or polysubstituted with F and / or in each case one or two C atoms can be monosubstituted, independently of one another, with Cl or Br and the H atom of an existing carboxy group or an H atom attached to an N atom can be substituted in each case with a cleavable group in vivo, the tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof. According to the first group of the preferred embodiments, the group A and the group R3 are not directly linked to each other. Therefore, group A has one of the meanings specified for Cy. According to the second group of the preferred embodiments, the group? and the group R3 are united in such a way of the formula I means a group of the partial formula II and Q means a group, selected from the partial formulas Illa to Illg - CR¾7- - lila, - CRS = CR? ~ í »» 3t - = CR "- | nic,. ™ N == N- - - Ifld, - -CO - - NR- - flte, CO [ttg.
The preferred meanings of the group Q are selected from the partial formulas Illb, Illd, lile, Illf and Illg, especially Illd, Ule, Illf and Illg. · The preferred meanings of substituents R6, R7, R8 and R3 independently of each other mean, H and C1_4 alkyl, especially H, methyl or ethyl. The substituents L1, L2, L3 preferably have, independently of one another, one of the following meanings: H, F, Cl, Br, CH3i 'CHF2, CF3, C2H5, C3H7, CH (C¾) 2, OCH3, OCHF2 / OCF3, OC2H5 , OC3H7 and .OCH (CH3) 2. Preferably only one of the substituents L1, L2, L3 has a different meaning from H, especially one of the meanings specified therein. Previous as preferred. Particularly preferable, the three substituents L1, L2, L3 are H. Preferably the groups R 1, R 2 independently of each other mean, H, C 1, C 4 alkyl, C 3-7 cycloalkyl, C 3 7 cycloalkyl, C 1 alkyl, C 2 3 alkyl hydroxy, C 1 alkoxy. -3-) -C2-3 alkyl, C1-4 alkoxycarbonyl ~ 3 alkyl, amino C2 alkyl-, Ci-3 alkylamino C2-4 alkyl or di- (C1-3.alkyl) -amino-C2-4 alkyl, phenyl or phenyl-C de alkyl, while in the groups and residues specified therein one or more C atoms may be mono- or polysubstituted by F and / or one or two carbon atoms. C may be monosubstituted, independently of each other, with Cl or * Br, and where the phenyl group may be mono- or polysubstituted with the group R12 defined above and / or may be monosubstituted with nitro. More preferably, the groups R 1, R 2 independently of each other mean, Ci_4 alkyl, C317 cycloalkyl, C3 cycloalkyl 7-C1.3 alkyl, C2-3 co-hydroxyC1-3 alkyl, C1- (alkoxy) C2-3 alkyl, Ci_4 alkyloxycarbonyl Ci_3 alkyl / where one of the groups R1, R2 can also mean H. Preferably, also, R1 and R2 preferably form a -alkylene bridge in such a way that R1R2N- is a selected group of azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-lH-pyrrole, 1, 2, 3, 6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepinyl, 2,3,6,7 -tetrahydro-lH-azepine, piperazine, where the free imine function can be substituted with R13, morpholine and thiomorpholine, where according to the general definition of R1 and R2 means one or more H atoms can be replaced by R14, and / or the groups mentioned in the foregoing in a manner indicated according to the general definition, R1 and R2 may be substituted with one or two identical or different carbocyclic or heterocyclic groups. Particularly preferable, the group is defined according to one of the following partial formulas wherein one or more H atoms of the heterocycle formed by the group R 1 R 2 N can be replaced by R 14 and the ring linked with the heterocycle formed by the group R N can be mono or polysubstituted on one or more C atoms with R 20, in the case of a phenyl ring, additionally also monosubstituted with nitro. More particularly preferred are the groups described above, in which R1 and R2 form with the N atom of the group RXR2N- a pyrrolidine, piperidine or 2,5-dihydro-lH-pyrrole ring, which can be substituted as Indian. Preferred meanings of the group R 14 are C 1-4 alkyl, C 1-4 cycloalkyl, hydroxy, C 1-4 alkoxy, C 1-4 alkyloxy C 1-3 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, alkoxycarbonyl of C 1-4 -alkyl Ci_3, alkoxycarbonylamino of C 1-4, alkoxycarbonylamino of CL_4-Ci_3 alkyl, amino, (alkyl of 0? _4) -amino, di- (C 1-4 alkyl) -amino, phenyl, phenyloxy , pyridinyl, pyridinyloxy. A piperidine group preferably substituted by the group Cy has the structure where Cy signifies, preferably, phenyl which can be substituted as indicated. Preferably, the alkylene bridge X does not have or has at most one NR4 group. The position of the NR4 group within the alkylene bridge X is preferably selected in such a way that together with the amino group N3 ^ 2 or another adjacent amino group, it does not form an amine function or two N atoms are adjacent to each other. For this reason, the alkylene bridge has, in the event that a -C¾ group is replaced by -NR4-, preferably, the meaning of C2-7-NR4 alkylene of C0_5, wherein the X-bridge presents in addition to the N atom a maximum of 7 bridges C atoms and where the C atoms can be replaced in the indicated way. Preferably, X- means a single bond or an unbranched bridge selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 alkyleneoxy, carbonyl, C 1-6 carbonylalkylene or Ci-6 alkyleneamino. wherein the amino group can be substituted with R 4, where one or two C atoms can be substituted according to the manner indicated in the general definition of X and / or the alkylene bridge can be linked with R 1 in the manner indicated. Preferably X means a "single bond, carbonyl or alkylene bridge selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, where one or two C atoms can be substituted, independently of each other, by a hydroxy group, co-hydroxyalkyl of Ci_3, co- (Ci-3 alkoxy) -Cl-3 alkyl and / or Ci_3 alkoxy and in each case with one or two equal or different? -4 alkyl groups , and in each case where one or more C atoms may be mono or polysubstituted by F and / or in each case one or two C atoms may be monosubstituted, independently of each other, with Cl or Br. If a group X one or two C atoms by a hydroxy group and / or Ci-3 alkoxy, the C atom preferably substituted is not directly adjacent to an amino group, especially -NÍ ^ R2 or -NR4. bridge X means a simple link, -CH2- or -CH (CH3) -, for the case that in bridge Z it will mean a group -CH2 replaced by -NR 5-, the position of the group NR5 within the group Z is preferably selected in such a way that together with the amino group -NR3- or another adjacent amino group an amine function is not formed or two N atoms are adjacent to each other. The preferred meanings of the Z-bridge are methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy and 1,4-butyleneoxy, where one or two C "atoms can be substituted, independently of each other, with a hydroxy,? -hydroxy-alkyl group of Ci_3,? - (Cx_3 alkoxy) -Cl_3 alkyl- and / or Ci_3 alkoxy and / or in each case with • one or two Cx ~ 4 alkyl groups the same or different, and in each case one or more C atoms may be mono- or polysubstituted by F and / or in each case one or two C atoms may be monosubstituted, independently of each other, with Cl or Br and where R3 can be linked with Z, including the N atom bound with R3, forming a heterocyclic group. If in the group Z, one or two C atoms are substituted by a hydroxy group and / or C1-3 alkoxy, the substituted C atom is not directly adjacent to an amino group, especially -NR3- or - NR5-. Particularly preferably, Z is selected from the group -CH2-, -CH2-CH2-, -C¾-CH (CH3) -CH2-C (CH3) 2-, -CH (CH3) -CH2-, -C (CH3) 2 -CH2- and -CH2-0-, especially -CH2-CH2- or -CH (CH3) -C¾- In addition, Z will mean linked with R3 according to a meaning of special preference in such a way that the group has an selected meaning of 1,3-pyrrolidinylene, 1,3-piperidinylene, 1, 2, 5, 6-tetrahydropyridin-l, 3-ylene and 3-hydroxy-1,3-piperidinylene. Preferably, the group R3 is selected from the group methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or 2-hydroxy-l-methyl-ethyl, where in the mentioned groups one, two or three H atoms can be replaced by F, or R3 is selected from the group H, amino-C2.3alkyl, C1-3alkylamino-C2_3alkyl or di- (Ci_3alkyl) -amino-C2_3alkyl. The particularly preferred meanings of the R3 group are H, methyl or ethyl, especially H or methyl. The preferred meanings of the groups R 4 and / or R 5 are H, C 1-4 alkyl, cycloalkyl. of C3_6 and C3-S-cycloalkyl-Cx3 alkyl, especially H and C1-4 alkyl. Preferred meanings of the R11 group are Ci_6 cycloalkyl, hydroxy, C ^ alkoxy, amino, Ci-4 alkylamino and di- (Ci_4 alkyl) -amino. Preferred meanings of the R20 group are halogen, hydroxy, cyano, Ci_4 alkyl, C3_7 cycloalkyl and C3 hydroxy-alkyl. Particularly preferable, R20 means F, Cl, Br,. I, OH, cyano, methyl, difluoromethyl, trifluoromethyl,. ethyl, n-propyl, isopropyl, methoxy, difluorornetoxy, trifluoromethoxy, ethoxy, n-propoxy or isopropoxy. The group Y is preferably selected from the amount of bivalent cyclic groups 1, 2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenethylene, 1,3- and 1,4-cyclohexylene, 1 , 3-phenylene, 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-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene or 1,4-piperazinylene, while the groups of 5 ,. 6 or 7 members mentioned in the foregoing may be attached through two common C atoms adjacent in a fused manner to a phenyl or pyridine ring, the cyclic groups mentioned in the foregoing may be mono- or polysubstituted in one or more atoms of C with R20, 'in the case of a phenyl group can additionally also be monosubstituted with nitro, and / or can be substituted on one or more N atoms by R21, and where R1 can be linked with Y and / or R3 can, join with And according to the form indicated in the general definition.
The meanings of group Y of special preference are selected from the group of cyclic structures composed of: while the cyclic groups can be mono- or di-substituted, preferably monosubstituted by R2Q, preferably with halogen, CF3, Ci_4 alkyl and / or alkoxy In addition, the group Y can also join with the group R1 in such a way that the group of the partial formula has a selected meaning of the following F The preferred meanings of the group A are selected from the group of bivalent cyclic groups 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, -cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1,3-pyrrolinylene, 1,3-pyrrolylene, 1, 4-piperidinylene,. 1, 4-tetrahydropyridinylene, 4S 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene, 1,4-piperazinylene, 7-aza-bicyclo [2.2.1] heptan-2,7-diyl and 8-aza-bicyclo [3.2.1 ] octane-3, 8-diyl, while the groups of 5, 6 or 7 members mentioned in the above can be linked through two adjacent common C atoms in a fused manner with a phenyl or pyridine ring, and the cyclic groups mentioned in the foregoing may be mono or polysubstituted on one or more C atoms with 20, in the case of a phenyl group additionally it may also be monosubstituted with nitro, and / or substituted on one or more N atoms with R21. The very special preference meanings of group A are selected from the group of cyclic structures composed of: while the cyclic groups can be mono- or di-substituted, preferably monosubstituted with R20, preferably with halogen, CF3, C1-4alkyl and / or alkoxy Ci_4. In the bivalent cyclic groups specified for Y and / or A, mirror-symmetric forms are also included, that is, the forms in which the union with the adjacent groups are exchanged, in the case of Y with X and Z, as well as in the case of A with CO and W. In this way, for ica both The divalent cyclic groups specified in the above for groups Y and A, are all imaginable isomers. The meanings "specified both before and after" are detailed below: the term tetrahydropyridinylene has the meanings 1, 2, 3, 4-tetrahydropyridin-l, 4- and -3,6-ylene, 1, 2, 3, 6-tetrahydropyridine -l, 4-, -2,5- and -3,6-ylene, 2,3,4,5-tetrahydropyridin-2, 5- and -3,6-ylene The meaning of preference means, in this case , 1, 2, 3, 6-tetrahydropyridin-1,4-ylene. "The di-hydropyridinylene meaning includes the meanings 1,4- and 1,2-dihydropyridin-1,4-ylene and 1,2-, 1,4 -, 1,6-, 2,3-, 2,5- ,. 3,4-, 4,5- and 5,6-dihydropyridin-2,5-ylene. The preferred meaning in this case is 1,2-dihydropyridin-1,4-ylene. Preferably the groups A and / or B are unsubstituted or mono or disubstituted by R20, preferably particular unsubstituted or monosubstituted by R20. The preferred meanings of the group B are selected according to a first preferred embodiment of the C! _ _6 alkyl, C C16 al alkenyl, Ci-6 alkynyl, C3_7 ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo ciclo 3 3 of Ci_3, C3_7 cycloalkyl-C1-3 alkenyl or C3_7-alkynyl cycloalkyl of Cx_3, where one or more C atoms may be mono or polysubstituted by halogen and / or may be monosubstituted by hydroxy or cyano and / cyclic groups may be mono or polysubstituted with R20, and W means a simple bond, '-O-, an alkylene group of Ci_4, alkenylene of C2-4, alkynylene of C2-4, alkyleneoxy of oxy-alkylene of Ci_4, alkylene of Ci-3 -CO-3-alkylene, imino, N- (C 1-3 -alkyl) -imino, Ci-4-imino alkylene, N- (C 1-3 -alkyl) -imino-C 1-4 -alkylene; alkylene C1-4-imino or alkylene of ??? -? - (C1-3 alkyl) -imino, where one or two C atoms can be substituted, independently of each other, with a hydroxy group,? -hydroxy-alkyl of Ci_3,? ~ (C1-3 alkoxy) -Cl_3 alkyl and / or Ci_3 alkoxy and / or with one or two Ci-4 alkyl groups equal or different, and k- means 0 or 1, especially 1 and R20 has one of the specified meanings. In preferred meanings mentioned in the above for B, k preferably has the value 1 and W preferably has the simple meaning bond, imino-or N- (Ci_3 alkyl) -imino, especially simple bond. Particularly preferably, the group B here means C3-6 alkynyl, especially C3_6 alkynyl and / or the group W means a simple bond, where k = 1; Preferred Group B according to a second embodiment meanings are selected from the set of cyclic groups cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl , dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, lH-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl and thienyl, wherein the connection with the group W or optionally directly with the group A is carried out through a C atom of the carbocyclic part or of the phenyl or pyridine ring optionally fused or through an N or C atom of the heterocyclic part, or B together with the group attached through a double bond is selected from the group cyclopentylidene-methyl, cyclohexylidene-methyl and cyclohexanone -4-ylidene-methyl, and the cyclic groups mentioned in the above may be mono or polysubstituted. in one or more C atoms with 20, in the case of a phenyl group additionally it may also be monosubstituted with nitro ,, and / or may be substituted in one or more N atoms with R21. More particularly preferably, the group B means phenyl which is mono, di or trisubstituted, preferably mono- or di-substituted with 2C. The meanings of B detailed in the above will mean all imaginable isomers of the corresponding groups. In this manner, the following isomers are included: cyclopenten-1-, 3- and 4-yl, cyclohexanon-4-yl, cyclohexen-1-, 3- and 4-yl, cyclohepten-1-, 3-, 4 - and 5-yl, "aziridine-l-yl, azetidin-l-yl, pyrrolidin-1-yl, pyrrolidin-l-yl, pyrrol-l-yl, piperidin-1- and 4-yl, pyridin-2- , -3- and -4-yl, azepan-l-yl, piperazin-l-yl, 4-methylpiperazin-l-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, lH-benzoimidazole-1-, 2 -, 4-, 5-, 6- and 7-yl The meaning "pyrazole" comprises the isomers lff-, 3H- and 4H-pyrazole Preferably, pyrazolyl means 1H-pyrazol-1-yl The imidazole meaning includes isomers 1H-, 2H- and 4H-imidazole A preferred meaning of imidazolyl is 1H-imidazol-1-yl The meaning tetrahydropyridine comprises the isomers 1,2,3,4-, 1,2,3,6- and 2, 3, 4, 5-tetrahydropyridine Preferably, tetrahydropyridinyl means 1,2,3,4- and 1,2,3,6-tetrahydropyr idin-1- ilo. The meaning dihydropyridine comprises the 1,2-, 1,4-, 2,3-, 2,5- and 4,5-dihydropyridine isomers. Preferably, dihydropyridinyl means 1,2- and 1,4-dihydropyridin-1-yl. The triazole meaning comprises the isomers 1H-, 3H- and 4H- [1,2,4] -triazole as well as 1H-, 2H- and 4H- [1,2,3] -triazole. Thus, the triazolyl meaning comprises 1 H- [1, 2, 4] -triazol-1, 3, and 5-yl, 3 H- [1,2, 4] -triazol-3 and 5-yl, 4 H - [1, 2, 4] -triazol-3-4- and '5-yl, 1H- [1, 2, 3] - riazol-1-, 4- and 5-yl, 2H- [1, 2, 3] -triazol-2-, 4- and 5-yl and 4H- [1, 2, 3] -triazol-4- and 5-yl. The term tetrazole comprises the isomers 1H-, 2H- and 5H-tetrazole. The meaning tetrazolyl comprises / therefore, 1H-tetrazol-1- and 5-yl,. 2H-tetrazol-2- and 5-yl and 5H-tetrazol-5-yl. The meaning indole comprises the isomers 1H- and 3H-indole. The term "indolyl" preferably means 1H-indol-1-yl. The meaning isoindol comprises the isomers 1H- and 2H-isoindole. The term isoindolyl means, preferably, 2H-isoindol-2-yl. In general , . the binding of the heterocyclic groups mentioned above, especially a pyrazolyl group, imidazolyl, tetrahydropyridinyl, dihydropyridinyl, triazolyl, tetrazolyl, indolyl or isoindolyl, .can be made via a C atom or optionally a- atom N of a function imina. Group B is preferably unsubstituted, mono, di or trisubstituted with R20., B is mono or disubstituted with R20. For the case that B is a six-membered substituted ring, it is preferably a substituent r 1 in position para to join the group A ~ † ~ --- The index k can adopt the values 0 or 1. In the case of preference, k = 1, the bridge W has the specified meanings, preferably the meanings of a simple link, -CH2- or -CH =. Preferred meanings of the partial formula -AWB are selected from the structures detailed in the list below, wherein V means a C or N atom, preferably a C atom, and the cyclic groups listed may be mono or polysubstituted in one or more C atoms with R20 and in the case of phenyl or phenol groups, additionally they may also be monosubstituted with nitro:. 53 More particularly preferred are the compounds of the formula I, in which k = 1 and W means a simple bond. The index k can also adopt the value 0. According to a first sub-variant, group A will be linked to group B through a common C atom forming a spirocyclic ring system, where group A means a group saturated carboxy or heterocyclic of 5-7 members and group B means a saturated heterocyclic carbo- or group of 4 to 7 members, and where the heterocyclic groups in each case have an N, O or S atom, and where in a Group B of 5 to 7 members can be fused a phenyl or pyridine ring through two adjacent C atoms, and the cyclic groups mentioned in the above can be mono or polysubstituted in one or more C atoms with R20, - in the In the case of an additionally fused phenyl ring, they can also be monosubstituted with nitro, and / or can be substituted in one or more N atoms with R21. The preferred meanings of the partial formula -AWB according to this second sub-variant are selected from the structures detailed in the table below, where the cyclic groups listed may be mono- or polysubstituted on one or more C atoms with R20 and in the case of the phenyl ring, they can additionally also be monosubstituted with nitro: According to 'a second sub-variant for the case k = 0, group B is linked with group A through two adjacent common atoms forming a' system of fused, saturated, unsaturated or aromatic bicyclic rings of 8 to 12 members, which may have one or more identical or different heteroatoms selected from N, O and / or S, and where the bicyclic ring system may be mono or polysubstituted in one or more C atoms with E20, in the case of a additionally fused phenyl ring may also be monosubstituted with nitro, and / or on one or more N atoms with R21. The preferred meanings of the partial formula -AWB according to this first sub-variant are selected from the structures detailed in the table below, where the cyclic groups listed may be mono- or polysubstituted on one or more C atoms with R20 and in the case of the phenyl ring, they can additionally also be monosubstituted with nitro.
Preferred are those compounds according to the invention in which one or more of the groups, residues, substituents and / or indices have one of the meanings specified in the above as preferred. The preferred meanings of the substituent R20 are selected from the group consisting of fluorine, chlorine, bromine, CF3, Ci_4 alkyl, and C1-4 alkoxy. Above all, those compounds according to the invention are preferred in which:. "And, A are selected, independently of each other, from the amount of bivalent cyclic groups 1, 4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2,3,6 -tetrahydro-pyridin-l, 4-ylene, 2, 5-pyridinylene and 1,4-piperazinylene, where A may also be attached with R3 according to claim 3, and the cyclic groups mentioned in the foregoing may be mono or polysubstituted in one or more C atoms with R20, in the case of a phenyl group additionally they can also be monosubstituted with nitro, and / or can be substituted in one or more N atoms with R21, B means phenyl or cyclohexyl, where the groups cited above may be mono or polysubstituted with R20 and / or the phenyl ring may be monosubstituted further with nitro, where R20 has the meanings specified in claim 1, and 'K has the value 1, W means a simple bond, -C¾- or -CH =, and Z is -CH2-C¾-, -CH2-CH (CH3) -, -C¾-C (C¾) 2-, -CH (C¾) -CH 2 -, -C (CH 3) 2 -CH 2 - or -CH 2 -O- or it is linked with R3 in such a way that the group of the partial formula la-formula I has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene. The compounds of particular preference according to the invention are detailed in the following group of formulas 1.1 to 1.14: ?? 60 wherein U, V independently from each other mean, C or N, 23, R24 independently of each other mean, H, F, methyl, trifluoromethyl, ethyl, isopropyl or n-propyl, while formulas 1.1 to 1.6 R24 can be linked with R3 so that the group of the partial formula has a selected meaning of 1,3-pyrrolidinylene and 1,3-piperidinylene, and R25, R26, R27 independently have one of the meanings specified for R2Q or in the case of a phenyl group also be simply nitro, where the residues R25, R2e, R27 that appear several times can have the same or different meanings, and j is 0, 1, 2, 3 or 4 and m, n independently of each other means, 0, 1 or 2. More particularly preferred are the compounds of the above formulas 1.1, 1.2, 1.8, 1.10 and 1.12. In particular, the compounds of particular preference can be described by means of the following formulas wherein the groups and substituents have the meanings listed before and after. Also preferred are the compounds according to the invention of the following partial formula wherein B is selected from the group of Ci_6 alkyl < alkenyl of 'Cx_6f alkynyl of 6, cycloalkyl of C3_7 alkyl of Ci_3, cycloalkenyl of C3-7-alkyl of Ci-3, cycloalkyl of C3_7-alkenyl of Ci_3 or cycloalkyl of C3_7-alkynyl of Cx_3, where one or more atoms of C may be mono or polysubstituted by halogen and / or may be monosubstituted by hydroxy or cyano and / or cyclic groups may be mono or polysubstituted with R20, and W means a simple bond, -O-, an alkylene group of Ci.4, C2_4alkenylene, C2_4alkynylene, C4_4alkyleneoxy, C4_4alkylene_alkyl, C1_3alkylene_alkylene_alkylene. 3, imino, N- (C 1 -C 3 alkyl) -imino, 0-, 0-, N- (C 1 -3 alkyl) -imino alkylene of C 1, C 4 -imino alkylene or alkylene of Ci_ 4_N- (C1-3 alkyl) -imino, where one or two C atoms can be substituted, independently of each other, with a hydroxy,? -hydroxy-C1-3 alkyl group (? - (C1-3 alkoxy) - C 1-3 alkyl "and / or Ci-3 alkoxy and / or with one or two identical or different C 3-4 alkyl groups, and k means 0 or 1. Further, according to this embodiment, those compounds are preferred wherein the group B is C 1-6 alkyl, C 1-6 alkynyl, C 3-7 cycloalkyl-C 1-3 alkyl or C 3-7 cycloalkyl-C 1-3 alkynyl, where one or more C atoms may be "mono- or polysubstituted by halogen and / or may be monosubstituted with hydroxy or cyano and / or cyclic groups may be mono- or polysubstituted with R20, and / or W means a simple bond, -O-, imino or N- (alkyl) Ci_3) -imino, where one or two atoms of C pu They can be substituted, independently of each other, with a hydroxy group, co-hydroxy-alkyl of Ci_3, co- (Cx_3 alkoxy) -C3 alkyl, and / or Ci -3 alkoxy and / or with or. -, 0 two. C1-4 alkyl groups the same or different and K = 1. The very special preference meanings of the -WB group according to this embodiment are selected from the group consisting of alkyl of ¾_8, -C C-Ci_6 alkyl, -CH = CH-Ci-S alkyl, -O-C 1-6 alkyl, -NH (C 1-6 alkyl) and -N (Ci_s alkyl) (Cx_3 alkyl), especially selected from the group consisting of C3-8, -C C-C3_6 alkyl, CH = CH-C3_6 alkyl, -O-C3_6 alkyl, -NH (C3_6 alkyl) and -N (C3_6 alkyl) (Ci_3 alkyl). More particularly preferred are those compounds according to the invention described as preferred in the foregoing, especially of partial formulas 1.1 to 1.15, in which the groups R1, R2, R3, L1, L2, L3 and / or group X they have one of the meanings in each case as preference. Especially preferred are those compounds according to the invention in which X is selected from '-CH2-, -CH (CH3) -O-C (CH3) 2-. Also especially preferred are those compounds of partial formulas 1.1 to 1.15, in which a) the group U is an atom of N and the group V is a C atom, or b) the group U is a C atom and the group V is an atom of N, or c) both groups U and V are, in each case, a C atom. In particularly preferred compounds according to the invention, the substituents. R25, R26, R27 independently of each other have a meaning selected from F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or isopropoxy, in the case of the substitution of a phenyl group also simply nitro, where the groups R25,. RS, R27 that appear several times may have the same or meanings. different, and J means 0, 1 or 2, and m, n independently of each other means, 0 or 1. The preferred meanings of the groups R6, R7, R8 and / or R9 in the compounds according to the invention described as preferred independently of each other they mean, H, methyl, trifluoromethyl, ethyl, isopropyl or n-propyl, in the case of R6, R7 also F.; The individual compounds of particular preference are selected from the group: (1) 7- (4-chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4- ona (2) 3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3-JT-guinazolin-4-one (3) 3- [2- (4-pyrrolidin- l-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3-T-quinazolin-4-one (4) 7- (4-methoxy-phenyl) -3- [2- (4-pyrrolidin- l-Ilethyr-phenyl) -ethyl] -3H-quinazolin-4-one (5) 7- (3,4-dichloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3ff-quinazolin-4 -one (6) 7- (4-fluoro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3-quinazolin-4-one (7) 7- (4-ethyl-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl) -ethyl] -3H-quinazolin-4-one (8) 2-methyl-3- [2- (4 -pyrrolidin-l-ylmethyl-phenyl) ethyl] -7- (4-trifluoromethyl-phenyl) -3Ji-quinazolin-4-one (9) '2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl phenyl) ethyl] -7-p-tolyl-3Ji-quinazolin-4-one - (10) 7- (4-chloro-phenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl- F enyl) -ethyl] -3JJ-quinazolin-4-one (11). 7- (4-chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl) -ethyl] -lH-quinazolin-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-one (17) '5- (4-fluoro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl- phenyl) -ethyl] -isoindole-1,3-dione (18) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4 '-chloro-biphenyl-4-carboxylic acid (19) . [2- (4-Diethylaminomethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid (20) [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide 4 '-chloro-biphenyl-4-carboxylic acid (21) [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide of 4' -methoxy-biphenyl-4-carboxylic acid (22) '[2- (4 4'-chloro-biphenyl-4-carboxylic acid (23) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide acid-diethylaminomethyl-phenyl) -methyl-amide 4- (4-Chloro-phenyl) -cyclohexancarboxylic acid (24) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4-methylphenyl-piperidine-l-carboxylic acid (25) [2- 4- (4-Chloro-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide (26) [2- (4- 4- (4-chloro-phenyl) -piperidine-l-carboxylic acid pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide (27) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -propyl] 4'-chloro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-benzyloxy) -amide acid amide 4'-chloro-biphenyl-4-carboxylic acid (29) 4-cyclohexyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide (30) [2- (3-methoxy 4'-chloro-biphenyl-4-carboxylic acid 4-pyrrolidin-l-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) ·. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (33) 7- (3-methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3Jf-quinazolin -4-one (34) .4- (4-oxo-cyclohexyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide (35) [2- (4-pyrrolidin- 4-cyclohexyl-1-cyclohexylcarboxylic acid (36) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4-benzyl-4-cyclohexyl-1-cyclohexylcarboxylic acid 4-cyclohexyl-piperidine-1-carboxylic acid (37) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide] (38) [2- (4-pyrrolidin- 4- (4-Chloro-phenyl) -piperazine-l-carboxylic acid (l, 4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, l-ylmethyl-phenyl) -ethyl] -amide. 4- (4-Fluoro-phenyl) -piperidine-l-carboxylic acid (40) [2- (4-pyrrolidin-l-ylmethyl-phenyl)] -ethyl] -4- (4-methoxy-phenyl) -piperazine-l-carboxylic acid - (41) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4-acid phenyl-piperidine-1-carboxylic acid (42) (4'-chloro-biphenyl-4-yl) - [3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidin-1-yl] -methanone (43) [2] 4-Chloro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide (44) [2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) - ethyl] 4'-chloro-biphenyl-4-carboxylic acid 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) [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) ethyl] -amide of 4 '-chloro-biphenyl-4-carboxylic acid (48) 5- (4-chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2, 3-dihydro-isoindol-l-one (49) 4-piperidin-l-l-N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide (50) 7- (4-chloro -phenyl) -3-. { 2- [4- (4-Hydroxy-4-phenylpiperidin-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-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one (52) 7- (4-chloro-phenyl) -3-. { 2- [4- (3-aza-spiro [5.5] unde-3-methylmethyl) -phenyl] -ethyl} -3Jí-benzo [d] [1,2,3] triazin-4-one (53) '7- (4-chloro-phenyl) -3- [2- [4- (4-hydroxy-4-phenylpiperidin -l-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one (54) 7- (4-chloro-phenyl) -3- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} .) .methyl) -3'-quinazolin-4-one (55) 6- (4-chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2Ji- isoquinolin-1-one (56) [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of 4 '-chloro-biphenyl-4-carboxylic acid (57) [2- ( 4'-chloro-biphenyl-4-carboxylic acid 3-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (58). { 2- [4- (i-ethyl-piperidin-2-yl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (59). { 2- [4- (4-acetyl-piperazin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (60). { 2- [4- (2-aza-bicyclo [2.2.1] hept-5-en-2-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (61). { 2- [4- (1, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide. (62) (2- {4- [(diisopropylamino) -methyl] -phenyl} -ethyl) -amide of 4'-chloro-biphenyl-4-carboxylic acid (63). { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (64). { 2- [4- (2-dimethylaminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (65). { 2- [4- (3-dimethylamino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amino-biphenyl-4-carboxylic acid (66) [2- (2-brorao-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4 '-chloro-biphenyl-4 -amide carboxylic (67) 4-pent-l-inyl-iV- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide (68) [2- (6-pyrrolidin-1-ylmethyl-pyridine- 3 '-chloro-biphenyl-4-carboxylic acid (3-yl) -ethyl] -amide of 4' acid [2- (1-pyrrolidin-1-yl-iridan-5-yl) -ethyl] -amide] -chloro-biphenyl-4-carboxylic acid (70) [2- (2-nitro-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid (71) [ 2 ', 4'-Dichloro-biphenyl-4-carboxylic acid 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (72). { 2- [4- (3-Amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amino-biphenyl-4-carboxylic acid amide (73). { 2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (74). { 2- [4- (2-methyl-2,6-diaza-spiro [3.4] oct-6-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid (75) [2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -amide of 4'-chloro-biphenyl- amide 4'-Chloro-biphenyl-4-carboxylic acid 4-carboxylic (76) [2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (77). { 2- [4- (2,5-dihydro-p-rol-l-ylmethyl) -phenyl] -ethyl} 4'-bromo-biphenyl-4-carboxylic acid amide (78) 4- (5-chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] 4'-chloro-biphenyl-4-carboxylic acid-benzamide (79) [2- (2-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (80) .. { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid amide. '| (81). [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid (82) [2- (4-pyrrolidin-1-ylmethyl- phenyl) -ethyl] -amide of 4 '-ethyl-biphenyl-4-carboxylic acid (83) Carbamate [l- (4- { 2- [(' -chloro-biphenyl-4-carbonyl) -amino] ] -ethyl.}. -benzyl) -pyrrolidin-2-ylmethyl] -tert-butyl ester (84). . { 2- [4- (2-methyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (85) '. { 2- [4- (2-methyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4 '-chloro-biphenyl-4-carboxylic acid (86) (2. {4 - [(cyclopropylmethyl-amino) -methyl] -phenyl} -ethyl) -amide of 4"- chloro-biphenyl-4-carboxylic acid (87). { 2- [4- (3, 4-dihydro-lH-isoquinolin-2-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide (88) [2- (4-. {[[(2-hydroxy-ethyl) -methyl-amino] -methyl] -phenyl) - ethyl] -amide of 4 '-chloro-biphenyl-4-carboxylic acid (89) Carbamate [1- (4- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-3-yl] -tert-butyl (90) (2- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide of the acid 4'-Chloro-biphenyl-4-carboxylic acid 4'-chloro-biphenyl-4-carboxylic acid (91) [2- (4-azetidin-l-ylmethyl-phenyl) -ethyl] -amide. '(92) [ 3- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 3,4-dichloro-biphenyl-4-carboxylic acid (93) [2- (4-pyrrolidin-l-ylmethyl-phenyl) - ethyl] -amide of 4 '-fluoro-biphenyl-4-carboxylic acid (94)' [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-3-fluoro- 2'-Fluoro-2-chloro-biphenyl-4-carboxylic acid biphenyl-4-carboxylic acid (95) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (96) [2- ( 4-pyrrolidin-l-ilmeti 5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid l-phenyl) -ethyl] -amide (97). { 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -4-chloro-biphenyl-4-carboxylic acid (98) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -ethyl] -amide of 4'-bromo-biphenyl-4-carboxylic acid (99) . { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide More particularly, the individual compounds detailed in the above of formulas (1), (2), (3), (4), (5), (6) are preferred , (7), (0), (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). Then the terms that are defined in more detail. they use before and after to describe the compounds according to the invention. The name halogen implies an atom selected from the group consisting of F, Cl, Br and I. La. Alkyl designation of Ci_n, where n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group of 1 to an C atoms. Examples of such groups include methyl, -ethyl, n-ropy, isopropyl, butyl , isobutyl, sec-butyl,. tert-butyl, n-pentyl, isopentyl, neo-pentyl, · ter-pentyl, n-hexyl, isohexyl, etc. The alkylene designation of, where n can have a value of 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge with 1 to C atoms. Examples of such groups include methylene (-C¾-), ethylene (-CH2) -CH2-), 1-methyl-ethylene (-CH (C¾) -CH2-), 1,1-dimethyl-ethylene (-C (C¾) 2-C¾-), n-prop-1,3-ylene ( -CH2-CH2-CH2-), 1-methylprop-1, 3-ylene '(-CH (C¾) -CH2-CH2-), 2-methylprop-1, 3-ylene (-CH2-CH (CH3) - C¾-), etc., -as well as the corresponding mirror-symmetric forms-. The term C2-n alkenyl, where n has a value of 3 to 6, designates 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, isopropenyl, 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, -hexenyl, 2,4-hexadienyl, 5-hexenyl, etc. The term "C1-n alkoxy" denotes an -O-alkyl group of ?? - ?, where the alkyl of Ci_n is defined as above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neo-pentoxy tert-pentoxy, n-hexoxy, isohexoxy, etc. . The term alkylthio of C3..n designates a group -S-alkyl of C ^, where the alkyl of Ci_n is defined as above. Examples of such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio / sec-butylthio, tert-butylthip, n-pentthylthio, isopentylthio, neo-pentthylthio, tert-pentthylthio, n-hexylthio. isohexylthio, etc. "The term alkylcarbonyl of Ci_n designates a group -C (= 0) -alkyl of ¾.", wherein the Cx_n alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butycarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, etc. The term cycloalkyl of C3.n designates a mono-, bi-, tri- or spirocarbocyclic saturated group with 3 an atoms of C. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicycle [3.2.1. ] octyl, spiro [4.5] decyl, - norpinyl, norbornyl, norcaryl, adamantyl, etc. The term, C3-n-cycloalkylcarbonyl designates a -C (= 0) -cycloalkyl group of C3.n, where the C3_n cycloalkyl is defined as above - The term "aryl" designates a system of aromatic carbocyclic rings such as, for example, phenyl , biphenyl, naphthyl, anthracenyl,. phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. He . The term "heteroaryl" used in this application designates aromatic heterocyclic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, 0 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, , 2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazyl, 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 (tianaphtenyl), inda.zolyl (benzoimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzoisoxazolyl, purinyl, quinazolinyl, quinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl , etc. The term "heteroaryl" also includes the partially hydrogenated aromatic heterocyclic ring systems, especially those listed above, Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc. The terms such as aryl-alkyl of Cx_n, heteroaryl-alkyl of Ci_n, etc. designate the alkyl Ci_n as defined above, which is is substituted by an aryl or heteroaryl group. Some of the terms detailed in the above can be used several times in the definition of a formula or group and have in each case, independently of each other, one of the specified meanings. The term "unsaturated carbocyclic group" or "unsaturated heterocyclic group", as used above all in the definition of the Cy group, comprises, in addition to the fully unsaturated groups, also the corresponding only partially unsaturated groups, especially mono and di-unsaturated groups. The term "optionally substituted" used in this application means that the group designated in this manner will mean unsubstituted or mono or polysubstituted with the specified substituents. In case . If the group in question is polysubstituted, the substituents may be the same or different. The residues and substituents described above may be mono or polysubstituted with fluorine as described. The fluorinated alkyl groups are preferably fluoromethyl, difluoromethyl 'and trifluoromethyl. The fluorinated alkoxy groups are preferably fluoromethoxy, difluoromethoxy and trifluoromethoxy. The fluorinated alkylsulfinyl and alkylsulfonyl groups are preferably trifluoromethylsulfinyl and trifluoromethylsulfonyl. . The compounds of the general formula I according to the invention can have acid groups, primarily carboxyl groups, and / or basic groups such as, for example, amino functions. For this reason, the compounds of the general formula I can exist as internal salts, such as salts with inorganic acids for pharmaceutical use such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as, for example, maleic acid, fumaric, acidic acid, tartaric acid or acetic acid) or as salts with bases for pharmaceutical use such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine, triethanolamine, and the like . The compounds according to the invention can be obtained using known synthesis processes. Preferably, the compounds are obtained according to the preparation processes according to the invention described in the foregoing and detailed below. The preparation process according to the invention of the first group of the preferred embodiments, that is to say, those compounds in which the group A and the group R3 are not directly linked to each other, basically distinguishes two cases of application. Those compounds of the formula I are included in the first case, in which the group A represents a nitrogen-containing heterocyclic group linked through a nitrogen atom with the carboxamide group, which may have, in addition to the nitrogen atom, one or more heteroatoms selected from N, O and S. The reaction of the amine of the formula Il with the secondary amine of the formula 1-2 is represented in the following general reaction scheme set out below: reaction scheme Preferably, the amine compound of formula 1-1 is first reacted with CDT (1,1 '-carbonyldi (1,2,4-triazole)) in a solvent or mixture of solvents and then reacted the reaction mixture with the amine compound of formula 1-2, wherein at least one base is added to the reaction mixture before and / or after the reaction of the amine compound with CDT. Advantageously, the amine compound of formula 1-1 with CDT is. it reacts in a temperature range of -20 ° C to 20 ° C and then this reaction mixture is reacted with the amine compound of formula 1-2 in a range of. temperatures from 40 ° C to 100 ° C in a molar ratio of the amine compound of formula 1-1: amine compound of formula 1-2: CDT-: base of 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 3 ± 1.5. Preferably, nitrogenous bases are used as bases, especially tertiary amines, such as, for example, triethylamine. In the case of the amine compound of the formula 1-2 it can be a saturated N-heterocyclic compound such as, for example, a piperazine derivative according to the following scheme of reaction 2.
Scheme The remaining compounds of the formula I are not included in the case of preparation 1, wherein group A is not linked to R3 directly. The reaction of the carboxylic acid of the compound of the formula 1-3 with TBTU (2- (IH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate) and the amine compound of the formula 1 1 in a solvent or mixture of solvents in the presence of at least one base is represented - in reaction scheme 3.
Reaction scheme 3: Preferably, in this case the carboxylic acid of the compound of formula 1-3 is reacted with TBTU in a solvent or mixture of solvents and then the reaction mixture is reacted with the amine compound of formula 1-1, where at least one base is added before and / or after the reaction of the carboxylic acid with TBTU to the reaction mixture. Instead of a carboxylic acid, the corresponding activated carboxylic acid derivatives can be applied, such as, for example, esters, ortho esters, carboxylic acid chlorides or anhydrides. Preferably, a nitrogenous base is used as the base, especially a tertiary amine such as, for example, triethylamine. The carboxylic acid compound of formula 1-3 is then reacted with TBTU and then this reaction mixture is applied. with the amine compound of the formula 1-1 in a temperature range from 0 ° C to 60 ° C in a molar ratio of the carboxylic acid compound of the formula 1-3: amine compound of the formula 1-1: TBTU: base of 1 + 0.25: 1 ± 0.25: 1 + 0.25: 1 to 4. The artida compound of the formula 1-3 can be obtained according to the processes known to the person skilled in the art. In this manner, biaryl compounds can be obtained by means of Suzuki coupling, for example, starting from acid derivatives, p-bromoarylcarboxylic acid and arylboronic acid derivatives in the presence of Pd [0] catalysts. The preparation process according to the invention for the second group of the preferred embodiments, ie those compounds in which the group A and the group R3 are linked together, distinguishes between seven cases of application according to the meanings Illa a Illg of group Q. According to the first case, in which Q means -CRe 7- (illa), an amine compound of formula Ia.l is reacted with an ester derived from o-bromomethyl-benzoic acid of formula la.2, which can be seen in the following reaction scheme 4, in which the substituents L1 were left out. L2, L3 in the phenyl ring for the purposes of better visualization.
Scheme of reaction. : 2G03 CH.CN Preferably, in this case, the ester derived from o-bromomethyl-benzoic acid of the formula la.2 is reacted with the amine compound of the formula la.l in a solvent or mixture of solvents, where at least one base is added. In place of an ester derived from o-bromomethyl-benzoic acid of the formula la.2, other esters derived from corresponding o-benzyl-benzoic acids (iodine or mesylate instead of bromine) can also be applied. Preferably, potassium carbonate or cesium carbonate is used as the base; tertiary amines such as triethylamine are also used. Advantageously, the ester derived from o-bromomethyl-benzoic acid of the formula la.2 is applied in acetonitrile with the amine of the formula la.ly and with potassium carbonate as a base in a temperature range of 40-80 ° C in a ratio molar of the ester derived from o-bromomethyl-benzoic acid of the formula la.2: amine of the formula Ia.l: potassium carbonate 1 + 0.25: l + _0.25: 3 + 0.50. According to the second case, in which Q means -CR6 = R7- | (111b), an isoquinolinone derivative of the formula Ib .3 is reacted with an electrophilic compound of the formula Ib.4 to form a isoquinoline derivative of the formula Ib.5 which is further derivatized according to known processes to obtain the compound of the formula I. The isoquinolinone derivative of the formula Ib .3 can be obtained from a cinnamic acid derivative of the formula Ib. 1 by reaction with (EtO) 2P (O) N3 The synthesis of the basic compound was described by M. Becker et al. In Bioorganic &; Medicinal Chemistry Letters 9 (1999), 2753-2758. The reaction can be seen in the following reaction scheme 5, in which the substituents L1, L2, L3 have been left out in the phenyl ring for the purposes of better visualization.
- Reaction scheme 5: A compound of the formula Ib.2 is advantageously obtained by means of the sequence of reactions described below. The acrylic acid derivative Ib. 1 is first reacted by the action of chlorinating agents such as thionyl chloride, phosphorus pentachloride or oxalyl chloride without a solvent or optionally in an inert solvent such as dichloromethane or to obtain the acid chloride at temperatures between 0 ° C and 80 ° C. This is converted by the action of sodium azide into a solvent or mixture of solvents in the azide derivative of acrylic acid. Solvents may be, for example, dioxane, tetrahydrofuran or water. Preferably, the synthesis of the isocyanate derivative Ib .2 is carried out directly by the action of the azide of the diphenyl ester of phosphoric acid on the derivative, of the acrylic acid Ib.l in the presence of a base in a solvent at temperatures between 0 ° C and 150 ° C. Suitable solvents are, for example, toluene or dioxane. Tertiary amines such as, for example, triethylamine can be used as bases. The above reactions have reaction times of between one and twelve hours. The reaction of the acrylic acid derivative Ib.l is preferably carried out with the azide of the diphenyl ester of phosphoric acid and triethylamine in a molar ratio of 1 + 0.25: 1 + 0.25: .1 + 0.25 in toluene as the solvent. The isocyanate derivative Ib.2 is heated in a solvent optionally in the presence of a base such as, for example, tributylamine and the isoquinolone derivative of the formula Ib is formed. Preferably, the reaction is carried out in diphenyl ether in the range of boiling point. Heating sources include oil, metal or microwave baths. The reaction of the isoguinolone derivative of the formula Ib.3 with the mesylate derivative of the formula Ib.4 to form the isoginolone derivative of the formula Ib.5 is carried out in a solvent in the presence of a base temperatures between .0 ° C and -150 ° C. Advantageously, the reaction of the isoquinolone derivative Ib. 3 is carried out 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 in DMF as solvent The isoquinolone derivative of the formula Ib.5 is first reacted in a solvent in the presence of an acid, a. order to convert the acetal into the. corresponding aldehyde. This is converted to the presence of a hydride transformer, an amine Y means an acid in a solvent in a compound of the formula Ib. As hydride converters, there are mentioned, for example, sodium triacetoxyborride, sodium borride and. sodium cyanoborride. Advantageously, the reaction of the aldehyde, liberated from the isoquinolone derivative Ib. 5, is carried out with an amine and sodium cyanoborride in a molar ratio of 1 + 0.25: 1 + 0.25: 0.8 + 0.25 in methanol and acetic acid at temperatures close to 20 ° C.
The synthesis of isoquinolines of the formula Ib, including. the starting compounds and the subsequent derivatization in amine is visualized by means of the following synthesis scheme of a specific compound, where the synthesis of the reactant 1 can be extracted from the following scheme 6 to prepare the phthalazinones (scheme 8). reaction scheme According to the third case, in which Q means -N = CR8- (lile), a phthalazinone derivative of the formula Ic.4 is reacted with an electrophilic compound of the formula Ic.5 to form a phthalazinone derivative of the formula Ic.6, which is further derivatized according to known processes to form the compound of the formula Ic. The phthalazinone derivative of the formula Ic.4 for R8 = hydrogen can be obtained starting from the phenyloxazole derivative of the formula Ic.l by acylation to form an o-oxazolyl-benzaldehyde derivative of the formula Ic.2 and subsequent cyclization to form a 3-hydroxy-3H-isobenzofuran-1-one derivative of the formula Ic.3. The synthesis of the basic compound was described by M. Napoletano et al., Bioorganic & Medicinal Chemistry Letters 12 (2002), 5-8. The reaction to form compounds of the general formula Ic is visualized in the following reaction scheme 7, in which the substituents L1, L2, L3 were left out in the phenyl ring for the purpose of better visualization.
Reaction scheme 7: In detail, the oxazoline derivative Ic.l is metallised with an appropriate organometallic reagent and then reacted with an equivalent of formaldehyde, such as, for example, dimethylformamide or an orthoformate at temperatures between -70 ° C and 20 ° C. , preferably at temperatures between -20 ° C and 0 ° C, to form a compound of formula Ic.2. Suitable solvents are, for example, dioxane, tetrahydrofuran or diethyl ether. By the action of aqueous sulfuric acid in a solvent such as, for example, ethanol, a compound of the general formula Ic.3a can be obtained at a temperature close to the boiling point of the solvent or the mixture of solvents in a period of 1 to 24 hours. . The phthalazinone derivative of the formula Ic.4 can be obtained by reacting a compound of the formula Ic.3 with a hydrazine derivative in acetic acid and optionally in a solvent in the temperature range between 20 and 120 degrees centigrade. The synthesis route to form a phthalazinone derivative of the formula Ic is carried out analogously to the reactions for the synthesis of a compound of the general formula Ib. The synthesis of phthalazinone derivatives of the formula Ic, especially of the starting compounds and the subsequent derivatization, is visualized by means of a synthesis scheme 8 of a specific compound, in which the abbreviations mean: LAH = lithium aluminum hydride, buLi = n-buti ' l-lithium, DMF = dimethylformamide, MeOH = methanol and s-Cl = methanesulfonic acid chloride.
Q means o-amino- and an appropriate nitrite compound and means an acid through a diazonium precursor in a benzotriazinone derivative of the formula Id. The reaction is shown in the following reaction scheme 9, in which they set aside the substituents L1, L2, L3 on the phenyl ring for the purposes of better visualization.
Reaction scheme 9: NaNOs / HCI Preferably, a compound of the general formula ld.1 is reacted in a solvent such as, for example, methanol in the presence of a mineral acid, for example, hydrochloric acid, and means a salt containing the nitrite ion at a temperature between -10 ° C and 30 ° C. Advantageously, the reaction. of the amino compound Id.l is carried out with sodium nitrite in a molar ratio of l + _0.25: 1.5 + 0.25 in methanol as solvent and in the presence of hydrochloric acid. According to the fifth case, in which Q means -CO-NR9- (lile), an o-amino-benzamide derivative of the formula Ie.l is reacted in the presence of CDI to form a guinazolindione derivative of the 'formula you. CDI is applied with respect to the benzamide derivative of the formula Ie.l in a molar ratio greater than or equal to 1 and the reaction is carried out at least in part in a temperature range of 35 ° C to 100 ° C, preferably in the range of the boiling temperature of the reaction mixture. The reaction is seen in the following reaction scheme 10, in which the substituents L1, L2, L3 were left out on the "phenyl ring for the purpose of better visualization.
Reaction scheme 10: CDI According to the sixth case, in which Q means -CR8 = N- (Illf), an o-aminobenzamide derivative of the formula If.l is reacted with a carboxylic acid R8COOH and / or a corresponding activated derivative of carboxylic acid to form a quinazolinone derivative of the formula If. Suitable activated carboxylic acid derivatives are, for example, esters, orthoesters, carboxylic acid chlorides and anhydrides. The optionally activated carboxylic acid is applied relative to the carboxamide compound of the formula If.l in a molar ratio greater than or equal to 1 and the reaction is carried out at least partially in a temperature range of 35 ° C to 100 ° C. , preferably 'in the range of the boiling temperature of the reaction mixture. The reaction is seen in the following reaction scheme 11, in which the substituents L1, L2, L3 were left out in the phenyl ring for the purposes of better visualization.
The synthesis of the quinazolinone derivatives of the formula If, especially of the starting compounds, is visualized by means of a synthesis scheme 12 of a specific compound, in which the abbreviations mean: CDI = carbonyldiimidazole, TBTU = tetrafluoroborate of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-emethyluronium and NEt3 triethylamine. First, the synthesis schemes of both starting compounds 1 and 2 are represented.
Reaction scheme 12 The starting compounds 1 and 2 are bonded together via an amide bond, using TBTU. The nitro group in ortho position with respect to the amide bond obtained is reduced to form the amine in the presence of Pt02. The ring closure in quinazolinone is carried out using a carboxylic acid, in this case formic acid. According to the seventh case, in which Q means -C0- (Illg), an isobenzofurandione derivative of the formula Ig.2 is reacted with an amine compound of the formula Ig.l to form an isoindoldione derivative of the Ig formula The reaction is seen in the following reaction scheme 13, in which the substituents L1, L2, L3 were left out in the phenyl ring for the purpose of better visualization. reaction burning In this case, the isobenzofurandione derivative Ig.2 is reacted in a solvent such as, for example, acetic acid with an amine of the general formula, · Ig.l in a molar ratio of 1 + 0.25 1.5 + 0.25. The temperature means, preferably - during the reaction, that of boiling the solvent. However, the isoindoldione derivative of the formula Ig can also be obtained according to the following scheme. synthesis 14. The represented synthesis of an individual compound can optionally be modified by the specialist to other compounds of the formula Ig. First, it is obtained from an isobenzofurandione derivative with the binding of a function of an amine, the isoindoldione function and then another aryl group is added by means of Suzuki coupling in the presence of Pd [0]. reaction scheme The possibilities of "synthesis of the compounds according to the invention represented in the above can be modified and / or completed by means of processes known at least in principle by the specialist, as described by way of example in Houben-Weyl" Methoden der organischen Chemie ", as for each of the compounds to be synthesized.-In the case of the reactions described in the above, the optionally existing reactive groups can be protected as -hydroxy, carboxy, amino or imino groups according to methods known in the art. During the reaction, the bibliography can be used by means of conventional protection groups, which are then split again after the reaction, in particular the protection groups customary in the chemistry of the peptides can be used. WO 98/11128 The stereoisomeric compounds of the formula (I) can be separated in principle by customary methods. The diastereomers result by virtue of their various physicochemical properties, for example, by fractional crystallization from appropriate solvents, by high pressure liquid chromatography - or by column chromatography, using chiral phases or, preferably, chiral stationary phases. As mentioned above, the compounds of the formula (I) can be converted into their salts, especially for pharmaceutical use, into their physiological and pharmacological tolerance salts. These salts may exist, on the one hand, as addition salts with acids of physiological and pharmacological tolerance of the compounds of the formula (I) with inorganic or organic acids. On the other hand, the compound of the formula (I) in the case of acidic hydrogen can also be converted by reaction with inorganic bases into physiologically and pharmacologically tolerated salts with alkali metal or alkaline earth metal cations as counter-ion. To obtain the addition salts with acids are taken into account, eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acid. acetic, fumaric acid, succinic acid,. lactic acid, citric acid, tartaric acid or maleic acid. In addition, mixtures of the aforementioned acids can be used. In order to obtain the alkali metal or alkaline earth metal salts of the compound of the formula (I) with acid-bound hydrogen, hydroxides and hydrides of alkali and alkaline earth metals are preferred, where hydroxides and hydrides are preferred. alkali metals, especially sodium and potassium, with particular preference being given to sodium and potassium hydroxide. The compounds of the present invention, including the physiologically tolerated salts, have an action as antagonists of the MCH receptor, especially the MCH-1 receptor, and show good affinity in studies of binding to MCH receptors. The pharmacological assay systems for antagonistic properties of MCH are described in the experimental part below. As MCH- receptor antagonists, the compounds according to the invention are suitable as pharmaceutical active ingredients for the prophylaxis and / or treatment of symptoms and / or diseases that are caused by HCM or that are causally related to HCM. . In general, the compounds according to the invention have a low toxicity, a good absorption capacity by oral administration and intracerebral transitivity, especially a good access to the brain. Therefore, MCH antagonists, which at least present a compound according to the invention. with the invention, they are especially suitable in mammals such as, for example, rats, mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs, cows, monkeys and humans, for the treatment and / or 'prophylaxis of symptoms and / or diseases that are caused by MCH or that are in another causal relationship with CH. The diseases that are caused by HCM or that are in another causal relationship with HCM, are mainly metabolic disorders such as, for example, obesity, and eating disorders such as, for example, bulimia, including. bulimia nervosa. The indication obesity comprises particularly exogenous obesity, hyperinsulinic obesity, hyperplasmic obesity, hyperpisary adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, trunk obesity, alimentary obesity, hypogonadal obesity, central obesity. In addition, in this area of indication should also be mentioned cachexia, anorexia and hyperphagia. The compounds according to the invention are especially suitable for reducing hunger, moderating the appetite, controlling eating behavior and / or causing a feeling of fullness. In addition, they also belong to diseases that are caused by HCM or that are in another causal relationship with HCM, hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, mastocytosis - systemic, emotional disorders, affective disorders, depressions, states of anguish, Reproductive disorders, memory disorders, forms of dementia and hormonal disorders. The compounds according to the invention are also suitable as active substances for the prophylaxis and / or treatment of other diseases and / or disorders, especially those which accompany obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological tolerance to glucose, cardiocirculatory diseases, especially arteriosclerosis and hypertension, and gonitis. The MCH antagonists and formulations according to the invention can be used advantageously in combination with a food therapy as, for example, a treatment of dietary diabetes, and e ercicio. . Another indication area for which the compounds according to the invention are advantageously suitable is the prophylaxis and / or treatment of voiding disorders such as, for example, urinary incontinence, overactive urinary bladder, urination, nocturia, enuresis, where overactive bladder and urination do not need to be associated with benign prostatic hyperplasia.
The necessary dose. to achieve the corresponding effect is conveniently in an intravenous or subcutaneous administration of 0.001 to 30 mg / kg of body weight, preferably 0.01 to 5 mg / kg of body weight, and in an oral, nasal or inhalative administration, of 0.01 to 50 mg / kg of body weight, preferably 0.1 to 30 mg / kg of body weight, in each case 1 to 3 times per day. For this, the compounds of the general formula I prepared according to the invention can be prepared, optionally in combination with other active substances, such as are described below -in greater detail, together with one or more excipients, inert carriers and / or customary diluents of physiological tolerance, for example with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their appropriate mixtures, in usual galenical preparations such as tablets, dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments or suppositories In addition to medicaments, the invention also comprises compositions containing at least s a carboxamide compound according to the invention and / or a salt according to the invention in addition to optionally one or more excipients of physiological tolerance. Such compositions may for example be edible, which may be solid or liquid, in which the compound according to the invention was made. For the combinations mentioned in the foregoing, other active substances are considered, especially those that enhance, for example, the therapeutic action of a .MCH antagonist. according to the invention with respect to one of the mentioned indications and / or allowing a dose reduction of an MCH antagonist according to the invention. Preferably, be. select one or more active substances 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 other than antagonists of MCH, active substances for the treatment of -hypertension, active substances for the treatment of hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, ..- '· - ·.'. 'active substances for the treatment of states of anguish, active substances for the treatment of depressions. Below are the classes of active substances mentioned based on examples. Examples of active substances for the treatment of diabetes are insulin sensitizers, insulin secretion accelerators, biguanides, insulins, α-glucosidase inhibitors, β3-adrenoreceptor agonists ... Insulin sensitizers comprise pioglitazones and their salts (with -preference, hydrochlorides), troglitazones / rosiglitazones and their salts (preferably, maleates),. JTT-501, GI-262570,. MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-2 7 / R-119702, GW-1929. Accelerators of insulin secretion include sulfonylureas, such as, for example, tolbutamides, chloropropamides, trazamides, acetohexamides, glidlopyramides and their ammonium salts, glibenclamides, gliclazides, glimepirides. Other examples of accelerators of insulin secretion are repaglinides, nateglinides, mitiglinides, (KAE-1229), JTT-608. "The biguanides include metformin, buformin, phenformin Insulins comprise insulins obtained from animals, especially from cattle or pigs, semi-synthetic human insulins that are synthesized enzymatically from insulin obtained from animals, human insulin obtained by genetic techniques, for example, of Escherichi coli or yeasts. Furthermore, insulin is understood as insulin-zinc (containing 0.45 to 0.9% by weight of zinc) and protamine-insulin-zinc obtained from zinc chloride, protamine sulfate and insulin. In addition, insulin can be obtained from fragments or insulin derivatives (eg, INS-1, etc.). Insulin may also comprise various classes, for example, regarding the action time and duration of the effect ("ultraimmediate action type", "immediate action type", "two-phase type", "intermediate type", "type of action"). long-acting ", etc.), which are selected depending on the pathological condition of the patient. O-glucosidase inhibitors comprise acarbose, voglibose, miglitol, emiglitytes. The p3-adrenoreceptor agonists comprise AJ-9677, BMS-196085, SB-226552, AZ40140. Other active substances mentioned for the treatment of diabetes include ergoset, pramlintide, leptin, BAY-27-9955 and inhibitors of glycogen phosphorylase, inhibitors of sorbitol. dehydrogenase, inhibitors of protein-tyrosine-phosphatase IB, inhibitors of dipeptidyl-protease, glipazide, glyburide. The active substances for the treatment of diabetic complications comprise, for example, aldose reductase inhibitors, glucagon inhibitors, protein kinase C inhibitors. The aldose reductase inhibitors are, for example, torlestat, eparlestat, imirestate. , zenarestato, SNK-860, zoporestato, ARI-50Í, AS-3201. An example of glucathione inhibitors is pimagedin. Inhibitors of protein kinase C are, for example, GF, LY-333531. Other active substances to those mentioned in the above for the treatment of diabetic complications include alprostadil, tiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedin (ALT-711). The active substances for the treatment of obesity, preferably different from the MCH antagonists, comprise lipase and anorexic inhibitors. A preferred example of a lipase inhibitor is orlistat. Examples of preferred anorexics are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, bayamine, (S) -Sibutramine, SR-141716, NGD-95-1.
Other active substances other than those mentioned in the above for the treatment of obesity comprise lipstatin. Furthermore, for the purposes of this application with respect to the group of active substances of the antiobesity active substances, the anorexics are also counted, where the p3-agonists, the thyromimetic active substances and the WPY antagonists should be highlighted. The scope of the substances that are taken into account as anti-obesity agents / anorexic agents preferably is indicated by way of example by way of the following list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin A agonist (hereinafter referred to as CCK-A), a monoamine reuptake inhibitor (such as, for example, sibutramine), a sympathomimetic active substance, a serotonergic active substance (such as, for example, dexfenfluramine or fenfluramine), a dopamine antagonist (as, for example, bromocriptine), an agonist or mimetic receptor for melanocyte-stimulating hormones, an analogue of the melanocyte-stimulating hormone, a cannabinoid receptor antagonist, an MCH antagonist, the OB protein (hereinafter referred to as leptin), a Leptin analogue, a leptin receptor agonist, a galanin antagonist, a GI lipase inhibitor or reducer (such as, for example, orlista to). Other anorexics comprise bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide 1 receptor agonists, eg, exendin and ciliary neurotrophic factors such as, for example, axoquinas. The active substances for the treatment of hypertension include inhibitors of the angiotensin-converting enzyme, calcium antagonists, potassium channel openers and angiotensin II antagonists. . Inhibitors of the angiotensin-converting enzyme comprise captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride). Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine: Potassium channel openers include levcromakalime, L-27152, AL0671, NIP-121. . Antagonists of angiotensin II include telmisartan, losartan, candesartan cilexetil, valsartan, irbeartan, CS-866, E4177. Active substances for the treatment of hyperlipidemia, including ... arteriesclerosis, comprise inhibitors of HMG-CoA reductase, fibrate compounds.
Inhibitors of H G-CoA reductase include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and its salts. The fibrate compounds include bezafibrates, clinofibrates, clofibrates and simfibrates. The active substances for the treatment of arthritis. they comprise ibuprofen. The active substances for the treatment of distressing states include chlorodiazephoxide, diazepam, oxozolam, medazepam, cloxazolam, bromoazepam, lorazepam, alprazolam, fludiazepam. The active substances for the treatment of depressions, include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline. The dose for significant active substances is conveniently 1/5 of the lowest recommended dose usually up to 1/1 of the normally recommended 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 above all on the fact that the compounds according to the invention may be appropriate for reducing hunger, moderating the appetite, control eating behavior and / or cause a feeling of fullness. The feeding behavior is advantageously influenced by the fact that food intake is reduced. For this reason, the compounds according to the invention are advantageously applied to reduce body weight. Another use according to the invention is to prevent an increase in body weight, for example, in humans, who in the foregoing had taken measures to lose weight and who are then interested in conserving reduced body weight. According to this modality, it is preferably a non-therapeutic use. Such non-therapeutic use may be a cosmetic application, for example to modify the external appearance, or a use to improve the general state of health. The compounds according to the invention are preferably used for mammals, especially humans, in a non-therapeutic manner, which do not present diagnostic disorders of feeding behavior, obesity, bulimia,. Diagnosed diabetes and / or diagnosed mictional disorders, especially urinary incontinence. Preferably, the compounds according to the invention are suitable for a non-therapeutic use for humans whose body weight index (BMI = body mass index), which is defined as the body weight measured in kilograms divided by the height (in meters) squared, it is below 30, especially below 25. The following examples should · further detail the invention: Previous observations: For prepared compounds, melting points, ^ H-NM and / or mass spectra usually exist. Unless otherwise indicated, the Rf values were determined using ready plates of DC with silica gel 60 F254 (E. Merck, Darmstadt, article No. 1.05714) without chamber saturation. The Rf values determined under the name Alox were determined using ready plates of 60 F254 aluminum oxide DC (E. Merck, Darmstadt,., Article No. 1.05713) without chamber saturation. The specified HPLC data were measured under the following parameters: Zorbax column (Agilent Technologies), SB (Stable Bond) -C18; 3.5 μt?, - 4.6 x 75 mm; Column temperature: 30 ° C; flow; of flow: 0.8 ml / min; injection volume: 5 ^ L; detection at 254 nm. Method A: water: acetonitrile: formic acid 9: 1: 0.01 then 1: 9: 0.01 for 9. min. Method B: water: acetonitrile: formic acid 9: 1: 0.01 then 1: 9: 0.01 'for 4 min, then 6 min 1: 9: 0.01. In case of lack of more data for the configuration, it remains to own judgment if it is pure enantiomers or if there was a partial or even total racemization.
The following abbreviations are used before and after BOC anhydride tert-butyloxycarbonyl anhydride CDI carbonyldiiraidazole CDT 1,1'-carbonyldi- (1,2,4-triazole) DMF dimethylformamide ethyl acetate / EtOAc ethyl acetate Ether diethyl ether HOBt 1-hydroxybenzotriazole hydrate base Hünig N, N-diisopropyl-ethylamine conc. Concentrate Me methyl MeOH methanol TA room temperature (approx 20 ° C) TBTU 2- (IH-benzotri- azol-l-yl) -1, 1,3, 3-tetramethyluronium tetrafluoroborate THF tetrahydrofuran eq. equivalent cale. calculated exp. experimental General work procedure I (coupling with TBTU): To a solution of carboxylic acid (1.0 eq.) In THF or DMF, triethylamine (1.5 eq.) And TBTU (1.0 eq.) Are added successively. The mixture is. stir according to the carboxylic acid for 10 min at 12 hours between room temperature and 40 ° C before adding the amine (1.0 eq.). The reaction is stirred for 30 min at 2 hours between room temperature and 40 ° C, before adding a half-saturated solution of NaHCO 3. After extracting the aqueous phase with an appropriate solvent (for example, ethyl acetate), the organic phase is dried over magnesium sulfate. The solvent is removed using the rotary evaporator; the subsequent "purification is carried out by column chromatography or HPLC." The reaction can also be carried out in an automated Chemspeed synthesis equipment.
General work procedure II (coupling with CDT): To a solution of the primary amine (1.0 eq.) In DMF (1 mmol / mL) is added at 0 ° C CDT. (1 eq.) And stirred at 0 ° C for another- '30 min. The reaction is heated to 25 ° C and triethylamine (3 eq.) Is added. Then the secondary amine (1.0 eq.) In DMF (0.25 mmol / mL) is added and the reaction solution is heated for 30 min. To 3 hours at 60-80 ° C. The DMF is removed in vacuo and the residue is taken up in dichloromethane and 5% Na 2 CO 3 solution or with water and tert-butylmethyl ether. The organic phase is extracted with water and optionally the solvent is removed using the rotary evaporator after drying over magnesium sulfate; the subsequent purification is carried out by column chromatography or crystallization. The reaction can also be carried out in the Chemspeed automatic synthesis equipment.
Example 1.1: 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one 1. 1.a. 4-Bromo-2-nitro-benzoic acid In a 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) are added in portions. mol) of potassium permanganate over eight hours. The reaction mixture is stirred for 12 hours at 60 ° C. Then another 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 added successively. The reaction mixture is stirred for 12 hours at 60 ° C, it is mixed with 200 ml of ethanol and heated at reflux for 30 minutes. The reaction mixture is then filtered while hot and the filtrate is concentrated by evaporation on a rotary evaporator. The remaining residue is basified with 10% sodium hydroxide and extracted with diethyl ether. The aqueous phase is separated and acidified with dilute hydrochloric acid. The crystals produced are filtered, washed with water, dried azeotropically with tetrahydrofuran and stirred by mixing with diisopropyl ether.
Yield: 37 g (32.8% of theory) C7H4BrN04 (M = 246 · .018) '. Cale: molar peak (M + Na) +: 268/270 Exp. : molar peak (M + Na) +: 268/270 Rf value: - 0.46 (silica gel, dichloromethane / methanol / acetic acid 8: 2: 0.1) - l.l.b. 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid To a solution of 1.92 g (7.81 min.) Of 4-bromo-2-nitro-benzoic acid in 30 ml of dioxane, 0.288 g (0.25 g) is added successively. mmol) of tetrakis- (triphenylphosphine) -palladium, 1.25 g (7.99 mmol) of 4-chloro-phenyl-boric acid in 30 ml of methanol and 2.31 g (21.7 mmol) of sodium carbonate in 14 ml of water. The reaction mixture is heated in a microwave for one hour at 300 Watt at 110 ° C. The reaction mixture is then concentrated by evaporation in a rotary evaporator, the residue is taken up in water and adjusted to pH = 3 with 1 M hydrochloric acid. The aqueous solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled using the rotary evaporator and the residue is stirred by mixing with diisopropyl ether. - | - '| Yield: 2.04 g- (93.9% of the theoretical) | C13H8C1N04 (M = 277,666) Cale: molar peak (MH) ": 276 Exp .: molar peak (MH) ~: 276 Rf value: 0.5 (gel silica, dichloromethane / methanol / acetic acid 9: 1: 0.1) l.l.c. Ethyl 4-cyanomethyl benzoate To a solution of 147.5 g (2.263 mol) of potassium cyanide in 250 ml of hot water is added dropwise a solution of 500 g (2.057 mol) of ethyl benzoate 4-bromomethyl in 1000 ml. of ethanol. The reaction mixture is heated at reflux for one hour and stirred for 12 hours at room temperature. Another 73.7 g (0.5 mol) of potassium cyanide are added and the mixture is heated at reflux for 2 hours. The solid substance present in the reaction mixture is filtered and the filtrate is filtered through a mixture of activated carbon silica gel. The filtrate obtained is concentrated by evaporation and the residue is poured into 1000 ml of water. The aqueous solution is extracted with tert-butylmethyl ether and the organic phase is extracted three times with water. The organic phase is then dried over magnesium sulfate and the solvent is distilled using the rotary evaporator. The purification is carried out by column chromatography on silica gel (petroleum ether / ethyl acetate 8: 2). Yield: 164.46 g (42.2% of theory) CiiHuNOa (M = 189.216) Cale .: molar peak (M + H) +: 190 Exp .: molar peak (M + H) +: 190 Rf value: 0.3 (silica gel , petroleum ether / ethyl acetate 8: 2) l.l.d. 4-Cyanomethyl-benzoic acid A solution of 10 g (53 mmol) of ethyl benzoate 4-cyanomethyl and 2.02 ml of a solution of 1M sodium hydroxide in 100 ml of ethanol is heated for one hour at reflux . Then, . the reaction solution is concentrated by evaporation and the residue is mixed with ice water. Concentrated hydrochloric acid is added dropwise in the reaction solution until no precipitate is produced. The precipitate is filtered, washed twice with water and dried. Yield: 4.7 g (55% of theory) C9H7N02 (M = 161.162) Cale: molar peak · (MH) ~: 160 Exp .: molar peak (MH) ": 160. 1.1 e. (4-hydroxymethyl-phenyl) acetonitrile In a solution of 4.7 g (29 mmol) of 4-cyanomethyl-benzoic acid in 250 ml of tetrahydrofuran, 5.17 g (32 mmol) of CDI are poured in and stirred until the gas production is completed. add dropwise 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 exceed 30 ° C. It is stirred for two hours and the reaction mixture is adjusted with a solution of potassium hydrogen sulphate at a pH value of 3-4, then extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is separated using the rotary evaporator. 60.9% of theory) C9H9NO (M = 147.178) Cale: molar peak (MH) ~: 146 Exp .: molar peak (MH) ": 146 1. 1. f. (4-bromomethyl-phenyl) -acetonitrile To a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl) -acetonitrile in 25 ml of tert-butyl methyl ether are added dropwise at 0 ° C 0.86 ml (9 mmol) of phosphorus tribromide. Once the reaction is finished, the reaction mixture is mixed with water at room temperature, the organic phase is separated and this is extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulfate and the solvent is distilled using the rotary evaporator. Yield: 2.9 g (78.1% of theory) CgHgBrN (M = 210.075) Cale. : molar peak (+ H) +: 209/211 Exp.: molar peak (M + H) +: 209/211 l.l.g. (4-pyrrolidin-l-ylmethyl-phenyl) -acetonitrile 0.446 ml (5.44 mmol) of pyrrolidine and 1366 g (9,882 mmol) of potassium carbonate are poured into 20 ml of dimethylformamide. While stirring, 1038 g (4,941 mmol) of (-brommethyl-phenyl) -acetonitrile are added and the mixture is stirred for 12 hours at room temperature. The reaction mixture is concentrated by evaporation in a rotary evaporator and the residue is extracted with ethyl acetate. of ethyl and water The organic phase is dried over magnesium sulfate and the solvent is removed using the rotary evaporator Yield: 0.732 g (74% of theory) C13H1SN2 (M = 200.286) Cale: molar peak (M + H) + : 201 Exp .: molar peak (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 A 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 ammonia methanol solution is hydrogenated for 9 hours at 50 ° C and 3 x 105 Pa (3 bar) of hydrogen. Yield: 0.72 g (96.4% of theory) CI3H2oN2 (M = 204.31) Cale: molar peak (+ H) +: 205 Exp .: molar peak (M + H) +: 205 Rf value: 0.23 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 1. i. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of '-chloro-3-nitro-biphenyl-4-carboxylic acid A solution of 0.4 (1.44 mmoles) of 4'-chloro- 3-Nitro-biphenyl-4-carboxylic acid; 0.29 g (1.44 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine, 0.46 g (1.44 mmol) of TBTU, 0.19 g (1.44 mmol) of HOBT and 0.42 ml (3 mmol) of triethylamine in 30 ml of tetrahydrofuran is stirred at room temperature for 14 hours. The reaction mixture is concentrated by evaporation in a rotary evaporator, extracted with water and ethyl acetate and dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia = 90: 10: 1). Yield: 0.47 g (70.3% of theory) C26H26CIN3O3 (M = 463.96) Cale: molar peak (M + H) +: 464/466 Ex,: molar peak (M + H) +: 464/466 Rf value: 0.36 - (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 1. j. [4 (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-3-amino-biphenyl-4-carboxylic acid A reaction mixture of 0.47 g (1.01 mmol) of [2- 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide and 0.1 g of Raney nickel in 50 ml of methanolic ammonia solution is hydrogenated for 24 hours. hours at 20 ° C and 3 x 10s Pa (3 bar) of hydrogen. The crude product is reacted without purification. Yield: 0.46 g crude C26H28CI 3O (M = 433.98) Cale: molar peak (M + H) +: 434/436 Exp.: Molar peak (M + H) +: 434/436 Rf value: 0.3 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. lk7- (4-chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one. 0.46 g (1.06 mmol) of [2] are stirred. - (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of '-chloro-3-amino-biphenyl-4-carboxylic acid and 5 ml of "formic acid for 3 hours at room temperature and 2 hours at 100 ° C. The reaction mixture is mixed with water, made alkaline with 6 N sodium hydroxide and the filtered precipitate is extracted The precipitate is taken up in dichloromethane and dried over magnesium sulfate The solvent is distilled using the rotary evaporator and the residue is triturated with diisopropyl ether Yield: 0.3 g (64.6% of theory) Melting point: 178-179 ° C C27H2SCI 3O (= 443.98) Cale: molar peak (M + H) +: 444 Exp .: molar peak (M + H) +: 444 Rf value 0.35 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) Example 1.2: 3- [2- (4-pyrrolidin-l-butyl-phenyl) -ethyl] -7-p-tolyl-3iT-quinazolin-4-one 1. 2.a. Α-methyl-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-methyl-phenyl-boric acid. Yield: 1.48 g (70.8% of theory) C14H11NO4 (M = 257.24) Cale: molar peak (MH) ~: 256 Exp.: Molar peak (MH) -: 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-l-ylmethyl-phenyl) -ethyl] -amide Prepared 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 theory) C27H29N3O3 (M = 443.55) Cale: molar peak (M + H) +: 444 Exp.: Molar peak (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-1-phenyl) -ethyl] -amide Prepared analogously to Example 1.1. j from 4'-methyl-3-nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide. Yield: 0.2 g (69.2% of theory) ¾8? 31? 30 (M = 413.56) Cale: molar peak (M + H) +: 414 Exp .: molar peak (M + H) +: 414 Rf value: 0.36 ( silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) Example 1.3: 3 - [2 - (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3l-quinazolin-4-one 1. 3.a. 4'-Trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example. 1.1. b from 4-bromo-2-nitro-benzoic acid and 4-trifluoromethyl-phenylboronic acid. Yield: 1.24 g (49% of theory) C14H8F3N04 (M = 311.21) Cale: molar peak (M-H) ~: 310 Exp. : molar peak (M-H) ~: 310"Value _Rf: 0.3 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1) 1. 3.b. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of acid 4 '-trifl oromethyl-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. i from 4 '-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine. Yield: 0.36 g (49.3% of theory) C27H26F3N303 (M = 497.52) Cale: molar peak (M + H) +: 498 Exp .: molar peak (M + H) +: 498 Rf value: 0.3 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 3. c. [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of 4'-trifluoromethyl-3-amino-bipheni-4-carboxylic acid A reaction mixture of 0.1 g (0.2 mmol) of [2- 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide and 0.08 g of platinum oxide in "50 ml of ethyl acetate is hydrogenated 20 ° C for 2.5 hours The catalyst is filtered The purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia = 90: 10: 1) Yield: 0.06 g (63.8%) from the theoretical) C27H2sN3N30 (M = 467.53) Cale: molar peak (M + H) +: 468 Exp.: molar peak (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-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one 1. 4.a. 4'-Methoxy-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. b from 4-bromo-2-nitro-benzoic acid and 4-methoxy-phenyl-boric acid. Yield: 0.38 g (48.9% of theory) C14H11NO5 (M = 273.24) Cale: molar peak (M-H) ": 272 Exp .: molar peak (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-l-ylmethyl-phenyl) -ethyl] -amide Prepared 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 theory) C27H29 3O4 (M = 459.55) Cale: molar peak (M + H) +: 460 Exp .: molar peak (M + H) +: 460 Rf value: 0.48, (gel silica, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 4. c. [4 (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4 '-methoxy-3-amino-biphenyl-4-carboxylic acid Prepared analogously to Example 1.3.c from 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide. Yield: 0.09 g (42% - of theory) C27H31 302 (M = 429.56) Cale: molar peak (M + H) +: 430 Exp .: molar peak (M + H) +: 430 Rf value.- 0.44 (gel silica, dichloromethane / methanol / ammonia 9: 1: 0.1) Example 1.5: 7- (3,4-dichloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one 1. 5.a. 3 ', 4'-Dichloro-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. b from 4-bromo-2-nitro-benzoic acid and 3-dichloro-phenyl-boric acid. '- Yield: 0.72 g (28.4% of theory) C13H7Cl2N04 (M. = 312.11) Cale: molar peak (MH) ": 310/312/314 Exp .: molar peak (MH)": 310/312/314 Rf Value : 0.39 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1) 1. 5. . [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of acid 3 ', 4'-dichloro-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. i 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 theory) C2SH25C12N303 (M = 498.41) Cale: molar peak (M + H) +: 498/500/502 Exp .: molar peak (+ H) +: 498/500/502 Rf value: 0.24 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 5. c. [3- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 3 ', 4'-dichloro-3-amino-biphenyl-4-carboxylic acid Prepared analogously to Example 1.3.ca from [2- 3 ', 4'-Dichloro-3-nitro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide. Yield: 0.11 g (25% of theory) C26H27Cl2N30 (M = 468.43) Cale: molar peak (M + H) '+: 468/470/472 Exp .: molar peak (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-ylmethyl-phenyl) -ethyl] - 1. 6.a. 3'-Methoxy-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. b from 4-bromo-2-nitro-benzoic acid and 3-methoxy-phenyl-boric acid. 'Yield: 0.39 g "(73.6% of theory) Ci4HnN05 (M = 273.24) Cale: molar peak (M + H) +: 274 Exp .: molar peak (M + H) +: 274 Rf value: 0.35 (gel silica, 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 Prepared analogously to Example 1.1. i from 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine. Yield: 0.39 g (57% of theory) C27H29N3C > 4 (M = 459.55) Cale: molar peak (M + H) +: 460 Exp .: molar peak (M + H) ÷: 460 Rf value: 0.23 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) I.6. C. 3 '-methoxy-3-amino-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide Prepared analogously to Example 1.1. j from [2- (4-pyrrolydin-l-ylmethyl-phenyl) -ethyl] -amide of 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid. Yield: 0.11 g (30.6% of theory) Cale: molar peak (M + H) +: 430 Exp .: peak, molar (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 1. 7.a. 4'-Fluoro-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. b from 4-bromo-2-nitro-benzoic acid and 4-fluoro-phenylboric acid. Yield: 1.3 g (61.2% of theory) C13HaFN04 (M = 261.21) Cale: molar peak (MH) ": 260 Exp .: molar peak (MH) ~: 260 Rf value: 0.34 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1) 1. 7.b. [4 (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4 '-fluoro-3-nitro-biphenyl-carboxylic acid Prepared "analogously to Example 1.1, starting from 4' -fluoro- 3-Nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine Yield: 0.38 g (57.8% of theory) C26H2SFN303 (M = 447.51) Cale: molar peak (M + H ) +: 448 Exp .: molar peak (M + H) +: 448 F value: 0.24 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 7. c. [2-Fluoro-3-amino-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide Prepared analogously to Example 1.3.ca from [2- (4-pyrrolidin 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid-l-ylmethyl-phenyl) -ethyl] -amide. Yield: 0.06 g (32% of theory) C26H28F 30 (M = 417.53) Cale: molar peak (M + H) +: 418 Ex. : molar peak (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- 1. 8.a. 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. b from bromo-2-nitro-benzoic acid and 4-vinyl-phenyl-boric acid. Yield: 0.58 g (53% of theory) C15H11N04 (M = 269.25) Cale: molar peak (MH) ": 268 Exp.: Molar peak (MH) ~: 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-pyrrolin-l-ylmethyl-phenyl) -ethyl] -amide Prepared analogously to Example. 1.1. i from '-vinyl-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine. Yield: 0.38 g (56.8% of theory) C28H28N3O3 (M = 455.56) Cale: molar peak (M + H) +: 456 Exp .: molar peak (M + H) +: 456 Rf value: 0.21 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) I.8. C. [4 (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4 '-ethyl-3-amino-biphenyl-4-carboxylic acid Prepared analogously to Example 1.3.ca from [2- (4- 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide. Yield: 0.15 g (63.9% of theory) C2aH33N30 (M = 427.59) Cale: molar peak (M + H) +: 428 Exp .: molar peak (M + H) +: 428 Rf value: '0.47 (silica gel , dichloromethane / methanol / ammonia 9: 1: 0.1) analogously to Example 1.1. k the following compounds were prepared: Value Rf.- A = (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 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-ylmethyl-phenyl) -ethyl] -amide (see Example 1.3.c.) in 4 ml. of acetic acid and 0.028 ml (0.3 mmol) of acetic anhydride were added. heat for 12 hours at reflux. The reaction solution is diluted with water, adjusted to a pH value of 8 with dilute sodium hydroxide, and extracted with dichloromethane. The organic phase is dried over magnesium sulfate. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 90: 10: 1) Yield: 0.008 g (11% of theory) C29H2SF3N3O (= 491.56) Cale: molar peak (M + H) +: 492 Ex. : molar peak (M + H) +: 492 Rf value 0.36 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) Analogously to Example 1.9.a, the following compounds were prepared: Example R20 Educto Formula Spectrum f Empirical Rf value of mass [° C] 1.9 4-trifluoromethyl-1.3-c C29H2SF3W30 492 [M + H] + wax 0.36 (A) phenyl 1.10 4-methyl-phenyl 1.2. c C29H31N30 437 [M + H] + wax 0.66 (A) " 1. 11 4-chloro-phenyl 1.1. j C28H2SC1N30 458/60 160- 0.40 (A) [M + H] + 163 Rf Value: A = (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) Example 1.10: 2-methyl-3- [2- (4-pyrrolidin-l-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 ethyl] -lH-quinazoline-2,4-dione A reaction mixture of 0.3 g (0.69 mmol) of 4'-chloro- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3-amino-biphenyl-4-carboxylic acid (see Example 1.1) and 0.1 g (0.65 mmol) of CDI in 50 ml of tetrahydrofuran is heated for 24 hours at reflux. Then another 0.1 g of CDI is added and the reaction mixture is heated for a further 24 hours at reflux. The reaction mixture is concentrated by evaporation in a rotary evaporator under vacuum. The purification is carried out by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia 60: 1: 0.1) Yield: 0.2 g (62.9%) of the theoretical) Melting point: 274-276 ° C C27H26C1N302 (M = 459.98) Cale: molar peak (M + H) +: 460/462 Exp. : molar peak (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- [4- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -3iT-quinazolin-4-one 1. 13. a [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -acetonitrile Prepared analogously to Example 1.1. g from 2- (S) -methoxymethyl-pyrrolidine and (4-bromomethyl-phenyl) -acetonitrile. Yield: 0.9 g (51.6% of theory) C15H2oN20 (M = 244.33) Cale: molar peak (M + H) +: 245 Ex. : molar peak (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 Prepared analogously to Example 1.1. h from [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -acetonitrile Yield: 0.5 g (54.7% of theory) C15H24N20 (M = 248.37) Cale: molar peak (M + H) +: 249 Exp .: molar peak (M + H) +: 249 'Rf value: 0.3' (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) 1. 13. c. { 2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-nitro-biphenyl-4-carboxylic acid amide Prepared analogously to Example 1.1. i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethylamine. Yield: 0.5 g (54.7% of theory) C28H30CIN3O4 (M = 508.02). Cale: molar peak (+ H) +: 508/510 Exp .: molar peak (M + H) +: 508/510 Rf value: 0.6 - (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) 1. 13.d. { 2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylic acid amide Prepared analogously to Example 1.3.c from. { 2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amino-3-nitro-biphenyl-4-carboxylic acid amide. Yield: 0.24 g (51% of theory) C28H32C1 302 (M = 478.03) Cale: molar peak (M + H) +: 478/480 Exp. : molar peak (M + H) +: 478/480 Rf 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 1. 14. a (4-dimethylaminomethyl-phenyl) -acetonitrile Prepared, analogously to Example 1.1. g from dimethylarine and (4-bromomethyl-phenyl) -acetonitrile. Performance: 1.0. g (30% of theory) C11H14N2 (M = 174.24) Cale: molar peak (M + H) +: 175 Exp. : molar peak (M + H) +: 175 Value f: 0.2 (silica gel, cyclohexane / ethyl acetate 1: 1) 1. 14. b 2- (4-dimethylaminomethyl-phenyl) -ethylamine Prepared analogously to Example 1.1. starting from (4-dimethylaminomethyl-phenyl) -acetoni ryl Yield: 1.0 g crude CnHxs a (M = 178.28) Cale: molar peak (M + H) +: 179 Exp .: molar peak (M + H) +: 179 Rf value: 0.2 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) 1. 14. 4'- • Chloro-3-nitro-biphenyl-4-carboxylic acid [2- (4-dimethylaminomethyl-phenyl) -ethyl] -amide. Prepared analogously to Example 1.1. ia from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-dimethylaminomethyl-phenyl) -ethylamine Yield: 0.5 g (63.4% of theory) C24H24C1 303 (M = 437.93) Cale: peak molar (M + H) +: 438/440 Exp .: molar peak (M + H) +: 438/440 Rf value: 0.35 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) 1. 14. 4'-Chloro-3-amino-biphenyl-4-carboxylic acid d- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -amide. Prepared analogously to the? J etnplo 1.3. ca from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid [2- (4-dimethylaminomethyl-phenyl) -ethyl] -amide yield: 0.2 g (43% of theory) C24H26C1N30 (M = 407.94) Cale: molar peak (M + H) +: 408/410 Exp. : molar peak (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-l-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4 -one 1. 15.a (4-piperidin-1-ylmethyl-phenyl) -acetonitrile Prepared analogously to Example 1.1. g from piperidine and (4-bromomethyl-phenyl) -acetonitrile. Yield: 1.6 g (39% of theory) C14H18N2 (M = 214.31) Cale: molar peak (M + H) +: 215 Exp.: Molar peak (M + H) +: 215 Rf value: 0.4 (silica gel, cyclohexane / ethyl acetate 1: 1) 1. 15.b 2- (4-piperidin-1-ylmethyl-phenyl) -ethylamine Prepared analogously to Example 1.1. starting from (4-piperidin-l-ylmethyl-phenyl) -acetonitrile Yield: 1.4 g (85.9% of theory) Ci4H22N2 (M = 218.34) Cale: molar peak (M + H) +: 219 Exp .: molar peak ( M + H) +: 219 Rf value: 0.2 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1) 1. 15. C [2- (4-piperidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-piperidin-1-ylmethyl-phenyl) -ethylamine. Yield: 0.07 g (40.7% of theory) C27H28CIN3O3 (= 477.99) Cale: molar peak (M + H) *: 478/480 Exp .: molar peak (M + H) +: 478/480 Value f: 0.5 (gel silica, dichloromethane / ethanol / ammonia 20: 1: 0.1) 1.15.d acid [2- (4-piperidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-amino-biphenyl-4- carboxylic Prepared analogously to Example 1.3.ca from [2- (4-piperidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid Yield: 0.05 g (76.4 g) % of theory) C27H30CI 3O (M = 448.01) Example 1.16: 7- (4-chloro-phenyl) -3- [2- (4-morpholin-4-ylmethyl-phenyl) -ethyl] -3H- 1. 16. a (4-morpholin-4-ylmethyl-phenyl) -acetonitrile Prepared analogously to Example 1.1. g from morpholine and (4-bromomethyl-phenyl) -acetonitrile. Yield: 1.63 g (98.9% of theory) C13H1SN20 (M = 216.28) Cale: molar peak (M + E) +: 217 Exp. : molar peak (M + H) +: 217 Rf value: 0.33 (silica gel, cyclohexane / ethyl acetate 1: 1) 1. 16.b 2- (4-morpholin-1-ylmethyl-phenyl) -ethylamine Prepared analogously to Example 1.1. starting from (4-morpholin-1-ylmethyl-phenyl) -acetonitrile Yield: 1.65 g (99.4% of theory) C13H20N2O (M = 220.31) Cale: molar peak (M + H) +: 221 Exp .: molar peak (M + H) +: 221 Value f: 0.54 (silica gel, dichloromethane / ethanol / ammonia '9: 1: 0.1) 1. 16. C [2- (4-morpholin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. i from '-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-morpholin-1-ylmethyl-phenyl) -ethylamine. Yield: 0.53 g (76.6% of theory) C26H26N304 (M = 47.9.97) Cale: molar peak (M + H) +: 480/482 Exp .: molar peak (M + H) +: Rf value: 0.5 (gel silica, dichloromethane / ethanol / ammonia 90: 1: 0.1) 1. 16.d [2- (4-morpholin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-amino-biphenyl-4-carboxylic acid Prepared analogously to Example 1.3.ca from [2- (4-morpholin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid yield: 0.45 g (90.6% of theory) C26H28C1 302 (M = 449.98) Cale: peak molar (M + H) +: 450/452 Exp. : molar peak (M + H) +: 450/452 Rf value: 0.67 (silica gel, dichloromethane / ethanol / ammonia 90: 1: 0.1) analogously to Example 1.1. k the following compounds were prepared: 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-methyl-piperazin-1-pyridin-3-yl] -ethyl.} - 3H-quinazolin-4-one 1. 17. a (6-Chloro-pyridin-3-yl) -acetonitrile To a solution of 6.91 g (41.66 mmoles) of potassium iodide and 2.24 g (49.01 mmoles) of. Sodium cyanide in 400 ml of an ethanol / water mixture (9: 1) is added dropwise a solution of 7.5 g - (41.66 mmol) of 2-chloro-5-chloromethyl-pyridine, dissolved in 100 ml of ethanol. The reaction mixture is then heated for 5 hours at 85 ° C. The solvent is distilled under vacuum and the residue is extracted with water and ethyl acetate. The organic phase is washed three times with water and dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol). Yield: 2.9 g (45.6% of theory) C7H5C1N2 (M = 152.58) Cale: molar peak (M + H) +: 151/153 Exp. : molar peak (M + H) +: 151/153. 1. 17.b [6- (4-methyl-piperazin-1-yl) -pyridin-3-? -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 nitrile. - butanol is heated for two hours in the microwave at 180 ° C. The solvent is distilled in vacuo, the residue is suspended in water and then extracted with ethyl acetate. The combined organic phases are extracted three times with water and dried over sodium sulfate. Purification is carried out by column chromatography on Alox (eluent: petroleum ether / ethyl acetate 1: 1). Yield: 1 g (24.6% of theory) Melting point: 58-59 ° C Cale: molar peak (M + H) +: 217 Exp .: molar peak (M + H) +: 217 Ef value: 0.35 (gel silica, dichloromethane / methanol / monane 9: 1: 0.1). 1. 17. c 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethylamine Prepared analogously to Example 1.1. i from [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -acetonitrile. Yield: 0.94 g (96% of theory) C12H20N4 (M = 220.32) Cale: molar peak (M + H) +: 221 Exp .: molar peak (+ H) +: 221. 1. 17.d acid. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} 4'-chloro-3-nitro-biphenyl-4-carboxylicamide Prepared 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 theory) Melting point: 158-159 ° C C25H26C1N503 (M = 479.97) Cale: molar peak (M + H) +: 480/482 Exp .: molar peak (+ H) +: 480/482. 1. 17.e acid. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide '-chloro-3-amino-biphenyl-4-carboxylic Prepared analogously to Example 1.1. i from "of { 2- [6- (4-Methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid. Yield: 0.1-2 g (64% of theory) Melting point: 198-199 ° C C25H27CIN5O (M = 449.98) Cale: molar peak (M + H) +: 450/452 Exp .: molar peak (M + H) +: 450/452. 1. 17.f 7- (4-chloro-phenyl) -3-. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} - 3 H -quinazolin-4 -one Prepared analogously to Example 1.1.1 from. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylic acid amide and formic acid. Yield: 0.06 g (53.5% of theory) Melting point: 263-264 ° C C26H2SC1WS0 (M = 459.98) Cale: molar peak (M + H) +: 460/462 Exp .: molar peak (M + H) + : 4460/462.
Example 1.18 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3-J-benzo [d] [1.2.3] triazin-4-one 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 To a solution of 0.27 g (0.62 mmol) of [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of 4-acid. '-chloro-3-amino-biphenyl-4-carboxylic acid (see example 11j) in 10 ml of methanol and 10 ml of 1 N hydrochloric acid is slowly added dropwise at a temperature between 0 ° C and 5 ° C. 0.09 g (0.93 mmol) of sodium nitrite in 2 ml of water. The reaction mixture is then stirred for three hours at room temperature, then diluted with 30 ml of water and made alkaline with ammonia solution.The aqueous solution is extracted with ethyl acetate.The combined organic phases are washed three times. water, dried over sodium sulfate and filtered on activated carbon, the solvent is removed and the residue washed with diisopropyl ether. Yield: 0.09 g (32.5% of theoretical) Melting point: 151 -152 ° C C26H25CI 4O (M = 444.96) Cale: molar peak (M + H) +: 445/447 Exp.: Molar peak (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 il-ethyl) -benzonitrile Prepared analogously to Example 1.1. g from piperidine and 4-bromomethyl-benzonitrile Yield: 2.4 g (85.9% of theory) C12H12N2 (M = 186.25) Cale: molar peak (M + H) +: 187 Exp .: molar peak (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 Prepared analogously to Example 1.1. h from 4- (1-pyrrolidin-1-yl-ethyl) -benzonitrile Yield: 2.42 g (98.7% of theory) C12Hi8N2 (M = 190.29) Cale: molar peak (M + H) +: 191 Exp. : molar peak (M + H) +: 191 Value f: 0.26 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1). 1. 19. C 4- (1-pyrrolidin-1-yl-ethyl) -benzylamide 4'-chloro-3-nitro-biphenyl-4-carboyl acid Prepared analogously to Example 1.1. The starting material is 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 theory) ) C25H24C1 303"(M = 449.94) Cale: molar peak, (M + H) +: 450/452 Exp .: molar peak (M + H) +: 450/452. 1. 19.d. 4- (1-pyrrolidin-1-yl-ethyl) -benzylamide 3-amino-4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.3.ca from 4- (1-pyrrolidin-1-yl) -ethyl) -benzylamide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid. Yield: 0.19 g (72.7% of theory) C25H26C1N30 (M = 419.95) ·; Cale :: molar peak (M + H) +: 420/422 Exp. : molar peak (M + H) +: 420/422. 1. 19.e 7- (4-chloro-phenyl) -3- [4- (l-pyrrolidin-1-yl-ethyl) -benzyl] -3H-benzo [d] [1.2.3] -triazin-4-one Prepared analogously to Example 1.18.aa from 4- (l-pyrrolidin-1-yl-ethyl) -benzylamide 3-amino-4'-chloro-biphenyl-4-carboxylic acid. Yield: .0.045 g (31.4% of theory) Melting point: 147-148 ° C Cale: molar peak (M + H) +: 431/433 Exp .: molar peak (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] -isoindole-1,3-dione 20. to 5-bromo-2-. { 2- [4- (l-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} oindol-1, 3-dione A soltieion- of 0.8 g (3.52 mmolea) of 5-bromo isobenzofuran-1,3-dione and 0.72 g (3.52 mmoles) of 2- (4-pyrrolidin-l-ylmethyl-phenyl) - Ethylamine (see example 1.1 h) in 10 ml of acetic acid is heated. for four hours at 110 ° C. The reaction mixture is then poured into water, made alkaline with 2N sodium hydroxide and the precipitate is filtered. The precipitate is washed several times with water and dried. Yield: 0.5 g (34.3% of theory) C2iH2iBrN202 (M = 413.31) Cale: molar peak (M + H) +: 413/415 Exp. : molar peak (M + H) +: 413/415. 1. 20.b. 5- (4-fluoro-phenyl) -2-. { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phen-1] -ethyl} -isoindole-1, 3-dione Prepared analogously to Example 1.1. b from 5-bromo-2- acid. { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} - Isoindol-1,3-dione and 4-fluoro-phenylboronic. Yield: 0.01 g (4.8% of theory) C27H25F 2O2 (M = 428.51) Cale: molar peak (M + H) +: 429 Exp .: molar peak (M + H) +: 429.
Example 1.21: 7- (4-chloro-phenyl) -3-. { 2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4 -one 1. 21.a [4- (4-phenyl-piperidin-1-yl-ethyl) -phenyl] -acetonitrile Prepared analogously to Example 1.1. g from 4-phenylpiperidine and; (4-bromomethyl-phenyl) -acetonitrile. Yield: 3.8 g (98% of theory) C20H22 2 (M = 290.41) Cale: molar peak (M + H) +: 291 Exp. : molar peak (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 Prepared analogously to Example 1.1. h from [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -acetonitrile. Yield: 3.6 g crude C20H2SN2 (M = 294.44) Cale: molar peak (M + H) +: 295 Exp .: molar peak (M + H) +: 295 Rf value: 0.49 (silica gel, dichloromethane / ethanol 20: 1) 1. 21. C acid. { 2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-nitro-biphenyl-4-carboxylic acid amide Prepared 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 theory) C33H32CIN3O3 (M = 554.09)., Cale: molar peak (M + H) +: 554/556, Exp. : molar peak (+ H) +: 554/556, * Rf value: 0.58. (silica gel, dichloromethane / ethanol / ammonia 10: 1: 0.1) ~ 1:21 d acid. { 2 - [4- (- phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylicamide Prepared analogously to Example 1.3.c from acid. { 2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid; 0.82 g (65.2% of theory) C33H34CIM3O ('= 524.11) Cale: molar peak (M + H) +: 524/526/528 Exp .: molar peak (M + H) +: 524/526/528 · Rf value : 0.65 (silica gel, dichloromethane / methanol 10: 1) Example 1.22: 7- (-chloro-phenyl) -3-. { 2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] - 1. 22.a '[4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -acetonitrile Prepared analogously to Example 1.1. g from 4-phenylpiperazine and (4-bromomethyl-phenyl) -acetonitrile. Yield: 3.7 g (97% of theory) C19H21N3. { M = 291.39) Cale: molar peak (M + H) +: 292 Exp. : molar peak (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 Prepared analogously to Example 1.1. from [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -acetonitrile Yield: 1.1 g (28.6% of theory) C19H25N3 (M = 295.43) Cale: molar peak (+ H) +: '296 Exp .: molar peak (M + H) +: 296 1. 22.c acid. { 2- [4- (4-phenyl-piperazin-1-yl-methyl) -phenyl] -ethyl} - amide 4'-chloro-3-nitro-biphenyl-4-carboxylic acid Prepared analogously to Example 1.1. 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% from the theoretical) C32H31C1M403 '(M = 555.08) Cale: molar peak (M + H) +: 555/557 Exp .: molar peak (M + H) +: 555/557 1. 22.d acid. { 2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylicamide Prepared analogously to Example 1.3.c from acid. { 2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-3-nitro-biphenyl-4-carboxylic Yield: 0.11 g (38.8% of theory) C32H33CIN4O (M = 525.09) Cale: molar peak (M + H) +: 525/527 Exp .: molar peak ( M + H) +: 525/527 Example 1.23: 7- (4-chloro-phenyl) -3-. { 2- [4- (4-hydroxy-4-phenyl-piperidin-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4 ~ ona 1. 23.a [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -acetonitrile Prepared analogously to Example 1.1. g from 4-hydroxy-4-phenylpiperidine and (4-bromomethyl-phenyl) -acetonitrile. Yield: 3.8 g (98% of theory) C20H22N2O (M = 306.41) Cale: molar peak (M + H) +: 307 Exp .: molar peak (M + H) +: 307 Rf value: 0.1 (silica gel, cyclohexane / ethyl acetate 1: 1) l.23.b 2- [4- (4-Hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethylamine Prepared analogously to Example 1.1. starting from [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -acetonitrile Yield: · 3.36 g (92.1% of theory) C2oH25N20 (M = 310.44) Cale: molar peak (M + H) +: 311 Exp .: peak molar (M + H) +: 311 Value Rf: 0.1 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1) " 1. 23.C acid. { 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-nitro-biphenyl-4-carboxylicamide Prepared analogously to Example 1.1. ia starting 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 theory) C33H32CIN3O4 (M = 570.09) Cale: molar peak (M + H) +: 570/572 Exp .: molar peak "(M + H) +: 570/572 Value f: 0.35 (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1) 1. 23.d acid. { 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylicamide Prepared analogously to Example 1.3.C from acid. { 2- [4- (4-hydroxy-4-phenyl-piperidin-l-ylmethyl) -phenyl] -ethyl-amide 4'-chloro-3-nitro-biphenyl-4-carboxylic. Yield: 1.04 g (91.5% of theoretical ) C33H34C1N302 (M = 540.11) Melting point: 175-180 ° C Cale: molar peak (M + H) +: 540/542/544 Exp .: molar peak (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} -3-quinazolin-4-one Prepared analogously to Example l.l.k. from acid. { 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylic acid amide. Yield: 0.025 g (8.2% of theory) Melting point: 204-205 ° C C34H32CIN3Ó2 (M = 550.10) Cale: molar peak, (M + H) +: 550/552 Exp .: molar peak (M + H) +: 550/552 R 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-'ona 1.24.a. 7- (4-chloro-phenyl) -3-. { 2- [4- (4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin ~ 4-one Prepared analogously to Example 1.l.k. from acid. { 2- [4- (4-idroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylicamide as a by-product in Example 123. e. Yield: 0.08 g (27.1% of theory) Melting point: 166-167 ° C C34H30ClN3O (M = 532.09) Cale: molar peak (M + H) +: 532/534 Exp. : molar peak (M + H) +: 532/534"Rf value: 0.57 (silica gel, dichloromethane / ethanol / ammonia 10: 1) Example 1.25: 7- (-chloro-phenyl) -3- (2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3-quinazolin-4- ona " 1. 25.a [4- (3-aza-spiro [5.5] undec-3-methylmethyl) -phenyl] -acetonitrile Prepared analogously to Example 1.1. g from 3-aza-spiro [5.5] undecane and (4-bromomethyl-phenyl) -acetonitrile. Yield: 3.38 g (98% of theory) C19H26N2 (M = .282.43) Cale: molar peak (M + H) +: 283 Exp .: molar peak (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] -ethylamine Prepared analogously to example 1.1. starting from [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -acetonitrile Yield: 3.33 g (96. "6% of theory) C19H30N2 (M = 286.46) Cale: molar peak ( + H) +: 287 Exp .: molar root (M + H) +: 287 Rf value 0.18 (silica gel, dichloromethane / ethanol 20: 1) 1. 25.C acid. { 2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -amide-3-chloro-biphenyl-4-carboxylic acid prepared analogously to Example 1.1. ia from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethylamine Yield: lg (52.5% from the theoretical) C32H36C1 303 (M = 546.11) Cale: molar peak (M + H) +: 546/548 Exp ..: molar peak (M + H) +: 546/548 Rf value: 0.3 (silica gel, dichloromethane / ethanol 20: 1) 1. 25.d acid. { 2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylic acid amide. Prepared analogously to example 1.3.c from acid. { 2 - [4- (3-aza-spiro [5.5] unde-3-ylmethyl) -phenyl] -ethyl} 4'-Chloro-3-nitro-biphenyl-4-carboxylicamide Yield: 0.8 g (84.7% of theory) C32H38CI 3O (M = 516.13) Cale: molar peak (M + H) +: 516/518 Exp .: molar peak (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- (pyridine- 2-yloxy) -piperidin-1-ylmethyl] -phenyl.}. -ethyl) -3Ji-quinazolin-4-one 1. 26.a. { 4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} - acetonitrile Prepared analogously to. example 1.1. g from 2- (piperidin-4-yloxy) -pyridine and (4-bromomethyl-phenyl) -acetonitrile. . Yield: 0.91 g (49.8% of theory) Ca9H21N30 (M = .307.39) 'Cale: molar peak (M + H) +: 308 Exp .: molar peak (+ 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 '| Prepared analogously to example 1.1.h from. { 4- [4- (pyridin-2-yloxy) -piperidin-1-methyl] -phenyl} -acetonitrile yield: 0.92 g (99.8% of theory) C1SH2SN30 (M = 311.43) Cale: molar peak (M + H) +:, 312 Exp .: molar peak (M + H) +: 312 Rf value: 0.16 (gel silica, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 26. C (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-chloro-3-nitro-biphenyl- 4-carboxylic Prepared analogously to example 1.1. i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-. { 4- [4- (pyridin-2-yloxy) -piperidin-1-methyl] -phenyl} -ethylamine Yield: 0.8 g (97.2% of theory) C32H31 CIN4O4 (M = 571.08) Cale: molar peak (M + H) +: 571/573 Exp. : molar peak (M + H) +: 571/573 Rf value: 0.52 (silica gel, dichloromethane / methanol / ammonium 9: 1: 0.1) 1. 26.d acid (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide '-chloro-3-amino-biphenyl-4 carboxylic acid prepared analogously to example 1.3.ca from (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide. -chloro-3-nitro-biphenyl-4-carboxylic Yield: 0.38 g (50% of theory) C32H33CI 4O2 | (M = 541.09) Cale: molar peak (M + H) +: 541/543 Exp .: molar peak ( M + H) + i 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 ? 1.27.a. { 4 - [4- (pyridin-2-ylamino) -piperidin-l-ylmethyl] -phenyl} -acetonitrile Prepared analogously to Example 1.1. g from 2- (piperidin-4-ylamino) -pyridine and (4-bromomethyl-phenyl) -acetonitrile. . Yield: 1.57 g (86.1% of theory) C19H22N4 (M = 306.41) Cale: molar peak (+ H) +: 307 Exp .: molar peak (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 Prepared analogously to example 1.1. h from . { 4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -acetonitrile Yield: 1.62 g (99.8% of theory) Cale: molar peak (M + H) +: 311 Exp.: Molar peak (M + H) +: 311 Rf value: 0.1 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 27. c (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-chloro-3-nitro-biphenyl- 4-carboxylic Prepared analogously to example 1.1. i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid Y 2-. { 4 ~ [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethylamine Yield: 0.36 g (43.8% of theory) - C32H32C1W503 (M = 570.09) Cale: molar peak (M + H) +: 570/572 Ex. : molar peak (M + H) +: 570/572 Rf value: 0.28 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1) 1. 27.d acid (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-chloro-3-amino-biphenyl- 4-carboxylic acid prepared analogously to Example 1.3.ca from (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} - ethyl) -amide. -chloro-3-nitro-biphenyl-4-carboxylic Yield: 0.29 g (85.7% of theory) - C32H34C1N50 (M = 540.11) Cale: molar peak (M + H) +: 540/542 Exp .: molar peak (M + H) +: 540/542 Rf value: 0.27 (silica gel, dichloromethane / methanol / ammonia - 9: 1: 0.1) Analogously to example 1.1. k the following computes were prepared Example R ¥ -BX- Educto 'Formula Spectrum Pf [° C] Empirical RE value of mass 1.21 i.2l.d C34H32C1N30 534/536 178-179 0.72 (E) [M + H] + 1.22 CU, 1.22.d C33H31C1N40 535/537 199-200 [M + H] + 1.23 Oo 1.23.d C34H32ClN302. 550/552 204-205 0.46 (F) [M + H] + 1.24 Cl. 1.23.d C34H30ClN3O 532/534 166-167 0.57 (E) [M + H] + 1.25 1.25.d C33H36C1N30 526/528 184-185 0.62 (E) [M + H] + 1.26 1.26.d C33H3iClN402 551/553 154 -158 0.46 (A) [M + H] + 1.27 t T i 1.27.d C33H32C1N50 550/552 164-166 0.45 (A) V1 VV [M + H] + 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) -1- l) - of 4'-chloro-3-amino-biphenyl-4-carboxylic acid. Yield: 0.13 g (-50.9% of theory) Melting point: 183-184 ° C C33H31ClN40 (M = 535.09) Cale: molar peak (M + H) +: 535/537 Exp. : molar peak (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} -3fí-benzo [d] [1.2.3] triazin-4-one 1. 29.a 7- (4-chloro-phenyl) -3-. { 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3íí-benzo [d] [1.2.3] triazin-4-one Prepared analogously to example 1.18.a from acid. { 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylic acid amide. Yield: 0.21 g (68.7% of theory) Melting point: 265-266 ° C. C33H31C1N402 (M = 551.09) Cale: molar peak (M + H) +: 551/553 Exp .: molar peak (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-] [1.2.3] triazin-4-one 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 Prepared analogously to example 1.18.a from acid. { 2- [4- (3-aza-spiro [5.5] unde-3-methylmethyl) -phenyl] -ethyl} 4'-chloro-3-amino-biphenyl-4-carboxylic acid amide. Yield: 0.14 g (54.9% of theory) Melting point: 165-166 ° C C32H35C1N40 (M = 527.11) Cale: molar peak (M + H) +: 527 Exp. : molar peak (M + H) +: 527 Ef value: 0.56 (silica gel, dichloromethane / ethanol 10: 1) Example 1.31: 6- (4-Chloro-phenyl) -2- [2- (4-pyrrolidyr-l-ylmethyl-phenyl) -ethyl] -2H- 1. 31.a. 2- [2- (4-bromo-phenyl) -ethoxy] -tetrahydro-pyran To a solution of 4.83 g (24.02 mmol) of 2- (4-bromo-phenyl) -ethanol in 12 ml of dichloromethane are added successively to 0o C 0.025 g of p-toluenesulfonic acid and 2.575 ml (28.22 mmoles) of dihydropyran. 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 carried out by chromatography on an Alox column (eluent: cyclohexane / ethyl acetate = 8: 2). Yield: 37 g (32.8% of theory) Cale: molar peak (M) +: 284/286 Exp. : molar peak (M) +: 284/286 1. 31.b 4- [2- (Tetrahydro-pyran-2-yloxy) -ethyl] -benzaldehyde To a solution of 5 g (17.53 mmol) of 2- [2- (4-bromo-phenyl) -ethoxy] -tetrahydropyran in 80 ml of tetrahydrofuran, 11.5 ml (18.41 mmol) of a 1.6 M n-butyllithium solution are added drse at -70 ° C and stirred for one hour at room temperature. Then 2.8 ml (36.46 mmoles) of dimethylformamide are added drse and the reaction mixture is stirred for two hours at -70 ° C. The reaction mixture is combined with an ammonium chloride solution and extracted with ethyl acetate. ethyl. The combined organic phases are extracted three times with saturated sodium chloride solution and dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 6: 4). Yield: 2.8 g (68.2% of theory) Ci4H1803 (M = 234.29) -. ' · '' Cale: molar peak (M + H) +: 235 Exp. : peak "molar (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 mmoles) of 4- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -benzaldehyde in a mixture of 48 ml of 1 M hydrochloric acid and 60 ml of acetone are stirred for 5 hours at 5 ° C. The reaction mixture is combined with 140 ml of saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic phases are extracted three times with water and dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate = 1: 1). Yield: 1.3 g (72.4% of theory) C9H10O2 (M = 150.17) | Cale. : molar peak (M + H) +: 151 Exp.: molar peak (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 mmoles) 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 heated at reflux 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 theory) C12H1603 (M = 208.26) Cale: molar peak (M + H) +: 209 Exp .: molar peak (M + H) +: 209 1. 31.e Acid - 2- (4- [1,3] dioxan-2-yl-phenyl) -ethyl methanesulfonic ester 8 g (38.41 mmol) of 2- (4- [1,3] dioxan-2-yl-phenyl) are dissolved - ethanol and 10.65 ml (42.25 mmoles) of triethylamine in 300 ml of dichloromethane and combine at 0 ° C with 3.27 ml of methanesulfonic 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. The purification is carried out by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1: 1). Yield: 7.7 g (70% of theoretical) Cale: molar peak (M + H) +: 287 Exp.: Molar peak (M + H) +: 287 Rf value:. 0.49 (silica gel, petroleum ether / ethyl acetate 1: 1) I.31.f (E) -3- (3-bromo-phenyl) -acyloilazide To a solution of 25 g (111.1 mmoles) of (E) -3- (3-bromo-phenyl) -acrylic acid and 15.26 my (110.10 mmol) of triethylamine in 800 ml of acetone are added dropwise at 0 ° C II.5 ml (121.11 mmol) of ethyl chloroformate. After 1 hour, 11.45 g (176.16 mmoles) of sodium azide, dissolved in 88 ml of distilled water, are added dropwise at 0 ° C. The reaction mixture is heated to room temperature and subsequently poured into 1.3 1 of ice water. The precipitate produced is filtered, washed. with water and dried in a circulating air dryer at 30 ° C. Yield: 21.1 g (76.1% of theory) CsH6BrN30 (M = 252.07) Cale: molar peak \ (M + H) +: 256/258 Exp. : molar peak (M + H) +: '256/258"' Rf value: 0.85 (silica gel, petroleum ether / ethyl acetate 1: 1) 1. 31.g 6-bromo-2H-isoquinolin-l-one 150 g of diphenyl ether and 7.08 ml (29.75 mmoles) of tributylamine are heated to 100 ° C. At this temperature 5 g (19.83 mmoles) of | ( E) -3- (3-bromo-phenyl) -acyloilazide y. then it is heated for two hours at 195-205 ° C. The reaction mixture is then left to cool and poured into chilled p-hexane. The precipitate is filtered and washed with a mixture of cold n-hexane and diethyl ether. Subsequently, the solid substance is dried in a circulating air dryer at 50 ° C. The solid substance is stirred with a mixture of diisopropyl ether and ethyl acetate and the drying step is repeated. Yield: 0.6 g (13.5% -the theoretical) C9HsBrN30 (M = 224.05) Cale: molar peak '(M + H) +: 224/226 Exp .: molar peak (M + H) +: 224/226 1. 31. h 6- (4-chloro-phenyl) -2H-isoquinolin-1-one A reaction mixture of 0.57 g (2.54 mmoles) of 6-bromo-2H-isoquinolin-l-one, 0.398 g (2.54 mmoles) ) of 4-chlorophenylboronic acid, 2.6 ml of a 2M sodium carbonate solution in 20 ml of dioxane and 5 ml of methanol is heated for two hours in the microwave at 110 ° C. The reaction mixture is then poured into .water, the precipitate is filtered and dried in a circulating air dryer at 40 ° C. Yield: 0.42 g (64.6% of theory) C15HioClNO (M = 255.70) Cale.:, molar peak (M + H) +: 256 / 258 Exp .: molar peak (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 is combined with 0.18 g (1.6 mmoles) of potassium terbutoxide and stirred for 30 minutes at 50 ° C. 0.46 g (1.6 mmol) of 2- (4- [1,3] dioxan-2-yl-phenyl) -ethyl methanesulfonic acid. The reaction mixture. It is heated for five hours at 180 ° C in the microwave and then poured into a 10% citric acid solution. Extract with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 3: 1 to 1: 1). Yield: 0.15 g (24.1% of theory) C2 H18C1N02 (M = 387.87) Cale.:, Molar peak (M + H) +: 388/390 Exp. : molar peak (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) -2ff-isoquinolin-1-one and 0.03 ml (0.36 mmol) are dissolved. pyrrolidine in 40 ml of dichloromethane. With glacial acetic acid, the pH is adjusted to a value of 3. Then 0.076 g (0.36 mmol) of sodium triacetoxyborohydride are added and stirred for 48 hours at room temperature. The reaction mixture is then extracted with sodium carbonate solution 2 and dried over sodium sulfate. Purification is carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol 10: 1 to 1: 1). Yield: 0.04 g (25% of theory) Melting point: 136-137 ° C C28H27C1 20 (M = 442.99) Cale: molar peak (M + H) +: 443 Exp. : molar peak (M + H) +: 443 Rf value: 0.5 (silica gel, dichloromethane / methanol 10: 1) Analogously to examples 1.1 to 1.31, the following compounds are prepared: 5 ?? ' Example 2.1: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 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 25 m 2 sodium carbonate solution. successively add 4.5 g (29.0 mmoles) of 4-chlorophenylboronic acid and 1.68 g (1.45 mmoles) of tetrakis- (triphenylphosphine) -palladium and the reaction is carried out for 6 hours at reflux. The hot reaction solution is absorbed through a filter. The filtrate is extracted with ethyl acetate.The aqueous phase is acidified with citric acid and stirred for one hour at 0 o C. The precipitate produced is filtered, washed with water and dried under vacuum. : 5.1 g '. (75.6% of theory) C13H9C102 (M- = 232.668) Cale: molar peak (MH) ": 231/233 Exp. : molar peak (M-H) ": 231/233. 2. 1 B. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl--carboxylic acid To a suspension of 251 mg (1.08 mmol) of 4'-chloro-biphenyl-4-acid carboxyl in .5 ml of THF are added at room temperature 471 mg (1.47 mmoles) of TBTU and 0.26 ml (1.47 mmoles) of Hünig base. The reaction mixture is stirred for 10 min and then 200 mg (0.98 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine is added (see example 1: 1h). The mixture is stirred overnight. The reaction solution is combined with saturated NaHCO 3 solution. The aqueous phase is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate. The solvent is completely distilled in a rotary evaporator and the residue is stirred with tert-butymethyl ether under heating. The solid substance produced is completely filtered, washed with little, methylterbutyl ether and dried in air. Yield: 210 mg (51.2% of theory) C2eH27ClN20 (M = 418,971) *. Cale.:, Molar peak (? +?) +: · 419/421 Ex. : molar peak (M + H) +: 419/421 - Rf value: 0.57 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1).
Example 2.2: [2- (4-Diethylaminomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 2. 2.a (4-diethylaminomethyl-phenyl) -acetonitrile 0.88 ml of (8.38 -inmoles) of diethylamine are dissolved in 30 ml of acetone. and 2.1 g (15.2 mmoles) of potassium carbonate and 1.6 g (7.62 mmoles) of (4-bromomethyl-phenyl) -acetonitrile are added successively (see 1.l.f). The reaction mixture is stirred for 2 hours at room temperature, filtered on a glass frit and washed with ethyl acetate. The filtrate is concentrated by evaporation in a vacuum in a rotary evaporator, extracted with water and ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed in a rotary evaporator. The subsequent purification is carried out by column chromatography on silica gel (eluent: dichloromethane / methanol 9: 1). Yield: 900 mg (58.4% of theory) Cale: molar peak (M + H) +: 203 Exp. : molar peak (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 is mixed with 100 mg of Raney nickel and stirred at 50 ° C and 5 x 105 Pa (5 bar) in an autoclave. After absorbing the catalyst, the solvent is removed in a rotary evaporator. Yield: 900 mg (98.0% of theory) C13H22N2 (M = 206.334) Calc .: molar peak (M + H) +: 207 Exp .: molar peak (M + H) +: 207 Value | Rf: 0.12 (gel silica, dichloromethane / methanol / NH3 9: 1: 0.1) 2. 2 C. [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to example 2.1.ba 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 theory) C26H29C1N20 (M = 420.987) Cale: molar peak (M + H) +: 421/423 Exp. : molar peak (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 2. 3.a. [2 - (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid | Analogously prepared; to Example 2.1.ab starting 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 theory) C27H29C1N20 (M = 432.998) Cale: molar peak (M + H) +: 433/435 Ex. : molar peak (M + H) +: 433/435 - Rf value: 0.57 (silica gel, 'dichloromethane / methanol / NH3 9: 1: 0.1).
Example 2.4: [2- (4-Diethylamomethyl-phenyl) -ethyl] -amide 4'-methoxybiphenyl-4-carboxylic acid il-4-?) -ethanone To a solution of 11.3 g (85.0 mmoles) of aluminum chloride in 100 ml of carbon sulfide is added 4-methoxybiphenyl.The mixture is heated to 40 ° C and then mixed thoroughly. slowly with 6.07 ml (81.4 mmoles) of acetyl chloride.
The reaction is boiled for one hour at reflux. After cooling, the reaction solution is poured into 100 g of ice and 25 ml of concentrated hydrochloric acid. After extracting 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 theory) Ci5H1402 (M = 226.278) Cale: molar peak. (M + H) +: 227 Exp .: molar peak (M + H) +: 227 '. * 2.4.b 4'-Methoxy-biphenyl-4-carboxylic acid To a solution of 15.6 g (390.9 'mmoles) of NaOH in 70 ml of water is added dropwise at 0 ° C 6.0 ml (117 mmol) of bromine . Then 8.8 g (39.1 mmol) of 1- (4'-methoxy-biphenyl-4-yl) -ethanone in 50 ml of dioxane are slowly added. ? After three hours the solid substance formed is completely filtered, recovered in dichloromethane and. it is filtered again. The filtrate is freed from the solvent in a rotary evaporator. Yield: 9.0 g (100.0% of theory) Ci5H1402 (M = 228.250) Cale: molar peak (M-H) \: 227 Exp.: Molar peak (M-H) ": 227 2. 4.c 4'-Methoxy-biphenyl-4-carboxylic acid chloride A solution of 3.0 g (0.013 mol) of 4'-methoxy-biphenyl-4-carboxylic acid in 47 ml (0.65 mol) of thionyl is stirred for three hours at 50 ° C. After removing the thionyl chloride in a rotary evaporator, the product is obtained as a yellowish solid substance which is stored in the refrigerator. Yield: 3.2 g (99.8% of theory) C15H14 02 (M = 246.696) Calc .: molar peak (M + H) +: 246/248 Exp. : molar peak (M + H) +: 246/248. 2. 4.d [2- (4-Diethylaminomethyl-phenyl) -ethyl] -amide 4'-methoxy-biphenyl-4-carboxylic acid? a solution of 200 mg (0.97 mmol) of 2- (4-diethylaminomethyl-phenyl) -ethylamine and 0.25 ml (1.45 mraols) of Hünig base in 5 ml of dichloromethane are added at 0 ° C 287 mg (1.16 mmoles) of acetyl. The reaction is stirred overnight and then combined with semi-saturated solution of. NaHC03. The aqueous phase is washed with dichloromethane and the combined organic phase is dried over magnesium sulfate. After removing the solvent on a rotary evaporator, the residue is triturated with tert-butyl methyl ether and the solid substance formed is absorbed. .3% of theory) Cale: molar peak (M + H) +: 417 Exp .: molar peak (M + H) +: 417. Rf value: 0.46 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1) Example 2.5 '[2- (4-Diethylaminomethyl-phenyl) -ethyl] -methyl-amide 4'-chloro-biphenyl-4-carboxylic acid 2. 5. to tert-butyl [2- (4-diethylaminomethyl-phenyl) -ethyl] -carbamate. To a solution of 700 mg (3.93 mmol) of 2- (4-diethylaminomethyl-phenyl) -ethylamine in 5.0 ml of dichloromethane and 0.52. t ?? (3.73 mmoles) of triethylamine is added 815 mg (3.73 mmoles) of BOC anhydride and stirred at room temperature overnight. The. mixture is combined with saturated aHC03 solution. The aqueous phase is washed with dichloromethane and the organic phase is dried over magnesium sulfate. After removing the solvent in a rotary evaporator, the residue is purified by silica gel column chromatography (eluent: dichloromethane / methanol / NH3-9: 1: 0.1). Yield: 600 mg (57.7% of theory) Ci8H30 2O2 (M = 306.452). Cale: molar peak (M + H) +: 307 Exp. : molar peak (M + H) +: 307. 2. 5.b [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amine To a suspension of 250 mg (6.59 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran is slowly added dropwise 600 mg ( 1.96 mmoles) of tert-butyl [2- (4-diethylaminomethyl-phenyl ') -ethyl] -carbaminate in THF. The reaction is stirred overnight and heated for a further hour at 50 ° C. The workup is carried out by successive addition of 0.25 ml of water, 0.25 ml of 15% NaOH solution and 0.75 ml of water. After filtering, the organic phase is dried over magnesium sulfate and the solvent is removed in a rotary evaporator. Yield: 350 mg (81.1% of theory) C14H24N2 (M = 220.361) Cale: molar peak (M + H) +: 221 Exp .: 'molar peak (M + H) +: 221. 2. 5. C [2- (4-Diethylaminomethyl-phenyl) -ethyl] -methyl-amide 4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to example 2.1.ba from 4'-chloro-biphenyl-4-acid carboxylic (222 mg, 0.95 mmol) and [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amine (175 mg, 0. 79 mmol). Yield: 60 mg (17.4% of theory) C27H3iClN20 (M = 435.014) Cale: molar peak '(M + H) +: 435/437 Exp .: molar peak (M + H) +:' 435/437 Rf Value: 0.39 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.6: 2. 6.a. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -cyclohexanecarboxylic acid Prepared according to general procedure I a. 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 theory) C26H33C1 20 (M = 425,019) Cale: molar peak (M + H) +: 425/427 Exp. : molar peak (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-JV- [2- (4-pyrroidin-1-ylmethyl-phenyl) -ethyl] -2,7-a 4-piperidin-1-yl-benzoic acid To a suspension of 0.5 ml (4.13 mmol) ethyl 4-fluoro-benzoate and 571 mg (4.13 mmol) of potassium carbonate in 20 ml of DMSO are added 0.41 ml of piperidine. The reaction mixture is stirred at 70 ° C all night, 1 ml more (2.44 mmol) of piperidine are added and the mixture is stirred for another 6 hours at 70 ° C. After filtering, it is mixed with water, extracted With ethyl acetate, the organic phase is separated and the solvent is removed on a rotary evaporator. The product is reacted without further purification. Yield: 706 mg (73.2% of theory) Ci4H19N02 (M = 233.313) Cale: molar peak (M + H) +: 234 Exp.: Molar peak (M + H) +: 234 HPLC retention time: 6.2 min (Method TO) 2. 7.b 4-piperidin-1-yl-benzoic acid To a solution of 350 mg (1.50 mmol) ethyl 4-piperidin-l-yl-benzoate in 10 ml of ethanol, 0.78 ml of (0.74 mmol) of NaOH are poured into it. , 2''W .. The reaction solution is stirred for 2 hours at 60 ° C and then the pH value is adjusted with HC1 1 N to 6-7, The precipitate produced is dried after filtering "at high Vacuum throughout the night Yield: 158 mg (51.3% of theory) C12H15N02 (M = 205.259) Cale: molar peak (M + H) +: 206 Exp .: molar peak (M + H) +: 206 Retention time HPLC: 6.2 min (Method A) 2. 7. c 4-piperidin-l-yl-V- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general procedure, work 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 theory) C25H33N3O (M = 391.561) Cale: molar peak (M + H) +: 392 Exp .: molar peak (M + H) +: 392 HPLC retention time: 4.4 min ( Method A) ? Use 2.8: 2. 8.a 4-benzyl-IV- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general procedure of work I described at the beginning from 'diphenyl-tetraethane-4' acid carboxylic acid (104 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -etalamine (100 mg, 0.49 mmol). Yield: 66 mg (33.9% of theory) C27H30N2O (M = 398.553) Cale: molar peak (M + H) +: 399 Exp .: molar peak (M + H) +: 399 R 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-ylmethyl) -ethyl] -benzamide 2. 9.a 4- (1,4-dioxa-spiro [4.5] dec-8-ylide.-methyl) -benzoic acid ethyl ester - - To a solution of 90.0 ml (0.63 mol) of diisopropylamine in 100 ml of THF add dropwise at -20 ° C 350 ml (0.56 mol, 1.6 M in hexane) of n-BuLi solution and the reaction solution is stirred for 30 min at -20 ° C. g (0.37 mol) ethyl 4- (diethoxyphosphorylmethyl) -benzoate in 100 ml of THF The reaction solution is stirred for 1 h at -20 ° C and then 58 g (0.37 mol) are added dropwise. of 1,4-dioxa-spiro [4.5] decan-8-one in 200 ml of THF.The reaction solution is stirred for 30 min at -12 ° C and then heated for 2 hours at room temperature. The aqueous phase is extracted with ether, ethyl acetate and dichloromethane.The organic phase is filtered on silica gel.With elimination of the solvent in a rotary evaporator, the residue 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 To a solution of 35 g (0.12 mol) of 4- (1,4-dioxa-spiro [4.5] ethyl dec-8-ylidemethyl) -benzoate in 150 ml of ethanol is added 20 g of NaOH in 130 ml of water and the mixture is refluxed for 2 hours. The reaction solution is poured into 400 g of ice and 60 ml of concentrated 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 theory). Melting point: 164-165 ° C. 2. 9. c 4- (4-oxo-cyclohexylidenemethyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general method of blocking or starting from acid 4- ( 1,4-dioxa-spiro [4.5] dec-8-ylidenemethyl) -benzoic acid (134 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (100 mg, 0.49 mmol). Yield: 57 mg (28.0% of theory) C27H32N2O2 (M = 416.568) Cale: molar peak (M + H) +: 417 Jan: molar peak (M + H) +: 417 Rf value: 0.36 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.10: 2. 10.a 4- (4-oxo-cyclohexyl) -N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general method of work 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 theory) C26H32N202 (M = 404.557) Cale: molar peak (M + H) +: "405 Jan: molar peak (M + H) +: 405 Rf value: 0.31 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1) -Example 2.11: [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide cyclohexyl-1-cyclohexylcarboxylic acid 2. .eleven. a 4-Cyclohexyl-1-cyclohexylcarboxylic acid To a solution of 500 mg (2.10 mmol) of 4- (4-chlorophenyl) -cyclohexanecarboxylic acid in 10 ml of methanol are added 0.44 ml of concentrated hydrochloric acid and 100 mg of platinum oxide. . The reaction mixture is stirred at 50 ° C and 5 bar of hydrogen for 3 hours. After separation of the catalyst, the solvent is removed using the rotary evaporator. Yield: "440 mg (99.9% of theory) Ci3H2aOa (M = 210.319) Cale: molar peak (M-H)": 209 Jan .: molar peak (M-H) ": 209 2. 11.b [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4-cyclohexyl-1-cyclohexylcarboxylic acid Prepared according to the general working method, the starting of 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 theory) C26H40N2O (M = 396.622) Cale: molar peak (+?) +: 397 Jan: molar pic. (M + H) +: 397 Rf value: 0.46 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.12: 2. 12.a [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-methylphenyl-piperidine-1-carboxylic acid Prepared according to the general, working method II described above from 4-methylphenyl-piperidine (175 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1. o 'mmol). | Yield: 90.0 mg (22.2% of theory) C26H35N3O (M = 405.558) Cale: molar peak (M + H) +: 406 Jan .: molar peak (M + H) +: 406 Rf value: 0.30 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.13: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid 2. 13.a 4- (4-chloro-phenyl) -1.2.3..6-tetrahydro-pyridine _A 100 ml (1.2 mol) of formalin solution (37% in water) and 32.1 g (0.6 mol) of sodium chloride Ammonium is added dropwise at 60 ° C 4-chloro-methylstyrene. The reaction mixture is stirred for 3 hours at 60 ° C and then cooled to room temperature. 100 ml of methanol are added and the mixture is stirred overnight. After evaporation of the solvent using the rotary evaporator, the residue is mixed with 150 ml of concentrated hydrochloric acid and stirred for 4 hours at 100 ° C. After cooling to room temperature it is added on ice and alkalized with NaOH lentils. After extracting several times with ether, the organic phase is dried over sodium sulfate. After removing the solvent using the rotary evaporator, the residue is purified by column chromatography on silica gel (eluent: ethyl acetate: methanol: N¾ 9: 1: 0.1). Yield: 17.0 g (29.3% of theory) CnHisClN (M = "193.678) 'Cale: molar peak (M + H) +: - 194 Jan.: molar peak (M + H) +: 194 Value ¾: 0.26 (gel silica, ethyl acetate / methanol / N¾ 6: 4: 0.4). 2. 13.b [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] .- amide 4- (4-chloro-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid Prepared in accordance with general working method 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 theory) C25H3oClN30 (M = 423.990) Cale: molar peak (M + H) +: 424/426 Jan. : molar peak (M + H) +: 424/426 Rf value. 0.30 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.14: 2. 14.a [3- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3,4,5,6-tetrahydro-2i- [4,4 '] bipyridinyl-l-carboxylic acid prepared according to the method General working II from 1, 2, 3, 4, 5, 6-hexahydro- [4. '] bipyridinyl (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 theory) C24H32N4O (M = 392.549) Cale: molar peak (M + H) +: 393 Jan .: molar peak (M + H) +: 393 Rf value: 0.14 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.15: 2. 15.a [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4-benzyl-piperidine-l-carboxylic acid Prepared according to the general method of work 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 theory) C26H35N30 (M = 405.6) · Cale: molar peak (M + H) +: 406 Jan .: molar peak (M + H) +: 406 Rf value: 0.36 (gel silica, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.16: 2. 16.a [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4 (lH-Indol-3-yl) -piperidine-1-carboxylic acid. Prepared according to the general method of Work II from 3-piperidin-4-yl-1-yl-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 theory) Cale: molar peak (M + H) +: 431 Jan: molar peak (M + H) +: 431 Rf value: 0.36 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.17: tyl-phenyl) -ethylcarbamoyl] - [4.4 '] tert-butyl bipiperidinyl-l-carboxylate Prepared according to general procedure II from [4.4'] -bipiperidinyl-l-carboxylic acid tert-butyl ester (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 theory) C29H46N403 (M = 49.8.7). Cale: molar peak (M + H) +: 499 Jan: molar peak (M + H) +: 499 Rf value: 0.40 (silica gel, ethyl acetate / methanol / NH3) 9: 1: 0.1).
Example 2.18: '[2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- 205 acid cyclohexyl-piperidine-1-carboxylic acid 2. 18.a 4-cyclohexyl-piperidine To a solution of 1.0 g (6.4 mmol) of 4-phenylpyridine in 20 ml of methanol are added 1:35 ml of concentrated hydrochloric acid and 200 mg of platinum oxide. The reaction mixture is stirred at 50 ° C and 3 x 105 Pa (3 bar) of hydrogen for 2.5 hours. After separation of the catalyst, the solvent is removed using the rotary evaporator, while the product is precipitated as the hydrochloride. Yield: 1.2 (91.4% of theory) CnH21N * HCl (= 203.758) Cale: molar peak (M + H) +: 168 Jan .: molar peak (M + H) +: 168. 2. 18.b [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-cyclohexyl-piperidine-1-carboxylic acid. Prepared according to the general method of work 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) ¾5? 39? 30 (M = 397.6) Cale: molar peak (M + E) +: 398 Ene .: molar peak (M + H) +: 398 Value ¾: 0.5 ( silica gel, ethyl acetate / methanol / N¾ 9: 1: 0.1). '' 206 Example 2.19: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -piperidine-l-carboxylic acid. 2. 19.a 4- (4-chloro-phenyl) -piperidine - To a solution of 5.0 g (21.7 mmol) of 4- (4-chloro-phenyl) -1,2,3,6-tetrahydro-pyridine (see 2.13 .a) in 500 ml of methanol, 500 mg of Pd / C are added. The reaction mixture is stirred at room temperature and 68947 Pa (10 psi) of hydrogen for 7 hours. After separation of the catalyst, the solvent is removed using the rotary evaporator. The additional purification is carried out by silica gel column chromatography (eluent: dichloromethane / methanol / ammonia = 5: 4.9: 0.1). Yield: 3.2 (75.3% of theory) CnH14ClN (M = 195.694) Cale: molar peak (M + H) +: 196/198 Jan: molar peak (M + H) +: 196/198. Value f: 0.37 (silica gel, diCloromethane / methanol / NH3 5: 4.9: 0.1). 2. l9.b [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -piperidine-1-carboxylic acid 207 Prepared according to the general method of work 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 theory) C25H32C1N30 (M = 426.0) Cale: molar peak (M + H) +: 426/428 Jan .: molar peak (M + H) +: 426/428 Value f: 0.49 ( silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.20: 4- low 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 theory) C2SH32F3W302 (M = 475.6) Cale: molar peak (M + H) +: 476 Jan: molar peak (M + H) +: 476 Rf value: 0.45 (silica gel. ethyl acetate / methanol / NH3 9: 1: 0.1). 208 E p 2.21: [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide phenyl-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid Prepared according to general working method 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). : 26.0 mg (12.5% of theory) C27H35 30 (M = 41 .6) Calc .: molar peak (M + H) +: 418 Jan. ': molar peak (M + H) +: 418 Rf value: 0.51 ( silica gel, ethyl acetate / methanol / NH: 9: 1: 0.1).
Example 2.22: 2. 22.a [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -piperazine-1-carboxylic acid Prepared according to general working method II from of 4- (4-chloro-phenyl) -piperazine (117 mg, 0.50 mmol) 209 ? 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol). Yield: 13.0 mg (6.1% of theory) C24H2 C1 40 (M = 427.0) Cale: molar peak (M + H) +: 427/429 Jan .: molar peak (M + H) +: 427/429 Rf Value: 0.42 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1) Example 2.23: 2. 23: a [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4-cyano-4-phenyl-piperidine-l-carboxylic acid Prepared according to the general method of work 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 theory) ¾6? 32 40 (M = 416.6) Cale: molar peak (+ H) +: 417 Jan: molar peak (M + H) +: 417 Value. Rf. 0.46 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1). 210 Example 2.24: 2. 24.a [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide-3-aza-spiro [5.5] undecan-3-carboxylic acid Prepared according to general working method II from 3 -aza-sspiro [5.5] undecane (76.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol). Yield: 24.0 mg (12.5% of theory) C24H37N30 (M = 383.6) Cale: molar peak (M + H) +: 384 Jan: molar peak (+ H) +: 384 Rf value: 0.49. (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.25: 2. 25.a [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-fluoro-phenyl) -piperidine-l-carboxylic acid Prepared according to the general method of work II from of 4- (4-fluoro-phenyl) -piperidine (108 mg, 0.50 211 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0. 50 mmol). Yield: 32.0 mg (15.6% of theory) C24H32FN30 (M = 409.6) Cale. : molar peak (M + H) +: 410 Ene: molar peak (M + H) +: 410 Rf Value:? .50 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.26: -l-ylmethyl-phenyl) -ethyl] -amide dihydro-1- (methylsulfonyl) -spiro [3 H -indole-3. '-piperidine] -1 carboxylic acid Prepared according to the general method of work II from 1.2-dihydro-1- (methylsulfonyl) -spiro [3 H -indol-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 theory) C27H3SN403S (M = 496.7) Cale: molar peak (M + E) +: 497 Jan.: molar peak (M + H) +: 497 Rf value: 0.42 '(silica gel ethyl acetate / methanol / NH3 9: 1: 0.1). 212 2. 27.a [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid Prepared according to the general method of Work 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 ). Performance:. 32.0 mg (14.5% of theory) C25H32C1 302 (M = 442.0) Cale: molar peak (M + H) +: 442/444 Jan .: molar peak (M + H) +: 442/444 Value f: 0.44 (gel silica, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.28: 2. 28.a [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-methoxy-phenyl) -piperazine-l-carboxylic acid Prepared according to general working method II from of 4- (4-methoxy-phenyl) -piperazine (133 mg, 0.50 213 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol). Yield: 35.0 mg (16.6% of theory) C25H34N402 (= 422.6) Cale: molar peak (M + H) +: 423 Jan: molar peak (+ H) +: 423 Rf value: 0.47 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.29: 2. 29. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (2- • methoxy-phenyl) -piperidine-l-carboxylic acid Prepared according to the general method of work 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). . Performance; 20.0 mg (9.5% of theory) C26H35N3O2 (M = 421.6). Cale. : molar peak (M + H) +: 422 Jan .: molar peak (M + H) +: 422 Rf value: 0.55. (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1). . 214 Example 2.30: 2. 30- [1,3-Dihydro-isoindol-2-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide Prepared in accordance with general working method II from 1.3- dihydro-isoindol (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 theory) C22H27 30 (M = 349.48) Cale ': molar peak (M + H) +: _ 350 Jan: molar peak (M + H) +: 350 Rf value: 0.30 (gel. "silica, dichloromethane / methanol / NH3 9: 1: 0.1).
Example 2.31: 2. 31.a [1,2,4,5-tetrahydro-benzo [d] azepine-3-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide. Prepared according to general method of work II a from 1.2.4.5-tetrahydro-benzo [d] azepine (73.6 mg, 0.50 mmol) and 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethylamine 215 (102 mg, 0.50 mmol).; • Yield: 12.0 mg "(6.4% of theory) C24H31N30 (M = 377.534) Cale: molar peak (M + H) +: 378 Jan .: molar peak (M + H) +: 378 Rf value: 0.33 (gel silica, dichloromethane / methanol / NH3 9: 1: 0.1) ,.
Example 2.32: 2. 32a 4-phenyl-piperidine-l-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide. Prepared according to the general method of work 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 theory) C2SH33N3O (M = 391.561) Cale: molar peak. (M + H) +: 392 Ene .: molar peak (M + H) +: 392 Rf value: 0.35 (silica gel, dichloromethane / methanol / NH3 9: 1: 0.1). ' ' Example 2.33: 4- (4-dimethylaminomethyl-phenyl) -piperidine-l-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide] 2. 33.a 4- '(4-.dimethylaminomethyl-phenyl) -4-hydroxy-piperidin-1-tert-butyl carboxylate To a solution of 81 g (0.38 mol) of 4-bromo-dimehylbenzylamine in 450 ml of THF are added drop a, drop at -65 ° C 236 ml (0.38 mol, 1.6 M in hexane) of n-BuLi for 35 min. 75 g (0.38 mol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 150 ml of THF are added dropwise over 60 min. so that the temperature does not exceed -60 ° C. The reaction solution is stirred for 2 hours at -65 ° C and for another 17 hours at room temperature. The reaction mixture is mixed with 300 ml of ether, cooled to 5 ° C and filtered by precipitated suction produced. The precipitate is mixed with 200 ml of water and 700 ml of ether and stirred for 10 min.The organic phase is dried over magnesium sulfate and the solvent is removed using the rotary evaporator.The product obtained is dried under vacuum. : 45 g (35.7% of theory) 2. 33.b Dimethyl- [4- (1.2.3.6-tetrahydro-pyridin-4-yl) -benzyl] -amine To a solution of 45 g (0.14 mol) 4- (4-dimethylaminomethyl-phenyl) -4-hydroxy- piperidin-1-carboxylic acid of tert-butyl in 140 ml of dichloromethane were added. add 70 ml of trifluoroacetic acid dropwise at -10 ° C. 'The solution is shaken 217 for 1.5 hours at room temperature, it is cooled to -10 ° C and 30 ml of concentrated sulfuric acid are added. After a half hour another 10 ml of sulfuric acid are added. After 1 hour, the solvent is removed using the rotary evaporator and poured into 300 g of ice. With a solution of 6H NaOH, the pH value is adjusted to 1-4. The aqueous phase is saturated with potassium carbonate and extracted twice with ether. The combined organic phases are concentrated using the rotary evaporator to dryness. Yield: 25.2 g (86.9 ¾.). 2. 33. c Dimethyl- (4-piperidin-4-yl-benzyl) -amine 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 is poured into Pd / BaSO4 The solution is stirred for 1 hour at room temperature under a hydrogen atmosphere, the catalyst is filtered and the solvent is removed using the rotary evaporator. The residue is dissolved in methanol, methanolic hydrochloric acid is added and then mixed with ether until turbidity.After storage at -20 ° C, the hydrochloride produced is suction filtered Yield: 16 g (84.9%) ,. 2. 33.d 4- (4-Dimethylaminomethyl-phenyl) -piperidine-l-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide] Prepared according to the general method of work 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 theory) C28H40N4O (M = 448.657) Cale: molar peak (M + H) +: 449 Jan: molar peak (M + H) +: 449 Rf value: 0.37 (silica gel, dichloromethane / methanol / NH3 9: 1: 0.1).
Example 2.34: 4'-chloro-bi enyl-4-yl) - [3- (4-pyrrolidin-l-ylmethyl-phenyl) - 'piperidin-1-yl] -methanone 2. 34.a 1- (4-bromo-benzyl) -pyrrolidine To a solution of 13.1 ml (0.16 mmol) of pyrrolidine and 200 ml of tetrahydrofuran are slowly added dropwise 20.0 g (0.080 mol) of 4-bromobenzyl bromide in THF, so that the temperature does not exceed 20 ° C. The reaction solution is stirred overnight and then mixed with ice 219 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 extracting with ether, the organic phase is dried over magnesium sulfate and the solvent is removed using the rotary evaporator. Yield: 18.1 g (94.2% of theory) CnH14BrN (M = 240.145) Cale: molar peak (M + H) +: 240/242 Jan: molar peak (M + H) +: 240/242 Rf value: 0.19 (gel silica, petroleum ether / ethyl acetate 8: 2). . ' 2. 34.b 3- (4-pyrrolidin-1-ylmethyl-phenyl) -pyridine 1.11 g (4.64 mmol) of l- (4-bromo-benzyl) -pyrrolidine are dissolved in 10 ml of dioxane and 5 ml of carbonate solution. 2 M sodium. 570 mg (4.64 mmol) of pyridine-3-boronic acid and 270 mg (0.23 mmol) of tetrakis- (triphenylphosphine) -palladium are successively added and the reaction is added successively and the reaction is heated to reflux for 6 hours. The reaction solution is absorbed through a glass fiber filter. The filtrate is extracted several times with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed using the rotary evaporator. The subsequent purification is carried out by 220 column chromatography on silica gel (eluent: ethyl acetate / methanol / NH3 = 8: 2: 0.1). Yield: 500 mg (45.2% of theory) C16H1BN2 (M = 238.335) ~ Cale. -, molar peak (M + H) +: 239 Jan: molar peak (M + H) +: 239 2. 34. c 3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidine To a solution of 500 mg (2.10 mmol) of 3- (4-pyrrolidin-1-ylmethyl-phenyl) -pyridine in 10 ml of ethanol was added. add 4 ml of 1 M hydrochloric acid 200 mg of platinum oxide. The reaction mixture is stirred at room temperature and 3 x 105 Pa (3 bar) of hydrogen for 4.5 hours. After the separation of. catalyst, the solvent is removed using the rotary evaporator, while the product is precipitated as the hydrochloride. Yield: 600 mg (100% of theory) Ci6H24N2 * HCl (M = 280.844) Cale: molar peak (M + H) +: 245 Jan.: molar peak (M + H) +: 245. 2. 34.d (4'-chloro-biphenyl-4-yl) - [3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidin-1-yl] -methanone Prepared according to the general method of work I from '-chloro-biphenyl-4-carboxylic acid (183 mg, 0.78 mmol) and 3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidine (200 mg, 0.71 mmol). 221 Yield: 20.0 mg (6.1% of theory) - C29H 20 (M = 459.036) Calc .: molar peak (M + H) +: 459/461 Jan: molar peak (M + H) +: 459/461 Value f: 0..58 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.35: -propyl] -amide of the 2. 35.a 2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propionitrile To a solution of 2.0 g (10.0 ramol) of (4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (see 1.1. g) in 50 ml of tetrahydrofuran, 3.4 g (30 mmol) of potassium tert-butoxide are added at room temperature. The reaction solution is stirred briefly, mixed with 1.9 ml (30 mmol) of methyl iodide, stirred for a further 2 hours at room temperature and then evaporated using the rotary evaporator to dryness. The residue is partitioned between water and ethyl acetate, the organic phase is washed with water and dried. dry on sulfate 'of 222 magnesium. The solvent is extracted using the rotary evaporator and the crude product is reacted without purification. Yield: 1.4 g (61.3% of theory) C15H20 2 (M = 228.340) Cale: molar peak. (M + H) +: 229 Jan .: molar peak (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 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 is added 150 mg of Raney nickel. The reaction mixture is stirred overnight at 50 ° C and 5 x 105 Pa (5 bar) of hydrogen atmosphere. After filtering the catalyst, the solvent is removed using the rotary evaporator. Yield: .1.4 g (98.3% of theory) C15H24 2 (M = 232.372) Cale: molar peak (M + H) +: 233 Jan: molar peak (M + H) +: 233 Rf value: 0.30 (silica gel, ethyl acetate / methanol / N¾ 9: 1: 0.1). 2. 35. c. [4-chloro-biphenyl-4-carboxylic acid 2-methyl-2- (4-pyrrolidin-l-ylmethyl-phenyl) -propyl] -amide 22-3 Prepared according to the general method of work I from 4'-chloro-biphenyl-4-carboxylic acid (233 mg, 1.0 mmol) and, 2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) ) -propylamine (232 mg (1.0 mmol) Yield: 400 mg (89.5% of theory) Ci5H31ClN20 (M = 447.025) 'Calc .: molar peak (M + H) +: 447/449 Jan: molar peak (M + H) +: 447/449 Rf value: 0.35 (silica gel, ethyl acetate / methanol / N¾ 9: 1: 0.1).
E p 2.36: 4'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -propyl] -amide - 2. 36.a 2- (4-pyrrolidin-1-ylmethyl-phenyl) -propionitrile To a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (see 1.1.g) in 50 g. Tetrahydrofuran are added at room temperature 1.12 g (10 mmol) of tert-butoxide. potassium. The reaction solution is stirred for 30 min and then mixed with .0.63 ml (10 mmol) of 224 g. methyl iodide. ' The reaction is stirred for 1 hour at 50 ° C and then evaporated using the rotary evaporator to dryness.The residue is partitioned between water and ethyl acetate, the organic phase is washed twice with water and dried over magnesium sulfate. The solvent is removed using the evaporator: rotary and the crude product containing approximately 20% of the dimethylated compound is reacted without purification Yield: 0.5 g (23.3% of theory) CI4H18N2 (M = 214.313) Cale: molar peak ( M + H) +: 215 Ene: molar peak (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 To a solution of 400 mg (1.87 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -propionitrile in 20 ml of solution Methanolic ammonia is added 100 mg of Raney nickel. The reaction mixture is stirred overnight at 50 ° C and 5 x 105 Pa (5 bar) of hydrogen atmosphere. After filtering the catalyst, the solvent is removed using the rotary evaporator. The amine that contains approximately 20%. The dimethylated compound is reacted without further purification. Yield: 0: 4 g (98.6% of theoretical) 225 C15H22N2 (= 218.345) Cale: molar peak (M + H) +: 219 Jan .: molar peak (M + H) +: 219 Rf value: 0.30 (silica gel, ethyl acetate / methanol / NH3 9: 1 : 0.1).; 2. 36.C [4 (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid Prepared according to general working method I from 4 'acid -chloro-biphenyl-carboxylic acid (233 rag, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -propylamine (218 mg, 1.0 mmol). Yield: 10 mg (2.3% of theory). C28H31ClN20, (M = 447.025) Cale: molar peak (M + H) *: 447/449 Jan: molar peak (M + H) +: 447/449 Rf value: 0.35 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.37: (4-pyrrolidin-1-ylmethyl-benzyloxy) -amide. ^ '- chloro-biphenyl-carboxylic acid 226 2. 37.a 2 - (4-pyrrolidin-l-ylmethyl-benzyloxy) -isoindole-1, 3-dione To a solution of "13.2 g (50 ramol) of a, '-dibromo-p-xylene in 125 ml of acetonitrile is added at room temperature a mixture of 8.2 g (50 mmol) of iV-hydroxy-phthalimide and 8.7 ml (50 mmol) of Hünig base in 125 ml of acetonitrile The reaction solution is stirred for 10 min, then 4.1 ml (50 mmol) of pyrrolidine are added and the mixture is stirred for an additional hour. mother liquors are concentrated by evaporation using the rotary evaporator to dryness. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia). The substance is converted back immediately after purification. Yield: 1.0 g (5.9% of theory) Value ¾: 0.60 (Alox, ethyl acetate / petroleum ether 1: 1). 2. 37.b O- (4-pyrrolidin-1-ylmethyl-benzyl) -hydroxylamine To a solution of 1.0 g (2.97 mmol) of 2- (4-pyrrolidin-1-ylmethyl-benzyloxy) -isoindole-1,3-dione in 50 ml of toluene, 50 ml of 40% methylamine solution in water are added and the mixture is stirred for 2.5 days at room temperature. Then separate. the organic phase, the aqueous phase is extracted twice with tert-butyl methyl ether. The combined organic phases are washed with water and dried over 227 sulfate. magnesium. The solvent is removed using the rotary evaporator and the product obtained is reacted without purification. Yield: 260 mg (42.4% of theory) C12H18N20 (M = 206.290). "'_ Cale: molar peak (M + H) +: 207 Ene .: .molar peak (M + H) +: 207. 2. 37.C (4-pyrrolidin-l-ylmethyl-benzyloxy) -amide of 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of locking or starting 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 theory) C20H25ClN2O2 (M = 420.943) Cale.-: molar peak (M + H) +: 421/423 Jan .: molar peak (M + H) +: 421/423 Rf Value : 0.38 (silica gel, ethyl acetate / methanol / NH3 3: 1: 0.!). l) -ethyl] -amide of 228 2. 38. (4-Pyrrolidin-1-ylmethyl-phenyl) -acetic acid ethyl ester 3.0 g (15 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (see - 1.1 g) is dissolved in Ethanolic hydrochloric acid (saturated) and heated to reflux for 4 hours. The solvent is removed using the rotary evaporaddr and the residue is absorbed with diluted solution of NaHCO3 and tert-butylmethylether. The organic phase is dried with sodium sulfate, absorbed on activated carbon and then the solvent is removed using the rotary evaporator. Yield: 3.4 g-. (91.6% of theory) C15H21 O2 (M = .247.340) |: | Cale: molar peak (M + H) +: 248 Jan .: molar peak (M + H) +: 248 Value. Rf: 0.25 (silica gel, ethyl acetate / methanol / N¾ 9: 1: 0.1). 2. 38.b 2-methyl-l- (4-pyrrolidin-1-ylmethyl-phenyl) -propan-2-ol? 13.3 ml (40 mmol) of a 3.0 M solution of methylmagnesium chloride in tetrahydrofuran are added dropwise at room temperature 3.4 g (13.8 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -acetic acid ethyl ester in 20 mi out of 229 tetrahydrofuran. Here the temperature rises to 40 ° C. The reaction mixture is stirred for one hour and then poured into 100 ml of ammonium chloride solution. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed using the rotary evaporator and the residue is purified by an Alox column chromatography. (activity 2-3) (eluent: cyclohexane: ethyl acetate 4: 1). Yield: 800 mg (24.9% of theory) C15H23 O (M = 233357) Cale: molar peak (M + H) +: 234 Jan .: molar peak (M + H) +: 234 Rf value: 0.50 (Alox, petroleum ether / ethyl acetate 6: 4). 2. 38. C JV- [1, 1-dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -formamide To a solution of 250 mg (5.0 mmol) of sodium cyanide in 2 ml of acetic acid A mixture of 2 ml of sulfuric acid and 1 ml of glacial acetic acid is added dropwise, so that the temperature of the reaction mixture does not exceed 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 are added dropwise. Here the temperature remains below 20 ° C. The reaction solution is stirred for one hour at room temperature and then poured 230 on 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 using the rotary evaporator and the product is reacted without purification Yield: 520 mg (58.2% of theory) C16H24N20 (M = 260.382) Cale: molar peak (M + H) +: 261 Jan: peak molar (M + H): 261. 2. 38. d. 1, 1-dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine To a solution of 520 mg (2 mmol) of N- [1,1-dimethyl-2- (4-pyrrolidin-l- ylmethyl-phenyl) -ethyl] -formamide in 10 ml of ethanol, add 25 ml of concentrated hydrochloric acid and heat overnight under reflux, after cooling the reaction solution, it is made alkaline with 25% aqueous sodium hydroxide. % and the aqueous phase is extracted several times with tert-butyl methyl ether.The combined organic phases are washed with water, dried over magnesium sulfate and filtered over activated carbon.The solvent is removed using the rotary evaporator. 380 mg (81.8% of theoretical) Cale: molar peak '(M + H) +: 233 Jan: peak "molar (M + H) +: 233 Value Rf =. 0.10 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1). 231 2, 38 e-l-chloro-biphenyl-4-carboxylic acid [i, l-dimethyl-2- (4-pyrr. solidin-l-ylmethyl-phenyl) -ethyl] -amide Prepared according to the general method of lock or split of 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 theory) C28H31C1N202 (M = 447.025) Cale: molar peak (M + H) +: 447/449 Jan: molar peak (M + H) +: | 447/449 Value R £: 0.48 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.39: 4- (2-pyrrolidin-1-yl-ethyl) -benzylamide of 4'-chloro biphenyl-4-carboxylic acid 2. 39.a 4- (2-pyrrolidin-1-yl-ethyl) -benzonitrile To a solution of 500 mg (2.74 mmol) of 4- (2-amino-ethyl) -benzonitrile in 50 ml of acetonitrile are successively added 91 mg (0.56 mmol) of potassium iodide, 453 mg (3.28 mmol) of potassium carbonate and 0.33 ml (2.74 mmol) of 232 1, -dibromobut no. The reaction is stirred for 6 hours at 78 ° C. Another 0.08 ml (0.66 mmol) of -1,4-dibromobutane are added and the reaction is stirred overnight at 78 ° C. After filtering, the filtrate is evaporated to dryness. The subsequent purification is carried out by column chromatography on silica gel (dichloromethane / methanol 8: 2). . Yield: 183.0 mg (33.4% of theoretical) ¾ ?? 6 2 (M = 200.286) Cale: molar peak (M + H) +: 201 Jan .: molar peak (M + H) +: 201. 2. 39.b 4- (2-pyrrolidin-1-yl-ethyl) -benzylamine To a solution of 183 mg (0.91 mmol) of 4- (2-pyrrolidin-1-yl-ethyl) -benzonitrile in 20 ml of ethanolic solution of ammonia are added 75 mg - Raney nickel. The reaction solution is stirred at 50 ° C and 3 x 105 Pa (3 bar) of hydrogen overnight. Add another 75 mg of Raney nickel and stir for a further 6 hours at 50 ° C and 3 x 105 Pa (3 bar) of hydrogen. The catalyst is filtered and the solvent is removed using the rotary evaporator. The crude product can be applied without further purification. Yield: 114.0 mg (61.0% of theory) C13H20N2 (M = 204.318) Cale: molar peak (M + H) +: 205 Ene. : molar peak (M + H) +: 205. 233 2. 39-C 4- (2-pyrrolidin-1-yl-ethyl) -benzylamide of 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work I from 4'-chloro-biphenyl acid 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 theory) C26H27C1N20 (M = 418.971) - Calc .: molar peak (M + H) +: 419/421 Jan: molar peak (M + H) +: 419/421 Rf value: 0.38 (silica gel, ethyl acetate / methanol / N¾ 9: 1: 0.1).
Example 2.40: 2. 40.a [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide [1, '] bipiperidinyl-1'-carboxylic acid Prepared according to the general method of work II from 4-piperidinpiperidine (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 theory) C24H38N40 (= 398.597) 234 Cale: molar peak (0.5M + H) +: 200 Jan .: molar peak (0.5M + H) +: 200 HPLC retention time: 1.59 min (method A) 2. 41.a 4-cyclohexyl-iV- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to general working method 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 theory) C26H34N2O (M = 390.574) Cale: molar peak (M + H) +: 391 Jan: molar peak- (M + H) +: 391 Rf value: 0.38 (silica gel, ethyl acetate / methanol / N¾ 9: 1: 0.1).
Example 2.42: [2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 235 2. 42. to 2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethylamine In a solution of 500 mg (2.45 min.) Of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (see Example 1.1. h) in 10 mL of methanol 1.52 mL of concentrated hydrochloric acid and 300 mg of platinum oxide were added. The reaction mixture is stirred at 50 ° C and 5 bar of hydrogen for 50 hours. After separation of the catalyst, the solvent was removed using the rotary evaporator. Further purification was carried out by column chromatography on silica gel (dichloromethane / methanol / ammonia 8: 2: 0.2). Yield: 130 mg (25.3% of theory) CI3H26 2 (M = 210".366) Cale: molar peak (M + H) +: 211 Jan .: molar peak (M + H) +: 211 Rf value: 0.14 (silica gel, dichloromethane / methanol / NH3 8: 2: 0.2). 2. 42.b [2- (4-pyrrolidin-l-ylmethyl-cyclohexyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work 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 theory) 236 C2SH33C1 20 (M = 425.019) Cale: molar peak (+ H) +: 425/427 Jan: molar peak (M + H) +: 425/427 Rf value: 0.16 (silica gel, ethyl acetate / methanol / NH3 9: 1: 0.1).
Example 2.43: [2- (3-Methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 2. 43.a 4-Cyanomethyl-2-methoxy-benzoic acid Prepared analogously to Example 1.1. starting from methyl 4-cyanomethyl-2-methoxybenzoate Yield: 6.5 g (69.8% of theory) C10H9NO3 (M = 191.18) Cale: molar peak (M + H) +: 192 Jan .: molar peak (M + H) +: 192 Rf value: 0.64 (silica gel, dichloromethane / ethanol 10: 1). 2. 3.b (4-hydroxymethyl-3-methoxy-phenyl) -acetonitrile Prepared analogously to Example 1.1. e from 4-cyanomethyl-2-methoxy-benzoic acid. Yield: 4.81 g (81% of theory) 237 C10HlaNO2 (M = 177.20) Cale: molar peak (M) +: 177 Jan .: molar peak (M) +: 177. 2. 43. c (4-Bromomethyl-3-methoxy-phenyl) -acetonitrile Prepared in a manner analogous to Example 1.1. fa from (4-hydroxymethyl-3-methoxy-phenyl) -acetonitrile Yield: 4.2 g (64.6% of theory) Ci0H10BrNO (M = 240.10) Cale: molar peak () +: 239/241 Jan .: molar peak (M ) +: 239/241 Rf value: 0.84 (silica gel, dichloromethane / ethanol 50: 1). 2. 43. d (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile Prepared analogously to Example 1.1. g from (4-bromomethyl-3-methoxy-phenyl) -acetonitrile and piperidine. Yield: 0.95 g (24.2% of theory) C14H18N20 (M = 230.31) Cale .: molar peak (M + H) +: 231 Jan.-, molar peak (M + H) +: 231. .43. e (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine Prepared analogously to Example 1.1. from (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile. The crude product is also reacted immediately without purification. 2. 43.f [2- (3-methoxy-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -238 acid amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work I from 2- (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 4'-chloro acid -biphenyl-4-carboxylic acid. Yield: 0.5 g (86.2% of theory) Melting point: 162 -163 ° C Cale: molar peak (M + H) +: 449/451 Jan: molar peak (M + H) +: 449/451 Rf Value : 0.85 (silica gel, dichloromethane / ethanol / ammonia 5: 1: 0.1).
Example 2.44: Acid. [2- (2-fluoro-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 2. 44.a (E) -3- (4-Cyano-2-fluoro-phenyl) -acrylic acid In a solution of 20.0 g (100 mmol) of 4-bromo-3-fluoro-benzonitrile in 200 mL of DMF were added 2.75 g (10 mmol) of palladium acetate and 7.0 g (25 mmol) of tri-o-tolyl-phosphane were added. Then 50 mL of 239 were added triethylamine and 30 mL (30 mmol) of ethyl acrylate. The reaction mixture was stirred for 3 hours at 100 ° CAfter cooling, it was diluted with 400 mL of dichloromethane and washed twice with water. The solvent was removed using the rotary evaporator and the residue was taken up in 250 mL of methanol under heating. The insoluble components are removed by suction filtration through a kieselguhr and the filtrate is evaporated in half in a rotary evaporator. After filtering again it was combined with 150 mL of THF, 100 mL of MeOH and 43 mL of 2N NaOH and stirred for 2 hours at room temperature. The solvent was removed using the rotary evaporator and the residue was combined with 100 mL of water. After extracting with ether, the aqueous phase was acidified with concentrated hydrochloric acid. The precipitated crystals were dissolved in 300 mL of hot ethyl acetate, the aqueous phase was separated. The ethyl acetate was extracted by distillation and the crystals obtained were suspended in ether and suspended by 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 combined with 4.0 g of 5% Pd / C and 24.4 g of potassium carbonate. The mixture is 240 stirred for 6 hours at room temperature and under normal pressure of hydrogen in the. autoclave After suction filtering the catalyst, the stock solution was acidified with concentrated hydrochloric acid. The precipitated crystals were dissolved in 250 mL of hot ethyl acetate and dried and the ethyl acetate was distilled off. The obtained crystals were stirred with ether / hexane and filtered by suction. Yield: 900 mg (98.0% of theory) Melting point: 102-106 ° C. 2. 44-c [2- (4-cyano-2-fluoro-phenyl) -ethyl] -carbamatete from ter. In a solution of 500 mg (2.6 mmol) of 3- (4-cyano-2-fluoro-phenyl) -propionic acid in 5 mL of tert-butanol, 1.25 mL of triethylamine and 0.61 mL (2.8 mmol) of diphenylphosphorylazide were added. . The reaction mixture was refluxed overnight and then the solvent was removed using the rotary evaporator. Purification was carried out by column chromatography on silica gel (dichloromethane / methanol 9: 1). Yield: 138 mg (20.2% of theory) C14Hi7FN202 (M = 264.302) Cale: molar peak (M + H) +: 265 Jan: molar peak (M + H) +: 265 241 2. 44.d [2- (4-aminomethyl-2-fluoro-phenyl) -ethyl] -carbaminate from ter. Butyl A solution of 138 mg (0.52 mmol) of [2- (4-cyano-2-fluoro-phenyl) -ethyl] -carbamate-tert-butyl ester in 15 mL of ethanolic ammonia solution was combined with 75 mg of Raney nickel and the mixture was stirred overnight at 50 ° C and 3 bar of hydrogen in an autoclave. After the catalyst has been filtered by suction, the solvent was removed using the rotary evaporator. Yield: 137 mg (97.8% of theory) C14H21FN2O2 (M = 268.334) Cale: molar peak (M + H) +: 269 Jan .: molar peak (M + H) +: 269. 2. 44. e [2- (2-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -carbamatete from ter. Butyl In a solution of 300 mg (1.12 mmol) of [2- (4-aminomethyl-2-fluoro-phenyl) -ethyl] -carbamate of ter. Butyl in 15 mL of acetonitrile were successively added 42 mg (0.25 mmol) of potassium iodide, 180 mg (1.30 mmol) of potassium carbonate and 0.13 mL (1.11 mmol) of 1, -dibromobutane. The reaction was stirred for 6 hours at 78 ° C. Another 0.08 mL (0.66 mmol) of 1,4-dibromobutane was added and the reaction was stirred overnight at 78 ° C. The solvent was removed using the rotary evaporator and the product was further reacted without purification. 242 Yield: 320 mg (88.8% of theory) C18H27FN202 (M = 322.426): Cale ..: molar peak (M + H) +: 323 Jan .: 'molar peak (M + H) +: 323. 2. 44.f 2- (2-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine In a solution of 232 mg (0.72 mmol) of [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) ) -ethyl] -carbaminate of ter. butyl in 5 mL of dichloromethane. 1.5 mL of trifluoroacetic acid was not added. The reaction mixture was stirred for 2 hours at room temperature. The solvent was removed using the rotary evaporator and the crude product was further reacted without purification. Yield: 160 mg (100% of theory) C13H19FN2 (M = 222.308) Cale: molar peak (M + H) +: 223 Jan: molar peak (M + H) +: 223. 2. 44.g [2- (2-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to general working method I from; of 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 theory) C26H2eClFN20 (M = 436.961) Cale. : molar peak (M + H) +: 437/439 Jan: molar peak (M + H) +: 243 437/439 '- HPLC retention time: 6.6 min (method A) E p 2.45: 4-pyridin-4-yl-2V- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide - 2. 45a. Methyl 4-pyridin-4-yl-benzoate dissolved '3.0 g (15 mmol) of 4-bromo-pyridine in 50 mL of dioxane and 15 mL of 2M sodium carbonate solution. 2.7 g (15 mmol) of 4-methoxycarbonylphenyl-boric acid and 1.73 g (2 mmol) of tetrakis- (triphenylphosphine) -palladium were successively added and the reaction was carried out. at reflux for 6 hours.- The hot reaction solution was filtered by suction through a glass fiber filter. The solvent was removed using the rotary evaporator and the purification was carried out by column chromatography on silica gel (dichloromethane / methanol 9: 1). Yield: 845 mg (26.4% of theory) C13H11 O2 (M = 213,238) Cale: molar peak (M + H) +: '214 Jan: molar peak (M + H) +: 214 HPLC retention time: 4.1 min ( method A) 244 2. 45b. 4-Pyridin-4-yl-benzoic acid In a 150 mg solution (0.70 mmol) of methyl 4-pyridin-4-yl-benzoate in 10 mL of ethanol 0.37 mL (0.74 mmol) of NaOH was added. 2 N. The reaction solution was stirred for 2 hours at S0 ° C and then the pH was adjusted to 6-7 with 1N HC1. After filtering the formed precipitate, it was dried under high vacuum overnight. Yield: 84 mg (60.0% of theory) C12H9N02 (M = 199.211) Cale: molar peak (M + H) +: 200 Jan: molar peak (M + H) +: 200 HPLC retention time: 2.5 min (method A ) 2. 45c. 4-pyridin-4-yl-I \ -T- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide · "Prepared according to the general working method I from 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (86 mg, 0.42 mmol) and methyl 4-pyridin-4-yl-benzoic acid (84 mg, 0.42 mmol). Yield: 65 mg (40.0% of theory) C25H27 3O (M = 385.513) Cale: molar peak. (M + H) +: 386 Jan.: molar peak (M + H) +: 386 HPLC retention time: 4.7 min (Stable Bond C18; 3.5 μp; water: acetonitrile: formic acid 91: 9: 0.01). 245 Example 2.46: 5- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one 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 hours at 45 °. C. The reaction solution was cooled overnight at room temperature and then the solvent was removed using the rotary evaporator. The residue was taken up in ether, filtered and the solvent was removed using the rotary evaporator. The residue was further reacted without purification. 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-methyl-benzoate are dissolved in 70 mL of dioxane and 7 mL of sodium hydroxide solution. 2M sodium carbonate. 1.07 g (6.83 mmol) of 4-chloro-phenyl-boronic acid and 0.40 g (0.34 mmol) of tetrakis- (triphenylphosphine) -palladium were successively added, the reaction was refluxed for 6 hours, and stirred for 10 minutes. - about 60 hours 246 additional at room temperature. The hot reaction solution was filtered by suction through a fiber filter. glass. The solvent was removed using the rotary evaporator. The residue was combined with water and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed using the rotary evaporator. The purification was carried out by column chromatography. on silica gel (petroleum ether / ethyl acetate 8: 2). Yield: 1.3 g (69.3% of theory) C16H15C102 (M = 274.750) Cale: molar peak (M + H) +: 275/277 Jan: molar peak (M + H) +: 275/277 Rf value: 0.67 (gel silica, petroleum ether / ethyl acetate 8: 2). 2. 46. Ethyl C 3-bromomethyl-4'-chloro-biphenyl-4-carboxylate In a solution of 1.3 g (4.73 mmoles) of ethyl 4'-chloro-3-methyl-biphenyl-4-carboxylate and 0.84 g ( 4.73 mmoles) of N-bromosuccinimide in 10 mL of carbon tetrachloride was added 78 mg (0.47 mmol) of 2,2'-azobis- (isobutyronitrile).
The reaction mixture was refluxed overnight.
After filtering the solvent, it was concentrated by evaporation in the rotary evaporator. Purification was carried out by column chromatography on silica gel (ether of -247 petroleum / ethyl acetate 8: 2). Yield: 1.6 g (62.1% of theory) C16H14BrCl02 (M = 353.646) Cale: molar peak (M + H) +: 353/355/357 Jan. : molar peak (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-l-one To a suspension of 800 mg (1.47 mmol) of ethyl 3-bromomethyl-4'-chloro-biphenyl-4-carboxylate and 508 mg (3.68 mmol) of potassium carbonate in 7.5 mL of acetonitrile were slowly added dropwise, at room temperature 375 mg (1.47 mmol). mmoles) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine. The reaction mixture was refluxed for 5 hours. After removing the solvent using the rotary evaporator, the residue was taken up in water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate. After removing the solvent using the rotary evaporator, the residue was dissolved in DMF and purified by HPLC chromatography (Stable Bond C18; 3.5 μt; water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 for 9 min). Yield: 82 mg (12.9% of theory) 248 C27H27C1N202 (M = 430,982) Cale: molar peak (M + H) +: 431/433 Jan .: molar peak (M + H) +: 431/433 HPLC retention time: 6.13 min (method A) Example 2.47: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- piperidin-1-ylmethyl-piperidine-1-carboxylic acid 2. 47.a 4-piperidin-1-ylmethyl-pyridine In a solution of 100 g (0.61 mol) of 4-chloromethylpyridine in 600 mL of dry methanol, 242 mL (2.44 moles) of piperidine were added dropwise and the mixture of The reaction was stirred for one hour at 50 ° C. The solvent was removed using the rotary evaporator. The residue was basified with 40% sodium hydroxide and the aqueous phase was extracted with ether. The organic phase was dried over sodium sulfate and after filtering over activated carbon, the solvent was removed using the rotary evaporator. The crude product was further reacted without purification. Yield: 106 g (98% of theory) 2. 47.b 4-piperidin-l-ylmethyl-piperidine 249 A solution of 106 g (0.6 mole) of 4-piperidin-1-ylmethyl-pyridine in 1.0 L of glacial acetic acid was combined with .7 g of platinum dioxide and stirred at room temperature and 3 bar of hydrogen in a autoclave After suction filtering the catalyst, the solvent was removed using the rotary evaporator. The crude product was also reacted without purification. Yield: 48 g (43.9% of theory) 2. 47.C [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- piperidin-1-ylmethyl-piperidine-1-carboxylic acid Prepared according to the general method of work 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 theory) C25H40N4O (M = 412.624) Cale: molar peak (M + H) +: 413 Ene !: molar peak (M + H) +: 413 HPLC retention time: 1.75- rain ( Stable Bond C18; 3.5 m; water: acetonitrile: formic acid 9: 1: 0.01 to 4: 6: 0.01 for 8 min).
Example 2.48: 250 2. 48.a; [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (lH-benzoimidazol-2-yl) -piperidine-l-carboxylic acid Prepared according to the general method of work II from 2-piperidin-4-yl-li-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 theory) Cale: molar peak (M + H) +: 432 Jan: molar peak (M + H) +: 432 HPLC retention time: 2.80 min (Stable Bond C18; 3.5μp? water: acetonitrile: formic acid 9: 1: 0.01 to 4: 6: 0.01 for 8 min).
Example 2.49: 4- (1-methyl-piperidin-4-yl) -N- [2 -. (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide - 2. 49.a methyl 4-piperidin-4-yl-benzoate 251 In 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 were added 4.0 mL of 1M hydrochloric acid and 200 mg of sodium oxide. platinum. The reaction mixture was stirred for 2 hours at room temperature and 3 bar of hydrogen. After 300 mg of platinum oxide and 6.0 mL of 1M hydrochloric acid were added, the mixture was stirred for an additional 16 hours at room temperature and 3 bar of hydrogen. After removing the catalyst, the solvent was removed using the rotary evaporator. The crude product was further reacted without purification. Yield: 589 mg (82.4% of theory) C13H17NO2 (M = 219.286) Cale: molar peak (M + H) +: 220 Jan: molar peak (+ H) +: 220 HPLC retention time: 3.5 min (method A) 2. 49.b Methyl 4- (l-methyl-piperidin-4-yl) -benzoate In a solution of 429 mg. (1.96 mmol) of methyl 4-piperidin-4-yl-benzoate in 10 mL of DMF were added in batchwise form under a nitrogen atmosphere at 0 ° C 48 mg (2.00 mmol) of sodium hydride. The reaction mixture was stirred for 11 hours at room temperature. 0.13 mL (2.10 mmol) of methyl iodide were added dropwise and the solution was stirred for two hours at room temperature. The reaction solution was combined with water, the aqueous phase was extracted with 252 ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was removed using the. rotary evaporator. Purification was carried out by column chromatography (silica gel, dichloromethane / methanol 8: 2). Yield: 70 mg (15.3% of theory) C14H19N02 (M = 233.313) Cale: molar peak (M + H) +: 234 Jan: molar peak (M + H) +: 234 HPLC retention time: 2.7 min (method A ) 2. 49.C 4- (1-methyl-piperidin-4-yl) -benzoic acid In a solution of 70 mg (0.30 mmol) of methyl 4- (1-methyl-piperidin-4-yl) -benzoate in 10 mL of ethanol were added 0.37 mL (0.74 mmol) of 2N NaOH. The reaction solution was stirred for 2 hours at 60 ° C and then adjusted to pH 6-7 using HC1 1N. After filtering the formed precipitate, it was dried under high vacuum overnight. Yield: 50 mg (76.0% of theory) C13H17N02 (M = 219.286) Cale: molar peak (M + H) +: 220 Ene .: molar peak (M + H) +: 220 HPLC retention time: 1.5 mi (method A) 2. 9. d 4- (l-methyl-piperidin-4-yl) -N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general working method 253 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 theory) C2sH35W30 (M = 405.588) - Calc .: molar peak (M + H) +: 406 Jan .: 'molar peak (M + H) +: 406 HPLC retention time: 2.4 min (method A) 1. 21.a Acid. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} 4'-chloro-biphenyl-4-carboxylicamide Prepared analogously to Example 1.1. i from 2- [s- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethylamine and acid 4'-chloro-biphenyl-4-carboxylic acid. Yield: 0.94 g (96% of theory) Melting point: 211-213 ° C C25H27C1 40 (M = 434.97) Cale: molar peak (M + H) +: 435/437 Jan: molar peak (M + H) + : 435/437 254.
Example 2.51: Acid. { 2- [4- (4-methyl-piperazine-1-carbonyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid 2. 51. a [4- (4-methyl-piperazin-1-carbonyl) -phenyl] -acetonitrile A solution. of '2 g (12.41' mmoles) of 4-cyanomethyl-benzoic acid, 1.25 g (12.5 mmoles) of N-methylpiperazine, 4.01 g (12.5 mmoles) of TBTU and 3.48 mL. (25 mmol) of triethylamine in 40 mL DMF was stirred for 12 hours at room temperature. The reaction mixture was then concentrated by evaporation in a small proportion and combined with water. This mixture was extracted with ethyl acetate and the solvent was removed by distillation using the rotary evaporator. The aqueous phase was also concentrated by evaporation and the organic phase was combined with the residue. Purification was carried out by column chromatography on silica gel (eluent: dichloromethane / ethanol / ammonia 30: 1: 0.1). Yield: 2.6 g (86% of theory) C14H17N30 (= 243.31): Cale: mole sting (M + H) +: 244 Jan: molar peak (M + H) +: 244 Value ¾: 0.35 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1). 255 2. 51.b [4- (2-Amino-ethyl) -phenyl] - (4-methyl-piperazin-1-yl) -me-anone Prepared analogously to Example 1.1. i from [4- (4-methyl-piperazin-1-carbonyl) -phenyl] -acetonitrile. Yield: 2.9 g (90% of theory) C14H2iN30 x HCl (= 283.80) Rf value: 0.25 (silica gel, dichloromethane / ethanol / ammonia 10: 1: 0.1). 2. 51. c (2- [4- (4-Methyl-piperazin-1-carbonyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work 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 theory) Melting point: 217-218 ° C C27H28C1N302 (M = 461.99) Cale: molar peak (M + H) +: 462/464 Jan: molar peak (M + H) +: 62/464 Rf value : 0.25 (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1).
Example 2.52: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-bromo-256 acid biphenyl-4-carboxylic acid 2. 52a. 4'-methyl biphenyl-4-carboxylate Dissolve 0.54 g. (2.5 mmoles) of methyl 4-bromo-benzoate in 10 mL-dioxane and 2.5 mL of 2M sodium carbonate solution. C. 0.6 g (3 mmol) of 4-bromophenyl-boronic acid and 0.12 g (0.1 mmol) of tetrakis- (triphenylphosphine) -palladium were successively added and the reaction was brought to reflux for 5 hours. The reaction mixture was combined with water and EtOAc, it was filtered and the phases separated. The aqueous phase was extracted with EtOAc · and the combined organic phases were dried over MgSO4. After removing the drying agent and the solvent, the residue was triturated with acetonitrile, filtered by suction and air dried. _. '' Yield: .100 mg (13.7% of theory) Ci4HnBr02 (= 291.15). Cale: peak .molar (M + H) +: 291/293 Jan: molar peak (M + H) +: 291/293 Value Rf; 0.68 (silica gel, petroleum ether / EtOAc 8: 2). 2. 52b. 4'-bromo-biphenyl-4-carboxylic acid A solution of 100 mg (0.34 mmol) 'of' -bromo-257 Methyl biphenyl-4-carboxylate in 3 mL of THF was combined with 3 mL of a 1M solution of NaOH in water and refluxed for 3 hours. The reaction mixture was concentrated by evaporation in vacuo, the aqueous residue was acidified with 1M HC1, the precipitated product was filtered off and air dried. Yield: 60 mg (63.1% of theory) CI3H9Br02 (M = 277.19) Cale: molar peak (MH) ": 275/277 Jan '.: molar peak (MH)": 275/277 HPLC retention time: 8.48 min ( method A) 2. 52.C [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-bromo-biphenyl-4-carb. Xylic acid Prepared according to the general method of work I from 45 mg. (0.22 mmol) of 2- (4-pyrrolidin-1-ylmethyl-1-phenyl) -ethylamine and 60 mg (0.22 mmol) of β-bromo-biphenyl-4-carboxylic acid. Yield: 28 mg (27.5% of theory) C26H27BrN20 (M = 463.42) Cale: molar peak (M + H) +: 463/465 Jan .: molar peak (M + H) +: 463/465 | _ '- · "'HPLC retention time: 6.46 min (method A) Example 2.53: 258 [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-ethyl-biphenyl-4-carboxylic acid Prepared according to general working method I from 102 mg (0.5 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 113 mg (0.5 mmol) of 4'-ethyl acid -biphenyl-4-carboxylic (Lancaster). Yield: 65 mg (31.5% of theory) C28H32N20 (M = 412.58) Cale: molar peak (M + H) +: 463 Jan .: molar peak (M + H) +: 463 HPLC retention time: 6.64 min ( method A) Example 2.54: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide biphenyl-4-carboxylic acid | Prepared according to the general method of work 259 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 theory) C26H28W20 (M = 384.53) Cale: molar peak (M + H) V 385 Jan .: molar peak (M + H) +: 385 HPLC retention time: 5.70 min (method TO) Example 2.55: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-fluoro-biphenyl-4-carboxylic acid 2. 55a. 4'-Fluoro-biphenyl-4-carboxylic acid 14.27 g (71 mmol) of 4-bromobenzoic acid are dissolved in 1.20 mL of dioxane and 70 mL of 2M Na2C03 solution. 10 g (71 mmol) were successively added. of 4-fluorophenyl-boronic acid and 4.1 g (4 mmol) of tetrakis- (triphenylphosphine) -palladium and the reaction was refluxed for 6 hours. The catalyst was filtered off with suction and washed with hot water. The reaction mixture was combined with EtOAc, the phases were separated and the aqueous phase was acidified with citric acid. The formed precipitate was filtered by suction, washed 260 with water and dried under vacuum at 45 ° C. . Yield: 4.9 g (31.9% of theory) C13H9F02 (M = 216.21). "" Cale: molar peak (MH) ~: 215 Ene .: molar peak (MH) ": 215 - - 2.55b. Acid [2- ( 4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-fluoro-biphenyl-4-carboxylic acid Prepared according to the general method of work 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 theory) C26H27F 2O (M = 402.52) Cale: molar peak (M + H] +: 403 Jan: molar peak (M + H) +: 403 HPLC retention time: 5.83 min ( method A) Example 2.56: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-hydroxy-3'-nitro-biphenyl-4-carboxylic acid general work 261 I from .102 mg (0.5 mmol) of 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethylamine and 130 mg (0.5 mmol) of 4 '-fluoro-3' -nitro biphenyl-4-carboxylic acid . Yield: 9 mg (4.0% of theory) C26H27N304 (M = 445.52) Cale: molar peak (M + H) +: 446 Jan. :. ico molar (M + H) +: 446 HPLC retention time: 5.83 min (method A) Example 2.57: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3'-chloro biphenyl-4-carboxylic acid 2. 57a. 3'-Chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.55a a. from 9.64 g (47.96 mmoles) of 4-bromo-benzoic acid and 7.5 g (47.96 mmoles) of 3-chlorophenyl-boric acid. Yield: 6.2 g (55.6% of theory) C13H9C102 (M = 232.67) Cale: molar peak (M-H) ": 231/233 Jan .: molar peak (-H)": 231/233. 2. 57b. Acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3'- 262 chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work 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 theory) C26¾7C1N20 (M = 418.97) Cale: molar peak (M + H) +: 419/421 Jan .:, molar peak (M + H) +: 419/421 |. . -. HPLC retention time: 6.20 min (method A) Example 2.58: • Acid - [2- (4-p.yrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3 ', 4'-dichloro-biphenyl-4-carboxylic acid 2. 58a. 3 ', 4'-Dichloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.55a from 5.27 g (26.20 mmoles) of 4-bromo-benzoic acid and 5.0 g (26.20 mmoles) of 3 ', 4'-dichloro-phenylboronic acid. Yield: 4.05 g (57.9% of theory) Cale. : molar peak (M-H) ~: 265/267/269 Jan.: molar peak (M-H) ": 263 265/267/269 2. 58b. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3 ', 4'-dichloro-biphenyl-4-carboxylic acid Prepared according to general working method 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 acid. Yield: 45 mg (19.8% of theory) C2sH2sCl2 20 (M = 453.42) Cale: molar peak (M + H) +: 453/455/457 Jan: molar peak (M + H) +: 453/455/457 Time HPLC retention: 6.45 min (method A) Example 2.59: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2'4'-dichloro-biphenyl-4-carboxylic acid 2. 59a. 2 ', 4'-Dichloro-biphenyl-4-carboxylic acid Prepared in a manner. Analogous to Example 2.55a from 5.23 g (26.0 mmoles) of 4-bromo-benzoic acid and 10.0 g (52.0 mmoles) of 2,4-dichlorophenyl-boronic acid, refluxing the reaction mixture for 48 hours. 264 Yield: 1.5 g (21.6% of theory) C13H8C1202 (M = 267.11) Cale: molar peak (M-H) ": 265/267/269 Jan .: molar peak (M-H)": 265/267/269 ' 2. 59b. [2- (4-pyrroiidi-l-ylmethyl-phenyl) -ethyl] -amide 2 ',' -dichloro-biphenyl-4-carboxylic acid Prepared according to the general blocking method or 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 acid. Yield: 72 mg (31.8% of theory) C26H26Cl2N20 (M = 453.42) Cale: molar peak (M + E) +: 453/455/457 Jan .: molar peak (M + H) +: 453/455/457 HPLC retention time: 6.84 min (method A) Example 2.60: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid 2. 60a. 2'-Fluoro-4-chloro-biphenyl-4-carboxylic acid 265 Prepared - analogously to Example 2.55a from 0.52 g (2.5 mmol) of l-bromo-4-chloro-2-fluorobenzene and 0.5 g (3.0 mmol) of 4-carboxyphenyl-boric acid. Yield: 0.5 g (79.8% of theory) C13HaClF02 (M = 250.66) Calc .: molar peak (MH) ~: 249/251 Jan .: molar peak (MH) ": 249/251" 'HPLC retention time: 8.39 min- (method A) 2. 60b. [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general working method, starting 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 acid. Yield: 36 mg (16.5% of theory) C26H2SC1FN20 (M = 436.96), Cale .: molar peak (M + H) +: 437/439 Jan .: 'molar peak (M + H) +: 437/439 HPLC retention: 6.32 min (method A) Example 2.61: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3,4'-dichloro-biphenyl-4-carboxylic acid 266 2. 61a. 3, 4'-Dichloro-biphenyl-4-carboxylic acid Prepared 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 acid -chlorophenyl-boric .. Yield: 0.55 g (82.4% of theory) C13H8C1202 (M = 267.11) Cale: molar peak (? -? G ·: 265/267/269 Jan .: molar peak (MH) ": 265 / 267/269: HPLC retention time: 8.83 min (method A) 2. 61b. Acid - [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3,4 '-dichloro-biphenyl-4-carboxylic acid Prepared according to general working method 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 acid. Yield: 24 mg (10.6% of theory) C26H26C12N20 (M = 453.42) Cale: molar peak (M + H) +: 453/455/457 Jan: molar peak (M + H) +: 453/455/457 HPLC retention: 6.41 min (method A) 267 Example 2.62: [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid. "· | -. · 2. 62a. Β-Chloro-3-fluoro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.55a from 0.55 g (2.5 mmoles) of 4-bromo-2-fluoro-benzoic acid and 0.47 g (3.0 mmoles) of acid 4-chlorophenyl-boric. Yield: 0.60. g (95.7% of theory) C13H8C1F02 (M = 250.66) Cale: molar peak (M-H) ": 249/251 Jan .: molar peak (M-H) ~: 249/251 HPLC retention time: 8.22 min" (method A) 2. 62b. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -et-yl] -amide 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid Prepared in accordance with the general method of work I from 102 mg (0.5 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 125 mg (0.5 mmol) of 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid. Yield: 37 mg (16.9% of theory) C26H26C1F 20 (M = 436: 96) 268 Cale: molar peak (M + H) +: 437/439 Jan: molar peak (M + H) +: 437/439 HPLC retention time: 6.45 min (method A) Example 2.63: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro- 2. 63a. 4'-Chloro-2-fluoro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.55a 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 theory) Ci3H8ClF02 (M = 250.66) Cale: molar peak (? -? G: 249/251 Jan ': molar peak (MH) -: 249 / 251 HPLC retention time: 8.50 min (method A) 2. 63b. [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid Prepared according to general working method I from 163 mg ( 0.8 mmol) of 2- (4-pyrrolidin-1-ylmethyl-269) phenyl) -ethylamine and 201 mg (0.8 tnmol) of 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid. Yield: 74 mg (21.2% of theory) Cale: molar peak (M + H) +: 437/439 Jan .: -molar peak (M + H) +: 437/439 'HPLC retention time: 6.61 min (method TO) Example 2.64: [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 3-nitro-biphenyl-4-carboxylic acid 2. 64a. 3-Nitro-biphenyl-4-carboxylic acid In a solution of 1.0 g (4.07 mmol) of 4-bromo-2-nitro-benzoic acid in 20 mL of toluene was added 150 mg (0.13 mmol) of tetrakis- (triphenylphosphine) - palladium and stirred for 10 min at room temperature. Then a solution of 0.5 g (4.10 mmol) of phenylboric acid in 10 mL of MeOH and a solution of 1.0 g of Na2CO3 in 10 mL of water was added. The reaction mixture was refluxed for 5 hours and stirred over the weekend at room temperature. The solvents were removed in vacuo, the residue was combined with 270 ' Water, acidified with concentrated HCl, extracted with EtOAc, the organic phase was dried over Na2SO4 and then the solvent was removed. . . Yield: 0.87 g (87.5% of theory) Rf value: 0.40; (silica gel, dichloromethane / ethanol 3: 1). 2. 64b. Acid - [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3-nitro-biphenyl-4-carboxylic acid. Prepared in accordance with the general method of work l starting. of 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 theory). Calc: molar peak (M + H) +: 430 Jan: molar peak (M + H) +: 430 HPLC retention time: 5.83 min (method A) phenyl) -ethyl] -amide 5- (4-chloro- 5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid 271 Prepared 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-boric acid. Yield: 0.23 g (39.4% of theory) -C12H8C1N02 (M = 233.66) Cale: molar peak (-H) ": 232/234 Jan: molar peak (MH)": 232/234 | -: HPLC retention time : 5.89 rain (method A) 2. 65b. [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 5- (4-chloro-phenyl) -pyridine-2-carboxylic acid Prepared according to the general method of work 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 acid . Yield: 7 mg (3.3% of theory) C25H26C1N30 (M = 419.96) Cale: molar peak (M + H) +: 420/422"Jan.: molar peak (M + H) +: 420/422 HPLC retention time : 6.40 min (method A) Example 2.66: iST- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -4-thiophen-3-yl-benzamide 272 2. 66a. Ethyl 4-thiophene-3-yl benzoate Prepared - analogously to Example 2.46a from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophene-3-boric acid . Yield: 348 mg (100% of theory) Ci3H1202S (M = 232.30) Cale: molar peak (? +?) +: · 233 Jan .: molar peak (M + H) +: 233 HPLC retention time: 6.20 min (method B) 2. 66b. 4-Thiophene-3-yl-benzoic acid Prepared analogously to Example 2.7b from 280 mg (1.5 mmol) of ethyl 4-thiophen-3-yl-benzoate. Yield: 146 mg (59.3% of theory) - CnHgOaS (M = 204.25) Cale: molar peak (M-H) ~: 203 Jan: molar peak (M-H) ~: 203 HPLC retention time: 7.60 min (method A) 2. 66c. N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -4-thiophen-3-yl-benzamide · · Prepared according to general working method I from.102 mg (0.5 mmol) ) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 102 mg (0.5 mmol) of .4-thiophene-3-yl-273 acid benzoic. Yield: 103 mg (53.0% of theory) C24¾sN20S (M = 390.55) Cale: molar peak (M + H] +: 391 Jan .: molar peak (M + H) +: 391 HPLC retention time: 6.10.min ( method A) Example 2.67: N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -4-thiophen-2-yl-benzamide 2. 67a. Ethyl 4-thiophen-2-yl-benzoate Prepared in a manner analogous to Example 2.46a from 414 mg (1.5 mmol) ethyl 4-iodobenzoate ethyl ester and 230 mg (1.8 mmol) thiophenic acid -2- boric. Yield: 348 mg (100% of theory) Ci3Hi202S (M = 232.30) Cale: molar peak. (M + H) +: 233 Jan: molar peak (M + H) +: 233 HPLC retention time: 6.29 min (method B) 2. 67b. 4-Thiophene-2-ylbenzoic acid Prepared analogously to Example 2.7b from 280 mg (1.5 mmol) of ethyl 4-thiophen-2-yl-benzoate. 274 Yield: 126 mg (51.2% of theory) CnH802S (= 204.25) Cale.:, molar peak (M-H) ": 203 Jan .: molar peak (M-H) ~: 203 HPLC retention time: 7.60 min (method A) 2. 67c. N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -4-thiophen-2-yl-benzamide Prepared according to the general method of work 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 theory) C24H2SN20S (M = 390.55) Cale: molar peak (M + H) +: 391 Jan .: molar peak (M + H) +: 391 HPLC retention time: 6.05 min (method TO) Example 2.68: 4- (5-Chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2. 68a. 4- (5-Chloro-thiophen-2-yl) -benzoic acid 275 Prepared analogously to Example 2.55a from 300 mg (1.52 mmoles) of 2-bromo-5-chlorothiophene and 277 mg (1.67 mmoles) of 4-carboxyphenylboronic acid, using a KHS04 solution to acidify the reaction mixture elaborated Yield: 76 mg (21.0% of theory) CnH7Cl02S (M = 238.69) - '' Cale: molar peak (MH) ~: 237/239 Jan: molar peak (-H) ~: 237/239 HPLC retention time:. 8.75 min (method A) 2. 68b. 4- (5-Chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Prepared in accordance, with the general working method starting from mg (0.3 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 71 mg (0.3 mmol) of 4- (5-chloro-thiophen-2-yl) -benzoic acid .. Yield: - 29 mg (22.9% of theory) -C24H25Cl 2OS (M =, 425.0) Cale: molar peak (M + H) +:, 425/427 Jan: molar peak (M + H) +: 425/427 Retention time HPLC: 6.65 min (method A) Example 2.69: 4-furan-2-yl-N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] - 276 benzamide 2. 69a. Acid ~ furan-2-yl-benzoic Prepared analogously to Example 2.68a from 302 mg (1.5 mmoles) of 4-bromo-benzoic acid and 201 'mg (1.8 mmoles) of furan-2-boronic acid. Yield: .166 mg (58.8% of theory) C1: H803 (M = 188.19) Cale: molar peak (MH) ": 187 Jan .: molar peak (MH)": 187 HPLC retention time: 6.82 min (method. TO) 2. 69b. 4-furan-2-yl-N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to general working method 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 theory) C24H26N2O2 (M = 374.49) Cale: molar peak (M + H) +: 375 Jan: molar peak (M + H) +: 375 HPLC retention time: 6.48 min (method A ) Example 2.70: 277 4- (5-methyl-pyridin-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide | 2. 70a. 4- (5-Methyl-pyridin-2-yl) -benzoic acid Prepared analogously to Example 2.55a from 430 mg (2.50 mmoles) of 2-bromo-5-methylpyridine and 498 mg (3.00 mmoles) of acid -carboxyphenyl-boric. Yield: 300 mg (56.3% of theory) CisHuNOa (M = 213.24) Cale: molar peak (M + H) +: 214 Jan .: molar peak (M + H) +: 214 HPLC retention time: 4.55 min (method TO) 2. 70b. 4- (5-Methyl-pyridin-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general method of work 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 theory) C2eH29N30 (M = 399.54) Calc .: molar peak (M + H) +: 400, Jan .: molar peak (M + H) +: 400 HPLC retention time: 3.98 'min (method A) 278 Example 2.71: 4- (6-Methyl-pyridin-3-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2. 71a. 4- (6-Methyl-pyridin-3-yl) -benzoic acid. Prepared analogously to Example 2.55a from 430 mg (2.50 mmol) of 5-bromo-2-methylpyridine and 498 mg (3.00 mmoles) of 4-carboxyphenyl-boric acid. Yield: 300 mg (56.3% of theory) C13H11NO2 (M = 213.24). . Cale: molar peak (M + H) +: 214 Jan: molar peak (M + H) +:. 214 HPLC retention time: 2.66 min (method A) 2. 71b. 4- (6-methyl-pyridin-3-yl) -N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general method of work 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 theory) C26H29 3O. (M = 399.54) | • 279 Cale: molar peak (M + H) +: 400 Jan: molar peak (+ H) +: 400 HPLC retention time: 3.06 min (method A) Example 2.72: [2- (4-Pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -thiophene-2-carboxylic acid 2. 72a. Methyl 4- (4-chloro-phenyl) -thiophene-2-carboxylate Dissolve 420 mg (1.25 mmol) of methyl 4-bromo-thiophene-2-carboxylate in 10 mL of dioxane and 5 mL of 2M solution of Na2C03. 196 mg (0.06 mmol) of 4-chloro-phenyl-boronic acid and 72 mg (0.06 mmol) of tetrakis- (triphenylphosphine) -palladium were successively added, the reaction was refluxed for 6 hours and stirred for a few hours. 60 additional hours at room temperature. After heating again, the hot reaction solution was filtered by suction through a glass fiber filter, washed with dioxane, combined with solution. NaHC03 was semisaturated and extracted with EtOAc. The combined organic phases were dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 9: 1). Yield: 150 mg (47.3% of theory) 280 C12¾C102S (M = 252; 72) Cale: molar peak (+?) +: 253/255 Jan .: molar peak (M + H) +: 253/255 - HPLC retention time: 6.21 min (method B) | - 2.72b. 4- (4-Chloro-phenyl) -thiophene-2-carboxylic acid In a solution of 150 mg of 4- (4-chloro-phenyl) -thiophene-2-carboxylic acid methyl ester in 10 mL of EtOH, 2 mL of 1M solution of .NaOH and the reaction solution was stirred over the weekend at room temperature. The solvent was concentrated by vacuum evaporationThe residue was combined with 2 mL of 1N hydrochloric acid and cooled to 0 ° C. The precipitated product was filtered by suction, washed with water and dried at 50 ° C. Yield: 140 mg (98.7% of theory) CHH7CIO2S (M = 238.69) Cale: molar peak (M + H) +: 239/241 Jan .: molar peak (+ H) +: 239/241 _ 'HPLC retention time : 8.31 min (method A) 2. 72c. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) -thiophene-2-carboxylic acid Prepared according to general working method I from 144 mg (0.70 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine 140 mg (0.59 mmol) of 4- (4-chloro-281 acid) phenyl) -thiophene-2-carboxylic acid. Yield: 78 mg (31.3% of theory) C26H23N30 (M = .425.00). - ": Cale: molar peak (M + H) +: 425/427 Jan: molar peak (M + H) 425/427 HPLC retention time: 3.90 min (method A) ? j 2.73: 4- (5-acetyl-thiophen-2-yl) -N -. [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide 2. 73a. 4-iodo-N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to general working method 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 theory) C20H23IN20 (M = 434.32) Cale: molar peak (M + H) '+: 435 Jan: molar peak (M + H) +: 435 HPLC retention time: 5.40. min (method A) 282 2. 73b. 4- (5-acetyl-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Prepared analogously to Example 2.46a from 250 mg (0.58 mmol) of 4-iodo-N- [2 - (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide and 118 mg (0.69 mmol) of 5-acetyl-2-thiophene-boronic acid. refluxing the reaction mixture for 15 hours. Yield: 50 mg (20.2% of theory) C26H28N202S (M = 432.59) Cale: molar peak (M + H) +: 433 Jan: molar peak (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 Prepared analogously to Example 2.46b from 250 mg (0.58 mmol) 'of 4-iodo-N- [2 ~ (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide. and 107 mg (0.69 mmol) of 5-formyl-2-thiophene-boronic acid, refluxing the reaction mixture for 15 hours. Yield: 22 mg (9.1% of theory) 283 C25H26N202S (M = 418.56), Cale: molar peak (M + H) +: 419 Jan: molar peak (M + H) +: 419 Retention time, HPLC: 3.82 min (method B) Example 2.75: [2- (4-Aminomethyl-phenyl) -ethyl] -amide '-chloro-biphenyl-carboxylic acid 2. 75a. 4- . { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} - ethyl benzoate In 9.31 g '(40 mmoles) of 4'-chloro-biphenyl-4-carboxylic acid, 20 mL of thionyl chloride and 1 mL of DMF were added dropwise The reaction mixture was heated for 2 hours at 60 ° C. Then the excess thionyl chloride was removed in vacuo at 50 ° C. and the residue was taken up in 200 ml of C¾C12.This solution was added dropwise to 9.19 g (40 mmol) of 4- (2-amino-ethyl). ) -ethylbenzoate, used as the hydrochloride, in 100 mL of 10% aqueous Na2CO3 solution and the reaction mixture was stirred for an additional hour at room temperature After adding water and CH2C12, the organic phase was separated, the aqueous phase was extracted with CH2C12, the combined organic phases were washed with semi-saturated solution of 284 NaHCO3 and water and dried over MgSO4. After removing the drying agent, the solution was filtered over activated carbon, concentrated by evaporation in vacuo, and the residue was recrystallized from tert-butylmethyl ether. Yield: 11.93 g (73.1% of theory) Cale: molar peak (M + H) +: 408 Jan .: molar peak (M + H) +: 408 HPLC retention time :. 9.8 min (method?) 2. 75b. 4- Acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic In a solution of 11.93 g (29.25 mmoles) of 4-. { 2- t ('-chloro-biphenyl-4-carbonyl) -amino] -ethyl} ethylbenzoate. In 150 mL of EtOH, 50 mL of 2M NaOH solution was added and stirred for 2 hours at room temperature. The. The reaction solution was adjusted to pH 6-7 with 1N HCl solution, the product was filtered off. precipitated and dried in the vacuum oven. _ Yield: 10.74 g (96.7% of theory) C22H1BC1N03 (M = 379.85) Cale: molar peak (M + H) +: .380 / 382 -Ene: molar peak (M + H) +: 380/382 Retention time HPLC: 8.0 min (method A) 2. 75c. [2- (4-Hydroxymethyl-phenyl) -ethyl] -amide 4'-chloro-285 acid biphenyl-4-carboxylic acid In a solution of 10.74 g (28.28 min.) of acid 4-. { 2- [(4'-chloro-biphenyl -carbonyl) -amino] -ethyl} -benzoic acid in 150 mL of dry THF 4.82 g (29.69 mmoles) of CDI were added and the reaction mixture was heated for 2 hours at 50 ° C. This solution was added in a suspension of 2.14 g (56.56 mmoles) of NaBH4 in 5 mL of water and. stirred vigorously for an additional hour at room temperature Using 1N HC1, the pH of the solution was adjusted to 6, then combined with EtOAc and filtered The filtrate was washed with a half-saturated solution of NaHCO3 and water and dried on MgSO4 After removing the drying agent and the solvent, as the residue still contains 4- {2- [4 '-chloro-biphenyl-4-carbonyl) -amino] -ethyl} acid. Unreacted benzoic acid, the previous reduction step is repeated The product obtained was dried at 40 ° C. Yield: 9.3 g (89.9% of theory) C22H20ClNO2 (M = 365.86) * Cale: molar peak (M + H) +: 366/368 Jan. ': molar peak (M + H) +: 366/368 HPLC retention time: 8.11 min (method A) 2. 75d. Acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid | In a solution of 7.9 g (21.59 mmol) of [2- (4-hydroxymethyl-phenyl)] -ethyl] -amide - 4'-chloro-biphenyl-4- 286 carboxyl in 300 mL of CH2Cl2 1.22 mL of PBr3 were added dropwise. The reaction mixture was stirred overnight at room temperature. The formed precipitate was filtered by suction and the filtrate was concentrated by evaporation. The residue was triturated with a little acetonitrile and CH2C12, filtered by suction, se. combined with the precipitate obtained first and dried in air. Yield: 8.6 g (92.9% of theory) C22Hi9BrClNO (M = 428.76) Cale: molar peak (M + H) +: 428/430/432 Jan.: molar peak (M + H) +: 428/430/432 - Value 'Rf: 0.40 (silica gel, CH2C12). 2. 75e. [2- (4-Aminomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid In a solution of 150 mg (0.35 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] acid ] -amide 4'-chloro-biphenyl-carboxylic acid in 10 mL of acetonitrile was added 3 mL of a 0.5 M solution of NH3 in dioxane and stirred for 3 days at room temperature. The reaction mixture was concentrated by evaporation and the residue was purified by chromatography, column (silica gel, CH2Cl2 / MeOH / NH3 9: 1: 0.1). Yield: 8 mg (6.3% of theory) Cale: molar peak (M + H) +: 365/367 Jan: molar peak (M + H) +: 287 365/367 HPLC retention time: 5.97 min (method A) Example 2.76: Acid (2- { 4- [(diisopropylamino) -methyl] ~ phenyl} -ethyl) -amide 4'-chloro-biphenyl-4-carboxylic acid In a suspension of 129 mg (0.3 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid and 55 mg (0.4 mmol) of K2C03 in 20 mL of acetonitrile 47 μ were added ?? (0.33 mmol) of diisopropylamine and the reaction mixture was stirred overnight at room temperature. - Diluted with CH2C12, filtered to remove insoluble inorganic salts and the. The filtrate was concentrated by evaporation. The residue was triturated with acetonitrile, filtered by suction and air dried. · Yield: 75 mg (55.7% of theory) C28H33C1N20 (M = .449.04) Cale: molar peak (M + H) +: 449/451 Jan: molar peak (M + H) +: 449/451 Value f: 0.35 (silica gel, CH2Cl2 / MeOH / NH3 95: 5: 0.5). 288 ethyl) -phenyl] -ethyl} -amide 4'- ·. | - | Prepared analogously. to Example 2.76 from 129. mg (0.3 ramol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid and 33 mg' (0.33 mmol) of piperazine- 2-one. Yield: 23 mg (17.1% of theory) C26H26C1N302 (M = 447.97) Cale: molar peak (M + H) +: 448/450 Jan: molar peak (M + H) +: 448/450 Rf value: 0.10 (gel silica, CH2Cl2 / MeOH / NH3 95: 5: 0.5).
Example 2.78: _ [(4- {2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -methyl-amino] -acetic acid ethyl ester Prepared analogously to Example 2 76 a part 289 257 mg (0.6 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid, 193 mg of K2C03 and 101 mg (0.66 mmol) of ester. Ethyl methylamino ethyl acetate (used as hydrochloride). Yield :, 152 mg (54.5% of theory) C27H2CNN203 (M = 465.0) Cale: molar peak (M + H) '+: 465/467 Jan: molar peak (M + H) +: 465/467 Value R ¿: 0.40 (silica gel, CH2Cl2 / MeOH / NH3 95: 5: 0.5).
Example 2.79: Acid. [(4- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} - benzyl) -methyl-amino] -acetic ' In a solution of 80 mg (0.17 mmol) of [(4- {2- ({(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -methyl-amino ] - ethyl acetate in 3 mL of EtOH 0.3 mL of 1M NaOH solution was added and refluxed for 1 hour. The solvent was concentrated by evaporation in vacuo and the residue was combined with water and 0.3 mL of 1M HCl. The precipitate was filtered by suction and dried at 40 ° C. Yield: 76 mg (100% of theory) 290 C2SH25 IN2O3 (M = 436.94) Cale: molar peak (M + H) +: '437/439 Jan: molar peak (M + H) +: 437/439 HPLC retention time: 6.35 min (method A) E p 2.80: Acid. { 2- [4- (4-acetyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.76 from 129 mg (0.3 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid and 42 mg (0.33 mmol) of 1 - piperazin-1-yl-ethanone. Yield: 60. mg (42.0% of theory) C28H3oClN302 (M = 476.02) Cale: molar peak (M + H) +: 476/478 Jan: molar peak (M + H) +: 476/478 Rf value: 0.15 (silica gel, CH2Cl2 / MeOH / N¾ 95: 5: 0.5).
Example 2.81: Acid. { 2- [4- (2-aza-bicyclo [2.2.1] hept-5-en-2-ylmethyl) -phenyl] -ethyl} ~ 4'-chloro-biphenyl-4-carboxylic acid amide 291 Prepared analogously to Example 2.76 from 129 mg (0.3 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid and 31 mg (0.33 mmol) of 2-azabicyclo [2 .. 2.1] hept-5-ene. Yield: 100 mg (75.2% of theory) Cale: molar peak (M + H) +: 443/445 Jan .: molar peak (M + H) +: 443/445 Rf value: 0.08 (silica gel, CH2Cl2 / MeOH / NH3 95: 5: 0.5).
Example 2.82: Acid. { 2- [4- (1, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.76 from 129 mg (0.3 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid, 97 mg of K2C03 and 51 mg (0.33 mg). mmol) of 2,3-dihydro-lH-isoindol (used as hydrochloride). Yield: 80 mg (57.1% of theory) 292 C3oH27ClN20 (M = 467.02) Cale: molar peak (? +?) +: 467/469 Jan: molar peak (M + H) +: 467/469 Rf value: 0.40 (silica gel, CH2Cl2 / MeOH / N¾ 95: 5: 0.5).
Example 2.83: Acid. { 2- [4- (7-methyl-2,7-diaza-spiro [4.4] ??? - 2-ylmethyl) -phenyl]. Ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.76 from 129 mg (? '3' mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid and 46 mg (0.33 g) mmol) of 2-methyl-2,7-diaza-spiro [4.4] nonane. Yield: 42 mg (28.7% of theory) C30H34CIN3O (M = 488.08) Cale: molar peak (M + H) +: 488/490 Jan: molar peak (M + H) +: 488/490 Rf value: 0.05 (gel silica, CH2Cl2 / MeOH / N¾ 95: 5: 0.5).
Example 2.84: Acid. { 2- [4- (3-diethylamino-azetidin-1-ylmethyl) -phenyl] -ethyl} - 4'-chloro-biphenyl-4-carboxylic amide 293 Prepared analogously to Example 2.76 from 129 mg (0.3 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid (138 mg of K2CO3 and 66 mg (0.33 mmol) of azetidin-3 - il-diethyl-amine · (used as bis-hydrochloride), the product was purified by column chromatography Yield: 15 mg (10.5% of theory) C29H34C1N30 (M = 476.07) Cale: molar peak (M + H) +: 476/478 Jan: molar peak (M + H) +: 476/478 Rf value: 0.10 (silica gel, CH2Cl2 / MeOH / NH3 95: 5: 0.1).
Example 2.85: (S) -l- (4- { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl] -benzyl) -pyrrolidin-2-carboxylic acid ethyl ester Prepared analogously to Example 2.76 from 294 257 mg (0.6 mmol) of [2- (-brommethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid, 193 mg of 2C03 and 119 mg (0.66 mmol) of (S) -pyrrolidin -2-ethyl carboxylate (used as the hydrochloride); the product was purified by column chromatography. Yield: 160 mg (54.3% of theory) C29H31C1N203 (M = 491.04). Cale: molar peak (M + H) +: 491/493 Jan: molar peak (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) -araino] -ethyl} -benzyl) -pyrrolidine-2-carboxylic acid Prepared analogously to Example 2.79 from 130 mg (0.27 mmol) of (S) -1- (4- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-2-carboxylate | ethyl. Yield: 120 mg (97.8% of theory) C27H27C1N203 (M = 462.98) .. Cale: molar peak (M + H) +: 463/465 Jan.: molar peak (M + H) +: 295 463/465. HPLC retention time: 6.20. min (method A) Example 2.87: [1- (4- { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl] -benzyl) -pyrrolidin-3-yl] -carbaminate of ter . butyl Prepared analogously to Example 2.76 from 429 mg (1.0 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide-4'-chloro-biphenyl-4-carboxylic acid and 205 mg (1.10 mmol) of pyrrolidin-3-l-carbaminate of ter. butyl. Yield: 500 mg (93.6% of theory) Cale: molar peak (M + H) +: 534/536 Jan: molar peak (M + H) +: 534/536 Value f: 0.33 (silica gel, C¾Cl2 / MeOH / NH3 95: 5: 0.5). ' 'Example 2.88: Acid. { 2- [4- (3-Amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid 296 In a solution of 500 mg (0.94 mmol) of [l- (4- {2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-3 -il] -carbaminate of ter. Butyl in 15 mL of CH2C12 was added 1 mL of trifluoroacetic acid and the reaction mixture was stirred overnight. It was then concentrated by evaporation, the residue was taken up in a little CH2C12 and combined with semi-saturated solution of NaHCO3. The precipitated product was filtered by suction, triturated with acetonitrile and dried at 40 ° C. Yield: 240 mg (59.1% of theory) C2SH28C1N30 (M = 433.99) Cale. : molar peak (M + H) +: 434/436 Jan.: molar peak (M + H) +: 434/436 Rf value: 0.22 (silica gel, C¾Cl2 / MeOH / NH3 9: 1: 0.1).
Example 2.33: Acid. { 2- [4- (3-dimethylamino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid In a solution of 60 mg (0.14 mmol) of acid. { 2- [4- 297 (3-Amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid in 5 mL of acetonitrile 0.12 ml of 37% formaldehyde aqueous solution, 28 mg (0.45 mmol) of NaB¾CN and one drop of glacial acetic acid were added. The reaction mixture was stirred overnight at room temperature and then combined with dilute NaOH-EtOAc solution. The phases were separated, the organic phase was dried over MgSO4 and then freed of the drying agent and the solvent. The residue was purified by column chromatography. Yield: 10 mg (15.7% of theory) C28H32CIN3O (M = 462.04) Cale: molar peak (M + H) +: 462/464 Jan: molar peak (M + H) +: 462/464 HPLC retention time: 5.16 min (method A) 'Example 2.90: [1- (4- { 2- [(' -chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-2-ylmethyl ] -carbaminate of ter. butyl 298 Prepared analogously to Example 2.76 from 230 mg (0.54 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid and 116 mg (1.10 mmol) of pyrrolidin-2-ylmethyl-carbamatete from ter. butyl. Yield: 230 mg (78.3% of theory) 032? 3801? 3? 3 (M = 548.13) Cale: peak .molar (M + H) +: 548/550 Jan: molar peak (M + H) +: 548 / 550 Rf Value: 0.35 (silica gel, CH2Cl2 / MeOH / NH3 95: 5: 0.5). . 'Example 2.91: Acid. { 2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} - 4'-chloro-biphenyl-4-carboxylic amide Prepared analogously to Example 2.88 from 230 mg (0.42 mmol) of [1- (4- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-2-ylmethyl] -carbaminate of ter. I use Yield: 188 mg (100% of theory) Cale. : molar peak (M + E + ^ 448/450 Jan.: molar peak (M + H) +: 299 448/450 Rf value: 0.35 (silica gel, CH2Cl2 / MeOH / NH3 9: 1: 0.1) Example 2.92: Acid. { 2- [4- (2-dimethylaminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid Example 2.89. From 40 mg (0.09 mmol) of acid. { 2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide '-chloro-biphenyl-4-carboxylic acid, 0. 08 mL of 37% aqueous solution of formaldehyde and 19 mg (0.30 mmol) of NaBH3CN. Yield: 10 mg (23.6% of theory) Cale: molar peak (M + H) +: 476/478 Jan: molar peak (M + H) +: 476/478 Rf value: 0.12 (silica gel, CH2Cl2 / MeOH / No. 9: 1: 0.1).
E p 2.93: Acid. { 2- [4- (2-methyl-2,6-diaza-spiro [3.4] oct-6-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid 300 Prepared analogously to Example 2.76 from 250 mg (0.58 mmol) of [2- (4-bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid, 97 mg of K2C03 and 81 mg ( 0.64 mmol) of 2-methyl-2,6-diaza-spiro [3.4] octane; the product was purified by HPLC. Yield: 20 mg (7.2% of theory) C29H32C1N30 (M = 474.05) Cale: molar peak (M + H) +: 474/476 Jan: molar peak (M + H) +: 474/476 Value ¾ ·. 0.20 (silica gel, CH2Cl2 / MeOH / NH3 9: 1: 0.1).
Example 2.94: 3 - [(4- {2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl acid. -ethyl-amino] -propionic A suspension of 257 mg (0.6 mmol) of acid [2- (4-301 bromomethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid, 166 mg (1.2 mmol) of K2C03 and 138 mg of 3-ethylamino-propionic acid (0.9 mmol, used as the 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 at 50 ° C for 3 hours. The reaction mixture was filtered, the filtrate was concentrated by evaporation and the residue was purified by HPLC. Yield: 50 mg (17.9% of theory) Cale: molar peak (M + H) +: 465/467 Jan: molar peak (M + H) +: 465/467 HPLC retention time: 5.85 min (method A) Example 2.95: (S) -1- (4-. {2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl] -benzyl) -pyrrolidin-2-methylcarboxylate 2. 95a. 4- . { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} ethyl benzoate .- '· Prepared from general working method I from 10.0 g (42.98 mmoles) of' -chloro-biphenyl-4-carboxylic acid and 9.87 g (42.98 mmoles) of 4- (2-amino-ethyl) 302 ethyl benzoate. Yield: 10.64 g (60.7% of theory) Cale: molar peak (M + H) +: 408/410 Jan .: molar peak (M + H) +: 408/410 Rf value: 0.87 (silica gel, CH2Cl2 / MeOH 95: 5). 2. 95b. 4- Acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic In a solution of 10.64 g (26.08 mmol) of 4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Ethylbenzoate in 100 mL of EtOH was added with 14 mL of 2M NaOH solution and the reaction mixture was heated overnight at 60 ° C. Then an additional 30 mL of NaOH solution was added and the mixture was kept at this temperature for an additional 3 hours. The reaction mixture was adjusted to pH 6-7 with 1M HCl solution, the precipitated product was filtered off and dried under vacuum. Yield: 7.65 g (77.2% of theory) Cale: molar peak (M + H) +: 380/382 Jan: molar peak (M + H) +: 380/382 HPLC retention time: 8.1 min (method A) 2. 95c. [2- (4-Hydroxymethyl-phenyl) -ethyl] -amide 4'-chloro-303 acid biphenyl-4-carboxylic acid In a solution of 7.2 g (18.97 mmoles) of 4- acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid in 150 mL of dry THF 3.24 g (20 mmol) of CDI were added and the reaction mixture was heated for 2 hours 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 an additional hour. The reaction mixture was adjusted to pH 6-7 with a 1M HCl solution and exhaustively extracted with EtOAc. The organic phase was washed with NaHCO3 solution and with water and dried over gSO4. After removing the drying agent and the solvent, the residue was purified by chromatography (silica gel, CH2Cl2 / MeOH 9: 1). As the product was still produced, the procedure described above was repeated with 50% of the reagents used. Yield: 2.85 g (41.0% of theory) Cale: molar peak (M + H) +: 366/368 Jan .: molar peak (M + H) +: 366/368 HPLC retention time: 8.0 min (method?) 2. 95d. 4- Methansulfonate. { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl In a solution of 1.0 g (2.73 mmol) of acid [2- (4-hydroxymethyl-phenyl-1) -ethyl] -amide 4'-chloro-biphenyl-4- 304 carboxylic acid in 100 mL dry THF were added 1.25 mL (9 mmol) of triethylamine and the mixture was cooled to -20 ° C. Then 0.64 mL (8.2 mmol) of methanesulfonic acid chloride were added dropwise and the mixture was stirred for another 2 hours at this temperature. 5% NaHC03 solution was added and the mixture was exhaustively extracted with EtOAc. The organic phase was dried over Ma 2 SO 4, the drying agent and the solvent were removed and the residue was dried under vacuum at 30 ° C. Yield: 1.21 g (99.7% of theory) C23H22C1N04S (M = 443.95) Cale: molar peak - (M + H) +: 444/446 Jan .: molar peak (M + H) +: 444/446 HPLC retention time : 8.8 min (method A) 2. 95e. (S) -l- (4-. {-2- [(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl] -benzyl) -pyrrolidine-2-carboxylic acid methyl ester Under an atmosphere of N2 was stirred a solution of 50 mg (0.3 mmol) of methyl (2S) -pyrrolidin-2-carboxylate (used as hydrochloride) and 0.7 mL (0.5 mmol) of triethylamine in 4 mL of DMF for 20 min at room temperature . Then 111 mg (0.25 mmol) of methane sulfonate of 4 was added. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and heated for 2 hours at 60 ° C. The reaction mixture was concentrated by evaporation in vacuo and the residue was purified by HPLC. 305 Yield: 4 mg- (3.4% of theory) C28H29C1W203 (M = 477.01) Cale .: molar peak (M + H) +: -477/479 Jan .: molar peak (M + H) +: 477/479 '. - | · '| HPLC retention time: 6.51 min (method A) Example 2.96: Acid,. { 2- [4- (2-methyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide '-chloro-biphenyl-4-carboxylic acid Prepared, analogously to "Example 2; 95e from 111 mg (0.42 mmol) of methanesulfonate of 4- {2 - [('- chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 35 / L (0.3 mmol) of 2-metipiperidine without using triethylamine. Yield: 7 mg (6.3%, theoretical) M + H) +: 447/449 Jan: molar peak (M + H) +: 447/449 ·. "'"' "'HPLC retention time: 6.4 min (method A) Example 2.97: Acid. { 2- [4- (2-methyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide 306 4'-chloro-biphenyl-4-carboxylic acid.
Prepared analogously to Example 2.95e from 111 mg (0.42 mmol) of methanesulfonate of 4-. { 2- [(4'-chloro-biphenyl-4-carbon'yl) -amino] -ethyl} -benzyl and 32 / L (0.3 mmol) of 2-methyl-pyrrolidine - without using t'-oxyethylamine. 0 Yield: 2 mg (1.8% of theory) C27H29C1N20 (M = 433.0.) - Cale: molar peak (M + H) +: 433/435 Jan: molar peak (M + H) +: 433/435 Time HPLC retention: 6.3 min (method A) 5 · | 'EXAMPLE 2.98: (2- {4- [[(Cyclopropylmethyl-amino) -methyl] -phenyl} -ethyl) -amide' -chloro-biphenyl -4-carboxylic _ 5 Prepared analogously to Example 2.-95e from 307 111 mg (0.42 mmol) of methanesulfonate from 4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 26 μ ?? (0.3 mmol) of cyclopropylmethylamine without using triethylamine. Yield: 4 mg (3.8% of theory) C2SH27C1 20 (M = -418.97) Cale: molar peak (M + H) +: 418/420 Jan: molar peak (M + H) +: 418/420 HPLC retention time : 6.4 min (method A) in-2-ylmethyl) -phenyl] - Prepared analogously to Example 2.95e from 111 'mg (0.42 mmol)' of methanesulfonate of 4-. { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 40 mg (0.3 mmol) of 1, 2, 3, 4-tetrahydroisoquinoline without using triethylamine. Yield: 21 mg (17.5% of theory) Calc .: molar peak (M + H) +: .481 / 483 Jan: molar peak (M + H) +: 481/483 HPLC retention time: 6.8 min (method A 308 Example 2100: Acid [2- (4-. {[[(2-hydroxy-ethyl) -methyl-amino] -methyl] -phenyl) -ethyl] -amide 4 | '-chloro-biphenyl-4- carboxylic Prepared analogously to Example 2.95e from 111 mg (0.42 mmol) of 4- methansulfonate. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 24 μ ?? (0.3 mmol) of 2-methylamino-ethanol without using triethylamine. Yield: 13 mg (12.3% of theory) C25H27C1N202 (M = 422.96) Cale: molar peak (M + H) +: 423/425 Jan: molar peak (M + H) +: 423/425 HPLC retention time: 5.8 min (method A) Example 2.101: Acid. { 2- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid 309 Prepared analogously to Example 2.95e from 111 mg (0.42 mmol) of methanesulfonate of 4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 41 μ?., (0.3 mmol) of 2,6-dimethylpiperidine without using triethylamine. Yield: 8 mg (6.9% of theory) C29H33C1N20 (M = 461.05) Cale: molar peak (M + H) V 461/463 Jan .: molar peak (M + H) +: 461/463 HPLC retention time: 6.6 min (method A) Example 2.102: [2- (4-Azetidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid to Example 2.95e from 4- sulfonate. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 20 μL (0.3 mmol) of azetidine without using triethylamine. Yield: 3 mg (3.0% of theory) C25H25C1N20 (M = 404.94) Calc .:_ molar peak (M + H) +: 405/407 Jan: molar peak (M + H) +: 405/407 HPLC retention time : 5.9 min (method A) 310 Example 2.103: Acid. { 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} - 4'-chloro-biphenyl-4-carboxylic amide Prepared analogously to Example 2.95e from 50 mg (0.11 mmol) of methane sulphate of 4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl and 11 μ? (0.14 mmol) of 2.5-dihydro-lH-pyrrole without using triethylamine. Yield: 18 mg (38.2%: theoretical) C26H25C1N20 (M = 416.95) Cale: molar peak (M + H) +: 417/419 Jan: molar peak (M + H) +: 417/419 'HPLC retention time: 6.2 min (method A) Example 2.104: Acid. { 2- [4- (2/5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide 4'-bromo-biphenyl-4-carboxylic acid 311 2. 104 4 '-bromo-biphenyl-4-ethyl carboxylate Prepared analogously to Example 2.46a from 1.22 mL (7.47 mmol) of ethyl 4-bromo-benzoate and 1.8 g (8.96 mmol) of 4-bromophenyl-boric acid , it was brought to reflux for 72 hours. The product was crystallized from acetonitrile. Yield: 293 mg (12.8% of theory) C15B.13Bx02 (M = 305.17) Cale: molar peak (M + H) +: 304/306 Jan: molar peak (M + H) +: 304/306 Rf value: 0.9 (silica gel, petroleum ether / EtOAc 6: 4). 2. 104b. 4'-Bromo-biphenyl-4-carboxylic acid In a solution of 270 mg (0.89 mmol) '- of 4'-bromo-biphenyl-4-carboxylic acid ethyl ester in 10 mL of EtOH se. they added 1.24 mL of 2M NaOH solution and the reaction mixture was stirred for 2 hours at room temperature. With HC1 1M the pH was adjusted to 6-7, the precipitated product was filtered off and dried. Yield: 205 mg (83.6% of theory) Ci3H9Br02 (M = 277.12) Cale: molar peak (MH) ": 275/277 Jan .: molar peak (MH)": 275/277 'HPLC retention time: 8.5 min (TA method) 312 2. 104c. [4- (2-Amino-ethyl) -phenyl] -methane! In 5.8 g (39.41 mmol) of (4-hydroxymethyl-phenyl) -acetonitrile (see example 1.le.) in 116 mL of methanol solution of NH3, 580 mg of Raney nickel was added and the reaction mixture was 'hydrogenated'. at 50 psi H2. After completion of the reaction, the catalyst was removed by filtration, the solvent was removed. and the residue was purified by chromatography (silica gel, EtOAc / MeOH / NH3 7: 3: 0.3) Yield: 3.9 g (65.4% of theory) C9H13NO (M = .151.21) Cale: molar peak. (M + H) +: - 152 Ene: molar peak (M + H) +: 152 Rf value: 0.18 (silica gel, EtOAc / MeOH / NH3 8: 2: 0.2). 2. 104d. [2- (4-Hydroxymethyl-phenyl) -ethyl] -carbaminate of ter. Butyl In a solution of 2.5 g - (16.53 mmol) of [4- (2-amino-ethyl) -phenyl] -methanol in 50 'mL of CH2Cl2, 17.36 mL of a 1M BOC anhydride in CH2C12 were added at room temperature. The reaction mixture was stirred overnight at room temperature. 100 mL of KHS04 solution was added, the organic phase was separated, washed with dilute NaHCO3 solution and water and dried over MgSO4. After removing the drying agent and the solvent, the desired product was obtained. Yield: 4.06 g (97.7% of theory) C14H21N03 (M = 251.33) 313 Cale: molar peak (M + H) +: 252 Jan: molar peak (M + H) +: 252 HPLC retention time: 6.4 min (method?) 2. 104e. [2- (4-chloromethyl-phenyl) -ethyl] -carbaminate from ter. Butyl In a solution of 2.6 g (10.35 mmol) of [2- (4-hydroxymethyl-phenyl) -ethyl] -carbaminate de ter. Butyl in 50 mL of CH2C12 was added 1 mL of pyridine, cooled. at 0 ° C and 1.03 mL (12.41 mmol) of thionyl chloride was added. It was kept for 1 hour at 0 ° C and then allowed to warm to room temperature. The reaction mixture was washed with water, diluted HS04 solution and again with water, dried with gSO4 and filtered on activated charcoal. After removing the solvent, the product was obtained as an oil, which was reacted without further purification. Yield: 1.8 g (64.5% of theory) C14H20ClNO2 (M = 269.77) '· Cale: molar peak (MH) ~: 268/270 Jan: molar peak (MH) ~: 268/270 Value ¾: 0.62 (silica gel , petroleum ether / EtOAc 7: 3). 2. 104f. . { 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -tert-butylcarbamate In a solution of 1.4 g (5.19 mmoles) of [2- (4-chloromethyl-phenyl) -ethyl] -carbaminate of ter. Butyl, in 50 mL of acetonitrile, 2.37 was added. g (17.13 mmoles) of 2C03 and 0.8 314 mL (10.38 mmol) of 2,5-dihydro-lH-pyrrole and the mixture was stirred overnight: at room temperature. The reaction mixture is diluted with CH2C12, washed with water and dried over MgSO4. After removing the drying agent from the solvent, the desired product was obtained. Yield: 1.46 g (93.0% of theory) ) +: 303 Jan: molar peak (M + H) +: 303 silica, petroleum ether / EtOAc 7: 3). 2,104 g 2- [4- (2, 5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethylamine in a solution of 1.21 g (4 mmol) of. {2- [4 - (2,5-, dihydro-pyrrol-l-ylmethyl) -phenyl] -ethyl-} -carbamate of ter. Utilo · 'in 50 mL of CH2C12 were added 5 mL of trifluoroacetic acid was stirred for 2 hours at room temperature The reaction mixture was concentrated by evaporation in vacuo, the residue was combined with water and CH2Cl2 and basified with K2C solution (0. The organic phase was separated, washed with water and dried over MgSO4. to remove the drying agent and the solvent, the desired product was obtained Yield: 0.35"g (43.3% of theory) C13H18N2 (M = 202.30) .Callow: molar peak (M + H) +: 203 Jan: peak molar (M + H) +: 203 Rf value: 0.05 (silica gel, EtOAc / MeOH / NH3 9: 1: 0.1). 315 2. 104h. Acid { 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} 4'-bromo-biphenyl-4-carboxylicamide Prepared according to general working method 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-pyrrol-l-ylmethyl) -phenyl] -ethylamine. Yield: 21 mg (9.1% of theory) C26H25BrN20 (M = 461.41) Cale: molar peak (M + H) +: 461/463 'Jan. : molar peak (M + H) +: 461/463 HPLC retention time: 6.46 min '(method A) Example 2.105: Acid. { 2- [4- (l-Ethyl-piperidin-2-yl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylicamide etonitrile. Prepared analogously to Example 2.46b from 0.52 mL (5.40 mmoles) of 2-bromo-pyridine and 1.0 g (5.96 mmoles) of 4-cyanomethylphenyl-boric acid. After removing the drying agent and the solvent, the residue triturated with diisopropyl ether and dried in air. Yield: 0.76 g (72.5% of theory) C13H10N2 (M = 194.24) Cale: molar peak (M + H) *: - 195 Jan: molar peak (M + H) +: 195 HPLC retention time: 3.5-6 min (method B) 2. 105b. 2- (4-Cyanomethyl-phenyl) -1-ethyl-pyridinium iodide In a solution of 760 mg (3.91 'mmoles) of (4-pyridin-2-yl-phenyl) -acetonitrile in 5 mL of DMF were added 0.38. mL (4.7 mmol) of ethyl iodide and stirred overnight at room temperature. To finish the reaction, the solution was treated for 20 min at 120 ° C in the microwave. The solvent was concentrated by evaporation in vacuo, the residue was combined with water and extracted with EtOAc The aqueous phase was concentrated by evaporation, the residue was triturated with THF and the suspension was cooled to 0 ° C. it was filtered by suction and dried at 50 ° C. Yield: 800 mg (58.4% of theory) C15H15IN2 (M = 350.; 21) Cale: molar peak (M) +: 223 Jan: molar peak (M) +: 223 Retention time "HPLC: 1.76 min (method A) 2. 105c. 2- [4- (l-Ethyl-piperidin-2-yl) -phenyl] -ethylamine In a solution of 800 mg (2.28 mmol) of 2- (4-cyanomethyl-phenyl) -1-ethyl-pyridinium iodide in 10 mL of NH3 317 methanolic were added 100 mg of Raney nickel and the reaction mixture was hydrogenated 20 psi and at room temperature for 24 hours in the autoclave. The catalyst was filtered by suction, the reaction solution was combined with 100 mg of Pt02 and hydrogenated from -new at room temperature and 20 psi for 30 hours. After removing the catalyst, the product was obtained (such as the hydroiodide), which was reacted without further purification. Yield: 700 mg (85.1% of theory) C15H24lN2 (M = 360.28) / "Cale: molar peak (M) +: 233 Jan: molar peak (M) +: 233 HPLC retention time: 0.93 min (isocratic water: acetonitrile : formic acid 95: 5: 0.01 for 8 min). 2. 105d. Acid { 2- [4- (1-ethyl-piperidin-2-yl) -phenyl-ethyl} -amide -chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work I from 480 mg (1.33 mmol) of 2- [4- (l-ethyl-piperidin-2-yl) -phenyl] -ethylamine (used as the hydroiodide) and 310 mg (1.33 mmol) of 4 'acid chloro-biphenyl-4-carboxylic acid. Yield: 20 mg (3.4% of theory) C28H31CIN2O (= 447.03) Cale: molar peak (+ H) +: 447/449 Jan: molar peak (M + H) +: 447/449 HPLC retention time: 6.68 min (method A) 318 dan-5-yl) -ethyl] -amide 4'-chloro¬ 2. 106a. (E) -3- (l-oxo-indan-5-yl) ethyl acrylate In a solution of 4.64 g (21.99 mmoles) of 5-bromo-indan-1-one in 110 mL of triethylamine under N2 were added 5.96 mL (55 mmol) of ethyl acrylate, 275 mg (1.21 mmol) of Pd (0Ac) 2 and 704 mg (2.31 mmol) of tri-o-tolifosphine and the reaction mixture was heated for 4 hours at 100 ° C. . The solvent was extracted by distillation, the residue was combined with 150 mL of EtOAc and 100 mL of ice water, acidified with concentrated HCl, the organic phase was washed with 100 mL of water and dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by chromatography (silica gel, hexane / EtOAc 9: 1 to 8: 2) Yield: 4.0.g (79.0% of theory) Melting point: 100- 102 ° C 2. 106b. ' (E) -3- (1-Oxo-indan-5-yl) -acrylic acid 319 In a solution of 4.0 g (17.0 mmol) of (E) -3- (1-oxo-indan-5-yl) -ethyl acrylate in 50 mL of MeOH, 10 mL of 2N NaOH-and the reaction mixture were added. it was refluxed for 30 min. It was then combined with 11 mL of 2N HC1 solution, the MeOH was distilled off, the crystals were filtered by suction and dried. Yield: 3.0 g (87.3% of theoretical) Melting point: 240-244 QC 2. 106c. 3- (l-Oxo-indan-5-yl) -propionic acid In a solution of 1.6 g (7.91 mmoles) of (E) -3- (l-oxo-indan-5-yl) -acrylic acid in 50 mL of MeOH were added 150 mg of 10% Pd / C and the reaction mixture was stirred at room temperature and 3 bar of ¾ until the theoretical absorption of H2 was obtained. 10 mL of 1N NaOH was mixed and the solvent was removed. The residue was acidified with dilute HCl, exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. After removing the drying agent and the solvent, the residue was triturated with tert-butyl methyl ether, the precipitate was suction filtered and dried. Yield: 500 mg (31.0% of theory) C12H1203 (M = 204.23) Cale: molar peak (MH) ": 203 Jan .: molar peak (? -? G: 203 Rf value: 0.45 (silica gel, CH2Cl2 / MeOH 9: 1). 320 2. 106d. [2 -. (L-oxo-indan-5-yl) -ethyl] -carbaminate of tert.butyl Under an argon atmosphere 1.6 g (7.83 mmoles) of. 3- (l-Oxo-indan-5-yl) -propionic acid in 25 mL of tert.butanol and 2.5 mL of triethylamine. To this solution, 2.22 mL (10.0 mmol) of diphenyl azido-phosphate was added and it was heated for 3 hours at 80 ° C. The reaction mixture was concentrated by evaporation in vacuo and the residue was purified by chromatography on silica gel. Yield: 750 mg (34.8% of theory) Ci6H2iN03 (M = 275.35) Calc .: molar peak (M) +: 275 Jan: molar peak (M) +: 275 Rf value: 0.65 (silica gel, CH2Cl2 / MeOH 95: 5). | 2.106e. [2- (l-hydroxy-indan-5-yl) -ethyl] -carbamate-tertiary butyl ester - In a solution of 700 mg (2.54 mmol) of [2- (1-oxo-indan-5-yl) - ethyl] -carbamate of tert.butyl in 70 mL of MeOH, 700 mg (18.5 mmol) of NaBH4 were added in a discontinuous manner and stirred overnight at room temperature.The reaction solution was carefully combined with 10% strength solution. KHS04 was diluted with water and exhaustively extracted with tert-butylmethyl ether The organic phase was washed with water and dried over MgSO4 After removing the drying agent and the solvent, the residue was purified by gel chromatography. of silica .. 321 Yield: 350 mg (49.7% of theory) C16H23N03 (M = 277.37) Cale: molar peak. (M) +: 277 Jan .: molar peak (M) +: 277 Rf value: 0.30 · (silica gel, petroleum ether / EtOAc 6: 4). 2. 106f. [2- (l-pyrrolidin-l-yl-indan-5-yl) -ethyl] -carbamatete of tert.butyl "|| · In a solution cooled to 0 ° C of 350 mg (1.26 mmol) of [2] - (L-hydroxy-indan-5-yl) -ethyl] -carbamate of tertbutyl in 7.5 mL of CH2C12 were slowly added dropwise. 109 μ ?? ' (1.5 mmoles) of thionyl chloride (dissolved in a little CH2C12) - stirring was continued for another 30 min at 10 ° C, the reaction solution was combined with ice cold NaHCO 3 solution, the organic phase was separated, washed, with cold water and dried over MgSO4. After removing the drying agent, the filtrate was cooled to 0 ° C, 417 μ were added by drip? (5.0 mmol) of pyrrolidine and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated by evaporation and the residue was purified by chromatography on silica gel. Yield: -120 mg (28.8% of theory) C20H30N2O2 (M- 333.47) Cale: molar peak- (M + H) +: 331 Jan: molar peak (M + H) +: 331 HPLC retention time: 5.6 min ( method A) 322 2. 106g. 2- (l-pyrrolidin-l-yl-in.dan-5-yl) -ethylamine In a solution of 100 mg (0.3 mmol) of [2- (l-pyrrolidin-l-yl-indan-5-yl) -ethyl] -carbaminate of ter. butyl in 10 mL of CH2C12. were added by slightly cooling 100 μL of trifluoroacetic acid and stirred for 1 hour at room temperature. To finish the reaction, others were added, 500 juL of trifluoroacetic acid with cooling and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated by evaporation in vacuo and the product (such as bis-trifluoroacetate) was further reacted without purification. Yield: 100 mg (72.7% of theory) Ci9¾4 F6N204 (M =, 458.51) Calc .: molar peak (M + H) +: 231 Jan: molar peak (M + H) +: 231 Value f: '0.3 (gel silica, CH2Cl2 / MeOH / NH3 9: 1: 0.1). 2. 106h. Acid [2- (l-pyrrolidin-l-yl-indan-5-yl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general working method, starting from 100 mg (0.29) mmol) of 2- (1-pyrrolidin-1-yl-indan-5-yl) -ethylamine (used as' bis-trifluoroacetate) and 70 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. Yield: 40 mg (30.0% of theory). C28H2sClN20 (M = 445.01) Cale: molar peak (M + H) +: 445/447 Jan .: molar peak (M + H) +: 445/447 - 323 HPLC retention time: 6.65 min (method A) Example 2.107: [2- (3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'acid - 2. 107a. Methyl 2-bromo-4-cyanomethyl-benzoate In a solution of 24.51 g (0.5 mol) of NaCN in 40 mL of water was added a solution of 98.55 g (0.32 mol) of 2-bromo-4-bromomethyl-benzoate. of methyl in 60 mL of EtOH and the reaction mixture was refluxed for 5 hours. 1 L of tert-butyl methyl ether and 500 L of water were added, the organic phase was separated, washed several times with water and dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel (petroleum ether / EtOAc 8: 2) '. Yield: 15.0 g (16.6% of theory) C10H8BrNO2 (M = 254.09 ); - "...." Cale: molar peak (M-H) ": 252/254 Jan: molar peak (M-H)": 252/254 2. 107b. 2-bromo-4-cyanomethyl-benzoic acid "In a solution of 7.9 g, (31.0 mmol) of 2-bromo-4-324 methyl cyanomethylbenzoate in 100 mL of EtOH was added 35 mL of 1M NaOH solution, the reaction mixture was refluxed for 1 hour and then stirred overnight at room temperature. Ice water was added and the mixture was acidified with dilute KHS04 solution. The precipitate was filtered by suction, washed with water and dried at 50 ° C. Yield: 6.2 g (83.3% of theory) C9HsBrN02 (M = 240.06) Cale: molar peak (M-H) ~. : 238/240 Jan: molar peak (M-H) ": 238/240 HPLC retention time: 3.99 min (method B) 2. 107c. (3-bromo-4-hydroxymethyl-phenyl) -acetonitrile In a solution of 2.4 g (10 mmol) of 2-bromo-4-cyanomethyl-benzoic acid in 50 mL of THF were added 1.78 g (11 mmol) of CDI and the water bath was heated until gas production had ceased. Then, in a solution of 0.76 g (20 mmoles) of NaBH4 in 50 mL of water, while the temperature did not exceed 30 ° C. Stirring was continued for a further 2 hours at room temperature, the reaction mixture was acidified carefully with dilute KHS04 solution, exhaustively extracted with tert-butyl methyl ether, the organic phase was washed with water and dried over MgSO4. It was filtered over activated carbon and the solvent was removed in vacuo. Yield: 2.2 g (97.3% of theory) 325 C9¾BrNO (M = 226.07) "" -. Cale: molar peak (? -?) ': 224/226 Jan: molar peak (M-H) ": 224/226' Rf value: 0.6 (silica gel, CH2Cl2 / MeOH 9: 1). -. . . 2.107d. (3-bromo-4-pyrrolidin-l-ylmethyl-phenyl) -acetonitrile In a solution of 1.9 g (8.4 mmol) of (3-bromo-4-hydroxymethyl-phenyl) -acetonitrile in 50 mL of CH2Cl2 was added 1.25 mL (9 mmol) of triethylamine was cooled to 0 ° C and a solution of 0.66 'mL (8.5 mmol) of methanesulfonic acid chloride in 10 mL of CH2Cl2 was added dropwise The mixture was stirred for 1 hour at 0 ° C. C and then a solution of 1.4 mL (17 mmol) of pyrrolidine in 10 mL of CH2C12 was added dropwise with ice, the reaction mixture was heated overnight at room temperature, combined with water, the organic phase was separated it was washed twice with water, filtered over activated charcoal and concentrated by evaporation in vacuo The residue was co-evaporated twice with toluene and the product obtained was further reacted without purification Yield: 2.25 g (95.9% of the theoretical) C13H15BrN2 (M = 279.18) Cale: molar peak (M + H) +: 279/281 Jan: molar peak (M + H) +: 279/281; Rf value: 0.5 (silica gel, CH2Cl2 / MeOH / N¾ 9: 1: 0.1). 326 2 · .107e. 2- (3-bromo-4-pyrrolidyr-l-ylmethyl-phenyl) -ethylamine In 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 were added 20 mg of Raney nickel and stirred for 1 hour: at room temperature and 5 psi of ¾ in a Parr autoclave. The catalyst was removed by filtration, the solvent was concentrated by evaporation in vacuo and the product was further reacted without purification. Yield: 225 mg (98.1% of theory) C13H19BrN2 (M = 283.21) Cale: molar peak (M + H) +: 283/285. Jan: molar peak (M + H) +: 283/285 - R £ value: 0.08 (silica gel, CH2Cl2 '/ eOH / NH3 9: 1: 0.1). 2. 107f. [2- (3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid hydrochloride ^ Prepared according to general working method I from 220 mg (0.78 mmol) of 2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 186 mg (0.8 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. After removing it. drying agent and the solvent, the residue is. The residue was taken up in isopropanol / tert-butyl methyl ether, combined with ethereal HC1 and concentrated by evaporation in vacuo. The residue was again taken up in 20 mL of isopropanol, triturated, filtered by suction, washed with a little isopropanol and dried at 50 ° C. '327 Yield: 165 mg '(39.6% of theory) C2SH27BrCl2N20 (M = 534.33) Cale: molar peak (M + H) +: 497/499/501 Jan. : molar peak (M + H) 497/499/501. . Rf value: 0.35 (silica gel, CH2Cl2 / MeOH / MH3 9: 1: 0.1).
Example 2.108: [2- (3-Methyl-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4-chloro-biphenyl-4-carboxylic acid of 150 mg (0.28 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid in 5 mL of dioxane was added 17.3 mg (0.28 mmol). Methylboronic acid, 2.5 mL of 2M Na 2 CO 3 solution and 32 mg (0.03 mmol) of tetrakis- (triphenylphosphine) -palladium and the reaction mixture was refluxed for 5 hours. The hot suspension was filtered by suction through a glass fiber filter, the filtrate was combined with half-saturated NaHCO 3 solution, exhaustively extracted with EtOAc and dried over MgSO 4. After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel (CH2Cl2 / MeOH 328 8: 2).; · \ Performance: 20 mg (16.4% of theory) Cale: molar peak (M + H) +: 433/435 Jan: molar peak (M + H) +: 433/435"- - HPLC retention time: 6.47 min '(method A) Example 2.109: [2- (2-Bromo-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide chloro-biphenyl-4-carboxylic acid 2. 109a. Ethyl 4- (2-amino-ethyl) -3-nitro-benzoate in one. solution cooled to -5 ° C of 12.0 g (52 mmol) of ethyl 4- (2-amino-ethyl) -benzoate in 80 mL of concentrated H2SO4 was added non-continuously 5.78 g (57 mmol) of KNO3 and stirred for 1 hour at this temperature. The reaction solution was slowly added dropwise in ice water (the temperature should not exceed 0 ° C) and stirred for 1 hour. The precipitate was filtered by suction, washed with water and dried at 50 ° C. Yield: 8.2 g (66.2% of theory). CnH ^ NaO * (M = 238.25) 329 Cale: molar peak (M + H) +: 239 Jan: molar peak (M + H) +: 239 HPLC retention time: 3.64 min (method A) 2. 109b. 4- '. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Ethyl-3-nitrobenzoate:. Prepared from general working method I from 8.2 g (34 mol) of 4- (2-amino-ethyl) -3-nitro-benzoate-ethyl and 7.91 g (34 mmol) of 4'-chloro acid -biphenyl-4-carboxylic acid. Yield: 7.7 g (50.0% of theory) C24H2iClN205 (M = 52:90) Cale: molar peak (M + H) +: 452/454 Jan: molar peak (M + H) +: 452/454 HPLC retention time : 6.14 min (method B) 2. 109c. 3-amino-4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -ethylbenzoate In a solution of 7.7 g (17 mmol) of 4-. { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Ethyl 3-nitrobenzoate in 200 mL of EtOAc was added 0.5 g of Raney nickel and the reaction mixture was stirred in the autoclave overnight at room temperature and 10 psi of H2. To finish the reaction, 50 mL of THF was added and the mixture was stirred for another 2 hours. The catalyst was filtered by suction, washed carefully with THF, the solvent was concentrated by vacuum evaporation, the residue was triturated with EtOAc, suction filtered again and air dried. Yield: 5.0 g (69.5% of theory) C24H23C1N203 (M = 422.92) '. '.. · Cale: molar peak (M + H) +: 423/425 Jan .: molar peak (M + H) +: 423/425 HPLC retention time. 5.71 min (method B) 2. 109d. 3-bromo-4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -ethylbenzoate In a solution of 5.0 g - (7.69 mmoles) of 3-amino-4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate · of ethyl in 20 mL of water were added 20 mL of 48% HBr and cooled to 0 ° C. Then a solution of 0.9 g (13 mmoles) of NaN0 in 5.2 mL of water was added dropwise so that the temperature did not exceed 5 ° C "and the mixture was stirred for another 10 min at 0 ° C. drip a solution of 1.87 g (13 mmol) of CuBr in 6.65 mL of 48% HBr at this temperature / The reaction mixture was then heated for 1 hour at 60 ° C. Water was added and the mixture was thoroughly extracted with water. EtOAc The organic phase was washed with water and dried over MgSO 4 After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel (petroleum ether / EtOAc 6: 4). : 1.3 g (34.7% of theory) 331 C24H21BrClN03 (M = .486.80) · Cale: molar peak (M + H) +: 486/488/490 Jan. : molar peak (M + H) +: 486/488/490 Rf value: 0.55 (silica gel, petroleum ether / EtOAc 6: 4). -; 2.109e. 3-bromo-4- acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic To a suspension of 1.3 g (2.67 mmoles) of 3-bromo ~ 4-. { 2- [('-chloro-biphenyl-4-carbonyl) -amino] -ethyl} ethylbenzoate in 20 mL of EtOH and 5 mL of THF were added 6 mL of 1N NaOH solution and the reaction mixture was stirred overnight at room temperature. It was concentrated by evaporation in vacuo, the residue was combined with water and neutralized with 1N HC1, with which the product was precipitated. It was stirred continuously for another hour. While it was cooled with ice, the mixture was filtered by suction, washed with water and the product was dried at 50 ° C. Yield: 1.2 g (97.9% of theory) C22H17BrClN03 '(M = 458.74) 'Cale: molar peak (M + H) +: 456/458/460 Jan: molar peak (M + H) +: 456/458/460. HPLC retention time: 5.51 min (method B) 2. 109f. Acid [2- (2-bromo-4-iiydroxymethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid-332 In a solution: from | 1.2 g (2.62 mmoles) of 3-bromo-4- acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid in 10 mL of DMF was added 0.64 -'g '(3.92 mmol) of CDI and the mixture was heated until gas production had ceased at 50 ° C. The reaction mixture was added in a solution of 0.3 g (7.85 mmoles) of NaBH and 10 mL of water, stirred for 1 hour at room temperature, acidified with dilute KHS04 solution and filtered. extracted exhaustively with EtOAc. The organic phase was washed with half saturated NaHCO 3 solution and dried over MgSO 4. After removing the drying agent and the solvent, the residue was further reacted without purification. Yield: 0.87 g (74.8% of theory): C22H19BrClN02 (M = 444.76) Cale: molar peak (M + H) +: 444/446/448 Jan: molar peak (M + H) +: 444/446/448 'HPLC retention time: 8.07 min (method' A) 2. 109 g. [2- (2-Bromo-4-chloromethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid In a solution of 0.87 g (1.96 mmoles) of [2- (2-bromo- 4-hydroxymethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid in 20 mL of CH2C12 was added 0.24 mL (2.93 mmol). of pyridine and cooled to 0 ° C. 0.21 mL (2.93 mmol) of thionyl chloride was added, the mixture was stirred 333 for 1 hour a. this temperature and then let it heat up. room temperature. Water was added, the mixture was filtered over Celite, the aqueous phase was extracted with CH2C12 and the combined organic phases were dried over gS04. After removing the drying agent and the solvent, the residue was further reacted with purification. Yield: 0.66 g. (72.8% of theory) C22H18BrCl2NO (M = 463.21) Cale: molar peak (M + H) +: 462/464/466 Jan .: molar peak (M + H) +: 462/464/466 HPLC retention time: 6.37 min (method B) 2. 109h. [2- (2-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid In a solution of 0.66 g (1.43 mmol) of acid [2- ( 2 ~ bromo-4-chloromethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid in 20 mL of acetonitrile and 6 mL of DMF were added .59 g (4.28 mmol) of K2C03 and 0.24 mL ( 2.85 mmole) of pyrrolidine and stirred for 5 hours at room temperature. It was washed with water, the mixture was exhaustively extracted with EtOAc, the organic phase was washed several times with water and dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel (CH2Cl2 / MeOH 9: 1). Yield: 0.2 g "(28.2% of theory) 334 C26H26BrClN20 (M = 497.87) '. Cale: molar peak (? +?) +: - 497/499/501 Jan: molar peak (M + H) + 497/499/501 HPLC retention time: 4.39 min (method B) Example 2.110: [2- (2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl) rboxxylic acid] Prepared analogously to Example 2.108 from 200 mg (0.40 mmol) of. [2- (2-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid and 27.3 mg (0.44 mmol) of methylboronic acid, being brought to reflux during only 2 hours and the product was purified by HPLC. Yield: 62 mg (35.6% del theoretical) C27H29C1N20 (M = 433.0) Cale: molar peak. (M + H) +: .433 / 435 Jan: molar peak (M + H) +: 433/435 HPLC retention time: 6.15 min (method A) Example 2.111: Acid [2 (2-nitro-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-335 chloro-biphenyl-4-carboxylic . || _ 2.Illa. 4- Acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoic acid In a solution of 200 mg (0.44 mmol) of 4-. { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Ethyl-3-nitro-benzoate (Example 2.109b) in 10 mL of EtOH was added 2 mL of 1N MaOH solution and the reaction mixture was stirred for 1 hr at room temperature. The mixture was concentrated by evaporation in vacuo, water and 2 mL of 1N HCl solution were added to the residue and the suspension was stirred for 30 min in an ice bath. The product was filtered by suction, washed with water and dried at 50 ° C. -Performance: 180 mg (95.9% of theory) C22H17C1N205 (M = 424.84) Cale: molar peak (M + H) +: 425/427 Jan .: molar peak (M + H) +: 425/427 Value ¾: · 0.07 (silica gel, EtOAc / MeOH / NH3 9: 1: 0.1). 2. 111b. [2- (4-Hydroxymethyl-2-nitro-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid. Prepared analogously to Example 2.109f from 336 180 mg (0.42 mmol) of 4- acid. { 2- [('-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoic acid. * Yield: 110 mg (63.1% of theory) C22H19C1N204 (M = 410.86) _. Cale: peak .molar (M + H) +: 411/413 Jan .: molar peak (M + H) +: 411/413 HPLC retention time: 8.27 min (method A) 2. 111c. [2- (2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid: In a solution cooled to 5 ° C of 110 mg (0.27 mmol) of [2- (4-hydroxymethyl-2-nitro-phenyl) -ethyl] -amide 4'- acid; Chloro-biphenyl-4-carboxylic acid and 4.8 / L-triethylamine in 5 mL of C¾C12 were slowly added dropwise 23 μL of methanesulfonic acid chloride. The solution was heated for 1 hour at 40 ° C, 5 mL of DMF and 115 / xL (1.34 mmol) of pyrrolidine were added and the mixture was heated for another hour at 80 ° C, during the time. which CH2Cl2 was evaporated. The reaction mixture was concentrated by evaporation in vacuo, the residue was combined with water, exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by HPLC. · Yield: 11 mg. (8.8% of theory) C26H26C1N303 (M = 463.97) 337 Cale: molar peak (M + H) +: 464/466 Jan: molar peak (M + H) +: 464/466 HPLC retention time: 6.44 min (method A) Example 2.112: Acid ·. [2 - (2-methanesulfonylamino-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 2. 112a. 4- . { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3- ethyl methanesulfonylamino-benzoate In a solution, cooled to 0 ° C, 200 mg (0.47 mmol) of. 3-amino-4-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Ethyl benzoate (Example 2.109c) in 5 mL of pyridine were slowly added dropwise 44 / xL (0.57 mmol) of methanesulfonic acid chloride and the reaction mixture was stirred for 1 hour at room temperature. It was combined with ice water, exhaustively extracted with EtOAc, the organic phase was washed several times with water and dried over MgSO4. After removing the drying agent and the solvent, the residue was further reacted without purification. Yield: 230 mg (97.1% of theory) C25H25C1N205S (M = 501.01) 338 Cale .: molar peak- (M + H) +: 501/503 Jan: molar peak (M + H) +: 501/503 -,. -. ·. HPLC retention time: 5.66, mi (method B) 2. 112b. 4- Acid. { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-methanesulfonylamino-benzoic prepared analogously to Example 2.111a from 230 mg (0.46 mmol) of 4- (2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl.} - Ethyl 3-methanesulfonylamino-benzoate Yield: 180 mg (82.9% of theory) C23H21C1N205S (M = 472.95) Cale: molar peak (MH) ~: 471/473 Jan: molar peak (MH) ": 471/473 HPLC retention: 7.67 min (method A) - 2.112c [2- (4-Hydroxymethyl-2-methanesulfonylamino-phenyl) -ethyl] -amide 4'-chloro-biphenyl-carboxylic acid Prepared analogously to Example 2.109fa from 180 mg (0.38 mmol) of 4- acid. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-methanesulfonylamino-benzoic acid. Yield: 150 mg (85.8% of theory) C23H23C1 204S (M = 458.97) Cale: molar peak (M + H) +: 459/461 Jan: peak, molar (M + H) +: 459/461 | HPLC retention: 7.53 min (method A) 339 2. 112d. Acid- [2- (2-Methanesulfonylamino-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.111ca from 150 mg (0.33 mmol) of [2- (4-hydroxymethyl-2-methanesulfonylamino-phenyl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid and 140. // L (1.64 mmol) of pyrrolidine. After purification by HPLC, the product was obtained as the formate salt. Yield: 18 mg (9.9% of theory) -C27H3oClM303S * CH202 (M = 558.10) 'Cale: molar peak (M + H) +: 512/514 Jan .: molar peak (M + H) +: 512/514 HPLC retention time: 6.13 min (method A) Example 2.113: [2- (3-pyridin-4-yl-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 340 Prepared analogously to Example 2.108 from 200 mg. { 0.40 mmol) of [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid and 74 mg (0.60 mmol) of pyridine acid. -4-boricum, the product was purified by HPLC. Yield: 13 mg (6.5% of theory) C31H30CIN3O (M = 496.06) Cale: molar peak (M + H) +: 496/498 Jan: molar peak (M + H) +: 496/498.: HPLC retention time : 6.37 min (method A) Example 2.11: 5-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Methyl-2-pyrrolidin-1-ylmethyl-benzoate 2. 114a. Methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl-benzoate In a solution of 500 mg (1.79 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (Example 2.107d) in 10 mL of; MeOH and 10 .mL of DMF were added 0.5 mL of triethylamine (3.58 mmol), 40 mg (0.18 mmol) of Pd (0Ac) 2 and 99 mg (0.18 mmol) of 1, 1-diphenylphosphino-ferrocene. The mixture of 341 The reaction was stirred, in an autoclave with 2 bar of CO for 15 hours at 5'0 ° C. To finish the reaction, 0.5 mL of triethylamine, 40 mg of Pd (OAc) 2 and 99 mg of 1,1"-diphenylphosphino-ferrocene were added, and the mixture was stirred for an additional 10 hours at 50 ° C and 2 bar. CO and overnight at 4 bar CO and 70 ° C. The solvents were concentrated by evaporation in vacuo, the residue was combined with EtOAc and extracted twice with water, the aqueous phase was saturated with K2C03, extracted exhaustively with EtOAc and dried over MgSO4 After removing the drying agent and the solvent, the remaining product is a black oil, which was further reacted without purification Yield: 380 mg (82.1% of theory) C15H18N202 (M = 258.32) Cale: molar peak (M + H) +: 259 Jan .: molar peak (M + H) +: 259 HPLC retention time: 2.49 min (method B) 2. 114b. Methyl 5- (2-amino-ethyl) -2-pyrrolidin-1-ylmethyl-benzoate In a solution of 380. mg (1.47 mmol) of methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl-benzoate in 20 mL of methanolic N se was added 100 mg of Raney nickel and the reaction mixture was hydrogenated at 20 psi of H2 for 27 hours at room temperature. The catalyst was filtered by suction, the solvent was removed and the residue was further removed. I hated to react 342 without purification. - Yield: 330 mg (85.5% of theoretical) ,. C15H22N202 (M = 262.36) Cale: molar peak. (M + H) +: 263 Jan .: molar peak (M + H) +: 263 HPLC retention time: 1.40 min (method A) 2. 114c. 5- . { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2- methyl pyrrolidin-l-ylmethyl-benzoate Prepared according to general procedure I from 330 mg (1.26 mmol) of 5- (2-amino-ethyl) -2-pyrrolidin-1-ylmethyl- Methyl benzoate and 293 mg (1.26 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ) Cale: molar peak (? +?) +: '477/479 Jan .: molar peak (M + H) +: 477/479 - · '|. - HPLC retention time: 6.82 min (method A) E p 2.115: Acid 5-. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2- pyrrolidin-l-ylmethyl-benzoic acid 343 Prepared in a manner "analogous to Example 2. Illa from .310 mg (0.65 mmol) of 5-. {2- 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl.}. Methyl 2-pyrrolidin-l-ylmethyl-benzoate Yield: 85 mg (28.2% of theory) Cale: molar peak (M + H) +: 463/465 Jan .: 'molar peak (M + H) +: 463/465 HPLC retention time: 6.30 min (method A). • '| |' Example 2.116: (5- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl.} -2-pyrrolidin-1-ylmethyl-phenyl) -carbamate of ter. butyl mg '(1.6 mmoles) of 5- acid. { 2- [(4'-chloro-biphenyl -carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-benzoic acid in 10 mL of tert.butanol were added 0.27 mL (1.92 mmol) of triethylamine and 0.41 mL (1.92 mmol) of diphenyl azido-phosphate and the mixture of. The reaction was refluxed for 5 hours. HE. evaporated in vacuo, the residue was combined with CH2Cl2, extracted with NaOH 344 solution 1N and the organic phase was dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel. Yield: 85 mg (28.2% of theory) C31H36C1N303 (M = 534.10) Cale: molar peak (M + H) +: 534/536 Jan: molar peak (M + H) +: 534/536 HPLC retention time: 4.82 . min (method B) Example 2.117: [2- (3-Ethyl-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4 'acid - 2. 117a. (4-pyrrolidin-l-ylmethyl-3-trimethylsilanylethynyl-phenyl) -acetonitrile A suspension of 0.36 g (1.29 mmol) of (3-bromo-4-pyrroline-1-ylmethyl-phenyl) -acetonitrile (Example 2.107d), 0.36 mL (2.58 mmol) - of trirnethylsilylacetylene, 0.36 mL (2.58 mmol) of triethylamine, 25 mg (0.13 mmol) of Cul and 0.15 g (0.13 mmol) of tetrakis- (triphenylphosphine) -palladium in 3 mL of DMF was stirred in he. microwave (CEM) for 15 min at 100 ° C and 200 Watt. After cooling the reaction mixture, it was 345 added saturated NaCl solution, the mixture was exhaustively extracted with EtOAc and the organic phase was dried over gS04. After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel (EtOAc). Yield: 50 mg (13.1% of theory) C18H2 N2SÍ (= 296.49) Cale: molar peak (M + H) +: 297 Jan.-: molar peak (M + H) +: 297 HPLC retention time: 6.39 min ( method A) 2. 117b. 2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamin; In one, 50 mg solution (0.17 mmol) of (4-pyrrolidin-l-ylmethyl-3-trimethylsilanylethynyl-phenyl) -acetonitrile in 5 mL of methanolic NH3 was added 20 mg of Raney nickel and the reaction mixture was stirred for 22 hours at room temperature and 3 bar of ¾. The catalyst was filtered by suction and the solvent was removed in vacuo. The crude product was further reacted without purification. Yield: 39 mg (100% of theory) C15H24N2 (M = 232.37) Cale: molar peak (+?) +: 233 Jan: molar peak (M + H) +: 233 2. 117c. [2- (3-Ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to. general method of work 346 I from 40 mg (0.17 mmol) of 2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 48 mg (0.21 mmol) of 4'-chloro-biphenyl-4-carboxylic acid . Yield: 2 mg (2.6% of theoretical) Cale: molar peak. (M + H) +: 447/449 Jan.: molar peak (M + H) +: 447/449 HPLC retention time: 6.87 min (method A) Example 2.118: [2- (6-Pyrrolidin-1-ylmethyl-pyridin-3-yl) -ethyl] -amide acid 4'- 2. 118a. 6-dibromomethyl-nicotinate. of methyl In a solution of 38.96 g (0.25 mol) of methyl 6-methyl-nicotinate in 1 L of CC14 were added 53.4 g (0.3 mol) of WBS and 2 g of dibenzoyl peroxide and the reaction mixture was brought to reflux during the night. Then another 26.7 g (0.15 mol) of NBS and 1 g of dibenzoyl peroxide were added and the mixture refluxed again for 24 hours. After cooling the reaction mixture, the precipitate was filtered by suction, the solvent was removed and the residue was removed. purified by chromatography. Yield: 15.0 g (19.4% of theory) C8H7Br2N02 (M = 308.96) Cale: molar peak (M + H) +: 308/310/312 Jan .: molar peak (M + H) +: 308/310/312. Value f: 0.6 (silica gel, petroleum ether / EtOAc 8: 2). 2".188.6 Methyl 6-dimethoxymethyl-nicotinate 13.9 mL of NaOMe in MeOH (30%, 75 mmol) in 100 mL of MeOH was heated to boiling a solution of 11.0 g was added dropwise to the boiling solution. (34.1 mmoles) of methyl 6-dibromomethyl-nicotinate in 10 mL of MeOH and refluxed overnight To finish the reaction, another 1.5 mL (8.1 mmol) of the NaOMe solution was added and the mixture was removed. reflux again for 24 hours The reaction mixture was concentrated by evaporation in vacuo, the residue was combined with dilute KHS04 solution, neutralized with dilute NaHC03 solution, extracted thoroughly with EtOAc, the organic phase was washed with Water and dried on MgSO.After removing the drying agent and the solvent, the residue was further reacted without purification Yield: 5.0 g (69.5% of theory) Ci0H13NO4 (M = 211.22) .Cal: molar peak (M + H) 212 Jan.: molar peak (M + H) +: 212 348 Rt value: 0.44 (silica gel, petroleum ether / EtOAc 6: 4) 2. 118c. 6-dimethoxymethyl-nicotinic acid In a solution of 2.8 g. (13.26 mmoles) of methyl 6-dimethoxymethyl-nicotinate in 50 ml MeOH was added 15 ml of 1N NaOH solution and se. stirred for 24 hours at room temperature. The reaction mixture was neutralized with 15 mL of HCl, 1N, concentrated by evaporation in vacuo, the residue was triturated with MeOH / THF, the precipitate was filtered off by suction and the filtrate was concentrated by evaporation. The product obtained was further reacted without purification. Yield: 2.6 g (99.4% of theory) C9HnN04 (M = 197.19) Cale: molar peak (M + H) +: 198 Jan: molar peak (M + H) +: 198 HPLC retention time: 3.65 min (method A ) 2. 118d. (6-dirnetoxymethyl-pyridin-3-yl) -methanol Prepared analogously to Example 2.109f from 2.7 g (13.7 mmol) of 6-dimethoxymethyl-nicotinic acid, using THF 'as solvent and tert-butyl methyl ether for extraction. Performance-. 2.1 g (83.7% of theory) Cale: molar peak (M + H) +: 184 Jan: molar peak (M + H) +: 184 'HPLC retention time: 2.85 min (method A). 349 2. 118e. 5 ~ chloromethyl-2-dimethoxymethyl-pyridine In a solution cooled to 0 ° C of 500 mg (2.73 mmol) of (6-dimethoxymethyl-pyridin-3-yl) -methanol in 10 mL CH2C12, 0.3 mL was slowly added dropwise ( 4.14 mmoles) "of thionyl chloride, dissolved in a little CH2Cl2, and stirred for another 30 min at this temperature, the reaction mixture was diluted with CH2C12, washed with cold NaHC03 solution and dried over MgSO4. After removing the drying agent and the solvent, the residue was also reacted without purification.-Yield: 500 mg (90.8% of theory) C9H12C1N02 (M = 201.65) Cale: molar peak (M + H) +: 202 / 204 Jan: molar peak (M + H) +: 202/204 Rf value: 0.3 (silica gel, petroleum ether / EtOAc 6: 4). 2. 118f. (6-Dimethoxymethyl-pyridin-3-yl) -acetonitrile To 5.21 g (80 mmol) of KCW in 5.2 mL of water was added dropwise to 20 mL of DMSO and a solution of 500 mg was added dropwise at 80 ° C. . (2.48 mmoles) of 5-chloromethyl-2-dimethoxymethyl-pyridine in 10 mL of DMSO, and the reaction mixture was maintained for another hour at 80 ° C. It was poured into 200 mL of water, saturated with NaCl, exhaustively extracted with EtOAc, the organic phase was dried over MgSO4 and filtered 350 on activated carbon. The filtrate was concentrated by evaporation and the residue was purified by chromatography on silica gel (C¾Cl2 / MeOH 9: 1). Yield: 330 mg (69.2% of theory) C10H12N2O2 (M = 192.22) Cale: molar peak (M + H) +: 193 Jan .: molar peak (M + H) +: 193 Rf value: 0.48 (silica gel, C¾Cl 2 / MeOH 9: 1). 2. 118g. 2- (6-Dimethoxymethyl-pyridin-3-yl) -ethylamine In a solution of 330 mg (1 .2 mmole) of (6-dimethoxymethyl-pyridin-3-yl) -acetonitrile in 10 mL of methanolic N se were added 50 mg of Raney nickel and the reaction mixture was hydrogenated in a Parr autoclave at 30 ° C for 15 hours at 3 bar of H2. The catalyst was removed by filtration, the solvent was concentrated by evaporation in vacuo and the residue was further reacted without purification. Yield: 340 mg (100% of theory) C10H16N2O2 (M = 196.25) Cale: molar peak (M + H) +: 197 Jan: molar peak (M + H) +: 197 HPLC retention time: 1.3 min (method A ) "" 2. 118h. [2- (6-Dimethoxymethyl-pyridin-3-yl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to general working method I from 340 mg (1.73 mmol) of 2 - (6-dimethoxymethyl- 351 pyridin-3-yl) -ethylamine 'and' 419 mg (1.80 rare) of 4'-chloro-biphenyl-4-carboxylic acid. 'Yield: 210 mg. (28.4% of theory) C23H23C1N203 (M = 410.90) Cale: molar peak '(M + H) +: 411/413 Jan .: molar peak (M + H) +: 411/413 Rf value: 0.4 (gel silica, CH2Cl2 / MeOH / NH3 9: 1: 0.1). 2. 118Í. Acid .. [2- (6-formyl-pyridin-3-yl) -ethyl] -amide 4'-chlorobiphenyl-4-carboxylic acid In a solution of 205 mg (0.5 mmol) of [2- (6-dimethoxymethyl- pyridin-3-yl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid in 10 mL. of MeOH, 5 mL of 12% HCl was added and the reaction mixture was stirred for 4 hours at room temperature and warmed; during the. night at 80 ° C. Another 2.5 mL of 12% HCl was added, the mixture was heated for another 8 hours at 80 ° C overnight at 100 ° C. The reaction mixture was combined with 50 mL of water, adjusted to pH 8 with a Na 2 CO 3 solution, exhaustively extracted with CH 2 C 12 and the organic phase was dried over MgSO 4. After removing the drying agent and the solvent, the residue was further reacted without purification. Yield: 180 mg (98.7% of theory) C21H17C1N202 (M = 364.84) Cale: peak .molar (M + H) +: 365/367 Jan: molar peak (M + H ') +: 352 365/367 HPLC retention time: 5.25 min (method A) 2. 118k. Acid '[2- (6-pyrrolidin-1-ylmethyl-pyridin-3-yl) -ethyl] -amide 4'-chloro-biphenyl: 4"Carboxylic In a solution of 180 mg (0.49 mmol) of acid [2- (6-formyl-pyridin-3-yl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid in 5 mL of acetonitrile were added 50 μ ?. (0.6 mmol) of pyrrolidine, 37.7 mg (0.6 mmol) of NaB¾CN and 2 mL of MeOH, the pH value was adjusted to 5-6 with glacial acetic acid and the mixture was stirred for 5 hours at room temperature.The reaction mixture was acidified with 1M KHS04 solution, alkalized with a Na2C03 2M solution was exhaustively extracted with CH2C12 and the organic phase was dried over MgSO4 After removing the drying agent and the solvent, the residue was purified by chromatography on silica gel (CH2Cl2 / MeOH / NH3 9: 1: 0.1) Yield: 25 mg (12.1% of theory) C25H26C1N30 (M = 419.96) Cale: molar peak (M + H) +: 420/422 Jan .: molar peak (M + H) +: 420/422 Rf value: 0.2 (silica gel, CH2Cl2 / MeOH / NH3.9: 1: 0.1).
Example 2.119: Acid _ [2- (5-pyrrolidin-l-ylmethyl-pyridin-2-yl) -ethyl] -amide 4'- 353 chloro-biphenyl-4-carboxylic 2. 119a. Methyl 6-hydroxymethyl nicotinate Prepared analogously to the Example. 2.109f from 5.0 g (27 ... 6 mmoles) of 5-methyl pyridin-2-5-dicarboxylate, using 'THF as solvent and tert-butyl methyl ether for extraction. Yield: 2.0 g (43.3% of theory) C8H9N03 (M = 167.17) 'Cale: molar peak (M + H) +: 168 Jan: molar peak (M + H) +: 168 Re Value: 0.2 (silica gel, CH2Cl2 / MeOH 95: 5). . . . - '2.119b. Methyl 6-chloromethyl-nicotinate In a solution. After cooling to 2.0 ° C (11.96 mmol) of methyl 6-hydroxymethyl-nicotinate in 100 mL of CH2C12, 1.06 mL (13 mmol) of pyridine were added at 0 ° C and 1.08 mL (13 mmol) of sodium chloride were slowly added dropwise. thionyl. It was stirred for another hour at 0 ° C and slowly warmed to room temperature. To finish the reaction, 1 mL more (12 mmol) of thionyl chloride was added and the mixture was stirred for 1 hour at room temperature. The reaction mixture is added with water, the organic phase was 354 separated, washed with dilute NaHCO 3 solution and water and dried over MgSO 4. It was filtered over activated carbon and the solvent was concentrated by evaporation in vacuo. The product obtained was further reacted without purification. Yield: 1.7 g (65.1% of theory) -CaH8ClN02 (M = 185.61) Cale: molar peak (M + H) +: 186/188 Jan: molar peak (M + H) +: 186/188 HPLC retention time: 6.7 min (method A) / |. 2.119c. Methyl 6-cyanomethyl-nicotinate Prepared analogously to Example 2.118f from 1.5 g '(8.08 mmoles) of methyl 6-chloromethyl-nicotinate and 5. 2 g (80 mmol) of KCN, using ^ cyclohexane / Et07Ac 8: 2 as eluent pax ~ to purification by chromatography on silica gel. Yield: 220 mg (15.5% of theory) C9H8N20 (M = 176.18) | - Cale: molar peak (M + H) +: 177 Ene .: molar peak (M + H) +: 177 Rf Value: 0.6 (gel silica, petroleum ether / EtOAc 1: 1). 2. 119d. Methyl 6- (2-amino-ethyl) -nicotinate In a solution of 75 mg (0.43 mmol) of methyl 6-cyanomethyl-nicotinate in 5 mL of methanolic N¾ was added 20 mg of Raney nickel and the reaction mixture was added. hydrogenated in a • 355 Autoclave at 30 ° C. for 6 hours at 3 bar of ¾ - The catalyst was removed by filtration, the solvent was concentrated by evaporation in vacuo and the residue was further reacted without purification. Yield: 70 mg (90.3% of theory) C9H12N202 (M = 180.21) Cale, -molar peak (? +?) +: · 181 Jan: molar peak (M + H) +: 181 HPLC retention time: 2.5 min ( method A) 2. 119e. 6- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} Methyl nicotinate Prepared from general working method I from 70 mg (0.39 mmol) of methyl 6- (2-amino-ethyl) -nicotinate and- 100 mg (0.43 mmol) of '-chloro- biphenyl-4-carboxylic acid. Yield: 150 mg (88.3% of theory) + H) +: 395/397 Jan: molar peak (M + H) +: 395/397 - HPLC retention time: 8.6 min (method A) 2. 119f. Acid 6- ,. { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -nicotinic In a solution of 150 mg (0.38 mmol) of 6-. { 2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -methylnicotinate in 356 25 mL of MeOH.se. 0.8 mL of 1M NaOH solution was added and the reaction mixture was refluxed for 1 hour. It was neutralized with 0.8 mL of 1N HCl, concentrated by evaporation in vacuo, the residue was stirred with water and the precipitate was removed by suction filtration. The solution was dissolved in THF, the solution was dried with MgSO 4, filtered and concentrated by evaporation in vacuo. The residue was further reacted without purification. Yield: 90 mg (62.2% of theory) C21H17CI 2O3 (M = 380.83) Cale: peak, molar (M + H) +: 381/383 Jan .:, molar peak (M + H) +: 381/383 Time of HPLC retention: 6.9 min (method A) 2. 119g. [2- (5-Hydrpxymethyl-pyridin-2-yl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid. Prepared analogously to Example 2.109f from 90 mg (0.24 mmol) of 6- acid. { 2- [(4'-C-Parroro-biphenyl-4-carbonyl) -amino] -ethyl} -nicotinic, using THF as solvent and ter-butyl methyl ether for 'extraction. Yield: 50 mg (56.8% of theory) C2iHigClN202 (M = 366.85) Cale: molar peak (M + H) +: 367/369 Jan.: molar peak (M + H) +: 367/369 '. Rf value: 0.5 (silica gel, CH2Cl2 / MeOH 9: 1) _: 357 2. 119h. [2- (5-Pyrrolidyr-l-ylmethyl-pyridin-2-yl) -ethyl] -amide '-chloro-biphenyl-4-carboxylic acid In a solution cooled to 0 ° C of 50 mg (0.14 mmol) of [2- (5-Hydroxymethyl-pyridin-2-yl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid in 5 mL of CH2Cl2, 22 μ? were added dropwise. of thionyl chloride and the reaction mixture was allowed to warm slowly to room temperature. After an hour at room temperature, another 22 μ ?, of thionyl chloride was added dropwise to finish the reaction and stirring was continued for 1 hour. The reaction mixture was diluted with 30 mL of CH2C12 / was combined with ice water, made alkaline with NaHCO3 solution, the organic phase was separated, washed with water and dried over MgSO4. After removing the drying agent, 50 μL (0.6 mmol) was added in this solution. of pyrrolidine and the reaction mixture was stirred overnight at room temperature. It was concentrated by evaporation in vacuo and the residue was purified by HPLC chromatography. Yield: 2.4 mg (4.1% of theory) C25H26C1N30 (M = 419.96) Cale: molar peak (M + H) +: 420/422 Jan .: molar peak (M + H) +: 420/422. · '- Rf value: 0.3 (silica gel, CH2Cl2 / MeOH 9: 1). HPLC retention time: 6.0 mi (method A). 358 Example 2.120: Acid. { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylicamide 2. 120a. [2- (4-acetyl-phenyl) -ethyl] -carbaminate of ter. Butyl In a solution of 4.99 g (25 mmol) of l- [4- (2-amino-ethyl) -phenyl] -ethanone (used as hydrochloride) in 100 mL CH2C12 was added 5.46 g (25 mmol) of BOC anhydride and 25 mL of 1W NaOH solution was slowly added dropwise at room temperature and after the end of the addition, it was stirred for 2 hours at room temperature, the reaction mixture was filtered over Celite, washed twice with water and filtered. dried over MgSO4, filtered over activated carbon, concentrated by evaporation in vacuo and the product was further reacted without purification Yield: 6.4 g (97.2% of theory) C15H21N03 (M = 263.34); molar (M + H) +: 262 Ene.: "molar peak (M + H) +: 262 Rf value: 0.88 (silica gel, CH2Cl2 / MeOH / NH3 9: 1: 0.1). 2. 120b. . { 2- [4- (l-hydroxy-ethyl) -phenyl] -ethyl} -carbaminato de ter. butyl 359 In a; 6.58 g (25 mmol) of [2- (4-acetyl-phenyl) -ethyl] -carbamate-tert-butyl ester in 250 mL of MeOH were added discontinuous at room temperature 4.72 g (125 mmol) of NaBH 4 and the reaction mixture was stirred over the weekend. It was acidified carefully with KHS04 solution, exhaustively extracted with tert-butyl methyl ether, the organic phase was washed with saturated NaCl solution and dried over MgSO4. After removing the drying agent, and the solvent, the product was removed as a slightly yellowish oil, which crystallized when allowed to stand. Yield: 5.4 g (81.4% of theory) Ci5H23 03 (M = 265.36) Cale: molar peak (M + H) +: 266 Jan .: molar peak (M + H) +: 266 Rf value: 0.4 (silica gel , petroleum ether / EtOAc 6: 4). 2. 120c. . { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -carbaminato de ter. butyl In a solution cooled to 0 ° C of 2.89 g (10.89 mmoles) of. { 2- [4- (1-hydroxy-ethyl) -phenyl] -ethyl} -carbamate of terbutyl in 50 mL of CH2Cl2 and 1.25 mL of triethylamine. 0.66 mL (8.5 mmol) of methanesulfonic acid chloride, dissolved in 10 mL of CH2C12, were added dropwise. Stirring was continued for 1 hour 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 360 it was stirred overnight at room temperature, combined with dilute KHS04 solution, the organic phase was separated, washed twice with diluted KHS04 solution, the combined aqueous phases were made basic with. solution of K2C03 and extracted exhaustively with tert-butyl methyl ether. The combined organic phases were washed several times with a little water and dried over MgSO4. After removing the drying agent and the solvent, the product was further reacted without purification. Yield: 0.3 g (8.7% of theory) Cale: molar peak (+ H) +: 319 Jan: molar peak (M + H) +: 319 F value: 0.22 (silica gel, CH2Cl2 / MeOH / NH3 9: 1: 0.1). 2. 120d. 2- [4- (1-pyrzOlidin-1-yl-ethyl) -phenyl] -ethylamine In a solution of -300 mg (0.94 mmol) of. { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -carbaminato de ter. butyl in 20 mL of CH2Cl2 was added -0.72 mL of trifluoroacetic acid and stirred for 1 hour at room temperature. To finish the reaction, 0.72 mL of trifluoroacetic acid was added again and the reaction mixture was kept for 1 hour at room temperature. The solvent was concentrated by evaporation in vacuo, the residue was taken up in water, made alkaline with 2N NaOH, exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. After eliminating the 361 drying agent and - the solvent, the product was further reacted without purification. Yield: 150 mg (72.9% of theory) Cale: molar peak (M + H) +: 219 Ene .: molar peak (M + H) +: 219 F value: 0.15 (silica gel, CH2Cl2 / MeOH / NH3 8: 2: 0.2). 2. 120e. Acid. . { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work 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 acid -carboxylic Yield: 150 mg (88.3% of theory) C2H2sClN20 (M = 433.0) Cale. : molar peak (M + H) +: 433/435 Jan: molar peak (M + H) +: 433/435 HPLC retention time: 6.33 min (method A) - Example 2.121: Acid. { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide 4'-chloro-biphenyl-4-carboxylic acid-methanol mmoles) -of (3-bromo-4- example 2.107c.) in 100 mL of THF and 50 mL of methanolic N se were added 100 mg of Raney nickel and the reaction mixture was stirred in a Parr autoclave for 5 hours at room temperature and 5 psi of ¾. The catalyst was removed by filtration, the solvent was removed and the product was further reacted without purification. Yield: 3.8 g (93.4% of theory) CsH12BrN0 (= 230.11) Cale: molar peak (M + H) +: 230/232 .Ene: molar peak (M + H) +: 230/232 HPLC retention time: 1.85 min (method A) · .. '2.121b. [2- (3-Bromo-4-hydroxymethyl-f-nyl) -ethyl] -carbamate-terylbutyl ·. In a solution of 3.8 g (16-.51 mmoles) of [4- (2-amino-ethyl) -2-bromo-phenyl] -methanol in 50 mL of CH2C12 was added 17 mL of a 1M solution of BOC anhydride. in CH2C12 and the reaction mixture was stirred overnight at room temperature. It was diluted with 100 mL of dilute KHS0 solution, the organic phase was separated, washed with dilute NaHCO3 solution and water and dried over MgSO4. After removing the drying agent and the solvent, the residue was purified by chromatography 363 on silica gel. Yield: 2.3 g (42.2% of theory) C14¾oBrN03 (M = 330.22) · Rf value: 0.44 (silica gel, petroleum ether / EtOAc 6: 4). : ' .- · | '2.121c. [2- (3-Bromo-4-chloromethyl-phenyl) -ethyl] -carbaminate. of ter. Butyl In a solution cooled to 0 ° C of 1.98 g (6.0 mmoles) of [2- (3-bromo-4-hydroxymethyl-phenyl) -ethyl] -carbamate of ter. Using 50 mL of CH2C12 and 0.53 mL of pyridine, 0.54 mL (6.5 mmol) of thionyl chloride was slowly added dropwise, stirred for another hour at 0 ° C and then warmed to room temperature. Water was added to the reaction mixture, the organic phase was washed; with dilute KHS04 solution and water and dried over MgSO4. After filtering on activated carbon and removing the solvent, the product was further reacted without purification. Yield: 2.0 g (95.6% of theory) C14 HlsBrClN02 (M = 348.67) Cale: molar peak. (M + H) +: 348/350/352 Jan: molar peak (M + H) +: 348/350/352 Rf value: 0.6 (silica gel, petroleum ether / EtOAc 6: 4). 2. 121d. . { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -carbaminato de ter. butyl 364 To a suspension of 1.9 g '(5.45 mraoles) of [2- (3-bromo-4-chloromethyl-phenyl) -ethyl] -carbamate of ter. Butyl and 2.5 g (18.1 mmol) of K2C03 in 50 mL of acetonitrile were added 0.84 mL (11 mmol) of 2,5-dihydro-1 H-pyrrole and the reaction mixture was stirred overnight at room temperature. The suspension was filtered, the filtrate was concentrated by evaporation in vacuo and the residue was purified by chromatography on silica gel. Yield: 0.5 g (24.1% of theory) Cale: molar peak- (M + H) +: 381/383 Jan: molar peak (M + H) +: 381/383 Rf value: 0.58 (silica gel, CH2Cl2 / MeOH 8: 2). 2. 121e. 2- [3-bromo-4- (2,5-dihydro-pyrrol-l-ylmethyl) -phenyl] -ethylamine | "In a solution of 500 mg (1.31 mmol) of. {2- [3-bromo- 4- (2,5-dihydro-pyrrol-l-ylmethyl) -phenyl] -ethyl-tert-butylcarbamate in 50 mL of CH2C12 were added with 5 mL of trifluoroacetic acid and the reaction mixture was stirred for 2 hours. The mixture was evaporated in vacuo, combined with water and CH2C12, adjusted to an alkaline pH with K2C03 solution, the organic phase was separated and washed again with water. The product was purified by chromatography on silica gel. 365 Yield: 350 mg (95.0% of theory) C13Ha7BrN2 (M = 281.20) Cale: molar peak (M + H) +: 281/283 Jan:: molar peak (M + H) +: 281/283 - 'Rf value: 0.08 (silica gel, CH2Cl2 / MeOH / NH3 95: 5: 0.5). '2.121f. Acid (2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} - amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the method General working I a- 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) of 4 β-Chloro-biphenyl-4-carboxylic acid Yield: 140 mg (56.5% of theory) C26H24BrClN20 (M = 495.85) Cale: molar peak (M + H) +: 495/497/499 Jan: molar peak (M + H) ) +: 495/497/499 'HPLC retention time: 6.6 min (method A) E p 2.122: Acid. { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid 366 2. 122a. 4'-Bromo-3-fluoro-biphenyl-4-carboxylic acid In a solution of 1.1 g (5 mmol) of 4-bromo-2-fluorobenzoic acid in 5 mL of DMF and 5 mL of dioxane were added in succession 1.04 g (5 mmol) of 4-bromophenylboronic acid, 115 mg (0.1 mmol) of tetrakis- (triphenylphosphine) -palladium and 2 mL of solution 2 of Na 2 CO 3 and the reaction mixture was refluxed for 2 hours. To finish the reaction, 250 mg (1.25 mmol) of 4-bromophenylboronic acid were added again and the mixture was refluxed for another 2 hours. The reaction mixture was filtered hot through a glass fiber filter, washed with water, acidified with dilute KHS04 solution, the formed precipitate was suction filtered and washed with water. The residue was triturated with acetonitrile and a little MeOH, filtered to remove insoluble matter, the filtrate was concentrated by evaporation, the residue was triturated with MeOH and the product was filtered by suction. Yield: 140 mg (9.5% of theory) C13H8BrF02 (M = 295.11) Cale: molar peak (M + H) +: 293/295 Jan.: molar peak (M + H) +: 293/295 Rf value: 0.5 ( silica gel, CH2Cl2 / MeOH 9: 1). 2. 122b. . Acid { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide '4' -bx-omo-3-fluoro-biphenyl-4-carboxylic acid 367 Prepared according to the general method of work 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 acid 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid. Yield: 10 mg (3.8% of theory) C26H23Br2FN20 (M = "558.29) - Cale: molar peak (+ H) + ': 557/559/561 Jan: molar peak (M + H) +: 557/559/561 HPLC retention time: 7.0 min (method A) '"Example 2.123: [2- (3-Amino-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro acid biphenyl-4-carboxylic acid 0 mg (0.08 mmol) of (5- {2 - [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-phenyl) -carbamate ter. Use (see Example 2.116) in 3 mL of CH2C12 0.12 mL of trifluoroacetic acid was added and the reaction mixture was stirred over the weekend at room temperature, concentrated by vacuum evaporation, combined with half-saturated NaHCO3 was extracted with EtOAc and the organic phase was dried over MgSO4. remove the agent from -drying and the. solvent, the residue was purified by HPLC. - Yield: 3 mg "(7.3% of theoretical) .- ... '| C26H28C1N30 * C2HF302, (M = 548.01)" Cale: molar peak (M + H) +: 434/436 Jan .: molar peak (M + H) +: 434/436 • HPLC retention time: 5.35 min (Stable Bond C18; 3.5 μ ?; Water: acetonitrile: formic acid 6: 4: 0.015) Example 2.124: Ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -ami 2. 124a. Ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine In a solution of 20 mg (1.0 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 0.17 mL of triethylamine in 5 mL of THF was trickled a solution of 89] ^ (1.1 mmol) of. Ethyl iodide in 1 mL of THF and the reaction mixture was stirred for 24 hours at room temperature. It was combined with saturated NaHCO 3 solution, extracted with EtOAc and the organic phase was dried over MgSO 4. After removing the drying agent and the solvent, the residue was also made 369 .react without purification. Yield: 70 mg (30.1% of theory). |2.124b. . Acid 'ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general method of work 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 acid. . Yield: 20 mg (14.9% of theory) C28H31CIN2O (M = 447.03) Cale '.: peak. molar (M + H) +: .447 / 449 Jan: molar peak (M + H) +: 447/449 HPLC retention time: 6.92 min (method A) Example 2.125: Acid. isobutyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid 2. 125a. Isobutyl- [2- (4-pyrrolidin-l-ylmethyl-f-nyl) -ethyl] -amine 370 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 acidified slightly with acetic acid. The reaction mixture was combined with 253 mg (1.2 mmol) of NaBH (0Ac) 3 and stirred overnight at room temperature, the reaction mixture was combined with half-saturated NaHCO 3 solution, exhaustively extracted with EtOAc; Saturated with K2CO3 and extracted with EtOAc The combined organic phases were dried over MgSO4. After removing the drying agent and the solvent, the residue was further reacted without purification. Yield: 250 mg (96.0% of theory). C17H28N2 (M = 260.43) Cale: molar peak (M + H) +: 261 Jan: molar peak (M + H) +: 261 Rf value: 0.4 (silica gel, CH2Cl2 / MeOH / NH3 8: 2: 0.2) . 2. 125b. Acid, isobutyl- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general working method, starting from 250 mg (0.96 mmol) ). of isobutyl- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amine and 244 mg (1.05 mmol) of 4'-chloro-bif nil-4-carboxylic acid. Yield: 67 mg (14.7% of theory) C3oH35ClN20 (M = 475.08) - Cale: molar peak '(M + H) +: -475/477 Jan. : molar peak (M + H) +: 371 475/477 HPLC retention time: 7.67 min (method A) Example 2.126: Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -oxic acid 2. 126a. Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine · Prepared analogously to Example 2.125a. 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 theory). , C20H30N2 (M = 298.48) 'Rf value:? .2 (silica gel, CH2Cl2 / eOH / NH3 8: 2: 0.2). 2. 126b. Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid Prepared according to general working method I from 100 mg (0.34 mmol) of cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine and 86. mg (0.37 mmol) of 4'-chloro-biphenyl-4-acid carboxylic 372 Yield: 46 mg (26.8% of theory) C33H37C1N20 (M = 513.13) - Calc .:. peak . molar (M + H) +: '513/515 Jan .: molar peak (M + H) 513/515 HPLC retention time: 8.20, min (method A) Example 2.127: Benzyl- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide 4-chloro-biphenyl-4-carboxylic acid 2. 127a. Benzyl- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amine Prepared analogously to Example 2.125a. from 204 mg (1.0 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 102 μ? (1.0 mmol) of benzaldehyde. Yield: 160_ mg (54.3% of theory). C2oH2sN2 (M = 294.44) Rf value: 0.28 (silica gel, CH3cÍ2 / MeOH / WH3 8: 2: 0.2). 2. 127b. Benzyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide. 4'-chloro-biphenyl-4-carboxylic acid Prepared according to the general working method, starting from 160 mg. mmol) of benzyl- [2- (4-pyrrolidin-I-373 ylmethyl-phenyl) -ethyl] -amine and 140 mg (0.60 mmoD of 4'-chloro-biphenyl-4-carboxylic acid.) Yield: 16 mg (5.8% of theory) C33H33C1N20 (M = 509.10) Cale .: peak molar- (M + H) +: 509/511 Jan: molar peak (M + H) +: 509/511 - ... HPLC retention time: 7.51 min (method A) Example 2.128: Cyclohexylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid . . 2.128a. Cyclohexylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine. . .. .| Prepared analogously to Example 2 ^ 125a. from 204 mg (1.0 mmol) of 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethylamine and 121 μ ?? (1.0 mmol) of cyclohexancarbaldehyde. · Yield: 100 mg (33.3% of theory). C2oH32N2 (M = 300.49) R'-value: 0.18 (silica gel, CH2Cl2 / MeOH / .H3 8: 2: 0.2). 2. 128b. Cyclohexylmethyl- [2- (4-pyrrolidin-1-ylmethyl-4-de) acid +: ] - ) - Prepared, analogously to Example 2.125a. from 204 mg (1.0 mmol) of 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethylamine and '75 μ ?. (1.0 mmol) of cyclopropancarbaldehyde. Yield: 100 mg (38.7% of theory). C17H26N2 (M = 258.41) 375 R £ value: 0.30 (silica gel, CH2Cl2 / MeOH / NH3 8: 2: 0.2). 2. 129b. . Cyclopropylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-biphenyl-4-carboxylic acid "Prepared according to the general method of work 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 acid -carboxylic Yield: 23 mg (12.6% of theory) Cale: molar peak (M + H) +: "473/475 Jan.: 'molar peak (M + H) +: 473/475 HPLC retention time: 7.45 min (method TO).
Example 2.130: 4-Pentyl-JV- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general method of work 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 theory) C25H34N2O (M = 378.56) Cale: molar peak (M + H) +: 379 Jan.: 'molar peak (M + H) +: 379 376 HPLiC retention time: 6.5 min (method A) methyl-phenyl) -ethyl] -benzamide Prepared according to the general working method, starting with 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 ramol) and 4-butyl-benzoic acid (89 mg, 0.50 mmol) . Yield: 60 mg (32.9% of theory) C2 H32N2O (M = 364.54) Cale: molar peak (M + H) +: 365 Jan: molar peak (M + H) +: 365 HPLC retention time: 6.0 min (method TO) ethyl-phenyl) -ethyl] - general method of work 377 I from "2- (4-pyrrolidin-1-iimethyl-phenyl) -ethylamine (204 rag, 1.0 mmol) and 4-bufilamino-benzoic acid (155 mg, 0.80 mmol) Yield: 30 mg (9.9% of the theoretical) "" · C24H33N3O (M = 379.55) Cale: peak, molar (M + H) ÷: 380 Ene .: molar peak (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] - Prepared disagreement with the general method of work 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 theory) C24H32N20 (M = 378.56) Cale: molar peak (+ H) +: '| 379 Jan. : molar peak. (M + H) +: 379 HPLC retention time: 4.3 min (method B) Ex. 2.134: · N- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -4- (4, 4, 4-trifluoro- 378) butoxy) -benzamide 2. 134a. Methyl 4- (4, 4, 4-trifluoro-butoxy) -benzoate In a solution of 304 mg (2.0 mmol) of methyl 4-hydroxybenzoate in 10 mL of DF were added 608 mg (4.4 mmol) of K2C03 and then 382 mg (2.0 mmol) of 1-bromo-4,4-rifluorobutane. The mixture was stirred overnight at room temperature, again combined with l-bromo-4, 4-trifluorobutane and. it was stirred an additional 24 hours at room temperature. The reaction solution was diluted with water and extracted twice, thoroughly - with EtOAc. The combined organic extracts were dried over MgSO4 > and concentrated by evaporation to the vacuum. The crude product was used without further purification in the next reaction step. Yield: 500 mg (95.3% of theory) Ci2Ha3F303 (M = .262.23) Cale: peak, molar (M + H) +: 263 Jan: molar peak (M + H) +: 263 Rf value: 0.9 (silica gel , petroleum ether / EtOAc 6: 4). 2. 134b. 4- (4,4,4-trifluoro-butoxy) -benzoic acid In a solution of 500 mg (1.9 mmol) of 4- (4,4,4-trifluoro-butoxy) -benzoate. methyl in 7 mL of THF were added 10.0 mL (10.0 mmol) of a 379 hydroxide solution sodium 1M. The mixture was stirred at reflux for 8 hours. THF was removed to the vacuum and the residue was acidified with hydrochloric acid. After filtering the precipitate formed, it was dried in air. '' Yield: 350 mg (73.9% of theory) ~ | C11H11F3O3 (M = 248.20) 'Cale: molar peak (MH) ": 247 Jan .: molar peak (MH) ~: 247 HPLC retention time: 7.5 min ( method A) '| 2. 134c. IV- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4- (4, 4, 4-trifluoro-butoxy) -benzamide Prepared according to the general method of work 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 ). _ '' _- .; Performance-. 37 mg (17.0% of theory) C24H29F3N202 (M = 434.51) '' Cale: molar peak (M + H) +: 435 Jan: molar peak (M + H) +: 435 HPLC retention time: 5.8 min (method A ) Example 2.135: 3-methyl-4-pent-l-inyl-IV- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide; 380 2. 135a. Methyl 3-methyl-4-pent-yl-inyl-benzoate In a solution of 458 mg (2.0 mmol) of methyl 4-bromo-3-methyl-benzoate in 3.0 mL of DMF were added in successive form 0.39. mL (4.0 mmol) of pentin, 0.56 mL (4.0 mmol) of triethylamine, 70 mg (0.1 mmol) of bis- (triphenylphosphine) -palladium (II) chloride and 19 mg (0.1 mmol) of copper iodide (I ). The reaction solution was stirred for 10 min at 200 Watt and 65 ° C in the microwave. Another 0.20 mL 0 (2.0 mmol) of pentin was added and the reaction solution was stirred for another 20 min at 200 Watt and 70 ° C in the microwave. The mixture was diluted with 30 mL of EtOAc, filtered over Celite and the filtrate was washed three times with 50 mL of water. The combined organic extracts were dried over MgSO4, filtered over activated charcoal and the solvent was removed in vacuo. Purification was carried out by column chromatography on silica gel (cyclohexane after cyclohexane / ethyl acetate. _ | '9: 1) .. · Performance': 200 mg (46.2% theoretical) or Ci4HiS02 (= 216.28). Cale: molar peak (M + H) +: 217 Jan: molar peak (M + H) +: 217 HPLC retention time: 6.8 min (method B) 2. 135b. 3-Methyl-4-pent-l-inyl-benzoic acid 5 In a solution of 200 mg (0.93 mmol) of 3-methyl-4-3.81 pent-l-inyl-benzoic acid in 3 mL of methanol was added 3.0 mL (3.0 quarts) of a 1M sodium hydroxide solution. The mixture was refluxed for 3 hours. The reaction solution was diluted with water and extracted once with 40 mL of EtOAc. The aqueous phase was acidified with 1M solution of KHS04 and extracted twice with 40 mL of EtOAC. The combined organic phases were dried over MgSO4. After removing the drying agent and the solvent, the crude product was used in the next reaction step without further purification. Yield: 50 mg (26.7% of theory) C13H1402 (M = 202.26) Cale: molar peak (M-H) ~: 201, Jan: molar peak (M-H) ": 201 HPLC retention time: 5.6 min (method B) 2. 135c. 3-methyl-4-pent-1-ynyl-iV- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide. Prepared according to the general method of work I a. from, 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethylamine (51 mg, 0.25 mmol) and 3-methyl-4-pent-1-yl-benzoic acid (50 mg, 0.25 mmol). . Yield: 22 mg (22.9% of theory) C26H32 2O (M = 388,558) Cale: molar peak (M + H) +: 389 Jan: molar peak (M + H) +: 389 HPLC retention time: 6.9 min (method A) 382 Example 2.136: 4-pent-l-inyl-Jí- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] - 2. 136a. Ethyl 4-pent-l-inyl-benzbato. In a solution of 552 mg (2.0 mmoles) of ethyl 4-iodobenzoate in 3 mL of DMF were added in. successive 0.39 mL (4 mmol) of l-pentin, - 0.56 mL of triethylamine, 70 mg (0.1 mmol) of bis- (triphenylphosphine) -palladium (II) chloride and 19 mg (0.1 mmol) of Cul. The reaction solution was stirred for 4 hours at 80 ° C. The mixture was diluted with 30 mL of EtOAc, filtered - over Celite, the filtrate was washed three times with 50 mL of. water in each case- and dried over MgSO4. After filtering, on activated carbon, the solvent was removed in vacuo. Purification was carried out by column chromatography on silica gel (cyclohexane after cyclohexane / ethyl acetate 9: 1). Yield: 150 mg (34.7% of theoretical) C14Hi602 (M = 216.282) | Cale: molar peak- (M + H) +: 217 -Ene .: molar peak (M + H) +: 217 HPLC retention time: 6.8 min (method B) 2. 136b. 4-pent-l-inyl-benzoic acid .383 Into - a solution of 150 mg (0.69 mmol) of ethyl 4-pentyl-inyl-benzoate in 3 mL of methanol was added 5.0 mL (5.0 mmol) of a solution of. 1M sodium hydroxide. The mixture was stirred at reflux for 3 hours. The reaction solution was diluted with water: and extracted once with 40 mL of EtOAc. The aqueous phase is. acidified with 1M KHS04 solution and extracted twice with 40 mL of. EtOAc. The combined organic extracts were dried over magnesium sulfate and the solvent was removed at: vacuum. The crude product was used in the next reaction step without further purification. Yield: 150 mg (115% of theory). , C12H1202 (M = 188.23). 'Cale: molar peak (M-H) ~:, 187 Jan .: molar peak. (M-H) ~: 187 Rf value: 0.2 (silica gel, petroleum ether / EtOAc 8: 2). . . -, · '' 2.136c. 4-pent-l-inyl-iT- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide Prepared according to the general method of work I from 2- (4-pyrrolidin-1) methyl-phenyl) -ethylamine (163 mg, 0.80 mmol) and 4-pent-1-inyl-benzoic acid (150 mg, 0.80 mmol). Yield: 122 mg (40.9% of theory) C25H3o 20 (M- 374.53) | ''. Cale: molar peak (M + H) +: 375 Jan: molar peak (M + H) +: 375 Rf value: 0.35 (silica gel, EtOAc / methanol / NH3 9: 1: 0.1). 384 Example 2.137: (4-pent-l-enyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide - 2. 137a. Methyl 4-pent-l-enyl-benzoate In a solution of 1.08 g (2.2 mmol) of (4-methoxycarbonyl-benzyl) -triphenyl-phosphonium bromide in 20 mL of THF under an argon atmosphere were added at 0 °. C 246 mg (2.2 mmol) of potassium tert-butoxide. The orange solution was stirred for a further 15 min at 0 ° C and then combined with 0.18 mL. (2.0 mmoles) of butyraldehyde. The reaction solution was refluxed for 3 hours and then diluted with EtOAc. The organic phase was washed twice with water, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with diisopropyl ether, filtered and the filtrate was concentrated by evaporation. . The further purification was carried out by column chromatography on silica gel (petroleum ether / EtOAc 6: 4). Methyl 4-pentyl-enylbenzoate was obtained as a 2: 1 mixture of E / Z isomers. Yield: 350 mg (56.5% of theory) Ci3H1602 (M = 204.27). Cale: molar peak (M + H) +: 204 Jan: molar peak (M + H) +: 204 - 385 Rf value: 0.90 (silica gel, petroleum ether / EtOAc 6: 4). 2. 137b. 4-pent-l-enyl-benzoic acid In a solution of 350 mg (1.71 mmol) of ethyl 4-pentyl-enyl-benzoate in 4 mL of methanol, 5.0 mL (5.0 mmol) of a hydroxide solution was added. of sodium 1M. The mixture was refluxed for 2 hours. The solvent was removed under vacuum and the residue was combined with 6M hydrochloric acid solution. The formed precipitate was filtered by suction and dried in a circulating air dryer at 35 ° C. The further purification was carried out by filtration through a column on silica gel (petroleum ether / EtOAc 6: 4). Yield: 300 mg (92.1%, theoretical) C12¾402 (M = 190.24) Cale: molar peak (MH) ~: 189 Jan: molar peak (MH) ": 189 Rf value: 0.4 (silica gel, petroleum ether / EtOAc 6: 4). 2. 137c. (4-pent-1-enyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide '- · Prepared according to general working method I from 2- ( 4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (306 mg, 1.50 mmol) y. 4-pent-l-enyl-benzoic acid (300 mg, 1.56 mmol) as a 2: 1 mixture of E / Z isomers. Yield: 130 mg (23.0% "of theory) C25H32N2O (M = 376.547) 386 Cale: molar peak (M + H) +: 377 Jan .: molar peak. (M + H) +: 377 HPLC retention time: '6.9 min (method A) Example 2.138: 3-chloro-4-cyclohexyl-I / - [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide "'.
Prepared according to the general method of work 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 theory) Cale: molar peak | (M + H) +: '425/427 Jan.: molar peak (M + H) +: 425/427. HPLC retention time: 4.7 min (method B) Some test methods are described below to determine the antagonistic activity of the HCM receptor.
In addition, other test methods known to the person skilled in the art are used, for example, to inhibit the HCM receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating 387 hormone and its receptor are expressed and functional in. human skin ", Biochem. Biophis, Res. Commun. ' 296 (2002) 698-701, and biosensory measurement of the binding of the HCM with the HCM receptor in the presence of antagonistic substances by plasmon resonance, as described by Karlsson OP and Lofas S. in "Flow-Mediated On -Surface Reconstitution of G-Protein Coupled Receptor for Applications - in Surface Plasmon Resonance Biosensors, "Anal Biochem 300 (2002), 132-138 Other test methods of antagonistic activity in HCM receptors are contained in the references and patent documents mentioned in the foregoing, and the description of the test methods used are hereby incorporated into this application.
HCM-1 receptor binding test Method .: -Connection of HCM to transfected cells hHCM-lR Species: "Human Test Cell: hHCM-lR Stably Transfected in CHO / Galphal6 Cells." - IC50 Values: Membranes from CHO / Galphal6 cells stably transfected with human hHCM-lR were resuspended using a syringe (0.6 needle). x 25 mm) and diluted in a test buffer (50- "mM of HEPES, 10 mM of MgCl2, 2 mM of EGTA, pH 7.00, 0.1% of bovine serum albumin (without protease), 0.021% 388 of bacitracin, 1 - / g / ml of aprotinin, "ig / ml of leupeptin and 1 μ of phosphoramidon) at a concentration of 5 to 15 μg / ml 200 microliters of this membrane fraction were incubated ( contains 1 to 3 μ of protein) for 60 minutes at room temperature with hormone γ, 125i-tyrosylmelanin concentrator (125 I-HCM that can be obtained commercially in NEN) and higher concentrations of the test compound in a final volume After the incubation the reaction was filtered using a cell harvester through a glass fiber filter treated with 0.5% PEI (GF / B, Unifilter Packard) .The radioactivity retained in the filter attached to the The membrane was determined after adding the scintillation substance (Packard Microscint 20) in a measuring device (Packard's TopCount) The non-specific binding was defined as the bound radioactivity in the presence of 1-micromolar HCM during the incubation period. The A Analysis of the concentration link curve was carried out, in the assumption of a receptor binding site. Standard: 'Unlabeled HCM competes with 125I-HCM labeled for the receptor link with an IC50 value between 0.06 and 0.15 nM. The KD value of the radioligand is 0.156 nM.
Mobilization test of Ca2 + coupled to the HC -1 389 receptor · - Method: - Test of, mobilization of calcium with human HCM (FLIPR384) -Species: Human '' Test cells: CHO / Galpha 16 cells stably transfected with hHCM-R1 Results: measurement:% stimulation of the reference (HCM 1CT6M) 2nd measurement: pKB value Reagents ':' . HBSS (lOx) (GIBCO) HEPES cushion (1M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) Probenecid (Sigma) HCM (Bachem) Bovine serum albumin (without protease) (Serva) DMSO (Serva) Ham's F12 (BioWhittaker) 'FCS (BioWhittaker) L-glutamine. (GIBCO) Hygromycin B (GIBCO) PENStrep (BioWhittaker) Zeocin (Invitrogen) Clonal cells, CH0 / Galphal6 hHCM-Rl were cultured. in Ham 's F12 cell culture medium (with L-glutamine; 390 BioWhittaker; . Cat. - Do not . : BE12-615F). It contains, for every 500 ml, 10% of FCS; 1% of PENStrep, - 5 ml of L-glutamine '(200 mM of stop solution.), - 3 ml of hygromycin B (50 mg / ml in PBS) and 1.25 ml of zeocin (100 μ / ta of stop solution). One day before the experiment, the cells were placed in a 384-well microtiter plate (black plates with a transparent bottom, manufactured by Costar) at a density of 2500 cells per well-cavity and cultured in the previous medium overnight at 37 °. C, 5% C02 and "95% relative humidity." On the day of the experiment, the cells were incubated with cell culture medium, to which 2 mM of Fluo-4 and 4.6 mM of Probenicide had been added. 37 ° C for 45 minutes After loading with fluorescent dye, the cells were washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which was combined with 0.07% Probenicide. were diluted in the Hanks' buffer solution, combined with 2.5% DMSO The background fluorescence of the unstimulated cells was measured in the presence of the substance in the 384-well microtiter plate five minutes later: de. the last stage of washing in the FLIPR384 device (Molecular Devices; Stimulation wavelength: - 488 nm; emission wavelength: bandpass 510 to 570 nm). For cell stimulation the HCM was diluted in Hanks buffer with 0.1% BSA, pipetted 35"minutes after the last washing step in a plate of 391 384 well cell culture and then the fluorescence stimulated with HCM was measured in the FLIPR384 device.
Analysis of data: . Measurement: The cellular mobilization of Ca2 + was measured as the peak of the relative fluorescence minus the background and was expressed as the percentage of the maximum signal of the reference (HCM 10"SM) This measurement serves to identify any possible agonizing effect of a test substance 2nd measurement: Cell mobilization of Ca2 + was measured as peak relative fluorescence minus background and was expressed as the percentage of the maximum reference signal (HCM 10"6M, the signal was normalizes at 100%) '. The EC50 values of the HCM dosing curve with and without test substance (defined concentration) were determined graphically by means of the GraphPad Prism 2.01 curves program. The HCM antagonists cause a shift to the right of the HCM stimulation curve in. the chart plotted Inhibition is expressed with the pKB value: pKB = log (EC50 (test substance + HCM) / EC50 (HCM) ~ 1) -log C (substance < je test) The compounds according to the invention, including their salts, show in the tests mentioned in the foregoing an antagonistic activity of the HCM receptor. Using the HCM-1 receptor binding test described above, an activity was obtained, antagonistic in a range 392 of doses of approximately 10"10 to 10 ~ 5 M, particularly from 102 to 10" 6 M. | The following IC50 values were determined using the HCM-1 receptor binding test described in the above: Composed according to ·. Value IC50 No. of Example 1.14 2.1 nM 2.4 3.5 nM 2.12 30.5 nM Below, some examples of the formulations are described,. where the term "active substance" means one or more compounds according to the invention, including their salts. In the case of one of the combinations with one or more active substances described, the term "active substance" also includes other active substances. " Example 3 Capsules for inhalation of powders containing 1 mg of active substance. ' Composition: · 1 capsule for inhalation of powders contains: active substance 1.0. mg lactose 20.0 mg 393 hard gelatin capsules 50.0 mg 71.0 mg Method of preparation: The active substance was crushed to the particle size required to inhale. The milled active substance was homogeneously mixed with the lactose. The mixture was filled into 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 μ? Method of preparation: The active substance and benzalkonium chloride were dissolved in water and packed in Respimat® cartridges.
Use 5 394 Inhalation solution for nebulizers containing 1 mg of active substance Composition: | 1 bottle contains: active substance 'sodium chloride benzalkonium chloride purified water ad Preparation method:. The active substance, sodium chloride and benzalkonium chloride were dissolved in water.
Example 6 Aerosol dosed with propellant gas containing 1 mg of active substance Composition:, -1 spray contains: active substance 1.0 mg lecithin. 0.1% propellant gas ad - 50.0 μ? Method of preparation: 395 The active substance "micronized was suspended in the mixture of lecithin and propellant gas in a homogeneous manner.The suspension was transferred into a pressure vessel containing 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 disodium edetate 0.05 mg purified water ad 0.1 ml Preparation method: . - - The active substance and the excipients were dissolved in water and transferred into a corresponding container.
Example 8 Injectable solution containing 5 mg of active substance per 5 ml Composition: active substance 5 mg 396 glucose · 250'tng human serum albumin 10 mg. glucofurol '250 mg ·.' ". -. | water for injections ad .5 mi '' - · '- |||:' Preparation: ·. -. '' They were dissolved - glucofurol | and glucose in water for injectable (Wfl). V was added human serum albumin, the active substance was dissolved under heating, was completed with Wfl to the specified volume, was transferred in ampoules under nitrogen gas.
Example 9 '· "'. - '' · - Injectable solution that 'contains 100 mg of active substance per 20 ml." Composition: active substance · 100 mg monopotassium diacid phosphate - KH2P0 12 mg phosphate disodium acid = Na2HP0 .2¾0 2 mg sodium chloride · -, 180 mg | human serum albumin 50 mg Polysorbate.80 20 mg water for injections ad 20 ral 397 Preparation: Polysorbate 80, sodium chloride, monopotassium diacid phosphate and disodium hydrogen phosphate were dissolved in water for injection (Wfl); human serum albumin was added; the active substance was dissolved under heating; was completed with Wfl up to the specified volume; Be transfused in ampoules. _ Example 10 Lyophilisate containing 10 mg of active substance Composition: Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg Preparation: | - '. _ 'Mannitol was dissolved in water for injection (Wfl); whey albumin was added. human; dissolved - the active substance under heating; was completed with Wfl up to the specified volume; It was transferred in jars, dried by freezing. ' Solvents for lyophilisate: Polysorbate 80 = Tween 80 20 mg 398 Mannitol 200 mg water for injections ¾ad 10 mi Preparation: - - | Polysorbate 80 and mannitol were dissolved in water for injection (Wfl); It was transferred in ampoules.
Example 11 '. Tablets with 20 mg of active substance "'Composition: -active substance 20 mg', lactose | · | - '120 mg · corn starch' - 40 mg magnesium stearate 2 mg Povidone K 25 18 mg Preparation: - Homogeneous active substance, lactose and corn starch were mixed homogeneously; it was granulated with an aqueous solution of Povidone; mixed with magnesium stearate; it was compressed in a tablet press; Weight of the tablets 200 mg.
Example 12 Capsules containing 20 mg of active substance 399 Composition: active substance 2 O mg corn starch '80 mg highly dispersed silica 5 mg magnesium stearate. 2.5 mg. .
Preparation: - Homogeneous active substance, corn starch and silica were mixed in a homogeneous manner; it was mixed with magnesium stearate; The mixture was packaged in an encapsulating machine in size 3 hard gelatin capsules.
Example 13 Suppositories containing 50 mg of active substance Composition: Active substance 50 - mg Hard fat (Adeps solidus) c.s. ad 1700 mg Preparation: Hard fat was melted at about 38 ° C; It dispersed in a way. homogenous the active substance crushed in the molten hard fat; after cooling to approximately 35 ° C, it was added in pre-cooled molds. 400 E x 14 Injectable solution containing 10 mg of active substance per 1 mi. · ',' "'.' Composition: active substance 10 mg -manitol | _ -50 mg human serum albumin 10 mg water for injections ad. 1 mi Preparation : . Mannitol was dissolved in water · for injection (Wfl); human serum albumin was added; the active substance was dissolved with heating; was completed with Wfl up to the specified volume; It was transferred in ampoules under nitrogen gas.

Claims (1)

  1. 401 CLAIMS Carboxamide compounds of the general formula H, a C 1-8 alkyl group or C 3-7 cycloalkyl optionally substituted with the group R 11 or a phenyl group optionally mono or polysubstituted with the group R 12 and / or monosubstituted with nitro, or R 1 and R 2 form an alkylene bridge of C2-s, wherein - one or two groups -CH2 can be independently replaced with -CH = N- or -CH = CH- and / or - one or two -CH2 groups can be independently replaced with each other with -0- , -S-, -C0-, -C (= C¾) - or -NR13 so that the heteroatoms are not directly bonded together, while the alkylene bridge defined above can be replaced by one or more H. R14, and / or the alkylene bridge defined in the above can be substituted with one or two identical or different cyclo- or heterocyclic groups such that the bond between the alkylene bridge and the group Cy is carried out - by means of a simple bond or double, - through a common C atom forming a spiral ring system or, - through two C and / or N atoms. adjacent commons forming a combined bicyclic ring system or - through three or more C atoms and / or 402 N, forming a ring system, R3 signifies H, Ci_6 alkyl, C3-7 cycloalkyl, C3_7 cycloalkyl Ci_4 alkyl, C3-7 cycloalkenyl, C3_7 cycloalkenyl-Ci_4 alkyl, phenyl, Ci-4-phenylalkyl, Ci_3-alkoxy-C2-6alkyl, C2_6-aminoalkyl, Ci-3-alkylamino-C2-6alkyl or di- (Ci_3alkyl) -amino-C2-6alkyl, X means a simple bond or an alkylene bridge of Ci_a, wherein - one or two groups -C¾ can be independently substituted with -CH = CH- or. -C = C- and / or - one or two groups -CH2 can be independently replaced with -O-, -S-, - (SO) -, - (S02) -7 -C0- or -NR4- of such so that two atoms of O, S or N or an O atom are not directly linked to each other with an S atom, while one or two C atoms can be independently replaced with a hydroxy group, o) -hydroxy - Ci-3 alkyl, - (C1.3 alkoxy) Ci_3 alkyl and / or Ci_3 alkoxy and / or in each case with one or two equal or different C1-6 alkyl groups, and / or the alkylene bridge can be linked to R1 so that it includes the N atom bound to R1 and X forming a heterocyclic group, Z means an alkylene bridge of C] _4, where two adjacent C atoms can be linked together with a bridge additional C1-4alkylene, while in group Z a -CH2 group can be replaced by -0- or -NR5-, and one or two C atoms of the alkylene bridge. they can be independently substituted with a hydroxy group, co-hydroxy-alkyl, Ci-3,? -. (Ci_3 alkoxy) -Cl_3 alkyl, alkoxy of 403 Ci_3, Ci_3 aminoalkyl, Ci_3 alkylamino Ci_3 alkyl or di- (Ci_3 alkyl) -aminoC 1-3 alkyl and / or with one or two identical or different grupos6 alkyl groups, and / or R3 may be linked with Z, so that it includes the atom attached to R3, forming a heterocyclic group, A, Y have. independently of each other one of the meanings, specified for Cy, while R1 may be linked with Y so that it includes the group X and the atom of N joined with R1 'y. X, -| forming, a heterocyclic group fused in Y, and / or R3 can be attached to Y so that it includes the group Z and the N atom bound with R3 and Z, forming a saturated or partially unsaturated heterocyclic group fused to And, or A and R3 can be linked together in such a way that the group of formula I means a group of partial formula II and Q means a. group, selected from the partial formulas Illa to Illg 404 CR-'R7 ':: - HIa GR6- - - GR' ílib | N = CRS ~ - | lile -N = N ind¬ -CO NRS- ine -CR? = N - Hit -CO- lüg L1, L2,. L3- independently of one another means one of the meanings specified for R20, B means Ci_s alkyl, Ci_6 alkenyl, Ci_6 alkynyl, C3 cycloalkyl. -alkyl of ¾_3, C3.7 cycloalkenyl-Ci-3 alkyl) cycloalkyl. of C3_7-alkenyl of C1-3 or C3_7-cycloalkyl of C1-3 alkynyl, wherein one or more C atoms may be mono- or polysubstituted by halogen and / or monosubstituted by hydroxy or cyano and / or cyclic groups mono or polysubstituted by R20, or 'one of the meanings specified for Cy, while the binding with the group W or optionally directly with group A is carried out through a. C atom of the "carbocyclic part or the phenyl or pyridine ring optionally fused or through a N or C atom of the" heterocyclic part, where for the case that k = 0 the group B can be linked with the group A through a common C atom forming a spirocyclic ring system or through two adjacent common atoms forming a fused bicyclic ring system, W means a simple bond, -O-, a group 405 alkylene of Ci_4, alkenylene of .Cs ..:. , C2-4 alkynylene, Ci_4 alkyleneoxy, Ci_4 oxyalkylene, Ci_3-oxy-alkylene alkylene of Ci_3, imino, N- (C1-3 alkyl) -imino, alkyleneimino of 4_, N- (alkyl) of Ci-3) -C 1-4 alkylene-alkylene, C 1-4 alkyleneimino or C 1 .N- (C 1-3 alkyl) -imino alkylene, while one or two C atoms can be independently substituted with one another. hydroxy group,? -hydroxy-C ^ alkyl,? - (C1-3 alkoxy) -C1-3 alkyl- and / or C1-3 alkoxy and / or with one or two equal CX-6 alkyl groups or different, and / or W - with the. definitions . of alkylene, oxyalkylene and alkyleneoxyalkylene "can be attached to B through a double bond, K means 0 or 1 / C means a carbocyclic or heterocyclic group selected from one of the following meanings - a saturated carbocyclic group of 3 to 7 members - an unsaturated carbocyclic group of 5 to 7 members, - a phenyl group, - a saturated heterocyclic group of 4 to 7 members or * unsaturated of 5 to 7 members with an atom of N, O or S as heteroatom , - a saturated or unsaturated heterocyclic group of 5 to 7 members with two or more N atoms or with one or two N atoms and a 0 or 0 atom. S as heteroatoms, - a heterocyclic aromatic group of 5 or 6 members with one or more identical or different heteroatoms selected from N, O and / or S, while the groups of 5, 6: 6 7. members mentioned in above may be joined through two adjacent common C atoms in a fused manner with a phenyl or pyridine ring, 406 and the groups of 5, -6 or 7 members mentioned in the above, one or two non-adjacent -CH2 groups can be replaced by a group -CO-, -C (= C¾), - (SO) or - (S02), and the 6 or 7 membered saturated groups mentioned above may also be present as bridged ring systems with an imino bridge, N ~ (Ci_4 alkyl) -imino, methylene, Ci_4 alkyl. methylene or di- (Ci-4 alkyl) -methylene, and the cyclic groups mentioned in the foregoing may be mono- or polysubstituted in one or more C atoms with R20, in the. case of a phenyl group additionally also monosubstituted with nitro, and / or on one or more N atoms with R21, R,. R5 independently have one of the meanings specified for R16, R6, R7, R8, R9, independently of one another, meaning H, an alkyl group of Ci_6, Ci-3-alkyl-CL_3 alkyl or? -hydroxy-alkyl of C1-3 and Rs, R7, R8 also independently of one another means halogen, R11 is R15-0-, R15-0-CO-, R1SR17N-, R18R19N-CO- or Cy-, R12 has one of the meanings specified for R20, R13 has one of the meanings specified for R17, R14 means halogen, CX-6 alkyl, R15-0-, R15-0-CO-, R16R17N-, R18R19N-CO-, R15-0-C1- alkyl 3, Rls-0-CO-alkyl of d_3, R1SR17N- alkyl of C! _3, R18R19N-CO-alkyl of < ¾._3 or Cy-C1-3 alkyl, R15 means H, Ci_4 / - C3-7 cycloalkyl, C3-7 cycloalkyl Ci_3 alkyl, phenyl, phenyl-Ci_3 alkyl or pyridinyl, R16 means H , Ci_e alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl C1-3 alkyl, C4_7 cycloalkenyl, 407 cycloalkenyl C4-7- alkyl of - ¾_.3? -hydroxy-C2_3 alkyl,? - (C3_alkoxy) -C2_3alkyl, Ci_6-amino-alkyl, Cli3-amino-alkyl-alkyl of Ca_s or di - (Ci_3 alkyl) -amino-Ci_s alkyl, R17 has one of the meanings specified for 16 or phenyl, phenyl-C1-3 alkyl, pyridinyl, dioxolan-2-yl, Ci_3 alkylcarbonyl, idroxycarbonyl-alkyl. - Ci-3i C1- alkoxycarbonyl, C1-3 alkylcarbonylamino- C2-3 alkyl, alkylsulfonyl of. Ci_3 or C1-3 alkyl sulfonylamino-C2-3 alkyl, -R18, R1S independently means H or Ci_e alkyl, R20 means, halogen, hydroxy, cyano, Ci_4 alkyl, C3_7 cycloalkyl, hydroxy alkyl, Ci-3, R22- alkyl of C ± .3 or has one of the meanings specified for R22, R21 means' C1-3 alkyl, co-hydroxy-C2-3 alkyl, phenyl, phenyl-0-3alkyl, C1-3alkylcarbonyl, carboxy, C1.4alkoxycarbonyl, Ci_3alkylsulfonyl, phenylcarbonyl or phenyl-Cx-3-alkyl carbonyl, R22 means pyridinyl, phenyl, phenyl-C1-3 alkoxy, Ci-3 alkoxy / CX_3 alkylthio, carboxy, .H-CO-, Ci-3 alkylcarbonyl, Ci-4 alkoxycarbonyl, aminocarbonyl, Ci_3 alkylaminocarbonyl, di- (C2_3) alkylaminocarbonyl, Ci_3-sulfonyl alkyl, Ci_3-sulfinyl alkyl, C1-3-alkylsulfonylamino, amino, alkylamino of 0? _3, di- (C1-alkyl) -3) -amino, phenyl-alkylamino of Ci_3 or N- (C1-3 alkyl) -phenyl- C1-3 alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl, (-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino or alkylam incarbonylamino while in the groups and residues A, B, W, X, Y, Z, R1 to 9 and R11 to R22 in each case one or more C atoms may be mono or polysubstituted with F and / or in each case one or two C atoms may be monosubstituted independently of each other, with Cl or Br, and / or in each case one or more phenyl rings independently present one, two or three substituents selected from the group F, Cl, Br , I, C1- alkyl, Ci-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, Ci-3 alkylamino / di- (C ^ J-amino alkyl, acetylamino, aminocarbonyl, CN, - difluoromethoxy, trifluoromethoxy, amino- C 3 alkyl, Ci_3 alkylamino Ci_3 alkyl and di- (C 1-3 alkyl) -amino-alkyl of Ca_3 and / or may be monosubstituted by nitro, - and the H atom of an existing carboxy group or an atom of H attached to an atom of N can be replaced by a stable group, in vivo, the "tautomers, enantiomers, mixtures of the isms and salts thereof. 2. Compounds carboxamide according to claim 1, characterized in that R3 is H, alkyl of Ci_6, cycloalkyl of C3-7, cycloalkyl of C3_7-alkyl of CI-, alkoxy of C1-3-alkyl of C2_s, aminoalkyl of C2-e, C1-3 alkylamino- 409 C2-6alkyl or di- (Ci_3j alkyl- C2_6aminoalkyl, B has one of the meanings specified for Cy, while the bonding of the group W or optionally directly with group A is carried out through a C atom of the carbocyclic part or - of the phenyl or pyridine ring optionally fused or through a N or C atom of the heterocyclic part while k = 0, the B group can be linked with the group A through an atom of C by forming a spirocyclic ring system or through two adjacent common atoms, forming a bicyclic fused ring system, R15 is H, C1-4 alkyl, C3-7 cycloalkyl, C3_7 cycloalkyl, C3-7 alkyl. Ci_3, phenyl o-phenyl-alkyl of C1..3, R17 has one of the meanings specified for R16 or phenyl, phenyl-C1_3 alkyl, dioxolan-2-yl, 3-hydroxycarbonyl-C1_ alkylcarbonyl -3, Ci-3 alkylcarbonylamino, C2_3 alkyl, Ci_3 alkylsulfonyl or alkyls Cr-3-C2-3 alkyl-hydrophilic acid. R22 is phenyl, 0-3 phenyl-alkoxy, 1-3-alkoxy, Ci -3-alkylthio, carboxy, -3-alkylcarbonyl, Ci-3-alkoxycarbonyl, aminocarbonyl, Ci-3-alkylaminocarbonyl, di- (alquilo-alkyl) .3-) -aminocarbonyl, -C ^ alkylsulfonyl, Ci-3 alkylsulfinyl, Cx-3 alkylsulfonylamino, amino, C1-3 alkylamino, di- (Ci_3 alkyl) -amino, phenyl-C1- alkylamino 3 or N- (C 1-3 alkyl) -phenyl-C 1 -3 alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino,. phenylcarbonylmethylamino, 410 hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl, (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) -carbonyl, (4-methyl-1-piperazinyl) oarbonyl, methylenedioxy, aminocarbonylamino or alkylaminocarbonylaird. no, while the groups and residues A, B, W, X / Y, Z, R1 to R9 and R11 to R22, e each case one or more C atoms may be mono or polysubstituted with F and / or in each case one or two C atoms may be monosubstituted, independently of one another, with Cl or Br and groups A, X, Y, Z, R1, R2, R4 to R9, R11 to R14, R15 and R18 to R21 and k have the meanings according to claim 1, the H atom of an existing carboxy group or an H atom attached to an N atom can be substituted in each case with a cleavable group in vivo, tautomers, diastereomers, enantiomers, mixtures of the same ones and the salts of the same ones. 3. Compounds of carboxamide according to claim 1 or 2, characterized in that group A has the meanings given for Cy in claim 1. 4. Carboxamide compounds according to one or more of claims 1 to 3, characterized because A and R3 can be linked together in such a way that the group of formula I | Means a group of the peace formula II 411 . and Q means a selected group of partial formulas Illa to lllg - CRSR7 Illa CR6 = CR7 Illb - = CR8 - Ule - ¡\ - - N ind. CO NR9 - CR½ = N llí 'CO - - ¡ííg and L1, L2, L3, \ LS, L7, L8 and L9 have the meanings given in claim 1. 1. Carboxamide compounds according to one or more of claims 1 to 4, characterized in that the groups R1, R2 independently of one another are, H, alkyl, alkyl, cycloalkyl, C3_7 cycloalkyl, C3_7 alkyl, C3_3alkyl, hydroxyC2_3alkyl, C3_3alkyl, C2_3alkyl, C1_4alkoxycarbonyl; C 1-3 alkyl, amino C 2-4 alkyl, Ci_3 alkylamino-C 2-4 alkyl or di- (C 1-3 alkyl) -amino C 2-4 alkyl, phenyl or phenyl-C 1 -C 3 alkyl , whereas in the groups and residues specified in the above one or more C atoms may be mono or polysubstituted by F and / or one or 412 two C atoms: may be monosubstituted, independently of one another, with Cl or Br, and where the phenyl group may be mono or polysubstituted with the group R12 defined above and / or may be monosubstituted with nitro. "6. Carboxamide compounds according to one or more of the claims l 4, characterized in that R1 and R2 form an alkylene bridge according to claim 1 such that 1R¾- forms a selected group of azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-lH-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 imine function can be substituted with R13, where of .. according to claim 1 one or more H atoms can be replaced by R 14, and / or can be replaced in the manner indicated in claim 1 by one or two identical or different C and C or heterocyclic groups, where R 13 , R14 and Cy have the meaning indicated in claim 1 or 2. 7. Carboxamide compounds according to claim 6, characterized in that • the group has a meaning according to one of the following partial formulas 413 414 ormado ring be in the ituido n -los 415 meanings indicated in claim 1 or 2. ' 8. Carboxamide compounds according to one or more of claims 1 to 7, characterized in that X means a single bond or an unbranched bridge selected from C 1-6 alkylene / C2-alkenylene, C2.5 alkynylene, alkylenoxy. of Ci_s, carbonyl, carbonyl-alkylene of C1-e or alkylene of Ci_6-amino, wherein the amino group can be substituted with R4, while one or two C atoms can be substituted as desired. indicated in claim 1 and / or the alkylene bridge can be linked with R 1 as set forth in claim 1. 9. Compounds of carboxamide according to claim 8, characterized in that X means a single bond, carbonyl or a selected alkylene bridge of methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, wherein one or two C atoms can be independently substituted with a hydroxy,? -hydroxy-alkylo group of? 1-3, ? - (C1-3 alkoxy) -C1-3alkyl- and / or C1_3alkoxy and / or with one or two identical or different Cx-4 alkyl groups and in each case · one or more C atoms they can be mono or polysubstituted with F and / or one or two C atoms can be independently monosubstituted with Cl or Br. 10. Carboxamide compounds according to one or more of claims 1 to 9, characterized in that Z means methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 416 methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy or 1,4-butyleneoxy, wherein one or two C atoms can be independently substituted with a hydroxy group, co-hydroxy-alkylation of Ci_3, (Cx_3 alkoxy) Ci_3 alkyl and / or C1-3 alkoxy and / or by one or two identical or different Ci-4 alkyl groups, and in each case one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms may be monosubstituted. independently of each other, with Cl or Br and R3 can be linked with Z, 'including the N atom bound with R3, forming a heterocyclic group. 11. Compounds of carboxamide according to claim 10, characterized in that Z is selected from the group of bridges -CH2-, -C¾-CH2-, -C¾-CH (CH3) -, -C¾-C (C¾) 2- , -CH (CH3) -CH2-, -C (CH3) 2-CH2- and -CH2-0- or because Z is linked with R3 in such a way that the group of the partial formula. tetrahydropyridin-1,3-ylene and 3-hydroxy-l, 3-piperidinylene. . 12. Carboxamide compounds according to one or more of the preceding claims, characterized in that R3 is selected from the group: methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl and -hydroxy-l-methyl-ethyl, while in the mentioned groups can 417 one, two or three H atoms are replaced by F, or selected from the group: H, C2_3 amino-alkyl, C3_3 alkylamino, C2_3 alkyl, and Ci_3- (C3_3 alkyl) -amino-alkyl C2-3. 13. Compounds of carboxamide according to one or more of the preceding claims, characterized in that the group Y is selected from the amount of bivalent cyclic groups 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1-cyclohexylene, 1,3-phenylene, 1,4-phenylene, 1,3- and 1-cyclohexenylene, 1,4-cycloheptylene, 1-cycloheptenylene, 1 , 3-pyrrolidinylene, 1,3-pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, "1,4-tetra-idropyridinylene, 1, -di-idropyridinylene, 2,5- and 2,5-pyridinylene or 1, -4-piperazinylene, while the groups of 5, 6 or 7 members mentioned in the above can be joined through two adjacent common C atoms in a fused manner with a phenyl or pyridine ring, the cyclic groups mentioned in the above can be mono or polysubstituted in one or more C atoms with R20, in the case of a phenyl group additionally also monosubstituted with nitro, and / or in one om N atoms with R21, while R1- can be attached to Y and / or R3 to Y. as indicated in claim 1, and R1, R3, R20 and R21 have the meanings indicated in claim 1 or 2. . 14. Compounds of carboxamide according to claim 13, characterized in that R1 is linked with Y in such a way that the group of partial formula 418 they have a meaning selected from the following partial formula 15. Carboxamide compounds according to one or more of claims 1, 2, 3 and 5 to 13, characterized in that the group A is selected from the amount of bivalent cyclic groups 1, 2-cyclopropylene, 1,3-cyclobutylene, 1, 3-cyclopentylene, 1,3-cyclopentenethylene, 1,3- and 1,4-cyclohexylene, 1,3- and 1, -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-tetrahydropyridinylene, 1, -dihydropyridinylene, 2,4- and 2,5-pyridinylene, 1,4-piperazinylene,. '7-aza-bicyclo [2.2.1] heptan-2,7-diyl and 8-aza-bicyclo [3.2, 1] octane-3,8-diyl, while the groups of 5, 6 or 7 members mentioned in The above can be united. "through two adjacent common C atoms in a fused manner with a phenyl or pyridine ring, and the cyclic groups mentioned above may be mono- or polysubstituted in one or more C atoms with R20, in the case of a ring phenyl is additionally also monosubstituted with nitro, and / or on one or more atoms of N with R21, and -R20, R21 and Y 419 have the meanings indicated in claim 1 or 2. 16. Compounds of carboxamide according to one or more of the preceding claims, characterized in that the group B is selected from the group: 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 with the group or optionally directly with group A is carried out through a C atom of the carbocyclic part or of the optionally fused phenyl or pyridine ring or through a N or C atom of the heterocyclic part or B together with the W group linked through a double bond is selected from the group: cyclopentylidene-methyl, cyclohexylidene-methyl and cyclohexanone-4-ylidene-methyl, and the cyclic groups mentioned in the above may be mono- or polysubstituted on one or more C atoms with R20 , in the case of a phenyl group additionally also monosubstituted with nitro, and / or in one or more atoms of N with R21, and R20 and R21 have the meanings indicated in the claim 1 or 2. 17. Carboxamide compounds according to one or 420 more of claims 1 to 15, characterized in that the group B is selected from the group: Ci_6 alkyl, Ci-6 alkenyl, Ci_6 alkynyl, C3_7 cycloalkyl Ci alkyl. 3 / C3-7 cycloalkenyl-Ci_3 alkyl, C3_7 cycloalkyl-C1-3 alkenyl or C3_7-cycloalkyl-C1-3 alkynyl, while one or more C atoms may be mono- or polysubstituted by halogen and / or monosubstituted with hydroxy or cyano and / or mono- or polysubstituted cyclic groups with R20, and W means a simple bond, -O-, an alkylene group of C-4, alkenylene of C2_4, alkynylene of C2-4, alkyleneoxy of Ci-, oxy-alkylene from 0 to 4. Ci-3-oxy-alkylene alkylene of Ci_3 / imino, N- (Ci_3 alkyl) -imino, imino-alkylene of C1-4, N- (Ci_3 alkyl) -imino-alkylene of Ci_4, alkylene imino or alkylene of Ci_4-N- (Ci_3 alkyl) -imino, where one or two C atoms can be independently substituted with each other, with a hydroxy,? -hydroxy-alkyl group of Ci_3, co- (Cx_3 alkoxy) - C1-3 alkyl and / or alkoxy of. Ci_3 and / or by one or two equal or different alkyl groups of ¾-4, and k means 0 or 1 and R20 has the meanings indicated in claim 1 or 2. 18. Carboxamide compounds according to one or more of claims 1 to 15, characterized in that k = 0 and the group α is linked to the group B through a common C atom forming a spirocyclic ring system, while the -group A means a saturated carbo-heterocyclic group of 5 to 7 members and the group - B means a carbo- or group 421 4- to 7-membered saturated heterocyclic, and the heterocyclic groups each have an N, O or S atom, and where in a B group of 5-7 members can be fused to a phenyl or pyridine ring through two carbon atoms; C adjacent, and the cyclic groups mentioned in the above may be mono or polysubstituted in one or more C atoms with R20, in the case of a phenyl ring combined · additionally also monosubstituted with nitro, and / or in 'one or more' N atoms with R21, wherein R20 and R21 have the meanings indicated in claim 1 or 2. 19. Carboxamide compounds according to one or more of claims 15, characterized in that k = 0 and group B is linked with group A through two adjacent common atoms forming a system of combined carbo- or heterocyclic rings, 'saturated, unsaturated or aromatic bicyclics of 8 to 12 members, while the heterocyclic ring system has one or more hetero equal or different atoms selected from W, 0. and / or S, and the bicyclic ring system may be mono or polysubstituted in one or more C atoms with, R20, in the case of a phenyl ring combined additionally it may also be monosubstituted with nitro, and / or on one or more N atoms with R21, where R20 and R21 have the meanings indicated in claim 1 or 2. 20. Compounds of carboxamide according to one or more of the. claims 1 to 16, characterized in that W 422 means a simple link, -C¾ ~ or -CH =. 21. Compounds of carboxamide according to one or more of the preceding claims, characterized in that Y, A are independently selected from the number of bivalent cyclic groups 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene , 1, 4-piperidinylene, 1, 2, 3, 6-tetra idro-piridin-1,4-ylene, 5-pyridinylene and 1,4-piperazinylene, while A can also be linked with R3 according to the claim 3, and the cyclic groups mentioned in the above may be mono- or polysubstituted in one or more C atoms: with R20, in the case of a phenyl group additionally also monosubstituted with nitro, and / or in one or more N atoms with R21, B means phenyl or cyclohexyl, while the mentioned groups may be mono- or polysubstituted with R20 and / or the phenyl ring may be additionally monosubstituted with nitro, where R20 has the meanings indicated in claim 1 or 2, and W means a simple link, -C ¾- or -CH =, and Z signifies -C¾ ~ CH2-, -CH2-CH (CH3) -, -CH2-C (CH3) 2-, -CH (CH3) -C¾-, -C (C¾) 2 -C¾- or -CH2 ~ 0-, or is linked to R3 such that the group of the partial formula of the formula I has the selected meaning of 1,3-pyrrolidinylene and 1,3-piperidinylene and R3, R20 and R21 have the meanings mentioned, in claims 423 1, 2 and / or 12. · 22. Carboxamide compounds according to one or more of the preceding claims selected from the amount of formula 1.1 to 1.14 where U, V are independently between are independently of each other, H, 426 trifluoromethyl, ethyl, iso-propyl or n-propyl, while in formulas 1.1 to 1.6 R24 can be linked with R3 in such a way that the group of the partial formula ¾-¾ p £ Ff has a - meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene, and R25, R2S, R27 independently have one of the meanings indicated for R20 according to claim 1 or 2 or in the case of a group phenyl also simply nitro, where the groups R25, R2e, R27 which occur several times may have the same or different meanings, and j is 0, 1, 2, 3 or 4 and m, n are independently of each other, 0, 1 or 2 and L1, L2, L3, R1, R2, R3, Rs, R7, R8, Rs, R20 and X have the meanings indicated in claims 1, 2, 5 to 9 and / or 12. 23. Carboxamide compounds according to one or more of the preceding claims, characterized by the formula I. where B is selected from the group: Ci_s alkyl, C al alkenyl, Ci_6 alkynyl, C3-7 cycloalkyl-Cx ^ alkyl, cycloalkenyl from 0.3-7-Ci-3 alkyl, cycloalkyl from 427 C3-7-alkenyl of ¾_3 or cycloalkyl of C3.7-alkynyl of Ci_3, where one or more C atoms may be mono- or polysubstituted with halogen and / or monosubstituted with hydroxy or cyano and / or mono- or polysubstituted cyclic groups with R20 , and W means a single bond, -O-, an alkylene group of -Ca, alkenylene of C2_4, alkynylene of C2-4 / alkyleneoxy of Ci-4, oxy-alkylene of ¾_4, Ci-3-alkyleneoxy- alkylene of C ± -3, imino, N- (C1-3 alkyl) -imino, imino-C1-4 alkylene, N- (C1-3 alkyl) -imino-alkylene of Ci_, alkylene imino of C1 -4- or C 1-4 alkylene-N- (C 1-3 alkyl) -imino, where one or two C atoms can be independently substituted with each other, with a hydroxy group, co-hydroxyalkyl of Cx_3, co- ( C1-3 alkoxy) -Ci "3 alkyl and / or C1-3 alkoxy and / or by one or two identical or different ¾ -4 alkyl groups, and k means 0 or 1 and U, V, R23, R24 , R2S, R27, m, n, L1, L2, L3, R1, R, R3, Rs, R7, R8, -R5, R20 and X have the indicated meanings in claim 22. 24. Carboxamide compounds according to claim 22 or 23, characterized in that U and V each mean a C atom. 25. Compounds of carboxamide according to claim 21 ', 22, 23 or 24, characterized in that R1, R2 independently have a meaning according to claim 5 and / or 6 and R3 has a meaning according to the invention. claim 12 and X has a meaning according to claim 8 or 9, while group 428 R '^ NX- may also have a meaning according to claim 7. - 26. Carboxamide compounds according to one or more of claims 21 to 25, characterized in that X is -CH2-, -CH (CH3) - or -C (CH3) 2-. 27. Compounds of carboxamide according to one or more of claims 21 to 26, characterized in that 25, R26, R27 independently of each other mean 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 a substitution of a phenyl group ,. also simply nitro, where the groups R25, R2S, R27 may have the same or different meanings, and] is 0, 1 or 2, and m, n are independently of each other, 0 or 1. 28. Compounds of carboxamide according to one or more than the preceding claims, characterized in that Re, R7, R8 and / or R9 are independently of each other, H, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl; in the case of R6, R7, also F. 29. Carboxamide compounds according to claim 1 or 2 selected from the amount of the formula (1) 7-. { 4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3-Jf-quinazolin-4-one, (2) 3 - [2- (4-pyrrolidin-l- ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one, (3) 3- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -7- (4- trifluoromethyl-phenyl) - 429 3H-quinazolin-4-one, (4) 7- (4-methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-guinazolin-4-one, ( 5) 7- (3, 4-dichloro-phenyl) -3- [2- (4-pyrrolidin-i-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one, (6) 7- (4- fluoro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3-quin-zolin-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) -3ff-quinazolin-4-one, (9) 2-methyl-3- [2- (4-pyrrolidin-1-yl-ethyl-phenyl) -ethyl] -7- p-tolyl-3H-quinazolin-4-one, (10) 7- (4-clpro-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] -liT-quinazoline-2,4-dione, (12) 7- (4-chloro-phenyl) -3-. { 2- [4- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -3Ji-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-one, (17) 5- (4-fluoro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl- phenyl) -ethyl] -isoindole-1, 3-dione, (18) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, ( 19) [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (20) [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] - 430 4'-chloro-biphenyl-4-carboxylic acid amide, (21), 4'-methoxy-biphenyl-4-carboxylic acid [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide, (22) [ 4'-Chloro-biphenyl-4-carboxylic acid 2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amide, (23) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] - 4- (4-chloro-phenyl) -cyclohexanecarboxylic acid amide, 4-methylphenyl-piperidine-1-carboxylic acid (24) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide, | (25) 4- (4-Chloro-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, (26 ) [4- (4-Chloro-phenyl) -piperidine-l-carboxylic acid 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, (27) [2- (4-pyrrolidin-1) 4'-chloro-biphenyl-4-carboxylic acid (4-chloro-biphenyl) -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) [2- (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide. 4'-chloro-biphenyl-4-carboxylic acid, (31) 7- (4-chloro-phenyl) -3-. { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -3-quinazolin-4-one, (32). { 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (33) 7- (3-methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3JÍ- quinazolin-4-one, (34) 4- (4-oxo-cyclohexyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide, (35) [2- (-pyrrolidin 4-cyclohexyl-l-cyclohexylcarboxylic acid-l-ylmethyl-phenyl) -ethyl] -amide, (36) [2- (4- 431 4-benzyl-piperidin-1-carboxylic acid pyrrolidinyl-l-ylmethyl-phenyl] -amide-, (37) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-cyclohexyl-piperidine-l-carboxylic acid, (38) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4- (4-chloro-phenyl) -piperazine-l-carboxylic acid, (39) 4- (4-Fluoro-phenyl) -piperidine-l-carboxylic acid [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, (40) [2- (4-pyrrolidine 4- (4-methoxy-phenyl) -piperazine-l-carboxylic acid-l-ylmethyl-phenyl) -ethyl] -amide, (41) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, of 4-phenyl-piperidine-l-carboxylic acid, (42) (4'-chloro-biphenyl-4-yl) - [3- (4-pyrrolidin-l-ylmethyl-phenyl) -piperidin-1- il] -metanone, (43) [2-methyl-2- (4-pyrrolidin-l-ylmethyl-phenyl) -propyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (44) [2 4'-Chloro-biphenyl-4-carboxylic acid (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) [2- (2-fluoro- 4'-Chloro-biphenyl-4-carboxylic acid 4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, (48) 5- (4-chloro-phenyl) -2- [2- (4-pyrrolidine -l-ylmethyl-phenyl) -ethyl] -2,3-dihydro-isoindol-l-one, (49) 4-piperidin-l-yl-W- [2- (4-pyrrolidin-l-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-ylmethyl) -phenyl] - 432 ethyl} -3H-quinazolin-4-one, (52) 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, (53) 7- (4-chloro-phenyl) -3-. { 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -et-il} -3H-quinazolin-4-one, (54) 7- (4-chloro-phenyl) -3- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] - phenyl.}. -ethyl) -3H-quinazolin-4-one, (55) 6- (4-chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2H -isoquinolin-1-one, (56) [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (57) [ [Beta] -chloro-biphenyl-4-carboxylic acid 2- (3-methyl-4-pyrrolidinyl) -l-methyl-phenyl) -ethyl] -amide, (58). { 2- [4- (l-Ethyl-piperidin-2-yl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (59). { 2- [4- (4-acetyl-piperazin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (60). { 2- [4- (2-aza-bicyclo [2.2.1] hept-5-en-2-ylmethyl) -phenyl] -ethyl} -amino-biphenyl-4-carboxylic acid amide, (61) ·. { 2- [4- (1, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (62) (2- {4- [(diisopropylamino) -methyl] -phenyl} -ethyl) -amide of 4'-chloro- biphenyl-4-carboxylic acid, (63). { 2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (64). { 2- [4- (2-dimethylaminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (65). { 2- [4- (3-dimethylamino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide of 4 '-chloro-biphenyl-4- 43.3 acid carboxylic acid, (66) [2- (2-bromo-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (67) 4-pent-l- inyl-IV- [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -benzamide, (68) [2- (6-pyrrolidin-l-ylmethyl-pyridin-3-yl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (69) [2- (1-pyrrolidin-1-yl-indan-5-yl) -ethyl] -amide of 4'-chloro-biphenyl-4-acid carboxylic acid, (70) [2- (2-nitro-4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (71) [2- (4- pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 2 ',' -dichloro-biphenyl-4-carboxylic acid, (72). { 2- [4- (3-Amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (73). { 2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (74). { 2- [4- (2-methyl-2,6-diaza-spiro [3.4] oct-6-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (75) [2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -amide of 4'-chloro-biphenyl- 4'-Chloro-biphenyl-4-carboxylic acid 4-carboxylic acid, (2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide, (77). { 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} 4'-bromo-biphenyl-4-carboxylic acid amide, (78) 4- (5-chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl ester ] -benzamide, (79) [2- (2-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide of '-chloro-biphenyl-4-carboxylic acid, (80). { 2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide of 4 '-bromo-3-fluoro-biphenyl-4-434 acid carboxylic acid, (81) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid, (82) [2- (4- 4'-ethyl-biphenyl-4-carboxylic acid pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, (83) Carbamate [1- (4- { 2- [(4'-chloro-biphenyl- 4-carbonyl) -amino] -ethyl.}. -benzyl) -pyrrolidin-2-ylmethyl] -tert-butyl ester, (84). { 2- [4- (2-methyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (85). { 2- [4- (2-methyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (86) (2. {4 - [(cyclopropylmethyl-amino) -methyl] -phenyl} -ethyl) -amide of 4 '- chloro-biphenyl-4-carboxylic acid, (87). { 2- [4- (3, 4-dihydro-lH-isoquinolin-2-ylmethyl) -phenyl] -ethyl} -amino-biphenyl-4-carboxylic acid amide, (88) [2- (4-. {[[(2-hydroxy-ethyl) -methyl-amino] -methyl} -phenyl) -ethyl] -amino-biphenyl-4-carboxylic acid amide, (89) Carbamate [1- (4- { 2- [(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl.}. -benzyl) -pyrrolidin-3-yl] -tert-butyl, (90). { 2- [4- (2,6-Dimethyl-piperidin-1-ylmethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide, (91) [2- (4-azetidin-l-ylmethyl-phenyl) -ethyl] -amide of 4'-chloro-biphenyl-4-carboxylic acid, (92) 3-4'-dichloro-biphenyl-4-carboxylic acid 2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide, (93) [2- (4-pyrrolidin-1-yl) 4'-Fluoro-biphenyl-4-carboxylic acid (4-methyl) -methyl] -amide, 4'-chloro (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide -3-fluoro-biphenyl-4-carboxylic acid, (95) [2- (4-pyrrolidin-yl-ylmethyl-phenyl) -ethyl] -amide of 2 '-fluoro-4'-435 acid chloro-biphenyl-4-carboxylic acid, (96) [2- (4-pyrrolidin-l-ylmethyl-phenyl) -ethyl] -amide of 5- (4-chloro-phenyl) -pyridine-carboxylic acid, (97) . { 2- [4- (2-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amino-biphenyl-4-carboxylic acid amide, (4,4-bromo-biphenyl-4-carboxylic acid (98) [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide, ( 99). { 2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} 4'-chloro-biphenyl-4-carboxylic acid amide. 30. Compounds of carboxamide according to claim 29 selected from the amount of the formula (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) a (99) 31. Process for preparing carboxamide compounds of formula I where A, B, W, X, Y, Zr R1, R2, R3 and k have one of the meanings indicated in claims 1 to 28, wherein in case A of a group R3 not linked to group A: a) for the case of ? 'means a nitrogen-containing heterocyclic group linked through a nitrogen atom with the carboxamide group, which can have, in addition to the nitrogen atom, one or more heteroatoms selected from N, O and S, 436. converts "at least one amino compound of formula 1-1 where R1, R2, R3, X,. Y and Z have the meanings indicated in the above, with CDT (1,1 '-carbonyldi (1, 2, 4-triazole)) and at least one secondary amino compound of formula 1-2. · • where A, B, W and k have the meanings indicated in the foregoing and group A presents the amine function sec. , in a solvent or, mixture of solvents in the presence of at least one base, and b) for the other cases, at least one carboxylic acid of formula 1-3 is converted wherein A, B, W and k have the meanings indicated in the foregoing, with TBTU (2- (1H-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate) and at least one amino compound of Formula 1-1 R1- IJJ Y, fci- J-l 1-1 437 where R1, R2, R3, X, Y and Z have the meanings indicated in the above, in a solvent or mixture of solvents in the presence of at least one base, and in case B of a group R3 linked with group A : a) for. the case of a group Q that presents the meaning -CR6R7- (Illa), where R6 and R7 are as defined in the above, converts an amino compound of formula la.l , Y and Z have the indicated meanings, with an ester derived from o-bromomethyl-benzoic acid of formula la.2. where R6, R7, W, B and k have the indicated meanings, b) in the case of a group Q that has the meaning -CR5 = CR7- (Illb), where Rs and R7 are as defined in the above, an isoquinolinone derivative of "formula Ib.2 is converted 438 where Rs, R7, W, B and k have the indicated meanings', with an electrophilic compound of formula Ib.3 wherein Y and Z have the indicated meanings and OMs means an appropriate leaving group, preferably mesylate, in an isoquinoline derivative of formula Ib.4 wherein R5, R7, W, B, Y, Z and k have the indicated meanings, and the isoquinoline derivative of formula Ib. it is further derivatised according to known procedures in the compound of formula I, c) in the case of a group 0 having the meaning -N = CR8-. (IIIc), where R8 is as defined above, a phthalazinone derivative of formula Ic.4 is converted where R, W, B and k have the meanings 439 indicated, with an electrophilic compound of formula Ic.5 wherein Y and: Z have the indicated meanings and OMs means a leaving group, preferably mesylate, in a phthalazinone derivative of the formula 'Ic .6 wherein R, W, B, Y, Z and k have the indicated meanings, and the phthalazinone derivative of formula Ic.6 obtained in this manner is further derivatized according to known procedures in the compound of formula I, wherein Q -N = CR8- (lile), d) for the case of a group Q having the meaning -N = N- (Illd) Q, an o-amino-benzamide derivative of formula Id.l is converted wherein R1, R2, W, B, X, Y, Z and k have the indicated meanings, in the presence of an appropriate nitrite compound and an acid in the compound of formula I, where Q-. N = N-, e) for the case, of a group Q that has the meaning -CO-NR9- (lile), where R9 is as defined in the above, 440 o-amino-benzamide of formula Ie.l wherein R1, R2, R9, W, B, X, Y, Z and k have the indicated meanings, and the presence of CDI (carbonyldiimidazole) in the compound of formula I, wherein Q means -CO-NR9-, f ) for the case of a group Q having the meaning -CR8 = N- (Illf), where R8 is as defined in the above, an o-amino-benzamide derivative of the formula If.l is converted wherein R1, R2, W, B, X, Y, Z and k have the indicated meanings, with a carboxylic acid R8COOH with the meaning indicated for R8 and / or a corresponding activated carboxylic acid derivative in the quinazolinone-derivative of formula I, where Q means ~ CR8 = N-, g) for the case of a group Q that has the meaning -CO- (Illg), an isobenzofurandione derivative of formula Ig.2 is converted where W, B and k have the indicated meanings, 441 with an amine of formula Ig.l wherein - R1, R2, X, Y and Z have the indicated meanings, in the compound of formula I, where Q = -CO-. 32. Physiologically acceptable salts of the carboxamide compounds according to one or more of claims 1 to 30. 33. The composition containing at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 optionally together with one or more physiologically acceptable excipients. 34. Pharmaceutical composition, which contain at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 in addition to optionally one or more carriers and / or inert diluents. 35. Use of at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 to influence the behavior. food of a mammal. 36. Use of at least one carboxamide compound according to one or more of claims 1 to 30 and / or a 442 salt according to claim 32 to reduce the body weight and / or to prevent an increase in the body weight of a mammal. 37. Use of at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 for preparing pharmaceutical composition with HCM receptor antagonist activity. at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 for preparing pharmaceutical composition, which is appropriate for the prophylaxis and / or treatment of symptoms and / or diseases caused by HCM or 'which are causally related to HCM 39. Use of at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 for preparing composition Pharmaceutical which is suitable for the prophylaxis and / or treatment of metabolic and / or alimentary disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia. 0. Use of at least one carboxamide compound according to an o. more of claims 1 to 30 and / or a salt. according to claim 32 to prepare 443 pharmaceutical composition that is appropriate for the prophylaxis and / or treatment of diseases and / or disorders that accompany obesity, especially diabetes, especially type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, resistance to insulin, pathological tolerance to glucose, encephalorrhagia, heart failure, cardiocirculatory diseases, especially arteriosclerosis and hypertension, artis and gonitis 41. Use of at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 for preparing pharmaceutical composition that is suitable for the prophylaxis and / or treatment of hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depressions, states of anguish, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders. 42. Use of at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 for preparing pharmaceutical composition that is appropriate for the prophylaxis and / or treatment of micturition disorders such as, for example, urinary incontinence, overactive urinary bladder, wishes of 444 urinating, nocturia and / or enuresis. 43. Process for preparing a pharmaceutical composition according to one or more of claims 33 to 38, characterized in that, by non-chemical means, at least one carboxamide compound according to one or more of claims 1 to 30 and / or a salt according to claim 32 in one or more carriers and / or inert diluents. 44. Drug containing a first active substance is selected from the compounds of. carboxamide according to one or more of claims 1 to 30 and / or the salts according to claim 32,. and a second active substance, which is 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 HCM antagonists, active substances for the treatment Üe. Hypertension, active substances for the treatment of hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of states of anguish and active substances for the treatment of depressions, as well as optionally one or more carriers and / or inert diluents.
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